Identification of novel small-molecule inhibitors of SARS-CoV-2 by chemical genetics.

There are only eight approved small molecule antiviral drugs for treating COVID-19. Among them, four are nucleotide analogues (remdesivir, JT001, molnupiravir, and azvudine), while the other four are protease inhibitors (nirmatrelvir, ensitrelvir, leritrelvir, and simnotrelvir-ritonavir). Antiviral resistance, unfavourable drug‒drug interaction, and toxicity have been reported in previous studies. Thus there is a dearth of new treatment options for SARS-CoV-2. In this work, a three-tier cell-based screening was employed to identify novel compounds with anti-SARS-CoV-2 activity. One compound, designated 172, demonstrated broad-spectrum antiviral activity against multiple human pathogenic coronaviruses and different SARS-CoV-2 variants of concern. Mechanistic studies validated by reverse genetics showed that compound 172 inhibits the 3-chymotrypsin-like protease (3CLpro) by binding to an allosteric site and reduces 3CLpro dimerization. A drug synergistic checkerboard assay demonstrated that compound 172 can achieve drug synergy with nirmatrelvir in vitro. In vivo studies confirmed the antiviral activity of compound 172 in both Golden Syrian Hamsters and K18 humanized ACE2 mice. Overall, this study identified an alternative druggable site on the SARS-CoV-2 3CLpro, proposed a potential combination therapy with nirmatrelvir to reduce the risk of antiviral resistance and shed light on the development of allosteric protease inhibitors for treating a range of coronavirus diseases.

Phenotypic presentation of MEN1 c.758delC (p.Ser253Cysfs *28) pathogenic variant: a case report.

MEN1 is a rare syndrome caused by mutations in the MEN1 gene. We describe a clinical case of MEN1 syndrome associated with a recently discovered pathogenic mutation of MEN1 gene. A 32-year-old man with a history of osteopenia, nephrolithiasis, hypercalcemia and hypophosphatemia, impaired fasting glucose, and asthenia was admitted to our outpatient unit. Primary hyperparathyroidism, sustained by three hyperplastic parathyroid glands, was diagnosed. Prolactin- and GH-secreting adenomas were ruled out. After undergoing subtotal parathyroidectomy, the patient was diagnosed with non-functioning pituitary adenoma, three pancreatic lesions, and Cushing syndrome sustained by left adrenal adenoma. The patient underwent left adrenal surgery; somatostatin analogue lanreotide was started for the pancreatic lesions; the pituitary adenoma, being small and non-secreting, was not treated. A genetic test was performed to confirm the diagnosis of MEN1 syndrome, finding an association with a recently discovered mutation: the (NM_130799.2):c.758delC (p.Ser253Cysfs*28) in exon 4.

Genetic Insights Into Leukemia Susceptibility in the Arab Population: A Scoping Review.

As per the Global Cancer Observatory, the WHO Eastern Mediterranean region (which includes the Arabic countries) ranks highest for age-standardized mortality rate at 4 per 100,000, thus indicating a probable role of genetic associations. Identifying the genes associated with leukemia in the Arab population is crucial for effective preventive and treatment strategies. This scoping review aimed to determine the nature and extent of research available on the genes associated with the major types of leukemia among the Arab population. As per the scoping review guidelines, a comprehensive search was conducted in PUBMED and Google Scholar for articles published before 01/10/2023 and focused on leukemia-related genes among the Arab population. In total 119 studies, focusing on genes associated with leukemia met the inclusion criteria. On reviewing these studies, 27 genes were found to be associated with ALL, 33 genes with AML, seven genes with CLL, and 14 genes with CML. The majority of these genes were associated with an increased risk for the disease. Notably, the 119 studies covered only nine out of the 22 Arab countries, with 56 studies carried out in Egypt, exhibiting an imbalance in the regional distribution of the research landscape. Thus, indicating the inadequacy of research on leukemia genetics in the Arab region in comparison to the Western studies. This finding highlights the need for extensive research in the Middle Eastern region to gain geographically heterogeneous genetic information about the Arab population. In conclusion, this scoping study highlights the genes associated with the major types of leukemia among the Arab population and also indicates the need for comprehensive and regionally balanced research on leukemia genetics in Middle Eastern countries. Addressing this gap is essential to provide robust genetic data that can be used for targeted interventions to improve leukemia outcomes in the Middle East. Increased research efforts in all Middle Eastern countries will contribute to a greater understanding of genetic predisposition and help develop effective prevention strategies and treatments tailored to this population.

