Connexins are tetraspan transmembrane proteins that form gap junctions and facilitate direct intercellular communication, a critical feature for the development, function and homeostasis of tissues and organs. In addition, a growing number of gap junction-independent functions are being ascribed to these proteins. The connexin gene family is under extensive regulation at the transcriptional and post-transcriptional level, and undergoes numerous modifications at the protein level, including phosphorylation, which ultimately affects their trafficking, stability and function. Here, we summarize these key regulatory events, with emphasis on how these affect their multi-functionality in health and disease.

In this review we extensively describe the main post-translational modifications that give rise to the multiple proteoforms characterized to date in the human salivary proteome and their potential role. Most of the data reported were obtained by our group in over twenty-five years of research carried out on human saliva mainly by applying a top-down strategy. At the beginning we describe the products generated by proteolytic cleavages, which can occur before and after secretion. In this section the most relevant families of salivary proteins are also described. Next, we report the current information concerning the human salivary phospho-proteome and the limited news available on sulfo-proteome. Three sections are dedicated to the description of the glycation and enzymatic glycosylation. Citrullination and N- and C- terminal PTMs and a miscellaneous of other modifications are described in the last two sections. Results highlighting the variation in the level of some proteoforms in local or systemic pathologies are also reviewed along the sections of manuscript to underline the impact and relevance of this information for the development of new diagnostic biomarkers useful in clinical practice.

One of the hallmarks of Alzheimer’s disease (AD) is the accumulation of beta-amyloid peptide (Aβ) leading to formation of soluble neurotoxic Aβ oligomers and insoluble amyloid plaques in various parts of the brain. Aβ undergoes post-translational modifications that alter its pathogenic properties. Aβ is produced not only in brain, but also in the peripheral tissues. Such Aβ, including its post-translationally modified forms, can enter the brain from circulation by binding to RAGE and contribute to the pathology of AD. However, the transport of modified forms of Aβ across the blood–brain barrier (BBB) has not been investigated. Here, we used a transwell BBB model as a controlled environment for permeability studies. We found that Aβ42 containing isomerized Asp7 residue (iso-Aβ42) and Aβ42 containing phosphorylated Ser8 residue crossed the BBB better than unmodified Aβ42, which correlated with different contribution of endocytosis mechanisms to the transport of these isoforms. Using microscale thermophoresis, we observed that RAGE binds to iso-Aβ42 an order of magnitude weaker than to Aβ42. Thus, post-translational modifications of Aβ increase the rate of its transport across the BBB and modify the mechanisms of the transport, which may be important for AD pathology and treatment.

The hypoxia signalling pathway enables adaptation of cells to decreased oxygen availability. When oxygen becomes limiting, the central transcription factors of the pathway, hypoxia-inducible factors (HIFs), are stabilised and activated to induce the expression of hypoxia-regulated genes, thereby maintaining cellular homeostasis. Whilst hydroxylation has been thoroughly described as the major and canonical modification of the HIF-α subunits, regulating both HIF stability and activity, a range of other post-translational modifications decorating the entire protein play also a crucial role in altering HIF localisation, stability, and activity. These modifications, their conservation throughout evolution and their effects on HIF-dependent signalling are discussed in this review.

Protein translational modifications (PTMs) generate an enormous, but as yet undetermined, expansion of the expressed proteoforms. In this Viewpoint, we firstly differentiate the concepts of proteoform and peptidoform by reviewing and discussing previous literature. We show that the current PTM biological investigation and annotation largely follow a PTM site-specific rather than proteoform-specific approach. We further illustrate a potentially useful matching strategy in which a particular “modified peptidoform” is matched to the corresponding “unmodified peptidoform” as a reference for the quantitative analysis between samples and conditions. We suggest this strategy could provide directly relevant information for learning the PTM site-specific biological functions. Accordingly, we advocate for the wider use of the nomenclature “peptidoform” in the future bottom-up proteomic studies.

Histone Deacetylase 6 (HDAC6) is a large multidomain protein that deacetylates lysine residues on cytoplasmic proteins, influencing a wide range of cellular processes. Both the catalytic and non-catalytic functions of HDAC6 are implicated in cancer development and progression. Over a decade of clinical trials with catalytic domain inhibitors, such as Ricolinostat (ACY1215), has shown that these drugs are well tolerated and can alleviate chemotherapy-induced peripheral neuropathies. However, their effectiveness in treating solid tumors remains uncertain due to the limited number of clinical trials and the small size of patient cohorts, leading to inconclusive results. HDAC6 activity is regulated by protein-protein interactions and post-translational modifications, which may allosterically influence its catalytic domains. Therefore, targeting HDAC6 in cancer therapy with small molecule inhibitors requires a more sophisticated understanding of its role within the tumor microenvironment, including whether its expression correlates with deacetylase activity. A comprehensive evaluation of both its enzymatic and non-enzymatic functions could be crucial in developing more effective strategies for targeting HDAC6 in cancer.

Protein glycation impacts enzymatic activity, disrupts metabolic processes, and is associated with chronic degenerative diseases. The human glycolytic enzyme triosephosphate isomerase (HsTIM, TPI1, or HsTPI) is associated with various disorders, such as enzymopathies originating from mutations. It also possesses moonlighting functions and is now recognized as a cancer marker. Previous reports of HsTPI mutants have demonstrated a significant increase of methyl-glyoxal (MGO) due to trioses accumulation. We compared how catalytic activity exerts differen-tial kinetic and structural stability effects due to mutations by tracking fluorescent argpyrimi-dine adduct (ARGp) through interaction with Arginine-MGO. Circular dichroism and fluores-cence spectroscopy were explored in HsTPI-WT and mutants HsTPI-C217K “Like-WT”, HsTPI-N16D accumulated in cancer, and HsTPI-E104D human deficiency mutant, by cysteines accessibility and time loss of activity and unfolding propensity in mutant enzymes with aggre-gates refractory to proteolysis in the C217K. Our study sheds new light on the increased suscep-tibility of mutants to generate MGO adducts due to TPI isomerization of MGO precursor sub-strates. Nevertheless, mutations enhance a negative feedback cycle, in which accumulated MGO access promotes accelerated loss of activity that leads to unfolding and aggregation. The cumu-lative and accelerated increase in MGO adducts, which probably are responsible for the patho-logical state in this TPI variant, are partially reversed by adding MGO-scavenger molecules.

Our understanding of Alzheimer’s disease (AD) pathogenesis has developed with several hypotheses over the last 40 years, including the Amyloid and Tau hypotheses, respectively. More recently, the p53 protein, well-known as ‘the guardian of the genome,’ has gained attention for its role in the early evolution of AD. This is due to p53’s central role in the control of oxidative stress and potential involvement in both Amyloid and Tau pathways. p53 is commonly regulated by post-translational modifications (PTMs), which affect its conformation, increasing its capacity to adopt multiple structural and functional states, including those that can influence several processes in AD. The following review will explore the impact of p53 post-translational modifications (PTMs) on its function and consequential involvement in AD pathogenesis.

Cys is one of the least abundant amino acids in proteins. However, it is often highly conserved and usually found in important structural and functional regions of proteins. Its unique chemical properties allow it to undergo several post-translational modifications, many of which mediated by reactive oxygen, nitrogen, sulfur or carbonyl species. Thus, in addition to their role in catalysis, protein stability and metal binding, Cys residues are crucial for redox regulation of metabolism and signal transduction. In this review, we discuss Cys post-translational modifications (PTMs) and their role in plant metabolism and signal transduction. These modifications include oxidation of the thiol group (S-sulfenylation, S-sulfinylation and S-sulfonylation), the formation of disulfide bridges, S-glutathionylation, persulfidation, S-cyanylation S-nitrosation, S-carbonylation, S-acylation, prenylation, CoAlation as well as the formation of thiohemiacetal. For each of these PTMs, we discuss the origin of the modifier, the mechanisms involved in PTM, as well as their reversibility. Examples of the involvement of Cys ​​PTMs in the modulation of protein structure, function, stability, and localization are presented to highlight their importance in the regulation of plant metabolic and signaling pathways.

Hepatitis D virus (HDV) infection represents the most severe form of chronic viral hepatitis. We have shown that the delivery of HDV replication-competent genomes to the hepatocytes using adenoassociated virus (AAV-HDV) as gene delivery vehicles offers a unique platform to investi-gate the molecular aspects of HDV and associated liver damage. Here, we generated HDV ge-nomes modified by site directed mutagenesis aimed to: i) prevent some post-translational modi-fications of HDV antigens (HDAgs) such as Large-HDAg (L-HDAg) isoprenylation or Short-HDAg (S-HDAg) phosphorylation ii) alter the localization of HDAgs within the subcellular compartments and iii) inhibit the right conformation of the delta ribozyme. First, the different HDV mutants were tested in vitro using plasmid-transfected Huh-7 cells and then in vivo in C57BL/6 mice using AAV vectors. We found that Ser 177 phosphorylation and the ribozymal ac-tivity are essential for HDV replication and HDAg expression. Mutation of the isoprenylation domain prevent the formation of infectious particles and increase cellular toxicity and liver dam-age. Finally, altering the intracellular localization od HDAg have a profound on viral replication in vivo but liver toxicity is maintained. Mutation in the nuclear export signal impair the for-mation of infectious viral particles. These findings contribute valuable insights into the intricate mechanisms of HDV biology and have implications for therapeutic considerations

Rett syndrome (RTT) is mainly caused by mutations in methyl CpG-binding protein 2, cyclin-dependent kinase-like 5, or forkhead box protein G1. These RTT-causing proteins harbor an intrinsically disordered region (IDR) whose conformation exhibits spatiotemporal heterogeneity, which not only confer versatility to the protein, but also implicates them in diseases. The IDR generally evolves more rapidly than an ordered structure. In this study, we examined the relationship between pathogenic RTT-associated point mutations in RTT-causing proteins and the evolutionary dynamics of sequence features including structural order–disorder, phosphorylation sites, and evolutionary rates. We also analyzed the molecular properties and evolution of proteins that interact with RTT-causing proteins in terms of phylogenetic profiles, tissue specificity, subcellular localization, expression level, and functions. The results indicate that constrained IDRs may function by forming contacts with other regions in the protein sequence causing pathogenic missense mutations likely to arise in the rapidly evolving IDR and affect molecular networks, leading to disease. The results also provide novel insights into the genetic basis for RTT and the evolution of the neocortex in higher vertebrates.

Several Lung diseases can result in lung damage structural changes, with lung transplantation as a only therapeutic option when the disease reaches an advanced progression, unfortunately, the success of lung transplantation is limited. In this context, lung bioengineering is considered a potential therapeutic alternative and the current approach is based on the use of the natural extracellular matrix (ECM) of the decellularized lung. The use of undifferentiated cells to seed an ECM can be a more practical strategy for lung bioengineering but the sterilization of the organ for this recellularization process is still a challenge. In this sense, Low-Level Laser Therapy (LLLT) can emerge as a potential treatment alternative. Therefore, the objective of this study was to verify if LLLT, can optimize lung recelularization with mesenchymal stem cells by cytokine modulation. For this, we decellularized lungs from C57BL/6 mice perfusing SDS 1% via pulmonary artery, sterilized with LLL (660nm, 100mW, 30s). Whole lung scaffolds were recellularized: (1) Recellularized Lung (2) Recellularized Lung + LLLT. Mesenchymal stem cells derived from human tooth pulp (DPSc) were seeded into lungs and incubated for 24 hours at 37ºC, 5% CO₂, in a bioreactor-like conditions, maintaining CPAP at 20cmH2O, 90% O2, and LLL at wavelength of 808nm, 100mW, 30s. Culture medium were analyzed at 24 hours. H&E, immunostaining, SEM and ELISA assay were performed. We produced viable biological scaffolds absent of DNA content, preserving glycosaminoglycans and collagen I, III and IV, fibronectin, laminin and elastin and lung structure (SEM). The levels of IL-6 and IL-8 were stable during the 24 hours of culture. IFN-γ levels showed significant difference in the DPSc and DPSc+LLLT group in the 24-hour evaluation. The levels of IL-10 decreased after LLLT. These findings highlight LLLT's role in cytokine regulation and contamination prevention during lung recellularization with mesenchymal stem cells. Overall, these results demonstrated that LLLT's modulated cytokine levels and could prevent contamination during the lung recellularization process with mesenchymal stem cells, offering promise for enhanced therapeutic strategies in lung bioengineering.

Biochirality is evident in the hierarchical relation of molecular and cellular physiology during organism development and aging. Chirality influences the higher levels of biological processes, such as perception, memory and cognition, through intermolecular interactions between DNA, proteins, and lipids. At the molecular level, an organism's aging is the accumulation of macro-molecules with the aberrant composition, chirality, and folding. Cellular aging is driven by the non-physiological phase transitions (PhTs) withing membrane-bound and membrane-less compartments. Genomic instability and protein aging, as the interconnected root-causes of cell and organism aging, share two essential feature – spontaneous nature and accumulation over a lifetime. Consequently, we will analyze the interaction between the enzymatic (Enz) and spontaneous (Sp) post-translational modifications (PTMs^Enz and PTMs ^Sp). Both forms of PTMs significantly contribute to the balance of L- and D-amino acids (L/D-AAs) in organisms, modulating the functions of nervous and immune systems. The most abundant form of PTM - enzymatic phosphorylation is bio-chemically associated with the spontaneous racemization (Rz^Sp). The crass talk of enzymatic phosphorylation and spontaneous racemization, as an essential determinant of protein aging and aggregation, associated with the aberrant autophagy, apoptosis, and cell signaling, is discussed in this review.

