Mendelian Research Articles

Population-based genetic carrier screening. A consensus statement from the Spanish societies: AEGH, AEDP, ASEBIR, SEAGEN, SEF and SEGCD.

Autosomal recessive or X-linked disorders are passed from parents to offspring through Mendelian inheritance patterns and may lead to severe clinical manifestations in early childhood development. Together, the Spanish Association of Human Genetics (AEGH), Association for the Study of Reproductive Biology (ASEBIR), Spanish Association of Genetic Counselling (SEAGEN), Spanish Fertility Society (SEF), Spanish Society of Clinical Genetics and Dysmorphology (SEGCD), and the Spanish Association of Prenatal Diagnostics (AEDP) developed a consensus statement for population-based genetic carrier screening (GCS). The presented opinion statement recommends that preconception GCS services be included in the public healthcare system to support couples' reproductive autonomy and timely medical decision-making. Program design and implementation strategies, as well as key technical, ethical, and legal considerations are discussed.

Genetic Etiology Investigation in Treatment-Resistant Nocturnal Enuresis Children: A descriptive study.

Our study aimed to evaluate the genetic etiology of treatment-resistant nocturnal enuresis in children who have undergone at least 6 episodes of behavioral therapy, urotherapy, alarm therapy, and medical treatment. A total of 21 patients were included in the study. Inclusion criteria for the study comprised children aged 5-18 years diagnosed with treatment-resistant enuresis according to the International Children's Continence Society (ICCS) guidelines. The capture-based Sophia Hereditary Disease Panel by Sophia Genetics was used specifically for nocturnal enuresis, consisting of a panel of 19 genes (AGXT, AQP2, AVPR2, BNC2, CLCNKB, DLG3, ELN, FA2H, FAM20A, FOXP1, HPSE2, KCNJ10, MLXIPL, NPHP3, RNF168, SLC12A3, SLC25A13, SLC5A2, SMARCA2). Patients were analyzed for genetic variations in genes associated with nocturnal enuresis, including AGXT, AQP2, AVPR2, BNC2, CLCNKB, DLG3, ELN, FA2H, FAM20A, FOXP1, HPSE2, KCNJ10, MLXIPL, NPHP3, RNF168, SLC12A3, SLC25A13, SLC5A2, and SMARCA2. No pathogenic changes potentially explaining the etiology of the disease were detected in 20 patients. One patient exhibited a variant in the AQP2 gene at hg19:Chr12:50344908 exon 1, c.295G>A locus, classified as a Variant of Uncertain Significance (VUS) according to the American College of Medical Genetic and Genomics (ACMG) 2015 guidelines. The AQP2 gene is associated with autosomal dominant and autosomal recessive inherited nephrogenic diabetes insipidus (type 2) in the OMIM (Online Mendelian Inheritance in Man) database. Our study resembles studies indicating that nocturnal enuresis cases do not have a monogenic etiology but occur with multifactorial effects and have a weak correlation between genotype and phenotype.

:How We Get Mendel Wrong, and Why It Matters: Challenging the Narrative of Mendelian Genetics

:<i>How We Get Mendel Wrong, and Why It Matters: Challenging the Narrative of Mendelian Genetics</i>

Network pharmacology and molecular docking analysis on the mechanism of Wensan tincture in the treatment of pulmonary nodules: A review.

