Bidirectional gene promoters affect the transcription of two genes, leading to the hypothesis that they should exhibit protection against genetic or epigenetic changes in cancer. Therefore, they provide an excellent opportunity to learn about promoter susceptibility to somatic alteration in tumors. We tested this hypothesis using data from genome-scale DNA methylation (14 cancer types), simple somatic mutation (10 cancer types), and copy number variation profiling (14 cancer types). For DNA methylation, the difference in rank differential methylation between tumor and tumor-adjacent normal matched samples based on promoter type was tested by Wilcoxon rank sum test. Logistic regression was used to compare differences in simple somatic mutations. For copy number alteration, a mixed effects logistic regression model was used. The change in methylation between non-diseased tissues and their tumor counterparts was significantly greater in single compared to bidirectional promoters across all 14 cancer types examined. Similarly, the extent of copy number alteration was greater in single gene compared to bidirectional promoters for all 14 cancer types. Furthermore, among 10 cancer types with available simple somatic mutation data, bidirectional promoters were slightly more susceptible. These results suggest that selective pressures related with specific functional impacts during carcinogenesis drive the susceptibility of promoter regions to somatic alteration.

Plant male sterility refers to the failure in the production of fertile pollen. It occurs spontaneously in natural populations and may be caused by genes encoded in the nuclear (genic male sterility; GMS) or mitochondrial (cytoplasmic male sterility; CMS) genomes. This feature has great agronomic value for the production of hybrid seeds and has been widely used in crops, such as corn, rice, wheat, citrus, and several species of the family Solanaceae. Mitochondrial genes determining CMS have been uncovered in a wide range of plant species. The modes of action of CMS have been classified in terms of the effect they produce in the cell, which ultimately leads to a failure in the production of pollen. Male fertility can be restored by nuclear-encoded genes, termed restorer-of-fertility (Rf) factors. CMS from wild plants has been transferred to species of agronomic interest through somatic hybridization. Somatic hybrids have also been produced to generate CMS de novo upon recombination of the mitochondrial genomes of two parental plants or by separating the CMS cytoplasm from the nuclear Rf alleles

Bananas and plantains (Musa spp.) cultivation holds significant global economic importance, but it faces numerous challenges, which may include diverse abiotic and biotic factors such as drought and various diseases caused by fungi, viruses, and bacteria. The genetic and asexual nature of cultivated banana varieties makes them unattractive for improvement via traditional breeding. To overcome these constraints, modern biotechnological approaches like genetic modification and genome editing have become essential for banana improvement. However, these techniques rely on somatic embryogenesis, which has only been successfully achieved in a limited number of banana cultivars. Therefore, developing new strategies for improving somatic embryogenesis in banana is crucial. This review article focuses on advancements in banana somatic embryogenesis, highlighting the progress, the various stages involved, cryopreservation techniques, and the molecular mechanisms underlying the process. Furthermore, the article discusses the factors that could influence somatic embryogenesis and explores the prospects for improving the process, especially in recalcitrant banana cultivars. By addressing these challenges and exploring potential solutions, researchers aim to unlock the full potential of somatic embryogenesis as a tool for banana improvement, ultimately benefiting the global banana industry.

Reducing overall food intake or lowering the proportion of protein relative to other macronutrients, can extend lifespan in diverse organisms. A number of mechanistic theories have been developed to explain this phenomenon, mostly assuming that the molecules connecting diet to lifespan are evolutionarily conserved. A recent study using Drosophila melanogaster females has pinpointed a single essential micronutrient that can explain how lifespan is changed by dietary restriction. Here, we propose a likely mechanism for this observation, which involves a trade-off between lifespan and reproduction, but in a manner that is conditional on the dietary supply of an essential micronutrient – a sterol. Importantly, these observations argue against previous evolutionary theories that rely on constitutive resource reallocation or damage directly inflicted by reproduction. Instead, they are compatible with a model in which the inverse relationship between lifespan and food level is caused by the consumer suffering from varying degrees of malnutrition when maintained on lab food. The data also indicate that animals on different lab foods may suffer from different nutritional imbalances and that the mechanisms by which dietary restriction benefits the lifespan of different species may vary. This means that translating the mechanistic findings from lab animals to humans will not be simple and should be interpreted in light of the range of challenges that have shaped each organism’s lifespan in the wild and the composition of the natural diets they would feed on.

Cancers have been interpreted either as somatic evolution of cheater cells that escape replication regulation or alternatively as non-healing wounds. Both the interpretations have substantial support as well as glaring anomalies but the two have not been put together to make a coherent synthesis. We argue here that mechanisms and pathways to escape the normal regulation of cell proliferation do not need to evolve de novo. Mechanisms to override the normal regulation have already evolved for wound healing and tissue regeneration. Almost all of the hallmarks of cancer are also seen in the wound healing process. This suggests that cancer develops not by any de novo gain of function but by exaptation of pre-evolved wound healing functions. Somatic evolution that makes the wound healing triggers constitutive is not mutation limited but selection limited and the selective forces are dependent on the tissue microenvironment. Some mechanisms for such selection have been suggested. Many more need to be investigated. A series of mechanisms have evolved to minimize the risk of cancers which may fail in an altered lifestyle context. We support our synthesis with multiple lines of evidence and also make differential testable predictions. This evolutionary perspective suggests novel lines of research and also has translatable implications for cancer prevention.

Ethylene is a plant hormone controlling physiological and developmental processes such fruit maturation, hairy root formation and leaf abscission. Its effect on regeneration systems, such as organogenesis and somatic embryogenesis (SE), has been studied and progresses in molecular biology techniques have contributed to unveil mechanisms behind its effects. This compound affects regeneration differently, depending on the species, genotype and explant. In some species, ethylene seems to revert recalcitrance in genotypes with low regeneration capacity. However, its effect is not addictive, since in genotypes with high regeneration capacity this ability decreases in the presence of ethylene precursors, suggesting that regeneration is modulated by ethylene. Several lines of evidence have shown that the role of ethylene on regeneration is markedly connected to biotic and abiotic stresses as well as to hormonal-crosstalk, in particular with key regeneration hormones and growth regulators of the auxin and cytokinin families. Transcriptional factors of the ethylene response factor (ERF) family are regulated by ethylene and strongly connected to SE induction. Thus, an evident connection between ethylene, stress responses and regeneration capacity is markedly established. In this review the effect of ethylene and the way it interacts with other players during organogenesis and somatic embryogenesis is discussed.

CCCTC-binding factor (CTCF) is a conserved transcription factor that performs diverse roles in transcriptional regulation and chromatin architecture. Cancer genome sequencing reveals diverse acquired mutations in CTCF, which we have shown, functions as a tumour suppressor gene. While CTCF is essential for embryonic development, little is known of its absolute requirement in somatic cells and the consequences of CTCF haploinsufficiency. We examined the consequences of CTCF depletion in immortalised human and mouse cells using shRNA knockdown and CRISPR/Cas9 genome editing and examined the growth and development of heterozygous Ctcf (Ctcf^+/-) mice. We also analysed the impact of CTCF haploinsufficiency by examining gene expression changes in CTCF-altered endometrial carcinoma. Knockdown and CRISPR/Cas9-mediated editing of CTCF reduced the cellular growth and colony-forming ability of K562 cells. CTCF knockdown also induced cell cycle arrest and a pro-survival response to apoptotic insult. However, in p53 shRNA-immortalised Ctcf^+/- MEFs we observed the opposite: increased cellular proliferation, colony formation, cell cycle progression and decreased survival after apoptotic insult compared to wild type MEFs. CRISPR/Cas9-mediated targeting in Ctcf^+/- MEFs revealed a predominance of in-frame microdeletions in Ctcf in surviving clones, however protein expression could not be ablated. Examination of CTCF mutations in endometrial cancers showed locus-specific alterations in gene expression due to CTCF haploinsufficiency, in concert with downregulation of tumour suppressor genes and upregulation of estrogen-responsive genes. Depletion of CTCF expression imparts a dramatic negative effect on normal cell function. However, CTCF haploinsufficiency can have growth-promoting effects consistent with known cancer hallmarks in the presence of additional genetic hits. Our results confirm the absolute requirement for CTCF expression in somatic cells and provide definitive evidence of CTCF’s role as a haploinsufficient tumour suppressor gene. CTCF genetic alterations in endometrial cancer indicate that gene dysregulation is a likely consequence of CTCF loss, contributing to, but not solely driving cancer growth.

Canine mammary tumors (CMTs) are among the most common disease in female dogs and share similarities with human breast cancer, which have placed these animals as a model of study in comparative oncology. Metabolic reprogramming is one of them and is known as a hallmark of carcinogenesis whereby cells undergo adjustments to supply the high bioenergetic and biosynthetic demands of rapidly proliferating cells. However, such alterations are also vulnerabilities that may serve as therapeutic strategies which have been tested mostly in human clinical trials, but poorly explored in CMTs. In this dedicated review, we compilated the metabolic changes described for CMTs emphasizing the metabolism of carbohydrates, amino acids, lipids, and mitochondrial function. We observed here key factors associated with the presence and aggressiveness of CMTs, such as the increase in glucose uptake followed by enhanced anaerobic glycolysis via upregulation of glycolytic enzymes, changes in glutamine catabolism due to overexpression of glutaminases, raise in fatty acid oxidation and distinct effects depending on the lipid saturation, in addition to mitochondrial DNA which is a hotspot for mutations. Therefore, more attention should be paid to this topic given that targeting metabolic fragilities could improve the outcome of CMTs.

Pediatric obstructive sleep apnea (OSA) has significant negative effects on health and behavior in childhood including depression, failure to thrive, neurocognitive impairment, and behavioral issues. It is strongly associated with an increased risk for chronic adult disease such as obesity and diabetes, accelerated atherosclerosis, and endothelial dysfunction. Accumulating evidence suggests that adult-onset non-communicable diseases may originate from early life through a process by which an insult applied at a critical developmental window causes long-term effects on the structure or function of an organism. Recently, much attention has been paid to the role of epigenetic mechanisms in the pathogenesis of adult disease susceptibility. Epigenetic mechanisms that influence adaptive variability include histone modifications, non-coding RNAs, and DNA methylation. This review will highlight what is currently known about the phenotypic associations of epigenetic modifications in pediatric OSA and will emphasize the importance of epigenetic changes as both modulators of chronic disease and potential therapeutic targets.

Pancreatic cancer is the third leading cause of cancer-related deaths in the United States. Pancreatic ductal adenocarcinoma (PDA) is the most common (90%) and aggressive type of pancreatic cancer. Genomic analyses of PDA specimens have identified the recurrent genetic mutations that drive PDA initiation and progression. However, the underlying mechanisms that further drive PDA metastasis remain elusive. Despite many attempts, no recurrent genetic mutation driving PDA metastasis has been found, suggesting that PDA metastasis is driven by epigenetic fluctuations rather than genetic factors. Therefore, establishing epigenetic mechanisms of PDA metastasis would facilitate the development of successful therapeutic interventions. In this review, we provide a comprehensive overview on the role of epigenetic mechanisms in PDA as a critical contributor on PDA progression and metastasis. In particular, we explore the recent advancements elucidating the role of nucleosome remodeling, histone modification, and DNA methylation in the process of cancer metastasis.

Huntington's disease (HD) is an inherited neurodegenerative disorder that usually starts during midlife with progressive alterations of motor and cognitive functions. The disease is caused by a CAG repeat expansion within the huntingtin gene leading to severe striatal neurodegeneration. Recent studies conducted on pre-HD children highlight early striatal developmental alterations starting as soon as 6 years old, the earliest age assessed. These findings, in line with data from mouse models of HD, raise the question of when during development do the first disease-related striatal alterations emerge or whether they contribute to the later appearance of the neurodegenerative features of the disease. In this review we will describe the different stages of striatal network development and then discuss recent evidence for its alterations in rodent models of the disease. We argue that a better understanding of the striatum’s development should help in assessing aberrant neurodevelopmental processes linked to the HD mutation.

Environmental darkness signal is transferred from the retina to the pineal gland triggering melatonin secretion. Melatonin influences the synthesis and release of the hypothalamic GnRH and the adenohypophyseal gonadotropin hormones and therefore, regulates testicular function in photoperiodic species. Besides the brain, direct actions of melatonin at the testicular level have also been described. Melatonin released from the pineal gland to the circulation is taken up by peripheral tissues including testes. Testicular synthesis of melatonin has also been reported. The two key somatic cell types in the testis, Leydig and Sertoli cells, express melatonergic receptors. Melatonin acts as a local modulator of the endocrine activity in Leydig cells. In Sertoli cells, melatonin influences the oxidation state and the energy metabolism, and consequently may regulate spermatogenesis. Melatonergic receptors were also described in testicular macrophages and mast cells of infertile patients. Whereas melatonin exerts anti-proliferative and anti-inflammatory effects on testicular macrophages, it provides protective effects against oxidative stress in testicular mast cells. These data pinpoints melatonin as a key player in the regulation of testicular physiology (i.e. steroidogenesis, spermatogenesis) mostly in seasonal breeders. More importantly, melatonin is also involved in the modulation of testicular inflammatory and oxidant/anti-oxidant states in patients with idiopathic infertility.

Triatoma infestans (Klug) is an insect recognized as not only an important vector of South-American trypanosomiasis (Chagas disease) but also a model of specific cellular morphofunctional organization and epigenetic characteristics. The purpose of the present review is to highlight certain cellular processes that are particularly unveiled in T. infestans, such as 1) somatic polyploidy involving nuclear and cell fusions that generate giant nuclei; 2) diversification of nuclear phenotypes in the Malpighian tubules during insect development; 3) heterochromatin compartmentalization into large bodies with specific spatial distribution and presumed mobility in the cell nuclei; 4) chromatin remodeling and co-occurrence of necrosis and apoptosis in the Malpighian tubules under stress conditions; 5) epigenetic markers; 6) unexplained response of heterochromatin to valproic acid, an epidrug that inhibits histone deacetylases and induces DNA demethylation in other cell systems. These cellular processes and epigenetic characteristics emphasize the role of T. infestans as an attractive model for cellular research.

The purpose of this study was to compare players anthropometric (AP) and body composition (BC) characteristics between different maturity bands (pre-PHV, circa-PHV, post-PHV)) in youth elite football. This study considered 320 male football players (mean age 13.8 y.) from U14 (n=157) and U15 (n=163) age-groups. The Khamis-Roche method was used for calculating the percentage of predicted adult height (PAH) at the time of observation based on which the players were further divided into maturity bands (pre-PHV ≤ 87%, circa-PHV = 88-95%, post-PHV > 95%). Height and weight were measured, body mass index (BMI), fat free mass (FFM), total body water (TBW), body fat mass (BFM), percentage of body fat (%BF), skeletal muscle mass (SMM), FFM of both upper limbs and lower limbs and FFM of trunk were estimated according to In-body 270. All observed AP and BC characteristics differed between maturity bands (F= 139.344 – 7.925; p< 0.001; large effect sizes) except the BFM (F= 2.998; p=0.051; small effect size). Current somatic maturity stage of athletes should be considered while evaluating BC results, otherwise there is a risk of misinterpretation.

