Exploring the Role of Plasma Lipids and Statins Interventions on Multiple Sclerosis Risk and Severity: A Mendelian Randomization Study

BACKGROUND: There has been considerable interest in statins due to their pleiotropic effects beyond their lipid-lowering properties. Many of these pleiotropic effects are predominantly ascribed to Rho small guanosine triphosphatases (Rho GTPases) proteins. We aimed to genetically investigate the role of lipids and statin interventions on multiple sclerosis (MS) risk and severity. METHOD: We employed two-sample Mendelian randomization (MR) to investigate: (1) the causal role of genetically mimic both cholesterol-dependent (via low-density lipoprotein cholesterol (LDL-C) and cholesterol biosynthesis pathway) and cholesterol-independent (via Rho GTPases) effects of statins on MS risk and MS severity, (2) the causal link between lipids (high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG)) levels and MS risk and severity; and (3) the reverse causation between lipid fractions and MS risk. We used summary statistics from the Global Lipids Genetics Consortium (GLGC), eQTLGen Consortium and the International MS Genetics Consortium (IMSGC) for lipids, expression quantitative trait loci and MS, respectively (GLGC: n = 188,577; eQTLGen: n = 31,684; IMSGC (MS risk): n = 41,505; IMSGC (MS severity): n =7,069). RESULTS: The results of MR using the inverse variance weighted method show that genetically predicted RAC2, a member of cholesterol-independent pathway, (OR 0.86 (95% CI 0.78 to 0.95), p-value 3.80E-03) is implicated causally in reducing MS risk. We found no evidence for the causal role of LDL-C and the member of cholesterol biosynthesis pathway on MS risk. MR results also show that lifelong higher HDL-C (OR 1.14 (95% CI 1.04 to1.26), p-value 7.94E-03) increase MS risk but TG was not. Furthermore, we found no evidence for the causal role of lipids and genetically mimicked statins on MS severity. There is no evidence of reverse causation between MS risk and lipids. CONCLUSION: Evidence from this study suggests that RAC2 is a genetic modifier of MS risk. Since RAC2 has been reported to mediate some of the pleiotropic effects of statins, we suggest that statins may reduce MS risk via a cholesterol-independent pathway (i.e., RAC2-related mechanism(s)). MR analyses also support a causal effect of HDL-C on MS risk

Regional climate impacts of a possible future grand solar minimum.

This is the final published version. It first appeared at http://www.nature.com/ncomms/2015/150623/ncomms8535/full/ncomms8535.html.Any reduction in global mean near-surface temperature due to a future decline in solar activity is likely to be a small fraction of projected anthropogenic warming. However, variability in ultraviolet solar irradiance is linked to modulation of the Arctic and North Atlantic Oscillations, suggesting the potential for larger regional surface climate effects. Here, we explore possible impacts through two experiments designed to bracket uncertainty in ultraviolet irradiance in a scenario in which future solar activity decreases to Maunder Minimum-like conditions by 2050. Both experiments show regional structure in the wintertime response, resembling the North Atlantic Oscillation, with enhanced relative cooling over northern Eurasia and the eastern United States. For a high-end decline in solar ultraviolet irradiance, the impact on winter northern European surface temperatures over the late twenty-first century could be a significant fraction of the difference in climate change between plausible AR5 scenarios of greenhouse gas concentrations.This work was supported by the Joint DECC/Defra Met Office Hadley Centre Climate Programme (GA01101) and also by the EU project SPECS funded by the European Commission’s Seventh Framework Research Programme under the grant agreement 308378 (Met Office Hadley Centre authors), by the NERC National Centre for Atmospheric Science (NCAS) Climate directorate (L.J.G. and A.C.M.), an ERC ACCI grant (A.C.M) and an AXA Postdoctoral Fellowship (A.C.M.)

Allanite U–Pb dating places new constraints on the high‐pressure to high‐temperature evolution of the deep Himalayan crust

During continental collision, crustal rocks are buried, deformed, transformed and exhumed. The rates, timescales and tectonic implications of these processes are constrained through the sequence and conditions of metamorphic reactions in major and accessory phases. Petrographic, isotopic and elemental data from metabasite samples in NW Bhutan, eastern Himalaya, suggest initial equilibration under high-pressure (plagioclase-absent and rutile-present) conditions, followed by decompression to lower pressure conditions at high-temperatures that stabilized plagioclase, orthopyroxene and ilmenite. Field observations and chemical indicators suggest equilibration under the lower pressure conditions is likely linked to the infiltration of melt from the host metasedimentary rocks. The metabasites preserve two metamorphic growth stages of chemically-and petrographically distinct allanite that temporally overlap two stages of zircon growth. Allanite cores and zircon mantles grew at c. 19 ± 2 and 17–15.5 Ma respectively, linked texturally and chemically to the high-pressure evolution. Symplectitic rims on embayed allanite cores, wholly symplectized Aln–Ilm and Aln–Cpx grains, and high U zircon rims grew at c. 15.5–14.5 Ma, linked chemically to the presence of melt and lower pressure, high-temperature conditions. A single garnet Lu–Hf date is interpreted as geologically meaningless, with the bulk rock composition modified by melt infiltration after garnet formation. The open system evolution of these rocks precludes precise determination of the reactive bulk composition during metamorphic evolution and thus absolute conditions, especially during the early high-pressure evolution. Despite these limitations, we show that combined geochemical and petrographic datasets are still able to provide insights into the rates and timescales of deep orogenic processes. The data suggest a younger and shallower evolution for the NW Bhutan metabasites compared to similar rocks in the central and eastern Himalayas

