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PubMed2002

A brief history of the political work of genetics.

The biological sciences have long been used to define distinctions between people and to define inequalities as a natural consequence of essential biological traits. Today, geneticists draw distinctions on the basis of genetic predispositions. Their population-based methods can reinforce stereotypes about race and ethnic differences, providing concepts, validated by science, through which group differences can be interpreted as biologically ordained. Cases suggest how genetic variants can be used in social policies as individuals are differentially treated, not on the basis of their individual condition, but because of predispositions attributed to their group.

Ethnicity↗

PubMed1983

[Structure of the paraphrenic syndrome in the clinical picture of paranoid schizophrenia].

Seventy-one patients with paranoid schizophrenia were examined to study the pattern and distinctive psychopathological features of the paraphrenic syndrome which developed following the paranoiac, paranoid and hallucinational-paranoid syndromes. Transformation of the paranoiac syndrome into the paraphrenic one was of a gradual nature, with delusional perception in a reduced variant comprising the phenomenological structure of delusion. The interpretative mechanism of delusional ideas remained constant. The transformation of the paranoid syndrome into the paraphrenic one was attended by a further extension of the syndrome of psychic automatisms. Ideas of grandeur were rather unstable and made up of delusional notions. The fact that the paraphrenic syndrome in this particular case is characterized by numerous psychopathological phenomena is shown to indicate a favourable course of disease. The idea of grandeur evolved in the context of verbal hallucinosis often transformed the hallucinational-paranoid syndrome into the paraphrenic one. This time course of delusional syndromes was characteristic of an unfavourable course of disease.

Adult↗

PubMed1980

Branching patterns of the hepatic artery in the dog: arteriographic and anatomic study.

Eleven arteriograms, 7 corrosion casts, and 40 dissection studies of 51 clinically normal dogs were examined for the branching patterns of the hepatic artery. An injection of radiopaque medium for selective arteriography was made initially to radiograph the celiac artery, after which a technique defined as superselective arteriography was done, advancing a catheter tip into the hepatic artery. Superselective arteriograms for study of the hepatic artery are described, and the anatomic variants of its branching are discussed. Three major types of hepatic artery branching patterns were identified. The first consists of a single hepatic artery trunk, and this pattern was found in four dogs. The second type with two separate branches of the hepatic artery was found in 27 dogs. The third type was seen in 20 dogs and consisted of 3, 4, or 5 branches that originated directly from the hepatic artery. The origin of the right gastric artery varied, as did the branching of the celiac artery. The most common termination of the celiac artery was as two branches in 31 dogs, and these branches were the hepatic artery and a gastrosplenic trunk. The gastrosplenic trunk subsequently divided to form the left gastric artery and the splenic artery. The usual description of the celiac artery is that it ends by trifurcating. A scheme was developed in which the three major types of hepatic artery branching patterns were outlined. This scheme encompases the hepatic lobar artery variants and can serve as a basis for interpretation of detailed hepatic arteriograms.

Animals↗

PubMed1993

Magnetic resonance imaging in the diagnostic management of diseases of the knee.

Magnetic resonance imaging (MRI) of the knee is fast assuming a major role in evaluating disorders of the knee. The major advantage of MRI is that it is a totally non-invasive procedure with superior soft tissue contrast resolution and multi-planar capabilities. In contrast to arthrography, intra-articular as well as extra-articular structures in the knee can be evaluated by MRI. Indications include studying abnormalities of the menisci, ligament, patella and quadriceps mechanisms, articular cartilage, bone, bursa and other soft tissue. A review of the literature comparing MRI to arthrography and arthroscopy of the knee, especially in relation to meniscal injuries and anterior cruciate ligament tears, shows wide ranges in the accuracy rates of MRI. There are pitfalls in the interpretation of meniscal tears on MRI like normal variants, tears at the free edge and healed or previously repaired tears. Arthrography remains a useful diagnostic modality in some of these settings.

Arthroscopy↗

PubMed1977

Correspondence analysis of HLA gene frequency data from 124 population samples.

