EMQN best practice guidelines for the molecular genetic testing and reporting of chromosome 11p15 imprinting disorders: Silver–Russell and Beckwith–Wiedemann syndrome

Molecular genetic testing for the 11p15-associated imprinting disorders Silver–Russell and Beckwith–Wiedemann syndrome (SRS, BWS) is challenging because of the molecular heterogeneity and complexity of the affected imprinted regions. With the growing knowledge on the molecular basis of these disorders and the demand for molecular testing, it turned out that there is an urgent need for a standardized molecular diagnostic testing and reporting strategy. Based on the results from the first external pilot quality assessment schemes organized by the European Molecular Quality Network (EMQN) in 2014 and in context with activities of the European Network of Imprinting Disorders (EUCID.net) towards a consensus in diagnostics and management of SRS and BWS, best practice guidelines have now been developed. Members of institutions working in the field of SRS and BWS diagnostics were invited to comment, and in the light of their feedback amendments were made. The final document was ratified in the course of an EMQN best practice guideline meeting and is in accordance with the general SRS and BWS consensus guidelines, which are in preparation. These guidelines are based on the knowledge acquired from peer-reviewed and published data, as well as observations of the authors in their practice. However, these guidelines can only provide a snapshot of current knowledge at the time of manuscript submission and readers are advised to keep up with the literature

Reductions in hypothalamic Gfap expression, glial cells and α-tanycytes in lean and hypermetabolic Gnasxl-deficient mice

BACKGROUND: Neuronal and glial differentiation in the murine hypothalamus is not complete at birth, but continues over the first two weeks postnatally. Nutritional status and Leptin deficiency can influence the maturation of neuronal projections and glial patterns, and hypothalamic gliosis occurs in mouse models of obesity. Gnasxl constitutes an alternative transcript of the genomically imprinted Gnas locus and encodes a variant of the signalling protein Gαs, termed XLαs, which is expressed in defined areas of the hypothalamus. Gnasxl-deficient mice show postnatal growth retardation and undernutrition, while surviving adults remain lean and hypermetabolic with increased sympathetic nervous system (SNS) activity. Effects of this knock-out on the hypothalamic neural network have not yet been investigated. RESULTS: RNAseq analysis for gene expression changes in hypothalami of Gnasxl-deficient mice indicated Glial fibrillary acid protein (Gfap) expression to be significantly down-regulated in adult samples. Histological analysis confirmed a reduction in Gfap-positive glial cell numbers specifically in the hypothalamus. This reduction was observed in adult tissue samples, whereas no difference was found in hypothalami of postnatal stages, indicating an adaptation in adult Gnasxl-deficient mice to their earlier growth phenotype and hypermetabolism. Especially noticeable was a loss of many Gfap-positive α-tanycytes and their processes, which form part of the ependymal layer that lines the medial and dorsal regions of the 3(rd) ventricle, while β-tanycytes along the median eminence (ME) and infundibular recesses appeared unaffected. This was accompanied by local reductions in Vimentin and Nestin expression. Hypothalamic RNA levels of glial solute transporters were unchanged, indicating a potential compensatory up-regulation in the remaining astrocytes and tanycytes. CONCLUSION: Gnasxl deficiency does not directly affect glial development in the hypothalamus, since it is expressed in neurons, and Gfap-positive astrocytes and tanycytes appear normal during early postnatal stages. The loss of Gfap-expressing cells in adult hypothalami appears to be a consequence of the postnatal undernutrition, hypoglycaemia and continued hypermetabolism and leanness of Gnasxl-deficient mice, which contrasts with gliosis observed in obese mouse models. Since α-tanycytes also function as adult neural progenitor cells, these findings might indicate further developmental abnormalities in hypothalamic formations of Gnasxl-deficient mice, potentially including neuronal composition and projections

Automated Research Review Support Using Machine Learning, Large Language Models, and Natural Language Processing