Toxins present in cigarette and e-cigarette smoke constitute a significant cause of illnesses and are known to have fatal health impacts. Specific mechanisms by which toxins present in smoke impair cell repair are still being researched and are of prime interest for developing more effective treatments. Current literature suggests toxins present in cigarette smoke and aerosolized e-vapor trigger abnormal intercellular responses, damage mitochondrial function, and consequently disrupt the homeostasis of the organelle’s biochemical processes by increasing reactive oxidative species. Increased oxidative stress sets off a cascade of molecular events, disrupting optimal mitochondrial morphology and homeostasis. Furthermore, smoking-induced oxidative stress may also amalgamate with other health factors to contribute to various pathophysiological processes. An increasing number of studies show that toxins may affect mitochondria even though exposure to secondhand or thirdhand smoke. This review assesses the impact of toxins present in tobacco smoke and e-vapor on mitochondrial health, networking, and critical structural processes including mitochondria fission, fusion, hyperfusion, fragmentation, and mitophagy. The efforts are focused on discussing current evidence linking toxins present in first, second, and thirdhand smoke to mitochondrial dysfunction

Despite more than hundred years of research since Sir Sherrington’s studies on reflexes, his questions are still somehow unanswered. On what anatomical stage do the play of spinal reflex interaction take place? What are the physiological properties of this anatomical substrate? In this paper, we address these questions in light of the most advanced theory of motor control and the anatomical discoveries on the fascia that are changing how we think about control of action and perception. There are two sides of the problem: the neurological (reflex) connections that are at the base of movement, and the anatomical substrate that regulates and coordinates the movement. We recently advanced a hypothesis on how these two elements are connected and how they interplay. Here we further explain the concept of the somatic equilibrium point – SEP – and its central role in movement control and coordination. It is our belief that the concept of SEP explains how the neuro-mechanical control of movement is organized at peripheral level. At this level, intrafusal and extrafusal muscle fibres are combined in myofascial units, organized in anatomical directions. Myofascial units are closed systems whose behaviour can be affected by neural (voluntary) control or changes in external forces. SEPs represent the intrinsic equilibrium of the myofascial units, and are connected through the continuum of the fascia so that mechanical transfer of tension from segment to segment pre-adjust muscle fibers length and hence their excitation level. This is how coordination between segments is achieved. Finally, we suggest SEPs create the neurological representation of the referent configuration for action, and configurations are linked to the architecture of the fascial system.

Glioma accounts for 80% of all malignant brain tumors and is the most common adult primary brain tumor. Age is an important factor affecting the development of cancer as somatic mutations accumulate with age. In this study, we aimed to analyze the significance of age-related non-silent somatic mutations in glioma prognosis. Histological tumor grade depends on age at diagnosis in patients with IDH1, TP53, ATRX, and EGFR mutations. The hierarchical clustering of patients was dominantly separated by IDH1 and EGFR mutations. Furthermore, patients with IDH1 mutation were dominantly separated by TP53 and ATRX double mutation and its double wildtype counterpart. Patients with the double mutation showed poorer prognosis than those with the double wild type genotype. In conclusion, among the many somatic mutations, those in IDH1, TP53, ATRX, and EGFR are important for glioma classification based on histological grade. Patients with EGFR mutation had the poorest prognosis, whereas those with only IDH1 mutation showed the best prognosis.

Peripheral arterial diseases (PAD) are complex cardiovascular conditions influenced by environmental factors and somatic mutations in multiple genes involved in hematopoiesis and inflammation. While traditional risk factors such as smoking, hypercholesterolemia, and hypertension have been extensively studied, the role of somatic mutations in PAD progression remains underexplored. This article aims to provide a comprehensive review of the molecular mechanisms, genetic landscape, prognostic significance, and clinical implications of somatic mutations in PAD. The expansion of clonal hematopoiesis of indeterminate potential (CHIP) clones in the circulating blood, named clonal hematopoiesis (CH), leads to the infiltration of these clones into atherosclerotic plaques and the production of inflammatory cytokines, increasing the risk of cardiovascular diseases including PAD. Furthermore, recent experimental evidence has demonstrated the involvement of somatically mutated TP53 genes with a high variant allele frequency (VAF) in PAD development and prognosis. The review delves into the relationship between CH and PAD, elucidating the prevalence, impact, and underlying mechanisms of this association. This understanding paves the way for novel therapeutic approaches targeting CHIP to promote tissue regeneration and improve outcomes in PAD patients. It emphasizes the need for further re-search to fully unravel the genetic footprint of the disease and highlights potential clinical implications. The findings presented in this article lay the foundation for personalized medicine approaches and open avenues for the development of targeted therapies based on somatic mutation profiling.

Somatic cell nuclear transfer (SCNT) is a reproductive biotechnology with great potential in the reproduction of different species of zootechnical interest, including sheep. This study aimed to carry out a bibliometric analysis of scientific papers published on the application of SCNT in sheep reproduction in the period 1997-2023. The search involved the Science Citation Index Expanded and Social Sciences Citation Index databases of the Main Collection of Web of Sciences with different descriptors. A total of 124 scientific papers were analyzed for different bibliometric indicators using VOSviewer software. Since 2001, the number of SCNT-related documents published concerning sheep reproduction increased and has fluctuated in ensuing years. The main authors, research groups, institutions, countries, documents and journals with the highest number of publications related to SCNT in sheep reproduction were identified, as well as the topics that address the research papers according to the terms: somatic cell, embryo, oocyte, gene expression, SCNT, and sheep.

Seemingly normal tissues progressively become populated by mutant clones over time. Most of these clones bear mutations in well-known cancer genes but only rarely do they transform into cancer. This poses questions on what triggers cancer initiation and what implications somatic variation has for cancer early detection. We analysed recent mutational screens of healthy and cancer-free diseased tissues to compare somatic drivers and the causes of somatic variation across tissues. We then reviewed the mechanisms of clonal expansion and their relationships with age and diseases other than cancer. We finally discussed the relevance of somatic variation for cancer initiation and how it can help or hinder cancer detection and prevention. The extent of somatic variation is highly variable across tissues and depends on intrinsic features, such as tissue architecture and turnover, as well as the exposure to endogenous and exogenous insults. Most somatic mutations driving clone expansion are tissue-specific and inactivate tumour suppressor genes involved in chromatin modification and cell growth signalling. Some of these genes are more frequently mutated in normal tissues than cancer, indicating a context-dependent cancer promoting or protective role. Mutant clones can persist over a long time or disappear rapidly, suggesting that their fitness depends on the dynamic equilibrium with the environment. The disruption of this equilibrium is likely responsible for their transformation into malignant clones and knowing what triggers this process is key for cancer prevention and early detection. Somatic variation should be considered in liquid biopsy, where it may contribute cancer-independent mutations, and in the identification of cancer drivers, since not all mutated genes favouring clonal expansion also drive tumourigenesis. Somatic variation and the factors governing homeostasis of normal tissues should be taken into account when devising strategies for cancer prevention and early detection.

Nervous systems and brains’ computational abilities are an evolutionary innovation, specializing and speed-optimizing ancient biophysical dynamics. Bioelectric signaling originated in cells’ communication with the outside world and with each other, in order to cooperate toward adaptive construction and repair of multicellular bodies. Here we review the emerging field of developmental bioelectricity, which links the field of basal cognition to state-of-the-art questions in regenerative medicine, synthetic bioengineering, cognitive science, and even machine learning and artificial intelligence. One of the predictions of this view is that regeneration and regulative development are able to restore correct large-scale anatomies from diverse starting states because, like the brain, they exploit bioelectric encoding of distributed goal states - in this case, pattern memories. Based on this idea, we propose a new interpretation of recent stochastic regenerative phenotypes in planaria, by appealing to computational models of memory representation and processing in the brain. Moreover, we discuss novel findings showing that bioelectric changes induced in planaria can be stored in tissue for over a week, thus revealing that somatic bioelectric circuits in vivo can implement a long-term, re-writable memory medium. A consideration of the mechanisms, evolution, and functionality of basal cognition makes novel predictions and provides an integrative perspective on the evolution, physiology, and biomedicine of information processing in vivo.

BRCA-associated hereditary breast and ovarian cancer syndrome (HBOC) implies increased absolute risk also for other malignancies such as cholangiocarcinoma (CCA). However, even if somatic mutations in CCA have been reported, there are no data on its utilization as predisposing genetic factor in a family. For the first time, we utilized CCA somatic BRCA mutation to individualize a family with HBOC. A 47-year-old woman (daughter of a patient died for CCA) accessed to our Genetic Councelling to evaluate her personal cancer risk. We performed a somatic BRCA1/2 NGS analysis on DNA extracted from formalin-fixed, paraffin-embedded CCA-tissue of her mother. After demonstration of pathogenic variant c.6468_6469delTC in BRCA2 gene mutation, the same germline pathogenic variant was found in DNA blood of one of two daugthers. So far, CCA tissue can be utilized, in addition to patient’s selection to specific therapeutic strategies, also to individualize families belonging to HBOC syndrome.

The cornea is the optical window to the brain. Its optical and structural properties are responsible for optical transparency and vision. The shape, elasticity, rigidity or stiffness are given by its biomechanical properties, whose stability results in ocular integrity and intraocular pressure dynamics. Here, we report in vivo observation of structural changes and biomechanical alterations of the human cornea induced by acoustic wave pressure within the frequency range of 50-350 Hz and 90 dB of sound pressure level. Central corneal thickness (CCT) and eccentricity (e2) were measured using Scheimpflug imaging and biomechanical properties [corneal hysteresis (CH) and intraocular pressure (IOP] were assessed with air-puff tonometry in 6 young healthy subjects. At the specific 150 Hz acoustic frequency, the variation in CCT and e2 were of 0.058 and 7.33 µm, respectively. Biomechanical alterations were also observed in both IOP (decrease of 3.60 mmHg) and CH that showed an increase of 0.40 mmHg.

The field of epigenetics, which explores how heritable traits or stable alterations of cell functions occur without changes to the DNA sequence and how environmental factors affect gene expression, is rapidly advancing. Epigenetics plays a critical role in memory formation, learning, and cognitive functioning, effectively bridging genetics with environmental influence. Maternal behavior in rats, for instance, can modify the stress response of their offspring through epigenetic mechanisms such as histone acetylation and DNA methylation. Understanding neurodegenerative diseases like Parkinson's disease (PD) depends on comprehending the mechanisms of epigenetic regulation. Epigenetic modifications, which alter proteins and DNA structure without changing the DNA sequence, can activate or suppress gene expression, assisting organisms in adapting to environmental changes. These modifications may influence genes involved in inflammation, synaptic plasticity, and neuroprotection, potentially contributing to cognitive deficits in PD patients. MicroRNAs (miRNAs), histone modifications, and DNA methylation are the epigenetic mechanisms that significantly influence cell differentiation and maintain normal cellular activity. Understanding the intricate molecular processes of epigenetics could lead to more targeted and effective therapies. Despite numerous findings on how epigenetics affects cognitive alterations in PD patients, only some studies coordinate and integrate these results. Here, we summarize recent findings on how epigenetic changes impact gene expression linked to cognitive impairments in PD.

Caseinolytic peptidase P (CLPP) plays a central role in mitochondrial unfolded protein response (mtUPR) by promoting the breakdown of misfolded proteins and setting in motion a cascade of reactions to re-establish protein homeostasis. Global germline deletion of Clpp in mice results in female infertility and accelerated follicular depletion. Telomeres, on the other hand, are tandem repeats of 5’-TTAGGG-3’ sequences found at the ends of the chromosomes. Telomeres are essential for maintaining chromosome stability during somatic cell division and their shortening is associated with cellular senescence and aging. In this study, we asked whether the infertility and ovarian aging phenotype caused by global germline deletion of Clpp is associated with somatic aging, and tested telomere length in tissues of young and aging mice. We found that impaired mtUPR caused by the lack of CLPP is associated with accelerated telomere shortening in both oocytes and somatic cells of aging mice. In addition, expression of several genes that maintain telomere integrity were decreased, and double strand DNA breaks were increased in telomeric regions. Our results highlight how impaired mtUPR can affect telomere integrity and demonstrate a link between loss of mitochondrial protein hemostasis, infertility, and somatic aging.

The soma, dendrites and axon of neurons may display calcium-dependent release of transmitters and peptides. Such release is named extrasynaptic for occurring in the absence of synaptic structures. This review describes cooperative actions of three calcium sources on somatic exocytosis. Emphasis is given to the release of serotonin by the classical serotonergic leech Retzius neuron, which has allowed detailed studies of each step between excitation and exoctytosis. Trains of action potentials induce transmembrane calcium entry through L-type channels. If the frequency of action potentials is above 5 Hz, summation of calcium transients upon individual action potentials increases the intracellular calcium concentration to activate calcium–induced calcium release. The amplified calcium wave activates motochondrial ATP synthesis that fuels the transport of vesicles to the plasma membrane. Serotonin that is released activates autoreceptors coupled to phospholipase C. Production of IP3 produces release of calcium that sustains the large-scale exocytosis. The swiss-clock workings of the release machinery for somatic exocytosis has a striking disadvantage. The essential calcium-releasing endoplasmic reticulum that lays between resting vesicles and the plasma membrane becomes an obstacle for the vesicle transport. Such architecture reduces drastically the thermodynamic efficiency of the vesicle transport and elevates its energy cost..

Functional copy number alterations (fCNAs) are DNA copy number changes with concordant differential gene expression. These are less likely to be bystander genetic lesions and could serve as robust and reproducible tumor biomarkers. To identify candidate fCNAs in neuroendocrine tumors (NETs), we integrated chromosomal microarray (CMA) and RNA-seq differential gene expression data from 31 pancreatic (pNET) and 33 small bowel neuroendocrine tumors (sbNET). Tumors were resected from 47 early disease progression (24 months) patients. Candidate fCNAs that accurately differentiated these groups in this discovery cohort were then replicated using fluorescence in situ hybridization (FISH) on formalin-fixed, paraffin-embedded (FFPE) tissues in a larger validation cohort of 60 pNETs and 82 sbNETs (52 early and 65 late disease progression samples). Logistic regression analysis determined the predictive ability of these biomarkers as well as the assay performance metrics of sensitivity, specificity, and area under the curve. Our results indicate that copy number changes at chromosomal loci 4p16.3, 7q31.2, 9p21.3, 17q12, 18q21.2, and 19q12 may be used as diagnostic and prognostic NET biomarkers. This involves a rapid, cost-effective approach to determine primary tumor site for patients with metastatic liver NETs and to guide risk stratified therapeutic decisions.

Chronic exposure to noise can cause several extraordinary effects and involve all the systems of the human organism. In addition to cardiovascular, gastrointestinal and immune effects, the data in the literature show alterations in behavioral disturbances, in memory capacity and cognitive performance. Through this systematic review, the authors try to find out which are the main neurobehavioral alterations, in case of occupational exposure to noise. Literature review included articles published in the major databases (PubMed, Cochrane Library, Scopus), using a combina-tion of some relevant keywords. This online search yielded 4434 references; after selection, the authors analyzed 41 articles (4 narrative reviews and 37 original articles). From this analysis, it appears that main symptoms are related to psychological distress, annoyance, sleep disturbances, cognitive performance. Regarding tasks, the most frequent employments concern school staff, followed by employees from various industrial sectors and office workers. Although the causes are still widely debated, it is essential to protect these workers against chronic exposure to noise. In fact, in addition to a hearing loss, they can manifest many other related discomforts over time and compromise their full working capacity, as well as expose them to a greater risk of accidents or absences from work.

