A Discrete Class of Intergenic DNA Dictates Meiotic DNA Break Hotspots in Fission Yeast

Meiotic recombination is initiated by DNA double-strand breaks (DSBs) made by Spo11 (Rec12 in fission yeast), which becomes covalently linked to the DSB ends. Like recombination events, DSBs occur at hotspots in the genome, but the genetic factors responsible for most hotspots have remained elusive. Here we describe in fission yeast the genome-wide distribution of meiosis-specific Rec12-DNA linkages, which closely parallel DSBs measured by conventional Southern blot hybridization. Prominent DSB hotspots are located ∼65 kb apart, separated by intervals with little or no detectable breakage. Most hotspots lie within exceptionally large intergenic regions. Thus, the chromosomal architecture responsible for hotspots in fission yeast is markedly different from that of budding yeast, in which DSB hotspots are much more closely spaced and, in many regions of the genome, occur at each promoter. Our analysis in fission yeast reveals a clearly identifiable chromosomal feature that can predict the majority of recombination hotspots across a whole genome and provides a basis for searching for the chromosomal features that dictate hotspots of meiotic recombination in other organisms, including humans

The ethnicity attainment gap among medical and biomedical science students: a qualitative study.

Background Black, Asian and Minority Ethnic (BAME) medical students and professionals frequently underachieve when compared with their White counterparts not only in the United Kingdom, but across the globe. There is no consensus for the definitive causes of this attainment gap, but suggestions contributing towards it include: increased feelings of isolation as a member of a minority culture or religion; a poorer higher education (HE) experience compared with White counterparts; and stereotype threat, whereby students underperform in exams from the stresses of fearing confirming to a negative-stereotype. Methods The aim of this study was to gather qualitative data on HE experiences of medical and biomedical science students to explore factors contributing to the attainment gap. Audio-recorded, semi-structured interviews and a novel approach for this research area of ethnically-homogenous student-led focus groups, were held with students and staff at a healthcare-based university in London, where lower attainment, slower rates of degree completion and lower levels of satisfaction with HE experience were identified in BAME students compared with White students. Thematic analysis was used to manage, summarize and analyse the data. Results Forty-one students and eight staff members were interviewed or took part in focus groups. The student data were best explained by two main themes: social factors and stereotyping, whilst staff data were also best explained by two main themes: social factors and student and staff behaviour. Social factors suggested ethnically-defined social networks and the informal transfer of knowledge impacted academic performance, isolating minority groups from useful academic information. BAME students may also be at a further disadvantage, being unable to attend social and academic functions for cultural or family reasons. Black students also mentioned changing their behaviour to combat negative stereotypes in a variety of contexts. Conclusions This study suggests that forms of discrimination, whether conscious or unconscious, may be negatively impacting the abilities of BAME students both in examinations and in coursework choice. It highlights the importance of social networks for the transfer of academic knowledge and the impact ethnicity may have on their formation, with issues around segregation and the sharing of information outside defined groups

A discrete class of intergenic DNA dictates meiotic DNA break hotspots in fission yeast.

Meiotic recombination is initiated by DNA double-strand breaks (DSBs) made by Spo11 (Rec12 in fission yeast), which becomes covalently linked to the DSB ends. Like recombination events, DSBs occur at hotspots in the genome, but the genetic factors responsible for most hotspots have remained elusive. Here we describe in fission yeast the genomewide distribution of meiosis-specific Rec12-DNA linkages, which closely parallel DSBs measured by conventional Southern blot hybridization. Prominent DSB hotspots are located ;65 kb apart, separated by intervals with little or no detectable breakage. Most hotspots lie within exceptionally large intergenic regions. Thus, the chromosomal architecture responsible for hotspots in fission yeast is markedly different from that of budding yeast, in which DSB hotspots are much more closely spaced and, in many regions of the genome, occur at each promoter. Our analysis in fission yeast reveals a clearly identifiable chromosomal feature that can predict the majority of recombination hotspots across a whole genome and provides a basis for searching for the chromosomal features that dictate hotspots of meiotic recombination in other organisms, including humans

