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PubMed1989

Nucleic acid related compounds. 57. Synthesis, x-ray crystal structure, lipophilic partition properties, and antiretroviral activities of anomeric 3'-azido-2',3'-dideoxy-2,6-diaminopurine ribosides.

Trimethylsilyl triflate-catalyzed transfer glycosylation of 2,6-diamino-9-(3-azido-2,3-dideoxy-alpha- and -beta-D-erythro-pentofuranosyl)purines (3 and 4) in low yields. Selective 2'-O-tosylation of 2,6-diamino-9-(beta-D-ribofuranosyl)purine (2,6-diaminopurine riboside, DAPR, 5) followed by our lithium triethylborohydride promoted 1,2-hydride rearrangement gave 2,6-diamino-9-(2-deoxy-beta-D-threo-pentofuranosyl)purine (7). Tritylation of 7 followed by mesylation at O3', deprotection, and displacement of the 3'-mesylate with azide provided a stereodefined synthesis of 2,6-diamino-9-(3-azido-2, 3-dideoxy-beta-D-erythro-pentofuranosyl)purine (AzddDAPR, 4). X-ray crystallographic analysis of 4 showed two orientations of the azido group, but consistent conformational features in the remainder of the molecule. In contrast, two independent conformations have been found for AZT. The azido function confers enhanced lipophilicity, which could be expected to contribute significantly to nonselective transport across membranes. A large difference in the octanol/water partition coefficients of the alpha (3) and beta (4) anomers wes found. The beta anomer (4) exerts potent inhibition of HIV-induced cytopathogenicity in human MT-4 cells (ED50: 0.3 microM). This concentration is an order of magnitude lower than that required for ddDAPR, AzddAdo, and AzddGuo. Potent inhibition of Moloney sarcoma virus induced transformation of murine C3H cells by AzddDAPR (4) was also observed. The alpha anomer (3) had no observed antiviral activity.

Animals↗

PubMed2006

Morphology of platinum electrodeposits in the three-dimensional sublayer to full layer range produced under different potential modulations on highly oriented pyrolytic graphite.

The topography of platinum electrodes produced by electrodeposition (19 to 200 mC cm-2) on highly oriented pyrolytic graphite (HOPG) under different potential modulations was investigated by atomic force microscopy, scanning tunneling microscopy, and H-atom electrosorption voltammetry. To modulate electrodeposition, (i) triangular potential cycling at 0.1 V s-1, (ii) a linear cathodic potential at 0.1 V s-1 and anodic potential step cycling, and (iii) square wave potential cycling at 5000 Hz were utilized. AFM and STM imaging showed that at lower platinum loading the HOPG surface was partially covered by a 3D sublayer of platinum. Electrodes produced by procedure (i) were made of faceted platinum aggregates of about 200 nm and nanoclusters in the range of 5-20 nm; those that resulted from procedure (ii) consisted of anisotropic aggregates of nanoclusters arranged as quasi-parallel domains. These electrodes from (i) and (ii) behaved as fractal objects. The electrodes resulting from procedure (iii) exhibited a flat surface that behaved as a Euclidean object. For all WEs, as the platinum loading was increased the HOPG surface was fully covered by a thin 3D layer of platinum aggregates produced by electrodeposition and coalescence phenomena. Large platinum loading led to electrodes with fractal geometry. Statistical parameters (root-mean-square height, skewedness, kurtosis, anisotropy, Abbot curve, number of protrusions and valleys, and fractal dimension) were obtained from the analysis of AFM and STM imaging data. Platinum electrodeposition coupled to either H-adatom formation for procedures (i) and (ii) or phonon dispersion for (iii) was involved in the surface atom rearrangements related to electrofaceting. The H-adatom electrosorption voltammetry data were used to evaluate the real electrode surface area via the voltammetric charge and to advance a tentative explanation of the contribution of the different crystallographic facets to the global electrochemical process dominated by weak H-Pt adsorption interactions.

Journal Article↗

PubMed2026

Developmental and cellular vulnerabilities underlie genetic architecture of schizophrenia.