Metabolomic Profile Alterations Associated with the SLC16A11 Risk Haplotype Following a Lifestyle Intervention in People With Prediabetes.

Background: A risk haplotype in SLC16A11 characterized by alterations in fatty acid metabolism emerged as a genetic risk factor associated with increased susceptibility to type 2 diabetes (T2D) in Mexican population. Its role on treatment responses is not well understood. Objectives: We aimed to determine the impact of the risk haplotype on the metabolomic profile during a lifestyle intervention (LSI). Methods: We recruited Mexican-mestizo individuals with ≥1 prediabetes criteria according to the American Diabetes Association with a body mass index between 25 and 45 kg/m2. We conducted a 24-wk quasiexperimental LSI study for diabetes prevention. Here, we compared longitudinal plasma liquid chromatography/mass spectrometry metabolomic changes between carriers and noncarriers. We analyzed the association of risk haplotype with metabolites leveraging repeated assessments using multivariable-adjusted linear mixed models. Results: Before the intervention, carriers (N = 21) showed higher concentrations of hippurate, C16 carnitine, glycine, and cinnamoylglycine. After 24 wk of LSI, carriers exhibited a deleterious metabolomic profile. This profile was characterized by increased concentrations of hippurate, cinnamoglycine, xanthosine, N-acetylputrescine, L-acetylcarnitine, ceramide (d18:1/24:1), and decreased concentrations of citrulline and phosphatidylethanolamine. These metabolites were associated with higher concentrations of total cholesterol, triglycerides, and low density lipoprotein cholesterol. The effect of LSI on the risk haplotype was notably more pronounced in its impact on 2 metabolites: methylmalonylcarnitine (ß: -0.56; P-interaction = 0.014) and betaine (ß: -0.64; P-interaction = 0.017). Interestingly, lower consumption across visits of polyunsaturated (ß: -0.038; P = 0.017) fatty acids were associated with higher concentrations of methylmalonylcarnitine. Covariates for adjustment across models included age, sex, genetic ancestry principal components, and body mass index. Conclusions: Our study highlights the persistence of deleterious metabolomic patterns associated with the risk haplotype before and during a 24-wk LSI. We also emphasize the potential regulatory role of polyunsaturated fatty acids on methylmalonylcarnitine concentrations suggesting a route for improving interventions for individuals with high-genetic risk.

Deletion of GBA in neurons, but not microglia, causes neurodegeneration in a Gaucher mouse model.

Gaucher disease, the most prevalent lysosomal storage disease, is caused by homozygous mutations at the GBA gene, responsible for encoding the enzyme glucocerebrosidase. Neuronopathic Gaucher disease is associated with microgliosis, astrogliosis, and neurodegeneration. However, the role that microglia, astrocytes, and neurons play in the disease remains to be determined. In the current study, we developed novel, inducible, cell-type specific GBA KO mice to understand the individual impacts of GBA deficiencies on microglia and neurons. GBA was conditionally knocked out either exclusively in microglia or neurons, or throughout the body. These novel mouse models were developed using a tamoxifen-inducible Cre system, with tamoxifen administration commencing at weaning. Microglia-specific GBA KO mice showed no signs of disease. However, the neuron-specific GBA KO resulted in a shortened lifespan, severe weight loss, and ataxia. These mice also had significant neurodegeneration, microgliosis, and astrogliosis accompanied by the accumulation of glucosylceramide and glucosylsphingosine, recapitulating Gaucher disease-like symptoms. These surprising findings reveal that, unlike the neuron-specific GBA deficiency, microglia-specific GBA deficiency alone does not induce disease. The novel neuronal Gaucher disease mouse model, with a median survival of 16 weeks, may be useful for future studies of pathogenesis and the evaluation of therapies.

Interplay between vertebrate adaptive immunity and bacterial infectivity genes: Bank vole MHC versus Borrelia afzelii OspC.