Cerebrospinal fluid (CSF)-contacting neurons (CSF-N) located in the surface of both brain ventricles and the central canal (cc) in the spinal cord. The cc and CSF maintain a proliferative niche for neural progenitor cells and play a vital role in development of the brain. The CSF circulates in the ventricles and the subarachnoid spaces with the CSF rhythmic flow: cardiac pulsation and respiratory fluctuation. A new concept of CSF motion may be contrary to the classical one that the direction of CSF motion may vary in direction and may be dynamic in its location. The CSF pressure may also depend on the body position. Moderate music-making has been considered a potential approach for rehabilitative and restorative therapy of brain dysfunctions. Recently, we find that the CSF-Ns are present in both the interior CFS in the cc and also exterior CSF around the surface of the spinal cord. We hypothesize that CSF-N as mechanical sensors in the spinal cord could sense motion of the spinal cord. The myodural bridge is a ligament connecting a pair of deep, upper-neck muscles to the dura mater, which envelops the arachnoid mater and contains the CSF surrounding the brain and the spinal cord. We figure out the term “CSF-static compartment” and classify CSF storage location as rostral pool and caudal pool to demonstrate our hypothesis. We presume that the somatic body movement with music-making and rehabilitation-based interventions would orchestrate the CSF motion with head movement, myodural bridge stretching and puling as well as spinal bending.

Metabolic bone diseases cover a broad spectrum of disorders that share alterations of bone metabolism leading to a defective skeleton, associated with increasing morbidity, disability, and mortality. There is a close connection between the etiology of metabolic bone diseases and genetic factors, being TP53 one of the genes associated therewith. The single nucleotide polymorphism (SNP) Arg72Pro of TP53 is a genetic factor associated with several pathologies, including cancer, stroke and osteoporosis. Here, we aim to analyze the influence of the TP53 Arg72Pro SNP on bone mass in the humanized Tp53 Arg72Pro knock-in mice. This work reported on the influence of TP53 Arg72Pro polymorphism in bone microarchitecture, OPG gene expression and apoptosis bone status. The results showed that the proline variant of TP53 Arg72Pro polymorphism (Pro72-p53) was associated with deteriorated bone tissue, lower OPG/RANK ratio and lower apoptosis in bone tissue. In conclusion, the TP53 Arg72Pro polymorphism modulates bone microarchitecture and may be a genetic biomarker to identify individuals with an increased risk of suffering metabolic bone alterations

Background: Alcohol consumption is associated with the development of cardiovascular diseases, cancer, and liver disease. The biological mechanisms are still largely unclear. Here, we aimed to use an agnostic approach to identify phenotypes mediating the effect of alcohol on various diseases. Methods: We performed an agnostic association analysis between alcohol consumption (red, and white wine, beer/cider, fortified wine, and spirits) with over 7,800 phenotypes from the UK biobank comprising 223,728 participants. We performed Mendelian randomisation analysis to infer causality. We additionally performed a Phenome-wide association analysis and a mediation analysis between alcohol consumption as exposure, traits in causal relationship with alcohol consumption as mediators, and various diseases as outcome. Results: Of 45 traits in association with alcohol consumption, 20 were in causal relationship with alcohol consumption. Gamma glutamyltransferase (GGT; β=9.44; CI,5.94-12.93; Pfdr=9.04×10-7), mean sphered cell volume (β=0.189; CI,0.11-0.27; Pfdr=1.00×10-4), mean corpuscular volume (β=0.271; CI,0.19-0.35; Pfdr=7.09×10-10) and mean corpuscular haemoglobin (β=0.278; CI,0.19-0.36; Pfdr=1.60×10-6) showed the strongest causal relationships. We also identified GGT and physical activity as mediators causing liver cirrhosis and alcohol dependence. Conclusion: Our study provides evidence of causality between alcohol consumption and 20 traits and a mediation effect for physical activity on health consequences of alcohol consumption.

Inflammatory granulocytes are characterized by oxidative burst, which may promote oxidative stress and lipid modification both in affected tissues and on systemic level. On the other hand, redox signaling involving lipid peroxidation products acting as second messengers of free radicals play important, not yet fully understood, roles in pathophysiology of inflammation and various stress-associated disorders. Therefore, the aim of this study was to evaluate the onset of oxidative stress and alterations of enzyme-dependent lipid metabolism resulting from redox imbalance in granulocytes and plasma obtained from patients with psoriasis vulgaris or psoriatic arthritis, in comparison to the healthy subjects. The results obtained revealed enhanced activity of pro-oxidant enzymes NADPH and xanthine oxidases in granulocytes, with a decrease of enzymatic and non-enzymatic antioxidants in plasma of psoriatic patients. The Nrf2 and its regulators were increased in both forms of psoriasis, while HO-1 levels were increased only in psoriasis vulgaris. Redox imbalance was associated with decreased levels of phospholipids and of free PUFAs, but with enhanced activity of enzymes involved in lipid metabolism (PLA2, PAF-AH COX1/2) and increased lipid peroxidation products 4-hydroxynonenal (4-HNE), isoprostanes and neuroprostanes. Increased endocannabinoids and GPR55 were observed in both forms of the disease, while expression of CB1 was increased only in pateints with psoriatic arthritis, opposite to CB2, which was increased only in psoriasis vulgaris. Protein modifications by ROS and lipid peroxidation product 4-HNE promoted apoptosis of granulocytes by increased caspases in both forms of psoriasis. This study indicates that excessive activation of granulocytes, causing oxidative stress and lipid modifications, is an important pathophysiology of psoriasis. Consequently, lower Nrf2 activity and CB2 expression may promote progression of psoriasis into advanced, arthritic form of the disease.

Canine lymphoma (CL) is one of the most common malignant tumors in dogs. The cause of CL remains unclear. Genetic mutations that have been suggested as possible causes of CL are not fully understood. Whole-exome sequencing (WES) is a time- and cost-effective method for detecting genetic variants targeting only protein-coding regions (exons) that are part of the entire genome region. A total of eight patients with B-cell lymphomas were recruited, and WES analysis was performed on whole blood and lymph node aspirate samples from each patient. A total of 17 somatic variants (GOLIM4, ITM2B, STN1, UNC79, PLEKHG4, BRF1, ENSCAFG00845007156, SEMA6B, DSC1, TNFAIP1, MYLK3, WAPL, ADORA2B, LOXHD1, GP6, AZIN1, and NCSTN) with moderate to high impact were identified by WES analysis. Through a Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of 17 genes with somatic mutations, a total of 16 pathways were identified. Overall, the somatic mutations identified in this study suggest novel candidate mutations for CL, and further studies are needed to confirm the role of these mutations.

Diabetic kidney disease (DKD) is a major cause of morbidity and mortality of type 2 diabetes mellitus (T2DM). Aim of this study was to investigate whether albumin structural alterations correlate with DKD severity and evaluate whether native and reduced albumin concentrations could complement the diagnosis of DKD. To this aim, one hundred and seventeen T2DM patients without (n=42) and with (n=75) DKD (DKD I-III upon KDIGO classification) were evaluated; total albumin concentration (tHA) was quantified by bromocresol green assay, while structural alterations were profiled assessed by liquid chromatography-high resolution mass spectrometry (LC-HRMS). The concentrations of albumin in native (eHA, effective albumin) and reduced (rHA) forms were then assessed. HRMS analyses showed a reduced relative amount of native albumin in DKD patients along with an increased abundance of altered forms, especially those bearing oxidative modifications. Accordingly, both eHA and rHA values varied along the stages of progressive renal failure, and alterations dose-dependently correlated with renal dysfunction. ROC curves analysis showed a significantly higher sensitivity and specificity of eHA and rHA with respect to tHA for the diagnosis of DKD. Importantly, at multivariable logistic regression analysis, eHA was identified as independent predictor of DKD.

Heterosis plays a significant role in enhancing variety, boosting yield, and raising economic value, but the molecular mechanism is still unclear. We analyzed the transcriptomes and 3D genomes of hybrid (F1) and its parents (w30 and 082). Analysis of the expression revealed a total of 485 specially expressed genes (SEGs), 173 differentially expressed genes (DEGs) above parental expression level, more actively expressed genes and up-regulated DEGs in F1. Further study revealed that the DEGs detected in F1 and its parents were mainly involved in response to auxin, plant hormone signal transduction, DNA metabolic process, Purine metabolism, starch and sucrose metabolism, which suggested that these biological processes may play a crucial role in the heterosis of B. rapa. The analysis of 3D genome data revealed that hybrid F1 tend to contain more transcriptionally active A compartments after hybridization. Additionally, F1 had a smaller TAD (topologically associated domain) genome length, but the number was the highest, and the expression change of activated TAD was higher than repressed TAD. More specific TAD boundaries were detected between parents and F1. Subsequently, 140 DEGs with genomic structural variants were selected as potential candidate genes. Among them, we found two DEGs with consistent expression changes in A/B compartments and TADs. Our findings suggest that genomic structural variants, such as TADs and A/B compartments, may affect gene expression and contribute to heterosis in B. rapa. This study provides further insight into the molecular mechanism of heterosis in B. rapa.

One of the hallmarks of microgravity-induced effects in several cellular models is represented by the alteration of oxidative balance with the consequent accumulation of Reactive Oxygen Species (ROS). It is well known that male germ cells are sensitive to oxidative stress and to changes of gravitational force even if published data on germ cell models are scarce. To gain more insights into the mechanisms of male germ cell response to altered gravity, a 3D cell culture model has been established from TCam-2 cells, a seminoma-derived cell line considered the only human cell line available to study in vitro mitotically active human male germ cells. TCam-2 cell spheroids were cultured for 24 hours under unitary gravity (Ctr) or simulated microgravity (s-microgravity) conditions, these last ones were obtained using the Random Positioning Machine (RPM). A significant increase in intracellular ROS and mitochondria superoxide anion levels has been observed after RPM exposure. In line with these results a trend of protein and lipid oxidation increase, and increased pCAMKII expression levels were observed after RPM exposure. The ultrastructural analysis by Transmission Electron Microscopy revealed that RPM-exposed mitochondria appeared enlarged and, even if seldom, disrupted. Notably, even the expression of the main enzymes involved in the redox homeostasis appears modulated by RPM exposure in a compensatory way, being GPX1, NCF1, and CYBB downregulated, whereas NOX4 and HMOX1 upregulated. Interestingly, HMOX1 is involved in the heme catabolism of mitochondria cytochromes, and therefore the positive modulation of this marker can be associated to the observed mitochondria alteration. All together, these data demonstrate TCam-2 spheroid sensitivity to acute SM exposure and indicate the capability of these cells to trigger compensatory mechanisms that allow to overcome the exposure to altered gravitational force.

Autism Spectrum disorder (ASD) and intellectual disability (ID) are the most frequent develop-mental disorders with a prevalence between 3% and 5% of the population. In addition, both ASD and ID can be found in the same patient. Mutations in several genes involved in the epigenetic regulation of gene expression have been linked to different ID associated with ASD features including alterations of the ly-sine-acetyltransferase 6A (KAT6A) gene in KAT6A syndrome. KAT6A enzyme participates in a wide range of critical cellular functions such as chromatin remodeling, gene expression, protein synthesis, cell metabolism, and replication. In this manuscript, we examined the pathophysiolog-ical alterations in fibroblasts derived from three patients harboring KAT6A mutations. We ad-dressed survival in stress medium, histone acetylation, protein expression patterns and tran-scriptome analysis as well as cell bioenergetics. In addition, we evaluated the therapeutic effec-tiveness of epigenetic modulators and mitochondrial boosting agents such as pantothenate and L-carnitine in correcting the mutant phenotype. Pantothenate and L-carnitine treatment increased histone acetylation and corrected protein and transcriptomic expression patterns in mutant KAT6A cells. Furthermore, cell bioenergetics of mutant cells was significantly improved. Our results suggest that pantothenate and L-carnitine can significantly correct the mutant phe-notype in cellular models of KAT6A syndrome.

Aging is a complex biological process, with gradual and progressive decline in structure and function in many organ systems. Our objective is to determine if structural changes produced by aging, vary with sex, in a stressful situation such as dehydration. The expression of Slc12a3 mRNA in renal cortex, α-smooth muscle actin (α-SMA) and fibronectin, was evaluated in male and female rats aged 3 and 18 months submitted or not to water deprivation (WD) for 48 hours. When comparing ages, 18-month-old males showed lower expression of Slc12a3 mRNA than 3-month-old males, and control and WD 18-moth-old male and female rats exhibited higher expression of α-SMA than respective 3-month-old rats. Fibronectin was higher in both control and WD 18-month-old males than respective 3-month-old males. In females, only control 18-month-old rats showed higher fibronectin than control 3-month-old rats. When we compared sex, control and WD 3-month-old female rats had lower expression of Slc12a3 mRNA than re-spective males. WD 18-month-old male rats presented higher expression of fibronectin and α-SMA than WD 18-month-old female rats. When we compared hydric condition, WD 18-month-old males displayed lower relative expression of Slc12a3 mRNA and higher α-SMA expression than control 18-month-old males. Aging, sex, and dehydration lead to alteration in kidney structure.

Cells receive external stimuli to incur structural and functional damages. On scanning acoustic microscopy (SAM), speed-of-sound (SOS), attenuation-of-sound (AOS), and thickness values are plotted on the screen to create cellular images, which are related to stiffness, viscosity, and cell size, respectively. The obtained digital data compared using statistical analysis. We aimed to investigate the effects of anticancer drugs, acidic fluids, and heat effects on the cells by using SAM. Anticancer drug cisplatin induced cancer cell apoptosis/necrosis and regeneration in culture, causing elevated SOS, reduced AOS, and thickness. During a more prolonged incubation, the SAM values fluctuated differently between the cisplatin-treated and untreated cells. The tannic and acetic acid and microwave stimuli induced SOS and AOS elevations. These stimuli altered the cell size, number, differentiation, viscosity, and stiffness, which corresponded well to the fluctuation of the SOS and AOS values after incubation. Different anticancer drugs interacted with cancer cells to induce the characteristic alterations of the SAM values. These structural and mechanical alterations induced in cells was difficult to observe on light microscopy. Cellular damages were statistically compared between different stimuli and time-lapse cellular changes were observed using a SAM analysis. SAM is a useful modality to evaluate cellular damage.

Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by progressive accumulation of a rare population of CD5+ B lymphocytes in peripheral blood, bone marrow and lymphoid tissues. CLL exhibits remarkable clinical heterogeneity, with some patients presenting with indolent disease and others progressing rapidly to aggressive CLL. The significant heterogeneity of CLL underscores the importance of identifying novel prognostic markers. Recently, the RAS-related gene RRAS2 has emerged as both a driver oncogene and a potential marker for CLL progression, with higher RRAS2 expression associated with poorer disease prognosis. Although missense somatic mutations in the coding sequence of RRAS2 have not been described in CLL, this study reports the frequent detection of three somatic mutations in the 3' untranslated region (3'UTR) affecting positions +26, +53, and +180 downstream of the stop codon in the mRNA. An inverse relationship was observed between these three somatic mutations and RRAS2 mRNA expression, which correlated with lower blood lymphocytosis and better prognosis. These findings highlight the importance of RRAS2 overexpression in CLL development and prognosis and point to somatic mutations in its 3'UTR as novel mechanistic clues. Our results may contribute to the development of targeted therapeutic strategies and improved risk stratification for CLL patients.