Insights into the Role of a Cardiomyopathy-Causing Genetic Variant in ACTN2

Pathogenic variants in ACTN2, coding for alpha-actinin 2, are known to be rare causes of Hyper-trophic Cardiomyopathy. However, little is known about the underlying disease mechanisms. Adult heterozygous mice carrying the Actn2 p.Met228Thr variant were phenotyped by echocar-diography. For homozygous mice, viable E15.5 embryonic hearts were analysed by High Reso-lution Episcopic Microscopy and wholemount staining, complemented by unbiased proteomics, qPCR and Western blotting. Heterozygous Actn2 p.Met228Thr mice have no overt phenotype. Only mature males show molecular parameters indicative of cardiomyopathy. By contrast, the variant is embryonically lethal in the homozygous setting and E15.5 hearts show multiple morphological abnormalities. Molecular analyses, including unbiased proteomics, identified quantitative abnormalities in sarcomeric parameters, cell cycle defects and mitochondrial dys-function. The mutant alpha-actinin protein is found to be destabilised, associated with increased activity of the ubiquitin-proteosomal system. This missense variant in alpha-actinin renders the protein less stable. In response, the ubiquitin-proteosomal system is activated; a mechanism which has been implicated in cardiomyopathies previously. In parallel, lack of functional al-pha-actinin is thought to cause energetic defects through mitochondrial dysfunction. This seems, together with cell cycle defects, the likely cause of death of the embryos. The defects also have wide-ranging morphological consequences

Western Indian Ocean marine and terrestrial records of climate variability: a review and new concepts on land-ocean interactions since AD 1660

We examine the relationship between three tropical and two subtropical western Indian Ocean coral oxygen isotope time series to surface air temperatures (SAT) and rainfall over India, tropical East Africa and southeast Africa. We review established relationships, provide new concepts with regard to distinct rainfall seasons, and mean annual temperatures. Tropical corals are coherent with SAT over western India and East Africa at interannual and multidecadal periodicities. The subtropical corals correlate with Southeast African SAT at periodicities of 16–30 years. The relationship between the coral records and land rainfall is more complex. Running correlations suggest varying strength of interannual teleconnections between the tropical coral oxygen isotope records and rainfall over equatorial East Africa. The relationship with rainfall over India changed in the 1970s. The subtropical oxygen isotope records are coherent with South African rainfall at interdecadal periodicities. Paleoclimatological reconstructions of land rainfall and SAT reveal that the inferred relationships generally hold during the last 350 years. Thus, the Indian Ocean corals prove invaluable for investigating land–ocean interactions during past centuries

Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10(-8), in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms

Linking basin-scale and pore-scale gas hydrate distribution patterns in diffusion-dominated marine hydrate systems

The goal of this study is to computationally determine the potential distribution patterns of diffusion-driven methane hydrate accumulations in coarse-grained marine sediments. Diffusion of dissolved methane in marine gas hydrate systems has been proposed as a potential transport mechanism through which large concentrations of hydrate can preferentially accumulate in coarse-grained sediments over geologic time. Using one-dimensional compositional reservoir simulations, we examine hydrate distribution patterns at the scale of individual sand layers (1-20 m thick) that are deposited between microbially active fine-grained material buried through the gas hydrate stability zone (GHSZ). We then extrapolate to two-dimensional and basin-scale three-dimensional simulations, where we model dipping sands and multilayered systems. We find that properties of a sand layer including pore size distribution, layer thickness, dip, and proximity to other layers in multilayered systems all exert control on diffusive methane fluxes toward and within a sand, which in turn impact the distribution of hydrate throughout a sand unit. In all of these simulations, we incorporate data on physical properties and sand layer geometries from the Terrebonne Basin gas hydrate system in the Gulf of Mexico. We demonstrate that diffusion can generate high hydrate saturations (upward of 90%) at the edges of thin sands at shallow depths within the GHSZ, but that it is ineffective at producing high hydrate saturations throughout thick (greater than 10 m) sands buried deep within the GHSZ. Furthermore, we find that hydrate in fine-grained material can preserve high hydrate saturations in nearby thin sands with burial