Network pharmacology and molecular docking methods were applied to elucidate the molecular mechanism of action of Wensan tincture (WST) in the treatment of pulmonary nodules. The Traditional Chinese Medicine Systems Pharmacology and the Traditional Chinese Medicine and Chemical Composition database were used to screen the active ingredients. Potential targets of WST were retrieved using Traditional Chinese Medicine Systems Pharmacology, SwissADME, and SwissTargetPrediction, while pulmonary nodule-associated targets were obtained from GeneCards and Online Mendelian Inheritance in Man databases. An active ingredient-target network was constructed using Cytoscape 3.9.1, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were conducted via the Database for Annotation, Visualization, and Integrated Discovery platform to identify core targets and signaling pathways. Molecular docking studies were performed using AutoDockTools. The results revealed 62 active ingredients and 344 corresponding targets within the tincture, alongside 1005 targets associated with pulmonary nodules. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses indicated that the potential therapeutic targets of WST include signal transducer and activator of transcription 3, mitogen-activated protein kinase-3, mitogen-activated protein kinase-1, Jun proto-oncogene, tumor protein 53, phosphoinositide-3-kinase regulatory subunit 1, heat shock protein 90 alpha family class A member 1, and AKT serine/threonine kinase 1. The primary pathways were the cancer pathway, mitogen-activated protein kinase signaling, advanced glycation end-products and their receptor signaling, epidermal growth factor receptor signaling, hypoxia-inducible factor-1 signaling, and the programmed cell death-ligand 1/programmed cell death protein 1 checkpoint pathways. Molecular docking demonstrated that quercetin exhibited the strongest binding affinity with mitogen-activated protein kinase-3, with a binding energy of -9.1 kcal/mol. Notably, key components of WST, such as quercetin, demonstrate considerable potential as drug candidates for the treatment of pulmonary nodules.

Exploring Gender Bias in Family Property Inheritance Through Women and the Law

This study was conducted to investigate the women’s awareness about property laws of inheritance in Bihar. For this purpose a sample of 300 women from five block of Patna district like Patna Sadar, Danapur, Phulwari Sharif, Punpun and Fatuhan were selected to collect the data through Purposive Random Sampling method. Results shows that educated women are more aware about the laws of property rights than uneducated women. Now women are taking legal helps in case of violating their property rights and education playing an important role into it. Thus raising the women education will help in achieving the goal of women empowerment and gender equality.

The Significance of Mendelism for Evolutionary Theory: A Reassessment.

It is well-known that the rediscovery of Mendelian genetics at the turn of twentieth century offered Darwin's theory a much-needed lifeline, by showing how Fleeming Jenkins' famous "blending" objection could be rebutted. However, Mendelism has another fortuitous consequence for evolutionary biology that is less widely appreciated. By bequeathing the notion of allelism to biology, Mendelism shows how two difficult conceptual issues for evolutionary theory can be resolved. The first issue concerns the notion of population. By definition, evolutionary change is change in the composition of a population, but what is the relevant definition of "population"? The second issue concerns Darwin's notion of "struggle for existence." Is this struggle an essential part of evolution by natural selection or not? In a Mendelian population, these issues can be simply resolved, since the selective competition is at root between alleles at a locus, who are necessarily playing a zero-sum game, rather than between organisms, who may or may not be doing so.

Examining the role of common variants in rare neurodevelopmental conditions.

Although rare neurodevelopmental conditions have a large Mendelian component1, common genetic variants also contribute to risk2,3. However, little is known about how this polygenic risk is distributed among patients with these conditions and their parents nor its interplay with rare variants. It is also unclear whether polygenic background affects risk directly through alleles transmitted from parents to children, or whether indirect genetic effects mediated through the family environment4 also play a role. Here we addressed these questions using genetic data from 11,573 patients with rare neurodevelopmental conditions, 9,128 of their parents and 26,869 controls. Common variants explained around 10% of variance in risk. Patients with a monogenic diagnosis had significantly less polygenic risk than those without, supporting a liability threshold model5. A polygenic score for neurodevelopmental conditions showed only a direct genetic effect. By contrast, polygenic scores for educational attainment and cognitive performance showed no direct genetic effect, but the non-transmitted alleles in the parents were correlated with the child's risk, potentially due to indirect genetic effects and/or parental assortment for these traits4. Indeed, as expected under parental assortment, we show that common variant predisposition for neurodevelopmental conditions is correlated with the rare variant component of risk. These findings indicate that future studies should investigate the possible role and nature of indirect genetic effects on rare neurodevelopmental conditions, and consider the contribution of common and rare variants simultaneously when studying cognition-related phenotypes.

A rare case of late-onset spondyloenchondrodysplasia with immune dysregulation presenting as adult-onset monogenic lupus.

