Mechanisms of human autoimmunity Rosenblum, Michael D; Remedios, Kelly A; Abbas, Abul K
The Journal of clinical investigation,
06/2015, Letnik:
125, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Autoimmune reactions reflect an imbalance between effector and regulatory immune responses, typically develop through stages of initiation and propagation, and often show phases of resolution ...(indicated by clinical remissions) and exacerbations (indicated by symptomatic flares). The fundamental underlying mechanism of autoimmunity is defective elimination and/or control of self-reactive lymphocytes. Studies in humans and experimental animal models are revealing the genetic and environmental factors that contribute to autoimmunity. A major goal of research in this area is to exploit this knowledge to better understand the pathogenesis of autoimmune diseases and to develop strategies for reestablishing the normal balance between effector and regulatory immune responses.
Large-scale brain networks are often described using resting-state functional magnetic resonance imaging (fMRI). However, the blood oxygenation level-dependent (BOLD) signal provides an indirect ...measure of neuronal firing and reflects slow-evolving hemodynamic activity that fails to capture the faster timescale of normal physiological function. Here we used fMRI-guided transcranial magnetic stimulation (TMS) and simultaneous electroencephalography (EEG) to characterize individual brain dynamics within discrete brain networks at high temporal resolution. TMS was used to induce controlled perturbations to individually defined nodes of the default mode network (DMN) and the dorsal attention network (DAN). Source-level EEG propagation patterns were network-specific and highly reproducible across sessions 1 month apart. Additionally, individual differences in high-order cognitive abilities were significantly correlated with the specificity of TMS propagation patterns across DAN and DMN, but not with resting-state EEG dynamics. Findings illustrate the potential of TMS-EEG perturbation-based biomarkers to characterize network-level individual brain dynamics at high temporal resolution, and potentially provide further insight on their behavioral significance.
Grit Duckworth, Angela L; Peterson, Christopher; Matthews, Michael D ...
Journal of personality and social psychology,
06/2007, Letnik:
92, Številka:
6
Journal Article
Recenzirano
The importance of intellectual talent to achievement in all
professional domains is well established, but less is known
about other individual differences that predict success. The
authors tested the ...importance of 1 noncognitive trait: grit.
Defined as perseverance and passion for long-term goals,
grit accounted for an average of 4% of the variance in
success outcomes, including educational attainment among 2
samples of adults (
N
= 1,545 and
N
= 690), grade point average among Ivy
League undergraduates (
N
= 138), retention
in 2 classes of United States Military Academy, West Point,
cadets (
N
= 1,218 and
N
=
1,308), and ranking in the National Spelling Bee
(
N
= 175). Grit did not relate positively
to IQ but was highly correlated with Big Five
Conscientiousness. Grit nonetheless demonstrated incremental
predictive validity of success measures over and beyond IQ
and conscientiousness. Collectively, these findings suggest
that the achievement of difficult goals entails not only
talent but also the sustained and focused application of
talent over time.
Multiple mating or group spawning leads to post‐copulatory sexual selection, which generally favours ejaculates that are more competitive under sperm competition. In four meta‐analyses we quantify ...the evidence that sperm competition (SC) favours greater sperm number using data from studies of strategic ejaculation. Differential investment into each ejaculate emerges at the individual level if males exhibit phenotypic plasticity in ejaculate properties in response to the likely risk and/or intensity of sperm competition after a given mating. Over the last twenty years, a series of theoretical models have been developed that predict how ejaculate size will be strategically adjusted in relation to: (a) the number of immediate rival males, with a distinction made between 0 versus 1 rival (‘risk’ of SC) and 1 versus several rivals (‘intensity’ of SC); (b) female mating status (virgin or previously mated); and (c) female phenotypic quality (e.g. female size or condition). Some well‐known studies have reported large adjustments in ejaculate size depending on the relevant social context and this has led to widespread acceptance of the claim that strategic sperm allocation occurs in response to each of these factors. It is necessary, however, to test each claim separately because it is easy to overlook studies with weak or negative findings. Compiling information on the variation in outcomes among species is potentially informative about the relevance of these assumptions in different taxa or mating systems.