Coevolution of parasites with their hosts may lead to balancing selection on genes involved in determining the specificity of host-parasite interactions, but examples of such specific interactions in wild vertebrates are scarce. Here, we investigated whether the polymorphic outer surface protein C (OspC), used by the Lyme disease agent, Borrelia afzelii, to manipulate vertebrate host innate immunity, interacts with polymorphic major histocompatibility genes (MHC), while concurrently eliciting a strong antibody response, in one of its main hosts in Europe, the bank vole. We found signals of balancing selection acting on OspC, resulting in little differentiation in OspC variant frequencies between years. Neither MHC alleles nor their inferred functional groupings (supertypes) significantly predicted the specificity of infection with strains carrying different OspC variants. However, we found that MHC alleles, but not supertypes, significantly predicted the level of IgG antibodies against two common OspC variants among seropositive individuals. Our results thus indicate that MHC alleles differ in their ability to induce antibody responses against specific OspC variants, which may contribute to selection of OspC polymorphism by the vole immune system.

Evaluation of a Master's in Genomic Medicine framework: a national, multi-professional programme to educate healthcare professionals in NHS England.

PURPOSE: Genomic medicine is revolutionising healthcare but requires healthcare professionals to update their understanding of genomics and its application to clinical practice for successful implementation. To meet this need, Heath Education England developed the 'Master's in Genomic Medicine', a national multi-professional programme to increase genomic literacy in the National Health Service workforce. This study summarises an evaluation of the programme which will inform its future development. METHODS: Underpinned by Moore's evaluation framework, a mixed methods approach was used to characterise (i) learner demographics, (ii) perceptions of the programme, (iii) knowledge and/or qualifications achieved, and (iv) the outcome(s) for practice in the workplace. RESULTS: Learners were a diverse cohort of healthcare professionals, including doctors, healthcare scientists, nurses and midwives. Participant satisfaction was high for all elements of the programme, including the curriculum, learning environment(s), and multi-professional cohort(s), despite the challenges of engaging working professionals in part-time learning. Both learners and their managers reported enhanced genomic practice after completion of their studies. CONCLUSION: The Master's in Genomic Medicine programme is an effective approach to professional education in genomic medicine. This broad multi-professional learning complements training aimed at specific groups of healthcare professionals.

The Role of Double Heterozygotes of SLC3A1 and SLC7A9 in the Prevalence of Cystine Stones.

PURPOSE: Cystine stones, an autosomal recessive disorder caused by cystinuria, result from pathogenic variants of SLC3A1 and SLC7A9. Previous publications revealed clinical prevalence is higher than genetically predicted prevalence. Heterozygous carriers in either gene are not stone formers. However, double heterozygotes (DH), individuals with two heterozygous pathogenic variants in both genes, were never evaluated and may explain the gap between clinical and genetic prevalence. METHODS: Due to the rarity of the condition, direct clinical observation is impractical. We perform this population study as a surrogate by identifying the observed DH, deriving the theoretical/expected DH, and testing the null hypothesis (NH) that the observed DH frequency is equal or greater than expected. This NH biologically correlates to DH are asymptomatic and without cystine stone. RESULTS: Using the 1000 Genome Database, we identified 0 DH. We derived the theoretical/expected DH with Hardy-Weinberg Equilibrium and Mendel's law of independent assortment, as 4.94x10-s. Population proportion test revealed Z= -0.353, and p= 0.362, the NH cannot be rejected. CONCLUSION: Statistical testing does not support that DH are symptomatic, i.e. DH of SLC3A1 and SLC7A9 may not present with cystine stone, and other factors responsible for the gap that current genetics knowledge cannot explain.

Host population structure and species resolution reveal prophage transmission dynamics.

