The generation of high-affinity Abs is essential for immunity and requires collaboration between B and T cells within germinal centers (GCs). By using novel mouse models with a conditional deletion ...of the p110δ catalytic subunit of the PI3K pathway, we established that p110δ is required in T cells, but not in B cells, for the GC reaction. We found the formation of T follicular helper (T(FH)) cells to be critically dependent on p110δ in T cells. Furthermore, by deleting phosphatase and tensin homolog deleted on chromosome 10, which opposes p110δ in activated T cells, we found a positive correlation between increased numbers of T(FH) cells and GC B cells. These results are consistent with the hypothesis that T cell help is the limiting factor in the GC reaction. P110δ was not required for the expression of B cell lymphoma 6, the downregulation of CCR7, or T cell entry into primary follicles. Instead, p110δ was the critical catalytic subunit for ICOS downstream signaling and the production of key T(FH) cytokines and effector molecules. Our findings support a model in which the magnitude of the GC reaction is controlled by the activity of the PI3K pathway in T(FH) cells.
Prevalence ranges to classify levels of wasting and stunting have been used since the 1990s for global monitoring of malnutrition. Recent developments prompted a re-examination of existing ranges and ...development of new ones for childhood overweight. The present paper reports from the WHO-UNICEF Technical Expert Advisory Group on Nutrition Monitoring.
Thresholds were developed in relation to sd of the normative WHO Child Growth Standards. The international definition of 'normal' (2 sd below/above the WHO standards median) defines the first threshold, which includes 2·3 % of the area under the normalized distribution. Multipliers of this 'very low' level (rounded to 2·5 %) set the basis to establish subsequent thresholds. Country groupings using the thresholds were produced using the most recent set of national surveys.
One hundred and thirty-four countries.
Children under 5 years.
For wasting and overweight, thresholds are: 'very low' (≈6 times 2·5 %). For stunting, thresholds are: 'very low' (≈12 times 2·5 %).
The proposed thresholds minimize changes and keep coherence across anthropometric indicators. They can be used for descriptive purposes to map countries according to severity levels; by donors and global actors to identify priority countries for action; and by governments to trigger action and target programmes aimed at achieving 'low' or 'very low' levels. Harmonized terminology will help avoid confusion and promote appropriate interventions.
Comprehensive benchmarking of clustering algorithms is rendered difficult by two key factors: 1) the elusiveness of a unique mathematical definition of this unsupervised learning approach and 2) ...dependencies between the generating models or clustering criteria adopted by some clustering algorithms and indices for internal cluster validation. Consequently, there is no consensus regarding the best practice for rigorous benchmarking, and whether this is possible at all outside the context of a given application. Here, we argue that synthetic datasets must continue to play an important role in the evaluation of clustering algorithms, but that this necessitates constructing benchmarks that appropriately cover the diverse set of properties that impact clustering algorithm performance. Through our framework, HAWKS, we demonstrate the important role evolutionary algorithms play to support flexible generation of such benchmarks, allowing simple modification and extension. We illustrate two possible uses of our framework: 1) the evolution of benchmark data consistent with a set of hand-derived properties and 2) the generation of datasets that tease out performance differences between a given pair of algorithms. Our work has implications for the design of clustering benchmarks that sufficiently challenge a broad range of algorithms, and for furthering insight into the strengths and weaknesses of specific approaches.
In the last decade, the view of circadian oscillators has expanded from transcriptional feedback to incorporate post-transcriptional, post-translational, metabolic processes and ionic signalling. In ...plants and animals, there are circadian oscillations in the concentration of cytosolic free Ca
(Ca
), though their purpose has not been fully characterized. We investigated whether circadian oscillations of Ca
regulate the circadian oscillator of Arabidopsis thaliana. We report that in Arabidopsis, Ca
circadian oscillations can regulate circadian clock function through the Ca
-dependent action of CALMODULIN-LIKE24 (CML24). Genetic analyses demonstrate a linkage between CML24 and the circadian oscillator, through pathways involving the circadian oscillator gene TIMING OF CAB2 EXPRESSION1 (TOC1).
Pyrin responds to pathogen signals and loss of cellular homeostasis by forming an inflammasome complex that drives the cleavage and secretion of interleukin-1β (IL-1β). Mutations in the B30.2/SPRY ...domain cause pathogen-independent activation of pyrin and are responsible for the autoinflammatory disease familial Mediterranean fever (FMF). We studied a family with a dominantly inherited autoinflammatory disease, distinct from FMF, characterized by childhood-onset recurrent episodes of neutrophilic dermatosis, fever, elevated acute-phase reactants, arthralgia, and myalgia/myositis. The disease was caused by a mutation in MEFV, the gene encoding pyrin (S242R). The mutation results in the loss of a 14-3-3 binding motif at phosphorylated S242, which was not perturbed by FMF mutations in the B30.2/SPRY domain. However, loss of both S242 phosphorylation and 14-3-3 binding was observed for bacterial effectors that activate the pyrin inflammasome, such as Clostridium difficile toxin B (TcdB). The S242R mutation thus recapitulated the effect of pathogen sensing, triggering inflammasome activation and IL-1β production. Successful therapy targeting IL-1β has been initiated in one patient, resolving pyrin-associated autoinflammation with neutrophilic dermatosis. This disease provides evidence that a guard-like mechanism of pyrin regulation, originally identified for Nod-like receptors in plant innate immunity, also exists in humans.
