Integrative multi-target analysis of Urtica dioica for gout arthritis treatment: a network pharmacology and clustering approach.

Urtica dioica (stinging nettle) has been traditionally used in Chinese medicine for the treatment of joint pain and rheumatoid arthritis. This study aims to elucidate the active compounds and mechanisms by which it acts against gout arthritis (GA). Gout-related genes were identified from the DisGeNet, GeneCards, and OMIM databases. These genes may play a role in inhibiting corresponding proteins targeted by the active compounds identified from the literature, which have an oral bioavailability of ≥ 30% and a drug-likeness score of ≥ 0.18. A human protein-protein interaction network was constructed, resulting in sixteen clusters containing plant-targeted genes, including ABCG2, SLC22A12, MAP2K7, ADCY10, RELA, and TP53. The key bioactive compounds, apigenin-7-O-glucoside and kaempferol, demonstrated significant binding to SLC22A12 and ABCG2, suggesting their potential to reduce uric acid levels and inflammation. Pathway enrichment analysis further identified key metabolic pathways involved, highlighting a dual mechanism of anti-inflammatory and urate-lowering effects. These findings underscore the potential of U. dioica in targeting multiple pathways involved in GA, combining traditional medicine with modern pharmacology. This integrated approach provides a foundation for future research and the development of multi-target therapeutic strategies for managing gout arthritis. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-024-00254-9.

A rare homozygous ALX4 mutation in a Bangladeshi girl with frontonasal dysplasia type-2 (FND2).

Background: Frontonasal dysplasia type-2(FND2), a rare phenotypically variable and heterogeneous developmental anomaly resulting from mutation of the ALX4 gene, is primarily characterized by malformation of the skull and facial skeleton. This study was designed to showcase a clinical, imaging, and genetic analysis of FND2 in a consanguineous family of Bangladeshi origin. Methodology: Clinical imaging and whole genome sequencing of mother, father and patient was done by using Nextera DNA flex library preparation kit (Illumina, USA) using Novaseq 6000 next generation sequencer to find out ALX4 mutation which causes FND2 in patient. Result: We report the clinical as well as molecular findings in an 8-year-old girl with FND2. The child presented with various characteristic features of skull and facial anomalies associated with FND 2 along with numerous other features many of which have not been described in previous literature. The parents also showed some key clinical, radiological, and genetic features of FND 2. The whole genome sequencing (WGS) revealed homozygosity for a 793C-T transition in the ALX4 gene, which resulted in premature termination at codon 265 (p.Arg265Ter). Both of her parents were heterozygous carriers of ALX4 mutation. Conclusions: This is the first report that associates clinical, imaging, and genomics analyses in a Bangladeshi patient for better understanding the disease FND2. These results will facilitate diagnosis and genetic counseling of the future FND2 patients.

Valorization of pawpaw (Carica papaya L.) leaves as a source of polyphenols by ionic liquid-based microwave-assisted extraction: Comparison with other extraction methods and bioactivity evaluation.

This study aimed to valorize pawpaw (Carica papaya L.) leaves as a rich source of polyphenols through the application of ionic liquid-based microwave-assisted extraction (ILMAE). Initially, the ILMAE process was optimized using response surface methodology (RSM), resulting in a total polyphenols yield of 27.84 ± 0.33 mg GAE/g DW under the optimal conditions: [BMIM]Br concentration of 0.57 mol/L, extraction time of 14 min, microwave power of 460 W, extraction temperature of 77 °C, solvent-to-material ratio of 30 mL/g, and three extraction cycles. Compared to conventional methods such as maceration extraction (ME), heat reflux extraction (HRE), and microwave-assisted extraction (MAE), the ILMAE method exhibited a significantly higher PLTP yield. Furthermore, the PLTP extracts demonstrated strong antioxidant activity against DPPH• and ABTS+• radicals, as well as a significant inhibitory effect on α-glucosidase activity. This work demonstrates that ILMAE is a green and efficient strategy for the valorization of pawpaw leaves.

