Abstract
Phago-mixotrophy, the combination of photoautotrophy and phagotrophy in mixoplankton, organisms that can combine both trophic strategies, have gained increasing attention over the past ...decade. It is now recognized that a substantial number of protistan plankton species engage in phago-mixotrophy to obtain nutrients for growth and reproduction under a range of environmental conditions. Unfortunately, our current understanding of mixoplankton in aquatic systems significantly lags behind our understanding of zooplankton and phytoplankton, limiting our ability to fully comprehend the role of mixoplankton (and phago-mixotrophy) in the plankton food web and biogeochemical cycling. Here, we put forward five research directions that we believe will lead to major advancement in the field: (i) evolution: understanding mixotrophy in the context of the evolutionary transition from phagotrophy to photoautotrophy; (ii) traits and trade-offs: identifying the key traits and trade-offs constraining mixotrophic metabolisms; (iii) biogeography: large-scale patterns of mixoplankton distribution; (iv) biogeochemistry and trophic transfer: understanding mixoplankton as conduits of nutrients and energy; and (v) in situ methods: improving the identification of in situ mixoplankton and their phago-mixotrophic activity.
Benefits of phosphate-lowering interventions on clinical outcomes in patients with CKD are unclear; systematic reviews have predominantly involved patients on dialysis. This study aimed to summarize ...evidence from randomized controlled trials (RCTs) concerning benefits and risks of noncalcium-based phosphate-lowering treatment in nondialysis CKD.
We conducted a systematic review and meta-analyses of RCTs involving noncalcium-based phosphate-lowering therapy compared with placebo, calcium-based binders, or no study medication, in adults with CKD not on dialysis or post-transplant. RCTs had ≥3 months follow-up and outcomes included biomarkers of mineral metabolism, cardiovascular parameters, and adverse events. Outcomes were meta-analyzed using the Sidik-Jonkman method for random effects. Unstandardized mean differences were used as effect sizes for continuous outcomes with common measurement units and Hedge's g standardized mean differences (SMD) otherwise. Odds ratios were used for binary outcomes. Cochrane risk of bias and GRADE assessment determined the certainty of evidence.
In total, 20 trials involving 2498 participants (median sample size 120, median follow-up 9 months) were eligible for inclusion. Overall, risk of bias was low. Compared with placebo, noncalcium-based phosphate binders reduced serum phosphate (12 trials, weighted mean difference -0.37; 95% CI, -0.58 to -0.15 mg/dl, low certainty evidence) and urinary phosphate excretion (eight trials, SMD -0.61; 95% CI, -0.90 to -0.31, low certainty evidence), but resulted in increased constipation (nine trials, log odds ratio OR 0.93; 95% CI, 0.02 to 1.83, low certainty evidence) and greater vascular calcification score (three trials, SMD, 0.47; 95% CI, 0.17 to 0.77, very low certainty evidence). Data for effects of phosphate-lowering therapy on cardiovascular events (log OR, 0.51; 95% CI, -0.51 to 1.17) and death were scant.
Noncalcium-based phosphate-lowering therapy reduced serum phosphate and urinary phosphate excretion, but there was an unclear effect on clinical outcomes and intermediate cardiovascular end points. Adequately powered RCTs are required to evaluate benefits and risks of phosphate-lowering therapy on patient-centered outcomes.
In embryonic stem cell (ESC) models for early development, spatially and temporally varying patterns of signaling and cell types emerge spontaneously. However, mechanistic insight into this dynamic ...self-organization is limited by a lack of methods for spatiotemporal control of signaling, and the relevance of signal dynamics and cell-to-cell variability to pattern emergence remains unknown. Here, we combine optogenetic stimulation, imaging and transcriptomic approaches to study self-organization of human ESCs (hESC) in two-dimensional (2D) culture. Morphogen dynamics were controlled via optogenetic activation of canonical Wnt/β-catenin signaling (optoWnt), which drove broad transcriptional changes and mesendoderm differentiation at high efficiency (>99% cells). When activated within cell subpopulations, optoWnt induced cell self-organization into distinct epithelial and mesenchymal domains, mediated by changes in cell migration, an epithelial to mesenchymal-like transition and TGFβ signaling. Furthermore, we demonstrate that such optogenetic control of cell subpopulations can be used to uncover signaling feedback mechanisms between neighboring cell types. These findings reveal that cell-to-cell variability in Wnt signaling is sufficient to generate tissue-scale patterning and establish a hESC model system for investigating feedback mechanisms relevant to early human embryogenesis.
