There is significant debate regarding whether B cells and their antibodies contribute to effective anti-cancer immune responses. Here we show that patients with metastatic but non-progressing ...melanoma, lung adenocarcinoma, or renal cell carcinoma exhibited increased levels of blood plasmablasts. We used a cell-barcoding technology to sequence their plasmablast antibody repertoires, revealing clonal families of affinity matured B cells that exhibit progressive class switching and persistence over time. Anti-CTLA4 and other treatments were associated with further increases in somatic hypermutation and clonal family size. Recombinant antibodies from clonal families bound non-autologous tumor tissue and cell lines, and families possessing immunoglobulin paratope sequence motifs shared across patients exhibited increased rates of binding. We identified antibodies that caused regression of, and durable immunity toward, heterologous syngeneic tumors in mice. Our findings demonstrate convergent functional anti-tumor antibody responses targeting public tumor antigens, and provide an approach to identify antibodies with diagnostic or therapeutic utility.
•Patients with metastatic but non-progressing cancers exhibit increased blood plasmablasts.•Sequencing of their plasmablast repertoires revealed clonal families of affinity matured B cells.•Recombinant antibodies from clonal families bound non-autologous tumor tissue and cell lines.•Paratope sequence motifs shared across patients exhibit increased rates of binding.•Select antibodies caused regression of heterologous syngeneic tumors in mice.
Although midbrain dopamine (DA) circuits are central to motivated behaviors, our knowledge of how experience modifies these circuits to facilitate subsequent behavioral adaptations is limited. Here ...we demonstrate the selective role of a ventral tegmental area DA projection to the amygdala (VTADA→amygdala) for cocaine-induced anxiety but not cocaine reward or sensitization. Our rabies virus-mediated circuit mapping approach reveals a persistent elevation in spontaneous and task-related activity of inhibitory GABAergic cells from the bed nucleus of the stria terminalis (BNST) and downstream VTADA→amygdala cells that can be detected even after a single cocaine exposure. Activity in BNSTGABA→midbrain cells is related to cocaine-induced anxiety but not reward or sensitization, and silencing this projection prevents development of anxiety during protracted withdrawal after cocaine administration. Finally, we observe that VTADA→amygdala cells are strongly activated after a challenge exposure to cocaine and that activity in these cells is necessary and sufficient for reinstatement of cocaine place preference.
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•Unbiased RABV screen identifies drug-induced changes in rodent brain•BNSTGABA→midbrain cell activity is elevated after a single cocaine exposure•BNSTGABA→VTADA→amygdala pathway controls cocaine-induced anxiety and reinstatement•VTADA→amygdala cells are necessary and sufficient to drive general anxiety states
Tian et al. show that an elevation of BNSTGABA→midbrain cell activity is related to withdrawal anxiety that manifests after a single cocaine exposure. Inhibition or activation of the BNSTGABA→VTADA→amygdala pathway bidirectionally controls cocaine-induced withdrawal anxiety. Activation of VTADA→amygdala cells is also sufficient to drive robust reinstatement of cocaine-induced place preference.
"Fascinating and exhilarating-Sean B. Carroll at his
very best."-Bill Bryson, author of The Body: A Guide for
Occupants From acclaimed writer and biologist Sean B. Carroll,
a rollicking, ...awe-inspiring story of the surprising power of chance
in our lives and the world Why is the world the way it is?
How did we get here? Does everything happen for a reason or are
some things left to chance? Philosophers and theologians have
pondered these questions for millennia, but startling scientific
discoveries over the past half century are revealing that we live
in a world driven by chance. A Series of Fortunate Events
tells the story of the awesome power of chance and how it is the
surprising source of all the beauty and diversity in the living
world. Like every other species, we humans are here by accident.
But it is shocking just how many things-any of which might never
have occurred-had to happen in certain ways for any of us to exist.
From an extremely improbable asteroid impact, to the wild gyrations
of the Ice Age, to invisible accidents in our parents' gonads, we
are all here through an astonishing series of fortunate events. And
chance continues to reign every day over the razor-thin line
between our life and death. This is a relatively small book about a
really big idea. It is also a spirited tale. Drawing inspiration
from Monty Python, Kurt Vonnegut, and other great thinkers, and
crafted by one of today's most accomplished science storytellers,
A Series of Fortunate Events is an irresistibly
entertaining and thought-provoking account of one of the most
important but least appreciated facts of life.
