Hsp90 is an essential chaperone that guards proteome integrity and amounts to 2% of cellular protein. We now find that Hsp90 also has the ability to directly interact with and deform membranes via an ...evolutionarily conserved amphipathic helix. Using a new cell-free system and in vivo measurements, we show this amphipathic helix allows exosome release by promoting the fusion of multivesicular bodies (MVBs) with the plasma membrane. We dissect the relationship between Hsp90 conformation and membrane-deforming function and show that mutations and drugs that stabilize the open Hsp90 dimer expose the helix and allow MVB fusion, while these effects are blocked by the closed state. Hence, we structurally separated the Hsp90 membrane-deforming function from its well-characterized chaperone activity, and we show that this previously unrecognized function is required for exosome release.
Display omitted
•Hsp90 has a previously unrecognized membrane-remodeling function•This novel activity occurs via an evolutionarily conserved amphipathic helix•Compounds that lock the Hsp90 dimer in a closed state inhibit membrane deformation•Hsp90 membrane-deforming ability promotes exosome release in vitro and in vivo
Hsp90 is a master regulator of protein homeostasis. Lauwers et al. now find that Hsp90 directly binds and deforms membranes in addition to operating as chaperone. This novel activity of Hsp90 promotes the fusion of multivesicular bodies with the plasma membrane and the subsequent release of exosomes.
Pressure ulcers (PU) are wounds located mainly on bone surfaces where the tissue under pressure suffers ischemia leading to cellular lesion and necrosis , its causes and the healing process depend on ...several factors. The aim of this study was evaluating the gene expression of inflammatory/reparative factors: IL6, TNF, VEGF, and TGF, which take part in the tissue healing process under effects of low-level laser therapy (LLLT). In order to perform lesion area analysis, PUs were photographed and computer analyzed. Biochemical analysis was performed sa.mpling ulcer border tissue obtained through biopsy before and after laser therapy and quantitative real-time PCR (qRT-PCR) analysis. The study comprised eight individuals, mean age sixty-two years old, and sacroiliac and calcaneous PU, classified as degree III and IV according to the National Pressure Ulcer Advisory Panel (NPUAP). PUs were irradiated with low-level laser (InGaAIP, 100 mW, 660 nm), energy density 2 J/cm
2
, once a day, with intervals of 24 h, totaling 12 applications. The lesion area analysis revealed averaged improvement of the granulation tissue size up to 50% from pre- to post-treatment. qRT-PCR analysis revealed that IL6 values were not significantly different before and after treatment, TNF gene expression was reduced, and VEFG and TGF-β gene expression increased after treatment. After LLLT, wounds presented improvement in gross appearance, with increase in factors VEFG and TGF-β, and reduction of TNF; despite our promising results, they have to be analyzed carefully as this study did not have a control group.
ObjectiveTo evaluate whether the addition of colchicine to standard treatment for COVID-19 results in better outcomes.DesignWe present the results of a randomised, double-blinded, placebo-controlled ...clinical trial of colchicine for the treatment of moderate to severe COVID-19, with 75 patients allocated 1:1 from 11 April to 30 August 2020. Colchicine regimen was 0.5 mg thrice daily for 5 days, then 0.5 mg twice daily for 5 days. The primary endpoints were the need for supplemental oxygen, time of hospitalisation, need for admission and length of stay in intensive care unit and death rate.ResultsSeventy-two patients (36 for placebo and 36 for colchicine) completed the study. Median (and IQR) time of need for supplemental oxygen was 4.0 (2.0–6.0) days for the colchicine group and 6.5 (4.0–9.0) days for the placebo group (p<0.001). Median (IQR) time of hospitalisation was 7.0 (5.0–9.0) days for the colchicine group and 9.0 (7.0–12.0) days for the placebo group (p=0.003). At day 2, 67% versus 86% of patients maintained the need for supplemental oxygen, while at day 7, the values were 9% versus 42%, in the colchicine and the placebo groups, respectively (log rank; p=0.001). Two patients died, both in placebo group. Diarrhoea was more frequent in the colchicine group (p=0.26).ConclusionColchicine reduced the length of both, supplemental oxygen therapy and hospitalisation. The drug was safe and well tolerated. Once death was an uncommon event, it is not possible to ensure that colchicine reduced mortality of COVID-19.Trial registration numberRBR-8jyhxh.
