Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction ...meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Myriapods (e.g., centipedes and millipedes) display a simple homonomous body plan relative to other arthropods. All members of the class are terrestrial, but they attained terrestriality ...independently of insects. Myriapoda is the only arthropod class not represented by a sequenced genome. We present an analysis of the genome of the centipede Strigamia maritima. It retains a compact genome that has undergone less gene loss and shuffling than previously sequenced arthropods, and many orthologues of genes conserved from the bilaterian ancestor that have been lost in insects. Our analysis locates many genes in conserved macro-synteny contexts, and many small-scale examples of gene clustering. We describe several examples where S. maritima shows different solutions from insects to similar problems. The insect olfactory receptor gene family is absent from S. maritima, and olfaction in air is likely effected by expansion of other receptor gene families. For some genes S. maritima has evolved paralogues to generate coding sequence diversity, where insects use alternate splicing. This is most striking for the Dscam gene, which in Drosophila generates more than 100,000 alternate splice forms, but in S. maritima is encoded by over 100 paralogues. We see an intriguing linkage between the absence of any known photosensory proteins in a blind organism and the additional absence of canonical circadian clock genes. The phylogenetic position of myriapods allows us to identify where in arthropod phylogeny several particular molecular mechanisms and traits emerged. For example, we conclude that juvenile hormone signalling evolved with the emergence of the exoskeleton in the arthropods and that RR-1 containing cuticle proteins evolved in the lineage leading to Mandibulata. We also identify when various gene expansions and losses occurred. The genome of S. maritima offers us a unique glimpse into the ancestral arthropod genome, while also displaying many adaptations to its specific life history.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting ...glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Compartmentalised flow reactors allow biocatalytic cascades that would be impossible using standard methods, as described by Sebastian C. Cosgrove, Sabine L. Flitsch, and co‐workers in their Research ...Article on page 18660. Carbonyl intermediates were continuously generated via biocatalytic oxidation, then converted into different amine products using immobilised aminating enzymes. The use of flow equipment allowed exquisite control of the paths and enabled a range of new biocatalytic cascades to be constructed, paving the way for fully automated continuous biocatalytic cascades.
Abstract
Giant cell tumor of bone (GCTB) is a rare, benign, osteolytic neoplasm that most commonly occurs in early adulthood and often involves the long bones of the body. Although GCTB largely ...affects the epiphyses of long bones, several reports of GCTB involvement of the cranial and facial bones exist in the literature. In addition to reviewing other reported cases of GCTBs of the lateral skull base in the literature, the authors report here on the clinical presentation, radiographic findings, and neurosurgical management of a patient found to have a GCTB of the middle and infratemporal fossae, which was treated by aggressive en bloc resection of the lateral skull base.
Virus-specific CD8(+) T cells (T(CD8+)) are initially triggered by peptide-MHC Class I complexes on the surface of professional antigen presenting cells (pAPC). Peptide-MHC complexes are produced by ...two spatially distinct pathways during virus infection. Endogenous antigens synthesized within virus-infected pAPC are presented via the direct-presentation pathway. Many viruses have developed strategies to subvert direct presentation. When direct presentation is blocked, the cross-presentation pathway, in which antigen is transferred from virus-infected cells to uninfected pAPC, is thought to compensate and allow the generation of effector T(CD8+). Direct presentation of vaccinia virus (VACV) antigens driven by late promoters does not occur, as an abortive infection of pAPC prevents production of these late antigens. This lack of direct presentation results in a greatly diminished or ablated T(CD8+) response to late antigens. We demonstrate that late poxvirus antigens do not enter the cross-presentation pathway, even when identical antigens driven by early promoters access this pathway efficiently. The mechanism mediating this novel means of viral modulation of antigen presentation involves the sequestration of late antigens within virus factories. Early antigens and cellular antigens are cross-presented from virus-infected cells, as are late antigens that are targeted to compartments outside of the virus factories. This virus-mediated blockade specifically targets the cross-presentation pathway, since late antigen that is not cross-presented efficiently enters the MHC Class II presentation pathway. These data are the first to describe an evasion mechanism employed by pathogens to prevent entry into the cross-presentation pathway. In the absence of direct presentation, this evasion mechanism leads to a complete ablation of the T(CD8+) response and a potential replicative advantage for the virus. Such mechanisms of viral modulation of antigen presentation must also be taken into account during the rational design of antiviral vaccines.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Risk factors for endometrial cancer in Black women Sponholtz, Todd R.; Palmer, Julie R.; Rosenberg, Lynn ...