Coloration is one of the most variable characters among animals and is a rich source of models of phenotypic evolution. The great diversity of pigment patterns in
Drosophila, coupled with the ...availability of genetic approaches in both model and more exotic species, has recently spawned efforts to elucidate the genetic architecture and molecular basis of pigment pattern evolution. Pigmentation differences are often polygenic and correlate with regulatory changes in both transcription factor genes and structural genes. Understanding the developmental genetic basis of color differences in
Drosophila could provide inroads to classic evolutionary problems such as industrial melanism, mimicry and phenotypic convergence.
The 'verification phase' has emerged as a supplementary procedure to traditional maximal oxygen uptake (VO2max) criteria to confirm that the highest possible VO2 has been attained during a ...cardiopulmonary exercise test (CPET).
To compare the highest VO2 responses observed in different verification phase procedures with their preceding CPET for confirmation that VO2max was likely attained.
MEDLINE (accessed through PubMed), Web of Science, SPORTDiscus, and Cochrane (accessed through Wiley) were searched for relevant studies that involved apparently healthy adults, VO2max determination by indirect calorimetry, and a CPET on a cycle ergometer or treadmill that incorporated an appended verification phase. RevMan 5.3 software was used to analyze the pooled effect of the CPET and verification phase on the highest mean VO2. Meta-analysis effect size calculations incorporated random-effects assumptions due to the diversity of experimental protocols employed. I2 was calculated to determine the heterogeneity of VO2 responses, and a funnel plot was used to check the risk of bias, within the mean VO2 responses from the primary studies. Subgroup analyses were used to test the moderator effects of sex, cardiorespiratory fitness, exercise modality, CPET protocol, and verification phase protocol.
Eighty studies were included in the systematic review (total sample of 1,680 participants; 473 women; age 19-68 yr.; VO2max 3.3 ± 1.4 L/min or 46.9 ± 12.1 mL·kg-1·min-1). The highest mean VO2 values attained in the CPET and verification phase were similar in the 54 studies that were meta-analyzed (mean difference = 0.03 95% CI = -0.01 to 0.06 L/min, P = 0.15). Furthermore, the difference between the CPET and verification phase was not affected by any of the potential moderators such as verification phase intensity (P = 0.11), type of recovery utilized (P = 0.36), VO2max verification criterion adoption (P = 0.29), same or alternate day verification procedure (P = 0.21), verification-phase duration (P = 0.35), or even according to sex, cardiorespiratory fitness level, exercise modality, and CPET protocol (P = 0.18 to P = 0.71). The funnel plot indicated that there was no significant publication bias.
The verification phase seems a robust procedure to confirm that the highest possible VO2 has been attained during a ramp or continuous step-incremented CPET. However, given the high concordance between the highest mean VO2 achieved in the CPET and verification phase, findings from the current study would question its necessity in all testing circumstances.
CRD42019123540.
A plateau in oxygen uptake (Formula: see text) during an incremental cardiopulmonary exercise test (CPET) to volitional exhaustion appears less likely to occur in special and clinical populations. ...Secondary maximal oxygen uptake (Formula: see text) criteria have been shown to commonly underestimate the actual Formula: see text. The verification phase protocol might determine the occurrence of 'true' Formula: see text in these populations. The primary aim of the current study was to systematically review and provide a meta-analysis on the suitability of the verification phase for confirming 'true' Formula: see text in special and clinical groups. Secondary aims were to explore the applicability of the verification phase according to specific participant characteristics and investigate which test protocols and procedures minimise the differences between the highest Formula: see text values attained in the CPET and verification phase.
Electronic databases (PubMed, Web of Science, SPORTDiscus, Scopus, and EMBASE) were searched using specific search strategies and relevant data were extracted from primary studies. Studies meeting inclusion criteria were systematically reviewed. Meta-analysis techniques were applied to quantify weighted mean differences (standard deviations) in peak Formula: see text from a CPET and a verification phase within study groups using random-effects models. Subgroup analyses investigated the differences in Formula: see text according to individual characteristics and test protocols. The methodological quality of the included primary studies was assessed using a modified Downs and Black checklist to obtain a level of evidence. Participant-level Formula: see text data were analysed according to the threshold criteria reported by the studies or the inherent measurement error of the metabolic analysers and displayed as Bland-Altman plots.