Febrile seizures in early childhood can lead to developmental disorders in the CNS. However, the specific mechanisms behind the impact of febrile seizures on the developing brain are not well-understood. To address this gap in knowledge, we employed a hyperthermic model of febrile seizures in 10-day-old rats and tracked their development over two months. Our objective was to determine the degree to which the properties of the hippocampal glutamatergic system are modified. We analyzed whether pyramidal glutamatergic neurons in the hippocampus die after febrile seizures. Our findings indicate that there is a reduction in the number of neurons in various regions of the hippocampus in the first two days after seizures. The CA1 field showed the greatest susceptibility, and the reduction in the number of neurons in post-FS rats in this area appeared to be long-lasting. Electrophysiological studies indicate that febrile seizures cause a reduction in glutamatergic transmission, leading to decreased local field potential am-plitude. This impairment could be attributable to diminished glutamate release probability as evidenced by decreases in frequency of miniature excitatory postsynaptic currents and increases in pair-pulse ratio of synaptic responses. We also found higher threshold current causing hindlimb extension in the maximal electroshock seizure threshold test of rats 2 months after febrile seizures compared to control animals. Our research suggests that febrile seizures can impair glutamatergic transmission, which may protect against future seizures.

Prostate cancer is driven by acquired genetic alterations, including those impacting the epigenetic machinery. With African ancestry a significant risk factor for aggressive disease, we hypothesize that dysregulation among the roughly 656 epigenetic genes may contribute to prostate cancer health disparities. Interrogating prostate tumor genomic data from 109 men of southern African and 56 men of European Australian ancestry, we found African-derived tumors to present with a longer tail of epigenetic driver gene candidates (72 versus 10). Biased towards African-specific drivers (63 versus 9 shared), many are novel to prostate cancer (18/63) including several putative therapeutic targets (CHD7, DPF3, POLR1B, SETD1B, UBTF and VPS72). Through clustering of all variant types and copy number alterations, we describe two epigenetic PCa taxonomies capable of differentiating patients by ancestry and predicted clinical outcomes. We identified top genes in African and European-derived tumors that represent a multifunctional “generic machinery”, alteration to which may be instrumental in epigenetic dysregulation and prostate tumorigenesis. In conclusion, numerous somatic alterations in the epigenetic machinery drive prostate carcinogenesis but African-derived tumors appear to achieve this with greater diversity amongst such alterations. The greater novelty observed in African-derived tumors illustrates the significant clinical benefit to be derived from a much needed African tailored approach to prostate cancer healthcare aimed at reducing prostate cancer health disparities.

Rat is one of the most commonly used model animals for biological research. The organs and systems of human being are somewhat similar to that of rat in structure as well as functions, making it a valuable choice for research experimentation in biological sciences. A number of studies have been conducted to evaluate the potential risks and toxicity of different elements on the physiology and histology of rats. There is need to address certain environmental factors affecting rats condition during experimentation. Reproduction along with its pathologies is under investigation on larger scale throughout the world, being central for the existence of a species. These studies focus on the major factors that influence reproductive function. Review of literature clearly indicated the unwanted consequences of over nutrition, malnutrition, high or low temperature, non-enriched housing, improper handling, intense or poor light exposure and environmental pollution on histology and hormonal profile of reproductive system of rats.

The covid-19 pandemic has generated substantial changes in the lives of the population, such as increased physical inactivity, which can lead to overweight and, consequently, repercussions on glucose homeostasis. A population-based household epidemiological survey was conducted by stratified, multistage probability cluster sampling (October and December 2020) in Brazil. Participants were classified as physically active or inactive during leisure time according to the recommendations of the World Health Organization. HbA1c levels were categorized as normal (≤6.4%) or with glycemic changes (≥ 6.5%). The mediating variable was excess weight (overweight and obese). Multivariate logistic regression analyzes were performed to examine the association between physical inactivity and glycemic changes. Mediation was analyzed using the Karlson–Holm–Breen method to verify the influence of excess weight on the association. We interviewed 1,685 individuals, mostly women (52.4%), 35–59 years old (45.8%), race/ethnicity brown (48.1%), and excess weight (56.5%). The mean HbA1c was 5.68% (95% CI: 5.58-5.77). Individuals physically inactive were 2.62 times more likely to have glycemic alterations (OR:2.62.95% CI:1.29-5.33), and 26.87% of this association was mediated by excess weight (OR:1.30:95% CI:1.06-1.57). Physical inactivity in leisure time increases the chances of glycemic alterations, and part of this association can be explained by excess weight.

Microcystins (MCs) are cyanobacterial toxins and potent inhibitors of protein phosphatases 1 (PP1) and 2A (PP2A), which are involved in plant cytoskeleton (microtubules and F-actin) organization. Therefore, studies on the toxicity of cyanobacterial products on plant cells have so far being focused on MCs. In this study, we investigated the effects of extracts from 16 (4 MC-producing and 12 non-MC-producing) cyanobacterial strains from several habitats, on various enzymes (PP1, trypsin, elastase), on the plant cytoskeleton and H2O2 levels in Oryza sativa (rice) root cells. Seedling roots were treated for various time periods (1, 12 and 24h) with aqueous cyanobacterial extracts and underwent either immunostaining for α-tubulin or staining of F-actin with fluorescent phalloidin. DCF-DA staining was performed for H2O2 imaging. The enzyme assays confirmed the bioactivity of the extracts of not only MC-rich (MC+), but also MC-devoid (MC-) extracts, which induced major time-dependent alterations on both components of the plant cytoskeleton. These findings suggest that a broad spectrum of bioactive cyanobacterial compounds, apart from MCs or other known cyanotoxins (such as cylindrospermopsin), can affect plants by disrupting the cytoskeleton.

Contamination with Arsenic, a toxic metalloid, is increasing in the marine environment. Additionally, global warming can alter metalloids toxicity. Polychaetes are key species in marine environments. By mobilizing sediments, they play vital roles in nutrient and element (including contaminants) cycles. Most studies with marine invertebrates focused on the effects of metalloids on either adults or larvae. Here we bring information on the effects of temperature increase and arsenic contamination on the polychaete Hediste diversicolor in different growth stages and water temperatures. Feeding activity and biochemical responses – neurotransmission, indicators of cell damage, antioxidant and biotransformation enzymes and metabolic capacity - were evaluated. Temperature rise combined with As imposed alterations on feeding activity and biochemical endpoints at different growth stages. Small organisms have their antioxidant enzymes increased, avoiding lipid damage. However, larger organisms are the most affected class due to inhibition of superoxide dismutase, which resulted in protein damage. Oxidative damage was observed on smaller and larger organisms exposed to As and 21 °C, demonstrating higher sensibility to the combination of temperature rise and As. The observed alterations may have ecological consequences, affecting the cycle of nutrients, sediment oxygenation and the food chain that depend on the bioturbation of this polychaete.

Pathologies of the blood brain barrier (BBB) have been linked to a multitude of CNS disorders whose pathology is poorly understood. Cortical spreading depression (CSD) has long been postulated to be involved in the underlying mechanisms of these disease states, yet full understanding remains elusive. This study utilized an in vitro model of the BBB with b.End3 murine endothelial cells to investigate the role of CSD in BBB pathology by characterizing effects of the release of major pronociceptive substances on BBB functional integrity using TEER screening, transcellular uptake, and immunoreactive methods in concert with global proteome and phospho-proteomic approaches. Findings demonstrated relocalization and functional alteration to proteins associated with the cytoskeleton and endothelial tight junctions. Pathologic mechanisms induced by individual substances released during CSD were found to have unique phosphorylation signatures in phospho-proteome analysis, identifying Zona Occludens 1 as a possible pathologic “checkpoint” of the BBB. Utilizing these phosphorylation signatures, possible novel diagnostic methods may be developed for neurological diseases and warrants further investigation.

Abstract: Fanconi anemia (FA), a chromosome instability syndrome, is caused by inherited pathogenic variants in any of 22 FANC genes, that cooperate in the FA/BRCA pathway. This pathway regulates the repair of DNA interstrand crosslinks (ICLs) through homologous recombination. In FA proper repair of ICLs is impaired, and accumulation of toxic DNA double strand breaks occurs. In order to repair this type of DNA damage, FA cells activate alternative error-prone DNA repair pathways, that may lead to the formation of gross structural chromosome aberrations of which radial figures are the epitome and origin of subsequent aberrations like translocations, dicentrics and acentric fragments. The deficiency in DNA repair has pleiotropic consequences in the phenotype of patients with FA, including developmental alterations, bone marrow failure and an extreme risk to develop cancer. The mechanisms leading to the physical abnormalities during embryonic development have not been clearly elucidated, however FA has features of premature aging with chronic inflammation mediated by pro-inflammatory cytokines, that results in tissue attrition, selection of malignant clones and cancer onset. Moreover, the effect of the FA/BRCA pathway in germinal cells, evidenced by infertility in patients with FA attests of chromosomal instability and cell death also occurring in the germinal compartment.

Coffee Coffea arabica L. depends on abundantly distributed rainfall and drought impacts their development, fruit production, bean quality, and ultimately, beverage quality. Plant Biotechnology by means of genetic manipulation and plant regeneration by the somatic embryogenic process is an alternative technology to overcome these prob-lems. In the present work we used the molecular approach of the trehalose/trehalase role in plant surviving in extreme drought/salt environments. We used a cassette containing the antisense C. arabica L. trehalase gene under the RD29 promoter from A. thaliana and the NOS terminator to genetically modified an em-bryogenic coffee C. arabica L. cv typica line under osmotic stress supplemented with mannitol (0.3M) and sorbitol (0.3M) containing medium. Drought resistant SE lines were recovered and regenerate plants. Resistant SE lines showed a higher rate of competence to induce secondary SE capacity. A transcrip-tome analysis was performed from high competent SE lines to understand the acquired molecular mechanisms to developed SE. From the up-regulated genes, a PPI network made by STRING v12.0 with high confidence (0.700) revealed the presence of the 10 modules. The cell cycle, chromatin remodeling, somatic embryogenesis, oxidative stress, generic transcription pathway, carbon metabolism, phenylpropanoid biosynthesis, trehalose biosynthesis, proline bio-synthesis and glycerolipid metabolism.

The advent of high throughput sequencing has enabled researchers to systematically evaluate the genetic variations in cancer, resulting in identifying many cancer-associated genes. Although cancers in the same tissue are widely categorized in the same group, they demonstrate many differences concerning their mutational profiles. Hence there is no “silver bullet” for the treatment of a cancer type. This reveals the importance of developing a pipeline to identify cancer-associated genes accurately and re-classify patients with similar mutational profiles. Classification of cancer patients with similar mutational profiles may help discover subtypes of cancer patients who might benefit from specific treatment types. In this study, we propose a new machine learning pipeline to identify protein-coding genes mutated in a significant portion of samples to identify cancer subtypes. We applied our pipeline to 12270 samples collected from the International Cancer Genome Consortium (ICGC), covering 19 cancer types. Here we identified 17 different cancer subtypes. Comprehensive phenotypic and genotypic analysis indicates distinguishable properties, including unique cancer-related signaling pathways, in which, for most of them, targeted treatment options are currently available. This new subtyping approach offers a novel opportunity for cancer drug development based on the mutational profile of patients. We also comprehensive study the causes of mutations among samples in each subtype by mining the mutational signatures, which provides important insight into their active molecular mechanisms. Some of the pathways we identified in most subtypes, including the cell cycle and the Axon guidance pathways, are frequently observed in cancer disease. Interestingly, we also identified several mutated genes and different rates of mutation in multiple cancer subtypes. In addition, our study on “gene-motif” suggests the importance of considering both the context of the mutations and mutational processes in identifying cancer-associated genes. The source codes for our proposed clustering pipeline and analysis are publicly available at: https://github.com/bcb-sut/Pan-Cancer.

Anthracnose, caused by the fungus Colletotrichum lindemuthianum, poses a significant and widespread threat to the common bean crop. The use of plant genetic resistance has proven to be the most effective strategy for managing anthracnose disease. The Amendoim Cavalo (AC) Andean cultivar has resistance against multiple races of C. lindemuthianum, which is conferred by the Co-AC gene. Fine mapping of this resistance gene to common bean chromosome Pv01 enabled the identification of Phvul.001G244300, Phvul.001G244400, and Phvul.001G244500 candidate genes for further validation. In this study, we assessed the relative expression of Co-AC candidate genes, as well as other putative genes in vicinity of this locus and known resistance genes, in the AC cultivar following inoculation with the race 73 of C. lindemuthianum. Gene expression analysis revealed significantly higher expression levels of Phvul.001G244500. Notably, Phvul.001G244500 encodes a putative Basic Helix-Loop-Helix transcription factor, suggesting its involvement in the regulation of defense responses. Furthermore, we observed a significant modulation of the expression of defense related genes PR1a, PR1b, and PR2, in a time-course experiment. These findings contribute to the development of improved strategies for breeding anthracnose-resistant common bean cultivars, thereby mitigating the impact of this pathogen on crop yields and ensuring sustainable bean production.

Bioactive lipids are involved in cellular signalling events with links to human disease. Many of these are involved in inflammation under normal and pathological conditions. Despite being attractive molecules from a pharmacological point of view, detection and quantification of lipids has been a major challenge. Here, we have optimised a liquid chromatography dynamic multiple reaction monitoring targeted mass spectrometry (LC-dMRM-MS) approach to profile eicosanoids and fatty acids in biological samples. In particular, by applying this analytic workflow to study a cellular model of Chronic Myeloid Leukaemia (CML), we found that intra- and extra-cellular 2-Arachidonoylglycerol (2-AG), intracellular Arachidonic Acid (AA), and extracellular Prostaglandin F_2α (PGF_2α), 5-Hydroxyeicosatetraenoic acid (5-HETE), Palmitic acid (PA, C16:0) and Stearic acid (SA, C18:0) were altered in response to immunomodulation by type I Interferon (IFN-I), a currently approved treatment for CML. Our observations indicate changes in eicosanoid and fatty acid metabolism with potential relevance in the context of cancer inflammation and CML.

Changes in food preferences after bariatric surgery may alter its effectiveness as a treatment for obesity. We aimed to compare food reward for a comprehensive variety of food categories between patients who received a sleeve gastrectomy (SG) or a Roux-en-Y gastric bypass (RYGB) and to explore whether food reward differs according to weight loss. In this cross-sectional exploratory study, food reward was assessed using the Leeds Food Preference Questionnaire (LFPQ). We assessed liking and wanting of eleven food categories. Comparisons were done regarding type of surgery and Total Weight Loss (TWL; based on tercile distribution). Fifty-six patients (30 SG and 26 RYGB) were included (women: 70%; age: 44.0 (11.1) y). Regarding the type of surgery, scores were not significantly different between SG and RYGB, except for ‘non-dairy products – without color’ explicit liking (p = 0.04). Regarding TWL outcomes, explicit liking, explicit wanting and implicit wanting, scores were significantly higher for Good responders than Low responders for ‘No meat – High fat’ (post-hoc corrected p-value: 0.04, 0.03 and 0.04, respectively). Together, our results failed to identify major differences in liking and wanting regarding the type of surgery and tended to indicate that higher weight loss might be related to a higher reward for high protein-content food. Rather to focus only on palatable foods, future studies should also consider a broader range of food items, including protein reward.