Schizophrenia (SZ) is a highly heritable neuropsychiatric condition with complex polygenic architecture. Elucidating the cellular and developmental substrates vulnerable to the genetic risk is essential for understanding the underlying neurobiological mechanisms. Here, we integrated genome-wide association study (GWAS) and whole-exome sequencing (WES) data with a developmental multi-omics atlas of the human cortex (including 5 cortical regions), comprising about 3 million single-nucleus RNA sequencing (snRNA-Seq) and single-nucleus assay for transposase-accessible chromatin using sequencing (snATAC-Seq) profiles across 8 neurodevelopmental processes, to map cell-type-specific enrichment of SZ genetic risk. Our enrichment analyses revealed that both common and rare genetic liabilities converged on broad excitatory and inhibitory neuronal classes. Across different statistical frameworks, we identified genetic enrichment within intratelencephalic (IT) projection neurons and layer 6b excitatory neurons (Ex-L6b) networks across multiple cortical regions. Stage-resolved developmental mapping in the frontal cortex showed that genetic liabilities, particularly the rare variants, are predominantly concentrated within early developmental processes, namely neurogenesis and neuronal migration. Differential expression analysis in postmortem frontal cortex snRNA-Seq datasets cross-validated the cellular substrates of the genetic liabilities. Collectively, our findings establish a high-resolution cellular and temporal framework of SZ susceptibility, implicating mature associative IT microcircuits, deep-layer thalamocortical-regulating networks, and early developmental specification windows as primary points of genetic convergence in SZ.

Journal Article↗

PubMed2026

Integration of multi-omics data uncovers novel germline susceptibility candidates in early-onset colorectal cancer.

Colorectal cancer (CRC) is increasingly diagnosed in individuals under 50 years of age, yet the underlying genetic predisposition remains largely unexplained, particularly in mismatch repair (MMR)-proficient cases. This study aimed to identify novel hereditary CRC susceptibility genes by integrating germline and tumour whole-exome sequencing (WES) with transcriptomic profiling across a cohort of early-onset CRC (EOCRC) patients. Tumours were categorised using Consensus Molecular Subtypes (CMS) classification and analysed for mutational signature and burden. We used a novel 'All vs One' multi-omic integration approach to identify loss-of-function rare germline variants with concordant gene expression alterations in tumour tissue. Five candidate genes (ADCY4, NOXO1, CDHR2, ARHGAP10, EEF2K) were prioritised based on this approach and potential biological relevance in CRC. These findings highlight the molecular heterogeneity of EOCRC and demonstrate the utility of multi-omic approaches in refining germline variant interpretation. Integrating tumour transcriptomics enhances gene discovery efforts and supports a more comprehensive understanding of CRC heritability in younger individuals.

Humans↗

PubMed2026

Genomic and computational analysis of variants in telomere regulatory genes in subjects with bone marrow failure.

Telomere Biology Disorders (TBDs) are a genetically heterogeneous and often under-recognized cause of Bone Marrow Failure Syndromes (BMFS), driven by defective telomere maintenance and progressive telomere attrition. We performed an integrated genomic, telomeric and computational analysis in 118 subjects presenting clinical features of BMFS to delineate the contribution of Telomere Regulatory Genes (TRGs) variants to disease pathogenesis. Whole exome sequencing (WES) identified pathogenic (18.18%), likely pathogenic (27.27%) and rare variants of uncertain significance (54.54%) in 27 subjects (22.9%) across five TRGs: RTEL1, TERT, TINF2, NOP10, and WRAP53. Telomere Length (TL) assessment revealed significant telomere shortening in TRG variant-positive subjects compared with age-matched controls, with the most profound attrition observed in individuals harboring de novo TINF2 gene variants. RTEL1 emerged as the most frequently affected gene, with recurrent clustering of variants within its C-terminal regulatory region. A familial NOP10 variant, Asp12His, segregated with cutaneous pigmentation and hematological abnormalities consistent with the established role of NOP10 in dyskeratosis congenita, further broadening the known mutational spectrum of the gene. Structure-guided in-silico analyses predicted that both novel and recurrent variants disrupt protein stability, telomerase assembly or trafficking and shelterin complex integrity. Reduced TERT expression and a significant inverse correlation between telomere length and clinical severity further underscored the functional impact of TRG defects. Collectively, this study provides the first comprehensive characterization of TRG variants in the Indian BMFS cohort and highlights the utility of integrating genomic sequencing, telomere length measurement and computational modeling to improve diagnostic precision, variant interpretation and clinical stratification in TBDs.

