Miracle-dz/UniFAR-FTUs huggingface dataset:
Four different components contribute to outward current in rat ventricular myocytes.

In rat ventricle, two Ca2+-insensitive components of K+ current have been distinguished kinetically and pharmacologically, the transient, 4-aminopyridine (4-AP)-sensitive I to and the sustained, tetraethylammonium (TEA)-sensitive I K. However, a much greater diversity of depolarization-activated K+ channels has been reported on the level of mRNA and protein. In the search for electrophysiological evidence of further current components, the whole cell voltage-clamp technique was used to analyze steady-state inactivation of outward currents by conditioning potentials in a wide voltage range. Peak ( I peak) and late ( I late) currents during the test pulse were analyzed by Boltzmann curve fitting, producing three fractions each. Fractions a and b had different potentials of half-maximum inactivation ( V 0.5); the third residual fraction, r, did not inactivate. Fractions a for I peak and I late had similar relative amplitudes and V 0.5 values, whereas size and V 0.5 of fractions b differed significantly between I peak and I late. Only b of I peak was transient, suggesting a relation with I to, whereas a, b, and r of I late appeared to be three different sustained currents. Therefore, four individual outward current components were distinguished: I to( b of I peak), I K( a), the steady-state current I ss( r), and the novel current I Kx( b of I late). This was further supported by differential sensitivity to TEA, 4-AP, clofilium, quinidine, dendrotoxin, heteropodatoxin, and hanatoxin. With the exception of I to, none of the currents exhibited a marked transmural gradient. Availability of I K was low at resting potential; nevertheless, I K contributed to action potential shortening in hyperpolarized subendocardial myocytes. In conclusion, on the basis of electrophysiological and pharmacological evidence, at least four components contribute to outward current in rat ventricular myocytes.
A twentieth century major soluble ion record of dust and anthropogenic pollutants from Inilchek Glacier, Tien Shan

Using a high‐resolution (~18 samples/year) major soluble ion record (Na+, K+, Mg2+, Ca2+, Cl−, NO3−, and SO42−) covering the period 1908–1995 A.D. from the Inilchek Glacier, Tien Shan, Kyrgyzstan, we provide a detailed climate and environmental proxy record for the region. Chemical concentrations, empirical orthogonal function analyses, and noncrustal excess calculations are used to identify natural and potential anthropogenic depositional trends. Dominant dust proxy species (i.e., Ca2+) reveal highest concentrations during the 1950s–1970s, with declining decadal trends through the end of the record. These trends likely reflect decreases in central Asian dust storm activity post‐1950, which has been associated with coupled atmospheric circulation variability and anthropogenic activities. Comparison between Ca2+ and ERA‐Interim (1979–1995) climate reanalysis data indicates a strong relationship to spring (March–May) geopotential height patterns in northwest China and southern Siberia associated with the Siberian High. Noncrustal contribution (excess) estimates of NO3−, K+, SO42−, and Cl− concentrations suggest discernable anthropogenic inputs began between the 1950s and 1970s, increased into the middle/late 1980s, and declined in the 1990s. Excess trends coincide with Former Soviet Union consumption, production, and emission of fossil fuels and fertilizers, reflecting the rapid growth of agriculture and industry, as well as economic declines in the middle to late 1980s/early 1990s. Excess‐Cl− trends reflect timings that coincide with the construction of the Pavlodar Chemical Plant and the military production of Cl2 in Kazakhstan. NOAA Hybrid Single‐Particle Lagrangian Integrated Trajectory back trajectory frequency analysis suggests eastern Uzbekistan (e.g., Fergana Valley), Kyrgyzstan, and southern Kazakhstan as the primary pollutant sources to the study region.
Identifying Biomarkers of Wharton’s Jelly Mesenchymal Stromal Cells Using a Dynamic Metabolic Model: The Cell Passage Effect