Spondyloenchondrodysplasia is classified as an interferonopathy resulting from recessive mutations in the ACP5 gene and manifests with various clinical features, including distinctive skeletal dysplasia, neurological abnormalities, immune dysfunction resembling systemic lupus erythematosus (SLE) and Sjogren's syndrome. While SLE is typically considered multifactorial and more prevalent in adulthood, a subset of approximately 10%-25% of childhood cases arise from monogenic form. Among these, spondyloenchondrodysplasia accounts for only a rare fraction of monogenic lupus cases, with only 22 reported instances in the literature. This paper presents a new case of spondyloenchondrodysplasia-immune dysregulation (SPENCDI) in an adult patient born to nonconsanguineous parents. The patient was diagnosed with SPENCDI and exhibited immune neutropenia, anti-dsDNA positivity, platyspondyly, immune deficiency, and a homozygous variant (c.155A > C, p. Lys52Thr) in the ACP5 gene, previously classified as pathogenic. Notably, the patient achieved successful clinical management through the initiation of baricitinib treatment, a Janus kinase inhibitor. SPENCDI represents an uncommon cause of SLE in adulthood. Clinicians should be vigilant of underlying Mendelian inheritance when encountering patients with associated features. While treatments for both Mendelian and non-Mendelian SLE are similar, Janus kinase inhibitors like baricitinib show potential for managing interferon-signature monogenic SLE cases.

Survival cost sharing among altruistic full siblings in Mendelian population.

We focus on Haldane's familial selection in monogamous families in a diploid population, where the survival probability of each sibling is determined by altruistic food sharing with its siblings during starvation. An autosomal recessive-dominant or intermediate allele pair uniquely determines the altruistic or selfish behavior, which are coded by homozygotes. We focus on the case when additive cost and benefit functions determine the survival probability of each full sibling. We provide conditions for the existence of the altruistic and selfish homozygote. We show that the condition of evolutionary stability of altruism depends on the genotype-phenotype mapping. Furthermore, if the offspring size increases then the condition of evolutionary stability of altruism becomes stricter. Contrary to that, for the evolutionary stability of selfish behavior it is enough if the classical Hamilton's rule does not hold. Moreover, when the classical Hamilton's rule holds and the condition of evolutionary stability of altruism does not hold, then the selfish and altruistic phenotypes coexist. In summary, the classical Hamilton's rule is a sufficient condition for the existence of altruism, but it alone does not imply the evolutionary stability of the pure altruistic homozygote population when the altruistic siblings share the cost of altruism.

The Therapeutic Mechanisms of Huayu Quban Capsule in Treating Acne Vulgaris Are Uncovered Through Network Pharmacology and Molecular Docking

ABSTRACTPurposeTo uncover how the Huayu Quban (HYQB) capsule treats acne vulgaris (AV) through the use of network pharmacology and molecular docking technology.MethodsThe traditional Chinese medicine system pharmacology database (TCMSP) was used to identify the components and potential targets of HYQB capsule. Targets related to AV were identified by screening the GeneCards, Disease Gene Network (DisGeNET) and Online Mendelian Inheritance in Man (OMIM) databases. The protein–protein interaction (PPI) network between targets of active ingredients and AV targets was built using the STRING database. Cytoscape3.7.2 software was used to create the visualization network for the ‘herb‐component‐target’ and identify the key targets. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were utilized for functional enrichment analysis of the primary targets. Subsequently, molecular docking technology was employed to confirm the interaction between key components and core targets.ResultsThe technique discovered 50 different active substances and 270 associated therapeutic targets in the HYQB capsule as well as predicting 70 targets for treating acne vulgaris. Cytoscape hubba plug‐in identified 19 key target genes, with the top 5 being TNF, IL1B, CCL2, SIRT1, IFNG, and IL10. Analysis of KEGG pathways revealed significant enrichment of immune‐related pathways, including TNF and IL‐17 signaling pathways, among the target genes. The HYQB capsule also involves lipid and atherosclerosis, Th17 cell differentiation, and the AGE‐RAGE signaling pathway in diabetic complication signaling pathways. Molecular docking results showed that quercetin, luteolin, kaempferol, and wogonin, the core components of HYQB, had good binding ability with the first 4 core targets.ConclusionsThe HYQB capsule may have a synergistic effect on inhibiting sebaceous adipogenesis and sebum cell differentiation and play an effect on AV through anti‐inflammatory and antioxidant effects of different signaling pathways.

