Atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) are associated with dysregulation and overactivation of the complement alternative pathway. Typically, gene analysis for aHUS and ...C3G is undertaken in small patient numbers, yet it is unclear which genes most frequently predispose to aHUS or C3G. Accordingly, we performed a six-center analysis of 610 rare genetic variants in 13 mostly complement genes (
,
,
,
,
,
,
,
,
,
,
,
, and
) from >3500 patients with aHUS and C3G. We report 371 novel rare variants (RVs) for aHUS and 82 for C3G. Our new interactive Database of Complement Gene Variants was used to extract allele frequency data for these 13 genes using the Exome Aggregation Consortium server as the reference genome. For aHUS, significantly more protein-altering rare variation was found in five genes
,
,
,
, and
than in the Exome Aggregation Consortium (allele frequency < 0.01%), thus correlating these with aHUS. For C3G, an association was only found for RVs in
and the N-terminal C3b-binding or C-terminal nonsurface-associated regions of
In conclusion, the RV analyses showed nonrandom distributions over the affected proteins, and different distributions were observed between aHUS and C3G that clarify their phenotypes.
International collaboration is becoming increasingly important for the advancement of science. To gain a more precise understanding of how factors such as international collaboration influence ...publication success, we divide publication success into two categories: journal placement and citation performance. Analyzing all papers published between 1996 and 2012 in eight disciplines, we find that those with more countries in their affiliations performed better in both categories. Furthermore, specific countries vary in their effects both individually and in combination. Finally, we look at the relationship between national output (in papers published) and input (in citations received) over the 17 years, expanding upon prior depictions by also plotting an expected proportion of citations based on Journal Placement. Discrepancies between this expectation and the realized proportion of citations illuminate trends in performance, such as the decline of the Global North in response to rapidly developing countries, especially China. Yet, most countries' show little to no discrepancy, meaning that, in most cases, citation proportion can be predicted by Journal Placement alone. This reveals an extreme asymmetry between the opinions of a few reviewers and the degree to which paper acceptance and citation rates influence career advancement.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hearing impairment is the most common sensory disorder, present in 1 of every 500 newborns. With 46 genes implicated in nonsyndromic hearing loss, it is also an extremely heterogeneous trait. Here, ...we categorize for the first time all mutations reported in nonsyndromic deafness genes, both worldwide and more specifically in Caucasians. The most frequent genes implicated in autosomal recessive nonsyndromic hearing loss are GJB2, which is responsible for more than half of cases, followed by SLC26A4, MYO15A, OTOF, CDH23 and TMC1. None of the genes associated with autosomal dominant nonsyndromic hearing loss accounts for a preponderance of cases, although mutations are somewhat more frequently reported in WFS1, KCNQ4, COCH and GJB2. Only a minority of these genes is currently included in genetic diagnostics, the selection criteria typically reflecting: (1) high frequency as a cause of deafness (i.e. GJB2); (2) association with another recognisable feature (i.e. SLC26A4 and enlarged vestibular aqueduct); or (3) a recognisable audioprofile (i.e. WFS1). New and powerful DNA sequencing technologies have been developed over the past few years, but have not yet found their way into DNA diagnostics. Implementing these technologies is likely to happen within the next 5 years, and will cause a breakthrough in terms of power and cost efficiency. It will become possible to analyze most – if not all – deafness genes, as opposed to one or a few genes currently. This ability will greatly improve DNA diagnostics, provide epidemiological data on gene-based mutation frequencies, and reveal novel genotype–phenotype correlations.
Summary
Microcystis is a cyanobacterium that forms toxic blooms in freshwater ecosystems around the world. Biological variation among taxa within the genus is apparent through genetic and phenotypic ...differences between strains and via the spatial and temporal distribution of strains in the environment, and this fine‐scale diversity exerts strong influence over bloom toxicity. Yet we do not know how varying traits of Microcystis strains govern their environmental distribution, the tradeoffs and links between these traits, or how they are encoded at the genomic level. Here we synthesize current knowledge on the importance of diversity within Microcystis and on the genes and traits that likely underpin ecological differentiation of taxa. We briefly review spatial and environmental patterns of Microcystis diversity in the field and genetic evidence for cohesive groups within Microcystis. We then compile data on strain‐level diversity regarding growth responses to environmental conditions and explore evidence for variation of community interactions across Microcystis strains. Potential links and tradeoffs between traits are identified and discussed. The resulting picture, while incomplete, highlights key knowledge gaps that need to be filled to enable new models for predicting strain‐level dynamics, which influence the development, toxicity and cosmopolitan nature of Microcystis blooms.
Animal metacognition is an active, growing research area, and one part of metacognition is flexible information-seeking behavior. In Roberts et al. (2009), pigeons failed an intuitive ...information-seeking task. They basically refused, despite multiple fostering experiments, to view a sample image before attempting to find its match. Roberts et al. concluded that pigeons’ lack of an information-seeking capacity reflected their broader lack of metacognition. We report a striking species contrast to pigeons. Eight rhesus macaques and seven capuchin monkeys passed the Roberts et al. test of information seeking—often in their first testing session. Members of both primate species appreciated immediately the lack of information signaled by an occluded sample, and the need for an information-seeking response to manage the situation. In subsequent testing, macaques demonstrated flexible/varied forms of information management. Capuchins did not. The research findings bear on the phylogenetic distribution of metacognition across the vertebrates, and on the underlying psychological requirements for metacognitive and information-seeking performances.
