Lower cutoff levels in screening programs have led to an increase in the proportion of detected cases with transient hypothyroidism, leading to increase of the overall incidence of primary congenital hypothyroidism (CH) in several countries. We have performed retrospective evaluation on the data from 251,008 (96.72%) neonates screened for thyroid-stimulating hormone (TSH) level in dried blood spot specimens taken 48 hours after birth, between 2002 and 2015, using DELFIA method. A TSH value of 15 mIU/L was used as the cutoff point until 2010 and 10 mIU/L thereafter. Primary CH was detected in 127 newborns (1/1976) of which 81.1% had permanent and 18.9% had transient CH. The incidence of primary CH was increased from 1/2489 until to 2010 to 1/1585 thereafter (p=0.131). However, the incidence of permanent CH was slightly increased (p=0.922), while the transient CH incidence had 8-fold increasing after lowering the TSH cutoff level (p<0.001). In cases with permanent CH, we observed lower frequency for thyroid dysgenesis (82.7 vs. 66.7%) and higher frequency for normal in-situ thyroid gland (17.3 vs. 33.3%), for the period with reduced TSH cutoff value. Our findings support the impact of lower TSH cutoff on the increasing incidence of congenital hypothyroidism.

Pulmonary arterial hypertension is a rare disease with high mortality despite recent therapeutic advances. The disease is caused by both genetic and environmental factors, and likely gene x environment interactions. While PAH can manifest across the lifespan, pediatric-onset disease is particularly challenging because it is frequently associated with a more severe clinical course and comorbidities including lung/heart developmental anomalies. In light of these differences, it is perhaps not surprising that emerging data from genetic studies of pediatric-onset PAH indicate that the genetic basis is different than that of adults. There is a greater genetic burden in children, with rare genetic factors contributing to at least 36% of pediatric-onset idiopathic PAH (IPAH) compared to ~11% of adult-onset IPAH. De novo variants are frequently associated with PAH in children, and contribute to at least 15% of all pediatric cases. The standard of medical care for pediatric PAH patients is based on extrapolations from adult data. However, the increased etiologic heterogeneity, poorer prognosis and increased genetic burden for pediatric-onset PAH calls for a dedicated pediatric research agenda to improve molecular diagnosis and clinical management. A genomics-first approach will improve the understanding of pediatric PAH and how it is related to other rare pediatric genetic disorders.

(1) Background: Cardiorespiratory fitness (CRF) is a prognostic factor regarding long time morbidity and mortality. To assess CRF the well-known gold standard is cardiopulmonary exercise testing (CPET), which is a time consuming and expensive test. Therefore, alternative methods for routine evaluation of CRF are needed for the general population as well as for specific patient groups such as children and young adults with congenital heart disease. The Stair Climbing Test (SCT) is a simple and resource saving test reported in the current literature. This test is used in various settings to assess different health associated risk factors including cardiorespiratory fitness, muscular resilience, therapy effectiveness or pre- and postoperative morbidity and mortality.

Turner syndrome (TS) is caused by a complete or partial absence of an X or Y chromosome, including chromosomal mosaicism, affecting 1 in 2,500 female live births. Sister chromatid exchange (SCE) is used as a sensitive indicator of spontaneous chromosome instability. Cells from mosaic patients constitute useful material for SCE evaluations as they grow under the influence of the same genetic background and endogenous and exogenous factors. We evaluated proliferation dynamics and SCE frequencies of 45,X and 46,XN cells of 17 mosaic TS patients. In two participants, 45,X cells exhibited a proliferative disadvantage in relation to 46,XN cells after 72h of cultivation. The analysis of mean PI showed significant differences between 45,X and 46,XN lineages; however there were no intraindividual differences. On the other hand, mean SCE frequencies showed no differences between the two lineages, but there were intraindividual differences in 5 patients. The absence of mean SCE frequency differences between 45,X and 46,XN lineages may indicate that both were equally unstable, as more than 70% of the 46,XN lineages had an anomalous karyotype. However, 46,XN had a higher mean PI, suggesting that the amount of cells with a karyotype distinct from 45,X may increase with time in mosaic TS women.

Music has the innate potential to reach all parts of the brain, stimulates certain brain areas which are not achievable through other modalities. Music Therapy (MT) is being used for more than a century to treat individuals who needs personalized care. MT optimizes motor, speech and language responsibilities of the brain and improves cognitive performance. Pervasive developmentdisorder (PDD) is a multifaceted, neuro developmental disorder and autism spectrum disorder (ASD) comes under PDD, which is defined by deficiencies in three principal spheres: social connection with others, communicative and normal movement skills. The conventional imaging studies illustrate reduced brain area connectivity in people with ASD, involving selected parts of the brain cortex. People with ASD express much interest in musical activities which engages the brain network areas and improves communication and social skills.The main objective of this review is to analyze the potential role of MT in treating the neurological conditions, particularly ASD. Evidence based studies have reported the extensive therapeutic application of music on various part of the brain in a nonverbal child with autism through hearing or making music.Hence we hypothesized that MT intervention can improve the communication capacity in people with ASD, than customary neurorestoration therapy alone.

Furthermore, the nasal congestion typical of rhinitis can contribute to upper airway obstruction and sleep-disordered breathing. A vicious circle is created between asthma and sleep-disordered breathing: uncontrolled asthma and sleep-disordered breathing can worsen each other. In children with genetic obesity, despite alterations in the immune system, fewer allergies are found compared to the general population. The causes of this reduced allergenicity are unclear but probably involve genetic, immunological, and environmental factors. Further studies are needed to understand the mechanisms. The study emphasizes the importance of jointly evaluating and managing allergies, obesity, and sleep-disordered breathing in children, considering their close interconnection.

From 2008 to 2024, the Newborn Screening Translational Research Network (NBSTRN), part of the National Institute of Child Health and Human Development (NICHD) Hunter Kelly Newborn Screening Program, served as a robust infrastructure to facilitate groundbreaking research in newborn screening (NBS), rare disease, and genomics. Over fifteen years, NBSTRN developed into a significant international network, supporting innovative research on novel technologies to screen, diagnose, treat, manage, and understand the natural history of more than 280 rare diseases. A key component of these efforts has been the development of resources and expertise for the newborn screening community in ethical, legal, and social issues (ELSI). This paper presents findings from a survey conducted by the NBSTRN team with input from one of theNBSTRN's expert workgroups, the Bioethics and Legal Workgroup. With responses from 88 members of the NBS community including researchers and state NBS programs, the survey found that individuals rely on internal and collegial ELSI resources and highlighted a substantial demand for structured, accessible training and resources. The survey’s insights emphasize the importance of privacy and informed consent in NBS research, and suggested a need for improved collaborative tools and educational programs focused on ELSI for the NBS community. The survey results may inform future efforts in ELSI and NBS research including the development of expanded ELSI tools that leverage digital platforms and consultative services.

Spinocerebellar ataxia type 3 is a neurodegenerative disease caused by an abnormal expansion of CAG repeats in the disease gene ATXN3, leading to prolonged polyglutamine (polyQ) tracts in the respective protein ataxin-3. The polyQ-expanded protein forms polyQ-containing aggregates in several brain regions which leads to neuronal cell loss. Autophagy is thought to play a significant role in clearing these polyQ-containing protein aggregates. Therefore, the autophagy mechanism was investigated in SCA3 with focus on the autophagic protein p62/sequestosome-1. Human and mouse RNA sequencing data were analyzed to determine RNA expression level of autophagic genes. Additionally, autophagy was studied in the SCA3 304Q knock-in mouse model and through several cell culture experiments using HEK-293T cells transfected with ATXN3 of differ-ent polyQ lengths. For cell culture experiments, autophagy was induced with rapamycin treat-ment, proteasomal degradation was blocked with MG132 and degradation of autophagic pro-teins was investigated using cycloheximide treatment. Here, we report an increased autophagy impairment with SCA3 disease progression seen in HEK-293T cells transfected with ATXN3 plasmid with expanded polyQ tracts, higher aged 304Q-knock-in mice, or human post-mortem brain material. Furthermore, co-localized aggregation of the autophagic protein p62 and the dis-ease protein ATXN3 was observed in the course of SCA3 disease. Therefore, we suggest a signifi-cant role for p62 in aggregate formation seen in the neurodegenerative disease SCA3.

Europium is one of the most reactive lanthanides and humans use it in many different applica-tions, but we still know little about its potential toxicity and cellular response to its exposure. Two strains of the eukaryotic microorganism model Tetrahymena thermophila adapted to high concentrations of two Eu(III) compounds (EuCl3 or Eu2O3) were obtained and compared to a control strain and cultures treated with both compounds. In this ciliate, EuCl3 is more toxic than Eu2O3. LC50 values show that this microorganism is more resistant to these Eu(III) compounds than other microorganisms. Oxidative stress originated mainly by Eu2O3 is minimized by overexpression of genes encoding important antioxidant enzymes. The overexpression of metallothionein genes under treatment with Eu(III) compounds supports the possibility that this lanthanide may interact with the -SH groups of the cysteine residues from metallothi-oneins and/or displace essential cations of these proteins during their homeostasis function. Both lipid metabolism (lipid droplets that fuse with europium-containing vacuoles) and au-tophagy are involved in the cellular response to europium stress. Bioaccumulation, together with a possible biomineralization to europium phosphate, seems to be the main mechanism of Eu(III) detoxification in these cells.

Background: The control of energy metabolism is fundamental for cell growth and function, and anomalies are implicated in complex diseases and ageing. It is important for cells to carefully tune metabolic pathways to optimize their function in response to different nutrient or physiological conditions. Metabolism in yeast cells can be easily manipulated by supplying different carbon sources: on glucose yeast rapidly proliferates by fermentation, analogous to tumour cells growing by aerobic glycolysis, whereas on non-fermentable carbon sources metabolism shifts towards respiration. Results: We screened deletion libraries of fission yeast to identify over 200 genes required for respiratory growth. The growth medium and auxotrophic mutants strongly influenced respiratory metabolism. Most genes uncovered in the mutant screens have not been implicated in respiration in budding yeast. We applied gene expression profiling approaches to compare steady-state fermentative and respiratory growth and to analyse the dynamic adaptation to respiratory growth. The transcript levels of most genes functioning in key energy metabolism pathways were coherently tuned, reflecting anticipated differences in metabolic flows between fermenting and respiring cells. We show that the acetyl-CoA synthase, rather than the citrate lyase, is essential for acetyl-CoA synthesis in fission yeast. We also investigated the transcriptional response to mitochondrial damage by genetic or chemical perturbations, defining a retrograde response that involves the concerted regulation of distinct groups of nuclear genes that may avert harm from mitochondrial malfunction. Conclusions: These systematic and targeted analyses provide a rich framework of the genetic and regulatory basis of fundamental metabolic states to guide future studies on energy metabolism in fission yeast and beyond. Our study pinpoints weaknesses of commonly used auxotroph mutants for investigating energy metabolism. As a model for cellular energy regulation, fission yeast provides an attractive and complementary system to budding yeast.

Understanding morphological and genetic diversity of forest trees is essential to facilitate their conservation, sustainable management and genetic improvement for addressing the economic and environmental demands and challenges. We have examined variation in morphometric seed and pod traits and seed germination of multipurpose and widely distributed forest tree Albizia lebbek (Indian siris) from 12 provenances covering the species’ range in northern India and its relationships with bioclimatic factors. Highly significant inter-provenance variation was observed in seed size (seed length (SL), seed width (SW), SW/SL, SL×SW), seed mass (1000 seed weight), pod size (pod length (PL), pod width (PW), PW/PL), seed germination, number of seeds per pod, and insect infected seeds (IIS). The provenance effect contributed a major portion to the total phenotypic variance. Morphometric variation in all traits except for IIS was not clinal related to longitude, latitude, altitude or rainfall. There was an indication of the presence of ecotypic variation. IIS showed clinal variation with significant negative correlation with latitude. Most seed size and pod size traits showed positive correlations with several temperature bioclimatic factors and negative correlations with several precipitation bioclimatic factors. Our results have significance for genetic improvement, population genetics and genomics studies and conservation and sustainable management of A. lebbek genetic resources.

Severe early childhood caries remains the most common chronic disease affecting children. Its multifactorial etiology has established a controversy about which risk factors were more significant to its development. Therefore our study aimed through meticulous statistical analysis to arrange the “well agreed upon” common risk factors in order of significance, to aid the clinician in tailoring an adequate preventive program for this affected age group. The study reshuffled the risk factors contributing to severe early childhood caries and placed them in the order of their significance as follows: snacking of sugary food several times a day, increased number of siblings to 3 or more, night feeding, child self-employed brushing, mother caries experience, 2 siblings, on demand feeding, once/day sugary food, sharing utensils, 1 Sibling, male gender, father’s education, late first child dental visit, brushing time, mother’s education, no dental visit, decreased brushing frequency & no night brushing.

Cysteine and its derivatives, including H2S, can influence bacterial virulence and sensitivity to antibiotics. In minimal sulfate media, H2S is generated under stress to prevent excess cysteine and, together with incorporation into glutathione and export into the medium, is a mechanism of cysteine homeostasis. Here, we studied the features of cysteine homeostasis in LB medium, where the main source of sulfur is cystine, whose import can create excess cysteine inside cells. We used mutants in the mechanisms of cysteine homeostasis and a set of microbiological and biochemical methods, including real-time monitoring of sulfide and oxygen, determination of cysteine and glutathione, and expression of the Fur, OxyR, and SOS regulons genes. During normal growth, the parental strain generated H2S when switching respiration to another substrate. The mutations affected the onset time, intensity and duration of H2S production, cysteine and glutathione levels, bacterial growth and respiration rates, and induction of defense systems. Exposure to chloramphenicol and high doses of ciprofloxacin increased cysteine content and GSH synthesis. A high inverse relationship between log CFU/ml and bacterial growth rate before ciprofloxacin addition was revealed. The study points to the important role of maintaining cysteine homeostasis during normal growth and antibiotic exposure in LB medium.