Correspondence analysis, a variant of principal components analysis, is used to interpret and compare gene frequencies of the HLA system for 124 samples from different populations studied in the Fifth and Sixth International Histocompatibility Workshops. The major advantage of this analysis is that populations and HLA genes are represented simultaneously with respect to the same axes in multidimensional space. This permits the visual interpretation of genetic differences between populations, the relative participation of each gene in the dispersion, and the correspondence between populations and genes. By this method a clear separation of ethnic groups in the world is obtained. Furthermore, within Europe the separation of samples from different countries is concordant with their geographical distances. The HLA system appears sufficiently polymorphic to define a population by its gene frequencies.

Asian People↗

PubMed1996

Neuron death in the substantia nigra of weaver mouse occurs late in development and is not apoptotic.

Weaver is a spontaneous mutation in mice characterized by the postnatal loss of external granule cells in the cerebellum and dopaminergic neurons of the midbrain, especially in the substantia nigra. We have shown previously that natural cell death with the morphology of apoptosis occurs in the substantia nigra of normal rodents during postnatal development. We therefore sought to determine whether the loss of dopaminergic neurons in homozygous weaver mice occurs during the period of natural cell death in the substantia nigra and whether it has the morphology of apoptosis. We have found, using a silver stain technique, that although apoptotic cell death does occur early postnatally in homozygous weaver substantia nigra, it also does so with equal magnitude in wild-type and heterozygous weaver littermates. Unique to homozygous weavers is the occurrence of degenerating neurons in the nigra that are not apoptotic. These degenerating neurons are observed at postnatal day 7, and they are most abundant on postnatal days 24-25. The nonapoptotic nature of this cell death is confirmed by negative in situ end labeling of nuclear DNA fragmentation and by ultrastructural analysis. Ultrastructural studies reveal irregular chromatin aggregates in the nucleus, as well as marked cytoplasmic changes, including the formation of vacuoles and distinctive stacks of dilated cisternae of endoplasmic reticulum. We interpret these changes as indicative of either a variant morphology of programmed cell death or a pathological degenerative process mediated by an as yet unknown mechanism related to the recently described mutation in the GIRK2 potassium channel.

Aging↗

PubMed2026

RNA sequencing resolves a novel noncanonical splice-region variant in PHKA2 causing glycogen storage disease type IX α2: a case report.

BACKGROUND: Glycogen storage disease type IX α2 (GSD IX α2) is an X-linked hepatic glycogenosis caused by pathogenic variants in PHKA2. Noncanonical splice-region variants located outside the invariant GT/AG dinucleotides pose significant interpretive challenges, as in silico predictions alone are often insufficient for definitive classification. CASE DESCRIPTION: We report a 2.9-year-old boy presenting with short stature, hepatomegaly, markedly elevated aminotransferases, fasting hypoglycemia with ketonuria, hypercholesterolemia, coagulation parameter abnormalities (decreased fibrinogen and prolonged thrombin time), and histological evidence of early hepatic fibrosis as demonstrated by Masson's trichrome staining (portal fibrosis and perisinusoidal fibrosis). Whole-exome sequencing (WES) identified a hemizygous, previously unreported PHKA2 variant [NM_000292.3:c.2517+5G>T, genomic location (GRCh38): NC_000023.11: g.18907895G>T], initially classified as a variant of uncertain significance (VUS) under American College of Medical Genetics and Genomics (ACMG) criteria. RNA sequencing of peripheral blood leukocytes demonstrated predominant exon 22 skipping in 94.2% of informative junction reads, predicting a frameshift and premature termination codon [p.(Gly788Profs*74)] with predicted loss of the C-terminal CBL 2 subdomain. Incorporating this transcript-level evidence, the variant was reclassified as pathogenic (PVS1 + PM2_Supporting + PP4). Following dietary management with uncooked cornstarch supplementation, the patient showed progressive biochemical improvement over a 2.2-year follow-up. CONCLUSIONS: This case expands the mutational spectrum of PHKA2 and demonstrates that RNA sequencing of accessible tissues is a practical and diagnostically informative strategy for resolving noncanonical splice-region variants in pediatric hepatic GSD. Early hepatic fibrosis detected by histological examination before age 3 years underscores the importance of longitudinal hepatic surveillance in GSD IX α2.

