The genetic basis of human sex development is slowly being elucidated, and >40 different genetic causes of differences (or disorders) of sex development (DSDs) have now been reported. However, ...reaching a specific diagnosis using traditional approaches can be difficult, especially in adults where limited biochemical data may be available.
We used a targeted next-generation sequencing approach to analyze known and candidate genes for DSDs in individuals with no specific molecular diagnosis.
We studied 52 adult 46,XY women attending a single-center adult service, who were part of a larger cohort of 400 individuals. Classic conditions such as17
-hydroxysteroid dehydrogenase deficiency type 3, 5
-reductase deficiency type 2, and androgen insensitivity syndrome were excluded. The study cohort had broad working diagnoses of complete gonadal dysgenesis (CGD) (n = 27) and partially virilized 46,XY DSD (pvDSD) (n = 25), a group that included partial gonadal dysgenesis and those with a broad "partial androgen insensitivity syndrome" label. Targeted sequencing of 180 genes was undertaken.
Overall, a likely genetic cause was found in 16 of 52 (30.8%) individuals (22.2% CGD, 40.0% pvDSD). Pathogenic variants were found in sex-determining region Y (SRY; n = 3), doublesex and mab-3-related transcription factor 1 (DMRT1; n = 1), NR5A1/steroidogenic factor-1 (SF-1) (n = 1), and desert hedgehog (DHH; n = 1) in the CGD group, and in NR5A1 (n = 5), DHH (n = 1), and DEAH-box helicase 37 (DHX37; n = 4) in the pvDSD group.
Reaching a specific diagnosis can have clinical implications and provides insight into the role of these proteins in sex development. Next-generation sequencing approaches are invaluable, especially in adult populations or where diagnostic biochemistry is not possible.
This study investigated the effect of carbohydrate (CHO) dose and composition on fuel selection during exercise, specifically exogenous and endogenous (liver and muscle) CHO oxidation. Ten trained ...males cycled in a double‐blind randomized order on 5 occasions at 77% V˙O2max for 2 h, followed by a 30‐min time‐trial (TT) while ingesting either 60 g·h−1 (LG) or 75 g·h−1 13C‐glucose (HG), 90 g·h−1 (LGF) or 112.5 g·h−1 13C‐glucose‐13C‐fructose (2:1 HGF) or placebo. CHO doses met or exceed reported intestinal transporter saturation for glucose and fructose. Indirect calorimetry and stable mass isotope 13C tracer techniques were utilized to determine fuel use. TT performance was 93% “likely/probable” to be improved with LGF compared with the other CHO doses. Exogenous CHO oxidation was higher for LGF and HGF compared with LG and HG (ES > 1.34, P < 0.01), with the relative contribution of LGF (24.5 ± 5.3%) moderately higher than HGF (20.6 ± 6.2%, ES = 0.68). Increasing CHO dose beyond intestinal saturation increased absolute (29.2 ± 28.6 g·h−1, ES = 1.28, P = 0.06) and relative muscle glycogen utilization (9.2 ± 6.9%, ES = 1.68, P = 0.014) for glucose‐fructose ingestion. Absolute muscle glycogen oxidation between LG and HG was not significantly different, but was moderately higher for HG (ES = 0.60). Liver glycogen oxidation was not significantly different between conditions, but absolute and relative contributions were moderately attenuated for LGF (19.3 ± 9.4 g·h−1, 6.8 ± 3.1%) compared with HGF (30.5 ± 17.7 g·h−1, 10.1 ± 4.0%, ES = 0.79 & 0.98). Total fat oxidation was suppressed in HGF compared with all other CHO conditions (ES > 0.90, P = 0.024–0.17). In conclusion, there was no linear dose response for CHO ingestion, with 90 g·h−1 of glucose‐fructose being optimal in terms of TT performance and fuel selection.
This study investigated the effect of carbohydrate (CHO) dose and composition (60 and 75 g·h−1 of glucose, and 90 and 112.5 g·h−1 of glucose‐fructose 2:1 ratio) on fuel selection during exercise, specifically exogenous and endogenous (liver and muscle) CHO oxidation. A 13C stable mass isotope tracer technique was used to determine fuel source utilization in Ten trained males who cycled on 5 occasions at 77% V˙O2max for 2 h, followed by a 30‐min time‐trial (TT). There was no linear dose response for CHO ingestion, with 90 g·h−1 of glucose‐fructose being optimal in terms of TT performance and fuel selection.
Abstract Antibodies against glutamic acid decarboxylase (GAD) are involved in the pathophysiology of stiff-person syndrome (SPS) and type 1 diabetes. GAD catalyses the conversion of glutamate to ...gamma-aminobutyric acid (GABA). GABA acts as a neurotransmitter between neurones, while in pancreatic beta cells it plays an integral role in normal insulin secretion, hence the clinical presentation of muscular spasms in SPS and insulin deficiency in diabetes. Despite this apparent major overlap in pathophysiology, SPS only rarely occurs in individuals with type 1 diabetes. We report the case of a 41-year-old man presenting with a simultaneous diagnosis of both these conditions. His case is unusual in that it is the first reported case in the literature of these conditions occurring in someone with celiac disease (CD) and dermatitis herpetiformis. We discuss why SPS and type 1 diabetes co-exist in only a minority of cases and speculate on the underlying mechanism of the association with CD and dermatitis herpetiformis in our patient.