Database construction and comparative genomics analysis of genes involved in nutritional metabolic diseases in fish.

Nutritional metabolic diseases in fish frequently arise in the setting of intensive aquaculture. The etiology and pathogenesis of these conditions involve energy metabolic disorders influenced by both internal genetic factors and external environmental conditions. The exploration of genes associated with nutritional and metabolic disorder has sparked considerable interest within both the aquaculture scientific community and the industry. High-throughput sequencing technology offers researchers extensive genetic information. Effectively mining, analyzing, and securely storing this data is crucial, especially for advancing disease prevention and treatment strategies. Presently, the exploration and application of gene databases concerning nutritional and metabolic disorders in fish are at a nascent stag. Therefore, this study focused on the model organism zebrafish and five primary economic fish species as the subjects of investigation. Using information from KEGG, OMIM, and existing literature, a novel gene database associated with nutritional metabolic diseases in fish was meticulously constructed. This database encompassed 4583 genes for Danio rerio, 6287 for Cyprinus carpio, 3289 for Takifugu rubripes, 3548 for Larimichthys crocea, 3816 for Oreochromis niloticus, and 5708 for Oncorhynchus mykiss. Through a comparative systems biology approach, we discerned a relatively high conservation of genes linked to nutritional metabolic diseases across these fish species, with over 54.9 % of genes being conserved throughout all six species. Additionally, the analysis pinpointed the existence of 13 species-specific genes within the genomes of large yellow croaker, tilapia, and rainbow trout. These genes exhibit the potential to serve as novel candidate targets for addressing nutritional metabolic diseases.

Multicentric Osteolysis Nodulosis Arthropathy Syndrome Simulating Juvenile Idiopathic Arthritis in an Adult Female: A Case Report and a Literature Review.

Multicentric osteolysis, nodulosis, and arthropathy (MONA) syndrome is one of the rare genetic skeletal dysplasias, inherited as an autosomal recessive disorder, which predominantly involves carpal and tarsal bones with characteristic osteolytic lesions and can be misdiagnosed as juvenile idiopathic arthritis or rheumatoid arthritis. MONA syndrome includes diseases involving two genes: the matrix metalloproteinase 2 (MMP2) gene and matrix metalloproteinase 14 (MMP14). Both genes are assumed to cause phenotype variants of the same disease. Older patients may manifest some arthritic features, especially in the wrist, and minute pathological fractures can occur as well. These patients may be misdiagnosed as inflammatory arthritis and physicians might prescribe corticosteroid and disease-modifying immunosuppressive agents. Therefore, physicians should carefully evaluate genetic skeletal dysplasia to make a correct diagnosis and avoid unnecessary pharmacological intervention. We report a case of MONA syndrome in an adult female who came to our facility for an intensive rehabilitation program.

Advances in genetic etiology, diagnosis and treatment of developmental and epileptic encephalopathy.

Developmental and epileptic encephalopathy (DEE) is a clinically and genetically heterogeneous group of age-dependent neurological disorders characterized by onset of refractory seizures in infancy or early childhood and affected individuals with delayed or regressive psychomotor development. With the development of next-generation sequencing technology, especially the application of whole-exome sequencing technology, more and more genes have been found to be associated with DEE.These discoveries provide a basis for the detection of pathogenic genes for DEE in clinical work, and also help to deepen our understanding of the pathogenesis of DEE. In this review, we provide a comprehensive review of the genetic etiology, diagnosis and treatment of DEE, in order to assist clinicians in early identification of relevant gene mutations, thereby expediting disease diagnosis and timely implementation of optimal treatment.

PheSom: a term frequency-based method for measuring human phenotype similarity on the basis of MeSH vocabulary.