Adult stem cells (ASCs) can be cultured with difficulty from most tissues, often requiring chemical or transgenic modification to achieve adequate quantities. We show here that mouse primary fibroblasts grown in suspension change from the elongated and flattened morphology observed under standard adherent culture conditions generating rounded cells with large nuclei and scant cytoplasm expressing the mesenchymal stem cell (MSC) marker (Sca1; Ly6A) within 24hrs. Based on this initial observation, we describe here a suspension culture method that, irrespective of the lineage used, mouse fibroblast, primary human somatic cells (fibroblasts, hepatocytes and keratinocytes), is capable of generating a high yield of cells in spheroid form which display expression of ASCs surface markers, circumventing the anoikis which often occurs at this stage. Moreover, mouse fibroblasts-derived spheroids can be differentiated into adipogenic and osteogenic lineages. Analysis of single cell RNA sequence data identified 8 distinct cell clusters with one in particular comprising approximately 10% of the cells showing high levels of proliferative capacity expressing high levels of genes related to MSCs and self-renewal as well as extracellular matrix (ECM). We believe the rapid, high-yield generation of proliferative, multi-potent ASC-like cells by the process we term suspension-induced stem cell transition (SIST) could have significant implications for regenerative medicine.

Anticancer regimens for Hodgkin lymphoma (HL) patients include highly genotoxic drugs that have been very successful in killing tumor cells and providing a 90% disease-free survival at five years. However, these treatments do not have a specific cell target, damaging both cancerous and normal cells. Thus, HL survivors have a high risk of developing new primary cancers, both hematologic and solid tumors, that have been related to treatment. Several studies have shown that after-treatment, HL patients and survivors present persistent chromosomal instability, including non-clonal chromosomal aberrations. The frequency and type of chromosomal abnormalities appear to depend on the type of therapy and the cell type examined. For example, MOPP chemotherapy affects hematopoietic and germ stem cells leading to long-term genotoxic effects and azoospermia, while ABVD chemotherapy affects transiently sperm cells, with most of the patients showing recovery of spermatogenesis. Both regimens have long-term effects in somatic cells, presenting non-clonal chromosomal aberrations and genomic chaos in a fraction of non-cancerous cells. This is a source of karyotypic heterogeneity that could eventually generate a more stable population acquiring clonal chromosomal aberrations and leading towards the development of a new cancer.

The MLL1 gene located on chromosome 11q23, is crucial for histone lysine-specific methylation and is frequently implicated in various leukemia types. Despite prior in silico investigations into non-synonymous single nucleotide polymorphisms (nsSNPs) associated with leukemia in the MLL1 gene, there is a dearth of comprehensive studies evaluating their impact on the protein's structure, function, and post-translational modifications. Addressing this, our study screened 2049 nsSNPs from the dbSNP database, identifying 62 high-risk variants. A thorough domain analysis revealed that these nsSNPs are distributed across seven domains of the MLL1 protein, potentially affecting their functions. Our conservation analysis highlighted 31 nsSNPs as deleterious, suggesting their potential effects on protein stability and function. Furthermore, utilizing the MutPred2 tool, we identified mutations affecting metal-binding, protein loop structures, and post-translational modifications, which could alter the MLL1 protein's native functionality. Interaction network analysis underscored the role of MLL1 in hematopoietic cell development, implying that mutations may influence hematological malignancies. Additionally, a subset of non-coding SNPs was found to possess regulatory capabilities, potentially affecting gene expression and chromatin modification. Most significantly, using CScape and CScape-somatic tools, four nsSNPs were predicted to be oncogenic, with two classified as cancer drivers, underscoring their potential role in leukemia development. The oncogenic nsSNP, D2724G, located between the FY-rich N and FY-rich C domain of the MLL1 protein, has raised significant interest due to its potential impact on proteolytic cleavage. Predictive analyses, such as those by Mutpred2, suggest a loss of cleavage at D2724 caused by this mutation, potentially affecting the formation of essential MLL1 fragments, p320 and p180. These fragments play a crucial role in creating a stable multiprotein complex that localizes to a specific subnuclear region. Therefore, mutations like D2724G can potentially alter gene expression patterns, influencing cellular behavior and possibly fostering a cancer-prone environment. In conclusion, our research provides an in-depth assessment of the effects of nsSNPs in the MLL1 gene on leukemia, offering potential avenues for personalized treatment strategies, early detection, prognosis, and a better understanding of hematological malignancy genesis.

Objective: To examine whether 1) immune and nitro-oxidative stress (IO&NS) biomarkers are associated with premenstrual syndrome (PMS); and 2) changes in IO&NS biomarkers during the menstrual cycle (MC) are associated with PMS symptoms and plasma estradiol and progesterone. Methods: Forty-one women completed the Daily Record of Severity of Problems (DRSP) rating scale during 28 consecutive days and MC Associated Syndrome (MCAS) was diagnosed when the summed DRSP score during the MC is > 0.666 percentile. We assayed plasma levels of complement C3 and C4, highly sensitive C-reactive protein (hsCRP), haptoglobin (Hp), advanced oxidation protein products (AOPP), lipid hydroperoxides (LOOH), nitric oxide metabolites (NOx), total radical-trapping antioxidant parameter (TRAP), sulfhydryl (-SH) groups and the activity of paraoxonase (PON)1 at days 7 (D7), 14 (D14), 21 (D21) and 28 (D28) of the MC. Results: All biomarkers, except hsCRP, showed significant alterations during the MC. Arylesterase (AREase) was lowered at D28, while LOOH increased at D14 and C4 at D21 in women with MCAS. The total DRSP score was predicted by the combined effects of C4 (positively) and AREase and malondialdehyde (MDA) (both inversely associated). Progesterone lowered levels of LOOH, AOPP and C3 and estradiol lowered levels of Hp while both sex hormones increased 4-(chloromethyl)phenyl acetate (CMPA)ase and AREase activities and levels of -SH groups. Conclusion: PMS/MCAS is not accompanied by a peripheral inflammatory response. Lowered MDA and antioxidant defenses and increased C4 may play a role in MC-associated symptoms while sex hormones may have a protective effect against oxidative stress toxicity.

Background: high-altitude work exposes individuals to reduced oxygen levels, imposing physi-ological adaptations. These conditions can induce alterations in the cardiovascular system, po-tentially exacerbating pre-existing health issues and impacting overall well-being of workers in such environments. This study has investigated the cardiovascular challenges for the high-altitude worker on Etna volcano. Methods: Through an observational study, ten healthy, non-smoking male participants underwent cardiovascular and pulmonary function tests at alti-tudes below 500m and above 3000m, simulating work conditions on the volcano. Results: signif-icant findings include elevated systemic blood pressure and heart rate, indicating an increased cardiovascular workload necessary for adaptation to hypoxia. Conclusions: the study highlights the importance of acclimatization to high altitude for minimizing cardiovascular risks among workers. It calls for the development of safety protocols, underlining the critical role of preven-tative measures and specific safety protocols for high-altitude workers.

Dendritic spines are essential for synaptic function because they constitute the neurons' postsynaptic compartment that receives the most excitatory input. The extracellularly shorter variant of the presynaptic cell adhesion molecules neurexins, β-neurexins, has been implicated in various aspects of synapse function including neurotransmitter release. However, its role in developing or stabilizing dendritic spines as fundamental computational units of excitatory synapses remained unclear. Here, we show by morphological analysis that the deletion of β-neurexins in hippocampal neurons in vitro and in hippocampal tissue in vivo affects presynaptic dense-core vesicles and, unexpectedly, postsynaptic spine structure. Specifically, we observed that the absence of β-neurexins led to an increase in longer spinous protrusions in vitro and more mature mushroom-type spines in the CA1 region of adult knockout mice. In addition, deletion of β-neurexins caused alterations in spine head dimension and more spines with perforations of their postsynaptic density but no change in the overall number of spines or synapses. Our results indicate that presynaptic β-neurexins play a role across the synaptic cleft, possibly by aligning with postsynaptic binding partners and glutamate receptors via transsynaptic columns.

The study of the mechanisms underlying stem cell differentiation is under intensive research, and includes the contribution of a metabolic switch from glycolytic to oxidative metabolism. While mitochondrial biogenesis has been previously demonstrated in number of differentiation models, it is only recently that the role of mitochondrial dynamics has started to be explored. The discovery of asymmetric distribution of mitochondria in stem cell progeny has still strengthened the interest for the field. This review attempts to summarize the regulation of mitochondrial asymmetric apportioning by the mitochondrial fusion, fission and mitophagy processes, as well as to emphasize how asymmetric mitochondrial apportioning in stem cells affects their metabolism, and thus epigenetics, and determines cell fate.

Background: Proteins targeted by the Ubiquitin Proteasome System (UPS) are identified for degradation by the proteasome, which has been implicated in the development of neuro-degenerative diseases. Major histocompatibility complex (MHC) molecules present peptides broken down by the proteasome and are involved in neuronal plasticity, regulating synapse number and axon regeneration in the central or peripheral nervous system during develop-ment and in brain diseases. The mechanisms governing these effects are mostly unknown, but evidence from different compartments of the cerebral cortex indicates the presence of im-mune-like MHC receptors in the central nervous system. Methods: We have used human induced pluripotent stem cells (iPSC) differentiated to neural stem cells and then to motor neurons as a developmental model to better understand the structure of the proteasome in developing motor neurons. We perform a proteomic analysis of starting human skin fibroblasts, their matching iPSC, differentiated neural stem cells and motor neurons that highlighted significant differences in the constitutive proteasome and immunoproteasome subunits during development towards motor neurons from iPSC. Results: Proteomic analysis showed that the catalytic proteasome subunits expressed in fi-broblasts differ to those in neural stem cells and motor neurons. Western blot analysis con-firmed the proteomic data, particularly the decreased expression of Beta5i (PSMB8) subunit immunoproteasome. Conclusion: The constitutive proteasome subunits are upregulated in iPSC from HFF and the immunoproteasome subunit beta 5i expression is higher in MN than NSC suggesting a im-munoproteasome phenotype in MN. The immunoproteasome may have implications on motor neuron development and neurodevelopmental diseases that warrants further investi-gation.

Environmental factors as maternal high-fat diet (HFD) intake can increase the risk of age-related cognitive decline in adult offspring. The epigenetic mechanisms are a possible link between diet effect and neurodegeneration across generations. Here, we found a significant decrease in triglyceride levels in a high-fat diet with resveratrol HFD+RV group and the offspring. Firstly, we obtained better cognitive performance in HFD+RV groups and their offspring. Molecularly, a significant increase in 5-mC levels, as well as increased gene expression of Dnmt1 and Dnmt3a in HFD+RV F1 group, were found. Furthermore, a significantly increased of m6A levels in HFD+RV F1 were found, and there were changes in gene expression of its enzymes (Mettl3 and Fto). Moreover, we found a decrease in gene expression levels of pro-inflammatory markers such as Il1-β, Il-6, Tnf-α, Cxcl-10, Mcp-1 and Tgf-β1 in HFD+RV and HFD+RV F1 groups. Moreover, there was increased gene expression of neurotrophins such as Ngf and Nt3 and its receptors TrkA and TrkB. Likewise, an increase in protein levels of BDNF and p-Akt in HFD+RV F1 was found. These results suggest that maternal RV supplementation under HFD intake prevents cognitive decline in SAMP8 adult offspring, promoting a reduction in triglycerides and leptin plasma levels, changes in the pro-inflammatory profile, restoring the epigenetic landscape as well as synaptic plasticity.

Neuroendocrine neoplasms (NENs) comprise a heterogeneous group of rare malignancies mainly originated from hormones secreting cells, which are widespread in human tissues. The identification of mutations in ATRX/DAXX genes in sporadic NENs, as well as the high burden of mutations scattered throughout MEN-1 gene in both sporadic and inherited syndromes, provided new insights into the molecular biology of tumour development. Other molecular mechanisms, such as the NOTCH signaling pathway, have shown to play an important role in the pathogenesis of NENs. NOTCH receptors are expressed on neuroendocrine cells and generally, act as tumour suppressor proteins, but in some contexts can function as oncogenes. The biological heterogeneity of NENs suggests that to fully understand the roles and the potential therapeutic implications of gene mutations and NOTCH signaling in NENs, a comprehensive analysis of genetic alterations, NOTCH expression patterns and their potential roles across all NEN subtypes is required.

Significant changes have occurred at Arabian Gulf Coast of Saudi Arabia over the last three decades. The area of mangrove was reduced by about 55%. Thus the economic, social, and environmental value of mangroves must be assessed over short -to long-term scales and employ these assessments for the awareness rising at local communities. This study provides a preliminary assessment of the risks on mangrove vegetation; it will provide database to mitigate the tremendous pressures due to coastal development and urban activities. The effects of human development on the mangrove plant cover in Eastern Region of KSA were recognised, during 2013 to 2016. The mean variations of physio-chemical characteristics in water and sediment were recorded. With regard to water analyses including; nitrogen, phosphorus, TSS, TDS, BOD, and turbidity were evaluated. On the other hand, for sediment: TDS, nitrogen, phosphorus, sulphate and total organic carbon were assessed. Moreover, the growth parameters: plant height, and size index, of Avicennia marina were recorded and estimated. It is concluded that human impact and urban developments have exerted drastic effects on the coastal ecosystems and its environments.

Udder health of dairy cows is related to their productivity and welfare. The period from dry-off to calving and early lactation is crucial. Ultrasonography is a useful and practical tool for the examination of the mammary parenchyma and blood flow. This observational study investigated the relationship between udder echotexture features, blood flow volume (BFVol) in the milk vein, milk somatic cell count (SCC) and daily milk yield (DMY) from late lactation, throughout dry period and consecutive early lactation. Seventeen repeated measurements were performed on 21 Holstein cows. The udder parenchyma was examined with B-mode ultrasonography. Udder echotexture was studied using 15 features: Numerical Pixel Value (NPV), Pixel Standard Deviation (PSD), Skewness, Excess, Contrast, Homogeneity, Correlation, Entropy, Run Percentage, Long Run Emphasis, Grey Value Distribution, Runlength Distribution, Gradient Mean Value, Gradient Variance and Percentage of Non-zero Gradients. Blood flow in the milk vein was examined with spectral Doppler. Linear mixed effects models were employed to investigate relationships between BFVol, udder echotexture features, SCC and DMY, throughout the study period. Our models showed that a 1-kg increase in DMY was associated with a significant increase of 0.25 L/min in the expected BFVol, and that a 1,000,000-cells/mL increase in SCC was associated with a significant BFVol decrease of 0.49 L/min, keeping all other variables constant. Multivariable models showed significant associations between DMY and NPV, PSD and Long Run Emphasis, and between SCC and NPV, PSD, Gradient Mean Value, Homogeneity, Gradient Variance and Entropy. In conclusion, udder echotexture and BFVol in the milk vein are related to SCC and milk yield. Ultrasonography can be used for the comprehensive assessment of udder health in the direction of precision dairy farming.