Small molecule modulators of epigenetic processes are currently sought as basic probes for biochemical mechanisms, and as starting points for development of therapeutic agents. N(ε)-Methylation of ...lysine residues on histone tails is one of a number of post-translational modifications that together enable transcriptional regulation. Histone lysine demethylases antagonize the action of histone methyltransferases in a site- and methylation state-specific manner. N(ε)-Methyllysine demethylases that use 2-oxoglutarate as co-factor are associated with diverse human diseases, including cancer, inflammation and X-linked mental retardation; they are proposed as targets for the therapeutic modulation of transcription. There are few reports on the identification of templates that are amenable to development as potent inhibitors in vivo and large diverse collections have yet to be exploited for the discovery of demethylase inhibitors.
High-throughput screening of a ∼236,000-member collection of diverse molecules arrayed as dilution series was used to identify inhibitors of the JMJD2 (KDM4) family of 2-oxoglutarate-dependent histone demethylases. Initial screening hits were prioritized by a combination of cheminformatics, counterscreening using a coupled assay enzyme, and orthogonal confirmatory detection of inhibition by mass spectrometric assays. Follow-up studies were carried out on one of the series identified, 8-hydroxyquinolines, which were shown by crystallographic analyses to inhibit by binding to the active site Fe(II) and to modulate demethylation at the H3K9 locus in a cell-based assay.
These studies demonstrate that diverse compound screening can yield novel inhibitors of 2OG dependent histone demethylases and provide starting points for the development of potent and selective agents to interrogate epigenetic regulation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
An evaluation was made of the recently developed risk assessment methodologies for new and existing chemicals in the European Communities. The evaluation also included the methodologies to prioritize ...chemicals and procedures for risk management, i.e., the (draft) guidance document for the development of strategies for risk reduction. The way in which chemicals are prioritized is accepted with only very few comments. Clear progress has been made in the development and harmonization of risk assessment methodologies and the application of estimation methodologies. Nevertheless, improvements are necessary for the estimation of consumer and occupational exposure, the derivation, use and transparency of assessment factors for chemicals and classes of chemicals based on the mode of toxic action, environmental exposure models and their validation and relation with monitoring data. As far as risk management is concerned it was recommended to improve the integration of the myriad of directives and regulations, to clarify definitions, to provide clear guidance on the determination and weighing of advantages and implications of risk reduction measures and to develop tools, including voluntary agreements, to speed up the slow chemical-by-chemical approach.
Two-dimensional nanomaterials such as MoS2 are of great interest both because of their novel physical properties and their applications potential. Liquid exfoliation, an important production method, ...is limited by our inability to quickly and easily measure nanosheet size, thickness or concentration. Here we demonstrate a method to simultaneously determine mean values of these properties from an optical extinction spectrum measured on a liquid dispersion of MoS2 nanosheets. The concentration measurement is based on the size-independence of the low-wavelength extinction coefficient, while the size and thickness measurements rely on the effect of edges and quantum confinement on the optical spectra. The resultant controllability of concentration, size and thickness facilitates the preparation of dispersions with pre-determined properties such as high monolayer-content, leading to first measurement of A-exciton MoS2 luminescence in liquid suspensions. These techniques are general and can be applied to a range of two-dimensional materials including WS2, MoSe2 and WSe2.
Updated annually to keep up with the increasingly fast pace of change in the field, the Information Security Management Handbookis the single most comprehensive and up-to-date resource on information ...security (IS) and assurance. Facilitating the up-to-date understanding required of all IS professionals, the Information Security Management Handbook, Sixth Edition, Volume 5reflects the latest issues in information security and the CISSP® Common Body of Knowledge (CBK®).
This edition updates the benchmark Volume 1with a wealth of new information to help IS professionals address the challenges created by complex technologies and escalating threats to information security. Topics covered include chapters related to access control, physical security, cryptography, application security, operations security, and business continuity and disaster recovery planning.
The updated edition of this bestselling reference provides cutting-edge reporting on mobile device security, adaptive threat defense, Web 2.0, virtualization, data leakage, governance, and compliance. Also available in a fully searchable CD-ROM format, it supplies you with the tools and understanding to stay one step ahead of evolving threats and ever-changing standards and regulations.
We hypothesized that mutations in homologous recombination repair (HRR) genes beyond
and
improve outcomes for ovarian carcinoma patients treated with platinum therapy and would impact the relative ...benefit of adding prolonged bevacizumab.
We sequenced DNA from blood and/or neoplasm from 1,195 women enrolled in GOG-0218, a randomized phase III trial in advanced ovarian carcinoma of bevacizumab added to carboplatin and paclitaxel. Defects in HRR were defined as damaging mutations in 16 genes. Proportional hazards models were used to estimate relative hazards for progression-free survival (PFS) and overall survival (OS).
Of 1,195 women with ovarian carcinoma, HRR mutations were identified in 307 (25.7%). Adjusted hazards for progression and death compared with those without mutations were lower for women with non-
HRR mutations HR = 0.73; 95% confidence interval (CI), 0.57-0.94;
= 0.01 for PFS; HR = 0.67; 95% CI, 0.50-0.90;
= 0.007 for OS and
mutations (HR = 0.80; 95% CI, 0.66-0.97;
= 0.02 for PFS; HR = 0.74; 95% CI, 0.59-0.94;
= 0.01 for OS) and were lowest for
mutations (HR = 0.52; 95% CI, 0.40-0.67;
< 0.0001 for PFS; HR = 0.36; 95% CI, 0.25-0.53;
< 0.0001 for OS). A test of interaction showed no difference in the effect of bevacizumab on PFS between cases with and without mutations.
HRR mutations, including non-
genes, significantly prolong PFS and OS in ovarian carcinoma and should be stratified for in clinical trials. The benefit of adding bevacizumab was not significantly modified by mutation status.
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