Enveloped viruses represent a significant category of pathogens that cause serious diseases in animals. These viruses express envelope glycoproteins that are singularly important during infection of host cells by mediating fusion between the viral envelope and host cell membranes. Despite low homology at protein levels, three classes of viral fusion proteins have, as of yet, been identified based on structural similarities. Their incorporation into viral particles is dependent upon their proper sub-cellular localization after being expressed and folded properly in the endoplasmic reticulum (ER). However, viral protein expression can cause stress in the ER, and host cells respond to alleviate the ER stress in the form of the unfolded protein response (UPR); the effects of which have been observed potentiating or inhibiting viral infection. One important arm of UPR is to elevate the capacity of the ER-associated protein degradation (ERAD) pathway, which is comprised of host quality control machinery that ensures proper protein folding. In this review, we provide relevant details regarding viral envelope glycoproteins, UPR, ERAD, and their interactions in host cells.

Members of the genus Armillaria are widespread forest pathogens against which effective protection has not yet been developed. Due to their longevity and the creation of large-scale cloning of Armillaria individuals, the use of mycoviruses as biocontrol agents (BCAs) against these pathogens could be an effective alternative. This work describes the screening of double-stranded RNA banding patterns as a first approach for potential virus discovery and the use of stranded total RNA-seq for viral detection and characterization in Armillaria spp. collected in the Czech Republic. A total of five single-stranded RNA viruses were detected in Armillaria ostoyae and A. cepistipes, including the first virus of the family Tymoviridae found infecting a member the genus Armillaria and four viruses belonging to the recently described virus group "ambiviruses" with circular ambisense genome organization. Both hammerhead (HHRz) and hairpin (HpRz) ribozymes were detected in all the ambiviricot sequences. Armillaria viruses were compared by phylogenetic analysis and confirmed their specific host by direct RT-PCR, which showed the occurrence of interspecies transmission.

Many fundamental molecular techniques (PCR, Microarray, Southern and northern hybridization, siRNA, CRISPR/Cas9 etc.) developed so far shows errors. I wish to highlight these molecular techniques are developed on basis of Watson-Crick DNA model, ignoring the concept of parallel stranded DNA. Through this opinion article, I wish to highlight specificity and accuracy of these molecular techniques can be enhanced by considering both parallel and anti parallel hybridization of DNA. Hopefully my views will also solve issue of irreproducibility in life science research.

Background Homologous recombination deficiency (HRD) evolved into a major diagnostic marker in high grade ovarian cancer (HGOC) predicting the response to poly (Adenosine diphosphate-ribose) polymerase inhibitors (PARPi) and also platinum-based therapy. In addition to HRD, the type of peritoneal tumor spread influences treatment response and patient survival; miliary type tumor spread has poorer predicted outcome than non-miliary type tumor spread. Methods Known methods for HRD assessment were adapted for our technical requirements and the Predictive-value Integrated Genomic Instability Score (PIGIS) for HRD assessment evolved as an outcome. PIGIS was validated in HGOC samples from 122 patients. We used PIGIS to analyze whether the type of tumor spread correlated with HRD status and whether this had an impact on survival. Results We demonstrated that PIGIS can discriminate HRD positive from HRD negative samples. Tumors with miliary tumor spread are HRD negative and have a very bad prognosis with a progression free survival (PFS) of 15.6 months and an overall survival (OS) of 3.9 years. However, HRD negative non-miliary spreading tumors in our cohort had a much better prognosis (PFS 35.4 months, OS 8.9 years), similar to HRD positive tumors (PFS 34.7 months, OS 8.9 years). Conclusions Our results indicate that in a predominantly PARPi naïve cohort the type of tumor spread might be a better predictor of response to platinum sensitivity than HRD. It remains to be determined, whether this also applies for sensitivity to PARPi.

The treatment of acute myeloid leukemia (AML) with adverse genetics remains unsatisfactory, with very low response rates to standard chemotherapy and shorter durations of remission commonly observed in these patients. The complex biology of AML with adverse genetics is continuously evolving. Herein, we discuss recent advances which have investigated the contribution of cell intrinsic mechanisms as well as of the immune system to myeloid leukemogenesis in this specific subset of AML. We focus on the biological rationales for combining targeted therapy and immunotherapy, which are currently being investigated in ongoing trials, and could hopefully ameliorate the poor outcomes for these patients

Beaches are among the habitats most frequented by migratory birds for breeding and/or wintering. However, threats such as human pressure and sea level rise can reduce the availability of these habitats for different species. The presence of alternative areas, such as salt pans and brackish habitats, is essential for many migratory shorebird populations. This study addresses the post-breeding dispersal of the Kentish plover (Charadrius alexandrinus) in the Iberian Peninsula by analysing C and N isotopes in feathers. The study was conducted at six locations along the Iberian coast, which were categorized in three areas: NW Atlantic coast, the Atlantic coast of Andalusia and the Mediterranean coast. Although linear mixed models did not reveal any significant effects of sex or coastal area on isotopic levels, the variability in the data suggests different habitat-use strategies in the post-reproductive period. Birds from the northwest of the Iberian Peninsula exhibit greater fidelity to a single habitat type, i.e. coastal beaches, while populations from the Mediterranean coast and the Atlantic coast of Andalusia show different individual dispersal strategies, occupying coastal habitats and freshwater wetlands. The lack of alternative habitats for the northwest Iberian population, the reduction in available habitat due to rising sea levels and human pressure together pose a serious threat to the survival of this species, already with an unfavourable conservation status.

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.

Genetic enhancement of grain production and quality is a priority in wheat breeding projects. In this study, we assessed two key agronomic traits - grain protein content (GPC) and thousand kernel weight (TKW) - across 179 Bulgarian contemporary and historic varieties, and landraces in three growing seasons. Significant phenotypic variation existed for both traits among genotypes and seasons, and no discernible difference was evident between the old and modern accessions. To understand the genetic basis of the traits, we conducted a genome-wide association study with MLM using phenotypic data from the crop seasons, best linear unbiased estimators, genotypic data from the 25K Infinium iSelect array, and a Bonferroni-adjusted p-value. As a result, 776 significant quantitative trait nucleotides (QTNs) organized into quantitative trait loci were discovered, including 25 loci associated with GPC, and 35 loci linked to TKW. Additionally, 14 environmentally stable QTNs were identified for TKW. Certain loci on chromosomes 2A, 3A, and 6B favorably in-fluenced GPC, while the locus on chromosome 6D impacted TKW positively. These loci may reflect novel associations to the two traits. Annotations for proteins involved in the remobilization of carbon and nitrogen from vegetative tissues to developing grain during senescence, as well as in the following buildup of resources required for seed germination, have been found for selected pu-tative candidate genes. These include genes coding for 11S globulin seed storage protein, glutamine synthetase, metalloendopeptidase, components of the ubiquitin/proteasome system, sucrose transporter, alpha-amylase, NAC and bZIP transcription factors. Our findings highlight promising genomic regions for targeted breeding programs aimed at improving grain yield and protein content.

Aim: To evaluate the panmacular subthreshold micropulse laser treatment results among patients with central serous chorioretinopathy (CSC) and their correlation with functional and morphological parameters. Material and methods: The examined group included 10 non-treated and 41 treated patients with acute, recurrent, and chronic CSC (13 F, 38 M, mean age 44.11±6.5) and 14 healthy controls (6 F, 8 M, mean age 45±9.3). The BCVA examination, ophthalmoscopy, microp-erimetry, angio-OCT and OCT were performed. The medical history regarding chronic general disorders and known risk factors were recorded. Results: Complete resorption of SRF was obtained in 100% aCSC, 86.66% cCSC, and 63.63% r CSC. BCVA and RetSens significantly improved most of the patients treated in aCSC. The lowest BCVA and RetSens, but the largest pachyvessel and disease duration, were found in rCSC. A strong negative correlation between final BCVA and disease duration was found. No patient demonstrated laser lesions following treatment. Conclusions: The panmacular MPLT therapy leads to long-term enhancement of functional and morphological parameters in all CSC patients. The acute CSC patients showed the most significant improvement. The procedure is safe and could be considered a preferred treatment option for all active CSC cases. Timely treatment is crucial for beneficial outcomes.

Lynch syndrome (LS) is one of the most common hereditary cancer syndrome in human populations, associated with germline variants in MLH1, MSH2/EPCAM, MSH6 and PMS2 genes. The advent of next generation sequencing has proven a significant impact in germline variant detection in the causative genes; however, a large proportion of patients with clinical criteria still receive uncertain or negative results. PMS2 is the least frequent reported gene, associated with up to 15% of LS cases with late-onset disease and low penetrance phenotype; however, the proportion of PMS2-LS cases is considered to be highly underestimated. In this context, we consulted public available databases (ClinVar, LOVD) for missense and intronic PMS2 variants and performed an in silico analysis of the genomic sequence. Splicing bioinformatics tools proven effective in other genes were used to assess both the wild-type DNA sequence and reported genetic variants. Splicing alterations were predicted in silico and using GTEx short-read RNA expression data. Out of the 2384 missense variants discovered, 90% were classified with uncertain significance (VUS). 4.9% of missense variants were shown to have a potential splicing consequence (DS &gt; 0.2) using SpliceAI. As described in the original publication, SpliceAI-visual was proven effective in annotation of short intronic variants (&lt; 50 bp). Four short intronic variants were identified using SpliceAI-visual as potentially splicing disturbing, in spite of using a lower threshold (DS &gt; 0.1). Moreover, we observed that Splicing Regulatory Elements (SREs) may play a fundamental role in alternative splicing in PMS2 gene, ESE motifs being overrepresented in highly expressed exons 5, 11 and 14. Computational analysis performed in our study serves as a valuable filtering step for guiding further RNA sequencing experiments. Additional functional data is necessary to evaluate the significance of our findings.

Accurate diagnosis for the 400 million people with rare diseases is critical for healthcare decisions, prognosis, understanding disease mechanisms, and identification of treatments. Despite advances in genome sequencing, barriers such as high interpretation costs, diagnostic expertise, throughput associated delays, and uncertain variant classifications persist, with demand exceeding capacity. Many variant classification methods focus narrowly on specific consequences, leading to the use of complex integrative pipelines that often overlook transcript variability and lack prediction transparency. To overcome these limitations, we introduce DITTO. This transparent, transcript-aware machine-learning method demonstrates superior overall performance in accuracy, recall, and precision when compared to existing tools. DITTO is publicly available at https://github.com/uab-cgds-worthey/DITTO

Introduction. Intra-abdominal cystic formations represent heterogeneous pathologies with varied localization and clinical manifestation. The first challenge of a giant intra-abdominal cystic lesion is identifying the organ of origin. The clinical presentation of intra-abdominal cystic lesions varies from acute manifestations to non-specific symptoms or accidental discovery. Case presentation: A 2-year-old girl presents to the emergency unit with a fever of 38.5 Celsius, loss of appetite, and apathy. The investigations showed a gigantic intra-abdominal mass whose organ belonging could not be specified. Postoperatively, a giant mesenteric lymphangioma was evident, which was completely excised. Discussions Giant cystic formations modify the anatomical reports and become space-replacing formations, and the starting point is even more challenging to assess preoperatively. Nevertheless, the careful evaluation of the characteristics of the formation, the effect on the adjacent organs, the age of the patient, and the clinical picture can provide elements of differential diagnosis.

Background: Post-acute sequelae of SARS-CoV-2 infection (PASC) is a complicated disease that affects millions of people all over the world. Previous studies have shown that PASC impacts 10% of SARS-CoV-2 infected patients of which 50-70% are hospitalized. It has also been shown that 10-12% of those vaccinated against COVID-19 were affected with PASC and its complications. The severity and the later development of PASC symptoms is positively associated with the early intensity of the infection. Results: The generated health complications caused by PASC involve a vast variety of organ systems. Patients affected by PASC have been diagnosed with neuropsychiatric and neurological symptoms. Cardiovascular system also has been involved and several diseases such as myocarditis, pericarditis, and coronary artery diseases were reported. Chronic hematological problems such as thrombotic endothelialitis and hypercoagulability were described as a condition that could increase the risk of clotting disorders and coagulopathy in PASC patients. Chest pain, breathlessness, and cough in PASC patients were associated with respiratory system in long COVID-19 causing respiratory distress syndrome. The observed immune complications were notable, involving several diseases. Renal system also was impacted and result in raising the risk of diseases such as thrombotic issues, fibrosis, and sepsis. Endocrine gland malfunction can lead to diabetes, thyroiditis, and male infertility. Symptoms such as diarrhea, nausea, loss of appetite and taste were also among reported observations due to several gastrointestinal disorders. Skin abnormalities might be an indication of infection and long-term implications such as persistent cutaneous complaints were linked to PASC. Conclusions: Long COVID is a multidimensional syndrome with considerable public health implications, affecting several physiological systems and demanding thorough medical therapy as well as more study to address its underlying causes and long-term effects.

Background: By 2025, road traffic injuries are projected to rank third in the global burden of disease, posing a significant challenge that affects health, social well-being, and economic aspects. According to data from the Romanian Police National Statistics Center, there has been an average of 342 traffic accidents per year involving pediatric patients over the past 10 years. Materials and Methods: A retrospective research study was conducted, encompassing 358 cases of road traffic accidents identified for the study. Data collection was conducted at "St. Mary’s" Emergency Hospital for Children in Iasi, Romania, from January 2015 to December 2022. To facilitate statistical analyses, participants were categorized into three specific age groups, correlating between the anatomical region affected and different types of accidents was examined, and the classification of injury types was determined based on the characteristics of the harm inflicted. Results: An oscillating trend is observed from 2015 to 2020, with its lowest value recorded in 2017 at around 6.8% and its peak in 2019 at 20.1%. Notably, post-pandemic (Covid-19), the cases underwent a substantial decline of approximately 50%. At least 78.7% of those who did not undergo orthopedic reduction required surgery, whereas among those who underwent orthopedic reduction, only 23.4% needed surgery. Regarding the frequency of complications 7,9% of the total cases experienced complications. Conclusion: The increased frequency of pediatric traffic accidents is attributed to the extensive services provided by "St. Mary’s" Emergency Hospital for Children, Iasi, to a significant number of patients from both rural and urban areas across the seven counties of the Moldova, Romania.