The extent (or lack) of phylogenetic signal for key ecological traits reveals the role of evolutionary processes on present‐day ecosystem function and hints on future ecological trends under climate ...change scenarios. This approach has been applied to South American tropical moist forests, but not to the highly threatened seasonally dry tropical forests (SDTF), despite the acknowledgement of their unique evolutionary history. To fill this knowledge gap, we investigated the legacy of evolutionary processes on vital ecological characteristics among SDTF trees: regional dominance, tree size and soil preference.
We used tree community data on 313 plots of SDTF (12.52 ha) and locally collected soil data in central‐eastern Brazil. For each assessed trait (three for regional dominance, three for tree size and nine for soil preference), we investigated the legacy of evolution using two different approaches: calculating the extent of phylogenetic signal and comparing the fit of four different models of evolution.
Above‐ground woody biomass and tree size showed strong phylogenetic signal. Most of the SDTF biomass stock was concentrated on a few large‐sized and closely related tree genera. Among the soil preference variables, only phosphorus displayed significant, albeit weak, phylogenetic signal.
Synthesis. Our study is the first to show that evolutionary constraints related to tree size significantly determine regional biomass stocks of seasonally dry tropical forests (SDTF) in a few closely related tree lineages. This suggests that even isolated SDTF fragments with low taxonomic and phylogenetic diversity can play an important role in the global carbon cycle, storing disproportionally large amounts of carbon in trees that belong to high‐biomass lineages. Whether these lineages also share climate change‐induced mortality risk deserves future investigation, as they are largely responsible for the maintenance of regional SDTF biomass stocks.
Resumo
A extensão (ou falta) de sinal filogenético para características ecológicas revela o papel de processos evolutivos em funções ecossistêmicas atuais e sugere futuras tendências ecológicas sob o cenário das mudanças climáticas. Esta abordagem já foi aplicada às florestas úmidas tropicais da América do Sul, mas não às ameaçadas florestas tropicais sazonalmente secas (FTSS), apesar de seu histórico evolutivo único. Para preencher esta lacuna, nós investigamos o legado de processos evolutivos em características ecológicas essenciais entre árvores de FTSS: dominância regional, tamanho de árvores e preferência edáfica.
Usamos dados da comunidade arbórea e dados de solo localmente coletados em 313 parcelas (12,52 hectares) de FTSS do centro‐leste brasileiro. Para cada característica avaliada (três para dominância regional, três para tamanho de árvores e nove para preferência edáfica), investigamos o legado da evolução a partir de duas abordagens: calculando a extensão do sinal filogenético e comparando o ajuste de quatro modelos de evolução.
Encontramos forte sinal filogenético para biomassa lenhosa acima do solo e tamanho de árvores. A maior parte do estoque de biomassa das FTSS esteve concentrado em alguns gêneros aparentados que possuem grandes árvores. Entre as variáveis de preferência edáfica, somente fósforo apresentou sinal filogenético significativo, ainda que fraco.
Síntese. Nosso estudo é o primeiro a mostrar que restrições evolutivas relacionadas ao tamanho de árvores determinam significativamente o estoque regional de biomassa de FTSS em linhagens aparentadas de árvores. Isto sugere que mesmo fragmentos isolados de FTSS com baixas diversidades taxonômica e filogenética podem ter um papel importante no ciclo de carbono global, estocando quantidades desproporcionalmente grandes de carbono em árvores que pertencem a linhagens de alta biomassa. Também merece ser investigado se estas linhagens compartilham risco de mortalidade induzido pelas mudanças climáticas, uma vez que elas são amplamente responsáveis pela manutenção dos estoques regionais de biomassa em FTSS.