Background: Phenotype similarity calculation should be used to help improve drug repurposing. In this study, based on the MeSH terms describing the phenotypes deposited in OMIM, we proposed a method, namely, PheSom (Phenotype Similarity On MeSH), to measure the similarity between phenotypes. PheSom counted the number of overlapping MeSH terms between two phenotypes and then took the weight of every MeSH term within each phenotype into account according to the term frequency-inverse document frequency (FIDC). Phenotype-related genes were used for the evaluation of our method. Results: A 7,739 × 7,739 similarity score matrix was finally obtained and the number of phenotype pairs was dramatically decreased with the increase of similarity score. Besides, the overlapping rates of phenotype-related genes were remarkably increased with the increase of similarity score between phenotypes, which supports the reliability of our method. Conclusion: We anticipate our method can be applied to identifying novel therapeutic methods for complex diseases.

An activator of voltage-gated K+ channels Kv1.1 as a therapeutic candidate for episodic ataxia type 1.

Loss-of-function mutations in the KCNA1(Kv1.1) gene cause episodic ataxia type 1 (EA1), a neurological disease characterized by cerebellar dysfunction, ataxic attacks, persistent myokymia with painful cramps in skeletal muscles, and epilepsy. Precision medicine for EA1 treatment is currently unfeasible, as no drug that can enhance the activity of Kv1.1-containing channels and offset the functional defects caused by KCNA1 mutations has been clinically approved. Here, we uncovered that niflumic acid (NFA), a currently prescribed analgesic and anti-inflammatory drug with an excellent safety profile in the clinic, potentiates the activity of Kv1.1 channels. NFA increased Kv1.1 current amplitudes by enhancing the channel open probability, causing a hyperpolarizing shift in the voltage dependence of both channel opening and gating charge movement, slowing the OFF-gating current decay. NFA exerted similar actions on both homomeric Kv1.2 and heteromeric Kv1.1/Kv1.2 channels, which are formed in most brain structures. We show that through its potentiating action, NFA mitigated the EA1 mutation-induced functional defects in Kv1.1 and restored cerebellar synaptic transmission, Purkinje cell availability, and precision of firing. In addition, NFA ameliorated the motor performance of a knock-in mouse model of EA1 and restored the neuromuscular transmission and climbing ability in Shaker (Kv1.1) mutant Drosophila melanogaster flies (Sh5). By virtue of its multiple actions, NFA has strong potential as an efficacious single-molecule-based therapeutic agent for EA1 and serves as a valuable model for drug discovery.

Exploring the mechanism of physcion-1-O-ß-D-monoglucoside against acute lymphoblastic leukaemia based on network pharmacology and experimental validation.

Objective: To explore the mechanism of PG against acute lymphoblastic leukaemia (ALL) by network pharmacology and experimental verification in vitro. Methods: First, the biological activity of PG against B-ALL was determined by CCK-8 and flow cytometry. Then, the potential targets of PG were obtained from the PharmMapper database. ALL-related genes were collected from the GeneCards, OMIM and PharmGkb databases. The two datasets were intersected to obtain the target genes of PG in ALL. Then, protein interaction networks were constructed using the STRING database. The key targets were obtained by topological analysis of the network with Cytoscape 3.8.0 software. In addition, the mechanism of PG in ALL was confirmed by protein‒protein interaction, gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. Furthermore, molecular docking was carried out by AutoDock Vina. Finally, Western blotting was performed to confirm the effect of PG on NALM6 cells. Results: PG inhibited the proliferation of NALM6 cells. A total of 174 antileukaemic targets of PG were obtained by network pharmacology. The key targets included AKT1, MAPK14, EGFR, ESR1, LCK, PTPN11, RHOA, IGF1, MDM2, HSP90AA1, HRAS, SRC and JAK2. Enrichment analysis found that PG had antileukaemic effects by regulating key targets such as MAPK signalling, and PG had good binding activity with MAPK14 protein (-8.9 kcal/mol). PG could upregulate the expression of the target protein p-P38, induce cell cycle arrest, and promote the apoptosis of leukaemia cells. Conclusion: MAPK14 was confirmed to be one of the key targets and pathways of PG by network pharmacology and molecular experiments.

Electrophysiology of ataxia-telangiectasia-like disorder 1.