Glycogen storage disease type IX α2 (GSD IX ↗

PubMed1997

Glucose turnover in humans in the basal state and after intravenous glucose: a comparison of two models.

This study investigated the ability of two models to represent glucose kinetics in the basal steady state and during an intravenous glucose tolerance test (IVGTT). Six young nonobese male subjects were studied after an overnight fast. Two bolus injections of [U-13C]glucose were given 150 min apart, the first without and the second together with concomitant injection of unlabeled glucose. [3-3H]glucose was constantly infused throughout the study and served to provide an independent means for evaluation of system responses. A linear time-invariant three-compartmental model and the two-compartment time-variant model proposed by Caumo and Cobelli were used to interpret measured time courses of [U-13C]glucose and to reconstruct endogenous glucose production and glucose removal. The ability of the two models to describe the glucose tracer time course was comparable. Simulation studies showed that the two-compartmental time-variant system better predicted measured [3-3H]glucose concentration profiles than did the three-compartmental time-invariant model. However, endogenous glucose production and the integral of excess glucose removal over basal during the IVGTT derived from the two models were almost identical.

Adult↗

PubMed1991

Decreased potassium-stimulated release of [3H]D-aspartate from hippocampal slices distinguishes encephalopathy related to acute liver failure from that induced by simple hyperammonemia.

The calcium-dependent, high (65 mM) potassium-evoked release of the L-glutamate analogue [3H]D-aspartate (D-Asp) was measured in hippocampal slices derived from rats with (a) hepatic encephalopathy (HE) induced with a hepatotoxin, thioacetamide, (b) hyperammonemia produced by i.p. administration of ammonium acetate, and (c) in normal slices preincubated for 30 min with 1 mM ammonium acetate. HE (variant a) inhibited the release by about 30%, which was interpreted to indicate depressed exocytosis of synaptic glutamate. This phenomenon is likely to lead to a decrease of glutamate-mediated neural excitation, which in turn could contribute to the neural inhibition typical of HE. By contrast, and in agreement with earlier reports, hyperammonemia (variant b) did not affect D-Asp release, whereas in vitro treatment of the slices with ammonium acetate (variant c) resulted in a 60% increase of the release. Hence, impairment of synaptic glutamate exocytosis is the phenomenon that distinguishes HE related to toxic liver failure from simple hyperammonemia. This result emphasizes the role of other factors than ammonia in the pathophysiological mechanism of HE.

Acetates↗

PubMed2026

An interpretable deep learning framework uncovers features governing CRISPR-Cas9 genome-editing efficiency.

MOTIVATION: CRISPR-Cas9 genome-editing efficiency is strongly influenced by the sequence composition and positional context of single-guide RNAs (sgRNAs). Although numerous deep learning-based models have been developed to predict Cas9 efficiency from sgRNA sequences, most operate as black boxes, offering limited insight into the sequence determinants underlying Cas9 activity. In addition, previous studies often overlook how the positional context of sequence motifs within sgRNAs influences their effects on Cas9 binding or cleavage. RESULTS: We introduce DeepCC9, an interpretable machine learning framework that combines explicit sequence feature extraction with a residual block-based deep architecture to improve interpretability and identify composition- and position-based motifs governing Cas9 genome-editing efficiency. We applied this method to multiple Cas9 variant datasets, achieving superior predictive performance compared with existing methods while enabling direct interpretation of sequence motifs and their positional effects. Our analysis uncovered 74 sequence motifs enriched or depleted at specific positions within sgRNAs and strongly associated with Cas9 efficiency, providing mechanistic insight into sequence features that influence guide performance. Together, these results establish DeepCC9 as a generalizable and interpretable framework for modeling sequence-function relationships and advancing the understanding of the sequence determinants underlying CRISPR-Cas9 genome editing. AVAILABILITY AND IMPLEMENTATION: The authors have implemented their algorithm in the Python programming language (version 3.X), which is accessible using (https://zenodo.org/records/20073890).

Deep Learning↗

PubMed2004

Influence of decreased penicillin susceptibility on growth rate of beta haemolytic streptococci.