Researchers studying bystander behavior in the context of sexual violence are informed by the five-step process of bystander intervention that was described by Latané and Darley (
1969
). According ...to this process an individual must first recognize a situation as problematic prior to intervening. The behaviors that are easily recognized or taught in college programming as problematic are generally indicative of sexual assault and rape; however, behaviors that feed into sexual violence exist on a continuum, allowing for a range of opportunities for intervention. The goal of the current study was to expand the conceptualization of bystander behavior to include precursors to what has been traditionally considered bystander behavior (e.g., directly intervening on behalf of a potential victim) through the creation and initial validation of the Critically Conscious Bystander Scale (CCBS). The CCBS moves beyond traditional measures of bystander behavior by considering sexual harassment and sexual assault separately. Further, the CCBS incorporates sociopolitical involvement and critical consciousness education within bystander behavior. Through exploratory and confirmatory factor analyses and relation to similar and related constructs with two separate U.S. college samples (
n
s = 409 and 502), the CCBS demonstrated initial reliability and validity encompassing four related, but unique, factors present among the retained items: Sexual Harassment Bystander Behavior, Consciousness Raising, Advocacy/Activism, and Sexual Assault Bystander Behavior. Implications for the CCBS, including how this measure can help to provide a nuanced picture of bystander behavior, are discussed.
Among more than 3000 hospitalized patients with Covid-19, recipients of high-titer convalescent plasma had a lower mortality at 30 days than recipients of low-titer plasma. The effect of high-titer ...plasma was greatest in the subgroup of patients who were not receiving mechanical ventilation.
Summary Background There is a paucity of evidence to guide the best strategy for prevention of peritoneal-dialysis-related infections. Antibacterial honey has shown promise as a novel, cheap, ...effective, topical prophylactic agent without inducing microbial resistance. We therefore assessed whether daily application of honey at the exit site would increase the time to peritoneal-dialysis-related infections compared with standard exit-site care plus intranasal mupirocin prophylaxis for nasal carriers of Staphylococcus aureus. Methods In this open-label trial undertaken in 26 centres in Australia and New Zealand, participants undergoing peritoneal dialysis were randomly assigned in a 1:1 ratio with an adaptive allocation algorithm to daily topical exit-site application of antibacterial honey plus standard exit-site care or intranasal mupirocin prophylaxis (only in carriers of nasal S aureus ) plus standard exit-site care (control group). The primary endpoint was time to first infection related to peritoneal dialysis (exit-site infection, tunnel infection, or peritonitis). The trial is registered with the Australian New Zealand Clinical Trials Registry, number 12607000537459. Findings Of 371 participants, 186 were assigned to the honey group and 185 to the control group. The median peritoneal-dialysis-related infection-free survival times were not significantly different in the honey (16·0 months IQR not estimable) and control groups (17·7 months not estimable; unadjusted hazard ratio 1·12, 95% CI 0·83–1·51; p=0·47). In the subgroup analyses, honey increased the risks of both the primary endpoint (1·85, 1·05–3·24; p=0·03) and peritonitis (2·25, 1·16–4·36) in participants with diabetes. The incidences of serious adverse events (298 vs 327, respectively; p=0·1) and deaths (14 vs 18, respectively; p=0·9) were not significantly different in the honey and control groups. 11 (6%) participants in the honey group had local skin reactions. Interpretation The findings of this trial show that honey cannot be recommended routinely for the prevention of peritoneal-dialysis-related infections. Funding Baxter Healthcare, Queensland Government, Comvita, and Gambro.