Because of their unique ability to modulate the immune system, mesenchymal stromal cells (MSCs) are widely studied to develop cell therapies for detrimental immune and inflammatory disorders. However, controlling the final cell phenotype and determining immunosuppressive function following cell amplification in vitro often requires prolonged cell culture assays, all of which contribute to major bottlenecks, limiting the clinical emergence of cell therapies. For instance, the multipotent Wharton’s Jelly mesenchymal stem/stromal cells (WJMSC), extracted from human umbilical cord, exhibit immunosuppressive traits under pro-inflammatory conditions, in the presence of interferon-γ (IFNγ), and tumor necrosis factor-α (TNFα). However, WJMSCs require co-culture bioassays with immune cells, which can take days, to confirm their immunomodulatory function. Therefore, the establishment of robust cell therapies would benefit from fast and reliable characterization assays. To this end, we have explored the metabolic behaviour of WJMSCs in in vitro culture, to identify biomarkers that are specific to the cell passage effect and the loss of their immunosuppressive phenotype. We clearly show distinct metabolic behaviours comparing WJMSCs at the fourth (P4) and the late ninth (P9) passages, although both P4 and P9 cells do not exhibit significant differences in their low immunosuppressive capacity. Metabolomics data were analysed using an in silico modelling platform specifically adapted to WJMSCs. Of interest, P4 cells exhibit a glycolytic metabolism compared to late passage (P9) cells, which show a phosphorylation oxidative metabolism, while P4 cells show a doubling time of 29 h representing almost half of that for P9 cells (46 h). We also clearly show that fourth passage WJMSCs still express known immunosuppressive biomarkers, although, this behaviour shows overlapping with a senescence phenotype.
Theoretical and Experimental Studies on Inclusion Complexes of Pinostrobin and β-Cyclodextrins

Pinostrobin (PNS) belongs to the flavanone subclass of flavonoids which shows several biological activities such as anti-inflammatory, anti-cancerogenic, anti-viral and anti-oxidative effects. Similar to other flavonoids, PNS has a quite low water solubility. The purpose of this work is to improve the solubility and the biological activities of PNS by forming inclusion complexes with β-cyclodextrin (βCD) and its derivatives, heptakis-(2,6-di-O-methyl)-β-cyclodextrin (2,6-DMβCD) and (2-hydroxypropyl)-β-cyclodextrin (HPβCD). The AL-type diagram of the phase solubility studies of PNS exhibited the formed inclusion complexes with the 1:1 molar ratio. Inclusion complexes were prepared by the freeze-drying method and were characterized by differential scanning calorimetry (DSC). Two-dimensional nuclear magnetic resonance (2D-NMR) and steered molecular dynamics (SMD) simulation revealed two different binding modes of PNS, i.e., its phenyl- (P-PNS) and chromone- (C-PNS) rings preferably inserted into the cavity of βCD derivatives whilst only one orientation of PNS, where the C-PNS ring is inside the cavity, was detected in the case of the parental βCD. All PNS/βCDs complexes had a higher dissolution rate than free PNS. Both PNS and its complexes significantly exerted a lowering effect on the IL-6 secretion in LPS-stimulated macrophages and showed a moderate cytotoxic effect against MCF-7 and HeLa cancer cell lines in vitro.
Effects of Coffee Extracts with Different Roasting Degrees on Antioxidant and Anti-Inflammatory Systems in Mice

Coffee roasting affects the taste, color, and aroma of coffee. The Maillard reaction, a major reaction during the roasting process, produces melanoidin, which affects the overall antioxidant capacity and anti-inflammatory effects of coffee. In this experiment, coffee roasting was divided into four degrees: Light, Medium, City, and French. To examine the in vivo antioxidant and anti-inflammatory effects of coffee extracts with different roasting degrees, we used 10-week-old male C57BL/6 mice. Mice were pre-treated with coffee extracts for 10 days by oral gavage (300 mg/Kg.B.W). After the last pre-treatment, lipopolysaccharide (LPS, 15 mg/Kg.B.W) was injected intraperitoneally for immune stimulation. Histopathological analysis showed that hepatic portal vein invasion and liver necrosis were severe in the LPS-treated group. However, these phenomena were greatly ameliorated when mice were pre-treated with Light- or Medium-roasted coffee extracts. Hepatic glutathione level was increased in the French group but decreased in the LPS-stimulated group. When mice were treated with LPS, mRNA expression level of tumor necrosis factor-alpha (TNF-α) was increased, whereas TNF-α expression was significantly reduced in the Light and Medium groups. Treatment with coffee extracts decreased the mRNA expression levels of interleukin 6 (IL-6) in mice stimulated by LPS, regardless of coffee roasting degrees. These effects decreased with the increasing coffee roasting degree. Results of luciferase reporter assay revealed that these effects of coffee extracts were transcriptionally regulated by the NF-κB pathway. Taken together, these results suggest that the roasting degree affects the antioxidant and anti-inflammatory effects of coffee extracts.
Making collection operations optimal with aggressive JIT compilation

Functional collection combinators are a neat and widely accepted data processing abstraction. However, their generic nature results in high abstraction overheads -- Scala collections are known to be notoriously slow for typical tasks. We show that proper optimizations in a JIT compiler can widely eliminate overheads imposed by these abstractions. Using the open-source Graal JIT compiler, we achieve speedups of up to 20x on collection workloads compared to the standard HotSpot C2 compiler. Consequently, a sufficiently aggressive JIT compiler allows the language compiler, such as Scalac, to focus on other concerns. In this paper, we show how optimizations, such as inlining, polymorphic inlining, and partial escape analysis, are combined in Graal to produce collections code that is optimal with respect to manually written code, or close to optimal. We argue why some of these optimizations are more effectively done by a JIT compiler. We then identify specific use-cases that most current JIT compilers do not optimize well, warranting special treatment from the language compiler.
Midlife Predictors of Health-Related Quality of Life in Older Women