Considering the worldwide impact of heart failure, it is crucial to develop approaches that can help us comprehend its root cause and make accurate predictions about its outcome. This is essential for lowering the suffering and death rates connected with this widespread illness. Cardiomyopathies frequently result from genetic factors, and the study of heart failure genetics is advancing quickly. Dilated cardiomyopathy (DCM) is the most prevalent kind of cardiomyopathy, encompassing both hereditary and nongenetic abnormalities. It is distinguished by the enlargement of the left ventricle or both ventricles, accompanied by reduced contractility. The discovery of the molecular origins and subsequent awareness of the molecular mechanism is broadening our knowledge of DCM development. Additionally, it emphasizes the complicated nature of DCM and the necessity to formulate several different strategies to address the diverse underlying factors contributing to this disease. Genetic variations that can be transmitted from one generation to another can be a significant contributor to causing family or isolated DCM. Genetic variation also plays a significant role in determining susceptibility for acquired triggers for DCM. The genetic causes of DCM can have a diverse range of phenotypic expressions. It is crucial to select the most probable patients to have advantages from genetic testing. The purpose of this research is to emphasize the significance of identifying genetic DCM, the crucial relationships between genotype and phenotype, and the usefulness of genetic testing in the therapeutic care of both those affected and their relatives. This approach is expected to gain importance once treatment is guided by genotype-specific advice and disease-modifying medications.

Injury to the peritoneum during surgery is followed by a healing process that frequently results in the attachment of adjacent organs by a fibrous mass, referred to commonly as adhesions. Because injuries to the peritoneum during surgery are inevitable, one must understand the mechanisms of adhesion formation to prevent its occurrence. This requires a thorough understanding of the molecular sequence that results in the attachment of injured peritoneum and the development of fibrous tissue. Recent data show that fibroblasts from the injured peritoneum may play a critical role in forming adhesion tissues. Therefore, identifying changes in gene expression patterns in the peritoneal fibroblasts during the process may provide clues to the mechanisms by which adhesion develops. This review presents many papers discussing genes implied in peritoneal adhesion.

This study focuses on the potential medicinal properties of Campsis radicans L. extracts and its aim is to investigate the antioxidant and antiproliferative effects of these extracts on the human colon adenocarcinoma cell line (HT-29). Cytotoxic activity in the HT-29 cell line was evaluated, and the 3-dimensional structures of phenolic compounds were obtained using the GC-MS method. Docking simulations were performed with AutoDock Vina, targeting proteins that are crucial in the apoptotic pathway (Bax, Bcl-2, and Caspase-3). Drug similarities and ADMET estimates of the phenolic compounds were obtained from databases. The highest antioxidant activity of Campsis radicans L. plant was observed in ethanol and water extracts, with notable inhibition capacities. While the total phenolic content was highest in ethanol, water, and ether extracts respectively the total flavonoid content was highest in ethanol, then ether, and water extracts. Certain elements were undetectable in mineral determination, and others exceeded the toxic doses for plants. The water extract exhibited dose-dependent cytotoxic activity in the HT-29 cell line, with an IC50 value of 4.47 mg/mL. Molecular docking results revealed the binding of phenolic molecules to the active sites of apoptotic pathway proteins. The findings suggest that Campsis radicans L. plant possesses cytotoxic properties, significant phenolic and flavonoid content, and a high antioxidant capacity. These properties make it a potential candidate for treatment use, emphasizing its potential therapeutic value in the HT-29 cell line. Further research and exploration on the identified phenolic compounds could contribute to the development of novel therapeutic agents.

The African continent has the highest prevalence of hypertension globally, with South Africa reporting the highest prevalence in Southern Africa. While the influence of genetic variability in the pathogenesis of hypertension is well described internationally, limited reports are available for African populations. This study aimed to assess the association of genetic variants and essential hypertension in a cohort of two ethnic South African population groups. Two hundred and seventy-seven hypertensive and one hundred and seventy-six normotensive individuals were genotyped for 79 variants. Genotyping was performed using the Illumina GoldenGate Assay and allele-specific polymerase chain reaction. The association of variants was assessed using the Fisher Exact test under the additive and allelic genetic models, while multivariate logistic regression was used to predict the development of hypertension. Five variants (CYP11B2 rs179998, AGT rs5051 and rs699, AGTR1 rs5186 and ACE rs4646994) were significantly associated with essential hypertension in the cohort under study. Furthermore, AGTR1 rs5186 and AGT rs699 were identified as risk factors for the development of hypertension in both ethnic groups. In two ethnic South African populations an association was observed between Renin-Angiotensin-Aldosterone System (RAAS) related genes and the development of hypertension.

Background:Fontan completion is the last stage of univentricular repair, which drains the inferior vena cava against gravity to a higher-pressure pulmonary arterial circulation. The passivity and anti-gravity nature of this circulation render a failing Fontan, not an uncommon encounter, twenty years ago, Rodefeld and colleagues, decided to explore the feasibility of vascular pumps to support the passive nature of Fontan circulation, and since then, trials are still ongoing, and we aimed through this review to wrap up the results of these trials. Methods:A literature review has been conducted, to identify any in vivo or in vitro trial of a Fontan assist device. Several outcome parameters determined whether the trial will be included or not in this review, including, the flow rate of a pump if applicable, the number of compressions per minute if a compression device has been used, the resultant flow rate, the inferior and superior vena cava pressures, associated with each setting of the respective device, and any evidence of hemolysis or clotting within the circuit. Results:A total of ten trials have been included, with 23 different settings. Three designs have been identified, out of which two fall within the pump design, namely the connecting chamber and the intravascular pump designs; only one trial explored the possible use of a compression device. The commonest design encountered in in-vivo trials was the intravascular pump (67%). No reports of significant hemolysis or thrombosis were found. An increasing flow rate beyond 5L/min was associated with a negative outcome in the connecting chamber design, increasing upstream pressure in the SVC, while intravascular pumps did not display this limitation. Conclusion:Univentricular heart patients are a relatively small population, with very extensive needs, despite twenty years of trials, no study has yet concluded the optimal design or settings for a Fontan assist device. In this review, we identified that the intravascular pump remains the most practical design, due to its easy mode of insertion, and that it is not faced with the limitation or risk of increasing upstream resistance. There is still a long way to conclude its use as other designs such as compression devices have not yet been fully studied.

Retrospective information about the climate system and plant ecophysiology are key inputs in climate and Earth system modelling. Dendrochronology provides such information with large spatiotemporal coverage, and stable carbon isotope (¹³C/¹²C) analysis across tree-ring series is among the most advanced dendrochronological tools. For the past seventy years, this analysis was performed on whole molecules, and, to this day, ¹³C/¹²C variation is attributed to ¹³C discrimination during CO₂ diffusion into leaves and assimilation by rubisco. By contrast, ¹³C discrimination by post-rubisco processes is presumed constant. Here, recently reported results on the first dataset of intramolecular ¹³C discrimination in tree rings were synthesised by variance component analysis. The emerging picture is not consistent with the classical (DR-discrimination-centred) concepts and practices of carbon-isotope dendrochronology. Specifically, leaf and stem post-rubisco discrimination each account for more variation in the data than diffusion-rubisco discrimination, i.e., post-rubisco discrimination is not constant. Furthermore, diffusion-rubisco discrimination is used widely as proxy of leaf intrinsic water-use efficiency (iWUE), a key determinant in the responses of global biogeochemical cycles to climate change. However, since diffusion-rubisco discrimination is a small component of the total data variance, whole-molecule analysis yields confounded iWUE estimates, yet intramolecular analysis will likely offer solutions. Lastly, all currently observed ¹³C/¹²C-climate relationships are attributed to diffusion-rubisco discrimination. However, here, relationships with temperature and radiation derive from leaf-level post-rubisco discrimination while relationships with precipitation derive from stem-level post-rubisco discrimination. That said, advances in mass spectrometry may soon make intramolecular ¹³C/¹²C analysis broadly available taking carbon-isotope dendrochronology to the next level.

Introduction: The association of gene variants for interleukin 6(IL-6) (rs1800796), interleukin 10 (IL-10) (rs1800896) and tumor necrosis factorα (TNFα (rs1800629) with the occurrence of spontaneous preterm birth (PTB) was investigated to determine whether these genetic variants are a risk factor. Materials and methods: 199 blood samples from pregnant women who had given birth prematurely and 200 control blood samples were analyzed to determine single nucleotide polymor-phisms (SNPs) of genes for IL-6 (rs1800796), IL-10 (rs1800896) and TNFα (rs1800629). The control samples were samples from pregnant women with term delivery. Isolation of DNA was per-formed on mini-spin columns according to the manufacturer's protocol. The quality and purity of the isolated DNA were tested using a Qubit 3 fluorometer. Genotyping was performed with an ABI PRISM 7500 SDS using TaqMan SNP genotyping assays. The genotypes obtained were an-alyzed using the 7500 Software v2.3 package. Results: Carriers of the A/A genotype for the rs1800629 of the TNFα gene have 4.81 times greater chance of late-onset PTB compared to carriers of the G/G and A/G genotypes in the recessive inheritance model. The presence of the G/G genotype in the recessive inheritance model compared with the G/A and A/A genotypes for the rs1800896 of the IL-10 gene represents a potentially protective factor, with mothers in the term-birth group having an almost 2-fold lower odds of PTB in general and an almost 10-fold lower odds of early PTB. On the other hand, carriers of the A/G genotype of rs1800896 have a 1.54-fold higher chance of preterm birth in general and a 1.6-fold higher chance of late preterm birth in the super dominant inheritance model compared to the A/A and G/G genotypes in the group of mothers with PTB. In this study, no association was found between PTB and rs1800796 of the IL-6 gene. Conclusion: rs1800629 in mothers was associated with PTB. rs1800896 shows a potentially protective effect for the occurrence of PTB in this study. No association was found between PTB and rs1800796.

Pediatric psychology action in the pediatric clinical-surgical high complexity unit has become increasingly necessary. It allows for the possibility of integrating complex pediatric clinical-surgical operations by reducing painful effects on the emotional world of children and adolescents. The pediatric psychologist in a pediatric unit continuously oversees children and adolescents (C/A) throughout the entire therapeutic process, extending activity to parents and healthcare personnel. In ill children and adolescents, physical pain and psychological suffering follow, with minimal temporary variations, the same clinical path with continuous changes which put a strain on the ability of children, adolescents, parents and healthcare staff to cope with stress.

Depressive disorder in childhood and adolescence is a highly prevalent mood disorder that tends to recur throughout life. Untreated mood disorders can adversely impact a patient's quality of life and cause socioeconomic loss. Thus, an accurate diagnosis and appropriate treatment is crucial. However, until now, diagnoses and treatments are conducted according to clinical symptoms. Objective and biological validation are lacking. This may result in a poor outcome for patients with depressive disorder. Research has been conducted to identify the biomarkers that are related to depressive disorder. Cumulative evidence has revealed that certain immunologic biomarkers in-cluding brain-derived neurotrophic factor (BDNF) and cytokines, gastrointestinal biomarkers, hormones, oxidative stress, and certain hypothalamus-pituitary axis biomarkers are associated with depressive disorder. This article reviews the biomarkers related to the diagnosis and treatment of pediatric depressive disorders. To date, clinical biomarker tests are not yet available for diagnosis or for the prediction of treatment prognosis. However, cytokines such as Interleukin-2, interfer-on-gamma, tumor necrosis factor-alpha, and BDNF have shown significant results in previous studies of pediatric depressive disorder. These biomarkers have the potential to be used for diagnosis, prognostic assessment, and group screening for those at high risk.

Introduction Blunt carotid injuries (BCI) in pediatric trauma are quite rare. Due to the low number of cases, only a few reports and studies have been conducted on this topic. This review will discuss how frequent BCI/ BCVI on pediatric patients after blunt trauma is, what routine diagnostics look like, if a CT/ CTA scan on pediatric patients after blunt trauma is always necessary and if there are any negative health effects? Methods This literature review includes reviews, systematic reviews, case reports and original studies in english language between 1999 and 2020 that have dealt with pediatric blunt trauma and the diagnostics of BCI and BCVI. Furthermore, publications on the risk of radiation exposure on children were included in the study. For literature research, Medline (PubMed) and the Cochrane library were used. Results Pediatric BCI/ BCVI, shows an overall incidence between 0.03 – 0.5% of confirmed BCI/ BCVI cases due to pediatric blunt trauma. 1.1 – 3.5% of pediatric blunt trauma patients underwent CTA to detect BCI. Only 0.17 – 1.2% of all CTA scans shows a positive diagnosis for BCI. In children, the median volume CT dose index on a non-contrast head CT is 33 milligray, a computed tomography angiography needs at least 138 mGy. A cumulative doses of about 50 mGy almost triples the risk of leukemia, and doses of about 60 mGy triples the risk of brain cancer. Discussion Knowing that a BCI could have extensive neurologic consequences for children, it is necessary to evaluate routine pediatric diagnostics after blunt trauma. Computed tomography scans (CT) and computed tomography angiography (CTA) are mostly used in routine BCI diagnostics. However, since radiation exposure in children should be as low as reasonably achievable, it should be asked if other diagnostic methods could be used to identify risk groups. Trauma guidelines and clinical scores like the McGovern score are reflect established BCI screening options, as well as using duplex ultrasound.

Background: Endoscopic sphincterotomy (EST) has been employed for the endoscopic treatment of common bile duct stones (CBDSs), and a high success rate of stone removal has been reported. However, EST is associated with the risk of bleeding, perforation, and sphincter of Oddi function disruption. To avoid these risks, endoscopic papillary balloon dilation (EPBD) is an option for CBDS. Sphincter of Oddi function preservation decreases long-term biliary infection and gallstone recurrence. EPBD may have advantages in children who require a long follow-up. However, there have been few reports on pediatric cases, particularly in infants. Methods: From September 2017 to December 2023, we performed EPBD for four pediatric CBDSs. The patients were aged from 5 months to 8 years; including two infants aged 5 and 6 months. Furthermore, we reviewed the stone removal rate and complications of 545 ESTs performed at high-volume centers and 13 EPBD-reported cases in children with CBDSs. Results: CBDSs of all patients who underwent EPBD in our institution were successfully removed. No bleeding or perforation was noted, and pancreatitis was observed in three patients. In an analysis of 545 ESTs in children, the stone removal rate was high, ranging from 83% to 100% (mean, 96%). The incidence of pancreatitis was 0%–9.6% (mean, 4.4%), and the grade of pancreatitis was almost mild. The bleeding frequency was 1.3%–5.4% (mean, 2.7%). According to the grade of bleeding, seven and four cases were mild (64%) and moderate (36%), respectively, Compared with adult cases who underwent EST, the frequency of pancreatitis and bleeding was almost similar in children.; however once bleeding occur, it has a higher risk of leading to blood transfusion in children. Stone removal by EPBD in children was 100% successful. All complications were pancreatitis, and its frequency was 46% (6/13 patients, including five mild cases and one moderate case), which is higher than that of EST and adult cases who underwent EPBD. In most children with pancreatitis, pancreatic enzyme levels returned to normal within 2–3 days following EPBD, and no severe cases caused by EPBD were reported. Conclusions: CBDS removal by EPBD in children has a high success rate with very low risk of bleeding and perforation. Although pancreatitis frequently occurs, most cases are mild. Sphincter of Oddi function preservation by EPBD is expected to prevent long-term stone recurrence and biliary tract infection, and EPBD is considered an effective method for CBDS removal in children.