Much knowledge about bacteriophages has been obtained via genomics and metagenomics over the last decades. However, most studies dealing with prophage diversity have rarely conducted phage species delimitation (aspect 1) and have hardly integrated the population structure of the host (aspect 2). Yet, these two aspects are essential in assessing phage diversity. Here, we implemented an operational definition of phage species (clustering at 95% identity, 90% coverage) and integrated the host's population structure to understand prophage diversity better. Gathering the most extensive data set of Acinetobacter baumannii phages (4,152 prophages + 122 virulent phages, distributed in 46 countries in the world), we show that 91% (875 out of 963) of the prophage species have four or fewer prophages per species, and just five prophage species have more than 100 prophages. Most prophage species have a narrow host range and are geographically restricted; yet, very few have a broad host range being well spread in distant lineages of A. baumannii. These few broad host range prophage species are not only cosmopolitan but also the most abundant species. We also noted that polylysogens had very divergent prophages, belonging to different prophage species, and prophages can easily be gained and lost within the bacterial lineages. Finally, even with this extensive data set, the prophage diversity has not been fully grasped. Our study highlights how integrating the host population structure and a solid operational definition of phage species allows us to better appreciate phage diversity and its transmission dynamics. IMPORTANCE: Much knowledge about bacteriophages has been obtained via genomics and metagenomics over the last decades. However, most studies dealing with prophage diversity have rarely conducted phage species delimitation (aspect 1) and have hardly integrated the population structure of the host (aspect 2). Yet, these two aspects are essential in assessing phage diversity. Here, we implemented an operational definition of phage species (clustering at 95% identity, 90% coverage) and integrated the host's population structure to understand prophage diversity better. Gathering the most extensive data set of Acinetobacter baumannii phages, we show that most prophage species have four or fewer prophages per species, and just five prophage species have more than 100 prophages. Most prophage species have a narrow host range and are geographically restricted; yet, very few have a broad host range being well spread in distant lineages of A. baumannii. These few broad host range prophage species are cosmopolitan and the most abundant species. Prophages in the same bacterial genome are very divergent, and prophages can easily be gained and lost within the bacterial lineages. Finally, even with this extensive data set, the prophage diversity has not been fully grasped. This study shows how integrating the host population structure and clustering at the species level allows us to better appreciate phage diversity and its transmission dynamics.

[Genetic diagnostics of mental health disorders in adulthood]. / Genetische Diagnostik bei psychischen Erkrankungen im Erwachsenenalter.

This review article provides insights into the role of genetic diagnostics in adult mental health disorders. The importance of genetic factors in the development of mental illnesses, from rare genetic syndromes to common complex genetic disorders, is described. Current clinical characteristics that may warrant a genetic diagnostic work-up are highlighted, including intellectual disability, autism spectrum disorders and severe psychiatric conditions with specific comorbidities, such as organ malformations or epilepsy. The review discusses when genetic diagnostics are recommended according to current guidelines as well as situations where they might be considered even in the absence of explicit guideline recommendations. This is followed by an overview of the procedures and the currently used diagnostic methods. Current limitations and possible developments in the field of genetic diagnostics in psychiatry are discussed, including the fact that, for many mental health conditions, genetic testing is not yet part of standard clinical practice; however, in summary genetic causes should be considered more frequently in certain clinical constellations, and genetic diagnostics and counselling should be offered where appropriate.

Cancer stem cells in meningiomas: novel insights and therapeutic implications.

Meningiomas (MGs), which arise from meningothelial cells of the dura mater, represent a significant proportion of primary tumours of the central nervous system (CNS). Despite advances in treatment, the management of malignant meningioma (MMG) remains challenging due to diagnostic, surgical, and resection limitations. Cancer stem cells (CSCs), a subpopulation within tumours capable of self-renewal and differentiation, are highlighted as key markers of tumour growth, metastasis, and treatment resistance. Identifying additional CSC-related markers enhances the precision of malignancy evaluations, enabling advancements in personalised medicine. The review discusses key CSC biomarkers that are associated with high levels of expression, aggressive tumour behaviour, and poor outcomes. Recent molecular research has identified CSC-related biomarkers, including Oct-4, Sox2, NANOG, and CD133, which help maintain cellular renewal, proliferation, and drug resistance in MGs. This study highlights new therapeutic strategies that could improve patient prognosis with more durable tumour regression. The use of combination therapies, such as hydroxyurea alongside diltiazem, suggests more efficient and effective MG management compared to monotherapy. Signalling pathways such as NOTCH and hedgehog also offer additional avenues for therapeutic development. CRISPR/Cas9 technology has also been employed to create meningioma models, uncovering pathways related to cell growth and proliferation. Since the efficacy of traditional therapies is limited in most cases due to resistance mechanisms in CSCs, further studies on the biology of CSCs are warranted to develop therapeutic interventions that are likely to be effective in MG. Consequently, improved diagnostic approaches may lead to personalised treatment plans tailored to the specific needs of each patient.