Recurrent Pregnancy Loss (RPL) affects 1-2% of women, and its triggering factors are unclear. Several studies have shown the vaginal, endometrial, and gut microbiota may play a role in RPL. A decrease in the quantity of Lactobacillus crispatus in local microbiota has been associated with an increase in local (vaginal and endometrial) inflammatory response and immune cell activation that leads to pregnancy loss. The inflammatory response may be triggered by gram-negative bacteria, lipopolysaccharides (LPS), viral infections, mycosis, or atypia (tumor growth). Bacterial structures and metabolites produced by microbiota could be involved in immune cell modulation and may be responsible for immune cell activation and molecular mimicry. Gut microbiota metabolic products may increase the amount of circulating pro-inflammatory lymphocytes, which, in turn, will migrate into vaginal or endometrial tissues. Local proinflammatory Th1 and Th17 subpopulations along with a decrease in Treg and tolerogenic NK cells are accountable for the increase in pregnancy loss. Local microbiota may modulate the local inflammatory response increasing pregnancy success. Analyzing local and gut microbiota may be necessary to characterize some RPL patients. Although oral supplementation of probiotics has not been shown to modify vaginal or endometrial microbiota, the metabolites produced by it may benefit patients. Lactobacillus crispatus transplantation into the vagina may enhance the required immune tolerogenic response to achieve a normal pregnancy. The effect of hormone stimulation and progesterone to maintain early pregnancy on microbiota has not been adequately studied, and more research is needed in this area. Well-designed clinical trials are needed to ascertain the benefit of microbiota modulation in RPL.

Post-translational modifications (PTMs) represent a cornerstone in the complexity of the proteome, significantly contributing to diversifying protein structure and function. PTMs can significantly influence protein function, stability, localization, and interactions with other molecules. Therefore, it is important when choosing a protein expression system to ensure the precise incorporation of PTMs during protein synthesis, which is paramount for producing biologically active proteins. Cell-free protein synthesis (CFPS) system has emerged as a powerful protein synthesis platform and research toolkit in synthetic biology. The open nature of the system allows the reaction environment to be tailored to any protein of interest to promote specific PTMs, thus allowing for the production of a protein with the desired modifications. This review presents various PTMs achieved in the CFPS systems, providing insights into the current challenges, successes, and future prospects.

Direct and indirect effects after mine operations cease must ideally be subject to perpetual monitoring routines in order to detect possible risks or avoid adverse effects on the surrounding ecosystems at an early stage. In this contribution, mining subsidence lakes created inside the nature reserve Kirchheller Heide and Hilsfeld Forest are subjected to analysis for a long-term monitoring scheme. For this purpose, we employ high-resolution unmanned aerial system (UAS)-based multispectral and thermal mapping tools to provide a fast, non-invasive and multitemporal environmental monitoring method. Specifically, we propose to monitor vegetation evolution through multispectral analysis, biotypes identification using machine learning algorithms, and water surface extent detection, together with their thermal behavior. The aim of this contribution is to present the proposed workflow and first results to establish a baseline for future analyses and subsequent surveys for longterm multi-temporal monitoring

LCK, a member of the Scr kinase family, is a non-receptor tyrosine kinase involved in immune cell activation, antigen recognition, tumor growth, and cytotoxic response. The enzyme has usually been linked to T lymphocyte activation upon antigen recognition. Lck activation is central to CD4, CD8, and NK activation. However, recently, it has become clearer that activating the enzyme in CD8 cells can be independent of antigen presentation and enhance cytotoxic response. The role of Lck in NK cytotoxic function has been controversial in a similar fashion as the role of the enzyme in CAR T cells. Inhibition of Lck has been mainly to treat hematologic malignancies with a high rate of success. They may be useful in treating other tumor types, and they may be useful to prevent cell exhaustion. New, more selective inhibitors have been documented, and they have shown inter-esting activities not only in tumor growth but in the treatment of autoimmune diseases, asthma, and graft vs host disease. Drug repurposing and bioinformatics can aid in solving several unsolved is-sues on the role of Lck in cancer. In summary, the role of Lck in immune response and tumor growth is not a simple event and requires more research.

During the last few years, the world witnessed one of the worst calamities to humankind- the COVID-19 pandemic. We also witnessed the development of vaccines at an unprecedented pace against the SARS-CoV-2- the causative agent. India was among the hard-hit countries by COVID-19, developed its indigenous vaccine and implemented vaccines developed in other countries as well. Initially, the antibody level and the neutralizing antibody titer against the pathogen were considered as the correlates of immune protection from the disease. However, the long-term protection from the pathogen was provided by the immune memory cells viz. T and B memory cells and their ability to efficiently make recall responses. In this regard, globally the research studies focused mainly on the mRNA-based vaccines. The studies on immune memory response, particularly- the B cell memory response bestowed by the vaccines given to Indians is relatively obscure. We studied the level of RBD specific memory B cells in the peripheral circulation of the study participants and the ability of B cells to secrete antigen-specific antibodies among Indians vaccinated with Covaxin (BBV152), Covishield (AZD1222), Corbevax (BECOV2D) and Sputnik Light (Gam-COVID-Vac) as well as unvaccinated individuals. Our study revealed that Corbevax and Sputnik Light conferred better antibody-secreting cell (ASC) responses.

Lactate, an important metabolic product, provides energy to neural cells during energy depletion or high demand and acts as a signaling molecule in the central nervous system. Recent studies revealed that lactate-mediated protein lactylation regulates gene transcription and influences cell fate, metabolic processes, inflammation, and immune responses. This review comprehensively examines the regulatory roles and mechanisms of lactylation in neurodevelopment, neuropsychiatric disorders, brain tumors, and cerebrovascular diseases. This analysis indicates that lactylation has multifaceted effects on central nervous system function and pathology, particularly in hypoxia-induced brain damage. Highlighting its potential as a novel therapeutic target, lactylation may play a significant role in treating neurological diseases. By summarizing current findings, this review aims to provide insights and guide future research and clinical strategies for central nervous system disorders.

Protein tyrosine sulfation (PTS), a vital post-translational modification, facilitates protein–protein interactions and regulates many physiological and pathological responses. Monitoring PTS has been difficult owing to the instability of sulfated proteins and the lack of a suitable method for detecting the protein sulfate ester. In this study, we combined an in situ PTS system with an ultra-high-sensitivity polysilicon nanowire field-effect transistor (pSNWFET)-based sensor to directly monitor PTS formation. A peptide containing the tyrosine sulfation site of P-selectin glycoprotein ligand (PSGL)-1 was immobilized onto the surface of the pSNWFET by using 3-aminopropyltriethoxysilane and glutaraldehyde as linker molecules. A coupled enzyme sulfation system consisting of tyrosylprotein sulfotransferase and phenol sulfotransferase was used to catalyze PTS of the immobilized PSGL-1 peptide. Enzyme-catalyzed sulfation of the immobilized peptide was readily observed through the shift of the drain current–gate voltage curves of the pSNWFET before and after PTS. To the best of our knowledge, this is the first study to describe in situ PTS and its direct observation by using semiconductor devices. We expect that this approach can be developed as a next generation biochip for biomedical research and industries.

This study investigated the effects of fish oil (FO) treatment, particularly enriched with eicosapentaenoic acid (EPA), on obesity induced by a high-fat diet (HFD) in mice. The investigation focused on elucidating the impact of FO on epigenetic modifications in white adipose tissue (WAT) and the involvement of adipose-derived stem cells (ASCs). C57BL/6j mice were submitted to a control diet or a HFD for 16 weeks, treated (or not) with FO for the last 8 weeks. WAT was removed for RNA and protein extraction, while ASCs were isolated, cultured, and treated with Leptin. All samples were analyzed using functional genomics tools, including PCR-array, RT-PCR and Western Blot assays. Mice receiving HFD displayed increased body mass, fat accumulation, and altered gene expression associated with WAT inflammation and dysfunction. FO supplementation attenuated these effects, a potential protective role against HFD-induced obesity. Analysis of H3K27 revealed HFD-induced changes in histone, which were partially reversed by FO treatment. The study further explored leptin signaling in ASCs, suggesting a potential mechanism for ASC dysfunction in the leptin-rich environment of obese WAT. Overall, FO supplementation demonstrated efficacy in mitigating HFD-induced obesity, influencing epigenetic and molecular pathways, and shedding light on the role of ASCs and leptin signaling in WAT dysfunction associated with obesity.

Among post-translational modifications of proteins, ADP-ribosylation has been studied for over fifty years, assigning to this PTM a large set of functions, including DNA repair, transcription and cell signaling. This review presents an update on the function of a large set of enzyme writers, the readers that are recruited by the modified targets, and the erasers that reverse the modification to the original amino acid residue, removing the covalent bonds formed. In particular, the review provides details on the involvement of the enzymes performing MAR/PAR cycling in cancers. Of note, there is potential for application of the inhibitors developed for cancer also in the therapy of non-oncological diseases such as the protection against oxidative stress, suppression of inflammatory responses, and the treatment of neurodegenerative diseases. This field of studies is not concluded, since novel enzymes are being discovered at a rapid pace.

The p53 tumor suppressor protein shows antiviral activity. The replication of viruses is also antagonized by interferons (IFNs) – cytokines, which control immunity genes by the STAT transcription factors. The best studied interferons belong to type I (e.g. IFNα) and type II (IFNγ) groups. IFNα and IFNγ both induce activating phosphorylation of STAT1 on Tyr701. Previously, we noticed that p53 activates SOCS1, which is a negative regulator of STAT1 phosphorylation. Thus, we hypothesized that p53 by activating SOCS1 expression reduces phosphorylation of STAT1 and attenuates activation of genes stimulated either by IFNα or IFNγ. To test this hypothesis, we exposed p53-proficient and p53-deficient cells to strong p53 activators, and either to IFNα or IFNγ. Subsequently, we estimated the phosphorylation status of STAT1 and the expression of genes regulated by either of these cytokines. Strong activation of p53 reduced the phosphorylation of STAT1 on Tyr701, however surprisingly it did not lead to reduced expression of most tested interferon-stimulated genes. On contrary, p53 and IFNγ synergized in the activation of CASP1, IFIT1 and IFIT3 genes. We conclude that the interactions between p53 and interferon-activated pathways are more complicated than initially expected, but the apparent cooperation between p53 and IFNγ deserves further studies.

The Sustainable Development Center of the University of Brasilia is one of the modernist buildings that make up the Darcy Ribeiro campus. The architectural project contains several recommendations for the execution of the flat roof waterproofing system, as well as details for rainwater runoff and drainage, which reveals a certain concern with watertightness. The research seeks to identify the relationship between the pathological manifestations recognized on the roof and the semicircular shape of the building, assessing the state of conservation through the use of damage maps as an analysis tool. The article is based on a field survey using aerophotogrammetry with a drone, the application of vector drawing software for graphic representation and discussion of the possible causes, agents and mechanisms of degradation at work. The results show the importance of mechanical protection for the good performance of the waterproofing system, as well as the need for correct sizing of expansion joints in order to absorb and relieve the stresses caused by hygrothermal variations. The methodology incorporated proved to be effective and economical in diagnosing and monitoring pathological manifestations, making it possible to plan maintenance actions that extend the useful life and preserve the intrinsic characteristics of building systems.

Amitriptyline is a tricyclic antidepressant commonly used for depressive disorders and pre-scribed off-label for several neurological conditions like neuropathic pain, migraine and anxiety. Amitriptyline potentiates the monoaminergic transmission by blocking the reuptake of norepi-nephrine and serotonin. However, antidepressants also act on additional targets that contribute to either therapeutic or adverse effects and may suggest new indications for their repurposing. Furthermore, since depression is often a co-morbidity in patients with chronic conditions (i.e. cancer, neurodegenerative diseases) the use of antidepressants interfering with pathways in-volved in cell homeostasis may affect the progression and outcome of these pathologies. Here we investigate the effects of amitriptyline on proliferation and autophagy in human SH-SY5Y neuroblastoma cells. Dose and time-dependent upregulation of the autophagy markers LC3II and autophagy receptor p62, with accumulation of LAMP1 positive compartments, were observed in SH-SY5Y cells exposed to amitriptyline. Alteration of autophagy was accompanied by reduced cell viability and decreased clonogenic capacity, without a significant induction of apoptosis. Decrease viability and clonogenic activity were still observed in autophagy deficient Atg5 -/- MEF and following pre-treatment of SH-SY5Y culture with the autophagy inhibitor chloroquine suggesting that the amitriptyline’s effects on cell proliferation were not caused by the modulation of autophagy. Our findings demonstrate that amitriptyline acts on pathways that are crucial for cell and tissue homeostasis and pose the basis for further studies on the potential application of these effects and the consequences during long-term antidepressant treatment.

The immune response is crucial in Pregnancy Loss (RPL), which affects 1-2% of women. In RPL, peripheral blood lymphocytes and local immune cells are activated with a concomitant decrease in the leukocyte tolerogenic response in the uterus and decidua. IL-17 plays an essential role in T cell activation, weakening tolerogenic responses of the T cells. The report aims to analyze the IL-17 genetic polymorphism, circulating IL-17 lymphocyte populations, the reaction upon lymphocyte priming, the amount of cytokine in serum, and the number of T-reg cells in a group of 50 RPL and 50 normal women from the admixed Venezuelan population. No differences were observed in the genetic polymorphisms rs2275913 and rs763780. A significant decrease (P<0.001) was observed in RPL patients compared to controls in the IL-17+ cell populations CD3+, CD8+, CD56+, and CD4CD25 FoxP3, but not in the CD4IL17+ cells. The response upon cell priming was significantly decreased (P<0.001) in all subpopulations of RPL as compared to controls. It is concluded that despite the increase in IL-17A in the serum of patients, the number of circulating IL-17 cells and the lymphocyte response to stimulation was significantly decreased (p<0.001). No differences in the genetic polymorphism compared to controls suggest that biological factors influence IL-17 levels in RPL patients, which must be carefully studied.

Klippel-Feil disease is a condition characterized by a defect in the spine, consisting in the fusion or non-separation of two or more vertebrae of the cervical tract. It usually affects 1 every 50.000 newborns, and the pathogenesis remains unknown to date, although the role of certain genes deputed in segmentation processes is being studied. A single case of gene Myosin Heavy Chain 3 (MYH3) mutation is described by researchers. Affected patients are often characterized by a relatively short neck and, therefore, poor mobility, a low hairline and obesity and may have other health problems of different nature. The frequent presence of comorbidities worsens the quality of life of these young patients. The following case describes the synergistic effect of Incobotulinum toxin type A and physiotherapy in a small patient with MYH3 mutation-related Klippel-Feil Syndrome (KFS) complicated by bilateral paraplegia, to improve the spasticity condition of the lower limbs. To assess improvements over time, the patient underwent rating scales to determine spasticity (Modified Ashworth Scale: MAS), the neck’s range of motion (ROM), and muscle tone by using MyotonProÒ. Specifically, measurements were taken on the day of the first medical examination (T0), the month after the injection and the startup of therapeutic exercise (T1), at three months (T2), and then once a month for a total of 6 months (T3, T4 and T5). This therapeutic approach led to entirely satisfactory results with the child’s well-being, prolonged until the sixth month and with a total absence of any side effects.