Two species of Caenis with straight forceps with a terminal tuft of spines are described from northern Australia. Male imagoes and nymphs of C. hanleyi n. sp. are described from reared material from ...the Alligator Rivers Region in the Northern Territory and C. binda n. sp. is described only from male imagoes collected from streams in the Wet Tropics of Queensland. C. hanleyi differs from C. binda by the structure of the forceps with C. binda being longer and narrower with longer apical spines. These are the first records of the genus Caenis in Australia.
Inherent in most definitions of adventure tourism is the fact that it takes place in natural outdoor settings. Yet, the influence of this setting on the behaviour of adventure tourism consumers has ...yet to be adequately addressed. This study, therefore, investigates the relative strength and nature of environmental influences on adventure tourists in both motivations for participation and in the context of the experience. The results are based on questionnaires collected from 459 participants in adventure tourism activities along the southern coast of South Africa. They show that, although the majority of research on adventure tourism focuses on the 'thrill' involved, the environment is increasingly recognized as influential. The assessment of motivations, using a push and pull factor approach, demonstrates that the environment not only plays an important role in attracting adventure tourists towards specific destinations, but that they also seek out interactions with nature. In addition, participants suggested that the environment is an especially significant component of their experiences. The fact that the findings demonstrate the importance of the environment in both the motivations and experiences of adventure tourism participants, means that such an approach would make a definite contribution to discussions, planning, and policy linked to the adventure tourism industry.
A missense variant of the sushi, von Willebrand factor type A, EGF and pentraxin domain containing protein 1 (SVEP1) is genome-wide significantly associated with coronary artery disease. The ...mechanisms how SVEP1 impacts atherosclerosis are not known. We found endothelial cells (EC) and vascular smooth muscle cells to represent the major cellular source of SVEP1 in plaques. Plaques were larger in atherosclerosis-prone Svep1 haploinsufficient (
ApoE
−/−
Svep1
+/−
) compared to Svep1 wild-type mice
(ApoE
−/−
Svep1
+/+
) and
ApoE
−/−
Svep1
+/−
mice displayed elevated plaque neutrophil, Ly6C
high
monocyte, and macrophage numbers. We assessed how leukocytes accumulated more inside plaques in
ApoE
−/−
Svep1
+/−
mice and found enhanced leukocyte recruitment from blood into plaques. In vitro, we examined how SVEP1 deficiency promotes leukocyte recruitment and found elevated expression of the leukocyte attractant chemokine (C-X-C motif) ligand 1 (
CXCL1
) in EC after incubation with missense compared to wild-type SVEP1. Increasing wild-type SVEP1 levels silenced endothelial CXCL1 release. In line, plasma Cxcl1 levels were elevated in
ApoE
−/−
Svep1
+/−
mice. Our studies reveal an atheroprotective role of SVEP1. Deficiency of wild-type Svep1 increased endothelial
CXCL1
expression leading to enhanced recruitment of proinflammatory leukocytes from blood to plaque. Consequently, elevated vascular inflammation resulted in enhanced plaque progression in Svep1 deficiency.
FOXP2, initially identified for its role in human speech, contains two nonsynonymous substitutions derived in the human lineage. Evidence for a recent selective sweep in Homo sapiens, however, is at ...odds with the presence of these substitutions in archaic hominins. Here, we comprehensively reanalyze FOXP2 in hundreds of globally distributed genomes to test for recent selection. We do not find evidence of recent positive or balancing selection at FOXP2. Instead, the original signal appears to have been due to sample composition. Our tests do identify an intronic region that is enriched for highly conserved sites that are polymorphic among humans, compatible with a loss of function in humans. This region is lowly expressed in relevant tissue types that were tested via RNA-seq in human prefrontal cortex and RT-PCR in immortalized human brain cells. Our results represent a substantial revision to the adaptive history of FOXP2, a gene regarded as vital to human evolution.
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•No support for positive selection at FOXP2 in large genomic datasets•Sample composition and genomic scale significantly affect selection scans•An intronic ROI within FOXP2 is expressed in human brain cells and cortical tissue•This ROI contains a large amount of constrained, human-specific polymorphisms
An in-depth examination of diverse sets of human genomes argues against a recent selective evolutionary sweep of FOXP2, a gene that was believed to be critical for speech evolution in early hominins.
Cardiopulmonary exercise testing (CPET) is an established method for evaluating dyspnea and ventilatory abnormalities. Ventilatory reserve is typically assessed as the ratio of peak exercise ...ventilation to maximal voluntary ventilation. Unfortunately, this crude assessment provides limited data on the factors that limit the normal ventilatory response to exercise. Additional measurements can provide a more comprehensive evaluation of respiratory mechanical constraints during CPET (e.g., expiratory flow limitation and operating lung volumes). These measurements are directly dependent on an accurate assessment of inspiratory capacity (IC) throughout rest and exercise. Despite the valuable insight that the IC provides, there are no established recommendations on how to perform the maneuver during exercise and how to analyze and interpret the data. Accordingly, the purpose of this manuscript is to comprehensively examine a number of methodological issues related to the measurement, analysis, and interpretation of the IC. We will also briefly discuss IC responses to exercise in health and disease and will consider how various therapeutic interventions influence the IC, particularly in patients with chronic obstructive pulmonary disease. Our main conclusion is that IC measurements are both reproducible and responsive to therapy and provide important information on the mechanisms of dyspnea and exercise limitation during CPET.
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