Aging is associated with decreased cognitive function. One theory posits that this decline is in part due to multiple neural systems becoming dedifferentiated in older adults. Exercise is known to ...improve cognition in older adults, even after only a single session. We hypothesized that one mechanism of improvement is a redifferentiation of neural systems. We used a within-participant, cross-over design involving 2 sessions: either 30 minutes of aerobic exercise or 30 minutes of seated rest (n = 32; ages 55–81 years). Both functional Magnetic Resonance Imaging (fMRI) and Stroop performance were acquired soon after exercise and rest. We quantified neural differentiation via general heterogeneity regression. There were 3 prominent findings following the exercise. First, participants were better at reducing Stroop interference. Second, while there was greater neural differentiation within the hippocampal formation and cerebellum, there was lower neural differentiation within frontal cortices. Third, this greater neural differentiation in the cerebellum and temporal lobe was more pronounced in the older ages. These data suggest that exercise can induce greater neural differentiation in healthy aging.
Transport of solutes through brain involves diffusion and convection. The importance of convective flow in the subarachnoid and paravascular spaces has long been recognized; a recently proposed ...'glymphatic' clearance mechanism additionally suggests that aquaporin-4 (AQP4) water channels facilitate convective transport through brain parenchyma. Here, the major experimental underpinnings of the glymphatic mechanism were re-examined by measurements of solute movement in mouse brain following intracisternal or intraparenchymal solute injection. We found that: (i) transport of fluorescent dextrans in brain parenchyma depended on dextran size in a manner consistent with diffusive rather than convective transport; (ii) transport of dextrans in the parenchymal extracellular space, measured by 2-photon fluorescence recovery after photobleaching, was not affected just after cardiorespiratory arrest; and (iii)
gene deletion did not impair transport of fluorescent solutes from sub-arachnoid space to brain in mice or rats. Our results do not support the proposed glymphatic mechanism of convective solute transport in brain parenchyma.
Community screening to guide preventive interventions for acute aortic disease has been recommended in high-risk individuals. We sought to prospectively assess risk factors in the general population ...for aortic dissection (AD) and severe aneurysmal disease in the thoracic and abdominal aorta.
We studied the incidence of AD and ruptured or surgically treated aneurysms in the abdominal (AAA) or thoracic aorta (TAA) in 30 412 individuals without diagnosis of aortic disease at baseline from a contemporary, prospective cohort of middle-aged individuals, the Malmö Diet and Cancer study. During up to 20 years of follow-up (median 16 years), the incidence rate per 100 000 patient-years at risk was 15 (95% CI 11.7 to 18.9) for AD, 27 (95% CI 22.5 to 32.1) for AAA, and 9 (95% CI 6.8 to 12.6) for TAA. The acute and in-hospital mortality was 39% for AD, 34% for ruptured AAA, and 41% for ruptured TAA. Hypertension was present in 86% of individuals who subsequently developed AD, was strongly associated with incident AD (hazard ratio HR 2.64, 95% CI 1.33 to 5.25), and conferred a population-attributable risk of 54%. Hypertension was also a risk factor for AAA with a smaller effect. Smoking (HR 5.07, 95% CI 3.52 to 7.29) and high apolipoprotein B/A1 ratio (HR 2.48, 95% CI 1.73 to 3.54) were strongly associated with AAA and conferred a population-attributable risk of 47% and 25%, respectively. Smoking was also a risk factor for AD and TAA with smaller effects.
This large prospective study identified distinct risk factor profiles for different aortic diseases in the general population. Hypertension accounted for more than half of the population risk for AD, and smoking for half of the population risk of AAA.
Increasing evidence for an elaborate subglacial drainage network underneath modern Antarctic ice sheets suggests that basal meltwater has an important influence on ice stream flow. Swath bathymetry ...surveys from previously glaciated continental margins display morphological features indicative of subglacial meltwater flow in inner shelf areas of some paleo ice stream troughs. Over the last few years several expeditions to the eastern Amundsen Sea embayment (West Antarctica) have investigated the paleo ice streams that extended from the Pine Island and Thwaites glaciers. A compilation of high-resolution swath bathymetry data from inner Pine Island Bay reveals details of a rough seabed topography including several deep channels that connect a series of basins. This complex basin and channel network is indicative of meltwater flow beneath the paleo-Pine Island and Thwaites ice streams, along with substantial subglacial water inflow from the east. This meltwater could have enhanced ice flow over the rough bedrock topography. Meltwater features diminish with the onset of linear features north of the basins. Similar features have previously been observed in several other areas, including the Dotson-Getz Trough (western Amundsen Sea embayment) and Marguerite Bay (SW Antarctic Peninsula), suggesting that these features may be widespread around the Antarctic margin and that subglacial meltwater drainage played a major role in past ice-sheet dynamics.
The human cerebral cortex develops through an elaborate succession of cellular events that, when disrupted, can lead to neuropsychiatric disease. The ability to reprogram somatic cells into ...pluripotent cells that can be differentiated in vitro provides a unique opportunity to study normal and abnormal corticogenesis. Here, we present a simple and reproducible 3D culture approach for generating a laminated cerebral cortex-like structure, named human cortical spheroids (hCSs), from pluripotent stem cells. hCSs contain neurons from both deep and superficial cortical layers and map transcriptionally to in vivo fetal development. These neurons are electrophysiologically mature, display spontaneous activity, are surrounded by nonreactive astrocytes and form functional synapses. Experiments in acute hCS slices demonstrate that cortical neurons participate in network activity and produce complex synaptic events. These 3D cultures should allow a detailed interrogation of human cortical development, function and disease, and may prove a versatile platform for generating other neuronal and glial subtypes in vitro.
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