This study delves into the dynamic field of medical education research, emphasizing the integration of research training within medical curricula. It seeks to understand the impact of such integration on the competencies of future medical professionals. The primary aim is to systematically categorize and analyze the current trends and future directions in medical education research. This involves assessing the influence of research training on medical students' skills and the methodologies used in such research. Methods: The research employs an extensive bibliographic literature review across multiple databases. It classifies studies into categories like experiential or case studies, editorials, and original research articles. This classification is based on criteria such as geographical location, research objectives, theoretical frameworks, and methodologies. Results: Findings reveal a diverse landscape in medical education research, with a significant emphasis on research training. The research showcases varying methodologies and approaches used globally, highlighting the thematic focus and geographical distribution of these studies. Conclusion: Medical education research is a globally expansive and evolving field. It underscores the importance of continuous investigation, particularly focusing on integrating research elements at curricular levels and exploring innovative educational strategies. The study also points out potential gaps in research, especially in underrepresented regions, indicating directions for future research efforts.

Critical aortic valve stenosis (CAVS) is a life-threatening cardiac disease of the newborn requiring urgent treatment. First-line therapy is still controversial. The aim of our study was (1) to analyze retrospectively the patients of our institution who underwent balloon aortic valvuloplasty (BAV) due to CAVS, and (2) to describe techniques for improved feasibility of the intervention using microcatheters and retrieval loops. Twelve patients underwent 23 BAVs: 1 BAV was performed in 3 patients, 2 BAVs in 7 patients, and 3 BAVs in 2 patients. Trans-valvular pressure gradient (Δp) and left ventricular shortening fraction (LVSF) improved significantly in the first two interventions; first BAV: Δp from 73.7 ±34.5 mmHg to 39.8 ±11.9 mmHg (p=0.003) and LVSF from 22.3 ± 13.5 % to 31.6 ±10.2 % (p=0.001); second BAV: Δp from 73.2 ±33.3 mmHg to 35.0 ± 20.2 mmHg (p&lt;0.001) and LVSF from 26.7 ±9.6 % to 33.3 ±7.4 % (p=0.004). Cardiac surgery during the neonatal period was avoided for all children; median time to valve surgery was 5.75 years. Few complications occurred: mild to moderate aortic regurgitation, one remediable air embolism, and one intimal injury of the ascending aorta. We conclude that BAV is a successful primary treatment for CAVS resulting in left ventricular relief, stabilization of the neonate, and a time gain until cardiac surgery.

The clinical features of increasing muscle weakening are shared by a diverse set of illnesses known as muscular dystrophies. In early childhood, males with Duchenne muscular dystrophy (DMD) exhibit proximal muscle weakening and calf enlargement, making it the most frequent X-linked disease of muscular dystrophy in children. Development of motor skills is typically delayed, and wheelchair confinement eventually leads to early death from heart or lung problems. In terms of function, ambulation, quality of life, and life expectancy, treatment approaches like corticosteroid therapy and intermittent positive pressure breathing have improved. This is a case report of a 6-year-old kid who had early ambulatory stage Duchenne Muscular Dystrophy and complained to the neuro-physiotherapy department about frequent falls, walking difficulties, and dyspnea when walking. Other grievances included being unable to get off the ground and having trouble ascending stairs. He had physiotherapy and dynamic neuromuscular stabilization for his complaints. The main goals of treatment were educating the family, respiratory training, preventing ankle plantar flexors, maintaining strength, balance and gait training.

The ultimate goal of our review is to draw clinician’s attention, especially of those who are managing pediatric patients with permanent, long-standing, ventriculoperitoneal or, less commonly, ventriculo-atrial shunts. This specific subgroup of patients may eventually suffer from severe, intractable headaches which may negatively impair their quality of daily living. In the absence of any other clinical condition that could be attributed as the cause of the headache, shunt overdrainage should not be overlooked but, on the contrary, should be seriously taken into consideration in the therapeutic armamentarium of such cases, that are difficult to be handled.

In recent years, the focus of disease resistance and susceptibility studies in cattle have been on determining patterns in the innate immune response of key proteins, such as Toll-like receptors (TLR). In the bovine genome, there are 10 TLR family members and, of these, TLR2, TLR4 and TLR6 are specialized in recognition of bacterial ligands. Indigenous cattle breeds of Anatolia have been reported to show fewer signs of clinical bacterial infections, such as bovine tuberculosis and mastitis, and it is hypothesized that this might be due to a less stringent genetic selection during breeding. In contrast, Holstein-Friesian cattle have been under strong selection for milk production, which may have resulted in greater susceptibility to diseases. To test this hypothesis, we have compared the TLR2, TLR4 and TLR6 genes of Anatolian Black (AB), East Anatolian Red (EAR), South Anatolian Red (SAR), Turkish Grey (TG), and Holstein (HOL) cattle using Next Generation Sequencing. The SAR breed had the most variations overall, followed by EAR, AB, TG and HOL. TG had the most variations for TLR2 whereas SAR had the most variations in TLR4 and TLR6. We compared these variants with those associated with disease and susceptibility traits. We used exon variants to construct haplotypes, investigated shared haplotypes within breeds and determined candidate haplotypes for disease resistance phenotype in Anatolian cattle breeds.

Elizabethkingia anophelis is an opportunistic pathogen causing lifethreatening infections in humans, particularly in immunocompromised patients, neonates and elderly. Infections caused by this species are exceptionally challenging to treat due to its multiresistance to antimicrobials. We report a case of central line-associated bloodstream infection by E. anophelis in a 2.5-year-old girl with acute lymphoblastic leukemia successfully treated with a combination of piperacillin/tazobactam and amikacin. The literature was also reviewed on paediatric infections caused by E. anophelis. Accurate identification with MALDI-TOF, or using molecular techniques, is crucial because of varying susceptibilities among species. Early, accurate diagnosis and prompt effective treatment optimize outcomes.

This research ventures into the critical public health challenge of childhood obesity by exploring the dynamic interplay between psychological well-being and Body Mass Index (BMI) throughout various developmental stages of childhood. It delves into how emotional regulation, attachment dynamics, and social relationships correlate with obesity from early childhood to adolescence. Highlighting key findings, such as the negative correlation between psychological resilience and higher BMI in young children, the impact of social relationships on obesity risk during pre-adolescence, and the link between adaptive emotional strategies and higher BMI in adolescents, this study brings to the fore the nuanced relationship between psychological factors and obesity. Utilizing the interdisciplinary process of bioinformatics, this research synergizes psychometric and biomedical data to unearth psychological markers critical for crafting targeted, age-appropriate interventions. This study advocates for a holistic healthcare approach, emphasizing the integration of psychological support within obesity prevention and management strategies, thereby underscoring the indispensable role of psychological factors in the fight against childhood obesity. The application of bioinformatics methods to analyze complex datasets demonstrates how collaboration across medical specialties can enrich our understanding and response to childhood obesity, contributing significantly to the development of comprehensive, bioinformatics-enhanced healthcare solutions.

Proteins need to be located in appropriate spatiotemporal contexts to carry out their diverse biological functions. Mislocalized proteins may lead to a broad range of diseases, such as cancer and Alzheimer’s disease. Knowing where a target protein resides within a cell will give insights into tailored drug design for a disease. As the gold validation standard, the conventional wet lab uses fluorescent microscopy imaging, immunoelectron microscopy, and fluorescent biomarker tags for protein subcellular location identification. However, the booming era of proteomics and high-throughput sequencing generates tons of newly discovered proteins, making protein subcel-lular localization by wet-lab experiments a mission impossible. To tackle this concern, in the past decades, artificial intelligence (AI) and machine learning (ML), especially deep learning methods, have made significant progress in this research area. In this article, we review the latest advances in AI-based method development in three typical types of approaches, including sequence-based, knowledge-based, and image-based methods. We also elaborately discuss existing challenges and future directions in AI-based method development in this research field.

A high intake of carbohydrates, associated with obesity, is one of the major causes of fatty liver disease in humans. This study investigated how high carbohydrate intake induces fatty liver disease in Blunt snout bream (Megalobrama amblycephala). Blunt snout bream were fed a high-carbohydrate diet (HCBD) for 60 days. Their growth indices were evaluated, and the transcriptomes, metabolites, biochemistry, and histology of their blood and livers were analyzed. The final weight, weight gain, specific growth rate, and feed conversion ratio were all higher in the HCBD group than in the control group, but not significantly so (P > 0.05). The hepatosomatic index (HSI) differed significantly in the two groups (P < 0.05), and the metabolomics results showed that a high carbohydrate intake induced significant increases in plasma α/β-glucose, succinate, and tyrosine, which could increase hepatic glycogen and triglyceride. Low levels of betaine were also found in the livers of the HCBD group. The histology and blood biochemistry results suggested abnormal liver, with excessive lipid accumulation and liver damage. A transcriptome analysis and quantitative reverse transcription–PCR (RT–qPCR) indicated that the expression of the factors INSR, IRS, PI3K, PDK, AKT, ACC, IL6, AP1, ChREBP-MLX, PEPCK, and FBP in the insulin signaling pathway was significantly upregulated and that of SOCS3, GSK3β, and AMPK significantly downregulated in the HCBD. This pattern is associated with the nonalcoholic fatty liver disease (NAFLD) pathway. This study extends our understanding of how high carbohydrate causes increased fat deposition in the liver, enhanced glycolysis (α/β-glucose) in the plasma, and reduced betaine in the liver. This leads to activation of hepatocyte insulin resistance and lipogenesis by regulating the expression of genes related to fatty liver disease.

In virology, the term reverse genetics refers to a set of methodologies in which changes are introduced into the viral genome and their effects on the generation of infectious viral progeny and their phenotypic features are assessed. Reverse genetics emerged thanks to advances in recombinant DNA technology, which made the isolation, cloning, and modification of genes through mutagenesis possible. Most virus reverse genetics studies depend on our capacity to rescue an infectious wild-type virus progeny from cell cultures transfected with an “infectious clone”. This infectious clone generally consists of a circular DNA plasmid containing a functional copy of the full-length viral genome, under the control of an appropriate polymerase promoter. For most DNA viruses, reverse genetics systems are very straightforward, since DNA virus genomes are relatively easy to handle and modify and are also (with few notable exceptions) infectious per se. This is not true for RNA viruses, whose genomes need to be reverse transcribed into cDNA before any modification can be done. Establishing reverse genetics systems for members of the Caliciviridae has proven exceptionally challenging, due to the low number of members of this family that propagate in cell culture. Despite the early successful rescue of a calicivirus from a genome-length cDNA more than two decades ago, reverse genetics methods are not routine procedures that can be easily extrapolated to other members of the family. Reports of calicivirus reverse genetics systems have been few and far between. In this review, we discuss the main pitfalls, failures, and delays behind the generation of several successful calicivirus infectious clones.

Centromeres, the chromosomal loci where spindle fibers attach during cell division to segregate chromosomes, are typically found within satellite arrays in plants and animals. Satellite arrays have been difficult to analyze because they comprise megabases of tandem head-to-tail highly repeated DNA sequences. Much evidence suggests that centromeres are epigenetically defined by the location of nucleosomes containing the centromere-specific histone H3 variant cenH3, independently of the DNA sequences where they are located; however, the reason that cenH3 nucleosomes are generally found on rapidly evolving satellite arrays has remained unclear. Recently, long read sequencing technology has clarified the structures of satellite arrays and sparked rethinking of how they evolve, while new experiments and analyses have helped bring both understanding and further speculation about the role these highly repeated sequences play in centromere identification.

(1) Background: Sudden Infant Death Syndrome (SIDS) represents unexplained and sudden deaths during the sleep of infants under one year of age, despite thorough investigation. Screening for prolonged QTc or Long QT Syndrome (LQTS) should be conducted on all newborns to reduce the incidence of SIDS. Neonatal electrocardiogram (ECG) could identify congenital heart defects (CHD) early, especially those not detected at birth. Infants with prolonged QT intervals typically undergo genetic analysis for Long QT Syndrome; (2) Methods: The study involved infants aged 20-40 days, born clinically healthy, with initial ECG screening. Infants with prenatal diagnoses or signs/symptoms of CHD identified immediately after birth, as well as those who underwent ECG or echocardiogram for other clinical or historical indications, were excluded from the study. The data were analyzed using SPSS version 22.0; (3) Results: Of the 42,200 infants involved, 2,245 were enrolled, with 39.9% being males. Subsequently, 164 children (37.8% males) with prolonged QT intervals underwent further diagnostic investigations. Genetic mutations were identified in 11 out of 18 tested children. The most common mutations were LQT1 (54.5%), LQT2 (36.4%), and LQT3 (1 patient). Medications used included propranolol (39.8%), nadolol (22.2%), inderal (11.1%), metoprolol (11.1%), and no treatment (16.7%). The most common abnormalities were focal right bundle branch block (54.5%), left axis deviation (9.2%), and nonspecific ventricular repolarization abnormalities (7.1%). Multiple anomalies were found in 0.47% of children with focal right bundle branch block. Structural abnormalities were associated with specific features in 267 patients (11.9%), primarily isolated patent foramen ovale (PFO) at 61.4%; (4) Conclusions: The screening has proven effective in early diagnosing Long QT Syndrome and other cardiac rhythm anomalies, with additional benefits in detecting mutations and/or QTc prolongations in family members. Identifying other ECG abnormalities and congenital heart malformations further enhances the benefits of the screening.