Ataxia-telangiectasia-like disorder-1 (ATLD1, OMIM # 604391) is a very rare clinical condition, characterized by slowly progressive ataxia with onset in childhood, associated with oculomotor apraxia and dysarthria. Laboratory findings reveal increased susceptibility to radiation, with a defect in DNA repair. Patients with ATLD1 show no telangiectasia, have no immunodeficiency, and also have preserved cognition. Reflexes might be initially brisk and later becomes reduced associated with axonal sensorimotor neuropathy. Brain magnetic resonance imaging (MRI) detects cerebellar atrophy. The condition is caused by mutations in the meiotic recombination 11 (MRE11A) gene. The present study reports on the neurophysiologic finding in eight Saudi patients, belonging to three Saudi families, who have genetically confirmed ATLD1. All investigated patients had cerebellar atrophy on brain MRI (5/5). Electrophysiologic studies showed normal motor conduction velocity (MCV) of the median (8/8) and tibial (2/2) nerves, while 5/6 (83%) had normal peroneal nerve MCV. The distal motor latency (DML) for median, tibial, and peroneal nerves was within the normal range in all examined patients. The amplitude of compound muscle action potential (CMAP) of median and tibial nerves was also normal, while that of the peroneal nerve was normal in 3/6 (50%). Two of seven (29%) patients had reduced amplitude of median nerve sensory nerve action potential (SNAP) while 3/8 (38%) had a reduction in the amplitude of sural nerve SNAP. These findings favour an axonal type of neuropathy predominately affecting the sensory fibres (axonal sensorimotor neuropathy). The present study constitutes the largest cohort of ATLD1 patients worldwide who had electrophysiologic tests.

Exploring Genes and Phenotypes Within Chromosomal Regions Using OMIM's GeneScout.

Structural variation in genomes, such as copy number variants (CNVs), is under scrutiny for its contribution to phenotypic expression and evolution. Regions of homozygosity (ROH) are ripe for phenotype-gene discovery. Determining the genes and related phenotypes within genomic regions is key to studying potential functional and phenotypic consequences. Because individuals have multiple CNVs and ROHs in their genome, identifying genomic regions that are phenotypically significant is challenging. GeneScout is a web-based tool that can be used to search genomic regions to display and filter the genes and their associated phenotypes within regions of interest. Phenotypes and their associated gene(s) can then be filtered to show only the genes with phenotypes that have a particular inheritance pattern and/or specific clinical feature(s). Phenotypes can then be selected to compare the clinical synopses side-by-side in Online Mendelian Inheritance in Man (OMIM® ). Additionally, two coordinate sets can be compared to determine either the regions of overlap or the unique regions (subtraction). The resulting coordinate ranges are displayed on the results page, and the results table displays only the genes and phenotypes present within the coordinate ranges. The interactive table includes gene-specific links to external resources such as ClinVar, ClinGen validity, ClinGen dosage, and gnomAD, and a diamond symbol next to the gene name indicates a gene that spans the start or end of a coordinate range. Searches and comparisons may be performed for coordinates in assemblies GRCh37 (hg19) and GRCh38 (hg38). The results page offers the option to liftover coordinates entered in GRCh37 to GRCh38 and updates the results table to display the gene content based on assembly GRCh38. The search coordinates and results table can be downloaded in a tab-delimited or Excel file. © 2022 Wiley Periodicals LLC. Basic Protocol: Searching GeneScout.

Functional Diversity and Evolution of the Drosophila Sperm Proteome.