Impact of Multiple COVID-19 Waves on Gynaecological Cancer Services in the UK

Funding: This research was funded by the British Gynaecological Cancer Society (EMSG1L5R) and Ovacome charity. It is supported by the National Cancer Research Institute Gynaecological Cancer Clinical Studies Group and the British Association of Gynaecological Pathologists. The funding bodies had no role in the study design, data collection, analysis, interpretation or writing of the report, or decision to submit for publication. The research team was independent of funders. Acknowledgments: The study is supported by researchers at the Barts Cancer Research United Kingdom Centre for Excellence, Queen Mary University of London (C16420/A18066). We are grateful for the endorsement and support from charities and patient support groups such as Ovacome, The Eve Appeal, Target Ovarian Cancer, Ovarian Cancer Action, Jo’s Cervical Cancer Trust, and GO Girls. We are grateful for the support received from the Royal College of Obstetricians and Gynaecologists, the National Cancer Research Institute Gynaecological Cancer Clinical Studies Group, and the British Association of Gynaecological Pathologists.Peer reviewedPublisher PD

Functional genomics provide key insights to improve the diagnostic yield of hereditary ataxia

Improvements in functional genomic annotation have led to a critical mass of neurogenetic discoveries. This is exemplified in hereditary ataxia, a heterogeneous group of disorders characterised by incoordination from cerebellar dysfunction. Associated pathogenic variants in more than 300 genes have been described, leading to a detailed genetic classification partitioned by age-of-onset. Despite these advances, up to 75% of patients with ataxia remain molecularly undiagnosed even following whole genome sequencing, as exemplified in the 100,000 Genomes Project. This study aimed to understand whether we can improve our knowledge of the genetic architecture of hereditary ataxia by leveraging functional genomic annotations, and as a result, generate insights and strategies that raise the diagnostic yield. To achieve these aims, we used publicly-available multi-omics data to generate 294 genic features, capturing information relating to a gene's structure, genetic variation, tissue-specific, cell-type-specific and temporal expression, as well as protein products of a gene. We studied these features across genes typically causing childhood-onset, adult-onset or both types of disease first individually, then collectively. This led to the generation of testable hypotheses which we investigated using whole genome sequencing data from up to 2,182 individuals presenting with ataxia and 6,658 non-neurological probands recruited in the 100,000 Genomes Project. Using this approach, we demonstrated a high short tandem repeat (STR) density within childhood-onset genes suggesting that we may be missing pathogenic repeat expansions within this cohort. This was verified in both childhood- and adult-onset ataxia patients from the 100,000 Genomes Project who were unexpectedly found to have a trend for higher repeat sizes even at naturally-occurring STRs within known ataxia genes, implying a role for STRs in pathogenesis. Using unsupervised analysis, we found significant similarities in genomic annotation across the gene panels, which suggested adult- and childhood-onset patients should be screened using a common diagnostic gene set. We tested this within the 100,000 Genomes Project by assessing the burden of pathogenic variants among childhood-onset genes in adult-onset patients and vice versa. This demonstrated a significantly higher burden of rare, potentially pathogenic variants in conventional childhood-onset genes among individuals with adult-onset ataxia. Our analysis has implications for the current clinical practice in genetic testing for hereditary ataxia. We suggest that the diagnostic rate for hereditary ataxia could be increased by removing the age-of-onset partition, and through a modified screening for repeat expansions in naturally-occurring STRs within known ataxia-associated genes, in effect treating these regions as candidate pathogenic loci

