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PubMed1990

The relationship among adiposity, diet, and hormone concentrations in vegetarian and nonvegetarian postmenopausal women.

The relationships among anthropometric variables, dietary nutrients, and plasma steroid, polypeptide, and binding-protein hormone concentrations were investigated in 24 Seventh-day Adventist postmenopausal women, 12 vegetarian (SV) and 12 nonvegetarian (SNV). Fasting blood and 7-d dietary intake information were collected. SVs consumed significantly more crude and dietary fiber and fewer saturated fatty acids than did SNVs. The thigh and sum of three skinfold-thickness measurements were significantly greater for SNVs than for SVs. Plasma concentrations of estradiol-17 beta were significantly lower in SVs than in SNVs. Significant relationships were observed for the combined groups (SV and SNV) between estradiol-17 beta and triceps and suprailiac skinfold thickness and body fat. Plasma concentrations of estradiol-17 beta of the combined groups revealed a significant negative relationship between their crude and dietary fiber intakes. Further study delineating the effects of adiposity and dietary nutrients on basal concentrations of sex hormones is warranted.

Adipose Tissue↗
PubMed1981

Use of a cloned double stranded cDNA coding for a major androgen dependent protein in rat seminal vesicle secretion: the effect of testosterone in gene expression.

The abundant class of poly(A+)RNA [poly(A+)RNA11S] from rat seminal vesicle was used to synthesize ds-cDNA11S. The ds-cDNA11S was inserted and cloned into the Pst I site of pBR-322 using E. coli RR1 as host. Colony filter hybridization and restriction mapping was used to demonstrate that a 620 NTP long insert in a plasmid clone (pSV2) represents the almost full length structural gene coding for a precursor to the seminal vesicle secretion protein IV (SVS IV). The entire insert was sequenced and the coding region was matched with the known amino acid sequence. Most of the signal peptide sequence was derived from the DNA sequence. The insert in pSV2 was labelled and used to study the effect of testosterone on the accumulation of mRNA SVS IV. Administration of testosterone to castrated rats resulted in the induction of mRNA SVS IV from a few molecules per cell to levels of over 100,000 after 96 h of hormone treatment.

Animals↗
PubMed2006

Acceptability of self-taken vaginal swabs and first-catch urine samples for the diagnosis of urogenital Chlamydia trachomatis and Neisseria gonorrhoeae with an amplified DNA assay in young women attending a public health sexually transmitted disease clinic.

OBJECTIVES: Public health efforts are needed to encourage young women to get tested for Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC). GOAL: To assess the acceptability and feasibility of 2 noninvasive diagnostic approaches. STUDY DESIGN: Participants of this cross-sectional survey were 413 young women (age 16-35) who underwent STD testing by self-taken vaginal swab (SVS) and a first-catch urine sample (FCU) by nucleic acid amplification test (BDProbTec) and filled out a questionnaire. RESULTS: CT and GC were diagnosed in 10.9% (45/413) and 1.5% (6/413). Eleven percent of the participants who never previously had an STD examination (68%) tested STD positive. SVS and FCU were almost uniformly reported as easy to perform and preferred above gynecologic examination. CONCLUSIONS: Using SVS combined with FCU can be an important enhancing tool in public health approaches. Acceptability among potential patients is high, enabling the noninvasive detection of STDs that would otherwise remain undetected and untreated.

Adolescent↗
PubMed2024

De novo structural variants in autism spectrum disorder disrupt distal regulatory interactions of neuronal genes.

Three-dimensional genome organization plays a critical role in gene regulation, and disruptions can lead to developmental disorders by altering the contact between genes and their distal regulatory elements. Structural variants (SVs) can disturb local genome organization, such as the merging of topologically associating domains upon boundary deletion. Testing large numbers of SVs experimentally for their effects on chromatin structure and gene expression is time and cost prohibitive. To address this, we propose a computational approach to predict SV impacts on genome folding, which can help prioritize causal hypotheses for functional testing. We developed a weighted scoring method that measures chromatin contact changes specifically affecting regions of interest, such as regulatory elements or promoters, and implemented it in the SuPreMo-Akita software (Gjoni and Pollard 2024). With this tool, we ranked hundreds of de novo SVs (dnSVs) from autism spectrum disorder (ASD) individuals and their unaffected siblings based on predicted disruptions to nearby neuronal regulatory interactions. This revealed that putative cis-regulatory element interactions (CREints) are more disrupted by dnSVs from ASD probands versus unaffected siblings. We prioritized candidate variants that disrupt ASD CREints and validated our top-ranked locus using isogenic excitatory neurons with and without the dnSV, confirming accurate predictions of disrupted chromatin contacts. This study establishes disrupted genome folding as a potential genetic mechanism in ASD and provides a general strategy for prioritizing variants predicted to disrupt regulatory interactions across tissues.