Spermatozoa are central to fertilization and the evolutionary fitness of sexually reproducing organisms. As such, a deeper understanding of sperm proteomes (and associated reproductive tissues) has proven critical to the advancement of the fields of sexual selection and reproductive biology. Due to their extraordinary complexity, proteome depth-of-coverage is dependent on advancements in technology and related bioinformatics, both of which have made significant advancements in the decade since the last Drosophila sperm proteome was published. Here, we provide an updated version of the Drosophila melanogaster sperm proteome (DmSP3) using improved separation and detection methods and an updated genome annotation. Combined with previous versions of the sperm proteome, the DmSP3 contains a total of 3176 proteins, and we provide the first label-free quantitation of the sperm proteome for 2125 proteins. The top 20 most abundant proteins included the structural elements α- and ß-tubulins and sperm leucyl-aminopeptidases. Both gene content and protein abundance were significantly reduced on the X chromosome, consistent with prior genomic studies of X chromosome evolution. We identified 9 of the 16 Y-linked proteins, including known testis-specific male fertility factors. We also identified almost one-half of known Drosophila ribosomal proteins in the DmSP3. The role of this subset of ribosomal proteins in sperm is unknown. Surprisingly, our expanded sperm proteome also identified 122 seminal fluid proteins (Sfps), proteins originally identified in the accessory glands. We show that a significant fraction of 'sperm-associated Sfps' are recalcitrant to concentrated salt and detergent treatments, suggesting this subclass of Sfps are expressed in testes and may have additional functions in sperm, per se. Overall, our results add to a growing landscape of both sperm and seminal fluid protein biology and in particular provides quantitative evidence at the protein level for prior findings supporting the meiotic sex-chromosome inactivation model for male-specific gene and X chromosome evolution.

Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability.

Robinow syndrome (RS) is a genetically heterogeneous disorder with six genes that converge on the WNT/planar cell polarity (PCP) signaling pathway implicated (DVL1, DVL3, FZD2, NXN, ROR2, and WNT5A). RS is characterized by skeletal dysplasia and distinctive facial and physical characteristics. To further explore the genetic heterogeneity, paralog contribution, and phenotypic variability of RS, we investigated a cohort of 22 individuals clinically diagnosed with RS from 18 unrelated families. Pathogenic or likely pathogenic variants in genes associated with RS or RS phenocopies were identified in all 22 individuals, including the first variant to be reported in DVL2. We retrospectively collected medical records of 16 individuals from this cohort and extracted clinical descriptions from 52 previously published cases. We performed Human Phenotype Ontology (HPO) based quantitative phenotypic analyses to dissect allele-specific phenotypic differences. Individuals with FZD2 variants clustered into two groups with demonstrable phenotypic differences between those with missense and truncating alleles. Probands with biallelic NXN variants clustered together with the majority of probands carrying DVL1, DVL2, and DVL3 variants, demonstrating no phenotypic distinction between the NXN-autosomal recessive and dominant forms of RS. While phenotypically similar diseases on the RS differential matched through HPO analysis, clustering using phenotype similarity score placed RS-associated phenotypes in a unique cluster containing WNT5A, FZD2, and ROR2 apart from non-RS-associated paralogs. Through human phenotype analyses of this RS cohort and OMIM clinical synopses of Mendelian disease, this study begins to tease apart specific biologic roles for non-canonical WNT-pathway proteins.

Transport Across Two Membrane Bilayers in E. coli by Efflux Pumps of Different Dimensions.

AcrAB-TolC and CusBAC are two of the most well-studied Resistance-Nodulation-Division (RND) family tripartite efflux pumps in E. coli. AcrAB-TolC is a multidrug efflux system, while CusBAC transports Cu(I), Cu(II) and Ag(I). The RND pump complexes span both the inner membrane (IM) and the outer membrane (OM). The long axis dimension of the fully assembled AcrAB-TolC is ∼3 nm longer than that of CusBAC. To probe if these two efflux systems with different dimensions affect each other when they need to work simultaneously in the same cell, two real-time assays were used to monitor the efflux activities of these two pumps and their impact on each other. The results showed that the presence of AcrAB-TolC substrates accelerated the accumulation of Cu(I) in BW25113 but not in BW25113ΔcusBA or BW25113ΔtolC strains. Similarly, the presence of Ag(I) slowed down the Nile red efflux in the parent strain more significantly than in the CusBA deficient mutant. To further investigate the impact of the OM/IM distance on the function of these tripartite complexes, we experimented with strains lacking the lipoprotein Lpp or containing Lpp mutant of different lengths. Data from efflux/accumulation assays and susceptibility tests revealed that mutation of Lpp resulted in functional deficiency of both AcrAB-TolC and CusBAC. In conclusion, this study demonstrated that when AcrAB-TolC and CusBAC functioned simultaneously, it took the cell a few minutes to adjust. Furthermore, the presence of Lpp of proper length is important to support full efflux activity of transporters spanning both membrane layers in E. coli.