(1) Background: Sleep disordered breathing represent a growing public health concern, especially among children and adolescents. Full-night polysomnography is considered the gold standard for diagnosing obstructive sleep apnea. Our goals are to identify personal and environmental risk factors for the onset and persistence of sleep respiratory disorders. We also want to investigate the differences in neuropsychological profiles; (2) Methods: This is an observational, retrospective cohort study. We collected information on adenoidectomy or adenotonsillectomy. We reviewed the clinical history and preoperative visits and collected data through a telephone questionnaire. Pediatric Sleep Questionnaire (PSQ) and the Pediatric Quality of Life Inventory (PedsQL) are questionnaires used for screening sleep respiratory disorders in children. The data were statistically analyzed it using SPSS version 22.0 for Windows (SPSS Inc., Chicago, IL); (3) Results: The study involved 138 patients, but only 100 parents participated. A higher percentage of patients with sleep disordered breathing were observed to have mothers who smoked during pregnancy. A smaller proportion of patients with sleep disordered breathing had a habit of using a pacifier. A rise in physical results is associated with a reduction in the PSQ at follow-up (p=0.051). An increase of overall academic achievement is associated with an average decrease in the PSQ at follow-up (p&lt;0.0001). A more significant proportion of patients undergoing adenotonsillectomy were observed to have a history of prematurity and cesarean birth (4) Conclusions: These results provide essential information on the effectiveness and effects of adenotonsillectomy intervention compared to adenoidectomy intervention and the factors associated with SDB in children undergoing these interventions.

The forest regeneration phase in Sweden commonly involves mechanical soil preparation followed by planting of Scots pine or Norway spruce seedlings. The prepared soil offers planting positions with different properties, including decreased damage by pine weevil (Hylobius abietis L.). Nitrogen fertilization can be applied at the time of planting to aid establishment of the seedlings. In this study we compared the effect of organic nitrogen-fertilization for different planting positions, and seedling sizes on early survival and growth of Scots pine and Norway spruce seedlings. The main planting positions were capped mound, hinge, and mineral soil. Seedlings planted close to organic material were categorized as “low quality positions”, since proximity to organic material increase pine weevil attraction. Higher mortality rates related to pine weevil damage were recorded for seedlings planted in the low-quality positions, regardless of seedling size or N-fertilization. Pine weevil attack rates increased with increasing seedling size. Growth was in general lowest in mineral soil positions. The effect of organic N-fertilization on growth was positive for spruce regardless of planting positions and seedling size, while depending on planting position and seedling size for pine, indicating that effects of organic N-fertilization depend on seedling species, -size and planting position.

Pediatric onset multiple sclerosis (POMS), characterized by the onset of multiple sclerosis before the age of 18, is gaining increased recognition. Approximately 5 percent of MS cases manifest before the age of 18, with less than 1 percent occurring before the age of 10. Despite its rarity, pediatric MS exhibits distinct characteristics, with an association between younger age at onset and a comparatively slower disease progression. Despite this slower progression, individuals with POMS historically reach disability milestones at earlier ages than those with adult-onset multiple sclerosis. While various immunomodulatory agents demonstrate significant benefits in MS treatment, such as reduced relapse rates and slower accumulation of brain lesions on magnetic resonance imaging (MRI), the majority of disease-modifying therapies (DMTs) commonly used in adult MS lack evaluation through pediatric clinical trials. Current evidence is predominantly derived from observational studies. This comprehensive review aims to consolidate existing knowledge on the mechanisms of action, efficacy, safety profiles, and recommended dosages of available DMTs specifically in the context of pediatric MS. Furthermore, the review outlines recent advancements and explores potential medications still in developmental stages, providing a thorough overview of the current landscape and future prospects for treating POMS.

Familial Mediterranean fever (FMF) is a systemic autoinflammatory disorder caused by inherited mutations in the MEFV (Mediterranean FeVer) gene located on chromosome 16 (16p13.3) and coding pyrin protein. Despite the existing data on MEFV mutations, the exact mechanism of their effect on the development of pathological processes leading to autoinflammation observed in FMF, remains unclear. Induced pluripotent stem cells (iPSCs) are considered an important tool for studying the molecular genetic mechanisms of various diseases due to their ability to differentiate into any cell type, including macrophages, which contribute to the development of FMF. In this study, we developed iPSCs of an Armenian patient with FMF having M694V, p.(Met694Val) (c.2080A&gt;G, rs61752717) pathogenic mutation in exon 10 of the MEFV gene. As a result of direct differentiation, macrophages expressing CD14 and CD45 surface markers were obtained. In addition, we found that the morphology of patient macrophages derived from iPSCs with MEFV mutation was significantly different from that of differentiated from iPSCs of a healthy donor carrying wild-type MEFV gene.

The genetic bases of Alzheimer's disease (AD) and frontotemporal dementia (FTD) have been comprehensively studied, which is not the case for atypical cases not classified into these diagnoses. In the present study, we aim to contribute to the molecular understanding of the development of non-AD and non-FTD dementia by surveying rare pathogenic variants. The analysis was performed on 91 patients, the DNA samples of which were pooled and then subjected to whole exome sequencing. Among detected variants two are rare pathogenic and show significant difference in frequency between the analyzed pool and gnomAD Bulgarian control exomes. The rs373478202, G&gt;T, B9D1 variant, most likely present in heterozygous state; is causative for the autosomal recessive ciliopathy- Joubert syndrome, which involves specific CNS malformation. The rs148918985, C&gt;T, ASS1 variant leads to arginosuccinate enzyme deficiency and in compound heterozygosity with other rare pathogenic variant detected in the same gene causes the late-onset form of citrullinemia type I. This disorder causes high ammonia levels, which can lead to cerebral dysfunction. In conclusion, the detected rare pathogenic variants suggest that, in certain cases, the development of non-AD and non-FTD dementia can be mediated by structural alterations in neuronal cilia or by hyperammoniemia.

Attention-Deficit/Hyperactivity Disorder (ADHD) exhibits a notable prevalence across diverse populations, with estimates ranging from 4% to 6%. This wide range prompts an investigation into the evolutionary and genetic underpinnings of ADHD, especially considering the markedly different environments faced by ancestral human populations compared to today's structured societies. This study examines the potential adaptive advantages of ADHD-associated traits in hunter-gatherer contexts, where hyperactivity, impulsivity, and novelty-seeking behaviors may have conferred survival benefits. We employ the principles of population genetics, including Hardy-Weinberg equilibrium, selection coefficients, and genetic drift, to model the dynamics of ADHD allele frequencies over time. Additionally, we discuss balancing selection as a mechanism for maintaining genetic diversity and how gene-environment interactions (GxE) contribute to the expression of ADHD in contemporary settings. Our analysis suggests that traits associated with ADHD, while potentially maladaptive in modern structured environments, could have been preserved through evolutionary processes due to their adaptive value in ancestral contexts. Understanding these dynamics provides a comprehensive view of ADHD's prevalence and highlights the significance of genetic and environmental interplay in shaping human behavior.

Novel genetic risk markers have helped to advance the field of cardiovascular epidemiology and refine our current understanding and risk stratification paradigms. Discovery and analysis of variants can help to tailor prognostication and management. However, populations underrepresented in cardiovascular epidemiology and cardiogenetics research may experience inequities in care if prediction tools are not applicable to them clinically. Therefore, the purpose of this article is to outline the barriers that underrepresented populations can face in participating in genetics research, describe current efforts to diversify cardiogenetics research, and outline strategies that researchers in cardiovascular epidemiology can implement to include underrepresented populations. Mistrust, a lack of diverse research teams, improper use of sensitive biodata, and constraints of genetic analyses are all barriers for including diverse populations in genetics studies. Current work is beginning to address the paucity of ethnically diverse genetics research and has already begun to shed light on the potential benefits of including underrepresented and diverse populations. Reducing barriers for individuals, utilizing community-driven research processes, adopting novel recruitment strategies, and pushing for organizational support for diverse genetics research are key steps that clinicians and researchers can take to develop equitable risk stratification tools and improve patient care.

Habituation is the most ancient and fundamental form of learning. As a firewall that protects our brain from sensory overload, it is indispensable for higher cognitive processes. Studies in humans and animal models provide a growing body of evidence that habituation is affected in autism and related monogenic neurodevelopmental disorders (NDDs). An integrated application of habituation assessment in NDDs and their animal models has currently unexploited potential for fundamental neuroscience and medical care.With the aim to gain mechanistic insights, we systematically retrieved genes that have been demonstrated in the literature to underlie habituation. We identified 258 evolutionarily conserved genes across species, describe the biological processes they converge on, and highlight regulatory pathways and drugs that may alleviate the habituation deficits associated with their dysregulation. We also summarize current habituation paradigms and extract the most decisive arguments from the literature that support the crucial role of habituation for cognition in health and disease. We conclude that habituation is a conserved, quantitative, cognition- and disease-relevant process that can connect preclinical and clinical work, and hence is a powerful tool to advance research, diagnostics,’’ and treatment of NDDs.

Vascular anomalies are a diverse group of abnormal blood vessel developments that can occur at birth or shortly afterward. Embolization and sclerotherapy have been utilized as a treatment option for these malformations but may cause moderate to severe pain. This study aims to evaluate the utilization of peripheral nerve blocks in opioid consumption, pain scores, and length of stay. A retrospective chart review was conducted at the UPMC Children's Hospital of Pittsburgh for all patients who underwent embolization and sclerotherapy between 2011 and 2020. Patient data was collected to compare opioid consumption, pain scores, and length of stay. Eight hundred fifty-four procedures were performed on 347 patients. The morphine milligram equivalent per kilogram mean ratio between groups was 0.9 (0.86, 0.95) with a p-value of &lt;0.001. The pain score mean ratio was –1.17 (–2.2, -0.1) and a p-value of 0.027. Length of stay had a mean ratio of 0.94 (0.4, 2) and a p-value of 0.875. By decreasing opioid consumption and postoperative pain scores, peripheral nerve blocks may have utility in patients undergoing embolization and sclerotherapy while not clinically increasing the length of stay for patients. Their use should be individualized and carefully discussed with the interventional radiologist.

Lectins are carbohydrate-interacting proteins playing a pivotal role in multiple physiological and developmental aspects of all organisms. They can specifically interact with different bacterial and viral pathogens through the carbohydrate-recognition domains (CRD). In addition, lectins are also of biotechnological interest because of their potential use as biosensor for capturing and identification of bacterial species. In this work, we have characterized the bacterial agglutination properties of three C-type lectins from the Lepidoptera Spodoptera exigua. One of these lectins, BLL2, was able to agglutinate cells from a broad range of bacterial species at an extremely low concentration, becoming a very interesting protein to be used as biosensor or other biotechnological applications involving bacterial capturing.

Objective: The causes of vertigo and dizziness in children are diverse and require attention from various specialists. Numerous authors have reported that the commonest type of vertigo in children is migraine-associated vertigo (vestibular migraine and benign paroxysmal vertigo of childhood - BPV). We aimed to check whether this could be applied to our group of patients. Materials and methods: A retrospective case series of 257 consecutive pediatric vertigo and diz-ziness patients referred to the tertiary pediatric ENT clinic from 2015 to 2020. Patients received a complete audiovestibular workup and were referred to pediatric neurologists and other special-ists depending on the signs and symptoms. Results: Of 257 children aged 1-17 years, almost one fifth of them, 49/257 (19.1 %) had a central type of vertigo, 20/257 of them (7.8%) had benign paroxysmal vertigo of childhood and 4/257 (1.6%) had a migrainous type of vertigo. Most of the children, 112/257 (43.6%), remained unclas-sified, without a final diagnosis. Conclusion: Due to the numerous possible causes, a child presenting with dizziness and vertigo requires a multidisciplinary approach. In the majority of cases, vertigo spells are self-limiting. They stop spontaneously and sometimes remain clinically undiagnosed. The most prevalent reasons for pediatric vertigo may be temporary hemodynamic (vaso-vagal) and psychological imbalance.

Alzheimer´s disease (AD) is characterized by the brain deposition of senile plaques composed by amyloid-β peptides (Aβ) that increase inflammation. An endogenous peptide derived from the insulin-like growth factor (IGF)-I, glycine-proline-glutamate (GPE) has IGF-I-sensitizing and neuroprotective actions. Here, we examined the effects of GPE on Aβ levels and hippocampal inflammation generated by the intracerebroventricular infusion of Aβ25-35 during 2 weeks (300 pmol/day) in ovariectomized rats and the signaling-related pathways and levels of Aβ-degrading enzymes associated with these GPE-related effects. GPE prevented the Aβ-induced increase in the phosphorylation of p38 mitogen-activated protein kinase and the reduction in activation of signal transducer and activator of transcription 3, insulin receptor substrate-1 and Akt, as well as on interleukin (IL)-2 and IL-13 levels in the hippocampus. The functionality of somatostatin, measured as the percentage of inhibition of adenylate cyclase activity and the levels of insulin-degrading enzyme were also preserved by GPE co-treatment. These findings indicate that GPE co-administration may protect from Aβ insult by changing hippocampal cytokine content and somatostatin functionality through regulation of leptin- and IGF-I-signaling pathways that could influence the reduction in Aβ levels through modulation of levels and/or activity of Aβ proteases.

Bio-absorbable stents are a novel tool which relieve stenosis and then resorb as the patient grows, avoiding obligatory re-intervention. This case describes the novel use of an iron bio-absorbable stent in a child with surgically repaired Tetralogy of Fallot who post-operatively developed a severely stenotic right ventricular outflow tract.

Diseases pose a significant and pressing concern for the sustainable development of the aquaculture sector, particularly as their impact continues to grow due to climatic shifts such as rising water temperatures. While various approaches, ranging from biosecurity measures to vaccines, have been devised to combat infectious diseases, their efficacy is disease- and species-specific and contingent upon a multitude of factors. The field of genetics and genomics offer effective tools to control and prevent disease outbreaks in aquatic animal species. In this study, we present the key findings from our recent research, focusing on the genetic resistance to three specific diseases: White Spot Syndrome Virus WSSV) in white shrimp, Bacterial Necrotic Pancreatitis (BNP) in striped catfish and skin fluke (a parasitic ailment) in yellowtail kingfish. Our investigations reveal that all three species possess substantial heritable genetic components for disease resistant traits, indicating their potential responsiveness to artificial selection in genetic improvement programs tailored to combat these diseases. Also, we observed a high genetic association between disease traits and survival rates. Through selective breeding aimed at enhancing resistance to these pathogens, we achieved substantial genetic gains, averaging 10% per generation. These selection programs also contributed positively to the overall production performance and productivity of these species. Although the effects of selection on immunological traits or immune responses were not significant in white shrimp, they yielded favourable results in striped catfish. Furthermore, our genomic analyses, including shallow genome sequencing of pedigreed populations, enriched our understanding of the genomic architecture underlying disease resistance traits. These traits are primarily governed by a polygenic nature, with numerous genes or genetic variants, each with small effects. Leveraging a range of advanced statistical methods, from mixed models to machine and deep learning, we developed prediction models that demonstrated moderate to high levels of accuracy in forecasting these disease-related traits. In addition to genomics, our RNA-seq experiments identified several genes that undergo upregulation in response to infection or viral loads within the populations. Preliminary microbiome data, while offering limited predictive accuracy for disease traits in one of our studied species, underscore the potential for combining such data with genome sequence information to enhance predictive power for disease traits in our populations. Lastly, this paper briefly discusses the roles of precision agriculture systems, AI algorithms, and outlines the path for future research to expedite the development of disease-resistant genetic lines tailored to our target species. In conclusion, our study underscores the critical role of genetics and genomics in fortifying the aquaculture sector against the threats posed by diseases, paving the way for more sustainable and resilient aquaculture development.