Journal Article↗
PubMed2025

The landscape of structural variation in pediatric cancer.

Structural variants (SVs) account for over 60% of the driver variants in pediatric cancer, and in many cases act as the cancer initiating event. To study SVs from a pan-cancer perspective, we analyzed 1,616 pediatric cancer genomes in 16 major cancer types of hematological malignancies (n = 908), brain tumors (n = 183), and solid tumors (n = 525) and compared their profiles to those of 2,203 adult cancers. The SV burden varied ~100-fold across pediatric cancer types and demonstrated an 8- to 16-fold reduction compared to adult brain and solid tumors but was comparable in pediatric versus adult hematological malignancies. Recurrent SV hotspots occurred uniquely in pediatric acute lymphoblastic leukemias (ALLs) in proximity to RAG-mediated recombination signal sequences (RSS) and disrupted multiple immune-related loci as well as 69 genes, which often involved cryptic RSS sites. By contrast, such hotspots affected only immune-related loci but not driver genes in adult lymphoid cancers. Eight SV signatures extracted from the cohort had varying distributions across cancer types, with clustered translocations reflecting templated insertions in osteosarcoma, and medium-sized deletions (10 kb to 1 Mb) enriched in cancers with RAG-mediated deletions. Intra-patient evolutionary analysis in 13 patients with multiple spatiotemporally distinct samples revealed that RAG-mediated recombination in leukemia and complex rearrangements in solid tumors occurred both early in disease initiation and continuously during later diversification, contributing to clonal heterogeneity. Finally, we found that both driver genes and fragile sites were the two genomic regions most frequently disrupted by SVs. The unique and diverse SV landscapes that emerged from this comprehensive analysis expand the scope of RSS-mediated mutagenesis in pediatric ALL and will be a valuable resource for guiding future functional studies and the design of clinical genomic testing in pediatric cancer.

Journal Article↗
PubMed2025

Comprehensive benchmarking of somatic structural variant detection at ultra-low allele fractions.

Postzygotic mosaicism gives rise to somatic structural variants (SVs) at ultra-low variant allele fractions (VAFs), which pose challenges for detection due to the high-coverage sequencing required and noise introduced by sequencing artifacts. Although somatic SV detection has been extensively studied in cancer, these studies are not directly applicable to the study of tissue mosaicism, as they rely on matched normals, target higher VAF ranges, and are enriched for different types of SVs. We present comprehensive benchmark data and best practices for non-cancer somatic SV detection. We created a synthetic mosaic sample by combining six HapMap individuals at varying proportions, generating allele fractions as low as 0.25%. This sample was sequenced to ~2,300x total coverage using Illumina, PacBio, and Nanopore technologies across multiple sequencing centers. A high-confidence benchmark SV set containing over 21,000 pseudo-somatic insertions and deletions ≥50bp was derived from haplotype-resolved assemblies. We evaluated 12 SV discovery pipelines and identified caller-specific strengths and sequencing platform-specific shortcomings. We find that short read-based approaches show reduced recall for insertions and repeat-associated SVs, whereas long-read sequencing achieves high accuracy throughout the genome, increasing linearly with coverage. The best algorithm's sensitivity exceeded 80% for VAFs ≥4% and 15% for VAFs of 0.5-1% with 60x coverage. The publicly available benchmarking data and comparative analysis of current methods provide a foundation for robust discovery of SV mosaicism in non-cancer tissues..

Journal Article↗
PubMed2026

De novo structural variants in autism spectrum disorder disrupt distal regulatory interactions of neuronal genes.

