ATP-hydrolysis-coupled actin polymerization is a fundamental mechanism of cellular force generation
. In turn, force
and actin filament (F-actin) nucleotide state
regulate actin dynamics by tuning ...F-actin's engagement of actin-binding proteins through mechanisms that are unclear. Here we show that the nucleotide state of actin modulates F-actin structural transitions evoked by bending forces. Cryo-electron microscopy structures of ADP-F-actin and ADP-P
-F-actin with sufficient resolution to visualize bound solvent reveal intersubunit interfaces bridged by water molecules that could mediate filament lattice flexibility. Despite extensive ordered solvent differences in the nucleotide cleft, these structures feature nearly identical lattices and essentially indistinguishable protein backbone conformations that are unlikely to be discriminable by actin-binding proteins. We next introduce a machine-learning-enabled pipeline for reconstructing bent filaments, enabling us to visualize both continuous structural variability and side-chain-level detail. Bent F-actin structures reveal rearrangements at intersubunit interfaces characterized by substantial alterations of helical twist and deformations in individual protomers, transitions that are distinct in ADP-F-actin and ADP-P
-F-actin. This suggests that phosphate rigidifies actin subunits to alter the bending structural landscape of F-actin. As bending forces evoke nucleotide-state dependent conformational transitions of sufficient magnitude to be detected by actin-binding proteins, we propose that actin nucleotide state can serve as a co-regulator of F-actin mechanical regulation.
Summary Clear cell papillary renal cell carcinoma (CCP-RCC) has recently been recognized as a distinct subtype of renal cell carcinoma (RCC) due to its unique morphologic, immunohistochemical, and ...genetic features and indolent clinical behavior. However, the incidence of this tumor in a nephrectomy series for renal mass has not been fully investigated. Twelve cases of CCP-RCC were identified from a total of 290 consecutive partial (n = 137) or radical nephrectomies (n = 153) for RCC from 2010 to 2012 in our hospital. In this series, CCP-RCC was the fourth most common (4.1%) kidney tumor following clear cell (conventional) (70%), papillary (16.6%), and chromophobe (5.9%) RCCs. The average age of the CCP-RCC patients was 58.2 years (range, 18-81 years), with an equal sex distribution. Four cases (33.3%) were associated with end-stage renal disease. Of the 12 CCP-RCCs, 9 presented as solitary tumors; 2 coexisted with clear cell RCC; and 1 with papillary RCC. The average size of tumors was 2.5 cm (range, 0.8-6.0 cm). All tumors were pT1 (10 pT1a and 2 pT1b). Two cases were initially misclassified as clear cell RCC. Strong positive cytokeratin 7 stain and negative stains with α -methylacyl-CoA racemase and RCC marker differentiate CCP-RCC from low-grade clear cell RCC with similar histologic features. We conclude that CCP-RCC is a common renal neoplastic entity, representing the fourth most common (4.1%) RCC. It can be easily misclassified due to its overlapping features with low-grade clear cell RCC. In equivocal cases, immunohistochemical stains with a small panel of markers (cytokeratin 7, α -methylacyl-CoA racemase, RCC marker, or CD10) are warranted in making the correct histologic classification.
Combined evidence of published prospective outcome trials and meta-analyses substantiate elevated asleep blood pressure (BP) and blunted sleep-time relative BP decline (non-dipping), regardless of ...wake-time office BP and awake or 24 h BP means, are jointly the most highly significant independent prognostic markers of cardiovascular disease (CVD) risk and worthy therapeutic targets for prevention. Nonetheless, current guidelines continue to recommend the diagnosis of hypertension, when based on ambulatory BP monitoring (ABPM), rely, solely, on either the 24 h or “daytime” BP means. They also fail to recommend the time to treat patients. We conducted a systematic review of published human trials regarding ingestion-time differences in the effects of hypertension medications on asleep BP and sleep-time relative BP decline. Some 62 such trials published between 1992 and 2020, totaling 6120 hypertensive persons, evaluated 21 different single and 8 dual-fixed combination therapies. The vast (82.3%) majority of the trials substantiate the bedtime/evening vs. upon-waking/morning treatment schedule produces statistically significant better clinical benefits, including enhanced reduction of asleep systolic BP by an average 5.17 mmHg (95%CI 4.04, 6.31, P < 0.001 between treatment-time groups) without inducing sleep-time hypotension, reduced prevalence of the high CVD risk non-dipper 24 h BP pattern, improved kidney function, and reduced cardiac pathology. Furthermore, systematic and comprehensive review of the ABPM-based literature published the past 29 years reveals no single study that reported significantly better benefits of the most recommended, yet unjustified by medical evidence, morning hypertension treatment-time scheme.