Parental Reconstruction from a Half-Sib Population of Stoneless Jujube Ziziphus jujuba Mill. Based on Individual Specific SNP Markers Using Multiplex PCR.

The selection of unique and individual-specific SNPs is important as compared with universal SNPs for individual identification. Therefore, the main significance of this research is the selection of specific SNPs in male parent and the identification of offspring with these specific SNPs in their genome by multiplex PCR, which is utilized for genotyping of 332 half-sib plants of Ziziphus jujuba.This cost-effective method makes as much as possible to utilize the same amount of each pair of various targeted loci primers. After PCR amplification of targeted genome parts, the mixed products can be directly used in a next-generation sequencing platform. We concomitantly amplified 10 unique SNP loci at 10 different chromosomes of male JingZao 39 plants in 332 half-sib plants and sequenced them on the Illumina Novaseq 6000 platform. Analysis of SNP genotyping accuracy of 332 half-sib plants showed that all 10 unique SNPs in all 332 plants were correctly amplified in this multiplex PCR method. Furthermore, based on Mendelian inheritance, we identified 124 full-sib plants that have 10 unique SNPs in their genomes. These results were further confirmed by whole genome resequencing of 82 randomly selected half-sib plants, and the identity-by-descent values of all full-sib plants were between 0.4399 to 0.5652. This study displayed a cost-effective multiplex PCR method and proper identification of pollen parent through specific SNPs in half-sib progenies and firstly obtained a full-sib population between 'Wuhezao' and 'JingZao 39', segregating for stone and stoneless fruit.

Charcot‐Marie‐Tooth disease in children

AbstractCharcot‐Marie‐Tooth (CMT) disease represents a diverse group of inherited neuropathies with a broad spectrum of symptoms. It is the most prevalent inherited neuropathy, with an estimated prevalence ranging from 9.7 to 82 cases per 100,000 individuals. Despite this, CMT comprises only 118 of 853 inherited neuropathy entries in the Online Mendelian Inheritance in Man (OMIM) database. This comprehensive review offers a thorough examination of CMT's clinical features, subtypes, genetic underpinnings, and pathomechanisms in pediatric cases. CMT typically manifests as progressively worsening muscle weakness and atrophy, primarily affecting the distal extremities. Patients may also experience foot and ankle deformities, hand atrophy, and other systemic issues. To accurately diagnose CMT, a detailed family history, comprehensive clinical evaluation, nerve conduction studies, and relevant genetic testing are essential. Importantly, establishing a differential diagnosis is crucial during evaluation to rule out other conditions with similar presentations. This review aims to provide clinicians with a valuable resource for diagnosing and managing CMT, emphasizing the need for a streamlined and standardized approach considering advancements in genetic testing and the identification of various subtypes.

Clinical and genetic analysis of a case of Triadin knockout syndrome due to variant of TRDN gene and a literature review

To explore the genetic etiology and clinical phenotype of a child with Triadin knockout syndrome (TKOS), and to review the relevant literature of TKOS patients due to variants of TRDN gene. A child who was admitted to the Children's Hospital of Xi'an Jiaotong University on March 19, 2023 due to sudden cardiac arrest 3 days earlier was selected as the study subject. Peripheral blood samples (2 to 3 mL) were collected from the child and her parents for the extraction of genomic DNA and whole exome sequencing (WES). Pathogenic variants were searched from databases such as the Genome Aggregation Database (gnomAD) and Online Mendelian Inheritance in Man (OMIM), and were assessed based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). Sanger sequencing was carried out for family validation of the pathogenic variants. Using keywords such as "arrhythmias" "TRDN" and "Triadin" both in Chinese and English, relevant literature on TKOS patients due to variants of the TRDN gene was retrieved from the CNKI, Wanfang Data Knowledge Service Platform, and PubMed databases, and the time of literature retrieval was set from January 1, 2012 to December 1, 2023. This study has been approved by the Ethics Committee of the Affiliated Children's Hospital of Xi'an Jiaotong University (No. 20230097), and informed consent was obtained from the parents of the child. The child had experienced syncope and cardiac arrest after exercise. Electrocardiographic examination revealed QTc interval prolongation, T-wave inversion in precordial leads V1-V3, polymorphic ventricular premature beat (VPB), and ventricular tachycardia (VT) along with increased heart rate. WES and Sanger sequencing revealed that the child has harbored a homozygous c.463del(p.E155Kfs*20) variant of the TRDN gene, for which both of the parents were heterozygous. Based on the guidelines from the ACMG, the variant was classified as pathogenic (PVS1+PM2+PM3). The child was ultimately diagnosed with TKOS. In total 12 publications on TOKS cases caused by TRDN gene variants were retrieved, which involved 30 patients and 28 carriers of single heterozygous variant of the TRDN gene. Among the 30 TKOS patients, 20 had carried homozygous variants of the TRDN gene, and 10 had carried compound heterozygous variants, and all had exhibited significant clinical phenotype of arrhythmia, with most cases had experienced malignant arrhythmia induced by exercise and/or excitement during infancy or early childhood, leading to recurrent syncope and cardiac arrest. Of note, none of the 28 carriers of single heterozygous variant had abnormal clinical phenotype. The homozygous c.463del(p.E155Kfs20) variant of the TRDN gene probably underlay the pathogenesis of cardiac arrest in this child. Above discovery has enriched the mutational spectrum of the TRDN gene.

