Differential responsiveness of glabrous and non-glabrous skin to local transmural pressure elevations; the impact of 5 weeks of iterative local pressure loading

We examined the in vivo pressure-flow relationship in human cutaneous vessels during acute and repeated elevations of local transmural pressure. In 10 healthy men, red blood cell flux was monitored simultaneously on the non-glabrous skin of the forearm and the glabrous skin of a finger during a vascular pressure provocation, wherein the blood vessels of an arm were exposed to a wide range of stepwise increasing distending pressures. Forearm skin blood flux was relatively stable at slight and moderate elevations of distending pressure, whereas it increased ~3-4-fold at the highest levels (P = 0.004). Finger blood flux on the contrary, dropped promptly and consistently throughout the provocation (P < 0.001). Eight of the subjects repeated the provocation trial after a 5-week pressure-training regimen, during which the vasculature in one arm was exposed intermittently (40 min, 3 times･week-1) to increased transmural pressure (from +65 mmHg week-1 to +105 mmHg week-5). The training regimen diminished the pressure-induced increase in forearm blood flux by ~34% (P = 0.02), whereas it inhibited the reduction in finger blood flux (P < 0.001) in response to slight and moderate distending pressure elevations. The present findings demonstrate that, during local pressure perturbations, the cutaneous autoregulatory function is accentuated in glabrous compared to in the non-glabrous skin regions. Prolonged intermittent regional exposures to augmented intravascular pressure blunt the responsiveness of the glabrous skin, but enhance arteriolar pressure resistance in the non-glabrous skin.

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In VivoEfficacy of Anuran Trypsin Inhibitory Peptides against Staphylococcal Skin Infection and the Impact of Peptide Cyclization

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.04324-14 ◽

2015 ◽

Vol 59 (4) ◽

pp. 2113-2121 ◽

Cited By ~ 9

Author(s):

U. Malik ◽

O. N. Silva ◽

I. C. M. Fensterseifer ◽

L. Y. Chan ◽

R. J. Clark ◽

...

Keyword(s):

Antimicrobial Agents ◽

Cyclic Peptide ◽

Sequence Similarity ◽

Infection Model ◽

Content Type ◽

Wide Range ◽

Inhibitory Activities ◽

The Impact

ABSTRACTStaphylococcus aureusis a virulent pathogen that is responsible for a wide range of superficial and invasive infections. Its resistance to existing antimicrobial drugs is a global problem, and the development of novel antimicrobial agents is crucial. Antimicrobial peptides from natural resources offer potential as new treatments against staphylococcal infections. In the current study, we have examined the antimicrobial properties of peptides isolated from anuran skin secretions and cyclized synthetic analogues of these peptides. The structures of the peptides were elucidated by nuclear magnetic resonance (NMR) spectroscopy, revealing high structural and sequence similarity with each other and with sunflower trypsin inhibitor 1 (SFTI-1). SFTI-1 is an ultrastable cyclic peptide isolated from sunflower seeds that has subnanomolar trypsin inhibitory activity, and this scaffold offers pharmaceutically relevant characteristics. The five anuran peptides were nonhemolytic and noncytotoxic and had trypsin inhibitory activities similar to that of SFTI-1. They demonstrated weakin vitroinhibitory activities againstS. aureus, but several had strong antibacterial activities againstS. aureusin anin vivomurine wound infection model. pYR, an immunomodulatory peptide fromRana sevosa, was the most potent, with complete bacterial clearance at 3 mg · kg−1. Cyclization of the peptides improved their stability but was associated with a concomitant decrease in antimicrobial activity. In summary, these anuran peptides are promising as novel therapeutic agents for treating infections from a clinically resistant pathogen.

