Dydrogesterone and norethisterone regulate expression of lipoprotein lipase and hormones-sensitive lipase in human subcutaneous abdominal adipocytes

Aim: In premenopausal women, hyper-androgenicity is associated with central obesity and an increased cardiovascular risk. We investigated the effects of dydrogesterone (DYD)(a non-androgenic progestogen) and norethisterone (NET)(an androgenic progestogen) on lipoprotein lipase (LPL), hormone-sensitive lipase (HSL) and glycerol release in adipocytes isolated from subcutaneous abdominal adipose tissue. Methods: Adipose tissue was obtained from 12 non-diabetic women, mean age 51 years (range 37-78) and mean BMI 25.4kg/m2 (range 20.3-26.4). Adipocytes were treated with increasing doses of DYD and NET for 48 hours prior to protein extraction. Effects on lipogenesis and lipolysis were assessed using western blotting to determine the expression of key enzymes, LPL (56kDa) and HSL (84kDa) respectively. Measurement of glycerol release into the medium provided an assessment of lipolytic activity. Results: Expression of LPL was increased by DYD and NET (mean protein expression relative to control ± SEM); with greatest effect at 10-8M for DYD: 2.32±0.51(p0.05). Conclusions: DYD and NET significantly increased LPL expression relative to control whilst significantly reducing HSL expression. At the concentrations studied, similar effects were observed with the androgenic NET and the non-androgenic DYD despite differing effects on the lipid profile when taken in combination with estrogen. Further work in this area may improve knowledge about the effects of different progestogens on body fat distribution and enable progestogen use to be tailored to the individual to achieve maximal benefits

How do people type on mobile devices? Observations from a study with 37,000 volunteers

© 2019 Association for Computing Machinery. This paper presents a large-scale dataset on mobile text entry collected via a web-based transcription task performed by 37,370 volunteers. The average typing speed was 36.2 WPM with 2.3% uncorrected errors. The scale of the data enables powerful statistical analyses on the correlation between typing performance and various factors, such as demographics, finger usage, and use of intelligent text entry techniques. We report effects of age and finger usage on performance that correspond to previous studies. We also find evidence of relationships between performance and use of intelligent text entry techniques: auto-correct usage correlates positively with entry rates, whereas word prediction usage has a negative correlation. To aid further work on modeling, machine learning and design improvements in mobile text entry, we make the code and dataset openly available

Genome Biol.

With genome analysis expanding from the study of genes to the study of gene regulation, 'regulatory genomics' utilizes sequence information, evolution and functional genomics measurements to unravel how regulatory information is encoded in the genome

Remote sensing techniques and geochemical constraints on the formation of the Wadi El-Hima mineralized granites, Egypt: new insights into the genesis and accumulation of garnets

The Wadi El-Hima Neoproterozoic I- and A-type granites in the Southern Eastern Desert of Egypt are rich in garnets (up to 30 vol%) and are cut by NW–SE strike-slip faults, as confirmed from structure lineament extraction maps. These mineralized granites and garnet mineralization zones can be successfully discriminated using remote sensing techniques. Spectral angle mapper and matched filtering techniques are highly effective for mapping garnet-rich zones and show that the highest garnet concentrations occur along the intrusive contact zone of NW–SE striking faults. El-Hima granites have high SiO2 (73.5–75.1 wt%), Al2O3 (13.4–15.3 wt%) and total alkali (6.7–8.7 wt%) contents, suggesting that they were sourced from peraluminous (A/CNK > 1) parental magmas. Garnet-bearing trondhjemites are metasomatic in origin and formed after I-type tonalite-granodiorites, which originated in a volcanic arc tectonic setting. Garnet-rich syenogranites and alkali-feldspar granites are both post-collisional A-type granites: the syenogranites formed from peraluminous magmas generated by partial melting of lower crustal tonalite and metasedimentary protoliths during lithospheric delamination, and the alkali-feldspar granites crystallized from highly fractionated, felsic and alkali-rich peraluminous magmas in the upper crust. Garnets in El-Hima mineralized granites occur in three forms: (1) subhedral disseminated crystals, (2) vein-type crystals, and (3) aggregated subhedral crystals, reflecting different mechanisms of accumulation. All are dominantly almandine in composition (Alm76Sps10 Prp7Grs6Adr1) and have high average concentrations of heavy rare earth elements (HREE) (ΣHREE = 1636 ppm), Y = (3394 ppm), Zn (325 ppm), Li (39.17 ppm) and Ga (34.94 ppm). Garnet REE patterns show strong negative Eu anomalies with HREE enriched relative to LREE, indicating a magmatic origin. These magmatic garnets are late-stage crystallization products of Al-rich hydrous magmas, and formed at low temperature (680–730 °C) and pressure (2.1–2.93 kbar) conditions in the upper continental crust. Peculiar garnet concentrations in syenogranites near and along contact zones with alkali feldspar granites are related to peraluminous parent hydrous magma compositions. These garnets formed by in situ crystallization from A-type granite melts, alongside accumulation of residual garnets left behind after partial melting of the host garnet-rich granites along the intrusive contact. Magmatic-fluid flow along the NW–SE striking fault of Najd system enhanced garnet accumulation in melts, which formed clots and veins of garnet

