The communication between the intestinal epithelium and the enteric nervous system has been considered indirect. Mechanical or chemical stimuli activate enteroendocrine cells inducing hormone ...secretion, which act on sub-epithelial nerve ends, activating the enteric nervous system. However, we identified an epithelial cell that expresses NKAIN4, a neuronal protein associated with the β-subunit of Na+/K+-ATPase. This cell overexpresses Na+/K+-ATPase and ouabain-insensitive Na+-ATPase, enzymes involved in active sodium transport. NKAIN4-positive cells also express neuronal markers as NeuN, acetylcholine-esterase, acetylcholine-transferase, α3- and α7-subunits of ACh receptors, glutamic-decarboxylase, and serotonin-receptor-7, suggesting they are neurons. NKAIN4-positive cells show a polarized shape with an oval body, an apical process finished in a knob-like terminal in contact with the lumen, a basal cilia body at the base of the apical extension, and basal axon-like soma projections connecting sub-epithelial nerve terminals, lymphoid nodules, glial cells, and enterochromaffin cells, forming a network that reaches the epithelial surface. We also showed, using retrograde labeling and immunofluorescence, that these cells receive afferent signals from the enteric nervous system. Finally, we demonstrated that acetylcholine activates NKAIN4-positive cells inducing Ca2+ mobilization and probably serotonin secretion in enterochromaffin cells. NKAIN4-positive cells are neurons that would form a part of a duodenal sensory network for physiological or noxious luminal stimuli.
The enormous versatility of mesoporous silica nanoparticles permits the creation of a large number of nanotherapeutic systems for the treatment of cancer and many other pathologies. In addition to ...the controlled release of small drugs, these materials allow a broad number of molecules of a very different nature and sizes. In this review, we focus on biogenic species with therapeutic abilities (proteins, peptides, nucleic acids, and glycans), as well as how nanotechnology, in particular silica-based materials, can help in establishing new and more efficient routes for their administration. Indeed, since the applicability of those combinations of mesoporous silica with bio(macro)molecules goes beyond cancer treatment, we address a classification based on the type of therapeutic action. Likewise, as illustrative content, we highlight the most typical issues and problems found in the preparation of those hybrid nanotherapeutic materials.
Endurance runners are often advised to use 90 strides min(-1), but how optimal is this stride frequency and why? Endurance runners are also often advised to maintain short strides and avoid landing ...with the feet too far in front of their hips or knees (colloquially termed 'overstriding'), but how do different kinematic strategies for varying stride length at the same stride frequency affect economy and impact peaks? Linear mixed models were used to analyze repeated measures of stride frequency, the anteroposterior position of the foot at landing, V̇O2 , lower extremity kinematics and vertical ground reaction forces in 14 runners who varied substantially in height and body mass and who were asked to run at 75, 80, 85, 90 and 95 strides min(-1) at 3.0 m s(-1). For every increase of 5 strides min(-1), maximum hip flexor moments in the sagittal plane increased by 5.8% (P<0.0001), and the position of the foot at landing relative to the hip decreased by 5.9% (P=0.003). Higher magnitudes of posteriorly directed braking forces were associated with increases in foot landing position relative to the hip (P=0.0005) but not the knee (P=0.54); increases in foot landing position relative to the knee were associated with higher magnitudes (P<0.0001) and rates of loading (P=0.07) of the vertical ground reaction force impact peak. Finally, the mean metabolically optimal stride frequency was 84.8±3.6 strides min(-1), with 50.4% of the variance explained by the trade-off between minimizing braking forces versus maximum hip flexor moments during swing. The results suggest that runners may benefit from a stride frequency of approximately 85 strides min(-1) and by landing at the end of swing phase with a relatively vertical tibia.