CCC. Cancer causes & control/CCC, Cancer causes & control,
05/2023, Letnik:
34, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Purpose
The incidence of endometrial cancer (EC) has been increasing faster among Black women than among other racial/ethnic groups in the United States. Although the mortality rate is nearly twice ...as high among Black than White women, there is a paucity of literature on risk factors for EC among Black women, particularly regarding menopausal hormone use and severe obesity.
Methods
We pooled questionnaire data on 811 EC cases and 3,124 controls from eight studies with data on self-identified Black women (4 case–control and 4 cohort studies). We analyzed cohort studies as nested case–control studies with up to 4 controls selected per case. We used logistic regression to estimate multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs).
Results
We observed a positive association between BMI and EC incidence (
P
trend
< 0.0001) The OR comparing BMI ≥ 40 vs. < 25 kg/m
2
was 3.92 (95% CI 2.91, 5.27). Abdominal obesity among those with BMI < 30 kg/m
2
was not appreciably associated with EC risk (OR 1.21, 95% CI 0.74, 1.99). Associations of reproductive history with EC were similar to those observed in studies of White women. Long-term use of estrogen-only menopausal hormones was associated with an increased risk of EC (≥ 5 years vs. never use: OR 2.08, 95% CI: 1.06, 4.06).
Conclusions
Our results suggest that the associations of established risk factors with EC are similar between Black and White women. Other explanations, such as differences in the prevalence of known risk factors or previously unidentified risk factors likely underlie the recent increases in EC incidence among Black women.
Large-scale whole-genome sequencing studies have enabled analysis of noncoding rare-variant (RV) associations with complex human diseases and traits. Variant-set analysis is a powerful approach to ...study RV association. However, existing methods have limited ability in analyzing the noncoding genome. We propose a computationally efficient and robust noncoding RV association detection framework, STAARpipeline, to automatically annotate a whole-genome sequencing study and perform flexible noncoding RV association analysis, including gene-centric analysis and fixed window-based and dynamic window-based non-gene-centric analysis by incorporating variant functional annotations. In gene-centric analysis, STAARpipeline uses STAAR to group noncoding variants based on functional categories of genes and incorporate multiple functional annotations. In non-gene-centric analysis, STAARpipeline uses SCANG-STAAR to incorporate dynamic window sizes and multiple functional annotations. We apply STAARpipeline to identify noncoding RV sets associated with four lipid traits in 21,015 discovery samples from the Trans-Omics for Precision Medicine (TOPMed) program and replicate several of them in an additional 9,123 TOPMed samples. We also analyze five non-lipid TOPMed traits.
To describe a case of an isolated clival mucocele presenting asymptomatically after previous endoscopic sinus surgery and review the existing literature on the clinical characteristics associated ...with these lesions.
Case report and literature review.
We present a case of a clival mucocele that was found incidentally in a 66-year-old female undergoing hearing loss evaluation and had previously undergone endoscopic sphenoidotomy 17 years prior. The lesion was drained via an expanded endonasal endoscopic approach without complication and pathology confirmed the diagnosis of mucocele.
This case demonstrates the efficacy of a surgical approach to cystic lesions of the clivus and highlights the importance of regular follow-up after endoscopic sinus surgery to detect these potentially subtle lesions and prevent their symptomatic progression.
INTRODUCTIONConjunctival nevi are the most common tumor of the ocular surface. There are some rare reports of so-called 'giant' conjunctival nevi. We report a case of a 47-year-old female with a ...cutaneous and ocular surface giant congenital melanocytic nevus and describe her clinical course. CASE DESCRIPTIONThis is a retrospective case report of a single patient. A 47-year-old female with a history of biopsy-proven periorbital congenital melanocytic nevus, with an associated giant conjunctival nevus presented for structural and functional rehabilitation. Serial surgeries were performed and excised tissue was sent for histopathological and genetic examination. The conjunctival nevus had a low tumor mutation burden, and of the 647 somatic mutations, only one occurred within a protein coding region, namely NRAS p.Gln61Arg. CONCLUSIONThis is the first reported adult case including genomic analysis of an ocular surface giant congenital melanocytic nevus. The case shows a possible association between periorbital congenital melanocytic nevi and giant conjunctival nevi, and underscores the possible role that targeted drug therapies may have in malignant transformation of these conditions.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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