Our study is the first to show that evolutionary constraints related to tree size significantly determine regional biomass stocks of seasonally dry tropical forests (SDTF) in a few closely related tree lineages. This suggests that even isolated SDTF fragments with low taxonomic and phylogenetic diversity can play an important role in the global carbon cycle, storing disproportionally large amounts of carbon in trees that belong to high‐biomass lineages. Whether these lineages also share climate change‐induced mortality risk deserves future investigation, as they are largely responsible for the maintenance of regional SDTF biomass stocks.
Taste and smell play a key role in our ability to perceive foods. Overconsumption of highly palatable energy-dense foods can lead to increased caloric intake and obesity. Thus there is growing ...interest in the study of the biological mediators of fat taste and associated olfaction as potential targets for pharmacologic and nutritional interventions in the context of obesity and health. The number of studies examining mechanisms underlying fat taste and smell has grown rapidly in the last 5 years. Therefore, the purpose of this systematic review is to summarize emerging evidence examining the biological mechanisms of fat taste and smell. A literature search was conducted of studies published in English between 2014 and 2021 in adult humans and animal models. Database searches were conducted using PubMed, EMBASE, Scopus, and Web of Science for key terms including fat/lipid, taste, and olfaction. Initially, 4,062 articles were identified through database searches, and a total of 84 relevant articles met inclusion and exclusion criteria and are included in this review. Existing literature suggests that there are several proteins integral to fat chemosensation, including cluster of differentiation 36 (CD36) and G protein-coupled receptor 120 (GPR120). This systematic review will discuss these proteins and the signal transduction pathways involved in fat detection. We also review neural circuits, key brain regions, ingestive cues, postingestive signals, and genetic polymorphism that play a role in fat perception and consumption. Finally, we discuss the role of fat taste and smell in the context of eating behavior and obesity.
Roux‐en‐Y gastric bypass is one of the most common surgical treatments for obesity due to the effective long‐term weight loss and remission of associated comorbidities. Carvedilol, a third‐generation ...β‐blocker, is prescribed to treat cardiovascular diseases. This drug is a weak base with low and pH‐dependent solubility and dissolution and high permeability. As the changes in the gastrointestinal tract anatomy and physiology after roux‐en‐Y gastric bypass can potentially affect drug pharmacokinetics, this study aimed to assess the effect of roux‐en‐Y gastric bypass on the pharmacokinetics of carvedilol enantiomers. Nonobese (n = 15, body mass index < 25 kg/m2), obese (n = 19, body mass index ≥ 30), and post‐roux‐en‐Y gastric bypass subjects submitted to surgery for at least 6 months (n = 19) were investigated. All subjects were administered a single oral dose of 25‐mg racemic carvedilol, and blood was sampled for up to 24 hours. Plasma concentrations of (R)‐ and (S)‐carvedilol were determined by liquid chromatography–tandem mass spectrometry. The maximum plasma concentration (Cmax) and the area under the plasma concentration‐time curve (AUC) of (R)‐carvedilol were 2‐ to 3‐fold higher than (S)‐carvedilol in all groups. Obese subjects have shown reduced Cmax of (R)‐ and (S)‐carvedilol without changing the AUC. Post‐roux‐en‐Y gastric bypass subjects presented a 3.5‐fold reduction in the Cmax of the active (S)‐carvedilol and a 1.9 reduction in the AUC from time 0 to infinity compared to nonobese subjects. The time to reach Cmax of (S)‐carvedilol increased 2.5‐fold in post‐roux‐en‐Y gastric bypass subjects compared to obese or nonobese. Although the β‐blockade response was not assessed, the reduced exposure to carvedilol in subjects post‐roux‐en‐Y gastric bypass may be clinically relevant and require dose adjustment.