Pharmacokinetics of hypertension medications is significantly affected by circadian rhythms that influence absorption, distribution, metabolism and elimination. Furthermore, their pharmacodynamics is ...affected by ingestion-time differences in kinetics and circadian rhythms comprising the biological mechanism of the 24 h blood pressure (BP) pattern. However, hypertension guidelines do not recommend the time to treat patients with medications. We conducted a systematic review of published evidence regarding ingestion-time differences of hypertension medications and their combinations on ambulatory BP-lowering, safety, and markers of target organ pathology. Some 153 trials published between 1976 and 2020, totaling 23,869 hypertensive individuals, evaluated 37 different single and 14 dual-fixed combination therapies. The vast (83.7%) majority of the trials report clinically and statistically significant benefits – including enhanced reduction of asleep BP without inducing sleep-time hypotension, reduced prevalence of the higher cardiovascular disease risk BP non-dipping 24 h profile, decreased incidence of adverse effects, improved renal function, and reduced cardiac pathology – when hypertension medications are ingested at-bedtime/evening rather than upon-waking/morning. Non-substantiated treatment-time difference in effects by the small proportion (16.3%) of published trials is likely explained by deficiencies of study design and conduct. Systematic and comprehensive review of the literature published the past 45 years reveals no single study reported significantly better benefit of the still conventional, yet unjustified by medical evidence, upon-waking/morning hypertension treatment schedule.
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This study presents a green synthesis method for the exfoliation of FLG (few-layer graphene) and their functionalization with silver nanoparticles using the extract from the plant Jatropha Cordata. ...This is a competitive synthesis method, given that it uses graphite as the precursor material of graphene, and avoids using highly toxic compounds in the exfoliation, stabilization and functionalization processes. The relation between the intensity of the bands D and G, as well as the diverse contributions that make up band 2D suggest the exfoliation of graphene. The structural studies were performed using FFT (Fast Fourier Transform), which allowed the identification of crystalline planes on graphene and silver nanostructures. The vibrational study through FTIR (Fourier-transform Infrared Spectroscopy) allowed the identification of functional groups (hydroxyl, carbonyl and carboxyl) in the molecules of the extract. The silver nanostructures showed affinity towards the interaction of the edge of graphene layers.
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•Green synthesis of FLG functionalized with silver nanoparticles•Jatropha Cordata extract for stabilization of silver nanoparticles•Graphite to graphene green synthesis
This article reports the theoretical and experimental study of nonresonant mechanisms (CHEM) of surface‐enhanced Raman spectroscopy (SERS) of pyridine (Py). An improvement in the Raman dispersion ...intensity of Py is determined after the chemical absorption on CuO nanoparticles synthesized in NaCl. The density functional theory predicts the formation of new electronic states as result of the chemical bond (CB) established between the Py molecule and the (CuO)n clusters. This study is focused on the study of the most intense vibrational modes of Py before and after chemical adsorption. The CHEM by CB mechanisms is found as responsible for the SERS effect in Py.
CuO nanoparticles were obtained in NaCl matrix. Overall enhancement of the Raman linesof Py have been found, consequence of chemical bonding stablished with CuO Nps. The DFTcalculation of Py chemical adsorbed in cluster of (CuO)n, reveal the formation of new electronicstates conducing to spatial redistribution of HOMO‐LUMO orbitals and the increase of Ramanlines intensities until 103.The main contribution to the SERS effect of Py is attributed tochemical enhancement.
Abstract
Peer support is effective in improving self-management behaviors and health outcomes among individuals with Type 2 diabetes. Volunteer peer support programs offer a cost-effective resource ...for diabetes self-management support; however, factors affecting the retention of volunteer peer leaders remain understudied. Herein, we examined factors associated with volunteer retention and satisfaction among 34 predominantly Mexican-origin peer leaders who assisted patients from a Federally Qualified Health Center located on the US/Mexico border with their diabetes management. Peer leaders completed surveys with open- and close-ended questions at baseline, 6 months and 12 months. Quantitative and qualitative data analyses were guided by the Volunteer Process Model. Using nonparametric Mann–Whitney U tests, self-efficacy as a peer leader at 6 months was most associated with interest to continue volunteering (P = 0.01), and satisfaction with support from the program at 12 months was most associated with interest to continue volunteering (P = 0.01). The qualitative data indicated that the relationship between the peer leaders and their patients was the primary factor for a satisfying volunteer experience. Future research should focus on increasing peer leaders’ self-efficacy and satisfaction with program support and examine how organizations can support the development of the patient–peer relationship. Practitioners should consider appealing to volunteer peers’ motivations to promote their retention.