Three-dimensional genome organization plays a critical role in gene regulation, and disruptions can lead to developmental disorders by altering the contact between genes and their distal regulatory elements. Structural variants (SVs) can disturb local genome organization, such as the merging of topologically associating domains upon boundary deletion. Testing large numbers of SVs experimentally for their effects on chromatin structure and gene expression is time and cost prohibitive. To address this, we propose a computational approach to predict SV impacts on genome folding, which can help prioritize causal hypotheses for functional testing. We develop a weighted scoring method that measures chromatin contact changes specifically affecting regions of interest, such as regulatory elements or promoters, and implement it in the SuPreMo-Akita software. With this tool, we rank hundreds of de novo SVs (dnSVs) from autism spectrum disorder (ASD) individuals and their unaffected siblings based on predicted disruptions to nearby neuronal regulatory interactions. This reveals that putative cis-regulatory element interactions (CREints) are more disrupted by dnSVs from ASD probands versus unaffected siblings. We prioritize candidate variants that disrupt ASD CREints and validate our top-ranked locus using isogenic excitatory neurons with and without the dnSV, confirming accurate predictions of disrupted chromatin contacts. This study suggests that disrupted genome folding is a potential genetic mechanism in a subset of ASD cases and provides a general strategy for prioritizing variants predicted to disrupt regulatory interactions across tissues.

Humans↗
PubMed2026

A pangenome framework uncovers the role of deletions in repeated evolution of cave-derived traits.

Structural variants (SVs) are increasingly recognized as key contributors to adaptive evolution, yet they remain underexplored compared with single-nucleotide variation. To understand how large-scale genomic changes shape repeated evolution, we leveraged multiple levels of sequence data across the powerful evolutionary model system of the Mexican tetra fish (Astyanax mexicanus). We constructed one of the first pangenome graphs from a naturally evolving vertebrate, enabling comprehensive discovery of SVs among 120 fish from 11 populations. We discover substantial amounts of structural variation and explore the roles of genomic biases and selection in shaping the distribution of these variants. More than 2400 high-confidence cave-specific deletions are enriched in biological pathways involved in vision, metabolism, and behavior and cluster nonrandomly in quantitative trait loci linked to cavefish traits. Additionally, 67 genes harbor unique deletions between independent cavefish lineages. These reused genes show evidence of population-specific selection (99% contain selective sweeps compared with 8%-15% in genes lacking SVs), indicating that deletions likely rose in frequency through repeated positive selection rather than drift. Together, these results reveal that recurrent deletion events have repeatedly contributed to the evolution of cave-adapted phenotypes and highlight deletions as underexplored contributors of adaptive evolution in extreme environments.

Animals↗
PubMed1995

A modified Crowther and Blow T1 translation function for partial search models.

A simple modification to the fast T(1) translation function of Crowther & Blow [Crowther & Blow (1967). Acta Cryst. 23, 544-548] can reduce systematic error in cases where the input set of oriented search models represents a fraction of the scattering matter of the unknown crystal unit cell. The observed Patterson function is modified by a partial self-vector subtraction (SVS) and then the residual Patterson origin is removed. In a test case where a protein/DNA complex crystal was searched using a protein-only model, the highest signal- to-noise ratios for translation-search maps were obtained either with origin removal alone or partial SVS combined with origin removal. Origin removal is likely to be a generally useful alternative to SVS for the function.

Journal Article↗
PubMed1982

Structure of secretory protein IV from rat seminal vesicles.

The complete amino acid sequence of rat SVS-IV protein, consisting of 90 residues, has been determined. The sequence of rat SVS-IV protein is the first seminal vesicle secretory protein determined and it does not show any homology with other known protein sequences. The secondary structure of SVS-IV protein is analyzed by methods of Fasman and Chou indicates that this protein contains 53% alpha-helix, 36% beta-turn and 11% random coil.

Amino Acid Sequence↗
PubMed2007

The vesicular monoamine transporter 2 contains trafficking signals in both its N-glycosylation and C-terminal domains.