Epidemiological data highlight prostate cancer as a significant global health issue, with high incidence and substantial impact on patients' quality of life. The prevalence of this disease is associated with various factors, including age, heredity, and race. Recent research in prostate cancer genetics has identified several genetic variants that may be associated with an increased risk of developing the disease. However, despite the significance of these findings, genetic markers for prostate cancer are not currently utilized in clinical practice as reliable indicators of the disease. In addition to genetics, epigenetic alterations also play a crucial role in prostate cancer development. Aberrant DNA methylation, changes in chromatin structure, and microRNA (miRNA) expression are major epigenetic events that influence oncogenesis. Existing markers for prostate cancer, such as prostate-specific antigen (PSA), have limitations in terms of sensitivity and specificity. The cost of testing, follow-up procedures, and treatment for false-positive results and overdiagnosis contributes to the overall healthcare expenditure. Improving the effectiveness of prostate cancer diagnosis and prognosis requires either narrowing the risk group by identifying new genetic factors or enhancing the sensitivity and specificity of existing markers. Immunological biomarkers (both circulating and intra-tumoral), including markers of immune response and immune dysfunction, represent a potentially useful area of research for enhancing the diagnosis and prognosis of prostate cancer. Our review emphasizes the need for developing novel immunological biomarkers to improve the diagnosis, prognosis, and management of prostate cancer. We highlight the most recent achievements in the identification of biomarkers provided by circulating monocytes and tumor-associated macrophages (TAMs). We highlight that monocytes-derived and TAMs-derived biomarkers can enable to establish the missing links between genetic predisposition, hormonal metabolism and immune responses in prostate cancer.

Externalizing behavior in its more extreme form is often considered a problem to the individual, their families, teachers and society as a whole. Several brain structures have been linked to externalizing behavior and such associations may arise if the (co)development of externalizing behavior and brain structures share the same genetic and/or environmental factor(s). We assessed externalizing behavior with the Child Behavior Checklist and Youth Self Report, and brain volumes and white matter integrity (FA and MD) with magnetic resonance imaging in the BrainSCALE cohort, consisting of twins and their older siblings from 112 families measured longitudinally at ages 10, 13, and 18 years of the twins. Genes influenced externalizing behavior and changes therein (h2 up to 88%). More pronounced externalizing behavior was associated with higher FA (observed correlation rph up to +0.20) and lower MD (rph up to –0.20); with sizeable genetic correlations (FA ra up to +0.42; MD ra up to –0.33). Cortical gray matter (CGM; rph up to –0.20) and cerebral white matter (CWM; rph up to +0.20) volume were phenotypically but not genotypically associated with externalizing behavior. These results suggest a potential mediating role for global brain structures in the display of externalizing behavior during adolescence that are both partially explained by the influence from the same genetic factor.

Bioenergetics, genetic coding, and catalysis are all difficult to imagine emerging without pre-existing historical context. That context is often posed as a “Chicken and Egg” problem; its resolution is concisely described by de Grasse Tyson: “the egg was laid by a bird that was not a chicken”. The concision and generality of that answer furnish no details—only an appropriate framework from which to examine detailed paradigms that might illuminate paradoxes underlying these three life-defining biomolecular processes. We examine experimental aspects here of five examples that all conform to the same paradigm. The paradox in each example is resolved by coupling if, and only if, conditions for two related transitions between levels. One drives, and each restricts fluxes through, or “gates” the other. That reciprocally-coupled gating, in which two gated processes constrain one another, maps onto the formal structure of “strange loops”. That mapping may help unite the axiomatic foundations of genetics, bioenergetics, and catalysis. As a physical analog for Gödel’s logic, biomolecular strange-loops provide a natural metaphor around which to organize these data, linking biology to the physics of information, free energy, and the second law of thermodynamics.

Background: clubfoot is a common congenital deformity. The Ponseti technique, involving early corrective manipulations followed by the application of long leg casts and Achilles tenotomy, is widely accepted as the preferred treatment. Rapid healing of the tendon after surgery has been documented, but the aspect regarding tendon structure and properties is not known. Three cases of Achilles tendon rupture in adolescent previously treated for clubfoot have been described in the literature. Since rupture is a rare event in this age group a possible correlation with previous surgery has been hypothesized. The primary aim of the study was to compare the ultrasound findings of the Achilles tendon, in patients treated for clubfoot, between patients treated with casting alone and the ones who underwent surgery (percutaneous tenotomy or Z-plasty lengthening). Methods: 22 asymptomatic patients, (34 feet) median age 12 years, previously treated for clubfoot, were recruited for this study; the patients underwent an Achilles tendon ultrasound examination during a follow-up outpatient visit. Results: a greater thickness and structural alterations with presence of hypoechoic areas of the operated tendons compared to those treated with plaster alone were observed (p value: 0.0498 and

It has been shown that Human papillomavirus (HPV) infection is associated with several forms of cancer. Additionally, although there are more than 100 types of HPV, more than ten types of it, including types 16 and 18, are considered high-risk. The two proteins that make up the viral capsid of HPV 16 are L1, the major capsid protein, and L2, the minor capsid protein. FDA (The Food and Drug Administration) approved HPV vaccines mostly target L1 and L2 capsid proteins, which facilitate intracellular entry during infection. In this study, it was set out to analyze the creation of phylogenetic relations of L1 nucleic acid sequences of viral isolates. This study also analyzed sequences of three key elements within the amino acid sequences of HPV 16 L1: loops critical for structural stability, nuclear localization signal sequences, and residues implicated in viral attachment. As highlighted by the literature, these elements represent pivotal aspects of viral function. Furthermore, the report highlighted the particular inter-sequence variability within the HPV 16 L1 protein sequences. Overall analysis revealed clustering of sequences primarily due to geographical and characterized by more phylogenetic relatedness within location-specific clusters.

Background: DICER1, cancer predisposition syndrome (CPS), seems to escape timely diagnosis in pediatric patients. Case report 1: A 16-year-old female patient was referred to the endocrinology ward due to a large goiter. Her medical history indicated normal sexual maturation, with menarche occurring at 13.5 years. Over the past 2.5 years, she developed pronounced androgenic symptoms, including a deepened male voice, facial, back and neckline acne, hirsutism, and menstrual irregularities leading to secondary amenorrhoea. A thyroid ultrasound identified a multinodular goiter with cystic-solid lesions containing calcifi-cations. An abdominal ultrasound identified a 5.7x6.9 cm solid mass in the right adnexal region, displacing the uterus to the left. Histopathological examination confirmed a Sertoli-Leydig cell tumor. The patient was subjected to total thyroidectomy. Histopathology revealed benign follicular cell-derived neoplasms. Thyroid follicular nodular disease was diagnosed bilaterally. DNA analysis using NGS, confirmed by the Sanger method, revealed a pathogenic heterozygotic variant c.2953>T [p.Gln985*] in exon 18 of DICER1 gene. Case report 2: A 12-year-old male patient was admitted to the pediatric surgery unit due to a 33 ml goiter. A month prior to admission, the patient discovered a palpable nodule in his neck, accompanied by hoarseness. An ultrasound revealed a multinodular goiter. Molecular analysis revealed a pathogenic heterozygotic variant c.2782C>T [p.Gln928Ter] in exon 17 of DICER1 gene. Subsequently, a total thyroidectomy was performed, and histopathological examination revealed thyroid follicular nodu-lar disease bilaterally. Conclusion: Multinodular goiter, although rare in pediatric population, when accompanied by characteristic ultrasound and histopathological features, and by additional features such as androgen excess, warrants exclusion of DICER1 syndrome.

Sepsis is a serious disease that can lead to mortality. The etiology of the disease is connected to how the body as a host reacts toward microbes such as bacteria, viruses, and fungi invasion. Current research shows that during sepsis, the reaction toward microbe attacks takes two main phases. The first is known as a cytokine storm, while the second is a vicious cycle of pro-inflammatory responses followed by a strict anti-inflammatory response led by CD4+ Tregs. Various immunomodulatory therapies have been proposed to break the cycle of pro- and anti-inflammatory reactions to sepsis. However, clinical trials did not show promising results, indicating further research into the mechanism that Treg uses to inhibit proinflammatory reactions. We used next-generation sequencing (NGS) analysis of bulk RNA-seq and single-cell RNA-seq data to examine the exact molecular pathways used by Treg to inhibit the immune response in sepsis. Our approach identified ACOD1 (Aconitate Decarboxylase 1) as a primary mediator of Treg suppression of immune cells. We identified and validated CD36 as a downstream target of ACOD1. CD36 is a known metabolite regulator in Tregs. Taken together, our results indicate that targeting ACOD1 could prove valuable in regulating Treg function during sepsis.

Probabilistic and parsimony-based arguments regarding available genetics data are used to propose that Hardy and Higgin’s amyloid cascade hypothesis is valid but is commonly interpreted too narrowly to support, incorrectly, the primacy of the amyloid beta peptide (Aβ) in driving Alzheimer’s disease pathogenesis. Instead, increased activity of the βCTF (C99) fragment of APP is likely the critical pathogenic determinant altered by mutations in the APP gene. This model is consistent with the regulation of APP mRNA translation via its 5’ iron responsive element (IRE). Similar arguments support that the pathological effects of familial Alzheimer’s disease mutations in the genes PSEN1 and PSEN2 are not exerted directly via changes in APP cleavage to produce different ratios of Aβ length. Rather, these mutations likely affect the stability of presenilin holoprotein and/or γ-secretase multimers with consequences for γ-secretase activity and other important cellular functions. All fAD mutations in APP, PSEN1, and PSEN2 likely find unity of pathological mechanism in their actions on endolysosomal acidification and mitochondrial function, with detrimental effects on iron homeostasis and promotion of “pseudo-hypoxia” being of central importance. Aβ production is enhanced and distorted by oxidative stress and accumulates due to decreased lysosomal function. It may act as a disease-associated molecular pattern (DAMP) enhancing oxidative stress-driven neuroinflammation during the cognitive phase of the disease. We also discuss fascinating, but largely ignored, data on presenilin biology that may be important in understanding presenilins’ central role in familial Alzheimer’s disease.

Ploidy is a significant type of genetic variation, describing the number of chromosome sets per cell. Ploidy evolves in natural populations, clinical populations, and lab experiments, particularly in fungi. Despite a long history of theoretical work on this topic, predicting how ploidy will evolve has proven difficult, as it is often unclear why one ploidy state outperforms another. Here, we review what is known about contemporary ploidy evolution in diverse fungal species through the lens of population genetics. As with typical genetic variants, ploidy evolution depends on the rate that new ploidy states arise by mutation, natural selection on alternative ploidy states, and random genetic drift. However, ploidy variation also has unique impacts on evolution, with the potential to alter chromosomal stability, the rate and patterns of point mutation, and the nature of selection on all loci in the genome. We discuss how ploidy evolution depends on these general and unique factors and highlight areas where additional experimental evidence is required to comprehensively explain the ploidy transitions observed in the field and the lab.

The global pandemic of COVID-19 accounts for more than 14,000 deaths worldwide. However, little is known about the host genetics interaction with infection and COVID-19 progression. To better understand the role of host genetics, we review the current literature, aggregate readily available genetic resources, and provide some updated analysis relevant to COVID-19 and associated phenotypes. Using the unrelated individuals in UK Biobank (total n = 337,579 across 5 populations), we aggregate human leukocyte antigen and ABO blood type frequencies. We find significant and consistent risk reduction of blood group O reported in Zhao et al. and encourage broad sharing of ABO blood type frequencies that are readily accessible across COVID-19 with mild, moderate, and severe/critical symptoms for robust inferences at https://tinyurl.com/abo-covid19. In addition, we generate polygenic risk scores (PRSs) weights for 29 blood measurements, including clinically relevant haematological measurements for COVID-19, such as lymphocyte count and percentage. Focusing on the 8 most COVID-19 clinically relevant blood measurements, we performed PRS-PheWAS analysis across 44 disease antigen measurements (n = 6,643 unrelated individuals in White British group), infectious diseases and acute respiratory infections (n = 20,928 cases and 349,000 controls across 3 population groups) and deaths (n = 1,846 cases and 368,082 controls), recorded in hospital inpatient record and death registry data, respectively, in UK Biobank, and find host genetic PRS associations with disease risk. Taken together, we anticipate these resources (https://github.com/rivas-lab/covid19) will aid in improving our understanding of host genetic risk factors playing a role in SARS-CoV-2 infection and COVID-19 disease severity.

Von Hippel-Lindau disease (VHL) is a multiple organ neoplastic syndrome with autosomal dominant transmission, complete penetrance, and variable expression caused by mutations in the VHL gene. Although VHL disease is hereditary in many cases, new mutations cause up to 20 % of the incidence. Mutations in VHL may cause the development of cysts and tumors in many organs, including brain and spinal cord hemangioblastoma, renal cell carcinoma (RCC), retinal heman-gioblastoma (RH), pheochromocytoma, epididymal and broad ligament cystadenomas, endo-lymphatic sac tumor, pancreatic neuroendocrine tumors, and renal and pancreatic cysts. VHL is a syndrome associated with functional inactivation of the Von Hippel–Lindau protein (pVHL). pVHL is a tumor suppressor mainly known for its role as a regulator of hypoxia-inducible factor (HIF) activity. The prevalence of VHL disease is between 1 in 39 000 and 1 in 91 000 individuals in different regional populations. Here, we review the etiology, epidemiology, pathophysiology, genetics, clinical manifestations, diagnosis, and current treatments, as well as the molecular aspects of this disease. We also discuss the animal models used to study this disease, VHL biomarkers, and current VHL clinical trials for VHL according to NIH.