Association of single nucleotide polymorphisms and gene-environment interactions with major depressive disorder in Chinese.

We conducted a case-control study to investigate the effects of genetics and gene-environment interactions on major depressive disorders (MDD) in the Chinese population. Using targeted-exome sequencing, we included 984 patients with MDD and 508 healthy controls in our study. A logistic regression model was employed to analyze the association between single nucleotide polymorphisms (SNPs) and MDD. Additionally, a linear regression model was utilized to examine the associations between (1) gene-environment interaction and the 17-item Hamilton Depression Rating Scale, (2) SNPs and the Beck Scale for Suicide Ideation-Chinese version, and gene-environment interaction and the Beck scale for suicide ideation-Chinese version. The association analysis between SNPs and MDD revealed that the following loci reached genome-wide significance: rs2305554 of the cholinergic receptor nicotinic alpha 7 subunit, rs9459173 of synaptojanin 2, rs372369000 of beta-1,4-galactosyltransferase 6, rs866666526 of dopa decarboxylase, rs1254882194 of calcium/calmodulin dependent protein kinase ID, rs199880487 of reelin, rs1167948188 of reelin, rs1390140186 of QKI, KH domain containing RNA binding, and rs1776342 of period circadian regulator 3. The association analysis between SNPs and the Beck Scale for Suicide Ideation-Chinese version indicated that rs264272 and rs1774784888 of piezo type mechanosensitive ion channel component 2 reached genome-wide significance. These findings may enhance our understanding of MDD and contribute to the development of new potential targets for its diagnosis and treatment.

Investigating the prevalence of MFN2 mutations in amyotrophic lateral sclerosis: insights from an Italian cohort.

The MFN2 gene encodes mitofusin 2, a key protein for mitochondrial fusion, transport, maintenance and cell communication. MFN2 mutations are primarily linked to Charcot-Marie-Tooth disease type 2A. However, a few cases of amyotrophic lateral sclerosis and amyotrophic lateral sclerosis/frontotemporal dementia phenotypes with concomitant MFN2 mutations have been previously reported. This study examines the clinical and genetic characteristics of an Italian cohort of amyotrophic lateral sclerosis patients with rare, non-synonymous MFN2 mutations. A group of patients (n = 385) diagnosed with amyotrophic lateral sclerosis at our Neurology Units between 2008 and 2023 underwent comprehensive molecular testing, including MFN2. After excluding pathogenic mutations in the main amyotrophic lateral sclerosis-related genes (i.e. C9orf72, SOD1, FUS and TARDBP), MFN2 variants were classified based on the American College of Medical Genetics and Genomics guidelines, and demographic and clinical data of MFN2-mutated patients were retrieved. We identified 12 rare, heterozygous, non-synonymous MFN2 variants in 19 individuals (4.9%). Eight of these variants, carried by nine patients (2.3%), were either pathogenic, likely pathogenic or variants of unknown significance according to the American College of Medical Genetics and Genomics guidelines. Among these patients, four exhibited a familial pattern of inheritance. The observed phenotypes included classic and bulbar amyotrophic lateral sclerosis, amyotrophic lateral sclerosis/frontotemporal dementia, flail arm, flail leg and progressive muscular atrophy. Median survival after disease onset was extremely variable, ranging from less than 1 to 13 years. This study investigates the prevalence of rare, non-synonymous MFN2 variants within an Italian cohort of amyotrophic lateral sclerosis patients, who have been extensively investigated, enhancing our knowledge of the underlying phenotypic spectrum. Further research is needed to understand whether MFN2 mutations contribute to motor neuron disease and to what extent. Improving our knowledge regarding the genetic basis of amyotrophic lateral sclerosis is crucial both in a diagnostic and therapeutic perspective.

The evolutionary ecology of inbreeding depression in wild plant populations and its impact on plant mating systems.