In the context of translational research, there is growing interest in studying surgical orthopedic pain management approaches that are common to humans and dogs. The validity of postoperative pain ...assessment methods is uncertain with regards to responsiveness and the potential interference of analgesia. The hypothesis was that video analysis (as a reference), electrodermal activity, and two subjective pain scales (VAS and 4A-VET) would detect different levels of pain intensity in dogs after a standardized trochleoplasty procedure. In this prospective, blinded, randomized study, postoperative pain was assessed in 25 healthy dogs during a 48-hour time frame (T). Pain was managed with placebo (Group 1, n = 10), preemptive and multimodal analgesia (Group 2, n = 5), or preemptive analgesia consisting in oral tramadol (Group 3, n = 10). Changes over time among groups were analyzed using generalized estimating equations. Multivariate regression tested the significance of relationships between pain scales and video analysis. Video analysis identified that one orthopedic behavior, namely 'Walking with full weight bearing' of the operated leg, decreased more in Group 1 at T24 (indicative of pain), whereas three behaviors indicative of sedation decreased in Group 2 at T24 (all p<0.004). Electrodermal activity was higher in Group 1 than in Groups 2 and 3 until T1 (p<0.0003). The VAS was not responsive. 4A-VET showed divergent results as its orthopedic component (4A-VETleg) detected lower pain in Group 2 until T12 (p<0.0009), but its interactive component (4A-VETbeh) was increased in Group 2 from T12 to T48 (p<0.001). Concurrent validity established that 4A-VETleg scores the painful orthopedic condition accurately and that pain assessment through 4A-VETbeh and VAS was severely biased by the sedative side-effect of the analgesics. Finally, the video analysis offered a concise template for assessment in dogs with acute orthopedic pain. However, subjective pain quantification methods and electrodermal activity need further investigation.
We have investigated the effect of particle shape in Pickering emulsions by employing, for the first time, cubic and peanut-shaped particles. The interfacial packing and orientation of anisotropic ...microparticles are revealed at the single-particle level by direct microscopy observations. The uniform anisotropic hematite microparticles adsorb irreversibly at the oil–water interface in monolayers and form solid-stabilized o/w emulsions via the process of limited coalescence. Emulsions were stable against further coalescence for at least 1 year. We found that cubes assembled at the interface in monolayers with a packing intermediate between hexagonal and cubic and average packing densities of up to 90%. Local domains displayed densities even higher than theoretically achievable for spheres. Cubes exclusively orient parallel with one of their flat sides at the oil–water interface, whereas peanuts preferentially attach parallel with their long side. Those peanut-shaped microparticles assemble in locally ordered, interfacial particle stacks that may interlock. Indications for long-range capillary interactions were not found, and we hypothesize that this is related to the observed stable orientations of cubes and peanuts that marginalize deformations of the interface.
Tenofovir (TFV) disoproxil fumarate (TDF)±emtricitabine (FTC) are widely used for HIV treatment and chemoprophylaxis, but variable adherence may lead to suboptimal responses. Methods that quantify ...adherence would allow for interventions to improve treatment and prevention outcomes. Our objective was to characterize the pharmacokinetics of TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP) in red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs); to extend the RBC analysis to dried blood spots (DBSs); and to model how RBC/DBS monitoring could inform recent and cumulative drug exposure/adherence. Blood samples were collected from 17 HIV-negative adults at 5 visits over a 30-day pharmacokinetics study of daily oral TDF/FTC. Dosing was discontinued on day 30 and blood was collected on days 35, 45, and 60 during the washout period. Plasma/RBCs/PBMCs/DBSs were all quantified by liquid chromatography/tandem mass spectrometry. DBSs were paired with RBCs and plasma for comparisons. The median (interquartile range) RBC TFV-DP half-life was 17.1 (15.7-20.2) versus 4.2 (3.7-5.2) days in PBMCs. At steady state, TFV-DP was 130 fmol/10(6) RBCs versus 98 fmol/10(6) PBMCs. FTC-TP was not quantifiable in most RBC samples. TFV-DP in RBCs versus DBSs yielded an r(2)=0.83. TFV-DP in DBSs was stable at -20°C. Simulations of TFV-DP in RBCs/DBSs, when dosed from one to seven times per week, demonstrated that each dose per week resulted in an average change of approximately 19 fmol/10(6) RBCs and 230 fmol/punch. TFV and FTC in plasma versus DBSs was defined by y=1.4x; r(2)=0.96 and y=0.8x; r(2)=0.99, respectively. We conclude that DBSs offer a convenient measure of recent (TFV/FTC) and cumulative (TFV-DP in RBCs) drug exposure with potential application to adherence monitoring.
Abstract
Study Objectives
This study assessed changes in sleep quality before and after the peak of the SARS-CoV-2 pandemic in community dwellers enrolled in the Atahualpa Project.
Methods
Atahualpa ...residents aged ≥40 years were eligible if they had a Pittsburgh Sleep Quality Index (PSQI) 9 months before the pandemic and a lateral flow-based test for identification of SARS-CoV-2 antibodies during the peak of the pandemic. Six months later, individuals completed a follow-up PSQI. The independent relationship between SARS-CoV-2 infection and deterioration in sleep quality was assessed by fitting logistic mixed models for longitudinal data.