This article is devoted to the results of in-depth analysis of the system of binary-oppositional structures in DNA n-plet alphabets and their algebraic-matrix representations. These results show that the molecular complementary replication of DNA strands is accompanied by the presence of an algebraic version of the principle "like begets like" in matrix representations of DNA alphabets having internal structures. This algebraic version is based on binary-oppositional structures in the genetic molecular system, which can be represented by binary numbers and corresponding matrices of DNA alphabets. The received results allow thinking that the phenomenon "like begets like" (or a complementary replication in a wide sense) is systemic in the genetic organization and is connected with algebraic features of biological organization. Correspondingly, the biological principle "like begets like" can be additionally modeled by algebraic-matrix methods and approaches. Such algebra-matrix modeling of the genetic coding system gives new ways for studying and understanding the key role of the named principle in genetic and other inherited physiological complexes. On this way, the author discovered general rules of stochastic organization of information binary sequences of genomic DNAs of eukaryotes and prokaryotes. The presented rules are connected with information dichotomies of probabilities and corresponding fractal-like trees of probabilities, which fundamentally differ from constructional dichotomies in biological bodies. The received phenomenological data and rules lead to new biological ideas.

Nowadays, the human population is facing the third and may be the worst pandemic caused by human coronaviruses (CoVs). The virus was first reported in Wuhan, China on 31 December 2019 and spread within short time to almost all countries of the world. Genome analysis of the early virus isolates has revealed high similarity with SARS-CoV and hence the new virus was officially named SARS-CoV-2. Since CoVs have the largest genome among all RNA viruses, they can adapt many point mutation and recombination events; particularly in spike gene, that enable these viruses to rapidly change and evolve in nature. CoVs are known to cross the species boundaries by using different cellular receptors. SARS-CoV-2 is believed to originate in bats and transmitted to human being through an ill-defined intermediate host. In the current review, different aspects of SARS-CoV-2 biology and pathogenicity are discussed including virus genetics and evolution, spike protein and its role in evolution and adaptation to novel hosts, and virus transmission and persistence in nature. In addition, the immune response developed during SARS-CoV-2 infection is demonstrated with special reference to the interplay between immune cells and their role in disease progression. We believe that SARS-CoV-2 outbreak will not be the last and spillover of CoVs from bats will continue. Therefore, establishing intervention approaches to reduce the likelihood of future CoVs spillover from the natural reservoirs is a priority.

Biological control is widely successful for controlling pests, but effective biocontrol agents are now more difficult to obtain due to more restrictive international trade laws. Coupled with increasing demand, the efficacy of existing and new biocontrol agents needs to be improved with genetic and genomic approaches. Although they have been underutilised in the past, applying genetic and genomic techniques is becoming more feasible from both technological and economic perspectives. We review current methods and provide a framework for using them, incorporating evolutionary and ecological principles. First, it is necessary to identify which biocontrol trait to select and in what direction. Next, the genes or markers linked to these traits need be determined to better target their selection, followed by how to implement this information into a breeding program. Choosing a trait can be assisted by modelling to account for the proper agro-ecological context, and by knowing which traits have sufficiently high heritability values. We provide guidelines for designing genomic strategies in biocontrol programs, which depends on the organism, budget, and desired objective. Genomic approaches start with genome sequencing and assembly. We provide a guide for deciding the most successful sequencing strategy for biocontrol agents. Gene discovery involves quantitative trait loci (QTL) analyses, transcriptomic and proteomic studies, and gene editing. Improving biocontrol practices include marker-assisted selection, genomic selection and microbiome manipulation of biocontrol agents, and monitoring for genetic variation during rearing and post-release. We conclude by identifying the most promising applications of genetic and genomic methods to improve biological control efficacy.

The present study was performed to examine that transforming growth factor beta (TGF-β) in root-surrounding tissues on deciduous teeth during the physiological root resorption regulates the differentiation induction into odontoclast. We prepared root-surrounding tissues with (R) or without (N) physiological root resorption scraped off at three regions (R1-R3 or N1-N3) from the cervical area to the apical area of the tooth and measured both TGF-β and the tartrate-resistant acid phosphatase (TRAP) activities. The TGF-β activity level was increased in N1-N3, whereas the TRAP activity was increased in R2 and R3. In vitro experiments for RANKL-mediated osteoclast differentiation revealed that TGF-β in N1-N3 and R1-R3 enhanced the TRAP activity in RAW264 cells. A genetic study indicated that the mRNA level of TGF-β1 in N1 and N2 was significantly increased, and corresponded with that of osteoprotegerin (OPG). In contrast, the expression level of receptor activator of NF-κB ligand (RANKL) was increased in R2 and R3. Our findings suggest that TGF-β is closely related to the regulation of OPG induction and RANKL-mediated odontoclast differentiation depending on the timing of RANKL and OPG mRNA expression in the root-surrounding tissues of deciduous teeth during physiological root resorption.

(1) Background: Grapes and their associated by-products (as grape pomace, GP) stand out for their polyphenol content, which makes them a source of bioactive compounds with antioxidant capacity. The aim of this research was to determine if the inclusion of 50 g/kg of GP in the diet of hens could enrich egg with antioxidants and to study its effect on internal and external egg quality parameters. (2) Methods: A trial was conducted with two genetic lines of hens, which were fed either a control diet or a diet containing 50 g/kg of GP. Performance, internal and external egg quality, and egg yolk content of vitamins E and A, and gallic acid were determined; (3) Results: In eggs laid by hens fed GP diet, Haugh units and yolk colour score were enhanced, and eggshell became thinner, but without affecting the breaking strength. No dietary effect was observed on vitamin contents in yolk. Higher gallic acid content was observed in yolk of eggs laid by hens fed the GP diet, suggesting that some dietary phenolic compounds could be transferred to the eggs. Hen genetics influenced egg weight, albumen Haugh units, shell thickness and α- and γ-tocopherol concentration in yolks; (4) Conclusions: Dietary inclusion of GP improved the internal quality of eggs, enriching yolks with a phenolic compound, but reduced shell thickness.

Since the first published genome sequence of Trypanosoma cruzi in 2005, there has been tremendous technological advance in genomics, reverse genetics, and assay development for this elusive pathogen. However, there is still an unmet need for new and better drugs to treat Chagas disease. Here we introduce a T. cruzi assay strain that is useful for drug research as well as basic studies in host-pathogen interaction. Trypanosoma cruzi STIB980 is a strain of discrete typing unit TcI that grows well in culture as axenic epimastigotes or intracellular amastigotes. We have evaluated the optimal parameters for genetic transfection and constructed derivatives of T. cruzi STIB980 that express reporter genes for fluorescence- or bioluminescence-based drug efficacy testing, as well as a Cas9-expressing line for CRISPR/Cas9-mediated gene editing. The genome of T. cruzi STIB980 was sequenced by combining short-read Illumina with long-read Oxford Nanopore technologies. The latter served for the primary assembly, the former to correct mistakes and fill the gaps. This resulted in a high-quality nuclear haplotype assembly of 28 Mb in 400 contigs, containing 10,043 open-reading frames with a median length of 1077 bp. We believe that T. cruzi STIB980 is a useful addition to the antichagasic toolbox, and propose that it can serve as a DTU TcI reference strain for drug efficacy testing.

Programmed aging refers to the idea that mammals (and some other multiparous sexually reproducing organisms) evolved complex biological mechanisms that cause gradually increasing fitness deterioration and internally limit individual organism lifetimes. The rationale is that this process enhances the survival (non-extinction) of a species population. Evolvability theories propose that mammals have evolved design characteristics that aid their ability to evolve, that is, reduce the time required for a particular increment of evolutionary adaptation and/or increase the precision with which the adaptation can be performed. Because an increase in evolvability aids a population in escaping extinction, evolution selects the associated design characteristics. Both of these concepts conflict with traditional (Darwinian) theory regarding the nature of evolution. However, more recent genetics discoveries have exposed rich detail regarding the nature of the evolution process including the fact that biological inheritance involves the transmission of organism design information from parent to descendant in digital form. These discoveries have acted to support both programmed aging and evolvability theories. Acquisition traits are those that depend for their evolutionary (fitness) value on the acquisition of something that gradually accumulates during an organism’s life but is not transmitted genetically to descendants. This situation causes these traits including language, immunity, intelligence, and social status to represent a special need for evolvability and programmed aging.

G-protein-coupled receptors (GPCRs) are ubiquitous sensors and regulators of cellular functions. Each GPCR exists in complex aggregates with multiple resting and active conformations. Designed to detect weak stimuli, GPCRs can also activate spontaneously, resulting in basal ligand-free signaling. Agonists trigger a cascade of events leading to an activate agonist-receptor-G protein complex with high agonist affinity. However, the ensuing signaling process can further remodel the receptor complex to reduce agonist affinity, causing rapid ligand dissociation. The acutely activated ligand-free receptor can continue signaling, as proposed for rhodopsin and  opioid receptors, resulting in robust receptor activation at low agonist occupancy with enhanced agonist potency. Continued receptor stimulation can further modify the receptor complex, regulating sustained ligand-free signaling - proposed to play a role in opioid dependence. Basal, acutely agonist-triggered, and sustained elevated ligand-free signaling could each have distinct functions, reflecting multi-state conformations of GPCRs. This review addresses basal and stimulus-activated ligand-free signaling, its regulation, genetic factors, and pharmacological implications, focusing on opioid and serotonin receptors, and the growth hormone secretagogue receptor (GHSR). Ligand-free signaling of intracellular 5-HT2A receptors could mediate therapeutic effects of psychedelic drugs. Research avenues are suggested to close gaps in our knowledge of ligand-free GPCR signaling.

Revealing the time structure of physical or biological objects is usually performed thanks to the tools of signal processing like the fast Fourier transform, Ramanujan sum signal processing and many other techniques. For space-time topological objects in physics and biology, we propose a type of algebraic processing based on schemes in which the discrimination of singularities within objects is based on the space-time-spin group SL(2,C). Such topological objects possess an homotopy structure encoded in their fundamental group and the related SL(2,C) multivariate polynomial character variety contains a plethora of singularities somehow analogous to the frequency spectrum in time structures. Our approach is applied to an Akbulut cork in exotic R4, to an hyperbolic model of topological quantum computing based on algebraic surfaces and to microRNAs in genetics. Such diverse topics reveal the manifold of possibilities of using the concept of a scheme spectrum.

The wetlands in northeastern Bangladesh are home to some of the most prolific and valuable ecosystems on the planet, offering a wide range of benefits to both the local and wider communities. A limited number of research on this topic have been carried out in various wetlands in coastal hilsa, but none have been located in the northeastern region of Bangladesh. Thus, the goal of this study was to better understand the most commercially relevant species (anadromous hilsa) in northeastern Bangladesh as well as to assess the wetland ecosystem services more thoroughly with the contribution of their fish genetic resources. In addition to laboratory studies, fieldwork was done in the fishing settlements along the Surma River, Hakaluki Haor, and Tanguar Haor. The study classified 77 fish species into 21 subcategories of ecosystem services, of which 56% were not threatened, 17% were vulnerable, and 10% were highly endangered. The species Hilsa was found to be the most economically significant, accounting for 1% of the GDP overall. The study determined if the hilsa stock of the examined wetlands maintains a single or several subpopulations in comparison to other parts of the country when they migrate from saline water to northeastern Bangladesh (freshwater). But when compared to other groups, the FST score was between 0.000 to 0.017, indicating that the populations are identical and that there is genetic material sharing between them. Additionally, these statistics imply that the Sylhet haor and adjacent river systems contain a single stock of Hilsa fish. Nevertheless, a number of stresses and risks, including overexploitation, illicit and destructive fishing, siltation, and natural disasters like flash floods, have been linked to changes in the supply of hilsa and other ecosystem services. This study also emphasizes the necessity of policy attention and research to address the concerns.

Aim: The purpose of this study was to collect prevalence data of Hypomineralized Second Primary Molars (HSPM) and Molar Incisor Hypomineralization (MIH) among pediatric patients treated by dental practitioners in Northern Italy and assess the practitioners’ awareness of these conditions. Methods: A cross-sectional pilot study was conducted using a structured online questionnaire administered through Google Forms. The survey comprised 10 single-choice questions addressing the prevalence of opacities affecting molars and an index of HSPM and MIH in caries-free children aged 6-9 years, categorized by percentage. Results: A total of 315 dentists participated in the survey, yielding a response rate of 31.5%. The majority of respondents (59%) reported HSPM prevalence in 1-25% of their patients, while 18% observed no opacity in any of their patients. MIH was observed in HSPM patients in 1-25% and 25-50% of cases, as reported by 44% and 31% of respondents, respectively. Among non-HSPM patients, MIH was observed in 1-25% of children (reported by 74% of respondents). Conclusion: The findings from this pilot survey show substantial agreement with existing prevalence data on HSPM and MIH reported in the literature. The co-occurrence rate of HSPM and MIH defects supports the hypothesis of HSPM potentially serving as a predictor of MIH. The study underscores a significant need to enhance awareness of these defects for early diagnosis and effective management. Additionally, there is a call for the promotion of standardized diagnostic protocols to obtain more accurate epidemiological data.

Congenital heart disease (CHD) is a prevalent congenital disorder diagnosed with high frequency, affecting approximately 0.8% to 1.2% of all live births. Research has demonstrated that the use of pulse oximetry and clinical examination as a screening tool for CHD diagnosis has proven extremely valuable. We conducted a retrospective longitudinal study over a 3-year period that involved screening 1188 newborns admitted to the NICU during the first 72 hours of life within this timeframe. 201 newborns were diagnosed with CHD. Almost all (n=198) had a positive screening test during the 72-hour period, while 3 had a negative screening test, but were later diagnosed using echocardiography. The prevalence rate was 16.67%. A confusion matrix was constructed with 198 true positives (TP), 3 false negatives (FN), no false positives (FP), and 987 true negatives (TN). The sensitivity of the screening test was 98.51%, while the specificity 100%, with no false positives. In our study, a total of 9 deaths occurred. Using the Kaplan-Meier method, the survival probability appeared to be slightly above 0.9 (95.5%), indicating that almost all patients survived past 72 hours after being diagnosed with CHD. Pulse oximetry is an effective, low cost and easy-to-use method and a useful tool to assess and lead to the diagnosis of CHD.