Regardless of the SARS-CoV-2 pandemic containment, it remains paramount to comprehensively understand its underlying mechanisms to mitigate potential future health and economic impacts, comparable to those experienced throughout the course of the pandemic. The angiotensin-converting enzyme 2 (ACE2) provide anchorage for SARS-CoV-2 binding, thus implicating that ACE and ACE2 might contribute to the variability in infection severity. This study aimed to elucidate predisposing factors influencing the disease course among people infected by SARS-CoV-2, focusing on angiotensin-converting enzyme (ACE) and ACE2 polymorphisms. Notably, despite similar demographics and comorbidities, COVID-19 patients exhibit substantial differences in prognosis. Genetic polymorphisms in ACE and ACE2 have been implicated in disease progression, prompting our investigation into their role in COVID-19 evolution. Using next-generation sequencing (NGS), we analyzed ACE and ACE2 genes in a sample group comprising six subjects infected by SARS-CoV-2. Our findings revealed a correlation between specific polymorphisms and COVID-19 outcomes. Specifically, ACE and ACE2 intronic deletions were observed in all deceased patients, suggesting a potential association with mortality. These results highlight the significance of genetic factors in shaping the clinical course of COVID-19, emphasizing the importance of further research into the impact of genetic variations on COVID-19 severity.

More than 20 years after the discovery of the first anelloviruses (AVs), they still remain a mysterious group of viruses. To date, there is no clear understanding of their impact on the host organism, although information is emerging about their participation in various pathologies. However, it is well known that AVs are an important component of the human virome. In the current study we assessed the abundance of AVs in viromes from four nasal and pharyngeal samples from children with respiratory symptoms using a metagenomic approach. It is worth noting that three patients had known respiratory viruses and one did not have any. Regarding AVs, they were detected in all samples, namely Torque teno mini virus (TTMV). The greatest abundance and diversity of AVs (Torque teno virus (TTV), TTMV and Torque teno midi virus (TTMDV)) were shown in a diseased patient with an absence of respiratory viruses, which may indicate the potential involvement of AVs in the maintenance of respiratory symptoms. An activated immune system to combat the main pathogens, against the background of which the number of AVs decreases, is discussed as a possible reason for the reduced diversity of anellome in other patients. We also compared the results of the metagenomic approach and qPCR for major respiratory viruses, which were in agreement. In addition, metagenomic sequencing made it possible to obtain additional data on viral genomes in order to establish their taxonomic identification and characterize individual viral profiles in patients from the Siberian part of Russia.

Plantar fasciitis is one of the most common causes of foot pain; in a significant percentage it is also associated with bone edema of the heel. A prospective randomized clinical trial was designed, in which 48 patients suffering from plantar fasciitis, with or without bone edema, were treated with temperature controlled high energy adjustable multi-mode emission laser and exercises (laser group) or with exercises only (control group). Patients were evaluated at recruitment (T0), at 2 (T1) and 6 months (T2), monitoring pain (with Visual Analogue Scale), functionality (with Foot Function Index) and perception of improvement (with Roles and Maudsley Score) and fascia thickness (with ultrasound examination). In both groups there was a significant improvement in pain, functional recovery, perception of remission and a reduction in plantar fascia thickness at T1 and T2. The laser group presented statistically better values at T2 for the Roles and Maudsley Score (z: 2.21; 0.027). Regression analysis showed that a greater reduction in fascia thickness occurred in the laser group (p-value: 0.047). In conclusion, the two conservative treatments were effective in patients suffering from plantar fasciitis, even in the presence of bone edema, but with lesser results.

The “tubulin code” combines different α/β-tubulin isotypes with several post-translational modifications (PTMs) to generate microtubule diversity in cells. During cell division, specific microtubule populations in the mitotic spindle are differentially modified, but only recently has the functional significance of these modifications started to be elucidated. In particular, α-tubulin detyrosination of stable microtubules in the spindle was shown to guide chromosomes during congression to the metaphase plate and allow the discrimination of mitotic errors, whose correction is required to prevent chromosomal instability (CIN), a hallmark of human cancers. Although alterations in certain tubulin PTMs have been reported in human cancers, it remains unclear whether and how tubulin PTMs have any functional implications for cancer cell properties. Here we review the role of the tubulin code in chromosome segregation during mitosis, together with the emerging cancer tubulin code and discuss possible links, as well as the respective diagnostic, prognostic and therapeutic implications for human cancers.

Poverty has long been associated intricately with neurological disorders. Majority of the previous studies designed to describe the effects of poverty on neurological ailments have mostly linked the association of hypoxic ischemic encephalopathy and nutritional deficiency disorders with poverty. Authors herein try to delve deeper into this issue. The association of begging with neuropsychiatric disorders is robust. The burden of probable autosomal dominant neurological ailments is very common among beggars; followed by neurological disorders with social stigma like abnormal movements, facial dysmorphism and gait unsteadiness. Dearth of support from family members in autosomal dominant neurological disorders (as family members are likely to be suffering from similar neurodegenerative disorder ) and poor perception about neurological diseases, misconceptions, myths and low educational attainment at large in the society can be implicated as the often overlooked but important factors underneath this association of begging and neurological disorders.

Adeno-associated viruses (AAV) are widely used as viral vectors for gene delivery in mammalian cells. We focused on the efficacy of transduction of AAV 2/5, 2/6, 2/8 and 2/9 expressing GFP in 3T3-L1 murine preadipocyte cells by live imaging microscopy using IncuCyte S3 and flow cytom-etry. Three transduction modes were assessed: AAV transduction in 3T3-L1 preadipocyte cells with or without further differentiation into mature adipocyte-like cells and injection of AAVs in differ-entiated adipocyte-like cells. AAV2/6 demonstrated the highest transduction efficiency in 3T3-L1 preadipocytes, as it was 1.5–2-fold more effective than AAV2/5, and AAV2/8 in the range of viral concentrations from 2×104 to 1,6×105 VG/cell. AAV2/5 and AAV2/8 showed transduction effi-ciencies similar to each other. The expression of GFP under the CMV promoter remained stable for up to 20 days. The induction of 3T3-L1 differentiation in three days after AAV transduction did not alter the GFP expression level, and AAV2/6 showed the best transduction efficiency. AAV2/6 demonstrated the ability to transduce mature adipocytes. These results were confirmed by in vivo studies on C57BL6 mice AAV2/6 had the highest transducing activity on both inguinal and inter-scapular adipose tissue. Thus, AAV2/6 has demonstrated higher transduction efficacy compared to AAV2/5, AAV2/8 and AAV2/9 both in 3T3-L1 adipocytes and adipose tissue in vivo, which proves its usability along with AAV8 and AAV9 for gene delivery to adipocytes.

Over the past decade and a half, dynamic functional imaging has revolutionized the neuroimaging field. Since 2009, it has revealed low dimensional brain connectivity measures, has identified potential common human spatial connectivity states, has tracked the transition patterns of these states, and has demonstrated meaningful alterations in these transition and spatial patterns in neurological disorders, psychiatric disorders, and over the course of development. Recently, researchers have begun to analyze this data from the perspective of dynamic system and information theory in the hopes of understanding how these dynamics support less easily quantified processes, such as information processing, cortical hierarchy, and consciousness. Consciousness, in particular, appears to be strongly linked to entropy production in the brain. Little attention has been paid to the effects of psychiatric disease on entropy production in the human brain, however. Even disorders characterized by substantial changes in conscious experience have not been widely analyzed from this perspective. We begin to rectify this by examining the complexity of subject trajectories in state space through the lens of information theory. Specifically, we identify a basis for the dynamic functional connectivity state space and track subject trajectories through this space over the course of the scan. The dynamic complexity of these trajectories is assessed along each dimension of the proposed basis space. Using these estimates, we demonstrate that schizophrenia patients display substantially simpler trajectories than demographically matched healthy controls, and that this drop in complexity concentrates along specific dimensions. We also demonstrate that entropy generation in at least one of these dimensions is linked to cognitive performance. Overall, results suggest great value in applying dynamic systems theory to problems of neuroimaging and reveal a substantial drop in the complexity of schizophrenia patients’ brain function.

In patients with primary central nervous system lymphoma (PCNSL), the choice of surgical strategy for histopathologic assessment is still controversial, particularly in terms of preoperative corticosteroid (CS) therapy. To provide further evidence for clinical decision-making, we retrospectively analyzed data from 148 consecutive patients who underwent surgery at our institution. Although patients treated with corticosteroids preoperatively were significantly more likely to require a second or third biopsy (p=0.049), it was only necessary in less than 10% of the cases with preoperative corticosteroid treatment. The choice of surgical procedure did not affect diagnostic accuracy (p>0.05). Preoperative CSF sampling did not provide additional information but was associated with delayed surgery (p=0.02). Surprisingly, diagnostic accuracy was significantly lower when patients were treated with anticoagulation or dual antiplatelet therapy (p=0.015). In conclusion, preoperative CS therapy can challenge the histological diagnosis of PCNSL. At the same time, our data suggest that preoperative CS treatment only presents a relative contraindication for an early surgical intervention. The standard surgical approach is stereotactic biopsy, but other approaches can be individually considered. If a definitive diagnosis cannot be made after the first surgical intervention, the timing of a repeat biopsy after discontinuation of CS remains a case-by-case decision.

The oral microbiome, studied by sampling the saliva or oral rinse, has been long thought to have diagnostic capacity for head and neck cancers (HNC). However, previous reports on the HNC oral microbiome provide inconsistent results. The aim of this study is to consolidate these datasets and determine the oral microbial composition between HNC patients to healthy and premalignant individuals. We analyzed 16 published head and neck cancer (HNC) short-read 16S rRNA sequencing datasets, specifically targeting the V3V4, V4 and V4V5 regions. These datasets included saliva and oral rinse samples from donors with HNC, as well as from healthy and premalignant donors. Differences in diversities and microbial abundance were determined. HNC saliva displayed lower alpha diversity than healthy donors. In contrast, the opposite trend was observed for oral rinse samples. Beta diversity were largely similar across different patient types. Similar oral phyla were detected for all samples, but proportions were largely dependent on sample type (i.e. saliva or oral rinse) and primer set utilised for 16S rRNA sequencing. Neisseria, Leptotrichia and Megasphaera were elevated in healthy saliva, while Mycoplasma was elevated in HNC saliva. Oral rinse and saliva displayed similar enrichment for Fusobacterium, while Veillonella, Alloprevotella, and Campylobacter had conflicting results. The sparse partial least squares discriminant analysis model performed effectively in discriminating HNC from healthy or premalignant patients using V3V4 saliva (AUC = 0.888), and V3V4 oral rinse (AUC = 0.928), while poor discriminative capacity was observed for V4 saliva (AUC = 0.688). In conclusion, our meta-analysis highlighted the limitations of 16S rRNA sequencing, particularly due to variations across study batches, primer sets (i.e. V3V4, V4), and sample types. Hence, caution should be exercised when interpreting 16S rRNA sequencing results across studies, especially when different primer sets and sample types are used.

Transfer RNA (tRNA) modifications are essential for the temperature adaptation of thermophilic and psychrophilic organisms, as they control the rigidity and flexibility of transcripts. To further understand how specific tRNA modifications are adjusted to maintain functionality in response to temperature fluctuations, we investigated whether tRNA modifications represent an adaptation of bacteria to different growth temperatures (minimal, optimal, and maximal), focusing on closely related psychrophilic (P. halocryophilus and E. sibiricum), mesophilic (B. subtilis), and thermophilic (G. stearothermophilus) Bacillales. Utilizing an RNA sequencing approach combined with chemical pre-treatment of tRNA samples, we systematically profiled dihydrouridine (D), 4-thiouridine (s4U), 7-methyl-guanosine (m7G), and pseudouridine (Ψ) modifications at single-nucleotide resolution. Despite their close relation, each bacterium exhibited a unique tRNA modification profile. Our findings revealed increased tRNA modifications in the thermophilic bacteria at higher temperatures, particularly showing elevated levels of s4U8 and Ψ55 modifications compared to non-thermophilic bacteria, indicating a temperature-dependent regulation that may contribute to thermotolerance. Furthermore, we observed higher levels of D modifications in psychrophilic and mesophilic bacteria indicating an adaptive strategy for cold environments by enhancing local flexibility in tRNAs. Our method demonstrated high effectiveness in identifying tRNA modifications compared to an established tool, highlighting its potential for precise tRNA profiling studies.

About 14% of adolescents experience mental illnesses globally. The rate increased after the COVID-19 pandemic. This study aimed to estimate the prevalence of COVID-related major mental illnesses (depression and anxiety) and their predictors among adolescents. This community-based cross-sectional study was conducted among 350 adolescents aged 10-19 years, recruited from rural communities in West Bengal, India. The study areas included 27 subcenters in the Budge Budge II Block, which comprised 1,91,709 population and 45,333 households. Data were collected from randomly selected households by trained research assistants through house-to-house interviews. Pretested standardized questionnaires, Patient Health Questionnaire (PHQ) for depression, Generalized Anxiety Disorder (GAD) for anxiety, and a demographic questionnaire were used for data collection. The prevalence of anxiety was 35.7% (125 out of 350), and the prevalence of depression was 30.0% (105 out of 350). Females had significantly higher scores of anxiety (6.67 ± 4.76 vs. 3.42 ± 3.17, respectively, p <0.001) and depression (5.51 ± 4.99 vs. 3.26 ± 3.86, respectively, p <0.001) compared to males. Adolescents who had COVID-19 cases or deaths in the family had significaly higher scores of anxiety and depression compared to those who didn’t have these events. In multivariate analysis, the statistically significant predictors of anxiety were COVID-19 death in the family, COVID-19 cases in the family, female gender, and a lower income group (p <0.001 for all). For depression, the significant predictors included COVID-19 death in the family, COVID-19 cases in the family, female gender, a lower income group, and a higher age group in adolescents (p <0.001 for all). Based on the study results, we recommend that immediate attention is needed for adolescents’ mental health support and coping with stresses following COVID-19.

