99 research outputs found
Measuring the total infrared light from galaxy clusters at z=0.5-1.6: connecting stellar populations to dusty star formation
Massive galaxy clusters undergo strong evolution from z~1.6 to z~0.5, with
overdense environments at high-z characterized by abundant dust-obscured star
formation and stellar mass growth which rapidly give way to widespread
quenching. Data spanning the near- to far-infrared (IR) spectrum can directly
trace this transformation; however, such studies have largely been limited to
the massive galaxy end of cluster populations. In this work, we present ``total
light" stacking techniques spanning 3.4-500{\mu}m aimed at revealing the total
cluster IR emission, including low mass members and potential intracluster
dust. We detail our procedures for WISE, Spitzer, and Herschel imaging,
including corrections to recover the total stacked emission in the case of high
fractions of detected galaxies. We apply our stacking techniques to 232
well-studied massive (log M200/Msun~13.8) clusters across multiple z bins,
recovering extended cluster emission at all wavelengths, typically at >5sigma.
We measure the averaged near- to far-IR radial profiles and SEDs, quantifying
the total stellar and dust content. The near-IR radial profiles are well
described by an NFW model with a high (c~7) concentration parameter. Dust
emission is similarly concentrated, albeit suppressed at small radii
(r<0.2Mpc). The measured SEDs lack warm dust, consistent with the colder SEDs
expected for low mass galaxies. We derive total stellar masses consistent with
the theoretical Mhalo-M_star relation and specific-star formation rates that
evolve strongly with redshift, echoing that of massive (log Mstar/Msun>10)
cluster galaxies. Separating out the massive galaxy population reveals that the
majority of cluster far-IR emission (~70-80%) is provided by the low mass
constituents, which differs from field galaxies. This effect may be a
combination of mass-dependent quenching and excess dust in low mass cluster
galaxies.Comment: 32 pages, 16 figures, 7 tables. Submitted to MNRAS, comments welcome
FTO Obesity Variant Circuitry and Adipocyte Browning in Humans
Background
Genomewide association studies can be used to identify disease-relevant genomic regions, but interpretation of the data is challenging. The FTO region harbors the strongest genetic association with obesity, yet the mechanistic basis of this association remains elusive.
Methods
We examined epigenomic data, allelic activity, motif conservation, regulator expression, and gene coexpression patterns, with the aim of dissecting the regulatory circuitry and mechanistic basis of the association between the FTO region and obesity. We validated our predictions with the use of directed perturbations in samples from patients and from mice and with endogenous CRISPRâCas9 genome editing in samples from patients.
Results
Our data indicate that the FTO allele associated with obesity represses mitochondrial thermogenesis in adipocyte precursor cells in a tissue-autonomous manner. The rs1421085 T-to-C single-nucleotide variant disrupts a conserved motif for the ARID5B repressor, which leads to derepression of a potent preadipocyte enhancer and a doubling of IRX3 and IRX5 expression during early adipocyte differentiation. This results in a cell-autonomous developmental shift from energy-dissipating beige (brite) adipocytes to energy-storing white adipocytes, with a reduction in mitochondrial thermogenesis by a factor of 5, as well as an increase in lipid storage. Inhibition of Irx3 in adipose tissue in mice reduced body weight and increased energy dissipation without a change in physical activity or appetite. Knockdown of IRX3 or IRX5 in primary adipocytes from participants with the risk allele restored thermogenesis, increasing it by a factor of 7, and overexpression of these genes had the opposite effect in adipocytes from nonrisk-allele carriers. Repair of the ARID5B motif by CRISPRâCas9 editing of rs1421085 in primary adipocytes from a patient with the risk allele restored IRX3 and IRX5 repression, activated browning expression programs, and restored thermogenesis, increasing it by a factor of 7.