The development of protective self-detoxifying materials is an important societal challenge to counteract risk of attacks employing highly toxic chemical warfare agents (CWAs). In this work, we have ...developed bifunctional zirconium metal–organic frameworks (MOFs) incorporating variable amounts of nucleophilic amino residues by means of formation of the mixed ligand Zr6O4(OH)4(bdc)6(1–x)(bdc-NH2)6x (UiO-66-xNH 2 ) and Zr6O4(OH)4(bpdc)6(1–x)(bpdc-(NH2)2)6x (UiO-67-x(NH 2 ) 2 ) systems where bdc = benzene-1,4-dicarboxylate; bdc-NH2= benzene-2-amino-1,4-dicarboxylate; bpdc = 4,4′-biphenyldicarboxylate; bpdc-(NH2)2 = 2,2′-diamino-4,4′-biphenyldicarboxylate and x = 0, 0.25, 0.5, 0.75, 1. In a second step, the UiO-66-xNH 2 and UiO-67-x(NH 2 ) 2 systems have been postsynthetically modified by introduction of highly basic lithium tert-butoxide (LiO t Bu) on the oxohydroxometallic clusters of the mixed ligand MOFs to yield UiO-66-xNH 2 @LiO t Bu and UiO-67-x(NH 2 ) 2 @LiO t Bu materials. The results show that the combination of pre and postsynthetic modifications on these MOF series gives rise to fine-tuning of the catalytic activity toward the hydrolytic degradation of both simulants and real CWAs in unbuffered aqueous solutions. Indeed, UiO-66-0.25NH 2 @LiO t Bu is able to hydrolyze both CWAs simulants (diisopropylfluorophosphate (DIFP), 2-chloroethylethylsulfide (CEES), and real CWAs (soman (GD), sulfur mustard (HD)) quickly in aqueous solution. These results are related to a suitable combination of robustness, nucleophilicity, basicity, and accessibility to the porous framework.
The list of standard abbreviations for JDS is available at adsa.org/jds-abbreviations-24. Nonstandard abbreviations are available in the Notes.
This study was conducted to evaluate the effects of ...live or autolyzed yeast supplementation on dairy cow performance and ruminal fermentation. Two experiments were conducted to evaluate performance, feed sorting, total-tract apparent digestibility of nutrients, purine derivatives excretion, N utilization, ruminal fermentation, and the abundance of specific bacterial groups in the rumen. In experiment 1, 39 Holstein cows (171 ± 40 DIM and 32.6 ± 5.4 kg/d milk yield) were blocked according to parity, DIM, and milk yield and randomly assigned to the following treatments: control (CON); autolyzed yeast fed at 0.625 g/kg DM (AY; Levabon, DSM-Firmenich); or live yeast fed at 0.125 g/kg DM (LY; Vistacell, AB Vista). Cows were submitted to a 2-wk adaptation period followed by a 9-wk trial. In experiment 2, 8 ruminal cannulated Holstein cows (28.4 ± 4.0 kg/d milk yield and 216 ± 30 DIM), of which 4 were multiparous and 4 were primiparous, were blocked according to parity and enrolled into a 4 × 4 Latin square experiment with 21-d periods (the last 7 d for sampling). Cows within blocks were randomly assigned to treatment sequences: control (CON), LY (using the same product and dietary concentration as described in experiment 1), AY, or autolyzed yeast fed at 0.834 g/kg DM (AY2). In experiments 1 and 2, nutrient intake and total-tract apparent digestibility were not affected by treatments. Sorting for long feed particles (>19 mm) tended to be greater in cows fed yeast supplements than CON in experiment 1. Efficiency of N conversion into milk N was increased when feeding yeast supplements in experiment 1, and 3.5% FCM yield tended to be greater in cows fed yeast supplements than CON. Feed efficiency was increased when yeast supplements were fed to cows in relation to CON in experiment 1. In experiment 2, yield of FCM and fat were greater in cows fed yeast supplements compared with CON. Uric acid concentration and output in urine were increased when feeding yeast supplements when compared with CON. Neither ruminal pH nor total VFA were influenced by treatments. The current study did not reveal treatment differences in ruminal abundance of Anaerovibrio lipolytica, the genus Butyrivibrio, Fibrobacter succinogenes, Butyrivibrio proteoclasticus, or Streptococcus bovis. Yeast supplementation can increase feed efficiency without affecting nutrient intake and digestibility, ruminal VFA concentration, or ruminal abundance of specific bacterial groups. Supplementing live or autolyzed yeast, regardless of the dose, resulted in similar performance.