The p53 tumor suppressor protein is an activator of transcription. Diverse stress factors lead to various sets of posttranslational modifications of p53 what results in different sets of upregulat-ed genes. We noticed that actinomycin D and nutlin-3a (A+N) synergize in inducing activating phosphorylations of p53 and upregulation of selected p53-target genes. Here we found that one of these genes is DUSP13, which codes for poorly-studied, dual-specificity phosphatase having at least two isoforms, one expressed in testis and the other in skeletal muscles. In cancer cells ex-posed to A+N, DUSP13 is expressed from an alternative promoter in intron, what results in ex-pression of isoform named TMDP-L1. The luciferase reporter tests demonstrated that this pro-moter is activated by both endogenous and ectopically expressed p53. We showed for the first time that mRNA expressed from this promoter actually produces the protein, which can be de-tected by Western blotting in all examined cancer cell lines with wild-type p53 exposed to A+N. In some cell lines it is also induced by clinically relevant camptothecin or by nutlin-3a acting alone. This isoform, fused with green fluorescent protein localizes in perinuclear region of cells. Thus, TMDP-L1 isoform may be an important element of p53-regulated stress response system.

Weather-related risks in aviation are one of the main causes of accidents worldwide. This article aims to analyze aviation risks resulting from adverse weather conditions, using the case study of the Pucallpa accident that occurred on August 23, 2005, in eastern Peru. In this analysis, we have determined the relationship between meteorological information and aviation risks, presented a matrix of risks associated with the most predominant meteorological variables at Pucallpa airport, and drawn up three maps of meteorological risks indicating the month of the year in which their incidence is most relevant. Finally, we conclude that it is essential to emphasize the importance of considering the prevailing weather conditions at Pucallpa airport to help mitigate the potential risks that may occur during different phases of the flight.

Background: The cumulative exposure of UV radiation can result in dangerous consequences such as skin burns, photoaging, and skin cancer, hence the importance of using photoprotective formulations. Currently, the formulations seek to be more efficient, innovative and reach a wider audience. Many sunscreens are vegan, and have antioxidant substances to ensure additional photochemoprotective action. To evaluate biological, functional, and mechanical characteristics of them on the skin, biometric and rheologic methods can be used. Objective: Evaluate biophysical, rheological and sensorial parameters of Face Care Facial Moisturizing Cream® (P1) and a vegan formulation (P2) by in vitro and in vivo tests. Methods: A UV scan experiment was performed covering the range of 250 to 400 nm. Sun Protection Factor (SPF) was evaluated by Mansur method. Rheological profiles were obtained using a MARS II (Haake®) controlled shear stress and gradient rheometer. Biophysical parameters were analyzed: skin sebum content, hydration level, transepidermal water loss, erythema and melanin level, skin color, and skin pH. The acceptance profile of the formulations by the volunteers was determined using a 9-point hedonic scale and a 5-point purchase intention test. Results: The formulations effectively absorbed light covering the UV radiation spectrum from UVA to UVB. The SPF of P1 was 25.21 and of P2 was 12.10 by in vitro tests. They had also pseudoplastic and thixotropic behavior, it can contribute to better spreadability and to form a protective film. Biometric tests showed an increase in hydration and skin sebum, decreased erythema, and maintenance of skin pH after application of both formulations. The products also had similarly good acceptance and purchase intention by the volunteers. Conclusion: The comparation of a commercialized product and a vegan test version showed very similar rheological and great acceptance profiles. Therefore, the vegan formulation is a good alternative to reach a different market.

Extracellular vesicles (EVs) hold enormous potential in the diagnosis and treatment of diseases, benefit from their roles in intercellular signaling, as well as their plentiful presence and stability in body fluids. However, conventional EV isolation methods are labor-intensive, and harvest EVs with low purity and compromised recovery. In addition, the drawbacks, such as limited sensitivity and specificity of traditional EV analysis methods hinder the application of EVs in clinical use. Therefore, it is urgent to develop effective and standardized methods for isolating and detecting EVs. Microfluidics technology is a powerful and rapidly developing technology that has been introduced as a potential solution for the above bottlenecks. It holds the advantages of high integration, short analysis time, low consumption of samples and reagents. In this review, we summarize the traditional techniques alongside microfluidic-based methodologies for the isolation and detection of EVs. We emphasize the separation advantages of microfluidic technology in enhancing EV capture efficiency and precise targeting, while summarizing its analytical role in targeted detection and discussing the significance of EV detection in the tumor microenvironment, providing a direction for achieving automated and high-throughput EV detection in clinical samples.

Keywords: retinoblastoma, RB, gastric inhibitory polypeptide receptor, GIPR, trefoil factor family peptide, TFF1, CAM, tumorigenesis, MK0893, miR5-542-5p

In late December 2019 a novel RNA beta-coronavirus was recognized as the causative agent of previously pneumonia cases of unknown origin. The virus was successively named Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) as well as the respiratory illness that it causes Coronavirus disease 19 (COVID-19) (1, 2). The global spread of SARS-CoV-2 and the thousands of deaths caused by COVID-19 led the World Health Organization (WHO) to declare a pandemic on 11 March 2020. To date, the world has paid a high toll in this pandemic in terms of human lives lost, economic repercussions and increased poverty. Indeed, even if most patients with COVID-19 are asymptomatic or experience mild self-limiting disease, 14% of them progress to severe disease and 5% to critical illness with complications, such as interstitial pneumonia, respiratory failure with acute respiratory distress syndrome (ARDS) and multiple organ dysfunction syndromes (MODS) (3). It is accepted that SARS-CoV-2 primarily affects the respiratory system, although other organs are also involved (4). The virus enters host cells by attaching its Spike like surface projections to the angiotensin-converting enzyme-2 (ACE2) receptor which is mainly expressed on alveolar epithelial cells and in nearly all human organs in varying degrees. Thus, although the central target of SARS-CoV-2 infection is the lung, the wide distribution of ACE2 receptors in other organs may lead to cardiovascular, gastrointestinal, kidney, liver, central nervous system and ocular damages that have to be closely monitored during the disease (5, 6). The virus then activates the innate and adaptive immune system resulting in a large number of cytokines release, known as “cytokine storm”, that is directly correlated with tissue injury and unfavourable prognosis of severe lung disease (7). In particular, interleukin (IL)-6 seems to plays an important role in driving this cytokine release so that its increased levels have been recognized as a hallmark inflammatory signature in sera of COVID-19 patients (8). IL-6 is a polyfunctional cytokine with both anti-inflammatory and pro-inflammatory properties which exerts its several functions through two main signal transduction pathways (9). In the classical signal transduction pathway, IL-6 binds to IL-6-trans membrane receptor (IL-6R) to form a complex that, then, binds to the trans membrane glycoprotein gp130, inducing its homo-dimerization and initiating intracellular signal transduction. This kind of signaling is limited to cells (hepatocytes, macrophages, neutrophils, T cells, etc.) that express IL-6R on their cell surface (10). Nevertheless, cells do not express IL- 6R, as stromal and epithelial cells, are able to still respond to IL-6 because the soluble form of the receptor (sIL-6R) binds to IL-6 in circle and then anchors to membrane gp130 receptor, initiating the trans-signaling pathway. For this reason, sIL-6R is able to increase the function of IL-6 and is considered the agonist form of its receptor. When the level of IL-6 increases, its effects are widely expressed because gp130 molecules are ubiquitous and, therefore, also present in cells without IL-6R in the membrane form. On the contrary, a soluble form of the glycoprotein 130 (sgp130) can complex with sIL-6R to prevent the sIL-6R from binding to the membrane-bound gp130. In this case sgp130 is able to decrease the function of IL-6 and is considered the antagonist form of IL-6 receptor system (11). Based on the central role of IL-6 in the inflammatory pathology of COVID-19 and the consistent association between elevated levels of the cytokine and severe disease outcomes found in the first phase of infection, we sought to analysis IL-6 and its soluble receptor complex behavior during the different waves of COVID-19 pandemic, in order to evaluate the possible differences which occur among them and to hypothesize if they might be used as prognostic markers of disease severity.

The observation that certain therapeutic strategies for targeting inflammation benefit patients with distinct immune-mediated inflammatory diseases (IMIDs) is exemplified by the success of TNF blockade in conditions including rheumatoid arthritis, ulcerative colitis and skin psoriasis, albeit only for subsets of individuals with each condition. This suggests intersecting "nodes" in inflammatory networks at a molecular and cellular level may drive and/or maintain IMIDs, being “shared” between traditionally distinct diagnoses without mapping neatly to a single clinical phenotype. In line with this proposition, integrative tumour tissue analyses in oncology have highlighted novel cell states acting across diverse cancers, with important implications for precision medicine. Drawing upon advances in the oncology field, this narrative review will first summarise learnings from the Human Cell Atlas in health as a platform for interrogating IMID tissues. It will then review cross-disease studies to date that inform this endeavour, before considering future directions in the field.

A monocular vision pose estimation and identification algorithm used on a small spacecraft for future orbital servicing is studied in this paper. A tracker spacecraft equipped with a short-range vision system is proposed to recover the 3D structural model of a space target in orbit and automatically identify its solar panels and main body using only visual information from an onboard camera. The proposed reconstruction and identification framework is tested using structure-from-motion and point cloud identification methods. The Efficient Perspective-n-Points (EPnP) descriptor is used for pose estimation. Triangulated points are used for component segmentation by means of orientation histogram descriptors. Experimental results based on laboratory images of a spacecraft model show the effectiveness and robustness of our approach.

Our environment has been impacted by man-made pollutants mainly industries make substantial use of synthetic dyes which exhibit cytotoxicity and have significant environmental consequences. Effective photocatalyst-based approaches for degrading synthetic dyes into less toxic chemical are of great interest. Synthesizing NPs using biological approaches, particularly plant-based approaches offer advantages, decreasing the risk of NPs losing biocompatibility during synthesis, cost-effectiveness, and eco-friendliness. In this study, we employed a green synthesis method to produce manganese oxide nanoparticles (MnO NPs) utilizing leaf extract from the Lathyrus Aphaca plant. The synthesized MnOx NPs were characterized through various techniques; X-ray diffraction (XRD), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), Fourier-transform infrared spectroscopy (FTIR), and UV–visible spectroscopy. XRD analysis showed distinct peaks, indicated the presence crystallographic planes within the MnO₂ nanoparticles, thus confirming their crystalline structure. SEM study highlighted closely packed configurations with average size of approximately ≥ 50-70 nm, with well-defined boundaries. EDX analysis showed the presence of elemental manganese (Mn) in the samples, with peaks corresponding to Mn detected at lower energy levels, predominantly represented by MnO. FTIR, showed the presence of the O-O stretching mode at a frequency of 719 cm^-1, the presence of MnO₆ oxides of manganese, and peak at 548 cm^-1 corresponded to the Mn-O stretching mode. Furthermore, the green-synthesized manganese oxide nanoparticles exhibited promising photocatalytic and adsorption capabilities against Methylene Blue (MB) dye, leading to approximately 93.21% degradation of MB when treated with the green-synthesized MnO nanoparticles derived from plant extract. This highlights the efficacy and potential of these nanoparticles in environmental remediation applications, particularly in the degradation of methylene blue contaminants.

Core chlorophytes possess glycerol-3-phosphate dehydrogenases (GPDs) with an unusual bidomain structure, consisting of a glycerol-3-phosphate phosphatase (GPP) domain fused to canonical GPD domains. These plastid-localized enzymes have been implicated in stress responses, being required for the synthesis of glycerol under high salinity and triacylglycerols under nutrient deprivation. However, their regulation under varying environmental conditions is poorly understood. C. reinhardtii transgenic strains expressing constitutively bidomain GPD2 did not accumulate glycerol or triacylglycerols in the absence of any environmental stress. Although, the glycerol contents of both wild type and transgenic strains increased significantly upon exposure to high salinity. Cycloheximide, an inhibitor of cytoplasmic protein synthesis, abolished this response in the wild type. In contrast, GPD2 transgenic strains were still capable of glycerol accumulation when cultured in medium containing cycloheximide and NaCl. Thus, pre-existing GPD2 protein appears to become activated for glycerol synthesis upon salt stress. Interestingly, staurosporine, a non-specific inhibitor of protein kinases, prevented this post-translational GPD2 protein activation. Structural modeling analyses suggested that substantial conformational rearrangements, possibly triggered by high salinity, may characterize an active GPD2 GPP domain. Understanding this mechanism(s) may provide insights into the rapid acclimation responses of microalgae to osmotic/salinity stress.

Advanced glycation end-products (AGEs) form through non-enzymatic glycation of various proteins. Optic nerve degeneration is a frequent complication of diabetes, and retinal AGEs accumulation is strongly linked to diabetic retinopathy development. Type 2 diabetes mellitus (T2DM) is a major risk factor for Alzheimer's disease (AD), with patients often exhibiting optic axon degeneration in the nerve fiber layer. Notably, a gap exists in our understanding of how AGEs contribute to neuronal degeneration in the optic nerve within the context of both diabetes and AD. Our previous work demonstrated that glyceraldehyde (GA)-derived toxic advanced glycation end-products (TAGE) disrupt neurite outgrowth through TAGE-β-tubulin aggregation and tau phosphorylation in neural cultures. In this study, we further illustrated GA-induced suppression of optic nerve axonal elongation via abnormal β-tubulin aggregation in mouse retinas. Elucidating this optic nerve degeneration mechanism holds promise for bridging the knowledge gap regarding vision loss associated with DM and AD.

This article describes the POTENTIALS project, which aimed to develop business models for the reuse of former industrial and mining sites in different regions. The project focused on the creation of eco-industrial parks as a result to enable sustainable energy production and reduce waste and pollution. A key aspect was the Territorial Impact Assessment (TIA), a new and complex policy assessment tool. Therefore, the TEQUILA (Territorial Efficiency Quality and Identity Layer Assessment) approach is used to describe the TIA and emphasizes its application in assessing the impact of EU policies and projects on territorial cohesion. It underlines the need for a differentiated understanding of the regional characteristics and potential impacts of policies; and stresses the importance of regionalized impact models for the assessment. Furthermore, the process and results of applying the TEQUILA methodology to assess the territorial impact of different scenarios of business models within the POTENTIALS project is given.