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Inhibiting myosin-ATPase reveals a dynamic range of mitochondrial respiratory control in skeletal muscle

Biochemical Journal ◽

10.1042/bj20110366 ◽

2011 ◽

Vol 437 (2) ◽

pp. 215-222 ◽

Cited By ~ 93

Author(s):

Christopher G. R. Perry ◽

Daniel A. Kane ◽

Chien-Te Lin ◽

Rachel Kozy ◽

Brook L. Cathey ◽

...

Keyword(s):

Skeletal Muscle ◽

Dynamic Range ◽

Energy Charge ◽

Respiratory Control ◽

Basic Research ◽

Dependent Manner ◽

Atpase Inhibitor ◽

Wide Range ◽

The Impact

Assessment of mitochondrial ADP-stimulated respiratory kinetics in PmFBs (permeabilized fibre bundles) is increasingly used in clinical diagnostic and basic research settings. However, estimates of the Km for ADP vary considerably (~20–300 μM) and tend to overestimate respiration at rest. Noting that PmFBs spontaneously contract during respiration experiments, we systematically determined the impact of contraction, temperature and oxygenation on ADP-stimulated respiratory kinetics. BLEB (blebbistatin), a myosin II ATPase inhibitor, blocked contraction under all conditions and yielded high Km values for ADP of >~250 and ~80 μM in red and white rat PmFBs respectively. In the absence of BLEB, PmFBs contracted and the Km for ADP decreased ~2–10-fold in a temperature-dependent manner. PmFBs were sensitive to hyperoxia (increased Km) in the absence of BLEB (contracted) at 30 °C but not 37 °C. In PmFBs from humans, contraction elicited high sensitivity to ADP (Km<100 μM), whereas blocking contraction (+BLEB) and including a phosphocreatine/creatine ratio of 2:1 to mimic the resting energetic state yielded a Km for ADP of ~1560 μM, consistent with estimates of in vivo resting respiratory rates of <1% maximum. These results demonstrate that the sensitivity of muscle to ADP varies over a wide range in relation to contractile state and cellular energy charge, providing evidence that enzymatic coupling of energy transfer within skeletal muscle becomes more efficient in the working state.

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Computational and Experimental Study of Convection in a Vanadium Redox Flow Battery Strip Cell Architecture

Energies ◽

10.3390/en13184767 ◽

2020 ◽

Vol 13 (18) ◽

pp. 4767

Author(s):

Tugrul Y. Ertugrul ◽

Michael. C. Daugherty ◽

Jacob R. Houser ◽

Douglas S. Aaron ◽

Matthew M. Mench

Keyword(s):

Pressure Drop ◽

Current Distribution ◽

Vanadium Redox Flow Battery ◽

Local Concentration ◽

Total Current ◽

Local Pressure ◽

Large Current ◽

Cell Architecture ◽

Wide Range ◽

The Impact

The impact of convection on electrochemical performance, performance distribution, and local pressure drop is investigated via simple strip cell architecture, a cell with a single straight channel. Various channel depths (0.25, 0.5, 1, 2.5 mm) and flow rates (10–50 mL min−1 cm−2) are employed to induce a wide range of electrolyte velocities within the channel and electrode. Computational flow simulation is utilized to assess velocity and pressure distributions; experimentally measured in situ current distribution is quantified for the cell. Although the total current in the cell is directly proportional to electrolyte velocity in the electrode, there is no correlation detected between electrolyte velocity in the channel and the total current. It is found that the maximum achievable current is limited by diffusion mass transport resistance between the liquid electrolyte and the electrode surfaces at the pore level. Low electrolyte velocity induces large current gradients from inlet to outlet; conversely, high electrolyte velocity exhibits relatively uniform current distribution down the channel. Large current gradients are attributed to local concentration depletion in the electrode since the velocity distribution down the channel is uniform. Shallow channel configurations are observed to successfully compromise between convective flow in the electrode and the overall pressure drop.