Inflammation induced by influenza virus impairs human innate immune control of pneumococcus

Secondary bacterial pneumonia following influenza infection is a significant cause of mortality worldwide. Upper respiratory tract pneumococcal carriage is important as both determinants of disease and population transmission. The immunological mechanisms that contain pneumococcal carriage are well-studied in mice but remain unclear in humans. Loss of this control of carriage following influenza infection is associated with secondary bacterial pneumonia during seasonal and pandemic outbreaks. We used a human type 6B pneumococcal challenge model to show that carriage acquisition induces early degranulation of resident neutrophils and recruitment of monocytes to the nose. Monocyte function associated with clearance of pneumococcal carriage. Prior nasal infection with live attenuated influenza virus induced inflammation, impaired innate function and altered genome-wide nasal gene responses to pneumococcal carriage. Levels of the cytokine IP-10 promoted by viral infection at the time of pneumococcal encounter was positively associated with bacterial density. These findings provide novel insights in nasal immunity to pneumococcus and viral-bacterial interactions during co-infection

TESS Duotransit Candidates from the Southern Ecliptic Hemisphere

Discovering transiting exoplanets with long orbital periods allows us to study warm and cool planetary systems with temperatures similar to the planets in our own Solar system. The TESS mission has photometrically surveyed the entire Southern Ecliptic Hemisphere in Cycle 1 (August 2018 - July 2019), Cycle 3 (July 2020 - June 2021) and Cycle 5 (September 2022 - September 2023). We use the observations from Cycle 1 and Cycle 3 to search for exoplanet systems that show a single transit event in each year - which we call duotransits. The periods of these planet candidates are typically in excess of 20 days, with the lower limit determined by the duration of individual TESS observations. We find 85 duotransit candidates, which span a range of host star brightnesses between 8 < $T_{mag}$ < 14, transit depths between 0.1 per cent and 1.8 per cent, and transit durations between 2 and 10 hours with the upper limit determined by our normalisation function. Of these candidates, 25 are already known, and 60 are new. We present these candidates along with the status of photometric and spectroscopic follow-up.Comment: 25 pages, 16 figures, submitted to Monthly Notices of the Royal Astronomical Societ

Marine pelagic ecosystems: the West Antarctic Peninsula

The marine ecosystem of the West Antarctic Peninsula (WAP) extends from the Bellingshausen Sea to the northern tip of the peninsula and from the mostly glaciated coast across the continental shelf to the shelf break in the west. The glacially sculpted coastline along the peninsula is highly convoluted and characterized by deep embayments that are often interconnected by channels that facilitate transport of heat and nutrients into the shelf domain. The ecosystem is divided into three subregions, the continental slope, shelf and coastal regions, each with unique ocean dynamics, water mass and biological distributions. The WAP shelf lies within the Antarctic Sea Ice Zone (SIZ) and like other SIZs, the WAP system is very productive, supporting large stocks of marine mammals, birds and the Antarctic krill, Euphausia superba. Ecosystem dynamics is dominated by the seasonal and interannual variation in sea ice extent and retreat. The Antarctic Peninsula is one among the most rapidly warming regions on Earth, having experienced a 28C increase in the annual mean temperature and a 68C rise in the mean winter temperature since 1950. Delivery of heat from the Antarctic Circumpolar Current has increased significantly in the past decade, sufficient to drive to a 0.68C warming of the upper 300 m of shelf water. In the past 50 years and continuing in the twenty-first century, the warm, moist maritime climate of the northern WAP has been migrating south, displacing the once dominant cold, dry continental Antarctic climate and causing multi-level responses in the marine ecosystem. Ecosystem responses to the regional warming include increased heat transport, decreased sea ice extent and duration, local declines in icedependent Ade´lie penguins, increase in ice-tolerant gentoo and chinstrap penguins, alterations in phytoplankton and zooplankton community composition and changes in krill recruitment, abundance and availability to predators. The climate/ecological gradients extending along theWAPand the presence of monitoring systems, field stations and long-term research programmes make the region an invaluable observatory of climate change and marine ecosystem response