Plant use of the Maasai of Sekenani Valley, Maasai Mara, Kenya

Traditional plant use is of tremendous importance in many societies, including most rural African communities. This knowledge is however, rapidly dwindling due to changes towards a more Western lifestyle, and the influence of modern tourism. In case of the Sekenani Maasai, the recent change from a nomadic to a more sedentary lifestyle has not, thus far lead to a dramatic loss of traditional plant knowledge, when compared to other Maasai communities. However, in Sekenani, plants are used much less frequently for manufacturing tools, and for veterinary purposes, than in more remote areas. While the knowledge is still present, overgrazing and over-exploitation of plant resources have already led to a decline of the plant material available. This paper examines the plant use of the Maasai in the Sekenani Valley, North of the Masaai Mara National Reserve. The Maasai pastoralists of Kenya and Tanzania use a large part of the plants in their environment for many uses in daily life. The plant use and knowledge of the Sekenani Maasai is of particular interest, as their clan, the "Il-Purko", was moved from Central Kenya to this region by the British Colonial Administration in 1904. The results of this study indicate that despite their relocation 100 years ago, the local population has an extensive knowledge of the plants in their surroundings, and they ascribe uses to a large percentage of the plants found. One-hundred-fifty-five plant species were collected, identified and their Maa names and traditional uses recorded. Although fifty-one species were reported as of "no use", only eighteen of these had no Maasai name. Thirty-three were recognized by a distinctive Maa name. Thirty-nine species had a medicinal use, and 30 species served as fodder for livestock. Six species could not be identified. Of these plants five were addressed by the Maasai with distinct names. This exemplifies the Sekenani Maasai's in-depth knowledge of the plant resources. Traditionally, the Maasai attribute most illnesses to the effect of pollutants that block or inhibit digestion. These pollutants can include "polluted" food, contact with sick people and witchcraft. In most cases the treatment of illness involves herbal purgatives to cleanse the patient. There are alsofrequent indications of plant use for common problems like wounds, parasites, body aches and burns

Deletion at ITPR1 Underlies Ataxia in Mice and Spinocerebellar Ataxia 15 in Humans

We observed a severe autosomal recessive movement disorder in mice used within our laboratory. We pursued a series of experiments to define the genetic lesion underlying this disorder and to identify a cognate disease in humans with mutation at the same locus. Through linkage and sequence analysis we show here that this disorder is caused by a homozygous in-frame 18-bp deletion in Itpr1 (Itpr1Δ18/Δ18), encoding inositol 1,4,5-triphosphate receptor 1. A previously reported spontaneous Itpr1 mutation in mice causes a phenotype identical to that observed here. In both models in-frame deletion within Itpr1 leads to a decrease in the normally high level of Itpr1 expression in cerebellar Purkinje cells. Spinocerebellar ataxia 15 (SCA15), a human autosomal dominant disorder, maps to the genomic region containing ITPR1; however, to date no causal mutations had been identified. Because ataxia is a prominent feature in Itpr1 mutant mice, we performed a series of experiments to test the hypothesis that mutation at ITPR1 may be the cause of SCA15. We show here that heterozygous deletion of the 5′ part of the ITPR1 gene, encompassing exons 1–10, 1–40, and 1–44 in three studied families, underlies SCA15 in humans

Truncating Variants in RFC1 in Cerebellar Ataxia, Neuropathy, and Vestibular Areflexia Syndrome

INTRODUCTION: Cerebellar Ataxia, Neuropathy and Vestibular Areflexia Syndrome (CANVAS) is an autosomal recessive neurodegenerative disease characterized by adult onset and slowly progressive sensory neuropathy, cerebellar dysfunction, and vestibular impairment. In most cases, the disease is caused by biallelic (AAGGG)n repeat expansions in the second intron of the Replication Factor Complex subunit 1 (RFC1). However, a small number of cases with typical CANVAS do not carry the common biallelic repeat expansion. The objective of this study was to expands the genotypic spectrum of CANVAS by identifying point mutations in RFC1 coding region associated with this condition. METHODS: Fifteen individuals diagnosed with CANVAS and carrying only one heterozygous (AAGGG)n expansion in RFC1 underwent WGS or WES to test for the presence of a second variant in RFC1 or other unrelated gene. To assess the impact of truncating variants on RFC1 expression we tested the level of RFC1 transcript and protein on patients' derived cell lines. RESULTS: We identified seven patients from five unrelated families with clinically defined CANVAS carrying a heterozygous (AAGGG)n expansion together with a second truncating variant in trans in RFC1, which included: c.1267C>T (p.Arg423Ter), c.1739_1740del (p.Lys580SerfsTer9), c.2191del (p.Gly731GlufsTer6) and c.2876del (p.Pro959GlnfsTer24). Patient fibroblasts containing the c.1267C>T (p.Arg423Ter) or c.2876del (p.Pro959GlnfsTer24) variants demonstrated nonsense-mediated mRNA decay and reduced RFC1 transcript and protein. DISCUSSION: Our report expands the genotype spectrum of RFC1 disease. Full RFC1 sequencing is recommended in cases affected by typical CANVAS and carrying monoallelic (AAGGG)n expansions. Also, it sheds further light on the pathogenesis of RFC1 CANVAS as it supports the existence of a loss of function mechanism underlying this complex neurodegenerative condition

Global Profiling of DNA Replication Timing and Efficiency Reveals that Efficient Replication/Firing Occurs Late during S-Phase in S. pombe

10.1371/journal.pone.0000722PLoS ONE2