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Sensing through Non-Sensing Ocular Ion Channels

International Journal of Molecular Sciences ◽

10.3390/ijms21186925 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6925

Author(s):

Meha Kabra ◽

Bikash Ranjan Pattnaik

Keyword(s):

Ion Channels ◽

Visual Processing ◽

Signal Transmission ◽

Dominant Negative ◽

Dominant Negative Effect ◽

Cone Dystrophy ◽

Wide Range ◽

The Impact

Ion channels are membrane-spanning integral proteins expressed in multiple organs, including the eye. In the eye, ion channels are involved in various physiological processes, like signal transmission and visual processing. A wide range of mutations have been reported in the corresponding genes and their interacting subunit coding genes, which contribute significantly to an array of blindness, termed ocular channelopathies. These mutations result in either a loss- or gain-of channel functions affecting the structure, assembly, trafficking, and localization of channel proteins. A dominant-negative effect is caused in a few channels formed by the assembly of several subunits that exist as homo- or heteromeric proteins. Here, we review the role of different mutations in switching a “sensing” ion channel to “non-sensing,” leading to ocular channelopathies like Leber’s congenital amaurosis 16 (LCA16), cone dystrophy, congenital stationary night blindness (CSNB), achromatopsia, bestrophinopathies, retinitis pigmentosa, etc. We also discuss the various in vitro and in vivo disease models available to investigate the impact of mutations on channel properties, to dissect the disease mechanism, and understand the pathophysiology. Innovating the potential pharmacological and therapeutic approaches and their efficient delivery to the eye for reversing a “non-sensing” channel to “sensing” would be life-changing.

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Influence of Supraphysiologic Biomaterial Stiffness on Ventricular Mechanics and Myocardial Infarct Reinforcement

10.1101/2020.05.20.107276 ◽

2020 ◽

Author(s):

Ravi K. Ghanta ◽

Yunge Zhao ◽

Aarthi Pugazenthi ◽

Mathew J. Wall ◽

Lauren N. Russell ◽

...

Keyword(s):

Polyethylene Glycol ◽

Ventricular Remodeling ◽

Myocardial Infarct ◽

Design Criteria ◽

Peg Hydrogels ◽

Ventricular Mechanics ◽

Wide Range ◽

Adverse Remodeling ◽

The Impact

ABSTRACTInjectable intramyocardial biomaterials have promise to limit adverse ventricular remodeling through mechanical and biologic mechanisms. While some success has been observed by injecting materials to regenerate new tissue, optimal biomaterial stiffness to thicken and stiffen infarcted myocardium to limit adverse remodeling has not been determined. In this work, we present an in-vivo study of the impact of biomaterial stiffness over a wide range of stiffness moduli on ventricular mechanics. We utilized injectable methacrylated polyethylene glycol (PEG) hydrogels fabricated at 3 different mechanical moduli: 5 kPa (low), 25 kPa (medium/myocardium), and 250 kPa (high/supraphysiologic). We demonstrate that the supraphysiological high stiffness favorably alters post-infarct ventricular mechanics and prevents negative tissue remodeling. Lower stiffness materials do not alter mechanics and thus to be effective, must instead target biological reparative mechanisms. These results may influence rationale design criteria for biomaterials developed for infarct reinforcement therapy.

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Photopatterned Membranes and Chemical Gradients Enable Scalable Phenotypic Organization of Primary Human Colon Epithelial Models

10.26434/chemrxiv.9759605.v1 ◽

2019 ◽

Author(s):

Sam Hinman ◽

Yuli Wang ◽

Nancy Allbritton

Keyword(s):