We found strong evidence that, on average, males transfer larger ejaculates to higher quality females. The effect of female mating status was less straightforward and depended on how ejaculate size was measured (i.e. use of proxy or direct measure). There is strong evidence that ejaculate size increased when males were exposed to a single rival, which is often described as a response to the risk of SC. There is, however, no evidence for the general prediction that ejaculate size decreases as the number of rivals increases from one to several males (i.e. in response to a higher intensity of SC which lowers the rate of return per sperm released). Our results highlight how meta‐analysis can reveal unintentional biases in narrative literature reviews. We note that several assumptions of theoretical models can alter an outcome's predicted direction in a given species (e.g. the effect of female mating status depends on whether there is first‐ or last‐male sperm priority). Many studies do not provide this background information and fail to make strong a priori predictions about the expected response of ejaculate size to manipulation of the mating context. Researchers should be explicit about which model they are testing to ensure that future meta‐analyses can better partition studies into different categories, or control for continuous moderator variables.
Caustic ingestion Chirica, Mircea, Dr; Bonavina, Luigi, Prof; Kelly, Michael D, MS ...
The Lancet (British edition),
05/2017, Letnik:
389, Številka:
10083
Journal Article
Recenzirano
Summary Corrosive ingestion is a rare but potentially devastating event and, despite the availability of effective preventive public health strategies, injuries continue to occur. Most clinicians ...have limited personal experience and rely on guidelines; however, uncertainty persists about best clinical practice. Ingestions range from mild cases with no injury to severe cases with full thickness necrosis of the oesophagus and stomach. CT scan is superior to traditional endoscopy for stratification of patients to emergency resection or observation. Oesophageal stricture is a common consequence of ingestion and newer stents show some promise; however, the place of endoscopic stenting for corrosive strictures is yet to be defined. We summarise the evidence to provide a plan for managing these potentially life-threatening injuries and discuss the areas where further research is required to improve outcomes.
Somatic mutations have been extensively characterized in breast cancer, but the effects of these genetic alterations on the proteomic landscape remain poorly understood. Here we describe quantitative ...mass-spectrometry-based proteomic and phosphoproteomic analyses of 105 genomically annotated breast cancers, of which 77 provided high-quality data. Integrated analyses provided insights into the somatic cancer genome including the consequences of chromosomal loss, such as the 5q deletion characteristic of basal-like breast cancer. Interrogation of the 5q trans-effects against the Library of Integrated Network-based Cellular Signatures, connected loss of CETN3 and SKP1 to elevated expression of epidermal growth factor receptor (EGFR), and SKP1 loss also to increased SRC tyrosine kinase. Global proteomic data confirmed a stromal-enriched group of proteins in addition to basal and luminal clusters, and pathway analysis of the phosphoproteome identified a G-protein-coupled receptor cluster that was not readily identified at the mRNA level. In addition to ERBB2, other amplicon-associated highly phosphorylated kinases were identified, including CDK12, PAK1, PTK2, RIPK2 and TLK2. We demonstrate that proteogenomic analysis of breast cancer elucidates the functional consequences of somatic mutations, narrows candidate nominations for driver genes within large deletions and amplified regions, and identifies therapeutic targets.
The kynurenine pathway (KP) of tryptophan metabolism has emerged in recent years as a key regulator of the production of both neuroprotective (e.g. kynurenic and picolinic acid, and the essential ...cofactor NAD+) and neurotoxic metabolites (e.g. quinolinic acid, 3-hydroxykynurenine). The balance between the production of the two types of metabolites is controlled by key rate-limiting enzymes such as indoleamine-2,3-dioxygenase (IDO-1), and in turn, molecular signals such as interferon-γ (IFN-γ), which activate the KP metabolism of tryptophan by this enzyme, as opposed to alternative pathways for serotonin and melatonin production. Dysregulated KP metabolism has been strongly associated with neurological diseases in recent years, and is the subject of increasing efforts to understand how the metabolites are causative of disease pathology. Concurrent with these endeavours are drug development initiatives to use inhibitors to block certain enzymes in the pathway, resulting in reduced levels of neurotoxic metabolites (e.g. quinolinic acid, an excitotoxin and N-Methyl-d-Aspartate (NMDA) receptor agonist), while in turn enhancing the bioavailability of the neuroprotective metabolites such as kynurenic acid. Neurodegenerative diseases often have a substantial autoimmune or inflammatory component; hence a greater understanding of how KP metabolites influence the inflammatory cascade is required. Additionally, challenges exist in diseases like multiple sclerosis (MS) and motor neurone disease (MND), which do not have reliable biomarkers. Clinical diagnosis can often be prolonged in order to exclude other diseases, and often diagnosis occurs at an advanced state of disease pathology, which does not allow a lengthy time for patient assessment and intervention therapies. This review considers the current evidence for involvement of the KP in several neurological diseases, in biomarkers of disease and also the parallels that exist in KP metabolism with what is known in other diseases such as HIV, Alzheimer's disease/dementia, infection, immune privilege and cardiovascular disease.