Forty-three studies were included in the systematic review, whilst 30 presented quantitative information for meta-analysis. Within the 30 studies, the highest mean Formula: see text values attained in the CPET and verification phase protocols were similar (mean difference = -0.00 95% confidence intervals, CI = -0.03 to 0.03 L·min-1, p = 0.87; level of evidence, LoE: strong). The specific clinical groups with sufficient primary studies to be meta-analysed showed a similar Formula: see text between the CPET and verification phase (p > 0.05, LoE: limited to strong). Across all 30 studies, Formula: see text was not affected by differences in test protocols (p > 0.05; LoE: moderate to strong). Only 23 (53.5%) of the 43 reviewed studies reported how many participants achieved a lower, equal, or higher Formula: see text value in the verification phase versus the CPET or reported or supplied participant-level Formula: see text data for this information to be obtained. The percentage of participants that achieved a lower, equal, or higher Formula: see text value in the verification phase was highly variable across studies (e.g. the percentage that achieved a higher Formula: see text in the verification phase ranged from 0% to 88.9%).
Group-level verification phase data appear useful for confirming a specific CPET protocol likely elicited Formula: see text, or a reproducible Formula: see text, for a given special or clinical group. Participant-level data might be useful for confirming whether specific participants have likely elicited Formula: see text, or a reproducible Formula: see text, however, more research reporting participant-level data is required before evidence-based guidelines can be given.
PROSPERO (CRD42021247658) https://www.crd.york.ac.uk/prospero.
There is an ever growing coping and sports performance literature, with researchers using many different methods to assess performance and different classifications of coping. As such, it makes it ...difficult to compare studies and therefore identify how coping is related to performance. Furthermore, there are no quantitative syntheses of the results from these studies. A quantitative synthesis would facilitate a more comprehensive understanding of how coping is associated with athletic performance. In order to accurately compare studies, our first aim was to develop a new coping classification that would make this possible. Firstly, we reviewed the strengths and limitations of the different coping classifications and then identified the commonalities and differences between such classifications. We opted for a three-factor classification of coping, because the evidence suggests that a three-factor classification provides a superior model fit to two-factor approaches. Our new classification of coping was based on an existing model from the developmental literature, which received an excellent model fit. We made some adaptations, however, as our classification was intended for an athletic population. As such, we classified coping as mastery (i.e., controlling the situation and eliminating the stressor), internal regulation (i.e., managing internal stress responses), or goal withdrawal (i.e., ceasing efforts toward goal attainment). Undertaking a meta-analysis, our second aim was to identify which coping strategies correlated with sports performance and whether this relationship varied according to moderator variables. Articles were sourced from online electronic databases and manual journal searches. PRISMA guidelines were used to search, select, and synthesize relevant studies. Random effects meta-analyses were performed to identify associations between coping classification and sport performance.
, and
values assessed heterogeneity. Eighteen published investigations, including 3900 participants and incorporating fifty-nine correlations, indicated an overall positive effect for mastery coping, a negligible negative effect for internal regulation coping, and a negative effect for goal withdrawal strategies. The findings of this meta-analysis could be used by sports practitioners to help them deliver effective coping interventions. In order to maximize performance, practitioners could encourage the use of mastery coping, but advise their athletes not to use goal withdrawal strategies.
Modern systems biology requires extensive, carefully curated measurements of cellular components in response to different environmental conditions. While high-throughput methods have made ...transcriptomics and proteomics datasets widely accessible and relatively economical to generate, systematic measurements of both mRNA and protein abundances under a wide range of different conditions are still relatively rare. Here we present a detailed, genome-wide transcriptomics and proteomics dataset of E. coli grown under 34 different conditions. Additionally, we provide measurements of doubling times and in-vivo metabolic fluxes through the central carbon metabolism. We manipulate concentrations of sodium and magnesium in the growth media, and we consider four different carbon sources glucose, gluconate, lactate, and glycerol. Moreover, samples are taken both in exponential and stationary phase, and we include two extensive time-courses, with multiple samples taken between 3 hours and 2 weeks. We find that exponential-phase samples systematically differ from stationary-phase samples, in particular at the level of mRNA. Regulatory responses to different carbon sources or salt stresses are more moderate, but we find numerous differentially expressed genes for growth on gluconate and under salt and magnesium stress. Our data set provides a rich resource for future computational modeling of E. coli gene regulation, transcription, and translation.
Extremal limits and black hole entropy Carroll, Sean M; Johnson, Matthew C; Randall, Lisa
The journal of high energy physics,
11/2009, Volume:
2009, Issue:
11
Journal Article
PDF