Human Colon ◽

Cell Types ◽

Self Renewal ◽

Chemical Gradients ◽

Plate Spacing ◽

Wide Range ◽

Cell Compartmentalization ◽

The Impact

Biochemical gradients across the intestinal epithelium play a major role in governing intestinal stem cell compartmentalization, differentiation dynamics, and organ-level self-renewal. Advances in primary cell-derived in vitro models, in which a full suite of stem and differentiated cell types are present, have vastly accelerated our understanding of intestinal homeostasis and disease. However, scalable platforms that recapitulate the architecture and gradients present in vivo are absent. We present a platform in which individually addressable arrays of chemical gradients along the crypt long axis can be generated, enabling scalable culture of in vitro colonic epithelial replicas. The platform utilizes standardized well plate spacing, maintains access to basal and luminal compartments, and relies on a photopatterned porous membrane to act as diffusion windows while supporting the in vitro crypts. Simultaneous fabrication of 3,875 crypts over a single membrane was developed. Growth factor gradients were modelled and then experimentally optimized to promote long-term health and self-renewal of the crypts which were assayed in situ by confocal fluorescence microscopy. The cultured in vitro crypt arrays successfully recapitulated the architecture, stem/proliferative and differentiated cell compartmentalization, and luminal-to-basal polarity observed in vivo. Furthermore, known signaling regulators produced measurable and predictable effects on the proliferative and differentiated cell compartments. This platform is readily adaptable to the screening of tissue from individual patients to assay the impact of food and bacterial metabolites and/or drugs on colonic crypt dynamics. Importantly, the cassette is compatible with a wide range of sensing/detection modalities, and the developed fabrication methods should find applications for other cell and tissue types.

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Computational Electrostatics Predict Variations in SARS-CoV-2 Spike and Human ACE2 Interactions

10.1101/2020.04.30.071175 ◽

2020 ◽

Author(s):

Scott P. Morton ◽

Joshua L. Phillips

Keyword(s):

Electrostatic Interactions ◽

Spike Protein ◽

Angiotensin Converting Enzyme 2 ◽

Global Pandemic ◽

Wide Range ◽

Nasal Secretions ◽

Novel Virus ◽

Ph Range ◽

The Impact

ABSTRACTSARS-CoV-2 is a novel virus that is presumed to have emerged from bats to crossover into humans in late 2019. As the global pandemic ensues, scientist are working to evaluate the virus and develop a vaccine to counteract the deadly disease that has impacted lives across the entire globe. We perform computational electrostatic simulations on multiple variants of SARS-CoV-2 spike protein s1 in complex with human angiotensin-converting enzyme 2 (ACE2) variants to examine differences in electrostatic interactions across the various complexes. Calculations are performed across the physiological pH range to also examine the impact of pH on these interactions. Two of six spike protein s1 variations having greater electric forces at pH levels consistent with nasal secretions and significant variations in force across all five variants of ACE2. Five out of six spike protein s1 variations have relatively consistent forces at pH levels of the lung, and one spike protein s1 variant that has low potential across a wide range of pH. These predictions indicate that variants of SARS-CoV-2 spike proteins and human ACE2 in certain combinations could potentially play a role in increased binding efficacy of SARS-CoV-2 in vivo.

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Multi-tissue DNA methylation age predictor in mouse

10.1101/119206 ◽

2017 ◽

Author(s):

Thomas M. Stubbs ◽

Marc Jan Bonder ◽

Anne-Katrien Stark ◽

Felix Krueger ◽

Ferdinand von Meyenn ◽

...

Keyword(s):

Dna Methylation ◽

Absolute Error ◽

Biological Age ◽

Epigenetic Clock ◽

Cpg Sites ◽

Mouse Tissues ◽

Wide Range ◽

Dna Methylation Age ◽

The Impact

AbstractBackgroundDNA-methylation changes at a discrete set of sites in the human genome are predictive of chronological and biological age. However, it is not known whether these changes are causative or a consequence of an underlying ageing process. It has also not been shown whether this ‘epigenetic clock’ is unique to humans or conserved in the more experimentally tractable mouse.ResultsWe have generated a comprehensive set of genome-scale base-resolution methylation maps from multiple mouse tissues spanning a wide range of ages. Many CpG sites show significant tissue-independent correlations with age and allowed us to develop a multi-tissue predictor of age in the mouse. Our model, which estimates age based on DNA methylation at 329 unique CpG sites, has a median absolute error of 3.33 weeks, and has similar properties to the recently described human epigenetic clock. Using publicly available datasets, we find that the mouse clock is accurate enough to measure effects on biological age, including in the context of interventions. While females and males show no significant differences in predicted DNA methylation age, ovariectomy results in significant age acceleration in females. Furthermore, we identify significant differences in age-acceleration dependent on the lipid content of the offspring diet.ConclusionsHere we identify and characterize an epigenetic predictor of age in mice, the mouse epigenetic clock. This clock will be instrumental for understanding the biology of ageing and will allow modulation of its ticking rate and resetting the clock in vivo to study the impact on biological age.