This study assessed the impact of inoculation with plant growth-promoting bacteria (PGPB) on stress-resistance and growth-promoting metabolites in Salicornia europaea L. across controlled and field conditions. Salicornia europaea seeds, inoculated with Brevibacterium casei EB3 and Pseudomonas oryzihabitans RL18, were grown in controlled laboratory experiments and in a nat-ural field setting. Metabolite composition was analyzed using GC-MS and UHPLC-MS. Under controlled conditions, PGPB inoculation significantly increased levels of unsaturated fatty acids, sugars, citric acid, acetic acid, chlorogenic acids, and quercetin. Inoculation under field condi-tions increased glucose, fructose, quercetin, and apigenin, alongside decreased unsaturated fatty acids and sterols, indicating a stress response shift in plant metabolism. Under controlled condi-tions, enhanced metabolite profiles induced by inoculation likely contributed to augmented bio-mass production and environmental stress resistance. Field plants revealed distinct phytochemi-cal profiles, suggesting higher stress levels. However, the accumulated metabolites from inocula-tion could enhance the plant's ability to cope with adverse conditions and improving stress tol-erance. This study unveils the intricate metabolic adaptations of Salicornia europaea under con-trolled and field stress conditions, highlighting PGPB's potential to enhance plant stress tolerance. Elevated stress-related metabolites may fortify plant defense mechanisms, laying the ground-work for stress-resistant crop development through PGPB-based inoculants, especially in saline agriculture.

Epigenetic alterations are heritable and enduring modifications in gene expression that play a pivotal role in immune evasion. These include alterations to noncoding RNA, DNA methylation, and histone modifications. DNA methylation plays a crucial role in normal cell growth and development but alterations in methylation patterns such as hypermethylation or hypomethylation can enable tumor and viral cells to evade host immune responses. Histone modifications can also inhibit immune responses by promoting the expression of genes involved in suppressing normal immune function. In the case of T-cell lymphoma, adult T-cell Lymphomas (ALT) also undergo immune evasion through the exceptional function of its accessory and regulatory genes. Epigenetic therapies are emerging as a promising adjunct to traditional immunotherapy and chemotherapy regimens. Clinical trials are currently investigating the use of epigenetic therapies in combination with immunotherapies and chemotherapies for more effective treatment of ATL and other cancers. This review highlights epigenetic alterations that are widely found in T cell malignancies.

An increasing amount of evidence indicates the critical role of the cutaneous nervous system in the initiation and maintenance of psoriatic skin lesions by neurogenic inflammation. However, molecular mechanisms affecting cutaneous neurons are largely uncharacterized. Therefore, we reanalyzed a psoriatic RNA sequencing dataset from published transcriptome experiments of nearly 300 individuals. Using the Ingenuity Pathway Analysis software, we associated several hundreds of differentially expressed transcripts (DETs) to nervous system development and functions. Since neuronal projections were previously reported to be affected in psoriasis, we performed an in-depth analysis of neurite formation-related processed. Our in silico analysis suggests that SEMA-PLXN and ROBO-DCC-UNC5 regulating axonal growth and repulsion are differentially affected in non-lesional and lesional skin samples. We identified opposing expressional alterations in secreted ligands for axonal guidance signaling (RTN4/NOGOA, NTNs, SEMAs, SLITs) and non-conventional axon guidance regulating ligands, including WNT5A and their receptors, modulating axon formation. These differences in neuritogenesis may explain the abnormal cutaneous nerve filament formation described in psoriatic skin. The processes also influence T cell activation and infiltration, thus highlighting an additional angle of the crosstalk between the cutaneous nervous system and the immune responses in psoriasis pathogenesis, in addition to the known neurogenic pro-inflammatory mediators.

It has been proposed that tumourigenicity was an intrinsic feature of embryonic/germ cell developmental axis as well as embryonic/germ cell-related genes play a crucial role in tumourigenicity. Our previous studies indicated that primordial germ cell (PGC)-like potential could be reactivated in tumourigenesis. In this study, 4T1, 168FARN and 67NR cells which originated from the same mouse breast cancer were studied and the results indicated that the acquisition of embryonic/germ cell-like state is essential for tumourigenicity. We further demonstrated that somatic to PGC-like transformation (SPLT) was activated in 4T1 cells and that inhibition of PGC-like cell formation by depleting pluripotency and/or PGC specification-related genes markedly repressed SPLT and the tumourigenicity. Collectively, our findings reveal that tumourigenicity is linked to the acquisition of PGC-like state through SPLT in 4T1 cells, provide new insight into deeper understanding the biological nature of tumours and novel therapeutical strategies for cancer targeting.

Background: Physical and mental health of corporate employees is equally important, especially in international salespeople in the in vitro diagnostic (IVD) medical device industry. The rapid growth of the IVD market is driven by the increasing prevalence of chronic and infectious diseases. This study aims to identify the association of socio-demographic, occupational, organizational, and psychosocial factors with mental health outcomes for depression, anxiety, and somatic symptoms in Chinese IVD international salespeople. Methods: The study was a cross-sectional survey of ISs in IVD companies officially registered in China. An online survey was designed to collect data through email contact with IVD companies and social media between August 2022 and March 2023. Measured factors included effort-reward imbalance (ERI), health-promoting leadership (HPL), health climate (HC), inner strength (IS), and perceived social support (PSS). Mental health outcomes assessed using the Core Symptom Index (CSI) were depression, anxiety, and somatic symptoms. Results: A total of 244 salespeople responded to the survey. CSI scores indicated that 18.4% (n = 45) and 10.2% (n = 25) of the respondents had symptoms of major depression and anxiety, respectively. ERI was positively correlated, while the IS and PSS were negatively correlated with major depression, anxiety, and somatic symptoms (p < .01). Health climate was negatively correlated with major depression (p < .05). Education background was associated with somatic symptoms (p < .05). ERI, IS, and gender were significant predictors of major depression, anxiety, and somatic symptoms (p < .05). Conclusion: The prevalence of depression and anxiety in China’s IVD international salespeople was considered low compared with prevalence in Chinese populations during COVID-19, but higher than those before the pandemic. Effort–reward imbalance, inner strength, and gender were significant factors in major depression, anxiety, and somatic symptoms among IVD international salespeople.

Functional somatic disorders (FSD) characterized by persistent and disabling physical symptoms are common in adolescents. Diagnostic uncertainty and insufficient illness explanations are proposed perpetuating factors that may constitute barriers for treatment engagement. This study evaluates the impact of manualized assessment and psychoeducation on diagnostic certainty and various clinical outcomes in adolescents with multi-system FSD. Ninety-one adolescents (15-19 years) included in a randomized trial testing group-based therapy (AHEAD) received systematic assessment (4 hrs.) and a subsequent psychiatric consultation (1.5 hrs.). Clinical outcomes included self-reported physical health, symptom severity, illness perception, illness related behavior, and psychological flexibility assessed before and approximately two months after assessment, prior to specialized treatment. Data were analyzed using t-tests. Immediately following assessment 71 (80.7%) adolescents out of 88 reported a higher diagnostic certainty and 74 (84.1%) reported that attending assessment gave them positive expectations for future treatment. A clinically relevant improvement of physical health was not observed at two months but considerable reductions were seen on symptom severity, illness worry, negative illness perceptions, limiting illness behavior and psychological inflexibility. The results underpin the importance of systematic assessment and psychoeducation which may be effective in their own right in specialized treatment of adolescents with severe FSD.

Background: Protein CCDC186 is involved in the maturation of dense core vesicles in the trans-Golgi network in neurons and endocrine cells. To date, only one patient, within a large sequencing study of 1000 cases, and a single case report with variants in CCDC186 had previously been described. However, no functional studies in any of these two cases had been performed. Methods: Exome sequencing from one affected individual of each family was performed. In addition, Sanger sequencing of the parents and one of the affected siblings was also performed. CCDC186 protein was assessed in cultured fibroblasts or muscle tissue by western blot. Transcriptomic analysis was done by means of RNA sequencing. Results. We identified three patients from two gypsy families, unrelated to each other, with the same homozygous mutations in CCDC186 gene. Clinically, all patients presented with seizures, frontotemporal atrophy, hypomyelination, recurrent infections, and endocrine disturbances such as severe non ketotic hypoglycemia. Low levels of cortisol, insulin or growth hormone could only be verified in one patient. All of them had a neonatal onset and died between 7 months and 4 years of age. WES identified a homozygous variant in CCDC186 gene (c.2215C>T, p.Arg739Ter) in the index patients of both families. Protein expression studies demonstrated that the CCDC186 was practically undetectable in fibroblasts and muscle tissue. These observations correlated perfectly with the transcriptomic analysis performed in fibroblasts in one of the patients, which showed a significant reduction of CCDC186 mRNA levels. Conclusion. Our study provides functional evidence that mutations in this gene have a pathogenic effect on the protein and reinforces CCDC186 as a new disease-associated gene. In addition, mutations in CCDC186 could explain the combined endocrine and neurologic alterations detected in our patients

Recent studies show that repetitive transcranial magnetic stimulation (rTMS) improves cognitive and motor functions in patients with Parkinson’s Disease (PD). Gamma rhythm low-field magnetic stimulation (LFMS) is a new non-invasive rTMS technique that generates diffused and low-intensity magnetic stimulation to deep cortical and subcortical areas. To investigate potential therapeutic effects of LFMS in PD, we subjected an experimental mouse model to LFMS (as early treatment). We examined the LFMS effect on motor functions as well as neuronal and glial activities in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced male C57BL/6J mice. Mice received MPTP injection (30 mg/kg, i.p., once daily for 5 days) followed by LFMS treatment, 20 minutes each day for 7 days. LFMS treatment improved motor functions compared to the sham-treated MPTP mice. Further, LFMS significantly improved tyrosine hydroxylase (TH) and decreased glial fibrillary acidic protein (GFAP) levels, in substantia nigra pars compacta (SNpc) and non- significantly in striatal (ST) regions. LFMS treatment improved neuronal nuclei (NeuN) level in SNpc. Our findings suggest that early LFMS treatment improved the neuron survival and in turn, motor functions in MPTP intoxicated mice brain. Further investigation is required to clearly define the molecular mechanisms by which LFMS improves motor and cognitive function in PD patients.

It has been widely described that chronic intake of fructose causes metabolic alterations which can be associated with brain function impairment. In this study, we evaluated the effects of fructose intake on the sleep-wake cycle, locomotion and neurochemical parameters in Wistar rats. The experimental group was fed with 10% fructose in drinking water for five weeks. After treatment, metabolic indicators were quantified in blood. Electroencephalographic recordings were used to evaluate the sleep architecture and the spectral power of frequency bands. Likewise, the locomotor activity and the concentrations of orexin A and monoamines were estimated. Our results show that fructose diet significantly increased the blood levels of glucose, cholesterol, and triglycerides. Fructose modified the sleep-wake cycle of rats increasing the waking duration and conversely decreasing the non-rapid eye movement sleep. Furthermore, these effects were accompanied by increases of the spectral power at different frequency bands. Chronic consumption of fructose caused a slight increase in the locomotor activity as well as an increase of orexin-A and dopamine levels in the hypothalamus and brainstem. Specifically, immunoreactivity for orexin-A was increased in the ventral tegmental area after the intake of fructose. Our study suggests that fructose induces metabolic changes and stimulates the activity of orexinergic and dopaminergic neurons which may be responsible for alterations of the sleep-wake cycle.

Background: Capmatinib and savolitinib, selective MET inhibitors, are widely used to treat various MET-positive cancers. In this study, we aimed to determine the effects of these inhibitors on MET-amplified gastric cancer (GC) cells. Methods: After screening 37 GC cell lines, the following cell lines were found to be MET-positive with copy number variation &gt; 10: SNU-620, ESO51, MKN-45, SNU-5, and OE33 cell lines. Nest, we assessed the cytotoxic response of these cell lines to capmatinib or savolitinib alone using cell counting kit-8 and clonogenic cell survival assays. Western blotting was performed to assess the effects of capmatinib and savolitinib on the MET signaling pathway. Xenograft studies were performed to evaluate the in vivo therapeutic efficacy of savolitinib in MKN-45 cells. Results: Savolitinib and capmatinib exerted anti-proliferative effects on MET-amplified GC cell lines in a dose-dependent manner. Savolitinib inhibited the phosphorylation of MET and downstream signaling pathways, such as the protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) pathways, in MET-amplified GC cells. Additionally, savolitinib significantly decreased the number of colonies formed on the soft agar and exerted dose-dependent anti-tumor effects in a MKN-45 GC cell xenograft model. Furthermore, combination of trastuzumab and capmatinib exhibited enhanced inhibition of AKT and ERK activation in human epidermal growth factor receptor-2 (HER2)- and MET-positive OE-33 cells. Conclusions: Therefore, targeting MET with savolitinib and capmatinib efficiently suppressed the growth of MET-amplified GC cells. Moreover, these MET inhibitors exerted synergistic effects with trastuzumab on HER2- and MET-amplified GC cells.

Background: Patients undergoing brain tumor resection experience changes to their neurocognitive abilities, many of which can be difficult to predict. We hypothesized that changes in brain connectivity could predict changes in neurocognitive functioning, demonstrating the potential for brain connectivity aware surgical planning to provide enhanced outcomes for patients. Methods: Patients underwent functional and diffusion MR scanning and neuropsychological testing before tumor resection and two weeks post-resection. Using this functional and diffusion imaging, we measured changes in the topology of the functional and structural graph networks, respectively. From the neuropsychological testing scores, we derived a composite score that describes a patient’s overall level of neurocognitive functioning. We then used a multiple linear regression model to test if structural and functional connectivity measures could predict changes in composite scores. Results: Twenty-one subjects completed imaging and neuropsychological evaluation both before and after surgery. The multiple linear regression model showed that changes in functional local efficiency were inversely correlated with changes in composite score (p

Premalignant lesions in the bronchial epithelium represent early stages of squamous cell lung carcinoma, challenging to detect with conventional methods. While previous studies have focused on gene expression, here we examine transcriptomic alterations associated with lesion development with the emphasis on protein-coding transcripts. We reanalyzed publicly available RNAseq dataset on airway epithelial cells from 82 smokers with and without premalignant lesions. Transcript abundances were quantified using kallisto, and differential expression and transcript usage analysis was conducted using the sleuth and RATs packages. Functional characterization included overrepresentation analysis (clusterProfiler), weighted co-expression network analysis (WGCNA), and network analysis (Enrichr-KG). We detected 5,906 differentially expressed transcripts, with significant enrichment in pathways related to oxidative phosphorylation and mitochondrial function. Transcript-level WGCNA identified single module correlated with dysplasia status, enriched in cilium-related biological processes. Analysis of hubs within this module highlighted key genes including RABL2B, DNAH1, EFHC1 and VWA3A, and revealed transcription factors such as FOXJ1 and ZNF474 as potential regulators. Our findings underscore the value of transcript-level analysis in uncovering novel insights into premalignant lesion biology. By examining transcripts rather than genes, we identified potential biomarkers associated with early lung carcinogenesis.