The vesicular acetylcholine transporter (VAChT) and the vesicular monoamine transporter (VMAT) belong to the same transporter family that packages acetylcholine into synaptic vesicles (SVs) and biogenic amines into large dense core vesicles (LDCVs) and/or SVs, respectively. These transporters share similarities in sequence and structure with their N- and C-terminal domains located in the cytoplasm. When expressed in PC12 cells, VMAT2 localizes to LDCV, whereas VAChT is found mainly on synaptic-like microvesicles. Previous studies have shown that the cytoplasmic C-terminal domain of VAChT contains signals targeting this transporter to SVs. However, the targeting signals for VMAT have not been completely elucidated. To identify signals targeting VMAT2 to LDCV, the subcellular localization of VMAT2-VAChT chimeras was analyzed in PC12 cells. Chimeras having either the N-terminal region through transmembrane domain 2 of VMAT2 or the C-terminal domain of VMAT2 do not traffic to LDCV efficiently. In contrast, chimeras having both of these regions, or the luminal glycosylated loop in conjunction with transmembrane domains 1 and 2 and the C-terminal domain of VMAT2, traffic to LDCV. Treatment of PC12 cells with 1-deoxymannojirimycin, a specific alpha-mannosidase I inhibitor, causes VMAT2 to localize to synaptic-like microvesicles. The results indicate that both mature N-linked glycosylation and the C-terminus are important for proper trafficking of VMAT2 and that the locations of trafficking signals in VMAT2 and VAChT are surprisingly different.

Animals↗
PubMed1999

Experimental determination of section sensitivity profiles and image noise in electron beam computed tomography.

To determine the effect of continuous-volume scanning (CVS) on z-axis resolution, section sensitivity profiles were measured on an electron beam computed tomography (CT) scanner and compared with those obtained using the step-volume scanning (SVS) mode. A steel bead was imaged using different scan parameters, and the mean CT number over the bead was plotted against the z-axis position to determine section sensitivity profiles. From these profiles, full width at half maximum (FWHM), full width at tenth maximum (FWTM), and full width at tenth area (FWTA) were calculated. A uniform water phantom was imaged to measure noise. To determine the visual significance of changes in the section sensitivity profile, a section thickness and contiguity phantom was imaged. All section sensitivity profiles measured had an FWHM value within 0.5 mm of the nominal scan width. The FWTM and FWTA values increased with the CVS mode compared with the SVS mode. This broadening of the section sensitivity profiles was most significant with larger collimator widths. However, use of smaller collimator widths increased image noise. When all other parameters remained constant, increasing the exposure time to reduce image noise did not affect the section sensitivity profile. The CVS mode produced wider section sensitivity profiles than the SVS mode. This effect was minimized when the smallest collimator width was used, but at the expense of increased image noise.

Electrons↗
PubMed2026

Comprehensive transcriptomics and proteomics analysis of neointima formation in human saphenous vein: implications for bypass graft disease.

Human saphenous veins (SVs) are widely used as grafts in coronary artery bypass (CABG) surgery but often fail due to neointima formation. Little is known, however, regarding the cellular, transcriptomic, and proteomic dynamics of neointima formation in human veins. Here, we performed transcriptomics and proteomics analysis in an ex vivo tissue culture model of neointima formation in human SVs procured for CABG surgery. Histological examination demonstrated significant elastin degradation and neointima formation (indicated by increased neointima area and neointima-to-media ratio) in SVs subjected to tissue culture. Analysis of data from 72 patients suggests that the progression of SV remodeling and neointima formation differs according to sex and body mass index, which is negatively associated with neointima formation in males only. RNA sequencing demonstrated upregulation of proinflammatory and proliferation-related genes during neointima formation and identified novel processes, including increased cellular stress and DNA damage responses, reflecting tissue trauma associated with vein harvesting. Proteomic analysis identified upregulated extracellular matrix-related and coagulation/thrombosis proteins and downregulated metabolic proteins. Spatial transcriptomics, used to infer regionally enriched gene expression, suggested dynamic alterations in fibroblast and vascular smooth muscle cell (VSMC) states during neointima formation. Specifically, we identified the emergence of HES1+ and matrix metalloproteinase 2- and 14-positive (MMP2+/MMP14+) expression in VSMCs and fibroblasts, respectively, during neointima formation. Furthermore, our data suggest that MIR647, identified through screening, maintains VSMC contractile gene expression. Our findings suggest dynamic transcriptomic and proteomic changes during neointima formation in human veins and provide useful mechanistic information for the pathogenesis of SV graft disease.NEW & NOTEWORTHY Using multiomics and spatial transcriptomics, we uncover dynamic molecular and cellular changes driving neointima proliferation in human saphenous veins, the most common conduit for bypass surgery. Our study highlights sex- and body mass index-associated differences, novel fibroblast and smooth muscle cell states, and a role for microRNA-647 in preserving vascular contractile phenotype. These findings provide new insight into the mechanisms of vein graft failure and may guide future strategies to improve coronary bypass outcomes.