Results
Of 639 participants (mean age at baseline: 59 ± 12.8 years), 325 (51%) had SARS-CoV-2 antibodies. A total of 185 (29%) individuals at baseline and 311 (49%) at follow-up were poor sleepers (p < 0.001). Mixed logistic regression models demonstrated a significant increase in poor sleepers at follow-up (odds ratio OR: 2.85; 95% CI: 2.16 to 3.75), which was more marked among SARS-CoV-2 seropositive subjects (OR: 3.8; 95% CI: 2.48 to 5.81). The adjusted proportion of poor sleepers increased from 29% to 56.2% (95% CI: 50.9% to 61.6%) among SARS-CoV-2 seropositive individuals, but only to 40.7% (95% CI: 35.3% to 46.1%) in their seronegative counterparts (p < 0.001). Likewise, progression from a good to a poor sleeper status was higher among seropositive individuals than in their seronegative counterparts (38.1% vs 22.3%; p < 0.001), after adjusting for relevant covariates.
Conclusions
This study shows a deleterious effect of SARS-CoV-2 in sleep quality. An effect of SARS-CoV-2 in disrupting sleep-related pathways cannot be ruled out.
Trial registration
The Atahualpa Project has been registered at ClinicalTrials.gov; the identifier number is NCT01627600, and the date was: 10/02/2012 (https://clinicaltrials.gov/ct2/show/NCT01627600?cond=Atahualpa&draw=2&rank=1). The Sleep Disorders substudy has been registered at ClinicalTrials.gov; the identifier number is NCT01877616, and the date was: 06/13/2013 (https://clinicaltrials.gov/ct2/show/NCT01877616?cond=Atahualpa&draw=2&rank=4).
Claudins, the integral tight junction (TJ) proteins that regulate paracellular permeability and cell polarity, are frequently dysregulated in cancer; however, their role in neoplastic progression is ...unclear. Here, we demonstrated that knockout of Cldn18, a claudin family member highly expressed in lung alveolar epithelium, leads to lung enlargement, parenchymal expansion, increased abundance and proliferation of known distal lung progenitors, the alveolar epithelial type II (AT2) cells, activation of Yes-associated protein (YAP), increased organ size, and tumorigenesis in mice. Inhibition of YAP decreased proliferation and colony-forming efficiency (CFE) of Cldn18-/- AT2 cells and prevented increased lung size, while CLDN18 overexpression decreased YAP nuclear localization, cell proliferation, CFE, and YAP transcriptional activity. CLDN18 and YAP interacted and colocalized at cell-cell contacts, while loss of CLDN18 decreased YAP interaction with Hippo kinases p-LATS1/2. Additionally, Cldn18-/- mice had increased propensity to develop lung adenocarcinomas (LuAd) with age, and human LuAd showed stage-dependent reduction of CLDN18.1. These results establish CLDN18 as a regulator of YAP activity that serves to restrict organ size, progenitor cell proliferation, and tumorigenesis, and suggest a mechanism whereby TJ disruption may promote progenitor proliferation to enhance repair following injury.
The ^176Hf/^177Hf and ^143Nd/^144Nd of mid-ocean ridge basalts （MORB） and ocean island basalts （OIB） are significantly correlated and form the so-called Hf-Nd mantle array 1,2 （Fig. la）.
This study aims to analyse the impact of limited hamstring flexibility (HF) on specific football skills, such as sprinting and jumping ability, agility, and kicking speed in young football players. ...Forty-three male football players (aged 14-18) from a semi-professional football academy participated voluntarily in this study. Data about anthropometric measurements, HF (unilateral passive straight-leg raise test: PSLR), vertical jumping ability (countermovement jump: CMJ), sprinting ability (5, 10, 20 m: S5 m, S10 m, S20 m), agility (Balsom agility test: BAT), and kicking speed in terms of ball speed (dominant and non-dominant leg: KSdom and KSnon-dom) were collected. Cluster analysis grouped according to HF, dividing participants into a flexible group (FG, n = 24) and a non-flexible group (NFG, n = 19) in relation to performances on the PSLR test. Despite finding no significant differences between groups in body composition and age, the FG performed better in terms of sprint scores (S5 m: 6.12%, S10 m: 4.09%, S20 m: 3.29%), BAT score (4.11%), CMJ score (10.49%), and scores for KSdom (6.86%) and KSnon-dom (8%) than the NFG. The results suggest that HF is a key factor for performing football-specific skills, such as sprinting, jumping, agility, and kicking in young football players. These results support the rationale that muscle flexibility must be specifically trained in football players beginning at early ages.
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