Nanoparticles can enhance the intensity of susceptible vibrational modes through electromagnetic or chemical enhancement mechanisms responsible for the SERS effect (Surface-enhanced Raman ...spectroscopy). In the present work, copper nanoparticles (CuNP) with diameters between 3 and 10 nm were obtained by a simple method using rongalite and gelatin. The UV–Vis spectrum showed a well-defined absorption band centered at 570 nm, attributed to the surface plasmon resonance (SPR) of CuNP in a colloidal solution. The SERS effect was analyzed on the pyridine (Py) molecule, observing an enhancement in the radial breathing mode of Py. Complementarily, Cu
4n
clusters (with
n
= 1–5) were modeled under the DFT (Density Functional Theory) framework at the B3LYP (Becke, 3-parameter, Lee–Yang–Parr) approximation level in combination with the LANL2DZ base set (Los Alamos National Laboratory 2 Double-Zeta). After analyzing the molecular descriptors, the Cu
4n
-Py interaction study provided hints of SERS behavior.
The pharmacokinetics (PK) - absorption, distribution, metabolism, and elimination - and pharmacodynamics (PD) of hypertension medications can be significantly affected by circadian rhythms. As a ...consequence, the time when blood pressure (BP) lowering medications are ingested, with reference to the staging of all involved circadian rhythms modulating PK and PD, can affect their duration of action, magnitude of effect on features of the 24 h BP profile, and safety. We conducted a systematic and comprehensive review of published prospective human trials that investigated individual hypertension medications of all classes and their combinations for ingestion-time differences in BP-lowering, safety, patient adherence, and markers of hypertension-associated target organ pathology of the kidney and heart. The systematic review yielded 155 trials published between 1976 and 2020 - totaling 23,972 hypertensive individuals - that evaluated 37 different single and 14 dual-combination therapies. The vast (83.9%) majority of them reported clinically and statistically significant benefits - including enhanced reduction of asleep BP mean without induced sleep-time hypotension, reduced prevalence of the higher cardiovascular risk non-dipper 24 h BP profile, decreased incidence of adverse effects, improved kidney function, and reduced cardiac pathology - when hypertension medications are ingested at-bedtime/evening rather than upon-waking/morning. Nonetheless, the findings and conclusions of some past conducted trials are inconsistent, often due to disparities and deficiencies of the investigative protocols. Accordingly, we developed a quality assessment method based upon the eight items identified as crucial according to the recently published guidelines of the International Society for Chronobiology and the American Association for Medical Chronobiology and Chronotherapeutics for the design and conduct of human clinical trials on ingestion-time differences of hypertension medications. Among the most frequent deficiencies are: absence or miscalculation of minimum required sample size (83.2%), incorrect choice of primary BP endpoint (53.6%), and inappropriate arbitrary and unrepresentative clock hours chosen for tested treatment times (53.6%). The inability of the very small proportion (16.1%) of trials to verify the advantages of the at-bedtime/evening treatment strategy is likely explained by deficiencies of their study design and conduct. Nonetheless, regardless of the quality score of the 155 trials retrieved by our systematic review, it is most noteworthy that no single published prospective randomized trial reported significantly enhanced BP-lowering, safety, compliance, or other benefits of the unjustified by medical evidence, yet still most recommended, upon-waking/morning hypertension treatment-time scheme.
The eukaryotic genome is mainly transcribed into non-coding RNAs (ncRNAs), including different RNA biotypes, such as micro RNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), ...among others. Although miRNAs are assumed to act primarily in the cytosol, mature miRNAs have been reported and functionally characterized in the nuclei of different cells. Further, lncRNAs are important regulators of different biological processes in the cell nucleus as part of different ribonucleoprotein complexes. CircRNAs constitute a relatively less-characterized RNA biotype that has a circular structure as result of a back-splicing process. However, circRNAs have recently attracted attention in different scientific fields due to their involvement in various biological processes and pathologies. In this review, we will summarize recent studies that link to cancer miRNAs that have been functionally characterized in the cell nucleus, as well as lncRNAs and circRNAs that are bound by core components of the polycomb repressive complex 2 (PRC2) or the protein fused in sarcoma (FUS), highlighting mechanistic aspects and their diagnostic and therapeutic potential.
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