Humans are often exposed to various environmental contaminants, among which phthalates are prevalent due to their extensive use as plasticizers in various consumer goods. Di(2-ethylhexyl) phthalate (DEHP), a widely used phthalate, is recognized as an endocrine disruptor chemical (EDC). DEHP is reported to affect various organs. Few studies have addressed the effects of phthalates on bone. However, the effects of DEHP on the bone forming cells (osteoblasts) are obscure. The present study was peformed to determine the cytotoxic effects of DEHP on human osteoblasts in vitro and to delineate the mechansims. In this study, we exposed the human osteo-blastic cell line MG-63 to various concentrations of DEHP (1, 25, 50 and 100 µM) for 24, 48 and 72 h. Cell viability was assessed by MTT assay. Total RNA and protein were collected after 48 h treatment with 1 and 100 µM DEHP and determined for the mRNA and/or protein expression of alkaline phosphatase (ALP), sex steroid receptors (androgen and estrogen receptors), receptor activator of nuclear factor kappa-Β ligand (RANKL), runt-related transcription factor 2 (RUNX2) and peroxisome proliferator-activated receptor alpha (PPARα). The mRNA expression was stud-ied by real-time RT-PCR analysis and the protein expression was determined by western blot analysis. Statistical analyses were done by one-way analysis of variance (ANOVA) followed by the Students–Newman–Keuls (SNK) test. The exposure of MG-63 cells to DEHP caused a signifi-cant decrease in osteoblast viability in all the treatment groups and at all the time points stud-ied. Interestingly, DEHP exposure decreased the mRNA expression of ALP, a bone formation marker. DEHP had differential effects on estrogen receptor alpha (ERα) mRNA and protein ex-pression. However, DEHP treatment downregulated the mRNA and protein expression of ERβ, and androgen receptor (AR). Surprisingly, DEHP downregulated the RANKL mRNA expression. DEHP decreased the protein expression of RUNX2, the key transcription factor and master regu-lator of bone formation. Furthermore, DEHP increased the PPARα protein expression in the os-teoblasts. Importantly, DEHP increased the reactive oxygen species (ROS) molecules and thus oxidative stress in osteoblasts, as observed by increased hydrogen peroxide, hydroxyl radical levels and lipid peroxidation. On the other hand, it decreased the enzymatic and non-enzymatic antioxidant levels namely catalase, superoxide dismutase, glutathione peroxidase activity and reduced glutathione. Our study demonstrated that in vitro exposure to DEHP reduces the osteo-blast viability possibly through alterations in the oxidant-antioxidant system and modulation of the key genes involved in bone formation, highlighting the cytotoxic effects of DEHP on bone forming cells.

The coronavirus (COVID-19) pandemic limitations may negatively affect children and youth in terms of health behaviors, and it might be especially challenging for children who are diagnosed with neurodevelopmental disorders such as children and youth diagnosed with Autism Spectrum Disorder (ASD). The present study assessed alterations in physical activity, screen time, and sleep duration of ASD children and the prevalence of meeting the 24-hour movement guidelines during the COVID-19 outbreak. Forty-six Arab Israeli mothers of children with ASD were surveyed by an online cross-sectional survey. As reported by the mothers, the results show a significant decrease in physical activity, a significant increase in screen time, and a significant increase in sleep duration during the COVID-19 pandemic. Moreover, the proportion of the sample who gained the physical activity and screen time recommendations lessened while the percentage of children who met the sleep duration guidelines increased. The prevalence of ASD children who achieved the overall 24-hour movement guidelines was very small during the COVID-19 outbreak. The outcomes extend the body of knowledge regarding the negative effects of the COVID-19 pandemic on children diagnosed with neurodevelopmental disorders and highlight the need for instant healthcare and interventions and programs for children with ASD.

The wettability of the oil-brine-rock systems is very challenging mainly for the carbonate reservoirs and it plays a significant role to enhance the oil recovery (EOR). Carbonate rocks are mad-up of complex lithology, hence these requires careful treatments in controlling their wetting behavior for enhanced oil recovery. Therefore, it is extremely important to modify their wettability from an oil-wet rock behavior to a water-wet so that the residual oil can be produced efficiently. Thus, the present study has examined the effectiveness of alumina nanofluid as well as a new chemical methyl blue to alter the wettability. The methyl blue is released on massive scale from various industries i.e. pharma, textile and food industry which is a key environmental concern which contaminates the water table. Hence the study, explores the effects of MB and alumina nanofluid on the wettability. The effect of nanofluids formulated via dispersing the alumina nanoparticles in aqueous solutions at various concentration (0. 0.05, 0.3, 0.50, 0.75 and 1.0 wt. %) were tested for wettability modification under different physio-thermal conditions. Subsequently, the wettability change was examined for the samples treated with different concentrations of MB (10, 15, 30, 50 and 100 mg/L) for 7-days at two different temperatures of (25 and 50 0C). The results showed that hydrophobicity of the SML carbonate rock has significantly reversed while treating with alumina nanofluids and MB. Thus, the wettability modification/reversal via treatment of MB and alumina nanofluid can be an effective mechanism to hydrogen injection and for EOR processes.

Lead (Pb) is a non-essential, highly toxic, and persistent element widely recognised as one of the most concerning pollutants, and it is listed in the Priority List of Hazardous Substances. Widespread environmental contamination from Pb is a serious issue for human health and wildlife. The liver, a key compartment for metal detoxification and excretion, is also the organ in which Pb mainly accumulates in fish. Herein, we investigated for the first time the morphological and functional injuries induced in zebrafish (Danio rerio) liver by two very low and environmentally relevant concentrations of Pb (2.5 and 5 μg/L) after 48, 96, and 192 hours of exposure. We showed significant histological alterations in all the exposed samples, also demonstrating that the extent of injuries increased with dose and exposure time. The most common modifications observed were congestion of blood vessels and sinusoids, cytoplasmic vacuolizations, parenchyma dyschromia, and macrophage proliferation. Pb administration also resulted in a significant increase in lipid content and the upregulation of key genes involved in metal detoxification (mtf1) and the defensive response against oxidative stress (sod1 and cat). We showed that even very low doses of Pb can disrupt liver morphology and function.

Alzheimer’s disease (AD) is characterized by cognitive impairment and different non-cognitive deficits called “Behavioural and psychological symptoms of dementia” (BPSD) related to neurotrophin alterations, which differ from those presented in normal aging. Mouse models, both transgenics and inbreed mice models of AD, are a useful tool in understanding the underlying mechanisms of the disease. The SAMP8 (senescence-accelerated mouse prone 8) mice line was generated from AKR/J strain by Professor Toshio Takeda at the University of Kyoto. This strain exhibited a particular early-onset and accelerated aging phenotype. The present study characterizes and provides information regarding the non-cognitive and cognitive states as well as molecular alterations and their relationship, demonstrating the AD-like symptoms presented in older SAMP8 males. The cognitive impairment presented was accompanied by a reduction in sociability and an increase in aggressive as well as anxiety behaviours. Furthermore, changes in three of the most important neurotrophins, such as NT3, BDNF, and NGF as well as their receptors TrkA and TrkB, were found. Thus, the present results reveal new insights in this useful inbred mouse model of neurodegeneration and AD, demonstrating the potential relationship between neurotrophin alterations, cognitive impairment and neuropsychiatric disorders (ND).

Intramammary infections (mastitis) of dairy cows, along with other periparturient diseases, have become problematic within the dairy industry as they lead to loss of milk production. The main objective of this study was to determine whether elevated somatic cell counts (SCC) in cows prior to drying off are related to the incidence of other periparturient diseases. Additionally, we de-termined whether milk composition and milk yield are affected by a high SCC prior to drying off. Somatic cell counts of milk samples were determined prior to dry off (n = 140) and were used to classify cows in the study as high (>200,000 cells/mL) or low (<200,000 cells/mL) SCC. The com-position of milk was analyzed before drying off and at 1 and 2 weeks after calving. The results showed that an elevated SCC before drying off was related to the incidence of ketosis. Cows with a high SCC at drying off also showed an increased likelihood of retained placenta, metritis, and lameness postpartum; however, it was not statistically significant. Milk lactose was lower in cows with high SCC, while protein content was lower after parturition. Milk production was lower for cows with pre-drying elevated SCC, particularly for cows with retained placenta, keto-sis, and mastitis. In conclusion, cows with pre-drying elevated SCC were more likely to develop disease after parturition and produce less milk and with lower lactose and protein content.

Mitochondrial dysregulation is implicated in numerous neurological disorders. Mitochondrial dynamics, including biogenesis, fusion and fission, are essential components of mitostasis which is modulated by complex regulatory mechanisms. Although expression studies are often used to investigate mitochondrial dynamics, these studies may be limited by the interdependent and temporal nature of mitostasis. Transmission electron microscopy (TEM) and cryogenic preparation methods provide a direct approach to examine mitochondrial ultrastructure in neurons. We investigated the utility of TEM to visualize mitochondrial morphological changes in SH-SY5Y cells treated with propionic acid (PPA). We examined whether morphological alterations were associated with differences in membrane potential or expression of biogenesis, fusion and fission genes. PPA induced a significant decrease in mitochondrial area (p<0.01 5mM), Feret's diameter and perimeter (p<0.05 5mM), and in area2 (p<0.05 3mM, p<0.01 5mM) – consistent with a shift towards fission. Morphological changes were not associated with significant differences in mitochondrial membrane potential. However, we observed decreased gene expression of NRF1 (p<0.01), TFAM (p<0.05), and STOML2 (p<0.0001). These data support a disruption of the balance in dynamics to preserve function under stress. This demonstrates the utility of TEM to provide insight into mitochondrial dynamics and function which can inform targeted mechanistic investigations into neuropathology.

Traumatic brain injury (TBI) is a major leading cause of death and disability. While previous studies regarding focal pathologies following TBI have been done, there is a lack of information concerning the role of analgesics and their influences on injury pathology. Buprenorphine (Bup), an opioid analgesic, is a commonly used analgesic in experimental TBI models. Our previous studies investigated the acute effects of Buprenorphine-sustained release-Lab (Bup-SR-Lab) on diffuse neuronal/glial pathology, neuroinflammation, cell damage, and systemic physiology. The current study investigated the longer-term chronic outcomes of Bup-SR-Lab treatment at 4 weeks following TBI utilizing a central fluid percussion injury (cFPI) model in adult male rats. Histological assessments of physiological changes, neuronal damage, cortical and thalamic cytokine expression, microglial and astrocyte morphological changes, and myelin alterations were done, as we had done in our acute study. In the current study the Whisker Nuisance Task (WNT) was also performed pre- and 4w post-injury to assess changes in somatosensory sensitivity following saline or Bup-SR-Lab treatment. Bup-SR-Lab treatment had no impact on overall physiology or neuronal damage at 4w post-injury regardless of region or injury, nor did it have any significant effects on somatosensory sensitivity. However, greater IL-4 cytokine expression with Bup-SR-Lab treatment was observed compared to saline treated animals. Microglia and astrocytes also demonstrated region-specific morphological alterations associated with Bup-SR-Lab treatment, in which cortical microglia and thalamic astrocytes were particularly vulnerable to Bup-mediated changes. There were discernable injury-specific and region-specific differences regarding myelin integrity and changes in specific myelin basic protein (MBP) isoform expression following Bup-SR-Lab treatment. This study indicates that use of Bup-SR-Lab could impact TBI-induced glial alterations in a region-specific manor 4w following diffuse brain injury.

The understanding of structural alteration mechanisms due to relative humidity impact on organic supports of paintings is of crucial significance for the preventive conservation strategies in order to ensure the long-term preservation of important cultural identity artworks. The effort in this paper is to simulate Museum realistic relative humidity condition in a climate chamber while monitoring the structural responses through a quantitative interferometric method allowing the quantitative correlation between the physical values of deformation and mass alteration relevant to relative humidity fluctuations.

Background: We investigated the tumor immune response in gastric cancer patients receiving third line nivolumab monotherapy to identify immune-related biomarkers for better patient se-lection. Methods: Nineteen patients (10 males, median age 67 years) who received nivolumab as a third or later line therapy were enrolled. We analyzed the tumor immune response in durable clinical benefit (DCB) and non-DCB patients. Pre-treatment and early-on-treatment tumor transcriptomes were examined, and gene expression profiles, immunograms, and T cell receptor (TCR) repertoire were analyzed. Results: DCB was observed in 15.8% of patients, with comparable secondary endpoints (ORR, OS, PFS) to previous trials. Individual immunograms showed no significant changes before and ear-ly-on-treatment, nor consistent alterations among DCB cases. The intratumoral immune response was suppressed by previous treatments in most third or later line nivolumab recipients. TCR repertoire analysis revealed newly emerged clonotypes in on-treatment tumors, but clonal re-placement did not impact efficacy. High T cells/Tregs ratios and a low UV radiation response gene signature were linked to DCB and treatment response. Conclusions: This study emphasizes the tumor immune response's importance in nivolumab ef-ficacy for gastric cancer. High T cells/Tregs ratios and specific gene expression signatures show promise as potential biomarkers for treatment response. Larger cohort validation is crucial to optimize immune checkpoint inhibitors in gastric cancer treatment.

The 1884 Andalusia Earthquake, with an estimated Magnitude between 6.2 and 6.7, is one of the most destructive events that shook the Iberian Peninsula, causing around 1200 casualties. Ac-cording to paleoseismology studies and intensity maps, the earthquake source relates to the nor-mal Ventas de Zafarraya Fault (Granada, Spain). Diverse studies registered and later analyzed hydrological effects, such as landslides, rockfalls, soil liquefaction, all-around surge and loss of springs, alterations in the phreatic level, discharge in springs and brooks, and well levels, along with changes in water properties. Further insight into these phenomena found an interplay be-tween hydro-geomechanical processes and crust surface deformations, conditions, and properties. This study focuses on analyzing and simulating the features involved in the major 1884 event and aims at elucidating the mechanisms concerning the mentioned effects. This ex-post analysis builds on the qualitative effects and visible alterations registered by historical studies. It encompasses conceptual geological and kinematic models, and a 2D finite element simulation to account for the processes undergone by the Zafarraya Fault. The study focuses on the variability of hy-dro-geomechanical features and the time evolution of the ground pore-pressure distribution in both the preseismic and coseismic stages, matching some of the shreds of evidence found by field studies. This methodology can be applied to other events registered in the National Catalogues of Earth-quakes to achieve a deeper insight, further knowledge, and a better understanding of past earth-quakes.

In the Yucatán Peninsula, anthropogenic activities such as urbanization and final dispose of solid and wastewaters critically impact aquatic systems. Here, we evaluated the anthropogenic-related environmental alteration of Lake La Sabana, located in the northern limit of one of the main cities of the Mexican Caribbean. We evaluate lake water quality using physical, chemical, and microbiological indicators, and heavy metals in surficial sediments and fish tissue to evaluate the potential environmental risk. Multivariate analyses reveal that environmental conditions in La Sabana are spatial and temporal heterogeneous. Medium to bad water quality was determined within basins by the NSFWQI, related with the degree of anthropogenic influence. The center-south zones display critical microbiological values largely exceeding national standards. Heavy metals in sediments (Zn&gt;Hg) and fish tissue (Hg) were relatively low, but Hg concentration threat the ecological environment. Incipient wastewater treatment and final dispose in La Sabana is the main responsible of changes in the trophic status and nutrients availability, which in turn may have promoted changes in the biological structure and aquatic plant invasions. Lake La Sabana can be considered a model of the potential sequential effects of the anthropogenic alterations in oligotrophic karts tropical aquatic systems in Yucatán Peninsula.