Research expands the boundaries of a subject, economy, and civilization. Peerreview is at the heart of research and is understandably an expensive process. This work,with human-in-the-loop, aims to support the research community in multiple ways. Itpredicts quality, and acceptance, and recommends reviewers. It helps the authors andeditors to evaluate research work using machine learning models developed based on adataset comprising 18,000+ research papers, some of which are from highly acclaimed,top conferences in Artificial Intelligence such as NeurIPS and ICLR, their reviews, aspectscores, and accept/reject decisions. Using machine learning algorithms such as SupportVector Machines, Deep Learning Recurrent Neural Network architectures such as LSTM, awide variety of pre-trained word vectors using Word2Vec, GloVe, FastText, transformerarchitecture-based BERT, DistilBERT, Google’s Large Language Model (LLM), PaLM 2, andTF-IDF vectorizer, a comprehensive system is built. For the system to be readily usable andto facilitate future enhancements, a frontend, a Flask server in the cloud, and a NOSQLdatabase at the backend are implemented, making it a complete system. The work is novelin using a unique blend of tools and techniques to address most aspects of building asystem to support the peer review process. The experiments result in a 86% test accuracyon acceptance prediction using DistilBERT. Results from other models are comparable, withPaLM-based LLM embeddings achieving 84% accuracy

Cancer in Northwest Louisiana: 1988-1992, Volume 8, Issue 8

Mission: To collect and report complete, high-quality, and timely population-based cancer data in Louisiana to support cancer research, control, and prevention. Vision: To reduce suffering and death from cancer using information collected by the Louisiana Tumor Registry. History: Cancer registration in Louisiana began in 1947 at the Charity Hospital Tumor Registry in New Orleans. In 1974, as part of its Surveillance, Epidemiology and End Results (SEER) Program, the National Cancer Institute provided funds for a population-based cancer incidence and survival registry covering Jefferson, Orleans, and St. Bernard parishes. Five years later, the Louisiana Tumor Registry (LTR) was transferred to the state Office of Public Health, which expanded the LTR catchment area in 1983 to include all 35 parishes of South Louisiana (Regions I-V). In 1988, when the 29 parishes of North Louisiana (Regions VI-VIII) were added, statewide coverage was achieved. Milestones in the history of the LTR include: 1974: The LTR became one of the original participants in the National Program of Cancer Registries, funded by the Centers for Disease Control and Prevention (CDC). 1995: The LTR was transferred from the Office of Public Health to the LSU Board of Supervisors. Since then, the LSU Health Sciences Center in New Orleans has been responsible for the cancer registry program, providing the state funding. 2001: The Louisiana Tumor Registry was selected as one of four new expansion registries to join the prestigious SEER Program after a rigorous competitive application process. Oversight of the registry is exercised by the Louisiana Cancer and Lung Trust Fund Board. Members of this board represent various health institutions throughout the state and are appointed by the governor.https://digitalscholar.lsuhsc.edu/soph_wp/1121/thumbnail.jp

Novel substituted methylenedioxy lignan suppresses proliferation of cancer cells by inhibiting telomerase and activation of c-myc and caspases leading to apoptosis

Conventional solvent fractionation and bioactivity based target assays were used to identify a new anti-cancer molecule from Phyllanthus urinaria, a herbal medicinal plant used in South India. At each step of the purification process the different fractions that were isolated were tested for specific anti-proliferative activity by assays measuring the inhibition of [3H]thymidine incorporation, and trypan blue drug exclusion. The ethyl acetate fraction that contained the bioactivity was further purified and resolved by HPLC on a preparative column. The purity of each of the fractions and their bioactivity were checked. Fraction 3 demonstrated a single spot on TLC and showed maximum anti-proliferative activity. This fraction was further purified and the structure was defined as 7′-hydroxy-3′,4′,5,9,9′-pentamethoxy-3,4-methylene dioxy lignan using NMR and mass spectrometry analysis. The pure compound and the crude ethyl acetate fraction which showed anti-proliferative activities were examined for ability to target specific markers of apoptosis like bcl2, c-myc and caspases and for effects on telomerase. Four specific cancer cell lines HEp2, EL-1 monocytes, HeLa and MCP7 were used in this study. The results indicate that 7′-hydroxy-3′,4′,5,9,9′-pentamethoxy-3,4-methylene dioxy lignan was capable of inhibiting telomerase activity and also could inhibit bcl2 and activate caspase 3 and caspase 8 whose significance in the induction of apoptosis is well known. We believe that this compound could serve as a valuable chemotherapeutic drug after further evaluations