BACKGROUND & OBJECTIVES: Beta haemolytic streptococci (BHS), especially group A are still highly susceptible to penicillin. One possible explanation for this could be reduced growth capability in penicillin resistant BHS mutants. The present study was therefore undertaken to analyze the growth rates of BHS with decreased susceptibility to penicillin. METHODS: Serial passages in the medium with subinhibitory concentration of penicillin were done to induce resistance to this antibiotic in 12 clinical isolates of BHS serogroups A, B, C, and G. Both penicillin susceptible (parental) and variants with decreased susceptibility to penicillin (laboratory strains) were grown in three different media and their growth rates were determined by counting the number of bacterial colonies and by measuring optical density of bacterial culture. RESULTS: The lowest increase in minimal inhibitory concentration (MIC) value for penicillin (8-16 times) was obtained in BHS group A isolates, while the increase in MIC values of BHS groups B, C and G strains was higher (64-128 times) and they reached the level of complete resistance. Laboratory variants differed significantly from parental in their morphological and cultural characteristics. There were no statistically significant differences between the growth rates of penicillin susceptible and variants with decreased susceptibility to penicillin, though a delay in multiplication of the laboratory strains during exponential phase of growth was noted. INTERPRETATION & CONCLUSION: Though significant differences in phenotypic characteristics of penicillin susceptible and laboratory variants were noted, the results of this study provides no support to the assumption that variants of BHS with decreased susceptibility to penicillin of BHS were incapable for normal growth. Further studies needs to be done to find out the association between the decreased susceptibility to penicillin in the BHS and decreased growth capability in these bacteria.

Culture Media↗

PubMed2026

Pan-genomics and multi-omics for deciphering genetic variation and accelerating genetic improvement in ruminant livestock.

Livestock reference genomes have transformed the discovery of variants associated with production, reproduction, health, and environmental adaptation. Nevertheless, a single linear reference represents only one mosaic haplotype and incompletely captures sequence diversity within a species, particularly structural variants, copy-number changes, repeat-rich regions, and breed-specific sequences. Pangenomes address this limitation by integrating multiple high-quality assemblies or population-scale variants into a unified sequence or graph representation. Concurrently, multi-omics approaches connect genomic variation with transcriptomic, epigenomic, manuscriptproteomic, metabolomic, and microbiome responses, thereby improving biological interpretation of genotype-phenotype relationships. This review synthesizes recent progress in livestock pangenomics and multi-omics, with emphasis on cattle, goats, sheep, water buffalo, and chickens. It describes advances in long-read and haplotype-resolved sequencing, graph construction, structural-variant discovery and genotyping, functional annotation, and integrative analysis. Recent pangenome studies have uncovered substantial non-reference sequence, reduced reference bias, identified breed- and population-specific structural variants, and resolved candidate variants underlying pigmentation, body size, tail morphology, cashmere production, altitude adaptation, and other economically relevant traits. However, translation into routine breeding remains constrained by uneven population representation, inconsistent structural-variant definitions, limited functional annotation, computational demands, and insufficient validation across environments. Future progress will depend on diverse near-complete assemblies, graph-aware imputation and genomic prediction, long-read transcriptomics, single-cell and spatial omics, rigorous causal validation, and open, interoperable resources. Together, these developments can support more accurate, resilient, and biologically informed livestock improvement. Importantly, current dairy-cattle evidence indicates that pangenome-derived structural variants can substantially improve variant discovery and functional interpretation while yielding only marginal average gains in routine genomic prediction, favoring targeted augmentation rather than wholesale replacement of established SNP-based evaluations.

Animals↗

PubMed2025

Rare variants and survival of patients with idiopathic pulmonary fibrosis: analysis of a multicentre, observational cohort study with independent validation.