Magmatic, Metamorphic and Structural History of the Variscan Lizard Ophiolite and Metamorphic Sole, Cornwall, UK

The Lizard ophiolite, Cornwall, South-West England, is the largest and best-preserved ophiolite within the Variscan orogenic belt. It forms part of the Rheic-Rhenohercynian suture zone, and was obducted northwestward onto the passive continental margin of Avalonia (Laurussia) during the Middle Devonian. It comprises an almost complete thrust slice of oceanic crust with sheeted dykes, gabbros, Moho transition sequence, and upper-mantle peridotites, underlain by a metamorphic sole. Despite the importance of the Lizard ophiolite in understanding Variscan tectonics, the origin and age of the Lizard ophiolite are debated. We present new field observations, structural maps and cross-sections of the Lizard ophiolite from extensive re-mapping, integrated with U–Pb geochronology, petrology, thermobarometry, and whole rock geochemistry. We report new U–Pb zircon (CA-ID-TIMS and LA-ICPMS) ages of 386.80 ± 0.25/0.31/0.52 Ma (Givetian) from a plagiogranite dyke intruding the Crousa Gabbros at Porthoustock, and 395.08 ± 0.14/0.22/0.47 Ma (Emsian) from partial melts of the metamorphic sole Landewednack Amphibolites at Mullion Cove. These ages, respectively, precisely date the formation of the Lizard ophiolite oceanic crust, and the age of cooling post peak-metamorphism of the sole. Petrological modeling on the Landewednack Amphibolites suggests peak metamorphic conditions of 10 ± 2 kbar and 600 ± 75°C. We demonstrate that the Lizard ophiolite formed as a supra-subduction zone ophiolite overlying an inverted metamorphic sole, and we combine our observations and data into a new geodynamic model for the formation and obduction of the ophiolite. The current data supports an induced subduction initiation model

An Automated Method to Quantify Microglia Morphology and Application to Monitor Activation State Longitudinally In Vivo

Microglia are specialized immune cells of the brain. Upon insult, microglia initiate a cascade of cellular responses including a characteristic change in cell morphology. To study the dynamics of microglia immune response in situ, we developed an automated image analysis method that enables the quantitative assessment of microglia activation state within tissue based solely on cell morphology. Per cell morphometric analysis of fluorescently labeled microglia is achieved through local iterative threshold segmentation, which reduces errors caused by signal-to-noise variation across large volumes. We demonstrate, utilizing systemic application of lipopolysaccharide as a model of immune challenge, that several morphological parameters, including cell perimeter length, cell roundness and soma size, quantitatively distinguish resting versus activated populations of microglia within tissue comparable to traditional immunohistochemistry methods. Furthermore, we provide proof-of-concept data that monitoring soma size enables the longitudinal assessment of microglia activation in the mouse neocortex imaged via 2-photon in vivo microscopy. The ability to quantify microglia activation automatically by shape alone allows unbiased and rapid analysis of both fixed and in vivo central nervous system tissue