ADHD is a neurodevelopmental disorder that children and also adults can develop. A complex interplay of genetic and environmental factors may underlie interindividual variability in ADHD and potentially related aggressive behavior. Using high-resolution molecular biology techniques, we investigated the impact of some MAOA and SLC6A4 variations on ADHD and aggressive behavior in a group of 80 Italian children with ADHD and in 80 healthy controls.We found that homozygous genotypes of MAOA rs6323 and rs1137070 were associated with an increased risk of ADHD (p=0.02 and p=0.03, respectively), instead the heterozygous genotypes (GT of rs6323 and CT of rs1137030) (p=0.0002 and p=0.0006) were strongly linked to a lower risk of developing this disorder. In patients with aggressive behavior, we highligted only a weak negative association of both MAOA polymorphisms (heterozygous genotypes) with aggressiveness then, suggesting that these genotypes maybe protective towards specific changes in behavior (p=0.05). Interestingly, an increase of the GG genotype of rs6323 (p=0.01) and a decrease of GT genotype (p=0.0005) was also found in patients without aggressive behavior compared with controls. Regarding 5HTT gene genotyping, no allele and genotype differences have been detected among patients and controls. Our work shows that defining a genetic profile of ADHD may help to early detect those patients who are more vulnerable to ADHD and/or antisocial and aggressive behavior and to design precision-targeted therapies.

The accumulation of brown algae from the genus Sargassum has been increasing over the years in coastal regions of the Caribbean, Africa, Brazil, and Mexico. This causes harmful effects to the ecosystem, health, economy, and climate due to gas emissions from its decomposition process. There is the possibility of this biomass being reused in civil construction, and few studies have been carried out on its application to common Portland cement mortar. As such, the objective of this study is to evaluate the potential of sargassum ash as a mineral addition to partial replacement of fine aggregates in Portland cement mortar. Characterizations of the raw materials were carried out through X-ray fluorescence spectroscopy, loss on ignition, particle size distribution, Brunauer–Emmett–Teller (BET), real density, X-ray diffraction, scanning electron microscopy, and dispersion spectroscopy of electrons. The mortars were prepared by partially replacing the fine aggregate (sand) with sargassum ash, at 0%, 5%, 10% and 20%. Mortar performance was evaluated through water absorption, apparent porosity, apparent specific mass, compressive strength after 7, 28, and 63 days after curing. Lastly, a life cycle assessment in accordance with ISO standards 14040:2006 and 14044:2006. The results showed that replacing sand with sargassum ash increases water absorption, apparent porosity, and decreases the apparent specific mass and compressive strength as replacement increases. Nevertheless, the compressive strength results after 63 days, for 5 and 10% replacement did not differ statistically from reference values. The life cycle assessment indicates that mortars with partial replacement of sand by sargassum ash showed positive environmental impacts when compared to reference values for most categories regardless of the scenario analyzed, especially for mortar with 10% replacement. As such, the use of sargassum ash at 10% does not alter compressive strength values after 63 days while reducing its environmental impact. The application of this biomass in civil construction materials provides a destination for this algae that has been causing several social, environmental, and economic problems.

Correlations among estrus cycle, pyometra, and canine diabetes mellitus (CDM) have been described since the late 1950s, and substantial progress in understanding mechanisms beyond was achieved nowadays. Progesterone-related diabetes mellitus (PRDM) in dogs is known for its particular potential for diabetes remission. Thus, a deep understanding of the physiopathological aspects involved is crucial to postulate treatment guidelines to improve the PRDM remission rate, as well as to inform preventive measures. This narrative review aims to provide relevant detailed information on 1) canine estrus cycle and its impact on CDM etiology and management, 2) the role of pyometra as a further cause of insulin resistance, and 3) useful individual therapeutic and preventive strategies. Pharmacological annulment of progesterone effects, as well as inflammatory and progesterone-related conditions resolution in association with adequate exogenous insulin therapy, and residual beta cell function, are key aspects to achieve remission, or at least to improve diabetic clinical control. In this way, spaying should be considered mandatory in most PRDM cases. Preventive measures against CDM can include spaying recommendations; however, individual-based recommendations should be considered since castration may be associated with some long-term health issues.

Recurrent pregnancy loss (RPL) affects around 2 % of women of reproductive age. Primary RPL is defined by ≥2 pregnancy losses and no normal birth delivery. In secondary RPL, the losses are after a normal pregnancy and delivery. Most cases have no clear aetiology, although primary cases are the most complex. Several gene polymorphisms have been associated with RPL. Some polymorphisms are increased in women of Asian or Caucasian race. In admixed RPL populations, the information on possible genetic links is scarce and contradictory. The study aimed to assess the frequency of two SNP in different enzymes involved in medical conditions observed during pregnancy. Microsomal epoxy hydrolase (mEPH) is involved in detoxifying xenobiotics. It is present in ovaries, and it is hormonally regulated. The endothelial nitric oxide synthase forms nitric oxide from arginine and is involved in vascular tone. Two SNPs, rs1051740 and rs1799983, were assessed. The study included 26 controls and 63 primary RPL patients. Significant differences were observed in the frequencies of both SNP (p<0.05). The frequency of mutated alleles was higher in patients. Double mutated homozygotes were encountered only in RLP patients (p<0.05). Genetic polymorphisms rs1051740 and rs1799983 may be involved in primary RPL in the Venezuelan admix population. Genetic studies could provide crucial information on the aetiology of primary RPL.

The success of Toxoplasma gondii (intracellular parasite) host cell invasion relies on the apical complex, a specialized microtubule cytoskeleton structure associated with secretory organelles. The genome encodes three isoforms of both α- and β-tubulin which are altered by specific post-translational modifications (PTMs), changing the biochemical/biophysical proprieties of microtubules, and modulating their interaction with associated proteins. Tubulin PTMs are a powerful and evolutionarily conserved mechanism to generate tubulin diversity, forming a biochemical ‘tubulin code’ that can be ‘read’ by microtubule-interacting factors. The T. gondii tubulin PTMs are: α-tubulin acetylation, α-tubulin detyrosination, Δ5α-tubulin, Δ2α-tubulin, α- and β-tubulin polyglutamylation, and α- and α-tubulin methylation. Tubulin glutamylation is a key candidate to assist microtubule remodeling in Toxoplasma, being involved in the regulation of microtubule stability, dynamics, interaction with motor proteins, and severing enzymes. The correct balance of tubulin glutamylation is achieved by the coordinated action of polyglutamylases and deglutamylating enzymes. In this work we will review and discuss the current knowledge on T. gondii tubulin glutamylation. By in silico identification of mammalian protein orthologs we explored and updated the identification of putative proteins related to glutamylation, contributing to a better understanding of the role of tubulin glutamylation in T. gondii.

Sporotrichosis’ clinical manifestations, lesions in the cutaneous or subcutaneous tissues, it is caused by dimorphic fungi of the Sporothrix complex, is a cosmopolitan mycosis that affects humans and animals. This study aimed to identify prevalent species in Minas Gerais, Brazil, and characterize virulence profiles and antifungal susceptibility associated with Sporothrix isolates. Isolates were identified using macro and micro-morphological traits as well molecular biology techniques. Antifungal susceptibility was determined using the Minimal Inhibitory Concentration test, while, virulence factors such as growth at different temperatures, biofilm formation, melanin production, and urease activity were assessed. Our findings revealed S. brasiliensis as a predominant species isolated. Urease activity was a crucial factor associated with growth at 50°C in S. brasiliensis isolates, highlighting their high thermotolerance. Furthermore, strains isolated from humans produced a more robust biofilm compare to those from felines. Strains of S. brasiliensis isolated from Felis catus exhibited faster melanin production, decreased susceptible to antifungal agents tested, and superior growth capacity at 50°C to strains isolated from humans. Therefore, our study highlights the prevalence of S. brasiliensis causing sporotrichosis in both human and felines. However, it underscores the circulation of different strains, with varying levels of virulence and susceptibility to antifungal agents.

Human osteosarcoma (OS) is a rare tumor predominantly affecting long bones and characterized by a poor prognosis. Currently, the first line of intervention consists of surgical resection of primary tumors combined with radiotherapy and chemotherapy, with a profound impact on patient’s life. Since surgical removal of OS frequently results in large resection of bones the use of biomaterials to sustain the stability of remaining tissue and to stimulate bone regeneration is challenging. Moreover, residual neoplastic cells might be responsible for tumor recurrence. Here we explored the potential of doped-bioactive glass as novel therapeutic intervention to both eradicate residual malignant cells and promote bone regeneration. Bioactive glass (BAG) has been extensively studied and employed in the field of regenerative medicine, due to its osseointegration properties and ability to improve bone tissue regeneration. We found that the incorporation of tellurium in BAG selectively kills OS cells through ferroptosis while preserving the viability of hBMSCs, and stimulating their osteodifferentiation. Although the mechanism of Te toxicity is still unclear: i) Te-BAG generates lipid-ROS through LOXs activity but not iron overload; ii) Te-dependent ferroptosis is mediated by GPX4 down-regulation, and iv) abrogates the anti-ferroptotic activity of FSP1, which expression confers resistance of OS to canonical induction of ferroptosis.

We report the application of a recently proposed approach for modeling biological systems using a maximum entropy production rate principle in lieu of having in vivo rate constants. The method is applied in four steps: (1) a new ODE-based optimization approach based on Marcelin’s 1910 mass action equation is used to obtain the maximum entropy distribution, (2) the predicted metabolite concentrations are compared to those generally expected from experiment using a loss function from which post-translational regulation of enzymes is inferred, (3) the system is re-optimized with the inferred regulation from which rate constants are determined from the metabolite concentrations and reaction fluxes, and finally (4) a full ODE-based, mass action simulation with rate parameters and allosteric regulation is obtained. From the last step, the power characteristics and resistance of each reaction can be determined. The method is applied to the central metabolism of Neurospora crassa and the flow of material through the three competing pathways of upper glycolysis, the non-oxidative pentose phosphate pathway, and the oxidative pentose phosphate pathway are evaluated as a function of the NADP/NADPH ratio. It is predicted that regulation of phosphofructokinase (PFK) and flow through the pentose phosphate pathway are essential for preventing an extreme level of fructose 1, 6-bisphophate accumulation. Such an extreme level of fructose 1,6-bisphophate would otherwise result in a glassy cytoplasm with limited diffusion, dramatically decreasing the entropy and energy production rate and, consequently, biological competitiveness.

Objectives: To evaluate the effectiveness of hydrogen peroxide (HP) use in the hospital water network disinfection to control Legionella spp. colonization. Methods: Following the detection of high levels of Legionella contamination in a 136-bed general hospital water network, an HP treatment of the hot water (25 mg/L) was adopted. During a period of 34 months, the effectiveness of HP on Legionella colonization was assessed. Legionella was isolated in accordance with ISO-11731 and identification was carried out by sequencing of the mip gene. Results: Before HP treatment L.pneumophila sg 2-15 was isolated in all sites with a mean count of 9950±8279 CFU/L. After one month of HP-treatment, we observed the disappearance of L. pneumophila 2-15, however other Legionella species never cultured before appeared; Legionella pneumophila 1 was isolated in 1 out of 4 sampling sites (2,000 CFU/L) and other non-pneumophila species in all sites (mean load 3,000 ±2887 CFU/L). Starting from September 2013, HP-treatment was modified adding food-grade polyphosphates and in the following months we observed a progressive reduction of the mean load of all species (p<0.05), until to a substantial disappearing of Legionella colonization. Conclusion: Hydrogen peroxide demonstrated a good efficacy in controlling Legionella. Although in the initial phases of treatment it seemed unable to eliminate all the species, by keeping HP levels to 25 mg/L and adding food-grade polyphosphates, a progressive and complete control of colonisation was obtained.

The editorial explores the realm of emerging translational research in neurology and psychiatry, providing insights into various subjects, including neurodegenerative disorders and innovative therapeutic methods. The main objective is to study neurological and psychiatric disorders, such as Alzheimer's disease, with a particular emphasis on techniques for neural regeneration and repair. The editorial highlights the importance of taking a comprehensive approach to studying and treating complex neurological and psychiatric conditions. This involves thoroughly reviewing research papers on the causes, development, biomarkers, and treatment options for these conditions. The editorial emphasizes the necessity of using multidisciplinary and integrative methods to gain a deeper understanding and improve the treatment of these conditions. The development of an animal model for recurrent primary dysmenorrhea showcases the innovative techniques employed in the investigation of gynecological disorders, illustrating the capacity of translational research to connect fundamental scientific knowledge with practical medical applications. The cooperative endeavors of researchers and clinicians emphasized in this editorial lay the foundation for revolutionary advancements that hold the potential to enhance outcomes for individuals afflicted with neurological and psychiatric disorders globally.

Tubulin superfamily (TSF) proteins are widespread and known for multifaceted roles as cytoskeletal proteins underpinning many basic cellular functions including morphogenesis, division, and motility. In eukaryotes, tubulin assembles into microtubules, a major component of the dynamic cytoskeletal network of fibres, whereas the bacterial homolog FtsZ assembles the division ring at midcell. Functions of the lesser-known archaeal TSF proteins are beginning to be identified, and show surprising diversity, including homologs of tubulin and FtsZ, and a third archaea-specific family, CetZ, implicated in the regulation of cell shape and possibly other unknown functions. In this study, we defined sequence and structural characteristics of the CetZ family and CetZ1 and CetZ2 subfamilies, identified CetZ groups and diversity amongst archaea, and identified potential functional relationships through analysis of the genomic neighbourhoods of cetZ genes. At least three subfamilies of orthologous CetZ proteins were identified in the archaeal class Halobacteria, including CetZ1 and CetZ2 and a novel uncharacterized subfamily. CetZ1 and CetZ2 were correlated to one another and to cell shape and motility phenotypes across diverse Halobacteria. Amongst other known CetZ clusters in orders Archaeoglobales, Methanomicrobiales, Methanosarcinales, and Thermococcales, an additional uncharacterized group from Archaeoglobales and Methanomicrobiales affiliated strongly with Halobacteria CetZs, suggesting they originated via horizontal transfer. Subgroups of Halobacteria CetZ2 and Thermococcales CetZ genes were found adjacent to different type IV pili regulons, suggesting a potential utilization of CetZs by type IV systems. More broadly conserved cetZ gene neighbourhoods included nucleotide and cofactor biosynthesis (e.g., F420) and predicted cell surface sugar epimerase genes. The findings imply that CetZ subfamilies are involved in multiple functions linked to the cell surface, biosynthesis and motility.