BACKGROUND: Rare pathogenic variants in telomere-related genes are associated with poorer clinical outcomes in idiopathic pulmonary fibrosis (IPF). We aimed to assess whether rare qualifying variants in monogenic adult-onset pulmonary fibrosis genes are associated with IPF survival. Using polygenic risk scores (PRS), we also evaluated the influence of common IPF risk variants in patients carrying the qualifying variants. METHODS: We identified qualifying variants in telomere and non-telomere genes using whole-genome sequences from individuals clinically diagnosed with IPF and enrolled in the Pulmonary Fibrosis Foundation Patient Registry (PFFPR), a large multicentre, observational cohort study (March 29, 2016 to June 15, 2018, n=888). We also derived a PRS for IPF (PRS-IPF) from known common sentinel IPF variants. The primary outcome was the association between qualifying variants and survival. The secondary outcome was the association between qualifying variants and PRS-IPF. We used logistic regression models adjusted for sex, age at diagnosis, and principal components of genetic heterogeneity to examine the mutual relationship of qualifying variants and PRS-IPF. The association between qualifying variants and PRS-IPF with survival was tested using Cox proportional hazard models adjusted for baseline confounders. Validation of the results was sought in data from an independent multicentre, prospective, observational cohort study of IPF in the UK (PROFILE, May 17, 2010 to Sept 5, 2017, n=472), and results were meta-analysed under a fixed-effects model. FINDINGS: We included 888 patients from PFFPR and 472 from PROFILE, totalling 1360 participants. In the PFFPR, carriers of qualifying variants in monogenic adult-onset pulmonary fibrosis genes were associated with lower PRS-IPF (odds ratio 1·79 [95% CI 1·15-2·81]; p=0·010) and shorter survival (hazard ratio 1·53 [1·12-2·10]; p=7·33 × 10-3). Individuals with the lowest PRS-IPF also had worse survival (1·61 [1·25-2·07]; p=1·87 × 10-4). These findings were validated in PROFILE and the meta-analysis of the results showed a consistent direction of effect across both cohorts. INTERPRETATION: We found non-additive effects between qualifying variants and common risk variants in IPF survival, suggesting distinct disease subtypes and raising the possibility of using PRS to guide sequencing prioritisation. Assessing the carrier status for qualifying variants and modelling PRS-IPF promises to further contribute to predicting disease progression among patients with IPF. FUNDING: Instituto de Salud Carlos III; Instituto Tecnológico y de Eenergías Renovables; Cabildo Insular de Tenerife; Fundación DISA; National Heart, Lung, and Blood Institute of the US National Institutes of Health; and UK Medical Research Council.

Humans↗

PubMedDate not supplied

Intestinal malrotation in children: a problem-solving approach to the upper gastrointestinal series.

Intestinal malrotation, which is defined by a congenital abnormal position of the duodenojejunal junction, may lead to midgut volvulus, a potentially life-threatening complication. An evaluation for malrotation is part of every upper gastrointestinal (GI) tract examination in pediatric patients, particularly neonates and infants. Although the diagnosis of malrotation is often straightforward, the imaging features in approximately 15% of upper GI tract examinations are equivocal and lead to a false-positive or false-negative interpretation. The clinical manifestations and upper GI tract findings of malrotation in older children and adults are less specific than are those in younger patients, and for this reason diagnosis of the condition may be more difficult. Successful differentiation between a normal variant and malrotation requires the use of optimal techniques in acquiring and interpreting the upper GI series. Familiarity with the upper GI series appearance of both normal and abnormal anatomic variants allows the radiologist to increase both diagnostic accuracy and confidence in the diagnosis of malrotation.

Diagnosis, Differential↗

PubMed2006

Twenty-three novel BRCA1 and BRCA2 sequence variations identified in a cohort of Swiss breast and ovarian cancer families.

BRCA1 and BRCA2 are the major genes predisposing to breast-ovarian cancer (i.e., breast or ovarian cancer or both). Since 1994, hundreds of distinct germline alterations have been reported in these two genes. Besides pathogenic mutations resulting in loss of function of the protein, an increased number of variants of unknown clinical significance have been described. In a cohort of 350 Swiss breast-ovarian cancer families, the systematic search for BRCA1/BRCA2 germline mutations was carried out using denaturating high-performance liquid chromatography as the first screening procedure. The screening strategy resulted in the identification of 23 alterations not previously reported: 9 in BRCA1 and 14 in BRCA2. By using the available tools to assign a functional role to newly identified sequence variations, 5 (22%) of these were classified as new disease-causing mutations, 5 (22%) were classified as benign polymorphisms, and the remaining 13 (56%) alterations were considered as unclassified variants. These data illustrate the major challenge for clinical oncologists currently facing the interpretation of alterations identified in BRCA1 or BRCA2. The key points are to classify these genetic variations as pathogenic mutations, benign polymorphisms, or variants of unknown clinical significance and to adequately use this information for the management of high-risk individuals and their families.