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Immunotoxic Effects Induced by Microcystins and Cylindrospermopsin: A Review

Toxins ◽

10.3390/toxins13100711 ◽

2021 ◽

Vol 13 (10) ◽

pp. 711

Author(s):

Leticia Diez-Quijada ◽

Maria del Monte Benítez-González ◽

María Puerto ◽

Angeles Jos ◽

Ana M. Cameán

Keyword(s):

Immune System ◽

Scientific Literature ◽

Anthropogenic Activities ◽

In Vivo Studies ◽

Wide Range ◽

Full Picture ◽

Underlying Mechanisms ◽

The Impact

Cyanotoxin occurrence is gaining importance due to anthropogenic activities, climate change and eutrophication. Among them, Microcystins (MCs) and Cylindrospermopsin (CYN) are the most frequently studied due to their ubiquity and toxicity. Although MCs are primary classified as hepatotoxins and CYN as a cytotoxin, they have been shown to induce deleterious effects in a wide range of organs. However, their effects on the immune system are as yet scarcely investigated. Thus, to know the impact of cyanotoxins on the immune system, due to its importance in organisms’ homeostasis, is considered of interest. A review of the scientific literature dealing with the immunotoxicity of MCs and CYN has been performed, and both in vitro and in vivo studies have been considered. Results have confirmed the scarcity of reports on the topic, particularly for CYN. Decreased cell viability, apoptosis or altered functions of immune cells, and changed levels and mRNA expression of cytokines are among the most common effects reported. Underlying mechanisms, however, are still not yet fully elucidated. Further research is needed in order to have a full picture of cyanotoxin immunotoxicity.

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Diverse lipid conjugates for functional extra-hepatic siRNA delivery in vivo

10.1101/289439 ◽

2018 ◽

Author(s):

Annabelle Biscans ◽

Andrew Coles ◽

Reka Haraszti ◽

Dimas Echeverria ◽

Matthew Hassler ◽

...

Keyword(s):

Tissue Distribution ◽

Therapeutic Intervention ◽

Chemical Engineering ◽

Adrenal Glands ◽

Sirna Delivery ◽

Distribution Profile ◽

Wide Range ◽

The Impact ◽

Tissue Distribution Profile

AbstractRNAi-based therapeutics show promising clinical data for treatment of liver-associated disorders. However, siRNA delivery into extra-hepatic tissues remains an obstacle, limiting the use of siRNA-based therapies. Here we report on a first example of chemical engineering of lipophilic conjugates to enable extra-hepatic delivery. We synthesized a panel of fifteen lipophilic siRNA and evaluated the impact of their chemical configuration on siRNA tissue distribution profile. Generally, lipophilic conjugates allow siRNA distribution to a wide range of tissues, where the degree of lipophilicity defines the ratio of liver/spleen to kidney distribution. In addition to primary clearance tissues, several conjugates achieve significant siRNA distribution to lung, heart, adrenal glands, fat, muscle. siRNA tissue accumulation leads to productive silencing, shown with two independent targets. siRNA concentrations necessary for productive silencing are tissue and conjugate dependent, varying significantly from 5 to 200 ng/mg. The collection of conjugated siRNA described here enables functional gene modulation in vivo in lung, muscle, fat, heart, adrenal glands opening these tissues for future therapeutic intervention.

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