Inbreeding depression, the reduced fitness of inbred relative to outbred individuals was described more than two centuries ago, long before the development of population genetics. Its impact is central to evolutionary ecology and the evolution of mating systems, in particular self-fertilization in hermaphrodites. In the first half of the 20th century, population genetics revealed a mechanism for inbreeding depression through homozygosity. Numerous theoretical studies have modeled inbreeding depression as a function of genetic architecture and analyzed how it varies with population selfing rates. A major concept in these models is purging, i.e., the purging of recessive deleterious mutations through inbreeding. Consequently, inbreeding depression is expected to decrease with increasing population selfing rates. Along with these theoretical studies, many experimental studies, particularly on plants, have measured inbreeding depression using experimental crosses or directly in the field. The results of these studies have revealed that the evolutionary ecology of inbreeding depression is difficult to capture and that empirical data do not exactly match model predictions, specifically purging efficacy. In addition, the lability of inbreeding depression in natural populations can qualitatively affect the selective role of inbreeding depression in the evolution of mating systems. Recently, several studies have demonstrated the role of epigenetics in shedding new light on the dynamics of inbreeding depression in natural populations. This review provides a general overview of the studies on inbreeding depression and how various angles can help capture its selective role in natural populations.

In Memoriam: Professor Joseph Biederman's Contributions to Child and Adolescent Psychiatry.

OBJECTIVE: To provide an overview of Joe Biederman's contributions to child and adolescent psychiatry. METHOD: Nine colleagues described his contributions to: psychopharmacology, comorbidity and genetics, pediatric bipolar disorder, autism spectrum disorders, Tourette's and tic disorders, clinical and neuro biomarkers for pediatric mood disorders, executive functioning, and adult ADHD. RESULTS: Joe Biederman left us with many concrete indicators of his contributions to child and adolescent psychiatry. He set up the world's first pediatric psychopharmacology clinic and clinical research program in child adolescent psychiatry. As a young faculty member he began a research program that led to many awards and eventual promotion to full professor at Harvard Medical School. He was for many years the most highly cited researcher in ADHD. He achieved this while maintaining a full clinical load and was widely respected for his clinical acumen. CONCLUSION: The world is a better place because Joe Biederman was here.

Bivariate GWA mapping reveals associations between aliphatic glucosinolates and plant responses to thrips and heat stress.

Although plants harbor a huge phytochemical diversity, only a fraction of plant metabolites is functionally characterized. In this work, we aimed to identify the genetic basis of metabolite functions during harsh environmental conditions in Arabidopsis thaliana. With machine learning algorithms we predicted stress-specific metabolomes for 23 (a)biotic stress phenotypes of 300 natural Arabidopsis accessions. The prediction models identified several aliphatic glucosinolates (GLSs) and their breakdown products to be implicated in responses to heat stress in siliques and herbivory by Western flower thrips, Frankliniella occidentalis. Bivariate GWA mapping of the metabolome predictions and their respective (a)biotic stress phenotype revealed genetic associations with MAM, AOP, and GS-OH, all three involved in aliphatic GSL biosynthesis. We, therefore, investigated thrips herbivory on AOP, MAM, and GS-OH loss-of-function and/or overexpression lines. Arabidopsis accessions with a combination of MAM2 and AOP3, leading to 3-hydroxypropyl dominance, suffered less from thrips feeding damage. The requirement of MAM2 for this effect could, however, not be confirmed with an introgression line of ecotypes Cvi and Ler, most likely due to other, unknown susceptibility factors in the Ler background. However, AOP2 and GS-OH, adding alkenyl or hydroxy-butenyl groups, respectively, did not have major effects on thrips feeding. Overall, this study illustrates the complex implications of aliphatic GSL diversity in plant responses to heat stress and a cell-content-feeding herbivore.

A novel pathogenic germline chromosome 3 inversion in von Hippel-Lindau disease.

von Hippel-Lindau (VHL) is an autosomal-dominant hereditary tumour susceptibility disease associated with pathogenic germline variants in the VHL tumour suppressor gene. VHL patients are at increased risk of developing multiple benign and malignant tumours. Current CLIA-based genetic tests demonstrate a very high detection rate of germline VHL variants in patients with clinical manifestations of VHL. In this report, we describe a large family with canonical VHL manifestations, for which no germline alteration had been detected by conventional germline testing. We identified a novel 291 kb chromosomal inversion involving chromosome 3p in affected family members. This inversion disrupts the VHL gene between exon 2 and exon 3 and is thereby responsible for the disease observed in this family.