Journal Article↗

PubMed2025

Integrated genomic analysis of NF1-associated peripheral nerve sheath tumors: an updated biorepository dataset.

Neurofibromatosis type 1 (NF1) is an inherited neurocutaneous condition that predisposes to the development of peripheral nerve sheath tumors (PNST) including cutaneous neurofibromas (CNF), plexiform neurofibromas (PNF), atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP), and malignant peripheral nerve sheath tumors (MPNST). The Johns Hopkins NF1 biospecimen repository promotes the successful advancement of therapeutic developments for NF1-associated PNST through acquisition and genomic analysis of human tumor specimens. RNA sequencing (RNAseq) and whole exome sequencing (WES) data were generated from 73 and 114 primary human tumor samples, respectively. These pre-processed data, standardized for immediate computational analysis, are accessible through the NF Data Portal, allowing immediate interrogation. This dataset combines new and previously released samples, offering a comprehensive view of the entire cohort sequenced. As a dedicated effort to systematically bank tumor samples from people with NF1, in collaboration with molecular geneticists and computational biologists, the Johns Hopkins NF1 biospecimen repository offers access to tissue samples and genomic data to promote the advancement of NF1-related tumor biologic insights and therapies.

Humans↗

PubMedDate not supplied

A family showing inheritance of the Inab phenotype.

An 86-year-old white American woman was found to have a very rare red cell phenotype, the Inab phenotype. Her cells were Cr(a-), Tc(a-b-c-), Dr(a-), Es(a-), WES(a-b-), and IFC-. Unlike the two other Inab phenotype patients, she has no history of protein-losing enteropathy or any similar intestinal disorder. One of her four siblings also has the Inab phenotype, providing the first evidence that this phenotype may be inherited. Serum inhibitions showed that anit-Cra, -TCa, -Dra, -WESb, and -IFC are partially inhibited by sera from three siblings with the common red cell phenotype but not by serum from the Inab phenotype sibling. The serum of the proposita contained an antibody to a high-frequency antigen that showed characteristics of being a Cromer-related antibody.

Aged↗

PubMed2000

Molecular basis of Cromer blood group antigens.

BACKGROUND: The Cromer blood group system consists of 10 antigens located on decay-accelerating factor (DAF). Previous molecular genetic analysis has determined the basis for four of these antigens. The present study was undertaken to identify the mutations that determine the remaining antigens. STUDY DESIGN AND METHOD: Existing or new data were used to localize each Cromer system antigen to a specific short consensus repeat (SCR) domain of DAF. The exon encoding that SCR domain was amplified by using the polymerase chain reaction (PCR) on genomic DNA obtained from individuals of that Cromer phenotype, and the DNA product was subjected to DNA sequence analysis. RESULTS: The Tc(a)/Tc(c) polymorphism is due to an R18P amino acid substitution in SCR1 of DAF. The Es(a+)/Es(a-) polymorphism is due to an I46N mutation in SCR1 of DAF. The WES(b)/WES(a) polymorphism is due to an L48R mutation in SCR1 of DAF. The UMC+/UMC- polymorphism is due to a T216M substitution in SCR4 of DAF. CONCLUSIONS: With information from previous reports and the findings of this study, the molecular genetic basis of all known alleles of the Cromer blood group system has been elucidated. Single amino acid substitutions are responsible for 9 of the 10 antigens (all except the multiple-epitope antigen IFC).

Base Sequence↗

PubMed1982

[Fluorescein angiography of the choroid with elevated intraocular pressure (author's transl)].