Conclusions
Our results point to a pathway for adipocyte thermogenesis regulation involving ARID5B, rs1421085, IRX3, and IRX5, which, when manipulated, had pronounced pro-obesity and anti-obesity effects. (Funded by the German Research Center for Environmental Health and others.)National Institutes of Health (U.S.) (R01HG004037)National Institutes of Health (U.S.) (R01GM113708)National Institutes of Health (U.S.) (R01HG008155)National Institutes of Health (U.S.) (RC1HG005334
The Role of Epidemiology in the Introduction of Vi Polysaccharide Typhoid Fever Vaccines in Asia
Despite the availability of at least two licensed typhoid fever
vaccines-injectable sub-unit Vi polysaccharide vaccine and live, oral
Ty21a vaccine-for the last decade, these vaccines have not been widely
introduced in public-health programmes in countries endemic for typhoid
fever. The goal of the multidisciplinary DOMI (Diseases of the Most
Impoverished) typhoid fever programme is to generate policy-relevant
data to support public decision-making regarding the introduction of Vi
polysaccharide typhoid fever immunization programmes in China, Viet
Nam, Pakistan, India, Bangladesh, and Indonesia. Through
epidemiological studies, the DOMI Programme is generating these data
and is offering a model for the accelerated, rational introduction of
new vaccines into health programmes in low-income countries. Practical
and specific examples of the role of epidemiology are described in this
paper. These examples cover: (a) selection of available typhoid fever
vaccines to be introduced in the programme, (b) generation of
policy-relevant data, (c) providing the 'backbone' for the
implementation of other multidisciplinary projects, and (d) generation
of unexpected but useful information relevant for the introduction of
vaccines. Epidemiological studies contribute to all stages of
development of vaccine evaluation and introduction
A retrospective analysis of second-line chemotherapy in patients with advanced gastric cancer
<p>Abstract</p> <p>Background</p> <p>Because treatment of advanced gastric cancer (AGC) patients after failure with first-line chemotherapy remains controversial, we performed this retrospective analysis based on the data obtained from 1455 patients registered in a first-line treatment cohort with respect to receiving or not receiving subsequent chemotherapy.</p> <p>Methods</p> <p>The decision for administering second-line chemotherapy was, in most cases, at the discretion of the physician. Seven-hundred twenty-five (50%) received second-line chemotherapy after first-line failure. Univariate and multivariate analyses were performed on the recognized baseline parameters for survival.</p> <p>Results</p> <p>At the time of initiating second-line chemotherapy, the patients' median age was 56 years (range, 22 to 86) and 139 (19%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or more. Seven (1%) complete and 108 (15%) partial responses to second-line chemotherapy were observed for an overall response rate of 16% (95% confidence interval [CI], 13 to 19%). The median progression-free and overall survivals, calculated from the start of second-line chemotherapy, were 2.9 months (95% CI, 2.6 to 3.3) and 6.7 months (95% CI, 5.8 to 7.5), respectively. Multivariate analysis revealed that low baseline hemoglobin level (hazard ratio [HR], 0.74; 95% CI 0.61â0.90) and a poor performance status (HR, 0.66; 95% CI, 0.52â0.83) were independent negative prognostic factors for overall survival.</p> <p>Conclusion</p> <p>Performance status, along with baseline hemoglobin level, could be used to identify the subgroup of patients most likely to benefit from second-line chemotherapy for AGC.</p
The 5p15.33 Locus Is Associated with Risk of Lung Adenocarcinoma in Never-Smoking Females in Asia
Genome-wide association studies of lung cancer reported in populations of European background have identified three regions on chromosomes 5p15.33, 6p21.33, and 15q25 that have achieved genome-wide significance with p-values of 10â7 or lower. These studies have been performed primarily in cigarette smokers, raising the possibility that the observed associations could be related to tobacco use, lung carcinogenesis, or both. Since most women in Asia do not smoke, we conducted a genome-wide association study of lung adenocarcinoma in never-smoking females (584 cases, 585 controls) among Han Chinese in Taiwan and found that the most significant association was for rs2736100 on chromosome 5p15.33 (pâ=â1.30Ă10â11). This finding was independently replicated in seven studies from East Asia totaling 1,164 lung adenocarcinomas and 1,736 controls (pâ=â5.38Ă10â11). A pooled analysis achieved genome-wide significance for rs2736100. This SNP marker localizes to the CLPTM1L-TERT locus on chromosome 5p15.33 (pâ=â2.60Ă10â20, allelic riskâ=â1.54, 95% Confidence Interval (CI) 1.41â1.68). Risks for heterozygote and homozygote carriers of the minor allele were 1.62 (95% CI; 1.40â1.87), and 2.35 (95% CI: 1.95â2.83), respectively. In summary, our results show that genetic variation in the CLPTM1L-TERT locus of chromosome 5p15.33 is directly associated with the risk of lung cancer, most notably adenocarcinoma
Association of the PHACTR1/EDN1 genetic locus with spontaneous coronary artery dissection
Background:
Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene.