Comprehensive evaluation of coding region point mutations in microsatellite-unstable colorectal cancer

Microsatellite instability (MSI) leads to accumulation of an excessive number of mutations in the genome, mostly small insertions and deletions. MSI colorectal cancers (CRCs), however, also contain more point mutations than microsatellite-stable (MSS) tumors, yet they have not been as comprehensively studied. To identify candidate driver genes affected by point mutations in MSI CRC, we ranked genes based on mutation significance while correcting for replication timing and gene expression utilizing an algorithm, MutSigCV. Somatic point mutation data from the exome kit-targeted area from 24 exome-sequenced sporadic MSI CRCs and respective normals, and 12 whole-genome-sequenced sporadic MSI CRCs and respective normals were utilized. The top 73 genes were validated in 93 additional MSI CRCs. The MutSigCV ranking identified several well-established MSI CRC driver genes and provided additional evidence for previously proposed CRC candidate genes as well as shortlisted genes that have to our knowledge not been linked to CRC before. Two genes, SMARCB1 and STK38L, were also functionally scrutinized, providing evidence of a tumorigenic role, for SMARCB1 mutations in particular. © 2018 The Authors. Published under the terms of the CC BY 4.0 licensePeer reviewe

Repeated antibiotic exposure and risk of hospitalisation and death following COVID-19 infection (OpenSAFELY): a matched case–control study

Background Identifying potential risk factors related to severe COVID-19 outcomes is important. Repeated intermittent antibiotic use is known be associated with adverse outcomes. This study aims to examine whether prior frequent antibiotic exposure is associated with severe COVID-19 outcomes. Methods With the approval of NHS England, we used the OpenSAFELY platform, which integrated primary and secondary care, COVID-19 test, and death registration data. This matched case–control study included 0.67 million patients (aged 18–110 years) from an eligible 2.47 million patients with incident COVID-19 by matching with replacement. Inclusion criteria included registration within one general practice for at least 3 years and infection with incident COVID-19. Cases were identified according to different severity of COVID-19 outcomes. Cases and eligible controls were 1:6 matched on age, sex, region of GP practice, and index year and month of COVID-19 infection. Five quintile groups, based on the number of previous 3-year antibiotic prescriptions, were created to indicate the frequency of prior antibiotic exposure. Conditional logistic regression used to compare the differences between case and control groups, adjusting for ethnicity, body mass index, comorbidities, vaccination history, deprivation, and care home status. Sensitivity analyses were done to explore potential confounding and the effects of missing data. Findings Based on our inclusion criteria, between February 1, 2020 and December 31, 2021, 98,420 patients were admitted to hospitals and 22,660 died. 55 unique antibiotics were prescribed. A dose–response relationship between number of antibiotic prescriptions and risk of severe COVID-19 outcome was observed. Patients in the highest quintile with history of prior antibiotic exposure had 1.80 times greater odds of hospitalisation compared to patients without antibiotic exposure (adjusted odds ratio [OR] 1.80, 95% Confidence Interval [CI] 1.75–1.84). Similarly, the adjusted OR for hospitalised patients with death outcomes was 1.34 (95% CI 1.28–1.41). Larger number of prior antibiotic type was also associated with more severe COVID-19 related hospital admission. The adjusted OR of quintile 5 exposure (the most frequent) with more than 3 antibiotic types was around 2 times larger than quintile 1 (only 1 type; OR 1.80, 95% CI 1.75–1.84 vs. OR 1.03, 95% CI 1.01–1.05). Interpretation Our observational study has provided evidence that antibiotic exposure frequency and diversity may be associated with COVID-19 severity, potentially suggesting adverse effects of repeated intermittent antibiotic use. Future work could work to elucidate causal links and potential mechanisms. Antibiotic stewardship should put more emphasis on long-term antibiotic exposure and its adverse outcome to increase the awareness of appropriate antibiotics use. Funding Health Data Research UK and National Institute for Health Research