This study unveils verapamil's compelling cytoprotective and proliferative effects on pancreatic β-cells amidst diabetic stressors, spotlighting its unforeseen role in augmenting cholecystokinin (CCK) expression. Through rigorous investigations employing MIN6 β-cells and zebrafish models under type 1 and type 2 diabetic conditions, we demonstrate verapamil's capacity to significantly boost β-cell proliferation, enhance glucose-stimulated insulin secretion, and fortify cellular resil-ience. A pivotal revelation of our research is verapamil's induction of CCK, a peptide hormone known for its role in nutrient digestion and insulin secretion, which signifies a novel pathway through which verapamil exerts its therapeutic effects. Furthermore, our mechanistic insights reveal that verapamil orchestrates a broad spectrum of gene and protein expressions pivotal for β-cell survival and adaptation to immune-metabolic challenges. In vivo validation in a zebrafish larvae model confirms verapamil's efficacy in fostering β-cell recovery post-metronidazole inflic-tion. Collectively, our findings advocate for verapamil's reevaluation as a multifaceted agent in diabetes therapy, highlighting its novel function in CCK upregulation alongside enhancing β-cell proliferation, glucose sensing, and oxidative respiration. This research enriches the therapeutic landscape, proposing verapamil not only as a cytoprotector but also as a promoter of β-cell re-generation, thereby offering fresh avenues for diabetes management strategies aimed at pre-serving and augmenting β-cell functionality.

Hemoglobinopathies are a group of disorders in which the hemoglobin molecule has abnormal production or structure. The hemoglobin molecules in red blood cells (RBC) are impacted by the blood disease known as sickle cell disease (SCD), and Thalassemia is one of the major monogenic disorders that reduces hemoglobin production( Kohne et al ., 2011). This disorder results in a large number of red blood cells being destroyed, leading to anemia. India bears a huge burden of hemoglobinopathies; thalassemia is the most prevalent (Mondal SK et al., 2016). A key component of thalassemia prevention is a successful screening procedure to identify Thalassemia carriers. Effective screening programs have numerous obstacles, especially in environments with limited resources. Machine learning (ML) has been used to solve technical and domain-specific problems in a variety of prognostic and diagnostic medical jobs. In this work, we aimed to identify and analyze the most common mutation of β--thalassemia and sickle cell disease from the north Indian population by employing Machine learning-based algorithms. To accurately predict the carrier state from a simple blood test, and to predict pathogenic hemoglobin variants in a group of individuals, these results demonstrate the application of integrated bioinformatics and machine learning approaches. This study contributes to the validation of the models based on data from several individuals and hemoglobinopathies.

The purpose of this article is to highlight the new advancements in molecular and diagnostic genetic testing as well as properly classify all ovarian cancers. In this article we address statistics, histopathological classification, molecular pathways implicated in ovarian cancer, genetic screening panels and details about the genes, and also candidate genes. We hope to bring new information in the medical field as to better prevent and diagnose ovarian cancer.

There has been a revolution in crop breeding, the age-old technique of improving plant features for agricultural and nutritional purposes. The merging of Artificial Intelligence (AI) and genetics is the driving force behind these changes. The combination of AI-driven models, genomic data, and cutting-edge tools like CRISPR-Cas9 to speed up genetic improvements in crops is described in this abstract. From increased disease resistance and production potential to better nutritional content, AI plays a crucial role in the identification and improvement of crop features. The time it takes to review, select, and cross several generations of crops is reduced by AI's data-driven selection, precision editing, and predictive modeling. This innovative tool has the potential to transform farming by helping to combat issues like hunger, climate change, and malnutrition on a worldwide scale. Equal access, protecting genetic variety, and assessing risks are only some of the ethical and regulatory issues raised by AI-enhanced agricultural breeding. Responsible and equitable implementation of AI in agricultural breeding relies on successfully navigating these challenges. Finally, the use of artificial intelligence to improve crop breeding marks a revolutionary change in agriculture, speeding up genetic improvements to meet the needs of a growing global population while also addressing urgent environmental and nutritional concerns. This abstract provides a taste of the promise, difficulty, and ethical questions that characterize this innovative subject, where artificial intelligence and genetics join forces to grow a better future for agricultural production around the world.

Hereditary polyposis syndromes are rare but potentially devastating conditions which require multidisciplinary care from an early age. Societal guidelines serve as the framework for disease diagnosis, surveillance and treatment. Guidelines are based on expert opinion and ideally are evidence-based; however, recommendations may vary among different societies and can result in discordant care. This paper aims to summarize key differences in management based on societal guidelines for pediatric polyposis syndromes and identify some of the factors which may contribute to divergence in care.

Apple replant disease (ARD) is a complex issue caused by various fungal, oomycetes pathogens and parasites which can differ in their abundance between sites within a geographic region. Knowledge of the specific etiology of ARD at a particular site is required in order to develop commercially viable soil management strategies to combat specific/individual components of the disease. In this study we analyzed the soil from six ARD sites for the presence of fungal, bacterial and oomycetes communities and plant parasitic nematodes. Five fungal, and 17 bacterial classes were differentially represented in the microbiomes from different locations. Mortierellomycetes was the most abundant fungal taxa represented followed by Sordariomycetes. Mortierella exigua a fungal endophyte was the most abundant fungal amplicon sequence variant (ASV) in the core microbiome. Proteobacteria was the most prevalent phylum identified in orchard soils. Several potential phytopathogenic fungi involved in ARD and endophytes including Fusarium oxysporum, F. solani, Nectria ramulariae, Ilyonectria robusta and Nectriaceae were identfied in the orchard soil. Pythium attrantheridium (Globisporangium attrantheridium), P. monospermum and P. ultimum (Globisporangium ultimum) were the most abundant oomycete taxa identified in these soil samples. Six different groups of plant-parasitic nematodes were found across the six orchards soil. Root-lesion nematodes, Pratylenchus spp., which are commonly associated with ARD, were identified in all orchards soil at population densities ranging from 12 to 33/100 cm3 soil. This research contributes valuable understanding of the ARD complex as the apple industry needs alternative approaches to combat the disease.

Abstract: Congenital hyperinsulinism (CHI) is a rare disorder of glucose metabolism and is the most common cause of severe and persistent hypoglycemia (hyperinsulinemic hypoglycemia, HH) in the neonatal period and childhood. Most cases are caused by mutations in the ABCC8 and KCNJ11 genes that encode the ATP-sensitive potassium channel (KATP). We present the correlation between genetic heterogeneity and the variable phenotype in patients with early-onset hyperinsulinemic hypoglycemia caused by ABCC8 gene mutations. In the first patients, which presented persistent severe hypoglycemia since the first day of life, molecular genetic testing revealed the presence of a homozygous mutation in the ABCC8 gene [deletion in the ABCC8 gene c.(2390+1_2391-1)_(3329+1_3330- 1)del] correlated with a diffuse form of hyperinsulinism (the parents being healthy heterozygous carriers). In the second patient, the onset was on the third day of life with severe hypoglycemia, and genetic testing identified a heterozygous mutation in the ABCC8 gene c.1792C&gt;T (p.Arg598*) inherited on the paternal line, which led to the diagnosis of focal form of hyperinsulinism. To locate the focal lesions, (18)F-DOPA (3,4-dihydroxy-6-[18F]fluoro-L-phenylalanine) PET/CT was recommended (an investigation that cannot be carried out in the country), but the parents refused to carry out the investigation abroad. In this case, early surgical treatment could have been curative. In addition, the second child also presented secondary adrenal insufficiency requiring replacement therapy. At the same time, she developed early recurrent seizures that required antiepileptic treatment. We emphasize the importance and of molecular genetic testing for diagnosis, management and genetic counseling in patients with HH.

Prenatal maternal feeding plays an important role in fetal development and has potential to cause long-lasting epigenetic modifications. MicroRNAs (miRNAs) are non-coding, single-stranded RNAs that serve as one epigenetic mechanism. Though miRNAs have crucial roles in fetal programming, growth, and development, there are limited data regarding maternal diet and sheep miRNA expression. Therefore, weanalyzed high and low maternal dietary protein for miRNA expression in sheep fetal longissimus dorsi. Pregnant ewes were fed an isoenergetic high-protein (HP, 160–270 g/day), low-protein (LP, 73–112 g/day), or standard protein diet (SP, 119–198 g/day) during pregnancy. miRNA expression profiles were evaluated using the Affymetrix GeneChip miRNA 4.0 Array. Twelve up-regulated, differentially expressed miRNAs (DE miRNAs) were identified targeting 65 genes. The oar-3957-5p miRNA was highly up-regulated in LP and SP compared to HP. Previous transcriptome analysis identified integrin and non-receptor protein tyrosine phosphatase genes targeted by miRNAs detected in the current experiment. A total of 28 GO terms and 10 pathway-based gene sets were significantly (padj &lt; 0.05) enriched in target genes. Most genes targeted by identified miRNAs are involved in immune and muscle disease pathways. Our study shows dietary protein intake during pregnancy affects fetal skeletal muscle epigenetics via miRNA expression.

Aims/Hypothesis): Type 1 diabetes is an immune-mediated disease with destruction of the pancreatic β-cells, a process that is conditioned by multiple genes and other factors. HLA counts as the major susceptibility gene. Significant variations in HLA genetic susceptibility to type 1 diabetes between Caucasians, African and Asian and other ethnic groups may have led to the variation in incidence of type 1 diabetes globally. Type 1 diabetes is characterized upon HLA identification. In this chapter we discuss global variations in genetic susceptibility of HLA with regard to type 1 diabetes globally with a particular attention to Arab population. Methods): Haplotype configuration of HLA class I A, B, C and Class II –DR/DQ/DP were studied in Caucasians, African and Asian and in Arab population to see if that is responsible for the exponential rise in the rate of type 1 diabetes. Results): Although Arabs have one of the highest global incidence and prevalence rates of type 1 diabetes, unfortunately, there is a dearth amount of information regarding HLA genetic susceptibility to type 1 diabetes in the Arab world. HLA haplotype configurations contribute to its risk value. However, out of an insufficient present study there are examples of misjudgment of HLA risk according to HLA alleles rather than haplotypes. Conclusion): To date HLA outlooks for the characterization of type 1 diabetes. There is an ethnicity difference in HLA characteristics which is responsible for variation in type 1 diabetes. Although Arab population have contributed heavily in the rise of burden of type 1 diabetes, however, there is significantly a dearth amount of studies on HLA in Arab population. Obviously, any future prediction, prevention or cure of the disease will be based on the HLA genetics. There is a dire need for a systematic screening of HLA for Arab population with type 1 diabetes, identification of Arab HLA-risk values and identify those who are prone to get the disease.

Chronic pain is a serious health concern and potentially debilitating condition, leading to anxiety, depression, reduced productivity and functionality, and poor quality of life. This condition can be even more detrimental and incapacitating in the pediatric patient population. In low and middle income countries (LMICs), pain services are inadequate or unavailable, leaving most of the world's pediatric population with chronic pain untreated. Many of these children in LMICs are suffering without treatment, and often die in pain. Awareness and advocacy for this population must be prioritized. We reviewed the available literature on the chronic pediatric pain burden in LMICs, barriers to treatments, and current efforts to treat these patients.

The rest-breaking agent, hydrogen cyanamide (HC), can substitute insufficient chill unit accumulation in Vitis vinifera and induce uniform bud-break; however, due to its toxicity it is being banned. In South Africa, red seedless grapes, including V. vinifera Crimson Seedless (CS), are the largest table grape export group; therefore, replacing HC in V. vinifera CS is crucial. This study aimed to confirm the molecular triggers induced by HC and assess the bud-break-enhancing abilities of commercial plant biostimulants. Forced bud-break assay experiments using V. vinifera CS single-node cuttings and a small-scale field trial were performed. Results demonstrated that increased chill unit accumulation (CUA), reduced HC efficacy. Bud-break started between 10 and 20 days after treatment, irrespective of final CUA. The small-scale field trial found that HC3 % resulted in a slightly delayed bud-break rate, whilst biostimulants were similar to the negative control. The treatment of dormant grapevine compound buds with nitric oxide (NO), hydrogen peroxide (H2O2), and hypoxia trigger dormancy-release to a certain extent, supporting the molecular models proposed for HC action. NO, H2O2, and hypoxia, in combination with PBs, may potentially replace HC; however, this needs to be confirmed in future experiments.

The present work sets out the evaluation of composite laminates through optimization objective functions. Genetic Algorithms (GA), as well as Simulated Annealing (SA), were performed in order to determine the optimal ply orientations of a fiber-reinforced polymer laminate for three given load cases: 1) in-plane loads, 2) combined moments, and 3) in-plane loads and combined moments. It searches the optimal orientation layup, which fulfills at the same time both the maximum strain criterion and the Tsai-Wu failure criterion. Construction of an objective function based on the strains and the stresses involves a minimization process to deformations and a maximization of the safety factor. For the first load case, the initial solution is [±45/0/90/±45]s, and the best solution is [(45/135)2/452]s. For the second load case, [-45/45/45/-45/0/90]s is the initial layup sequence, then the best solution obtained is [(45/-45)2/452]s, where plies at 0° and 90º are not necessary even when axial loads are applied. For the third study case, the original layup sequence is [0/45/-45/45/0/90]s; meanwhile, the best solution calculated is [21/24/145/140/45/49]s. An interesting observation is that each pair of layers has a 5º gap. The simulations show that the qualitative results from the GA are better than the SA, but with a significantly higher computational cost. These kinds of computational tools are expected to be used as a reference guide for an optimal fiber configuration with respect to the common orientations used when composite laminates are designed for a structural application.

Iron deficiency (ID) is by far the most common nutritional disorder in developing and developed countries. When left untreated, ID leads to anemia. Although the usual recommended treatment for iron deficiency anemia (IDA) is oral iron therapy with countless products, such therapy necessitates administration for &gt;3-6 months with questionable patient compliance since most oral iron products have an unpleasant metallic aftertaste and cause intestinal side effects. In addition, in certain gastrointestinal conditions, such as inflammatory bowel diseases or untreated gluten-sensitive enteropathy, oral iron therapy is contraindicated or unsuccessful. Intravenous iron is considered safe in adults, where adverse events are mild and easily managed. The experience with parenteral iron in children is much more limited and many pediatricians appear reluctant to use it because of uncorroborated fears of serious anaphylactic reactions. In the current article, we thoroughly review the available pediatric literature on the use of all commercially available parenteral iron products except ferumoxytol, which was recently removed from the market. We conclude that parenteral iron appears to be safe in children, it works faster than oral iron and the newer third-generation products allow replacement of the total iron deficit at a single setting.