Artificially induced increases in intraocular pressure slow the influx of dye during fluorescein angiography sufficiently to permit a sparation in time of the filling of the retina and the choroidea. During the filling of the choroidea segmental filling patterns appear in the form of lobules: the size of these wes determined. Interarterial anastomoses between ciliar arteries were also demonstrated. The clarity of the photographs was enhanced by computer-assisted image evaluation.

Adult↗

PubMed1980

Structure of the alpha-fetoprotein gene in the mouse.

The mouse alpha-fetoprotein mRNA is the product of a single-copy gene whose mRNA coding sequences are represented discontinuously in the genome. Several EcoRI genomic fragments which contain portions of the alpha-fetoprotein gene have been cloned using the EK2 vector lambda gt WES . lambda B. In addition, a mouse genomic library has been screened to obtain a 15.75-kilobase segment of DNA that includes more than 85% of the alpha-fetoprotein coding sequence. Analyses by restriction endonuclease mapping and electron microscopy showed that the mRNA sequence is interrupted by at least 11 intervening sequences which occupy 90% of the cloned DNA.

Animals↗

PubMed1987

A mutation in the B chain coding region is associated with impaired proinsulin conversion in a family with hyperproinsulinemia.

Gruppuso et al. [Gruppuso, P.A., Gordon, P., Kahn, C. R., Cornblath, M., Zeller, W. P. & Schwartz, R. (1984) N. Engl. J. Med. 311, 629-634] have recently described a family in which hyperproinsulinemia is inherited in an autosomal dominant pattern, suggesting a structural abnormality in the proinsulin molecule as the basis for this disorder. However, unlike two previous kindreds with a similar syndrome, the serum proinsulin-like material in this family did not appear to be an intermediate conversion product but instead behaved like normal human proinsulin by several criteria. To further characterize this disorder we isolated and sequenced the insulin gene of the propositus. Leukocyte DNA was cloned into lambda-WES and recombinants containing the two insulin alleles, lambda MD41 and lambda MD51, were isolated by plaque hybridization. DNA sequencing of lambda MD51 showed that it contained the normal coding sequence for human preproinsulin. Sequence analysis of lambda MD41, however, revealed a single nucleotide substitution in the codon for residue 10 of proinsulin (CAC----GAC) that predicts the exchange of aspartic acid for histidine in the insulin B chain region. This mutation was also found in an insulin allele cloned from a second affected family member (propositus's father). These results, along with the linkage analysis of Elbein et al. [Elbein, S.C., Gruppuso, P., Schwartz, R., Skolnick, M. & Permutt, M.A. (1985) Diabetes 34, 821-824], strongly implicate this mutation as the cause of the hyperproinsulinemia in this family. Inhibition of the conversion of proinsulin to insulin may be related to altered folding and/or self-association properties of the [Asp10]proinsulin.

Cloning, Molecular↗

PubMed2002

Solanum paniculatum L. (Jurubeba): potent inhibitor of gastric acid secretion in mice.

Solanum paniculatum L. is used commonly in Brazilian folk medicine for the treatment of liver and gastrointestinal disorders. The freeze-dried aqueous extracts (WEs) obtained from distinct parts of the plant (flowers, fruits, leaves, stems and roots) were tested to determine their antiulcer and antisecretory gastric acid activities using mice. The aqueous extracts of roots, stems and flowers inhibited gastric acid secretion in pylorus-ligated mice with ED50 values of 418, 777 and 820 mg/kg body wt. (i.d.), respectively. Extracts of leaves (0.5-2 g/kg body wt., i.d.) did not affect gastric secretion, whereas fruit extracts (0.5-2 g/kg body wt., i.d.) stimulated gastric acid secretion. The stimulatory effect of the fruit extract was inhibited by pretreatment with atropine (5 mg/kg body wt., i.m.) but not with ranitidine (80 mg/kg body wt., i.p.) suggesting that the fruit extract activates the muscarinic pathway of gastric acid secretion. In contrast, administration of the root extract into the duodenal lumen inhibited histamine- and bethanechol-induced gastric secretion in pylorus-ligated mice. In addition, the aqueous extract of roots (ED50 value, 1.2 g/kg body wt., p.o.) protected the animals against production of gastric lesions subsequent to the hypersecretion induced in mice by stress following cold restraint. This effect was not reproduced when the lesions were induced by blockade of prostaglandins synthesis via subcutaneous injection of indomethacin. Thus, antiulcer activity of the plant extracts appears to be related directly to a potent anti-secretory activity. No toxic signs were observed following administration of different extracts up to 2 g/kg body wt., p.o. Collectively, the results validate folk use of Solanum paniculatum L. plant to treat gastric disorders.

