Fission yeast cells use Arp2/3 complex and formin to assemble diverse filamentous actin (F-actin) networks within a common cytoplasm for endocytosis, division, and polarization. Although these ...homeostatic F-actin networks are usually investigated separately, competition for a limited pool of actin monomers (G-actin) helps to regulate their size and density. However, the mechanism by which G-actin is correctly distributed between rival F-actin networks is not clear. Using a combination of cell biological approaches and in vitro reconstitution of competition between actin assembly factors, we found that the small G-actin binding protein profilin directly inhibits Arp2/3 complex-mediated actin assembly. Profilin is therefore required for formin to compete effectively with excess Arp2/3 complex for limited G-actin and to assemble F-actin for contractile ring formation in dividing cells.
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•In vitro, profilin favors formin- over Arp2/3 complex-mediated actin assembly•In fission yeast, profilin allows formin to compete with Arp2/3 complex for G-actin•Profilin antagonizes formation of Arp2/3 complex-mediated actin patches in vivo•Profilin inhibits Arp2/3 complex-mediated F-actin branch assembly in vitro
Cells generate diverse actin filament networks within a common cytoplasm. Suarez et al. show that the actin monomer binding protein profilin facilitates proper distribution of actin into networks assembled by different assembly factors. Profilin simultaneously inhibits actin filament branch formation by the Arp2/3 complex and enhances formin-mediated actin filament elongation.
3-phosphoinositide-dependent kinase 1 (PDK1) is an essential serine/threonine protein kinase, which plays a crucial role in cell growth and proliferation. It is often referred to as a 'master' kinase ...due to its ability to activate at least 23 downstream protein kinases implicated in various signaling pathways. In this study, we have elucidated the mechanism of phosphoinositide-driven PDK1 auto-activation. We show that PDK1 trans-autophosphorylation is mediated by a PIP
-mediated face-to-face dimer. We report regulatory motifs in the kinase-PH interdomain linker that allosterically activate PDK1 autophosphorylation via a linker-swapped dimer mechanism. Finally, we show that PDK1 is autoinhibited by its PH domain and that positive cooperativity of PIP
binding drives switch-like activation of PDK1. These results imply that the PDK1-mediated activation of effector kinases, including Akt, PKC, Sgk, S6K and RSK, many of whom are not directly regulated by phosphoinositides, is also likely to be dependent on PIP
or PI(3,4)P
.
The coronavirus disease 2019 (COVID-19) pandemic is an unprecedented challenge for society, affecting those already subject to unacceptable health inequalities and resulting in vast economic impacts. ...The pandemic reminds everyone of the value and necessity of public health.In the context of an era that will be shaped by COVID-19, we outline the coming series of challenges and transitions in public health and the needed actions over the next 5 years to reinvent our public health systems. Multiple limitations in current US and global public health systems have been uncovered by the pandemic, including insufficient preparedness and surveillance capabilities complicated by long-standing and worsening health inequalities and the rapid spread of misinformation that needs to be countered. We foresee 3 phases for public health over the next 5 years: (1) reactive crisis management, (2) efforts to maintain initial gains, and (3) efforts to sustain and enhance progress.A reinvented public health system will depend highly on leadership and political will, rethinking how we categorize and address population-level risk, employing 21st-century data sciences, and applying new communication skills.