Three Siblings With Woodhouse-Sakati Syndrome: A Case Report of A New Saudi Family.

Woodhouse-Sakati syndrome (WSS) is a rare autosomal recessive multi-system genetic disease caused by loss of function mutations in the DCAF17 gene on chromosome 2q31.1. The disease is characterized by gradual neurologic degeneration and polyendocrinopathy, particularly noteworthy for hypogonadism, beginning in early adolescence. Clinical features show wide variability with no clear genotype-phenotype correlation. The pathophysiology of WSS is unclear at present and no specific treatment is available other than hormone replacement which is administered in the course of individualized symptomatic multidisciplinary care. Genetic testing helps in confirming the diagnosis along with genetic counseling of the patient and family members. Here we report multiple cases of WSS in three siblings from a new Saudi Arabia family who were diagnosed with WSS as a consequence of a common founder mutation in the DCAF17 gene with DNA analysis showing a homozygous single nucleotide frameshift deletion (c.436delC) in exon 4 of the gene.

Multiple variants in XDH and MOCOS underlie xanthine urolithiasis in dogs.

Hereditary xanthinuria is a rare autosomal recessive disease caused by missense and loss of function variants in the xanthine dehydrogenase (XDH) or molybdenum cofactor sulfurase (MOCOS) genes. The aim of this study was to uncover variants underlying risk for xanthinuria in dogs. Affected dogs included two Manchester Terriers, three Cavalier King Charles Spaniels, an English Cocker Spaniel, a Dachshund, and a mixed-breed dog. Four putative causal variants were discovered: an XDH c.654G > A splice site variant that results in skipping of exon 8 (mixed-breed dog), a MOCOS c.232G > T splice site variant that results in skipping of exon 2 (Manchester Terriers), a MOCOS p.Leu46Pro missense variant (Dachshund), and a MOCOS p.Ala128Glyfs*30 frameshift variant that results in a premature stop codon (Cavalier King Charles Spaniels and English Cocker Spaniel). The two splice site variants suggest that the regions skipped are critical to the respective enzyme function, though protein misfolding is an alternative theory for loss of function. The MOCOS p.Leu46Pro variant has not been previously reported in human or other animal cases and provides novel data supporting this residue as critical to MOCOS function. All variants were present in the homozygous state in affected dogs, indicating an autosomal recessive mode of inheritance. Allele frequencies of these variants in breed-specific populations ranged from 0 to 0.18. In conclusion, multiple diverse variants appear to be responsible for hereditary xanthinuria in dogs.

Using Online Mendelian Inheritance in Man in low- and middle-income countries.

Online Mendelian Inheritance in Man (OMIM®), an online catalog of human genes and genetic disorders, has been used in the low- and middle-income countries largely as a tool for improving clinical care, teaching genetics and genomics, and for clinical and research analysis of next-generation sequencing. By facilitating free access to curated, updated, and comprehensive information in genetics and genomics, OMIM has led to better clinical care and research advancement in countries where clinicians and researchers in private or public hospitals and universities cannot afford to pay for other resources including journal subscriptions.

YPIBP: A repository for phosphoinositide-binding proteins in yeast.