Humans↗
PubMed2005

AP180 maintains the distribution of synaptic and vesicle proteins in the nerve terminal and indirectly regulates the efficacy of Ca2+-triggered exocytosis.

AP180 plays an important role in clathrin-mediated endocytosis of synaptic vesicles (SVs) and has also been implicated in retrieving SV proteins. In Drosophila, deletion of its homologue, Like-AP180 (LAP), has been shown to increase the size of SVs but decrease the number of SVs and transmitter release. However, it remains elusive whether a reduction in the total vesicle pool directly affects transmitter release. Further, it is unknown whether the lap mutation also affects vesicle protein retrieval and synaptic protein localization and, if so, how it might affect exocytosis. Using a combination of electrophysiology, optical imaging, electron microscopy, and immunocytochemistry, we have further characterized the lap mutant and hereby show that LAP plays additional roles in maintaining both normal synaptic transmission and protein distribution at synapses. While increasing the rate of spontaneous vesicle fusion, the lap mutation dramatically reduces impulse-evoked transmitter release at steps downstream of calcium entry and vesicle docking. Notably, lap mutations disrupt calcium coupling to exocytosis and reduce calcium cooperativity. These results suggest a primary defect in calcium sensors on the vesicles or on the release machinery. Consistent with this hypothesis, three vesicle proteins critical for calcium-mediated exocytosis, synaptotagmin I, cysteine-string protein, and neuronal synaptobrevin, are all mislocalized to the extrasynaptic axonal regions along with Dap160, an active zone marker (nc82), and glutamate receptors in the mutant. These results suggest that AP180 is required for either recycling vesicle proteins and/or maintaining the distribution of both vesicle and synaptic proteins in the nerve terminal.

Animals↗
PubMed2001

Changes in intracranial pressure after calvarial expansion surgery in children with slit ventricle syndrome.

The effect of calvarial expansion on symptom relief and intracranial pressure (ICP) in three children with slit ventricle syndrome (SVS) and intracranial hypertension despite a functioning ventricular shunt is reported. These children presented with a clinical picture of SVS, accompanied by slit-like ventricles on cranial computer tomography scan and intracranial hypertension. Calvarial expansion was performed by mans of an anterior approach in one case and a posterior approach (modified tiara plastic) in the other two cases. After calvarial expansion, symptoms of intracranial hypertension were abolished in one case and markedly reduced in two cases (observation period 25-36 months). Comparison of ICP before and after surgery was performed by means of new software (Sensometrics Pressure Analyser, version 1.2) that revealed a significant reduction in the number of abnormal ICP elevations after surgery. The results were not accompanied by changes in the size of the cerebral ventricles. This study demonstrates that in children with SVS and intracranial hypertension despite a functioning shunt, calvarial expansion may reduce ICP and produce long-lasting symptom relief. In these cases, we suggest that intracranial hypertension was caused by compromised intracranial volume.

Child↗
PubMedDate not supplied

The slit ventricle syndrome: advances based on technology and understanding.

Despite many articles on slit ventricle syndrome (SVS) over the last 25 years, accepted terminology regarding the definition of this condition is lacking. Any shunted individual with a severe headache disorder in the context of ventricles that are normal or smaller than normal can be said to suffer from SVS, even though there are at least five forms of the condition. Logical management of SVS requires an understanding of the specific pathogenesis of the problem in individual patients, whether based on monitoring of intracranial pressure (ICP) or observation at the time of shunt failure or symptoms. Overdrainage syndromes, whether intermittent proximal obstruction or low pressure states, are best managed with valve upgrades and the addition of devices that retard siphoning. Increased ICP without ventriculomegaly at the time of shunt failure is best managed by shunting devices that access the cortical subarachnoid space such as lumboperitoneal shunts or shunts involving the cisterna magna. Cranial expansion operations and subtemporal decompression should be limited to patients with craniofacial syndromes.