Clinical phenotype and genetic analysis of a child with partial duplication of 10q and a literature review

To explore the clinical phenotype and pathogenesis of a child with partial duplication in the long arm of chromosome 10 (10q), and conduct a review of relevant literature. A child presented at Lianyungang Maternal and Child Health Care Hospital in April 2018 for growth retardation, intellectual disability, and autism spectrum disorder (ASD) was selected as the study subject. Peripheral blood samples were collected from the child and his parents for G-banded chromosomal karyotyping analysis. Genomic DNA was also extracted for chromosomal microarray analysis (CMA). The clinical phenotype and relevant genes were searched in the Online Mendelian Inheritance in Man (OMIM) and the UK Database of Genomic Variation and Phenotype in Humans using Ensembl Resources (DECIPHER). The pathogenicity of chromosomal variation was analyzed based on guidelines from the American College of Medical Genetics and Genomics (ACMG). Relevant literature was searched from the CNKI, Wanfang Data, and PubMed databases by using keywords such as "10q" "duplication" and "trisomy", with the time set as from the establishment of database to December 1, 2023. This study has been approved by the Medical Ethics Committee of the Lianyungang Maternal and Child Health Care Hospital (No. XM2023030). The clinical phenotype of child had included growth retardation, intellectual disability, and ASD. G-banded chromosomal analysis suggested that the child has a karyotype of 46,XY,dup(10)(q23.31q24.33), whilst both of his parents were normal. CMA analysis of the child revealed that the child was arr[19]10q23.31q24.33(87603382_104948862)×3, with a 17.34 Mb duplication in the 10q23.31q24.33 region. Search of the OMIM database suggested that the duplicated segment has contained 171 genes associated with various diseases, and search of the DECIPHER database has identified cases with overlapping with the duplication. A search of the PubMed database has identified 2 publications involving 2 patients with chromosomal duplications overlapping the 10q23.31q24.33 region with a segment length of > 10 Mb. The 2 patients had mainly manifested growth retardation, intellectual disability, ASD, and facial and limb malformations. The main pathogenic genes had included PTEN, WNT8B, LZTS2, NFKB2, PAX2, KIF11, FRA10AC1, and CNNM2. No similar case was retrieved from the CNKI and Wanfang Data databases. The partial 10q duplication as a novel CNV involving genes such as PTEN and WNT8B probably underlay the growth retardation, intellectual disability and ASD in child 1 . This study has enriched the genotype-phenotype spectrum of patients with partial 10q23.31q24.33 duplications.