We developed a standardized method, possible poor treatment response (PPTR), to help ascertain efficacy endpoints in Study S31/A5349 (NCT02410772), an open-label trial comparing two 4-month ...rifapentine-based regimens with a standard 6-month regimen for the treatment of pulmonary tuberculosis (TB).
We describe the use of the PPTR process and evaluate whether the goals of minimizing bias in efficacy endpoint assessment and attainment of relevant data to determine outcomes for all participants were achieved.
A PPTR event was defined as the occurrence of one or more prespecified triggers. Each PPTR required initiation of a standardized evaluation process that included obtaining multiple sputum samples for microbiology.
Among 2,343 participants with culture-confirmed drug-susceptible TB, 454 individuals (19.4%) had a total of 534 individual PPTR events, of which 76.6% were microbiological (positive smear or culture at or after 17 wk). At least one PPTR event was experienced by 92.4% (133 of 144) of participants with TB-related unfavorable outcome and between 13.8% and 14.7% of participants with favorable and not-assessable outcomes. A total of 75% of participants with TB-related unfavorable outcomes had microbiological confirmation of failure to achieve a disease-free cure.
Standardized methodologies, such as our PPTR approach, could facilitate unbiased efficacy outcome determinations, improve discrimination between outcomes that are related and unrelated to regimen efficacy, and enhance the ability to conduct pooled analyses of contemporary trials.
Effective therapeutic interventions for chronic, idiopathic lung diseases remain elusive. Normalized T-cell function is an important contributor to spontaneous resolution of pulmonary sarcoidosis. ...Up-regulation of inhibitor receptors, such as programmed death-1 (PD-1) and its ligand, PD-L1, are important inhibitors of T-cell function.
To determine the effects of PD-1 pathway blockade on sarcoidosis CD4(+) T-cell proliferative capacity.
Gene expression profiles of sarcoidosis and healthy control peripheral blood mononuclear cells were analyzed at baseline and follow-up. Flow cytometry was used to measure ex vivo expression of PD-1 and PD-L1 on systemic and bronchoalveolar lavage-derived cells of subjects with sarcoidosis and control subjects, as well as the effects of PD-1 pathway blockade on cellular proliferation after T-cell receptor stimulation. Immunohistochemistry analysis for PD-1/PD-L1 expression was conducted on sarcoidosis, malignant, and healthy control lung specimens.
Microarray analysis demonstrates longitudinal increase in PDCD1 gene expression in sarcoidosis peripheral blood mononuclear cells. Immunohistochemistry analysis revealed increased PD-L1 expression within sarcoidosis granulomas and lung malignancy, but this was absent in healthy lungs. Increased numbers of sarcoidosis PD-1(+) CD4(+) T cells are present systemically, compared with healthy control subjects (P < 0.0001). Lymphocytes with reduced proliferative capacity exhibited increased proliferation with PD-1 pathway blockade. Longitudinal analysis of subjects with sarcoidosis revealed reduced PD-1(+) CD4(+) T cells with spontaneous clinical resolution but not with disease progression.
Analogous to the effects in other chronic lung diseases, these findings demonstrate that the PD-1 pathway is an important contributor to sarcoidosis CD4(+) T-cell proliferative capacity and clinical outcome. Blockade of the PD-1 pathway may be a viable therapeutic target to optimize clinical outcomes.
Deciphering the significance of length, sequence, and stereochemistry in block copolymer self-assembly remains an ongoing challenge. A dearth of methods to access uniform block co-oligomers/polymers ...with precise stereochemical sequences has precluded such studies. Here, we develop iterative exponential growth methods for the synthesis of a small library of unimolecular stereoisomeric diblock 32-mers. X-ray scattering reveals that stereochemistry modulates the phase behavior of these polymers, which we rationalize based on simulations carried out on a theoretical model system. This work demonstrates that stereochemical sequence can play a crucial role in unimolecular polymer self-assembly.
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