Algorithms↗
PubMed2006

Subtypes and one-year survival of first-ever stroke in Chinese patients: The Nanjing Stroke Registry.

BACKGROUND: Morbidity and mortality of stroke have been investigated extensively in Western populations, while data concerning case fatality and cause of death after stroke are very limited in mainland China. This study aimed to analyze the 1-year survival and predictors of case fatality in Chinese patients with first-ever stroke. METHODS: Subjects are patients registered in the Nanjing Stroke Registry Program. Information concerning cardiovascular risk factors and stroke characteristics were collected, and patients were followed after registration. Ischemic strokes were classified according to TOAST criteria as large-artery atherosclerosis (LAA), cardiac embolism stroke (CES), small-vessel stroke (SVS), or other determined and undetermined causes (UND). One-year case fatality was analyzed by the Kaplan-Meier method, and predictors of case fatality were evaluated by the Cox proportional hazards model. RESULTS: A total of 752 patients with first-ever stroke were included, of which 142 (18.9%) were identified as intracerebral hemorrhage (ICH), 120 (16.0%) as LAA, 123 (16.4%) as SVS, 160 (21.3%) as CES and 216 (28.7%) as UND. The overall survival rate was 86.4% at the end of the 1-year follow-up. Patients with SVS have the highest survival rate (92.7%), followed by UND (89.4%), CES (88.1%) and LAA (84.2%). Patients with ICH have the lowest survival rate (76.8%). Survival rates of patients with different subtypes of stroke presented a significant difference (chi2 = 19.3, p < 0.001). For patients deceased during the first year after the index stroke, 33.3% of deaths were caused by the first stroke, 18.6% by recurrent stroke, 16.7% by cardiovascular comorbidities, 14.7% by nonvascular conditions and 16.7% died of undetermined causes. Advanced age, hypertension, hyperlipidemia, diabetes mellitus (DM), atrial fibrillation (AF), history of transient ischemic attack and cigarette smoking were associated with an increased risk of death 1 year after stroke. CONCLUSIONS: The case fatality rate and predictors for mortality of Chinese patients with first-ever stroke are similar to those reported for other populations. The significant influence of cardiovascular disease on the first-year survival rate emphasizes the importance of acute stroke management and control of hypertension, DM, AF and other predictors for decreasing case fatality and improving prognosis.

Adult↗
PubMed1996

Morphometry of pineal synaptic ribbon profile numbers after cytochalasin D treatment.

Synaptic ribbons (SRs) are electron-dense, plate-shaped synaptic organelles, to which electron-lucent synaptic vesicles (SVs) are attached by tiny stalks. In the mammalian pineal gland SRs are dynamic organelles, waxing and warning in number under different physiological and experimental conditions. The way in which SRs are formed, or catabolized, is not known. Since it has been suggested that actin may be part of SRs, in the present study the effect of the actin-disrupting drug cytochalasin D (CD, 1 microgram/ml, for 4 h) was examined in cultured guinea pig and rat pineal glands. The glands were preincubated for 48 h so that intra-pineal sympathetic nerve fibres degenerate and no longer release noradrenaline which may distort the results. CD had no effect on SR profile numbers in guinea pigs, but decreased them in rats (p > 0.05). The nonsignificant depressive effect of CD in rats was verified in a second experiment. To clarify the issue, acutely cultured rat pineal glands were treated with CD for 4 h, without effect. The results taken together suggest to us that CD has no major effect on pineal SR profile numbers, but that in rats preincubation for 48 h makes them vulnerable to catabolic processes. In all the experiments, the electron-dense plate of the SRs was qualitatively unaffected. However, the SVs were often larger and more irregular in shape and the stalks linking the SVs with the SRs were less frequently seen in CD-treated glands. In guinea pig pineals, in which SRs frequently lie in groups and parallel to each other, neither the distance between neighboring SRs nor the thickness of individual SRs were affected by CD. It is concluded that actin is not a major component of the SRs and the connecting stalks.

Animals↗