Enhancement of the quality of mc-Si ingot grown by vacuum directional solidification furnace with growth rate increase reducing the cost of the wafer for PV application: Carbon and oxygen analysis

In this paper, we propose a numerical model to investigate the dissolution of oxygen atoms from the porous silica crucible, SiO gas formation, back diffusion of CO gas and segregation of carbon and oxygen during the growth of multi-crystalline silicon (mc-Si) by vacuum directional solidification (VDS) at different growth rates (3, 6 and 9 mm/h) by silt valve opening rate. The dissolution of oxygen decreases during the rapid growth of ingot because the reaction between the molten silicon and the porous silica crucible is constrained. This limitation on oxygen dissolution from the porous silica crucible further diminishes chemical reaction inside the VDS furnace. Consequently, the segregation pattern of the carbon and oxygen is affected at higher growth rate. During the VDS mc-Si growth, a growth rate of 9mm/h yields better quality of the VDS grown mc-Si ingots compared to other growth rates, this rate reduces SiC precipitation and SiO2 cluster formation due to lower concentration of carbon and oxygen. The obtained carbon concentration minimizes the wire saw defects. Based on these numerical results (9 mm/h), we have implemented experimental work. Prepared samples are analyzed using FTIR spectra and minority carrier lifetime measurements. The effect of oxygen concentration in the samples is analyzed in the minority carrier lifetime measurements. The oxygen and carbon concentrations are calculated by FTIR spectra and their results are compared with the numerical simulation.

Teaching School Genetics in the 2020s: Why "Naive" Mendelian Genetics Has to Go.

Whereas Mendelian genetics is an important research program in the life sciences, its school version is problematic. On the one hand, it contains stereotypical representations of Gregor Mendel's work that misrepresent his findings and the historical context. This deprives students from gaining an authentic picture of how science is done. On the other hand, what most students end up learning in schools are extremely simplistic accounts of heredity, whereby alleles directly control traits and phenotypes, and thus exclusively depend on which allele an individual has. Such oversimplifications of Mendelian genetics as those that we still teach in schools were exploited by ideologues in the beginning of the twentieth century to provide the presumed "scientific" basis for eugenics. This paper addresses these problems of the school version of Mendelian genetics, which I call "naive" Mendelian genetics. It also proposes a shift in school education from teaching how the science of genetics is done using model systems to teaching the complexities of development through which heredity is materialized.

Brisk walking pace offsets venous thromboembolism risk equivalent to established monogenic mutations.

Mendelian mutations in F2 and F5 genes are known risk factors for venous thromboembolism (VTE). This study aimed to explore the association between walking pace and VTE, compare its risk with Mendelian mutations, and identify if blood biomarkers mediate this effect. We followed 445,261 UK Biobank participants free of VTE at baseline. Walking pace was self-reported, and carrier status for F2 and F5 gene mutations was determined by rs1799963 and rs6025 genotypes. We used a Cox proportional hazard model to estimate walking pace's effect on VTE risk, bidirectional Mendelian randomization (MR) analysis to assess causality, and mediation analysis to explore blood biomarkers. Over a median follow-up of 12.8 years, 11,155 incident VTE cases were identified. The 10-year incidence rates for brisk and slow walking paces were 1.32% and 3.90%, respectively. For F5 carriers, the rates were 1.70% (brisk pace) and 3.62% (slow pace). Brisk walking pace reduced VTE risk in F5 carriers (2.65%) compared to non-carriers with a slow pace (3.66%). MR analysis confirmed a causal relationship from walking pace to VTE risk. Mediation analysis revealed that serum albumin and cystatin C mediated 8.7% to 11.7% of the effect of brisk walking pace on VTE risk. A slow walking pace is causally associated with increased VTE risk. A brisk walking pace mitigates VTE risk, particularly in individuals with F5 gene mutations, and this effect is partially mediated by serum albumin and cystatin C.

Mechanism of Asperosaponin VI Related to EGFR/MMP9/AKT/PI3K Pathway in Treatment of Rheumtoid Arthritis.