Adult↗

PubMed2026

WWOX-related developmental and epileptic encephalopathy (WOREE): A case series of seven patients from Argentina.

PURPOSE: WWOX-related developmental and epileptic encephalopathy (WOREE) is a rare autosomal recessive disorder caused by biallelic pathogenic WWOX variants, characterized by very early-onset epilepsy, profound developmental delay, and progressive brain abnormalities. Detailed electroclinical descriptions remain limited. METHODS: We conducted a retrospective study of seven patients with pathogenic/likely pathogenic WWOX variants. Clinical features, seizure evolution, EEG findings, brain MRI, and genetic data were reviewed. Epilepsy syndromes were classified according to International League against Epilepsy (ILAE) criteria. Variants were identified through next-generation sequencing and interpreted following American College of Medical Genetics and Genomics (ACMG) guidelines. RESULTS: Median seizure onset was 3 months (range 2-6). Five patients presented with focal seizures evolving to infantile epileptic spasms syndrome (IESS), while two had IESS at onset. Epilepsy was drug-resistant in all. Developmental delay was evident from birth with generalized hypotonia, acquired microcephaly, and impaired visual attention. Four patients had dysmorphic features. During the IESS period, EEG showed hypsarrhythmia in six patients and a severely disorganized encephalopathic background that did not strictly fulfill the criteria for hypsarrhythmia in one. Brain MRI revealed abnormalities in all patients, including frontotemporal atrophy and corpus callosum hypoplasia; delayed myelination was observed in one case. Eight pathogenic/likely pathogenic WWOX variants were found; including one novel variant (NM_016373.4:c.571C>T, p.(Gln191*)). The recurrent splice-site variant NM_016373.4:c.107+1G>A was identified in five patients, suggesting a possible regional founder effect. CONCLUSION: WOREE shows a recognizable electroclinical and neuroimaging profile with early drug-resistant epilepsy and profound developmental delay. Recognition of this pattern may facilitate early diagnosis and targeted genetic testing, particularly in populations with recurrent variants.

Developmental and epileptic encephalopathy↗

PubMed1990

The detection of anthelmintic resistance by the faecal egg count reduction test: an examination of some of the factors affecting performance and interpretation.

This study examines and compares the possible effects of several procedural variants with those of a currently recommended faecal egg count reduction test for the detection of anthelmintic resistance. The results suggest that the failure of an anthelmintic to reduce the arithmetic mean egg counts of 10-15 animals by at least 90%, from either their pre-treatment levels or from those of an untreated control group 5-10 days later, is likely to be an appropriate procedure. It is recommended that such evaluations of drench performance be regularly conducted on farms. Some suggestions as to how this might be encouraged are made, and the role of larval cultures both in increasing the sensitivity and in enhancing the value of the faecal egg count reduction test are discussed.

Journal Article↗

PubMed1986

The long-term course of airflow obstruction in obstructive variants of the fibrotic stage of sarcoidosis and of idiopathic pulmonary fibrosis.

We investigated patients with obstructive variants (FEV1/VC less than 65%) of FSS (N = 9) and IPF (N = 12) and assessed the course of the lung function parameters of AO during observation times of 2 to 10 years. Three groups of patients could be formed: group 1 (N = 9), no significant change of FEV1/VC and Raw; group 2 (N = 3), significant decrease of FEV1/VC and significant increase of Raw; group 3 (N = 7), divergent changes of FEV1/VC and Raw. Two patients died before they could be assigned to a group. The definite constancy of FEV1/VC (group 1 and the majority of group 3) assessed in this long-term study corroborated our previous results. Thus the great majority of our patients showed no deterioration of AO. "Divergency" of Raw (group 3) can at least partially be interpreted as "false positive." The prognosis of the obstructive variants is essentially not inferior to that of the nonobstructive groups in these two conditions.

Adult↗