Animals↗

PubMed1994

Changing the hours of shiftwork: a comparison of 8- and 12-hour shift rosters in a group of computer operators.

Twelve-hour shifts are currently regarded by many workers as one solution to the disruptive effects of shiftwork on health, well-being and lifestyle. Twelve-hour shifts offer larger and more frequent blocks of leisure time than do 8-h shifts. Nevertheless, concern must be addressed about the possible effects of working these additional hours on work quality and productivity and whether they are worked at significant extra cost to the worker. In a study of 75 computer operators, the effect of changing from a predominantly 8 h per shift irregular roster to a 12 h per shift regular roster was investigated. Operators completed a questionnaire covering demographic and health details including the General Health Questionnaire (GHQ), and details about general job satisfaction including the Work Environment Scale (WES). They also completed a 14-day diary of sleeping and eating patterns and mood state at the beginning and end of each shift for the same period. The questionnaires and diaries were completed first under the 8-h shift roster, then again 12 months later after the 12-h shift roster had been worked for 7 months. Work quality, productivity, staff turnover and sickness and other absence data were also collected under the two shift systems. The results showed that changing to the 12-h shift roster produced improvements in health, particularly in psychological health and in reduced feelings of tiredness throughout the work period. The change in working hours was at no cost to feelings of job satisfaction or the worker's perceptions of any particular aspects of the work environment, or to measures of productivity.

Absenteeism↗

PubMedDate not supplied

Perceived work environment and cognitive style.

Differences in perceived work environment are examined by age, gender, and occupation type, along with whether cognitive style predicts perceived work environment. The sample consists of 2185 men and women ranging in age from 21 to 93 years. Perceived work environment was measured using Moos's Work Environment Scale (WES) for the subscales of Autonomy, Control, and Innovation. The Test of Behavioral Rigidity (TBR) was used to measure cognitive style. Findings indicate significant mean level differences in perceived work environment based on gender, age, and occupation type. Hierarchical regression analyses indicated that perceived work environment predicted concurrent cognitive style beyond demographic variables.

Adult↗

PubMed2025

Clinical characteristic of isolated thrombocytopenia in patients with bone marrow failure-related germline variants: a retrospective study from a single centre.

BACKGROUND: Immune thrombocytopenia (ITP) comprises the majority of thrombocytopenia. Some patients respond poorly to first-line ITP therapy or develop pancytopenia years later. Recent studies link heterozygous germline variants in acquired aplastic anemia (AA), yet their role in isolated thrombocytopenia carrying bone marrow failure-related germline variants (ITGV-BMFs) remains unclear. While whole-exome sequencing (WES) detects these variants, its cost limits routine use. This study compares prognosis and clinical features of isolated thrombocytopenia in patients with ITGV-BMFsand those with classic ITP. METHODS: The clinical data of patients diagnosed with ITGV-BMFs were retrospectively analyzed and compared with those of patients with classic ITP from August 2018 to February 2024. The baseline characteristics, genomic systematically background, previous treatment response as well as their follow-up outcomes were compared. RESULTS: Patients with ITGV-BMFs demonstrated earlier onset age (p < 0.001), lower bleeding scores and CD34%, along with elevated mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and reticulocyte (RET) counts (p < 0.001). Multivariate logistic regression analysis showed that the patients with ITGV-BMFs may possess distinct characteristics, including an earlier age at onset (p = 0.014) and lower bleeding score (p = 0.048). Notably, MCV and RET showed promising performance in receiver operating characteristic (ROC) curve analysis. During the follow-up period, 57.69% (15/26) ITGV-BMFs patients were further confirmed as aplastic anemia (AA, n = 13) or myelodysplastic syndrome (MDS, n = 2), with a median progression-free survival (PFS) of 7.25 years (p < 0.0001). CONCLUSION: ITGV-BMFs may be diagnosed early using elevated MCV and reticulocyte counts, a diagnostic approach that may lead to earlier intervention and improved prognosis.