Abstract Context Demographic, personal, clinical, and behavioral factors predicting chemotherapy-induced nausea and vomiting (CINV) have been assessed in the past, but inconsistencies exist in the ...literature, studies have methodological shortcomings, and many risk factors have been examined in cross-sectional studies and univariate analyses. Objectives To evaluate the predictive power of personal and treatment-related characteristics in the development of CINV, using a large and prospectively evaluated sample of a heterogeneous group of cancer patients receiving routine chemotherapy. Methods This was a multicountry, multisite prospective study over three cycles of chemotherapy. Adult patients from eight European countries about to receive highly and moderately emetogenic chemotherapy were recruited. Clinicians completed a case report form at or before the initial chemotherapy treatment, recording patient demographic and baseline clinical characteristics. Participants completed a daily patient diary for six days per chemotherapy cycle describing their CINV experience. Baseline patient data also included a history of nausea/vomiting (yes/no), patient expectation of nausea (0–100 mm visual analogue scale VAS), prechemotherapy anxiety (0–100 mm VAS), and prechemotherapy nausea (0–100 mm VAS) measured during the 24-hour period before chemotherapy initiation. Results There were 991 evaluable patients with complete Cycle 1 data, 888 for Cycle 2 data, and 769 for Cycle 3 data. A complex picture of predictor variables was shown, with different contribution of variables to the acute, delayed, and overall phases of CINV. Key predictor variables included the use of antiemetics inconsistent with international guidelines, younger age, prechemotherapy nausea, and no CINV complete response in an earlier cycle (all at P < 0.05). Anxiety, history of nausea/vomiting, and expectations of nausea were important predictors for some phases and cycles but not consistently across the CINV pathway. Conclusion The results of this study provide clarity for the relative contribution of a set of characteristics in the development of CINV. Following evidence-based clinical antiemetic guidelines is of paramount importance, alongside treating patients with increased risk for CINV more aggressively, which both could lead to more optimal CINV management. These data can assist clinicians in making decisions about the antiemetic management of their patients.
To examine biomarkers of methylmercury (MeHg) intake in women and infants from seafood-consuming populations globally and characterize the comparative risk of fetal developmental neurotoxicity.
A ...search was conducted of the published literature reporting total mercury (Hg) in hair and blood in women and infants. These biomarkers are validated proxy measures of MeHg, a neurotoxin found primarily in seafood. Average and high-end biomarkers were extracted, stratified by seafood consumption context, and pooled by category. Medians for average and high-end pooled distributions were compared with the reference level established by a joint expert committee of the Food and Agriculture Organization (FAO) and the World Health Organization (WHO).
Selection criteria were met by 164 studies of women and infants from 43 countries. Pooled average biomarkers suggest an intake of MeHg several times over the FAO/WHO reference in fish-consuming riparians living near small-scale gold mining and well over the reference in consumers of marine mammals in Arctic regions. In coastal regions of south-eastern Asia, the western Pacific and the Mediterranean, average biomarkers approach the reference. Although the two former groups have a higher risk of neurotoxicity than the latter, coastal regions are home to the largest number at risk. High-end biomarkers across all categories indicate MeHg intake is in excess of the reference value.
There is a need for policies to reduce Hg exposure among women and infants and for surveillance in high-risk populations, the majority of which live in low-and middle-income countries.
The protein kinase Akt controls myriad signaling processes in cells, ranging from growth and proliferation to differentiation and metabolism. Akt is activated by a combination of binding to the lipid ...second messenger PI(3,4,5)P₃ and its subsequent phosphorylation by phosphoinositide-dependent kinase 1 and mechanistic target of rapamycin complex 2. The relative contributions of these mechanisms to Akt activity and signaling have hitherto not been understood. Here, we show that phosphorylation and activation by membrane binding are mutually interdependent. Moreover, the converse is also true: Akt is more rapidly dephosphorylated in the absence of PIP₃, an autoinhibitory process driven by the interaction of its PH and kinase domains. We present biophysical evidence for the conformational changes in Akt that accompany its activation onmembranes, show that Akt is robustly autoinhibited in the absence of PIP₃ irrespective of its phosphorylation, and map the autoinhibitory PH–kinase interface. Finally, we present a model for the activation and inactivation of Akt by an ordered series of membrane binding, phosphorylation, dissociation, and dephosphorylation events.
Significant elemental segregation is shown to exist within individual hollow silver–gold (Ag–Au) bimetallic nanoparticles obtained from the galvanic reaction between Ag particles and AuCl4 –. ...Three-dimensional compositional mapping using energy dispersive X-ray (EDX) tomography within the scanning transmission electron microscope (STEM) reveals that nanoparticle surface segregation inverts from Au-rich to Ag-rich as Au content increases. Maximum Au surface coverage was observed for nanoparticles with approximately 25 atom % Au, which correlates to the optimal catalytic performance in a three-component coupling reaction among cyclohexane carboxyaldehyde, piperidine, and phenylacetylene.