This article is part of the Special Issue entitled ‘The Kynurenine Pathway in Health and Disease’.
•KP involvement in neurological disease is complex and multifactorial.•Need to consider roles of systemic circulation and cells, as well as innate brain cells.•KP enzyme inhibitors or neutralizing antibodies are future therapeutic strategies in neurological disease.
Native Americans from the Amazon, Andes, and coastal geographic regions of South America have a rich cultural heritage but are genetically understudied, therefore leading to gaps in our knowledge of ...their genomic architecture and demographic history. In this study, we sequence 150 genomes to high coverage combined with an additional 130 genotype array samples from Native American and mestizo populations in Peru. The majority of our samples possess greater than 90% Native American ancestry, which makes this the most extensive Native American sequencing project to date. Demographic modeling reveals that the peopling of Peru began ∼12,000 y ago, consistent with the hypothesis of the rapid peopling of the Americas and Peruvian archeological data. We find that the Native American populations possess distinct ancestral divisions, whereas the mestizo groups were admixtures of multiple Native American communities that occurred before and during the Inca Empire and Spanish rule. In addition, the mestizo communities also show Spanish introgression largely following Peruvian Independence, nearly 300 y after Spain conquered Peru. Further, we estimate migration events between Peruvian populations from all three geographic regions with the majority of between-region migration moving from the high Andes to the low-altitude Amazon and coast. As such, we present a detailed model of the evolutionary dynamics which impacted the genomes of modern-day Peruvians and a Native American ancestry dataset that will serve as a beneficial resource to addressing the underrepresentation of Native American ancestry in sequencing studies.
Summary Background Neuroprotection with NA-1 (Tat-NR2B9c), an inhibitor of postsynaptic density-95 protein, has been shown in a primate model of stroke. We assessed whether NA-1 could reduce ...ischaemic brain damage in human beings. Methods For this double-blind, randomised, controlled study, we enrolled patients aged 18 years or older who had a ruptured or unruptured intracranial aneurysm amenable to endovascular repair from 14 hospitals in Canada and the USA. We used a computer-generated randomisation sequence to allocate patients to receive an intravenous infusion of either NA-1 or saline control at the end of their endovascular procedure (1:1; stratified by site, age, and aneurysm status). Both patients and investigators were masked to treatment allocation. The primary outcome was safety and primary clinical outcomes were the number and volume of new ischaemic strokes defined by MRI at 12–95 h after infusion. We used a modified intention-to-treat (mITT) analysis. This trial is registered with ClinicalTrials.gov , number NCT00728182. Findings Between Sept 16, 2008, and March 30, 2011, we randomly allocated 197 patients to treatment—12 individuals did not receive treatment because they were found to be ineligible after randomisation, so the mITT population consisted of 185 individuals, 92 in the NA-1 group and 93 in the placebo group. Two minor adverse events were adjudged to be associated with NA-1; no serious adverse events were attributable to NA-1. We recorded no difference between groups in the volume of lesions by either diffusion-weighted MRI (adjusted p value=0·120) or fluid-attenuated inversion recovery MRI (adjusted p value=0·236). Patients in the NA-1 group sustained fewer ischaemic infarcts than did patients in the placebo group, as gauged by diffusion-weighted MRI (adjusted incidence rate ratio 0·53, 95% CI 0·38–0·74) and fluid-attenuated inversion recovery MRI (0·59, 0·42–0·83). Interpretation Our findings suggest that neuroprotection in human ischaemic stroke is possible and that it should be investigated in larger trials. Funding NoNO Inc and Arbor Vita Corp.
We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). The LSST design is driven by four main science themes: probing dark energy and ...dark matter, taking an inventory of the solar system, exploring the transient optical sky, and mapping the Milky Way. LSST will be a large, wide-field ground-based system designed to obtain repeated images covering the sky visible from Cerro Pachón in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg2 field of view, a 3.2-gigapixel camera, and six filters (ugrizy) covering the wavelength range 320-1050 nm. The project is in the construction phase and will begin regular survey operations by 2022. About 90% of the observing time will be devoted to a deep-wide-fast survey mode that will uniformly observe a 18,000 deg2 region about 800 times (summed over all six bands) during the anticipated 10 yr of operations and will yield a co-added map to r ∼ 27.5. These data will result in databases including about 32 trillion observations of 20 billion galaxies and a similar number of stars, and they will serve the majority of the primary science programs. The remaining 10% of the observing time will be allocated to special projects such as Very Deep and Very Fast time domain surveys, whose details are currently under discussion. We illustrate how the LSST science drivers led to these choices of system parameters, and we describe the expected data products and their characteristics.
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