Bosentan, an endothelin-receptor antagonist (ERA), has potential anti-atherosclerotic properties. We investigated the complementary effects of bosentan and atorvastatin on the progression and composition of the atherosclerotic lesions in diabetic mice. Forty-eight male apoE-/- mice were fed high-fat diet (HFD) for 14 weeks. At week 8, diabetes was induced with streptozotocin and mice were randomized into 4 groups: 1) Control/COG: no intervention. 2) ΒΟG: bosentan 100 mg/kg/day per os. 3) ATG: atorvastatin 20mg/kg/day per os). 4) BO+ATG: Combined administration of bosentan and atorvastatin. The intra-plaque contents of collagen, elastin, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-a (TNF-a), matrix-metalloproteinases (MMP-2,-3,-9), and TIMP-1 concentrations were determined. The percentage of lumen stenosis significantly decreased across all treated groups: BOG: 19.5±2.2%, ATG: 12.8±4.8%, BO+ATG: 9.1±2.7% compared to controls (24.6±4.8%, p&lt;0.001). Both atorvastatin and bosentan significantly increased collagen content and fibrous cap thickness versus COG (p&lt;0.01). All intervention groups reduced the relative intra-plaque concentrations of MCP-1, MMP-3,-9, and increased TIMP-1 compared to COG (p&lt;0.001). Importantly, bosentan showed modest but additive to atorvastatin effects on the latter parameters compared COG (p&lt;0.05). Bosentan treatment in diabetic, atherosclerotic apoE-/- mice delayed the atherosclerosis progression and enhanced plaques’ stability, showing modest but complementary effects with atorvastatin, which are promising in atherosclerotic cardiovascular diseases.

Glioblastoma (GBL) is one of the more malignant primary brain tumors, currently treated by a multimodality strategy including surgery, radio- and chemotherapy, mainly consisting of Temozolomide(TMZ)-based chemotherapy. Tumor relapse often occurs due to the establishment of TMZ resistance, with a patient median survival <2 years. The identification of natural molecules having strong anti-tumor activity, led to combine these compounds with conventional chemotherapeutic agents, developing protocols of integrated anticancer therapies. Curcumin (CUR), Resveratrol (RES), and its glucoside Polydatin (PLD) are widely employed in the pharmaceutical and nutraceutical fields, and several studies demonstrated that the combination of these natural products was more cytotoxic than the single compound alone in different cancers. Some of us recently demonstrated the synergistic efficacy of the sublingual administration of a new nutraceutical formulation of CUR+PLD in reducing tumor size and improving GBL patient survival. To deepen some mechanistic aspects of these results, we investigated if the pretreatment with a combination of CUR+PLD, can improve TMZ cytotoxicity on GBL cells, by analyzing the effects on cell cycle, viability and morphology, on proteins related to cell proliferation, differentiation, apoptosis or autophagy, and on actin network. Cell viability was assessed by MTT or by the cell counter CytoSmart. CalcuSyn software was used to study the CUR+PLD synergism. Morphology was evaluated by optical and scanning electron microscopy, and protein expression was analyzed by Western Blot. Flow cytometry was used for cell cycle, autophagic flux, and apoptosis analyses. The results obtained provide evidence that CUR and PLD, acting in synergy with each other, strongly improve the efficacy of alkylating antitumor agents such as TMZ, also in drug-resistant GBL cells, through their abilities to affect survival, differentiation, and tumor invasiveness.

The main goal of optimization is to find factors values that bring minimum feedstock consumption or maximum final product or services of the production process. In a production process, the factors that make up the model that describes it are usually the properties of the final product. In the case of biodiesel, which is the final product of the process that is the object of study, among the various properties, the glycerol content is among the most important. The present study aims to maximize the model yield that defines glycerol content on the biodiesel composition. This optimization was executed by a hybrid metaheuristic algorithm (SAGAC),and its experimental results are compared with other optimization techniques named by RSM (Response Surface Methodology). After run the experimental assays, SAGAC algorithm has find the follow values of model factors: molar ratio = 3(mol/mol), catalyst content = 0.52 (wt%), reaction temperature = 49(^oC), Time = 45 (min) generating model yield of 14.46 that, match with EN 14105 standard value of 0.33 (wt%). Comparing results between SAGAC and RSM methodologies, SAGAC has presented an improvement of 31%.

It has been suggested that parasitic infections, common in Latin American populations, may amplify the inflammatory response of the airways. There are several reports in atopic and asthmatic patients, but few reports of parasitic infection in COPD patients. The study aimed to determine the prevalence of parasitic infections in COPD patients as compared to atopic and asthmatic patients attending the outpatient clinics of the Institute of Immunology and the pneumonology service of the University hospital. A case-control study was conducted: 100 patients with bronchial asthma, 100 patients with COPD, 100 individuals with atopy without respiratory symptoms, and 100 healthy individuals. Serum specific IgG antibody against the parasites Ascaris lumbricoides (Al), Strongyloides stercolaris (Ss) and Toxocara canis (Tc) were measured: by ELISA. IgE levels were used as an indirect indicator of atopy. Positive IgG for Al was observed in all groups, predominantly in atopic cohort, Ss positiveness was recorded only in 4 COPD patients and Tc positiveness was observed in all groups except in controls. There are significant correlations between the values of Al and IgE in controls, atopic and asthmatic patients not with COPD. No correlation was found for Tc. IgE levels and FEV1 correlate only in atopic and asthmatic patients. Parasitic infections are common in atopic patients and in moderate and severe asthmatic and COPD patients. Anti-inflammatory treatment may be responsible for the increase frequency of infection.

There has been significant increase of studies investigating plasma biomarkers of Alzheimer’s and their relationship to cognitive functioning. The impact of ethnicity on this relationship has not been extensively studied. The current research investigated the relationship between the plasma biomarkers of total tau, Aβ40, Aβ42 and NfL and neuropsychological test performance in a bi-ethnic sample of cognitively unimpaired, older community dwelling adults. The 1326 cognitively unimpaired participants drawn from The Health & Aging Brain Study – Health Disparities (HABS-HD) study included 765 Mexican American participants and 860 non-Hispanic White participants with complete plasma biomarkers and neuropsychological testing. Plasma samples were assayed using Simoa technology. Significant differences in concentrations were found for all of the plasma biomarkers. NHWs had significantly higher levels of each of the biomarkers with a lower Aβ42/ Aβ40. With none of the biomarkers related to performance on any of the neuropsychological tests. For MAs, Aβ40 was the only biomarker that was significantly related to neuropsychological test performance. Aβ40 levels were negatively related to performance on Trails A, Trails B and Digit Symbol Substitution. Results suggest that the relationship of these biomarkers to cognitive functioning is impacted by ethnicity and may be domain specific.

Background: Ensemble tree-based models such as Xgboost are highly prognostic in cardiovascular medicine, as measured by the Clinical Effectiveness Metric (CEM). However, their ability to handle correlated data, such as hospital-level effects, are limited. Objectives: The aim of this work is to develop a binary outcome mixed effects Xgboost (BME) model that integrates random effects at the hospital level. To ascertain how well the model handles correlated data in cardiovascular outcomes, we aims to assess its performance and compare it to fixed effects Xgboost and traditional logistic regression models. Methods: A total of 227,087 patients over 17 years of age, undergoing cardiac surgery from 42 UK hospitals between 1 Jan 2012 and 31 Mar 2019 were included. The dataset was split into two cohorts: Training/Validation (n = 157196; 2012-2016) and Holdout (n = 69891; 2017-2019). The outcome variable was 30 days mortality with hospitals considered as clustering variable. The logistic regression, mixed effects logistic regression, Xgboost and binary outcome mixed effects Xgboost (BME) were fitted to both standardized and unstandardized datasets across a range of sample sizes and the estimated prediction power metrics were compared to identify the best approach. Results: The exploratory study found high variability in hospital-related mortality across datasets, which supported the adoption of mixed effects models. Unstandardized Xgboost BME demonstrated marked improvements in predictor power over the Xgboost model at small sample size ranges, but performance differences decreased as dataset sizes increased. Generalized linear models (glm) and generalized linear mixed-effects models (glmer) models followed similar results, with Xgboost models excelling also at greater sample sizes. Conclusions: These findings suggest that integrating mixed effects into machine learning models can enhance their applicability in clinical settings where sample size is small such as rare conditions.

Protein tyrosine phosphatase receptor type E (PTPRE) is a member of the “classical” protein tyrosine phosphatase subfamily and regulates a variety of cellular processes in a tissue-specific manner by antagonizing the function of protein tyrosine kinases. PTPRE plays a tumorigenic role in different human cancer cells, but its role in retinoblastoma (RB), the most common malignant eye cancer in children, remains to be elucidated. Etoposide resistant RB cell lines and RB patients display significant higher PTPRE expression levels compared to chemosensitive counterparts and the healthy human retina, respectively. PTPRE promotor methylation analyses revealed that PTPRE expression in RB is not regulated via this mechanism. Lentiviral PTPRE knockdown (KD) induced a significant decrease in growth kinetics, cell viability, and anchorage independent growth of etoposide resistant Y79 and WERI RB cells. Caspase-dependent apoptosis rates were significantly increased and a re-sensitization for etoposide could be observed after PTPRE depletion. In vivo chicken chorioallantoic membrane (CAM) assays revealed decreased tumor formation capacity as well as reduced tumor size and weight following PTPRE KD. Expression levels of miR631 were significantly downregulated in etoposide resistant RB cells and patients. Transient miR631 overexpression resulted in significantly decreased PTPRE levels and concomitantly decreased proliferation and increased apoptosis levels in etoposide resistant RB cells, impacts mirroring PTPRE KD effects and indicating PTPRE regulation via this miR. Additionally, PTPRE KD led to altered phosphorylation of protein kinase SGK3 and - dependent on the cell line - also AKT and ERK1/2, suggesting potential PTPRE downstream signaling pathways. In summary, these results indicate an oncogenic role of PTPRE in chemoresistant retinoblastoma.

Plants are exposed to highly fluctuating effects of light, temperature, weather conditions and many other environmental factors throughout their life. As sessile or-ganisms, unlike animals, they are unable to escape, hide or even change their position. Therefore, the growth and development of plants is largely determined by interaction with the external environment, the success of this interaction depends on the ability of the phenotype plasticity, which is largely determined by epigenetic regulation. In addi-tion to how environmental factors can change the patterns of genes expression, epige-netic regulation determines how genetic expression changes during the differentiation of one cell type into another, and how patterns of gene expression are passed from one cell to its descendants. Thus, one genome can generate many 'epigenomes'. Epigenetic modifications acquire special significance during the formation of gametes and plant reproduction, when epigenetic marks are eliminated during meiosis and early embry-ogenesis and later reappear. However, during asexual plant reproduction, when meio-sis is absent or suspended, epigenetic modifications that have arisen in the parental sporophyte can be transmitted to the next clonal generation practically unchanged. In plants that reproduce sexually and asexually, epigenetic variability has different adap-tive significance. In asexuals, epigenetic regulation is of particular importance for im-parting plasticity to the phenotype, when the genotype remains unchanged for many generations of individuals. Of particular interest is the question of the possibility of transferring acquired epigenetic memory to future generations and its potential role for natural selection and evolution. All these issues will be discussed to some extent in this review. In the last two decades, a lot of data on the epigenetic regulation of plants has appeared, as well as works summarizing the accumulated knowledge (Verhoeven and Preite 2013; Pikaard and Scheid 2014; Gehring 2019; Ono and Kinoshita 2021), nevertheless, many questions remain unclear, and a number of results are contradic-tory. New in this area data is constantly emerging. We tried to take into account and discuss the main findings and conclusions in this field.

Trace amines are a separate, independent group of biogenic amines, close in structure to classical monoamine neurotransmitters such as dopamine, serotonin and norepinephrine. G protein-coupled Trace Amine-Associated Receptors (TAAR) are mostly investigated for their involvement in the pathogenesis of neuropsychiatric disorders, but expression of TAAR family receptors is observed also in various populations of cells of the immune system. The review is focused on the basic information on the interaction of trace amines and their receptors with cells of the general immune system of humans and other mammals, as well as on data on TAARs role in the function of individual populations of myeloid and lymphoid cells. With further research on the regulatory role of the trace amine system in the pathogenesis of the immune response and determination of the biological mechanisms for their action it would be possible to develop new methods for treating diseases related to immune system dysfunctions.

Ferroptosis, a regulated form of cell death characterized by iron-dependent lipid peroxide accumulation, plays a pivotal role in various pathological conditions, including neurodegenerative diseases. While reasonable evidence for ferroptosis exist e.g. in Parkinson’s disease or Alzheimer’s disease, there are only few reports on amyotrophic lateral sclerosis (ALS), a fast progressive and incurable neurodegenerative disorder characterized by progressive motor neuron degeneration. Initial studies, however, highlight that ferroptosis might be significantly involved in ALS. Key features of ferroptosis include oxidative stress, glutathione depletion, mitochondrial and dysfunction alterations in mitochondrial morphology, mediated by proteins such as GPX4, xCT, ACSL4 FSP1, Nrf2 and TfR1. Induction of ferroptosis involves small molecule compounds like erastin and RSL3, which disrupt system Xc- and GPX4 activity, respectively, yielding in lipid peroxidation and cellular demise. Mutations in Fused in Sarcoma (FUS) are associated with familial ALS. Pathophysiological hallmarks of FUS-ALS involve mitochondrial dysfunction and oxidative damage, implicating ferroptosis as putative cell death pathway in motor neuron demise. However, mechanistic understanding of ferroptosis in ALS, particularly FUS-ALS, remains limited. Here, we investigated ferroptosis vulnerability in a FUS-ALS cell model, revealing mitochondrial disturbance and increased susceptibility for ferroptosis in cells harboring the mutant FUS variant. This was accompanied by altered expression of ferroptosis-associated proteins, particularly by dramatic reduction of xCT expression, leading to cellular imbalance of the redox system and increased lipid peroxidation. Iron chelation with deferoxamine as well as inhibition of the mitochondrial calcium uniporter (MCU) significantly alleviated ferroptotic cell death and lipid peroxidation. These findings suggest a link between ferroptosis and FUS-ALS, offering potential therapeutic targets.

