76 research outputs found
Genome-wide homozygosity and multiple sclerosis in Orkney and Shetland Islanders
There is strong evidence for both genetic and environmental risk factors comprising the aetiology of multiple sclerosis (MS). While much progress has been made in recent years in identifying common genetic variants using genome-wide association studies, alternative approaches have remained relatively neglected. The prevalence of MS in Orkney and Shetland is among the highest in the world. Previous studies have suggested that a higher degree of parental relatedness in these isolated communities may contribute to the high rates of MS, indicating that recessive effects have an important role in MS aetiology. The Northern Isles Multiple Sclerosis (NIMS) study investigated the potential role of genome-wide homozygosity in MS risk by genotyping 88 MS patients, 89 controls matched by age, sex and ancestry, and a further 89 controls matched for sex and ancestry, but passed the majority of lifetime risk of developing MS (>70 years of age). Three participants were removed on the basis of pedigree-genomic anomalies (n=263). Three measures of genome-wide homozygosity were generated for each individual, and association with MS was assessed using logistic regression models. No effect of genome-wide homozygosity was detected, indicating that inbreeding and consanguinity are not risk factors for MS in this population
Gold Nanoparticle Delivery of Modified CpG Stimulates Macrophages and Inhibits Tumor Growth for Enhanced Immunotherapy
Gold nanoparticle accumulation in immune cells has commonly been viewed as a side effect for cancer therapeutic delivery;
however, this phenomenon can be utilized for developing gold nanoparticle mediated immunotherapy. Here, we
conjugated a modified CpG oligodeoxynucleotide immune stimulant to gold nanoparticles using a simple and scalable selfassembled
monolayer scheme that enhanced the functionality of CpG in vitro and in vivo. Nanoparticles can attenuate
systemic side effects by enhancing CpG delivery passively to innate effector cells. The use of a triethylene glycol (TEG) spacer
on top of the traditional poly-thymidine spacer increased CpG macrophage stimulatory effects without sacrificing DNA
content on the nanoparticle, which directly correlates to particle uptake. In addition, the immune effects of modified CpGAuNPs
were altered by the core particle size, with smaller 15 nm AuNPs generating maximum immune response. These TEG
modified CpG-AuNP complexes induced macrophage and dendritic cell tumor infiltration, significantly inhibited tumor
growth, and promoted survival in mice when compared to treatments with free CpG
A warm Jupiter transiting an M dwarf: A TESS single transit event confirmed with the Habitable-zone Planet Finder
We confirm the planetary nature of a warm Jupiter transiting the early M
dwarf TOI-1899, using a combination of available TESS photometry;
high-precision, near-infrared spectroscopy with the Habitable-zone Planet
Finder; and speckle and adaptive optics imaging. The data reveal a transiting
companion on an -day orbit with a mass and radius of $0.66\pm0.07\
\mathrm{M_{J}}1.15_{-0.05}^{+0.04}\ \mathrm{R_{J}}\mathrm{T_{eq}}\sim362$ K) gas giant orbiting an M0 star. Our observations
reveal that TOI-1899.01 is a puffy warm Jupiter, and we suggest additional
transit observations to both refine the orbit and constrain the true dilution
observed in TESS.Comment: 24 pages, 5 figures, 3 tables, published in A
Alterations in cerebral blood flow and cerebrovascular reactivity during 14 days at 5050 m
Upon ascent to high altitude, cerebral blood flow (CBF) rises substantially before returning to sea-level values. The underlying mechanisms for these changes are unclear. We examined three hypotheses: (1) the balance of arterial blood gases upon arrival at and across 2 weeks of living at 5050 m will closely relate to changes in CBF; (2) CBF reactivity to steady-state changes in CO2 will be reduced following this 2 week acclimatisation period, and (3) reductions in CBF reactivity to CO2 will be reflected in an augmented ventilatory sensitivity to CO2. We measured arterial blood gases, middle cerebral artery blood flow velocity (MCAv, index of CBF) and ventilation () at rest and during steady-state hyperoxic hypercapnia (7% CO2) and voluntary hyperventilation (hypocapnia) at sea level and then again following 2–4, 7–9 and 12–15 days of living at 5050 m. Upon arrival at high altitude, resting MCAv was elevated (up 31 ± 31%; P < 0.01; vs. sea level), but returned to sea-level values within 7–9 days. Elevations in MCAv were strongly correlated (R2= 0.40) with the change in ratio (i.e. the collective tendency of arterial blood gases to cause CBF vasodilatation or constriction). Upon initial arrival and after 2 weeks at high altitude, cerebrovascular reactivity to hypercapnia was reduced (P < 0.05), whereas hypocapnic reactivity was enhanced (P < 0.05 vs. sea level). Ventilatory response to hypercapnia was elevated at days 2–4 (P < 0.05 vs. sea level, 4.01 ± 2.98 vs. 2.09 ± 1.32 l min−1 mmHg−1). These findings indicate that: (1) the balance of arterial blood gases accounts for a large part of the observed variability (∼40%) leading to changes in CBF at high altitude; (2) cerebrovascular reactivity to hypercapnia and hypocapnia is differentially affected by high-altitude exposure and remains distorted during partial acclimatisation, and (3) alterations in cerebrovascular reactivity to CO2 may also affect ventilatory sensitivity
Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial
Background
Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy
Mutations in TOP3A Cause a Bloom Syndrome-like Disorder
Bloom syndrome, caused by biallelic mutations in BLM, is characterized by prenatal-onset growth deficiency, short stature, an erythematous photosensitive malar rash, and increased cancer predisposition. Diagnostically, a hallmark feature is the presence of increased sister chromatid exchanges (SCEs) on cytogenetic testing. Here, we describe biallelic mutations in TOP3A in ten individuals with prenatal-onset growth restriction and microcephaly. TOP3A encodes topoisomerase III alpha (TopIIIα), which binds to BLM as part of the BTRR complex, and promotes dissolution of double Holliday junctions arising during homologous recombination. We also identify a homozygous truncating variant in RMI1, which encodes another component of the BTRR complex, in two individuals with microcephalic dwarfism. The TOP3A mutations substantially reduce cellular levels of TopIIIα, and consequently subjects’ cells demonstrate elevated rates of SCE. Unresolved DNA recombination and/or replication intermediates persist into mitosis, leading to chromosome segregation defects and genome instability that most likely explain the growth restriction seen in these subjects and in Bloom syndrome. Clinical features of mitochondrial dysfunction are evident in several individuals with biallelic TOP3A mutations, consistent with the recently reported additional function of TopIIIα in mitochondrial DNA decatenation. In summary, our findings establish TOP3A mutations as an additional cause of prenatal-onset short stature with increased cytogenetic SCEs and implicate the decatenation activity of the BTRR complex in their pathogenesis
Haematopoietic stem cells in perisinusoidal niches are protected from ageing.
With ageing, intrinsic haematopoietic stem cell (HSC) activity decreases, resulting in impaired tissue homeostasis, reduced engraftment following transplantation and increased susceptibility to diseases. However, whether ageing also affects the HSC niche, and thereby impairs its capacity to support HSC function, is still widely debated. Here, by using in-vivo long-term label-retention assays we demonstrate that aged label-retaining HSCs, which are, in old mice, the most quiescent HSC subpopulation with the highest regenerative capacity and cellular polarity, reside predominantly in perisinusoidal niches. Furthermore, we demonstrate that sinusoidal niches are uniquely preserved in shape, morphology and number on ageing. Finally, we show that myeloablative chemotherapy can selectively disrupt aged sinusoidal niches in the long term, which is linked to the lack of recovery of endothelial Jag2 at sinusoids. Overall, our data characterize the functional alterations of the aged HSC niche and unveil that perisinusoidal niches are uniquely preserved and thereby protect HSCs from ageing
Stress and worry in the 2020 coronavirus pandemic : relationships to trust and compliance with preventive measures across 48 countries in the COVIDiSTRESS global survey
The COVIDiSTRESS global survey collects data on early human responses to the 2020 COVID-19 pandemic from 173 429 respondents in 48 countries. The open science study was co-designed by an international consortium of researchers to investigate how psychological responses differ across countries and cultures, and how this has impacted behaviour, coping and trust in government efforts to slow the spread of the virus. Starting in March 2020, COVIDiSTRESS leveraged the convenience of unpaid online recruitment to generate public data. The objective of the present analysis is to understand relationships between psychological responses in the early months of global coronavirus restrictions and help understand how different government measures succeed or fail in changing public behaviour. There were variations between and within countries. Although Western Europeans registered as more concerned over COVID-19, more stressed, and having slightly more trust in the governments' efforts, there was no clear geographical pattern in compliance with behavioural measures. Detailed plots illustrating between-countries differences are provided. Using both traditional and Bayesian analyses, we found that individuals who worried about getting sick worked harder to protect themselves and others. However, concern about the coronavirus itself did not account for all of the variances in experienced stress during the early months of COVID-19 restrictions. More alarmingly, such stress was associated with less compliance. Further, those most concerned over the coronavirus trusted in government measures primarily where policies were strict. While concern over a disease is a source of mental distress, other factors including strictness of protective measures, social support and personal lockdown conditions must also be taken into consideration to fully appreciate the psychological impact of COVID-19 and to understand why some people fail to follow behavioural guidelines intended to protect themselves and others from infection. The Stage 1 manuscript associated with this submission received in-principle acceptance (IPA) on 18 May 2020. Following IPA, the accepted Stage 1 version of the manuscript was preregistered on the Open Science Framework at https://osf.io/g2t3b. This preregistration was performed prior to data analysis.Peer reviewe
Residual cancer burden after neoadjuvant chemotherapy and long-term survival outcomes in breast cancer: a multicentre pooled analysis of 5161 patients
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