Viral infections cause metabolic dysregulation in the infected organism. The present study used metabolomics techniques and machine learning algorithms to retrospectively analyze the alter-ations of a broad panel of metabolites in the serum and urine of a cohort of 126 patients hospi-talized with COVID-19. Results were compared with those of 50 healthy subjects and 45 COVID-19 negative patients but with bacterial infectious diseases. Metabolites were analyzed by gas chro-matography coupled to quadrupole time-of-flight mass spectrometry. The main metabolites al-tered in the sera of COVID-19 patients were those of pentose glucuronate interconversion, ascorbate and fructose metabolism, nucleotide sugars, and nucleotide and amino acid metabolism. Alterations in serum maltose, mannonic acid, xylitol, or glyceric acid metabolites segregated positive patients from the control group with high diagnostic accuracy, while succinic acid seg-regated positive patients from those with other disparate infectious diseases. Increased lauric acid concentrations were associated with severity of infection and death. Urine analyses could not discriminate between groups. Targeted metabolomics and machine learning algorithms facilitated the exploration of the metabolic alterations underlying COVID-19 infection, and to identify po-tential biomarkers for the diagnosis and prognosis of the disease.

Definitive surgical resection is the preferred treatment for early-stage non-small-cell lung cancer (NSCLC). Research into genetic alterations, including epidermal growth factor receptor (EGFR) mutation, in early stage NSCLC remains insufficient. Here, we investigated the prevalence of genetic alterations in early-stage NSCLC and the association between EGFR mutation and recurrence after complete resection. Between January 2019 and December 2021, 659 patients with NSCLC who underwent curative surgical resection at a single regional cancer center were recruited. We compared the clinical and pathological data between the recurrence and non-recurrence groups. Multivariate logistic regression was used to predict the risk factors for recurrence. Among the 659 enrolled cases, the most common histology was adenocarcinoma (74.5%), followed by squamous cell carcinoma (21.7%). The prevalence of EGFR mutation was 43% (194/451). Among them, L858R point mutation and exon 19 deletion was 52.3% and 42%, respectively. ALK rearrangement was found at 5.7% (26/453), and ROS1 fusion was found at 1.6% (7/441). The recurrence rate of the entire population was 19.7%. In multivariate analysis, the presence of EGFR mutation, stage II or III (vs. stage I), and pathologic subtype (presence of solid type) were associated with recurrence. Among the recurred group, 86.5% of the patients with EGFR mutation experienced distant recurrence compared to only 66.7% of wild-type (p = 0.016), with no significant difference in median disease-free survival (p = 0.983). In conclusion, the prevalence of EGFR mutation, ALK rearrangement, and ROS1 fusion was 43.0%, 5.7%, and 1.6%, respectively in patients with early-stage NSCLC who underwent curative resection. Along with stage II/III and solid pathologic subtype, EGFR mutation was an independent risk factor for recurrence. In the recurrence group, the rate of distant metastasis was higher in patients with EGFR mutation than in those with wild-type.

The blood-brain barrier (BBB) is a selectively permeable boundary that separates the circulating blood from the extracellular fluid of the brain and is an essential component for brain homeostasis. In glioblastoma (GBM), the BBB of peritumoral vessels is often disrupted. Pericytes, being important to maintain the BBB integrity, can be functionally modified by GBM cells by inducing proliferation and cell motility via the TGF-β-mediated induction of central epithelial to mesenchymal transition (EMT) factors., We demonstrate that pericytes strengthen the integrity of the BBB in primary endothelial cell/pericyte co-cultures as in vitro BBB model, using TEER measurement of the barrier integrity. In contrast, this effect was abrogated by TGF-β or conditioned medium from TGF-β secreting GBM cells, finally leading to the disruption of a so far intact and tight BBB. TGF-β dramatically changed the metabolic behavior of pericytes, such as shutting down the TCA cycle, driving energy generation from oxidative phosphorylation towards glycolysis, and by shifting the cells towards the activation of pathways that are necessary to produce molecules used for proliferation and cell division. Furthermore, combined metabolomics and RNASeq analyses indicated that the observed functional changes of TGF-β-treated pericytes are closely connected with their behavior.

Nuclear protein of testis (NUT), a protein product of the NUTM1 gene (located on the long arm of chromosome 15) with highly restricted physiologic expression in post-meiotic spermatids, is the oncogenic driver of a group of emerging neoplasms when fused with genes involved in transcription regulation. Although initially identified in a group of lethal midline carcinomas in which NUT forms fusion proteins with bromodomain proteins, NUTM1-rearrangement has since been identified in tumors at non-midline locations, with non-bromodomain partners and with varied morphology. The histologic features of these tumors have also expanded to include sarcoma, skin adnexal tumors, and hematologic malignancies that harbor various fusion partners and are associated with markedly different clinical courses varying from benign to malignant. Most of these tumors have nondescript primitive morphology and therefore should be routinely considered in any undifferentiated neoplasm. The diagnosis is facilitated by the immunohistochemical use of the monoclonal C52 antibody, fluorescence in situ hybridization (FISH), and, recently, RNA-Sequencing. The pathogenesis is believed to be altered expression of oncogenes or tumor suppressor genes by NUT-mediated genome-wide histone modification. NUTM1-rearranged neoplasms respond poorly to classical chemotherapy and radiation therapy. Targeted therapies such as bromodomain and extraterminal domain inhibitor (BETi) therapy are being developed. This current review provides an update of NUTM1-rearranged neoplasms, focusing on the correlation between basic sciences and clinical aspects.

Evidence of familial inheritance in non-medullary thyroid cancer (NMTC) has accumulated over the last few decades. However, known variants account for a very small percentage of the genetic burden. Here, we focused on the identification of common pathways and networks enriched in NMTC families to better understand its pathogenesis with the final aim of identifying one novel high/moderate-penetrance germline predisposition variant segregating with the disease in each studied family. We performed whole genome sequencing on 23 affected and 3 unaffected family members from five NMTC-prone families and prioritized the identified variants using our Familial Cancer Variant Prioritization Pipeline (FCVPPv2). In total, 31 coding variants and 39 variants located in upstream, downstream, 5′ or 3′ untranslated regions passed FCVPPv2 filtering. Altogether, 210 genes affected by variants that passed the first three steps of the FCVPPv2 were analyzed using Ingenuity Pathway Analysis software. These genes were enriched in tumorigenic signaling pathways mediated by receptor tyrosine kinases and G-protein coupled receptors, implicating a central role of PI3K/AKT and MAPK/ERK signaling in familial NMTC. Our approach can facilitate the identification and functional validation of causal variants in each family as well as the screening and genetic counseling of other individuals at risk of developing NMTC.

Retention of placenta (RP) in crossbred cattle poses health, reproductive, and economic challenges linked to oxidative stress, hormonal imbalances, and complex causative factors. Emphasizing the key role of mitochondria in oxidative phosphorylation (OXPHOS) and hormone synthesis, our study is the first to explore differences in OXPHOS activity, mitochondrial content, and mtDNA-encoded gene expression between normal and RP. In addition, gross morphological examination of placental tissues from both groups revealed noticeable disparities in cotyledons of RP as compared to normal placenta. Moreover, OXPHOS complex I specific activity was decreased in RP, and RT-qPCR analysis unveiled a significant reduction in transcript levels of 10 mtDNA-encoded protein genes. While COX3 and ATP8 genes showed no significant changes, ND6 increased in RP. Whereas, mtDNA copy number varied between animals but showed no statistically significant differences among groups. Retained placenta manifests alterations in the transcript levels of various mitochondrial genes, complex activity, and mtDNA content, potentially linked to heightened energy demands or mitochondrial insufficiency, posing an elevated risk. Overall, our study suggests a link between mitochondrial abnormalities, gene expression, and RP. This connection could influence the removal of fetal membranes by affecting energy supply, hormonal balance, and oxidative stress. This study also offers novel insights and serves as a valuable animal model for studying placental insufficiency in humans. Moving forward, comprehensive investigations are imperative to unravel underlying mechanisms and intricate roles of mitochondria in the context of RP, paving the way for targeted interventions to mitigate health, reproductive, and economic challenges in crossbred cattle.

To understand the molecular mechanism underlying yellowing in pineapples during ripening, coupled with alterations in fruit quality, comprehensive metabolome and transcriptome investigations were carried out. These investigations were conducted using the pulp samples collected at three distinct stages of maturity: young fruit (YF), mature fruit (MF), and fully mature fruit (FMF). This study revealed a noteworthy increase in the levels of total phenols and flavones, coupled with a concurrent decline in lignin and total acid content, as the fruit transitioned from YF to FMF. Furthermore, the analysis yielded 167 differentially accumulated metabolites (DAMs) and 2194 differentially expressed genes (DEGs). Kyoto Encyclopedia of Genes and Genomes enrichment analysis based on DAMs and DEGs revealed that the biosynthesis of plant secondary metabolites, particularly the flavonol, flavonoid, and phenypropanoid pathways, plays a pivotal role in fruit yellowing. Additionally, a comprehensive regulatory network encompassing genes that contribute to metabolisms of flavones, flavonols, lignin, and organic acids was proposed. This network sheds light on the intricate processes that underlies fruit yellowing and quality alterations. These findings enhance our understanding of the regulatory pathways governing pineapple ripening and offer valuable scientific insight into the molecular breeding of pineapples.

Type 1 diabetes (T1D) is one of the most prevalent endocrinological diseases among children and young adults, with a growing incidence rate reaching up to 2.9 new cases per year per 100 000 persons below 15 years of age. We report the rare case of a 20-year-old female patient with T1D, hemoglobin D (HbD) heterozygote variant and high myopia of -10,00 spheric diopters and describe the retinal microvascular alterations visible on OCT angiography (angio-OCT). The patient also presented severe stature deficit (less than 3 standard deviations) and delayed puberty, which could not be explained only by suboptimal glycemic control, indicated a possible hypopituitarism. The HbA1c level evaluated with high performance liquid chromatography (HPLC) method was 6.5%, a falsely low value due to the HbD hemoglobinopathy. On ophthalmic evaluation the angio-OCT scan showed the following retinal microvascular alterations for the RE: the FAZ area vas 0.39 mm2, the FAZ perimeter was 2.88 mm and the circularity index was 0.58; for the LE: the FAZ area vas 0.34 mm2, the FAZ perimeter was 3.21 mm and the circularity index was 0.41. Clinicians should consider high performance retinal screening methods such angio-OCT evaluation for young T1D patients, especially for those with associated pathologies like high myopia and hemoglobinopathies. Moreover, multiple evaluation methods of the HbA1c values are mandatory as hemoglobinopathies can interfere with HbA1c assay methods accuracy.

Hyperacusis, i.e., an increased sensitivity to sounds, is described in several neurodevelopmental disorders (NDDs), including Fragile X Syndrome (FXS). The mechanisms underlying hyperacusis in FXS are still largely unknown and effective therapies are lacking. Big conductance calci-um-activated potassium (BKCa) channels have been proposed as a therapeutic target to treat several behavioral disturbances in FXS preclinical models, but their role in mediating their au-ditory alterations has not been specifically addressed. Furthermore, studies on the acoustic phe-notypes of FXS animal models have mostly focused on central rather than peripheral auditory pathways. Here we provided an extensive characterization of the peripheral auditory phenotype of the Fmr1-knockout (KO) mouse model of FXS at adulthood. We also assessed whether the acute administration of Chlorzoxazone, a BKCa agonist, could rescue the auditory abnormalities of mutant mice. Fmr1-KO mice both at 3 and 6 months showed a hyperacusis-like startle pheno-type with paradoxically reduced auditory brainstem responses associated with a loss of ribbon synapses in the inner hair cells (IHCs). BKCa expression was markedly reduced in the IHCs of KO mice, but only at 6 months, when Chlorzoxazone rescued mutant auditory dysfunction. Our findings highlight the age-dependent and progressive contribution of peripheral mechanisms and BKCa channels to hyperacusis in FXS, suggesting a novel therapeutic target to treat auditory dysfunction in NDDs.

Barth Syndrome, a rare X-linked disorder affecting 1:300,000 live births, results from defects in Tafazzin, an acyltransferase that remodels cardiolipin and is essential for mitochondrial respiration. Barth Syndrome patients develop cardiomyopathy, muscular hypotonia and cyclic neutropenia during childhood, rarely surviving to middle age. At present, no effective therapy exists and downstream transcriptional effects of Tafazzin dysfunction are incompletely understood. To identify novel, cell-specific, pathological pathways that mediate heart dysfunction, we performed single-nucleus RNA-sequencing (snRNA-seq) on wild-type (WT) and Tafazzin-knockout (Taz-KO) mouse hearts. We determined differentially expressed genes (DEGs) and inferred predicted cell-cell communication networks from these data. Surprisingly, DEGs were distributed heterogeneously across the cell types, with fibroblasts, cardiomyocytes, endothelial cells, macrophages, adipocytes and pericytes exhibiting the greatest number of DEGs between genotypes. One differentially expressed gene was detected for the lymphatic endothelial and mesothelial cell types, while no significant DEGs were found in the lymphocytes. A Gene Ontology (GO) analysis of these DEGs showed cell-specific effects on biological processes such as fatty acid metabolism in adipocytes and cardiomyocytes, increased translation in cardiomyocytes, endothelial cells and fibroblasts, in addition to other cell-specific processes. Analysis of ligand-receptor pair expression, to infer intercellular communication patterns, revealed the strongest dysregulated communication involved adipocytes and cardiomyocytes. For the knockout hearts, there was a strong loss of ligand-receptor pair expression involving adipocytes, and cardiomyocyte expression of ligand-receptor pairs underwent reorganization. These findings suggest that adipocyte and cardiomyocyte mitochondria may be most sensitive to mitochondrial Tafazzin deficiency and that rescuing adipocyte mitochondrial dysfunction, in addition to cardiomyocyte mitochondrial dysfunction, may provide therapeutic benefit in Barth Syndrome patients.

Myocilin is an enigmatic glaucoma-associated glycoprotein whose biological role remains incompletely understood. To gain novel insight into its normal function, we used transposon-mediated transgenesis to generate the first zebrafish line stably overexpressing myocilin [Tg(actb1:myoc-2A-mCherry)]. qPCR showed an approximately four-fold increased myocilin expression in transgenic zebrafish embryos (144 hpf). Adult (13 months old) transgenic animals displayed variable and age-dependent ocular anterior segment alterations. Almost 60% of two-years old male, but not female, transgenic zebrafish developed enlarged eyes with severe asymmetrical and variable abnormalities in the anterior segment, characterized by corneal limbus hypertrophy, and thickening of the cornea, iris, annular ligament and lens capsule. The most severe phenotype presented small or absent ocular anterior chamber and pupils, due to iris overgrowth along with dysplastic retinal growth and optic nerve hypertrophy. Immunohistochemistry revealed increased presence of myocilin in most altered ocular tissues of adult transgenic animals, as well as signs of retinal gliosis, and expanded ganglion cells and nerve fibers. The preliminary results indicate that these cells contributed to retinal dysplasia. Visual impairment was demonstrated in all old male transgenic zebrafish. Transcriptomic analysis of the abnormal transgenic eyes identified disrupted expression of genes involved in lens, muscular and extracellular matrix activities, among other processes. In summary, the developed transgenic zebrafish provides a new tool to investigate this puzzling protein and provides evidence for the role of zebrafish myocilin in ocular anterior segment and retinal biology, through the influence of extracellular matrix organization and cellular proliferation.