Humans and other animals change their behavior in response to unexpected outcomes. The orbitofrontal cortex (OFC) is implicated in such adaptive responding, based on evidence from reversal tasks. Yet ...these tasks confound using information about expected outcomes with learning when those expectations are violated. OFC is critical for the former function; here we show it is also critical for the latter. In a Pavlovian overexpectation task, inactivation of OFC prevented learning driven by unexpected outcomes, even when performance was assessed later. We propose this reflects a critical contribution of outcome signaling by OFC to encoding of reward prediction errors elsewhere. In accord with this proposal, we report that signaling of reward predictions by OFC neurons was related to signaling of prediction errors by dopamine neurons in ventral tegmental area (VTA). Furthermore, bilateral inactivation of VTA or contralateral inactivation of VTA and OFC disrupted learning driven by unexpected outcomes.
Hepatitis B is a serious public health problem across sub-Saharan Africa. Sierra Leone has no national hepatitis B strategy plan or high quality estimates of prevalence. Healthcare workers are ...perceived as an at-risk group for hepatitis B. We assessed the prevalence of hepatitis B among healthcare workers at two hospital sites in Freetown, Sierra Leone.
In October 2017, healthcare workers were offered voluntary testing for hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), hepatitis B core antibody (anti-HBc), hepatitis B e antigen (HBeAg) and hepatitis B e antibody (anti-HBe) using rapid lateral flow assay for all samples, followed by Enzyme Immunosorbent Assay to confirm positive results. Participants completed a questionnaire about knowledge, attitudes and practices concerning hepatitis B. HBsAg positive participants were invited to a clinic for further assessment.
Overall, 447 participants were tested for hepatitis B. Most (90.6%, 405/447) participants were nurses, 72.3% (323/447) were female and 71.6% (320/447) were 30 years or older. The prevalence of chronic hepatitis B (HBsAg positivity) was 8.7% (39 / 447, 95% CI 6.3-11.7%). There was no significant difference in prevalence by sex, age group, site of work or type of job. None of the 66.7% (26 / 39) of participants with chronic hepatitis B who attended the clinic met the 2015 WHO criteria to start treatment for hepatitis B on the basis of cirrhosis. Most participants (96.9% 432 / 446) stated that they were worried about their risk of hepatitis B at work.
Hepatitis B is highly prevalent among healthcare workers in Sierra Leone. It is unclear whether this reflects high community prevalence or is due to occupational risk. No participants with chronic hepatitis B needed to start treatment. In order to achieve the WHO target of elimination of viral hepatitis by 2030, introduction of birth dose vaccine for infants and catch-up vaccines for healthcare workers and healthcare students, together with a national hepatitis B screen and treat programme is advisable for Sierra Leone.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Anticipatory (prechemotherapy) nausea (AN) is a classic conditioned symptom not responding well to current antiemetics. Minimal work has been done to assess its risk factors and impact on ...chemotherapy-induced nausea and vomiting (CINV).
To evaluate risk factors for AN and assess its impact on CINV development.
We analyzed data (n = 991) from a prospective observational multisite study in eight European countries over three cycles of chemotherapy. Patient/treatment characteristics were collected before chemotherapy. History of nausea/vomiting (yes/no), patient expectation of CINV (0–100 mm visual analog scale, VAS), and prechemotherapy anxiety (0–100 mm VAS) also were collected before chemotherapy. A patient-completed diary during each chemotherapy cycle obtained information on AN in the 24 hours before chemotherapy administration and nausea and vomiting (episodes of vomiting and severity of nausea) daily for five days after administration of chemotherapy (0–100 mm VAS).
AN was reported by 8.3%–13.8% of patients, increasing in frequency and intensity over each cycle. Every 1 mm increase in AN on the VAS was significantly associated with 2%–13% of increase in the likelihood of CINV (all P-values <0.05). Key predictors of AN in Cycle 1 included metastatic disease and prechemotherapy anxiety. However, predictors of AN in subsequent cycles included prechemotherapy anxiety and AN and CINV experience in the previous cycle, the latter being the strongest predictor (odds ratio = 3.30–4.09 for CINV outcomes over the cycles).
AN is a challenging symptom, and its prevention needs to consider better CINV prevention in the previous cycles as well as managing prechemotherapy anxiety.
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