The huge advancement of Internet web facilities as well as the progress in computing and algorithm development, along with current innovations regarding high-throughput techniques enables the scientific community to gain access to biological datasets, clinical data, and several databases containing billions of information concerning scientific knowledge. Consequently, during the last decade the system for managing, analyzing, processing and extrapolating information from scientific data has been considerably modified in several fields including the medical one. As a consequence of the mentioned scenario, scientific vocabulary was enriched by novel lexicons such as Machine Learning (ML)/Deep Learning (DL) and overall Artificial Intelligence (AI). Beyond the terminology, these computational techniques are revolutionizing the scientific research in drug discovery pitch, from the preclinical studies to clinical investigation. Interestingly, between preclinical and clinical research, the translational research is benefitting from computer-based approaches, transforming the design and execution of the translational research, resulting in breakthroughs for advancing human health. Accordingly, in this review article, we analyze the most advanced applications of AI in translational medicine, providing an up-to-date outlook regarding this emerging field.

After decades of studies, the pathogenesis of Autism Spectrum Disorder (ASD) remains unclear and there still lackseffective treatment strategies for core symptoms. Our recent work, combined with others’ research in a diversity ofmodels and clinical trials, suggested a concise, but potentially rational theory that can illustrate the key of the pathogenesis and treatment of ASD from the aspect of damage control.

Lithium is the superior first-line treatment for bipolar disorder (BD). Yet the percentage of patients receiving lithium is abysmally low, especially in the USA. Since psychiatrists have failed to place lithium in its appropriate role, we make the case that patients with BD themselves need to be better educated about the unique characteristics and preeminence of the drug so that it can be used more often and appropriately. Lithium has a highly unfavorable popular reputation among would-be patients and many psychiatrists. Thus, a direct appeal to patients with BD appears appropriate to try to remediate this situation. The unique assets of lithium are underappreciated or not well known. Conversely, the side effects profile of lithium are overestimated. Here, we make the case that lithium’s image needs to be revised not only with better and more accurate information but with a wholesale re-naming and rebranding of the drug. We will not only outline the unique qualities and new information about the side effects of the drug but attempt to change some of the terminology conventionally used to refer to lithium so that its use may be appropriately applied earlier and at an increased frequency for patients with BD.

(1) Background: In this work, a series of benzimidazole derivatives containing colchicine-like and cathechol-like moieties with methyl group substitution in the benzimidazole ring were evaluated for their in vitro antiproliferative, pro-apoptotic and antioxidative activity against highly invasive breast cancer cell line MDA-MB-231 and related impairment of tubulin dynamics; (2) Methods: MTT assay was used to evaluate the antiproliferative activity. In vitro tubulin polymerization assay as well as docking analysis was applied to prove the alterations in tubulin polymerization. Immunofluorescent and DAPI staining reveal the pro-apoptotic potential of benzimidazole derivatives and the effect on tubulin’s dynamics in living cells. The antioxidant activity was evaluated by scavenging of H2O2 and hypochlorite ion and ortho-phenanthroline tests; (3) Results: The compounds containing colchicine-like moiety displayed significant growth inhibitory effect against cancer cell line as was highlighted the role of methyl functional group on the tubulin aggregation and blockage of mitosis. All compounds showed an ability to scavenge H2O2, while the compounds with cathecol-like moiety were more effective against hypochlorite ion and chelation of iron; (4) Conclusions: The benzimidazole derivative containing colchicine-like moiety and methyl group substitution in benzimidazole ring is a potential antiproliferative and microtubule destabilizing agent.

More than 90 different modified nucleosides have been identified in tRNA. Among the tRNA modifications, the 7-methylguanosine (m⁷G) modification is found widely in eubacteria, eukaryotes, and a few archaea. In most cases, the m⁷G modification occurs at position 46 in the variable region and is a product of tRNA (m⁷G46) methyltransferase. The m⁷G46 modification forms a tertiary base pair with C13-G22, and stabilizes the tRNA structure. Recently, we have proposed a reaction mechanism for eubacterial tRNA m⁷G methyltransferase (TrmB) based on the results of biochemical studies and previous biochemical, bioinformatic, and structural studies by others. However, an experimentally determined mechanism of methyl-transfer remains to be ascertained. The physiological functions of m⁷G46 in tRNA have started to be determined over the past decade. To be able to better respond to diseases and infections in which the m⁷G modification is considered to be involved, it is still necessary to further understand the catalytic mechanism of AdoMet and/or the tRNA bound form of m⁷G methyltransferases. In this review, information of tRNA m⁷G modifications and tRNA m⁷G methyltransferases are summarized and the differences in reaction mechanism between tRNA m⁷G methyltransferase and rRNA or mRNA m⁷G methylation enzyme are discussed.

Among bryophytes, the Plagiochila genus represents a large group of leafy liverworts, with over 500 species. Plagiochilins A-to-X are sesquiterpenoids isolated from Plagiochila species. The lead compound plagiochilin A (Plg-A), endowed with anticancer and anti-parasitic properties, has been characterized as a potent mitosis inhibitor, acting selectively at the late stage of cytokinesis termed abscission. The compound perturbs the dynamic of microtubules, blocking cell cycle progression and triggering the death of malignant cells. Based on the compound mechanism of action and the analogy with other natural products bearing a dihydro-pyrone moiety, we postulated that Plg-A could bind to the pironetin site of α-tubulin. A molecular docking analysis has been performed to compare binding of all 24 plagiochilins to α-tubulin and to establish structure-binding relationships. The identification of Plg-E and Plg-G as the best binders in the series pointed out to the importance of the C13-OH or C=O group for α-tubulin recognition. This observation led to the testing of the natural product ester plagiochilin A-15-yl n-octanoate and the corresponding alcohol (Plg-OH), both identified as robust α-tubulin binders. The study provides a rational to explain potentially the mechanism of action of Plg-A and to guide the design of new derivatives.

This study investigates the emerging applications of Artificial Intelligence (AI) in strategic management and its impact on organizational decision-making processes. As AI technology rapidly advances, it has become a crucial component in redefining organizational strategies. According to a global survey by the Boston Consulting Group, over 60% of executives believe that AI can significantly improve key performance indicators and enhance opportunities for strategic differentiation and sustainable competitive advantages. Using a descriptive-survey methodology and questionnaire-based data collection, this research examines the influence of AI on strategic decision-making in large organizations. The statistical population comprises senior managers across various industries, with sampling conducted through convenience sampling. Data analysis was performed using SMART-PLS software, revealing significant improvements in strategic decision-making processes through AI implementation. The study demonstrates that AI, by analyzing complex data sets and identifying hidden patterns, assists managers in making more optimal decisions. Furthermore, AI's predictive analytics capabilities contribute to enhanced strategic planning and risk mitigation in decision-making processes. The research findings indicate a statistically significant positive correlation (r = 0.72, p < 0.001) between AI adoption and the quality of strategic decisions. This paper concludes by proposing that organizations should leverage AI as a tool to strengthen their organizational strategies, while emphasizing the importance of ethical considerations and human oversight. The implications of this research extend to both academic and practical domains, offering insights into the integration of AI in strategic management processes and its potential to revolutionize organizational decision-making paradigms.

Purpose: This study investigates the influence of human brands on the formation of Generation Z's digital identity. Given the increasing importance of the digital space in this generation's life, understanding how their identity is shaped by human brands in this environment is crucial. Method: Using a netnographic approach, qualitative data was collected and analyzed from 500 posts and interactions of Gen Z users on Instagram and TikTok platforms. Thematic content analysis was conducted using NVivo 12 software, with inter-coder reliability confirmed (κ = 0.85). Findings: Results indicate that human brands influence Gen Z's digital identity through three main mechanisms: 1) lifestyle emulation (β = 0.42, p < 0.001), 2) value alignment (β = 0.38, p < 0.001), and 3) self-presentation modeling (β = 0.35, p < 0.01). Multiple regression analysis showed these three factors explain 67\% of the variance in digital identity formation (R² = 0.67, F(3,496) = 335.42, p < 0.001). Conclusion: This study demonstrates that human brands play a significant role in shaping Generation Z's digital identity. Understanding this influence can help marketers and policymakers design more effective strategies for engaging with this generation.

The COVID-19 pandemic has profoundly disrupted small businesses, exacerbating financial vulnerabilities and operational challenges. As these enterprises play a crucial role in economic stability and growth, identifying effective recovery strategies is imperative. This study investigates the legal and management solutions necessary for small businesses to recover and thrive post-pandemic. The research aims to examine the economic impact of the COVID-19 pandemic on small businesses, evaluate the effectiveness of existing legal and governmental support measures, and propose management strategies that enhance resilience and drive recovery. A mixed-methods approach was adopted, comprising both quantitative and qualitative analyses. A survey was conducted with 500 small businesses across various sectors to collect data on financial performance, operational disruptions, and the utilization of government support programs. Additionally, 30 in-depth interviews with small business owners provided qualitative insights into adaptive strategies and challenges faced. A review of relevant legal documents and policy frameworks was also performed to assess the support mechanisms in place. The study revealed that 68% of small businesses experienced substantial revenue losses, with 50% encountering severe liquidity crises. Government support measures, such as grants and low-interest loans, were pivotal but often marred by accessibility issues and delays. Successful management strategies identified included accelerating digital transformation, diversifying revenue streams, and optimizing supply chain management. Legal measures that temporarily eased regulatory requirements and offered tax relief significantly aided in alleviating immediate pressures. The economic recovery of small businesses post-COVID-19 hinges on comprehensive legal and management solutions. Enhancing the effectiveness and reach of government support programs is crucial, as is the adoption of agile and innovative management practices by small businesses. Policymakers and business leaders must work collaboratively to create an environment that fosters resilience and sustainable growth, ensuring small businesses can navigate future economic uncertainties.

In a wide range of lymphoid neoplasms, the process of malignant transformation is associated to somatic mutations in B cells that affect the epigenetic machinery. Consequential alterations in histone modifications contribute to disease-specific changes in the transcriptional program. Affected genes commonly play important roles in cell cycle regulation, apoptosis-inducing signal transduction and DNA damage response, thus facilitating the emergence of malignant traits that impair immune surveillance and favor the emergence of different B-cell lymphoma subtypes. In the last two decades, the field has made a major effort to develop therapies that target these epigenetic alterations. In this review, we discuss which epigenetic alterations occur in non-Hodgkin B-cell lymphoma. Furthermore, we aim to present in close to comprehensive manner the current state-of-the-art in the preclinical and clinical development of epigenetic drugs. We focus on therapeutic strategies interfering with histone methylation and acetylation as these are most advanced in being deployed from the bench-to-bedside and have greatest potential to improve the prognosis of lymphoma patients.

The classification of kidney tumors has undergone a remarkable evolution since the early 19th century, reflecting advances in medical science and technology. This historical overview traces the development of renal tumor classification, beginning with early clinical observations and macroscopic descriptions to the integration of molecular diagnostics in contemporary classifications. The establishment of international organizations like the World Health Organization (WHO) facilitated collaboration and standardization in tumor classification, leading to refined classifications and standardized nomenclature. Advancements in histological and molecular studies, particularly genetic analyses, revolutionized the understanding of renal cell carcinomas, enabling precise categorization based on molecular characteristics. The journey from rudimentary classifications to sophisticated systems based on detailed histological, immunohistochemical, and molecular criteria underscores the continuous evolution of kidney tumor classification. This article provides a comprehensive overview of this evolution, highlighting the contributions of scholars and the impact of technological advancements on our understanding and management of kidney tumors.

In pediatric burn care, achieving swift healing with minimal complications remains paramount. This investigation assesses polyhexamethylene biguanide (PHMB)'s role in managing superficial partial-thickness burns in children, focusing on the effects of various patient-specific factors on recovery. Through a retrospective analysis of 27 pediatric cases treated with PHMB, we explored the impact of age, burn size, dressing frequency, treatment delay, cold therapy application, and analgesic usage on the duration until reepithelialization. Notably, the majority of patients benefited from early cold therapy, yet only 1 in 3 patients received analgesics. The study reveals a mean healing time of 8.78 days, with the extent of the burn showing a strong correlation to recovery speed. Most treatments were managed outpatient, evidenced by a negligible average hospital stay. Impressively, the intervention recorded no complications. Our findings endorse PHMB as a promising treatment for second-degree burns in young patients, offering healing efficiency on par with or surpassing traditional methods, without increasing complication risks. This investigation underscores the necessity for continued exploration into the optimal application of prehospital interventions and the comprehensive benefits of PHMB in pediatric burn management, advocating for future research aimed at assessing long-term outcomes, including scar quality and patient satisfaction.

Gene regulation is vital for cellular function and homeostasis, involving diverse mechanisms controlling specific gene products and contributing to tissue-specific gene expression. Dysregulation leads to diseases, emphasizing the need for understanding these mechanisms. Non-coding regions, notably enhancers and super-enhancers (SEs), act as crucial gene regulators, orchestrating transcriptional activity via transcription factors (TFs). SEs, with high activity, are pivotal in cell identity and disease progression. Current computational approaches focus on individual regulators like TFs and miRNAs, neglecting SE interactions. We emphasize incorporating SEs into models to enhance understanding. Experimental studies have recently linked miRNAs and TFs to SEs. Chromatin immunoprecipitation followed by sequencing (ChIP-Seq) provides valuable SE information. In this review, we categorize computational methods leveraging TF and miRNA data into three areas and explore challenges integrating enhancers/SEs. These include unraveling indirect regulatory networks, identifying network motifs, and enriching pathway identification by dissecting gene regulators, including SEs. We hypothesize that addressing these challenges will enhance our understanding of gene regulation, aiding in identifying therapeutic targets and disease biomarkers. We believe that understanding the role of ChIP-Seq data in predicting the effect of miRNA on gene regulation is crucial to construct statistical/computational model that would tackle these challenges.

This study evaluated the presence of Human Papillomavirus (HPV) and Bovine Leukemia Virus (BLV) DNA in breast cancer (BC) samples from women in Northeastern Brazil. We analyzed 186 formalin-fixed, paraffin-embedded tissue block samples using PCR and qPCR to detect HPV and BLV DNA. BLV DNA was not detected in any BC patients. However, HPV DNA was found in 46.2\% of the BC samples: 44.6\% were positive for HPV16, 3.5\% for HPV31, and 2\% were coinfected with HPV16 and HPV31. Additionally, we found an association between HPV-positive BC and Ki-67 expression (P=0.03, OR=1.85; CI=1.02-3.34), as well as between HPV31-positive BC and mitotic index (P=0.047). Although BLV was not detected in BC patients from Northeastern Brazil, the association between HPV and cell proliferation markers warrants further investigation, as HPV may contribute to the aggressiveness of BC in these patients.