Diagnosis and management of Silver–Russell syndrome: first international consensus statement

This Consensus Statement summarizes recommendations for clinical diagnosis, investigation and management of patients with Silver–Russell syndrome (SRS), an imprinting disorder that causes prenatal and postnatal growth retardation. Considerable overlap exists between the care of individuals born small for gestational age and those with SRS. However, many specific management issues exist and evidence from controlled trials remains limited. SRS is primarily a clinical diagnosis; however, molecular testing enables confirmation of the clinical diagnosis and defines the subtype. A 'normal' result from a molecular test does not exclude the diagnosis of SRS. The management of children with SRS requires an experienced, multidisciplinary approach. Specific issues include growth failure, severe feeding difficulties, gastrointestinal problems, hypoglycaemia, body asymmetry, scoliosis, motor and speech delay and psychosocial challenges. An early emphasis on adequate nutritional status is important, with awareness that rapid postnatal weight gain might lead to subsequent increased risk of metabolic disorders. The benefits of treating patients with SRS with growth hormone include improved body composition, motor development and appetite, reduced risk of hypoglycaemia and increased height. Clinicians should be aware of possible premature adrenarche, fairly early and rapid central puberty and insulin resistance. Treatment with gonadotropin-releasing hormone analogues can delay progression of central puberty and preserve adult height potential. Long-term follow up is essential to determine the natural history and optimal management in adulthood

Using priorities between human and livestock bacterial antimicrobial resistance (AMR) to identify data gaps in livestock AMR surveillance.

BackgroundBacterial antimicrobial resistance (AMR) is a global threat to both humans and livestock. Despite this, there is limited global consensus on data-informed, priority areas for intervention in both sectors. We compare current livestock AMR data collection efforts with other variables pertinent to human and livestock AMR to identify critical data gaps and mutual priorities.MethodsWe globally synthesized livestock AMR data from open-source surveillance reports and point prevalence surveys stratified for six pathogens (Escherichia coli, Staphylococcus aureus, non-typhoidal Salmonella, Campylobacter spp., Enterococcus faecalis, Enterococcus faecium) and eleven antimicrobial classes important in human and veterinary use, published between 2000 and 2020. We also included all livestock species represented in the data: cattle, chickens, pigs, sheep, turkeys, ducks, horses, buffaloes, and goats. We compared this data with intended priorities calculated from: disability-adjusted life years (DALYs), livestock antimicrobial usage (AMU), livestock biomass, and a global correlation exercise between livestock and human proportion of resistant isolates.ResultsResistance to fluoroquinolones and macrolides in Staphylococcus aureus were identified as priorities in many countries but, less than 10% of these reported livestock AMR data. Resistance data for Escherichia coli specific to cattle, chickens, and pigs, which we prioritized, were also well collected. AMR data collection on non-typhoidal Salmonella and other livestock species were often not prioritized. Of 232 categories prioritized by at least one country, data were only collected for 48% (n = 112).ConclusionsThe lack of livestock AMR data globally for broad resistance in Staphylococcus aureus could underplay their zoonotic threat. Countries can bolster livestock AMR data collection, reporting, and intervention setting for Staphylococcus aureus as done for Escherichia coli. This framework can provide guidance on areas to strengthen AMR surveillance and decision-making for humans and livestock, and if done routinely, can adapt to resistance trends and priorities