Phosphoinositides (PIs) are a family of eight lipids consisting of phosphatidylinositol (PtdIns) and its seven phosphorylated forms. PIs have important regulatory functions in the cell including lipid signaling, protein transport, and membrane trafficking. Yeast has been recognized as a eukaryotic model system to study lipid-protein interactions. Hundreds of yeast PI-binding proteins have been identified, but this research knowledge remains scattered. Besides, the complete PI-binding spectrum and potential PI-binding domains have not been interlinked. No comprehensive databases are available to support the lipid-protein interaction research on phosphoinositides. Here we constructed the first knowledgebase of Yeast Phosphoinositide-Binding Proteins (YPIBP), a repository consisting of 679 PI-binding proteins collected from high-throughput proteome-array and lipid-array studies, QuickGO, and a rigorous literature mining. The YPIBP also contains protein domain information in categories of lipid-binding domains, lipid-related domains and other domains. The YPIBP provides search and browse modes along with two enrichment analyses (PI-binding enrichment analysis and domain enrichment analysis). An interactive visualization is given to summarize the PI-domain-protein interactome. Finally, three case studies were given to demonstrate the utility of YPIBP. The YPIBP knowledgebase consolidates the present knowledge and provides new insights of the PI-binding proteins by bringing comprehensive and in-depth interaction network of the PI-binding proteins. YPIBP is available at http://cosbi7.ee.ncku.edu.tw/YPIBP/.

Global Single Clustering of Phenotype-Associated Human Aging Genes in the Co-Expression and Physical Interaction Networks: An OMIM-Based Investigative Review.

BACKGROUND: While a large wealth of literature on aging pertains to in silico, experimental, and predicted genes, many of those genes do not have validated phenotypic consequences in human. Online Mendelian Inheritance in Man (OMIM) provides an exceptional compendium of authoritative, validated aging genes and phenotypes, the interactions among which may enhance the overall perspective of aging mechanisms in human. METHODS: Here, we reviewed and investigated the global clustering pattern of the OMIM-indexed aging genes (until April 2021) in the gene co-expression and physical interaction networks, using the two keywords "aging" and "ageing". To allow for validity check, we randomly selected six sets of genes from the human genome as control genes, each set consisting of a similar number of genes obtained from the OMIM search. STRING was implemented in the weighted setting and using the edge betweenness parameter, to construct the integrated and tissue-specific networks of the age-related and control genes. RESULTS: 286 aging (ageing) genes and a wide spectrum of 96 associated phenotypes were detected, including late-onset neurodegenerative disorders, cancers, osteoarthritis, and longevity. Despite the general terms used and the vast range of age-related phenotypes, we detected single clustering of the OMIM-extracted aging (ageing) genes in each of the integrated weighted co-expression and physical interaction networks (p<0.0005), as opposed to multiple clustering of the control genes (p≥0.04). TP53 was the overlapping hub gene in each of the networks. Three genes, TP53, APP, and SIRT1 were the consistent hub genes co-expressed across eleven selected human tissues frequently affected by age-related phenotypes. CONCLUSION: We propose predominant single clustering of the human phenotype-associated aging genes in the co-expression and physical interaction networks, and list the top pathways and genes involved.

Online Mendelian Inheritance in Man (OMIM®): Victor McKusick's magnum opus.

Victor McKusick's many contributions to medicine are legendary, but his magnum opus is Mendelian Inheritance in Man (MIM), his catalog of Mendelian phenotypes and their associated genes. The catalog, originally published in 1966 in book form, became available on the internet as Online Mendelian Inheritance in Man (OMIM®) in 1987. The first of 12 editions of MIM included 1486 entries; this number has increased to over 25,000 entries in OMIM as of April 2021, which demonstrates the growth of knowledge about Mendelian phenotypes and their genes through the years. OMIM now has over 20,000 unique users a day, including users from every country in the world. Many of the early decisions made by McKusick, such as to maintain MIM data in a computer-readable format, to separate phenotype entries from those for genes, and to give phenotypes and genes MIM numbers, have proved essential to the long-term utility and flexibility of his catalog. Based on his extensive knowledge of genetics and vision of its future in the field of medicine, he developed a framework for the capture and summary of information from the published literature on phenotypes and their associated genes; this catalog continues to serve as an indispensable resource to the genetics community.