Enteric pathogens have developed mechanisms to disrupt tight junctions and increase gut permeability. Many studies have analysed the ability of live probiotics to protect intestinal epithelial cells ...against tight junction damage caused by bacterial pathogens. Escherichia coli Nissle 1917 (EcN) is among the probiotics that positively modulates the intestinal epithelial barrier by regulating expression and distribution of tight junction proteins. We previously reported that regulation of ZO-1, claudin-14 and claudin-2 is mediated by EcN secreted factors, either free-released or associated with outer membrane vesicles (OMVs). Factors secreted by commensal ECOR63 elicited comparable effects in intact epithelial T-84 and Caco-2 cell monolayers.
Here we analyse the ability of OMVs and soluble secreted factors to protect epithelial barrier function in polarized T-84 and Caco-2 cells infected with enteropathogenic Escherichia coli (EPEC). Transepithelial electrical resistance, paracellular permeability, mRNA levels and subcellular distribution of tight junction proteins were monitored in the absence or presence of EcN and ECOR63 extracellular fractions. EPEC downregulated expression of ZO-1 ZO-2, occludin and claudin-14 and altered the subcellular localization of ZO-1, occludin and F-actin cytoskeleton. OMVs and soluble factors secreted by EcN and ECOR63 counteracted EPEC-altered transepithelial resistance and paracellular permeability, preserved occludin and claudin-14 mRNA levels, retained ZO-1 and occludin at tight junctions in the cell boundaries and ameliorated F-actin disorganization. Redistribution of ZO-1 was not accompanied by changes at mRNA level.
This study provides new insights on the role of microbiota secreted factors on the modulation of intestinal tight junctions, expanding their barrier-protective effects against pathogen-induced disruption.
Understanding the effects of intensification of Amazon basin hydrological cycling—manifest as increasingly frequent floods and droughts—on water and energy cycles of tropical forests is essential to ...meeting the challenge of predicting ecosystem responses to climate change, including forest “tipping points”. Here, we investigated the impacts of hydrological extremes on forest function using 12+ years of observations (between 2001–2020) of water and energy fluxes from eddy covariance, along with associated ecological dynamics from biometry, at the Tapajós National Forest. Measurements encompass the strong 2015–2016 El Niño drought and La Niña 2008–2009 wet events. We found that the forest responded strongly to El Niño‐Southern Oscillation (ENSO): Drought reduced water availability for evapotranspiration (ET) leading to large increases in sensible heat fluxes (H). Partitioning ET by an approach that assumes transpiration (T) is proportional to photosynthesis, we found that water stress‐induced reductions in canopy conductance (Gs) drove T declines partly compensated by higher evaporation (E). By contrast, the abnormally wet La Niña period gave higher T and lower E, with little change in seasonal ET. Both El Niño‐Southern Oscillation (ENSO) events resulted in changes in forest structure, manifested as lower wet‐season leaf area index. However, only during El Niño 2015–2016, we observed a breakdown in the strong meteorological control of transpiration fluxes (via energy availability and atmospheric demand) because of slowing vegetation functions (via shutdown of Gs and significant leaf shedding). Drought‐reduced T and Gs, higher H and E, amplified by feedbacks with higher temperatures and vapor pressure deficits, signaled that forest function had crossed a threshold, from which it recovered slowly, with delay, post‐drought. Identifying such tipping point onsets (beyond which future irreversible processes may occur) at local scale is crucial for predicting basin‐scale threshold‐crossing changes in forest energy and water cycling, leading to slow‐down in forest function, potentially resulting in Amazon forests shifting into alternate degraded states.
We studied tropical forest's response to hydrological extremes—2015–2016 El Niño drought and 2008–2009 La Niña wet events—at the K67 Tapajós National Forest, by analyzing 12+ years of micrometeorological and biometric data.
During the wet La Niña, transpiration increased while evaporation decreased, with little change in seasonal water fluxes. Conversely, El Niño's drought led to the breakdown of the strong meteorological control over transpiration as vegetation functions slowed (leaf shedding increased and stomatal conductance shutdown). Reduced evapotranspiration resulted in higher sensible heat fluxes, amplified by feedback effects (higher temperatures and atmospheric demand). The forest crossed a threshold, recovering slowly post‐drought.
PDF
