T follicular helper (Tfh) cells promote T cell-dependent humoral immune responses by providing T cell help to B cells and by promoting germinal center (GC) formation and long-lived antibody ...responses. However, the cellular and molecular mechanisms that control Tfh cell differentiation in vivo are incompletely understood. Here we show that interleukin-2 (IL-2) administration impaired influenza-specific GCs, long-lived IgG responses, and Tfh cells. IL-2 did not directly inhibit GC formation, but instead suppressed the differentiation of Tfh cells, thereby hindering the maintenance of influenza-specific GC B cells. Our data demonstrate that IL-2 is a critical factor that regulates successful Tfh and B cell responses in vivo and regulates Tfh cell development.
► IL-2 inhibits Tfh cell differentiation ► IL-2 blocks germinal center formation by suppressing Tfh cell differentiation ► IL-2 suppresses the differentiation of long-lived plasma cells ► IL-2 blocks Tfh cell differentiation independently of its effects on Treg cells
Memory B cells are found in lymphoid and non-lymphoid tissues, suggesting that some may be tissue-resident cells. Here we show that pulmonary influenza infection elicited lung-resident memory B cells ...(BRM cells) that were phenotypically and functionally distinct from their systemic counterparts. BRM cells were established in the lung early after infection, in part because their placement required local antigen encounter. Lung BRM cells, but not systemic memory B cells, contributed to early plasmablast responses following challenge infection. Following secondary infection, antigen-specific BRM cells differentiated in situ, whereas antigen-non-specific BRM cells were maintained as memory cells. These data demonstrate that BRM cells are an important component of immunity to respiratory viruses such as influenza virus and suggest that vaccines designed to elicit BRM cells must deliver antigen to the lungs.
Visual function depends on the accuracy of signals carried by visual cortical neurons. Combining information across neurons should improve this accuracy because single neuron activity is variable. We ...examined the reliability of information inferred from populations of simultaneously recorded neurons in macaque primary visual cortex. We considered a decoding framework that computes the likelihood of visual stimuli from a pattern of population activity by linearly combining neuronal responses and tested this framework for orientation estimation and discrimination. We derived a simple parametric decoder assuming neuronal independence and a more sophisticated empirical decoder that learned the structure of the measured neuronal response distributions, including their correlated variability. The empirical decoder used the structure of these response distributions to perform better than its parametric variant, indicating that their structure contains critical information for sensory decoding. These results show how neuronal responses can best be used to inform perceptual decision-making.
Highlights • 88 prospective, clinical trials (1996–2015) were analyzed in terms of survival of posterior composite restorations. • Significant findings were only observed for short-term studies and ...by including all studies (short- and long-term studies). • The observation period, the recall rate, the ratio of Class I/II fillings and the number of restorations/patients had a significant influence on the overall failure rate when including all studies (short- and long-term). • No influence of operator status, isolation method or bonding systems on the overall failure rate was found. • In this study a trend of excluding patients at-risk (e.g. high caries activity) and including patients with good oral hygiene was identified, which produces more favorable results.
Objective classification of extratropical cyclogenesis Graf, Michael A.; Wernli, Heini; Sprenger, Michael
Quarterly journal of the Royal Meteorological Society,
January 2017 Part B, 2017-01-00, 20170101, Letnik:
143, Številka:
703
Journal Article
Recenzirano
Extratropical cyclones experience vastly different genesis conditions at the first point of their tracks. A novel method is introduced to characterize this variability and classify genesis events by ...computing 30 diagnostic variables that describe the synoptic‐scale environment of 16 029 genesis events in the Northern Hemisphere extratropics, using ERA‐Interim reanalyses from 2000–2011. These variables are referred to as precursors and include parameters characterizing upper‐level forcing, low‐level baroclinicity, thermodynamic stability, surface fluxes and moist processes. The genesis events spread over a large portion of the 30‐dimensional precursor phase space and no obvious clusters occur, which highlights the high variability of cyclogenesis processes and indicates that they form in a continuum rather than a few distinct categories. A projection of the genesis events to the first two principle components (PC) of the precursor phase space allows reduction of the dimensionality and introduction of a meaningful segmentation of the genesis events in five classes. The first two PCs are characterized by upper‐level forcing (e.g. the amplitude of the upper‐level potential vorticity (PV) anomaly) and low‐tropospheric diabatic processes (e.g. precipitation and diabatically produced low‐level PV), respectively. The first of the five classes identified constitutes the centre of the PC1–PC2 phase space and represents average conditions. Composites reveal that the four classes of events characterized by large positive or negative scores of PC1 and PC2 occur in distinct and strongly differing flow regimes, characterized by the strength of the upper‐level forcing, the structure of the upper‐level jet and the amplitude of low‐level moist processes and baroclinicity. The four classes also have clearly differing geographical distributions. Many well‐known cyclogenesis events fall within classes characterized by strong low‐level moist processes with or without strong upper‐level forcing. Also discussed are the robustness of the method and the linkage to classical concepts of cyclone classifications.
Interaction among species through competition is a principle process structuring ecological communities, affecting behavior, distribution, and ultimately the population dynamics of species. High ...competition among large African carnivores, associated with extensive diet overlap, manifests in interactions between subordinate African wild dogs (Lycaon pictus) and dominant lions (Panthera leo) and spotted hyenas (Crocuta crocuta). Using locations of large carnivores in Hluhluwe-iMfolozi Park, South Africa, we found different responses from wild dogs to their two main competitors. Wild dogs avoided lions, particularly during denning, through a combination of spatial and temporal avoidance. However, wild dogs did not exhibit spatial or temporal avoidance of spotted hyenas, likely because wild dog pack sizes were large enough to adequately defend their kills. Understanding that larger carnivores affect the movements and space use of other carnivores is important for managing current small and fragmented carnivore populations, especially as reintroductions and translocations are essential tools used for the survival of endangered species, as with African wild dogs.