Objectives:
This study sought to test the association between the rs9349379 genotype and SCAD.
Methods:
Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD.
Results:
The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence.
Conclusions:
The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD
Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches
Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly
Ranbp2 haploinsufficiency mediates distinct cellular and biochemical phenotypes in brain and retinal dopaminergic and glia cells elicited by the Parkinsonian neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
25th annual computational neuroscience meeting: CNS-2016
The same neuron may play different functional roles in the neural circuits to which it belongs. For example, neurons in the Tritonia pedal ganglia may participate in variable phases of the swim motor rhythms [1]. While such neuronal functional variability is likely to play a major role the delivery of the functionality of neural systems, it is difficult to study it in most nervous systems. We work on the pyloric rhythm network of the crustacean stomatogastric ganglion (STG) [2]. Typically network models of the STG treat neurons of the same functional type as a single model neuron (e.g. PD neurons), assuming the same conductance parameters for these neurons and implying their synchronous firing [3, 4]. However, simultaneous recording of PD neurons shows differences between the timings of spikes of these neurons. This may indicate functional variability of these neurons. Here we modelled separately the two PD neurons of the STG in a multi-neuron model of the pyloric network. Our neuron models comply with known correlations between conductance parameters of ionic currents. Our results reproduce the experimental finding of increasing spike time distance between spikes originating from the two model PD neurons during their synchronised burst phase. The PD neuron with the larger calcium conductance generates its spikes before the other PD neuron. Larger potassium conductance values in the follower neuron imply longer delays between spikes, see Fig. 17.Neuromodulators change the conductance parameters of neurons and maintain the ratios of these parameters [5]. Our results show that such changes may shift the individual contribution of two PD neurons to the PD-phase of the pyloric rhythm altering their functionality within this rhythm. Our work paves the way towards an accessible experimental and computational framework for the analysis of the mechanisms and impact of functional variability of neurons within the neural circuits to which they belong
Understanding the social determinants of health among Indigenous Canadians: priorities for health promotion policies and actions
Background: Indigenous Canadians have a life expectancy 12 years lower than the national average and experience higher rates of preventable chronic diseases compared with non-Indigenous Canadians. Transgenerational trauma from past assimilation policies have affected the health of Indigenous populations. Objective: The purpose of this paper is to comprehensively examine the social determinants of health (SDH), in order to identify priorities for health promotion policies and actions. Design: We undertook a series of systematic reviews focusing on four major SDH (i.e. income, education, employment, and housing) among Indigenous peoples in Alberta, following the protocol Preferred Reporting Items for Systematic Reviews and Meta-Analysis-Equity. Results: We found that the four SDH disproportionately affect the health of Indigenous peoples. Our systematic review highlighted 1) limited information regarding relationships and interactions among income, personal and social circumstances, and health outcomes; 2) limited knowledge of factors contributing to current housing status and its impacts on health outcomes; and 3) the limited number of studies involving the barriers to, and opportunities for, education. Conclusions: These findings may help to inform efforts to promote health equity and improve health outcomes of Indigenous Canadians. However, there is still a great need for in-depth subgroup studies to understand SDH (e.g. age, Indigenous ethnicity, dwelling area, etc.) and intersectoral collaborations (e.g. community and various government departments) to reduce health disparities faced by Indigenous Canadians
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