To explore the mechanism of action of asperosaponin VI (AVI) in the treatment of rheumatoid arthritis (RA) and validate it in ex vivo experiments using network pharmacology and molecular docking methods. The predicted targets of AVI were obtained from PharmMaper, UniProt and SwissTarget Prediction platforms, the disease targets were collected from Online Mendelian Inheritance in Man, Therapeutic Target Database and GeneCards databases, the intersection targets of AVI and RA were obtained from Venny 2.1.0, and the protein-protein interaction (PPI) network was obtained from STRING database, which was analyzed by Cytoscape software and screened to obtain the core targets. Cytoscape software was used to analyze PPI network and screen the core targets. Based on the Database for Annotation, Visualization and Integrated Discovery database, Gene Ontology functional and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed, and Cytoscape software was used to construct the "Disease-Pathway-Target-Drug" network, which was finally verified by molecular docking and animal experiments. Network pharmacological studies showed that AVI was able to modulate 289 targets, with 102 targets for the potential treatment of RA, with the core pathway being the AKT/PI3K signaling pathway, and the core targets being the epidermal growth factor receptor (EGFR) and matrix metalloproteinase 9 (MMP9). Molecular docking results showed that AVI could produce strong binding with both of the 2 core targets. In vitro cellular experiments showed that AVI reduced nitric oxide, prostaglandin E2, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-1 β levels (P<0.05) and inhibited cyclooxygenase-2, nitric oxide synthase, EGFR, MMP9, phosphorylated phosphoinositide 3-kinase (p-PI3K), and phosphorylated serine-threonine kinase (p-AKT) proteins (P<0.05). The results of in vivo studies showed that AVI improved RA score and foot swelling thickness and decreased TNF-α, IL-6, p-PI3K and p-AKT levels in RA rats (P<0.05). AVI exerts anti-inflammatory and anti-RA effects which might be related to the EGFR/MMP9/AKT/PI3K pathway.

A meiotic driver hijacks an epigenetic reader to disrupt mitosis in noncarrier offspring

Killer meiotic drivers (KMDs) are selfish genetic elements that distort Mendelian inheritance by selectively killing meiotic products lacking the KMD element, thereby promoting their own propagation. Although KMDs have been found in diverse eukaryotes, only a limited number of them have been characterized at the molecular level, and their killing mechanisms remain largely unknown. In this study, we identify that a gene previously deemed essential for cell survival in the fission yeast Schizosaccharomyces pombe is a single-gene KMD. This gene, tdk1, kills nearly all tdk1Δ progeny in a tdk1+ × tdk1Δ cross. By analyzing polymorphisms of tdk1 among natural strains, we identify a resistant haplotype, HT3. This haplotype lacks killing ability yet confers resistance to killing by the wild-type tdk1. Proximity labeling experiments reveal an interaction between Tdk1, the protein product of tdk1, and the epigenetic reader Bdf1. Interestingly, the nonkilling Tdk1-HT3 variant does not interact with Bdf1. Cryoelectron microscopy further elucidated the binding interface between Tdk1 and Bdf1, pinpointing mutations within Tdk1-HT3 that disrupt this interface. During sexual reproduction, Tdk1 forms stable Bdf1-binding nuclear foci in all spores after meiosis. These foci persist in germinated tdk1Δ progeny and impede chromosome segregation during mitosis by generating aberrant chromosomal adhesions. This study identifies a KMD that masquerades as an essential gene and reveals the molecular mechanism by which this KMD hijacks cellular machinery to execute killing. Additionally, we unveil that losing the hijacking ability is an evolutionary path for this single-gene KMD to evolve into a nonkilling resistant haplotype.

Hereditary Rickets: A Quick Guide for the Pediatrician.

With the increased discovery of genes implicated in vitamin D metabolism and the regulation of calcium and phosphate homeostasis, a growing number of genetic forms of rickets are now recognized. These are categorized into calciopenic and phosphopenic rickets. Calciopenic forms of hereditary rickets are caused by genetic mutations that alter the enzymatic activity in the vitamin D activation pathway or impair the vitamin D receptor action. Hereditary forms of phosphopenic rickets, on the other hand, are caused by genetic mutations that lead to increased expression of FGF23 hormone or that impair the absorptive capacity of phosphate at the proximal renal tubule. Due to the clinical overlap between acquired and genetic forms of rickets, identifying children with hereditary rickets can be challenging. A clear understanding of the molecular basis of hereditary forms of rickets and their associated biochemical patterns allow the health care provider to assign the correct diagnosis, avoid non-effective interventions and shorten the duration of the diagnostic journey in these children. In this mini-review, known forms of hereditary rickets listed on the Online Mendelian Inheritance in Man database are discussed. Further, a clinical approach to identify and diagnose children with hereditary forms of rickets is suggested.