Neurodegeneration is a major problem in neuroscience and medicine as it causes and worsens many neurological and psychiatric disorders. It involves gradual loss of neurons at different levels of the brain, affecting cognition, emotion, behavior, consciousness, and attention. Understanding the causes and consequences of neurodegeneration is crucial for identifying the risk factors, biomarkers, and treatments. However, the current therapies are mostly symptomatic and ineffective. Therefore, new and innovative methods, such as noninvasive brain stimulation (NIBS), are needed to modulate brain activity and plasticity in a safe and reversible manner. This field is rapidly developing, with a focus on exploring new clinical applications, mechanisms, and combinations of NIBS and drugs. This special issue covers the latest progress and challenges in the study of neurodegeneration in cognitive impairment and mood disorders from the experimental, clinical, and translational perspectives. It addresses the complexity and diversity of these conditions, the lack of disease-modifying treatments, the ethical and practical issues of conducting research in vulnerable and diverse populations, the integration and interpretation of data from multiple sources and modalities, and the development and validation of novel methods such as NIBS, artificial intelligence, and drug repurposing. Collaborative efforts among various stakeholders are needed to improve our knowledge and treatment of neurodegeneration underlying cognitive impairment and mood disorders.

Abstract: Although the pathophysiology of fibromyalgia syndrome has been better understood in recent decades, a unified model of its pathogenesis and an effective therapeutic approach are still far from being realized. The main aim of this article will be to delve into the fundamental mechanisms of the pathophysiology of fibromyalgia conceptualized as stress intolerance syndrome. Using the biopsychosocial model of chronic pain syndromes, we will describe the potential role of the attachment system, C tactile fibers, and oxytocinergic system dysfunction in the pathophysiology of fibromyalgia syndrome and other central sensitivity syndromes. At the end of the article, the therapeutic implications of this new global and translational pathophysiological model will be briefly discussed.

Background - Compared to the da Vinci platform, there is limited experience with the Hugo RAS platform for colorectal surgery in Europe. This difference is especially notable when considering a single complex procedure, such as total colectomy. Aim - To demonstrate the feasibility and safety of using the Hugo RAS for assisted total colectomy. Clinical case- Female patient: eighteen-year-old with Familial Adenomatous Polyposis (FAP). Her IBM was 19. She underwent a total colectomy with ileorectal anastomosis using the Hugo RAS platform. The procedure took 230 minutes and had no complications. The postoperative period was uneventful. She was discharged from the hospital on the third postoperative day. Conclusion - The Hugo RAS platform is one of the emergent minimally invasive robotic platforms that can be used even in total colectomy if the proper patient selection is made. The placement choice of arms and trocars was crucial to obtain a similar operative time of the single laparoscopic approach. The certification of Hugo’s new instruments, such as energy devices and staplers, will make this platform even more competitive.

Cardiac arrest (CA) is a life-critical condition. Patients who survive after CA, they go into a defined post-cardiac arrest syndrome (PCAS). In this clinical context, the role of the echocardiogram in recent years has become increasingly important to assess the causes of arrest, the prognosis, and any direct and indirect complications dependent on cardiopulmonary resuscitation (CPR) maneuvers. The aim of our review is to evaluate the increasingly important role of the transthoracic and transesophageal echocardiogram in the CA phase and especially post-arrest, analyzing the data already present in the literature.

Anti-interferon (IFN)-γ autoantibodies are linked to varicella-zoster virus (VZV) infection. Given the elevated risks of herpes zoster (HZ) in rheumatoid arthritis (RA) patients treated with Janus kinase inhibitors (JAKi), we aimed to examine the relationship between anti-IFN-γ autoantibodies with HZ development in JAKi-treated patients. In twenty-four RA patients with new-onset HZ and forty-two without HZ, serum titers of anti-IFN-γ autoantibodies, plasma levels of IFN-γ, monocyte chemoattractant protein-1 (MCP-1), and IFN-γ inducible protein-10 (IP-10) were measured by ELISA. Significantly lower MCP-1 levels were observed in patients with HZ compared to those without (median, 98.21pg/ml, interquartile range (IQR) 77.63-150.30pg/ml versus 142.3pg/ml, IQR 106.7-175.6pg/ml, p&lt;0.05). There was no significant difference in anti-IFN-γ titers, IFN-γ levels, or IP-10 levels between patients with and without HZ. Three of 24 patients with HZ had severe HZ with multi-dermatomal involvement. Anti-IFN-γ titers were significantly higher in patients with severe HZ than in those with non-severe HZ (median 24.8ng/ml, IQR 21.0-38.2ng/ml versus 10.5ng/ml, IQR 9.9-15.0ng/ml, p&lt;0.005). In conclusion, patients with HZ had significantly lower MCP-1 levels than those without HZ, and patients with severe HZ had significantly higher titers of anti-IFN-γ than those with non-severe HZ. Given small sample size, our results need further validation in future studies.

Objectives: To assess the short-term impact of a single global stretching session on plantar pressures and lumbar range of motion (RoM) over one week in sedentary university students. Design: A randomised controlled trial with two parallel groups. Participants: Sixty-four university students were randomly assigned to a stretching group or control group. The stretching group received a single session of global stretching and the control group remained seated for the same length of time as the stretching session. Main outcome measures: Lumbar RoM and plantar pressures were assessed before, immediately after, 48 hours after, and 7 days after intervention. Results: Group-by-time interaction was significant for lumbar lateral flexion (p = 0.044), right maximal pressure (p = 0.003), left maximal pressure (p = 0.008), right mean pressure (p = 0.025), left mean pressure (p = 0.002), and maximal pressure minus mean pressure in right foot (p = 0.007). The model with plantar pressures showed a significant difference for group-by-time interaction (p = 0.010).Conclusion: Global stretching seems to counteract the ill-effects of prolonged sitting up to seven days with respect to plantar pressure in standing without improving lumbar ROM

The greatly diversified flowering plants (angiosperms) are the dominating and defining group in the current earth ecosystem. However, from which group by what way the flowers, especially their gynoecia (key characteristics of angiosperms), are derived have been the questions in botany unanswered over centuries. Such an embarrassing situation can be attributed to the lack of plants with partially enclosed ovules, which are supposed to be a post between gymnosperms and angi-osperms. Here we report a fossil plant that has an apparent coniferous vegetative and reproduc-tive morphologies but has a single seed partially wrapped by the subtending bract. Such a mor-phology suggests that the carpels in angiosperms may be equivalent to bracts enclosing their axil-lary seed(s). Such a non-traditional interpretation of the homology of angiosperm carpels is com-patible with various new progresses made in botany and is in line with Tomlinson’s recent hy-pothesis. Together with other fossil evidence reported recently, it appears that gynoecia in angio-sperms are derived in multiple ways.

Human induced pluripotent stem cell (iPSC)-based model systems can be used to produce blood cells for the study of both hematologic and non-hematologic disorders. This commentary discusses recent advances that have utilized iPSC-derived red blood cells, megakaryocytes, myeloid cells, and lymphoid cells to model hematopoietic disorders. In addition, we review recent studies that have defined how microglial cells differentiated from iPSC-derived monocytes impact neurodegenerative disease. Related translational insights highlight the utility of iPSC models for studying pathologic anemia, bleeding, thrombosis, autoimmunity, immunodeficiency, blood cancers, and neurodegenerative disease such as Alzheimer’s.

Tubulin and heat shock protein 27 (HSP27) are up-regulated in cancer cells, and play a critical role in cell division, and proliferation. Therefore, they are targets for discovery of anticancer therapy. The objective of this study is to design, characterize, and biologically evaluate the nimesulide analogues to combat female cancer such as ovarian cancer, and breast cancer. Herein, the nimesulide analogues are designed to target both tubulin and HSP27 functions. Ovarian cancer (SKOV3) and breast cancer (SKBR3) cell lines were used as surrogate models to test the nimesulide analogs biological activities using MTT assay. In the present study, four nimesulide analogues were designed, synthesized and the chemical structures were with the biological evaluation were studied. The synthesized agents were characterized by 1H-NMR, 13C-NMR, the molecular weight was confirmed using GC-MS technique, and melting point. Besides, the agent L4 structure was confirmed using X-ray crystallographic analysis. The present data revealed that nimesulide analogs have potent anticancer activity against SKOV3and SKBR3 cell lines. The IC50 values for both SKOV3 and SKBR3 cell lines treated with the agents showed a potent cell growth inhibition range of 0.23-2.02 µM and 0.50-3.73 µM respectively. In conclusion, the designed nimesulide analogues can target both tubulins, and HSP27 concurrently, and they are promising agents as future chemotherapy female cancers.

Myocardial hypertrophy is the most common condition that accompanies heart changings in children. Transcriptional pathways regulating gene expression playing a critical role both in cardiac embryogenesis and in the pathogenesis of congenital hypertrophic cardiomyopathy, neonatal posthypoxic myocardial hypertrophy and congenital heart diseases. This paper describes the state of cardiac gene expression and potential pharmacological modulators at different transcriptional levels. An experimental model of perinatal cardiac hypoxia showed downregulated expression of genes responsible for cardiac muscle integrity and overexpressed genes associated with energy metabolism and apoptosis, which may provide a basis for a therapeutic approach. Current evidence suggests that RNA drugs, theaflavin, neuraminidase, proton pump and histone deacetylase inhibitors are promising pharmacological agents in progressive cardiac hypertrophy. The different points of application of the above drugs makes combined use possible, potentiating the effects of inhibition in specific signaling pathways. The special role of N-acetyl cysteine in both the inhibition of several signaling pathways and the reduction of oxidative stress was emphasized.

Falls are a frequent and serious problem for older adults and especially those living with Parkinson’s. The relationship between falls and physical activity is complex and people often restrict activity following a fall. Exercise is an important aspect of re-ducing further risk of a fall and a key component of the management of Parkinson’s. The aim of this study was to understand the types of activity that are engaged in, the environments in which they take place and the experience of people with and without Parkinson’s who have fallen. 17 people with Parkinson’s and 13 older adults, who had experienced at least one fall in the previous year, were recruited to this mixed methods study. Activity levels were captured over one week using accelerometers and body worn cameras, allowing the type and location of activity to be recorded and analysed. This information informed an interview. Findings showed that although both groups often achieved up to 10,000 steps per day, this was in very short bouts of activity. Sedentary activity such as watching television dominated the findings. Participants were aware of the benefits of being active but described many barriers to achieving the level of activity they would like to.

The abundant and renewable resources from fruit byproducts are getting emphasis on their valorization. These byproducts are suspected of possible toxications during cultivation, harvesting, transporting, preservation, or processing. Hence, presenting scientific overviews of the toxicological qualities and detoxification trends of these byproducts is critical to implicating their possible valorization. This review emphasized the toxicological qualities of byproducts from fruits for which the maximum global production occurred in 2022. In this review, heavy metals (As, Cd, Co, Cr, Ni, Pb, and Hg), mycotoxins, toxicant organic compounds, anti-nutritional factors, and pesticide/fungicide residues of the selected fruit byproducts were discussed. Current trends to reduce possible toxicants of these byproducts during their valorization were emphasized. Novel functional foods valorized from these fruit byproducts and future perspectives of detoxification were also focused on in this review.

The COVID-19 pandemic has highlighted the critical need for telehealth and remote patient monitoring in healthcare delivery. Despite the growing use of on-body wearable sensors for continuous monitoring and predicting adverse events, such as hospitalizations or falls, their widespread adoption within the healthcare ecosystem remains a significant challenge. While the pandemic has accelerated the acceptance of these technologies, achieving widespread integration requires their sustained incorporation into routine healthcare practices beyond emergency situations. In this study, we extend the application of our previously developed remote patient monitoring system, originally designed for the geriatric frail population, to COVID-19 patients. Our objective is to assess whether the metrics obtained from this system, which includes physical activity and indoor localization sensors, along with vital sign monitoring, can provide additional insights into the recovery trajectory of individuals affected by COVID-19.

NSCLC is a very aggressive solid tumor, with a poor prognosis due to post-surgical recurrence. Analysis of the specific tumor and immune signatures of NSCLC samples is a critical step in prognostic evaluation and management decisions for patients after surgery. Routine histological assay has some limitations. Therefore, new diagnostic tools with the capability to quickly recognize NSCLC subtypes and correctly identify various markers are needed. We developed a technique for ex vivo expansion of cancer and immune cells from surgical tumor and lung tissue samples of patients with NSCLC (adenocarcinomas and squamous cell carcinomas) and their examination on ex vivo cell preparations and, parallelly, on histological sections after Romanovsky–Giemsa and immunofluorescent/immunochemical staining for cancer-specific and immune-related markers. As a result, PD-L1 expression was detected for some patients only by ex vivo analysis. Immune cell profiling in the tumor microenvironment revealed significant differences in the immunological landscapes between the patients’ tumors, with smokers’ macrophages with simultaneous expression of pro- and anti-inflammatory cytokines, neutrophils, and eosinophils being the dominant populations. The proposed ex vivo analysis may be used as an additional diagnostic tool for quick examining cancer and immune cells in whole tumor samples and avoiding false negatives in histological assays.

Although flow mixing and cooling can be greatly enhanced when considering the use of Fluidic Oscillators (FO), they are more commonly employed in Active Flow Control (AFC) applications where the injected pulsating flow interacts with the boundary layer in order to usually delay its separation. In fact, prior to any FO implementation in a given application, it is essential to study the range of frequencies and amplitudes it can generate as a function of the incoming mass flow and its dimensions. This point is what is being enlightened in the present manuscript for a rather novel FO configuration. We are numerically studding a standard FO configuration in three dimensions 3D and also using a two dimensional 2D approach. After comparing the 3D and the 2D results and analyzing the main differences, we modified some of the internal dimensions of the FO in order to evaluate the variation of its dynamic performance. The present results clarify which internal dimensional modifications are more effective in generating larger output frequencies and velocity field variations. Care is taken to analyze the origin of the self sustained oscillations. In fact, the present research needs to be seen as the continuation of a former one recently published , where the effect of several Reynolds numbers as well as some different internal dimensions was considered.