Humans↗

PubMed2003

De-worming school children and hygiene intervention.

Helminths or worm infestations refer to worms that live as parasites in the human body and are a fundamental cause of disease associated with health and nutrition problems beyond gastrointestinal tract disturbances. Globally, over 3.5 billion people are infected with intestinal worms, of which 1.47 billion are with roundworm, 1.3 billion people with hookworm and 1.05 billion with whipworm. School children aged 5 - 15 years suffer the highest infection rate and worm burden that attributes to poor sanitation and hygiene. About 400 million school-age children are infected with roundworm, whipworm and hookworm worldwide, a large proportion of whom are found in the East Asia region (Cambodia, China, Lao PDR, Thailand and Vietnam). These parasites consume nutrients from children they infect, thus retarding their physical development. They destroy tissues and organs, cause abdominal pain, diarrhoea, intestinal obstruction, anaemia, ulcers and other health problems. All of these consequences of infection can slow cognitive development and thus impair learning. De-worming school children by anthelmintic drug treatment is a curative approach for expelling the heavy worm load. However, drug therapy alone is only a short-term measure of reducing worm infection and re-infection is frequent. Control measures through improved sanitation, hygiene and de-worming are needed to prevent infection and re-infection. UNICEF has supported many governments in this (and other) regions to assist in the provision of water supply and sanitary facilities and intensive hygiene education in many schools through the Water, Environment and Sanitation (WES) programme. The UNICEF supported school sanitation and hygiene education (SSHE) programme, and other programmes, could effectively enhance behaviour change in children to break the routes of worm transmission and other waterborne diseases.

Adolescent↗

PubMed1980

[Investigations of the lysine requirement of fattening boars in dependence on their performance. 3. Influence of energy consumption on the fat and protein retention of the boars].

The results of the carcass analysis show a distinct influence of the duration of keeping on protein retention. The protein percentage was highest with those animals whose lysine requirement was met 100%. A lysine supplement of 20% of the valid norm had no infuence on the percental protein content. In both cases (100% and 120%) 17.1% protein were determined in the carcass. Concerning the daily protein retention, boars whose protein requirement wes met 120% and with a live weight of more than 90 kg achieved more favourable results than those of the norm variant. Up to 90 kg live weight no difference between the two variants could be detected. Animals which received feed rich in energy showed a very high daily protein retention during the first third of the fattening period, which decreased relatively much, however, in the course of growth.

Animals↗

PubMed2026

Managing workflow executions with WESkit.

SUMMARY: In biomedical research, managing computational workflows across numerous projects-with varying parameters, tools, and environments-creates major challenges in scalability, reproducibility, and collaboration. Here, we present WESkit, an implementation of the Global Alliance for Genomics and Health (GA4GH) Workflow Execution Service (WES) interface, designed to streamline the execution, monitoring, and documentation of data processing workflows. It addresses the complexities involved in managing numerous executions with varying parameters across diverse research projects. Supporting both Snakemake and Nextflow, the system enables consistent automation and centralized monitoring, which benefits research groups aiming for long-term reproducibility and scalable collaboration. Its suitability for larger teams and service units is further enhanced by seamless integration into cloud environments, contributing to the GA4GH cloud framework. AVAILABILITY AND IMPLEMENTATION: The software WESkit is available under MIT license at the GitLab repository (https://gitlab.com/one-touch-pipeline/weskit). The WESkit main repository is archived at Software Heritage (https://archive.softwareheritage.org/browse/origin/directory/?origin_url=https://gitlab.com/one-touch-pipeline/weskit/api.git) and can be found using "one-touch-pipeline/weskit" term in the search section.

Workflow↗