In healthy individuals, acute changes in cholesterol intake produce modest changes in plasma cholesterol levels. A striking exception occurs in sitosterolemia, an autosomal recessive disorder ...characterized by increased intestinal absorption and decreased biliary excretion of dietary sterols, hypercholesterolemia, and premature coronary atherosclerosis. We identified seven different mutations in two adjacent, oppositely oriented genes that encode new members of the adenosine triphosphate (ATP)-binding cassette (ABC) transporter family (six mutations in ABCG8 and one in ABCG5) in nine patients with sitosterolemia. The two genes are expressed at highest levels in liver and intestine and, in mice, cholesterol feeding up-regulates expressions of both genes. These data suggest that ABCG5 and ABCG8 normally cooperate to limit intestinal absorption and to promote biliary excretion of sterols, and that mutated forms of these transporters predispose to sterol accumulation and atherosclerosis.
Melanoma is an often fatal form of skin cancer which is remarkably resistant against radio- and chemotherapy. Even new strategies that target RAS/RAF signaling and display unprecedented efficacy are ...characterized by resistance mechanisms. The targeting of survival pathways would be an attractive alternative strategy, if tumor-specific cell death can be achieved. Bcl-2 proteins play a central role in regulating survival of tumor cells. In this study, we systematically investigated the relevance of antiapoptotic Bcl-2 proteins, i.e., Bcl-2, Bcl-xL, Bcl-w, Mcl-1, and A1, in melanoma cell lines and non-malignant cells using RNAi. We found that melanoma cells required the presence of specific antiapoptotic Bcl-2 proteins: Inhibition of Mcl-1 and A1 strongly induced cell death in some melanoma cell lines, whereas non-malignant cells, i.e., primary human fibroblasts or keratinocytes were not affected. This specific sensitivity of melanoma cells was further enhanced by the combined inhibition of Mcl-1 and A1 and resulted in 60% to 80% cell death in all melanoma cell lines tested. This treatment was successfully combined with chemotherapy, which killed a substantial proportion of cells that survived Mcl-1 and A1 inhibition. Together, these results identify antiapoptotic proteins on which specifically melanoma cells rely on and, thus, provide a basis for the development of new Bcl-2 protein-targeting therapies.
Hematopoietic stem cell transplantation is a common life-saving treatment for hematologic malignancies, though can lead to long-term functional impairment, fatigue, muscle atrophy, with decreased ...quality of life. Although traditional exercise has helped reduce these effects, it is inconsistently recommended and infrequently maintained, and most patients remain sedentary during and after treatment. There is need for alternative rehabilitation strategies, like neuromuscular electrical stimulation, that may be more amenable to the capabilities of hematopoietic stem cell transplant recipients. Patients receiving autologous HCT are being enroled in a randomized controlled trial with 1:1 (neuromuscular electrical stimulation:sham) design stratified by diagnosis and sex. Physical function, body composition, quality of life, and fatigue are assessed prior to hematopoietic stem cell transplant (prior to initiating preparatory treatment) and 24±5 days post hematopoietic stem cell transplant (Follow-up 1); physical function and quality of life are also assessed 6-months post hematopoietic stem cell transplant (Follow-up 2). The primary outcome is between-group difference in the 6-minute walk test change scores (Follow-up 1-Pre-transplant; final enrolment goal N = 23/group). We hypothesize that 1) neuromuscular electrical stimulation will attenuate hematopoietic stem cell transplant-induced adverse effects on physical function, muscle mass, quality of life, and fatigue compared to sham at Follow-up 1, and 2) Pre-transplant physical function will significantly predict fatigue and quality of life at Follow-up 2. We will also describe feasibility and acceptability of neuromuscular electrical stimulation during hematopoietic stem cell transplant. This proposal will improve rehabilitative patient care and quality of life by determining efficacy and feasibility of a currently underutilized therapeutic strategy aimed at maintaining daily function and reducing the impact of a potent and widely used cancer treatment. This trial is registered with clinicaltrials.gov (NCT04364256).
Frameshift mutations in the DMD gene, encoding dystrophin, cause Duchenne muscular dystrophy (DMD), leading to terminal muscle and heart failure in patients. Somatic gene editing by sequence-specific ...nucleases offers new options for restoring the DMD reading frame, resulting in expression of a shortened but largely functional dystrophin protein. Here, we validated this approach in a pig model of DMD lacking exon 52 of DMD (DMDΔ52), as well as in a corresponding patient-derived induced pluripotent stem cell model. In DMDΔ52 pigs
, intramuscular injection of adeno-associated viral vectors of serotype 9 carrying an intein-split Cas9 (ref.
) and a pair of guide RNAs targeting sequences flanking exon 51 (AAV9-Cas9-gE51) induced expression of a shortened dystrophin (DMDΔ51-52) and improved skeletal muscle function. Moreover, systemic application of AAV9-Cas9-gE51 led to widespread dystrophin expression in muscle, including diaphragm and heart, prolonging survival and reducing arrhythmogenic vulnerability. Similarly, in induced pluripotent stem cell-derived myoblasts and cardiomyocytes of a patient lacking DMDΔ52, AAV6-Cas9-g51-mediated excision of exon 51 restored dystrophin expression and amelioreate skeletal myotube formation as well as abnormal cardiomyocyte Ca
handling and arrhythmogenic susceptibility. The ability of Cas9-mediated exon excision to improve DMD pathology in these translational models paves the way for new treatment approaches in patients with this devastating disease.
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