Background Midlife represents an important time to evaluate health status and health behaviors that may affect health-related quality of life (HRQL) in later years. This study examines change in women's HRQL over 11 years from ages 47-59 to 57-69 and identifies midlife characteristics that predict HRQL at older ages. Methods Physical (PCS) and mental component summaries (MCS) of the SF-36 were used to assess HRQL from 2002 to 2013 in 2,614 women from the Study of Women's Health Across the Nation (SWAN), a multiethnic/racial cohort study. We used locally weighted scatterplot smoothing (LOESS) models to obtain unadjusted predicted mean trajectories of PCS and MCS as a function of age. Results LOESS predicted PCS declined from 51.6 to 47.1, whereas MCS increased from 49.2 to 53.1. In multivariable models, controlling for baseline PCS, higher baseline physical activity (p = .002) and increase in physical activity from baseline (p < .0001) predicted better PCS. Time since baseline (ie, aging; p < .001), higher baseline body mass index (p < .0001), increased body mass index over time (p < .0001), smoking (p < .05), two or more medical conditions (p < .0001), sleep problems (p < .0001), and urinary incontinence (p < .0001) were related to lower PCS. Early (p = .004) and late postmenopause (p = .001; vs. premenopause) and aging (p = .05) predicted higher MCS. Predictors of lower MCS were less than very good health (p < .0001), sleep problems (p < .0001), stressful life events (p < .0001), higher perceived stress (p < .0001), and higher trait anxiety (p = .004). Race/ethnicity was related to MCS, but not PCS. Conclusions Several potentially modifiable midlife factors, such as improved sleep hygiene, physical activity, and body mass index, might improve HRQL for older women.
Ca2+ influx inhibits voltage-dependent and augments Ca2+-dependent K+ currents in arterial myocytes.

These experiments were performed to determine the effects of reducing Ca2+ influx (Cain) on K+ currents ( I K) in myocytes from rat small mesenteric arteries by 1) adding external Cd2+ or 2) lowering external Ca2+ to 0.2 mM. When measured from a holding potential (HP) of -20 mV ( I K20), decreasing Cain decreased I K at voltages where it was active (>0 mV). When measured from a HP of -60 mV ( I K60), decreasing Cain increased I K at voltages between -30 and +20 mV but decreased I K at voltages above +40 mV. Difference currents (Δ I K) were determined by digital subtraction of currents recorded under control conditions from those obtained when Cain was decreased. At test voltages up to 0 mV, Δ I K60 exhibited kinetics similar to control I K60, with rapid activation to a peak followed by slow inactivation. At 0 mV, peak Δ I K60 averaged 75 ± 13 pA ( n = 8) with Cd2+ and 120 ± 20 pA ( n = 9) with low Ca2+ concentration. At test voltages from 0 to +60 mV, Δ I K60 always had an early positive peak phase, but its apparent "inactivation" increased with voltage and its steady value became negative above +20 mV. At +60 mV, the initial peak Δ I K60 averaged 115 ± 18 pA with Cd2+ and 187 ± 34 pA with low Ca2+. With 10 mM pipette BAPTA, Cd2+ produced a small inhibition of I K20 but still increased I K60between -30 and +10 mV. In Ca2+-free external solution, Cd2+ only decreased both I K20 and I K60. In the presence of iberiotoxin (100 nM) to inhibit Ca2+-activated K+ channels (KCa), Cd2+ increased I K60 at all voltages positive to -30 mV while BAY K 8644 (1 μM) decreased I K60. These results suggest that Cain, through L-type Ca2+ channels and perhaps other pathways, increases KCa(i.e., I K20) and decreases voltage-dependent K+currents in this tissue. This effect could contribute to membrane depolarization and force maintenance.
Intracellular H+ regulates the α-subunit of ENaC, the epithelial Na+ channel.

Protons regulate electrogenic sodium absorption in a variety of epithelia, including the cortical collecting duct, frog skin, and urinary bladder. Recently, three subunits (α, β, γ) coding for the epithelial sodium channel (ENaC) were cloned. However, it is not known whether pH regulates Na+ channels directly by interacting with one of the three ENaC subunits or indirectly by interacting with a regulatory protein. As a first step to identifying the molecular mechanisms of proton-mediated regulation of apical membrane Na+ permeability in epithelia, we examined the effect of pH on the biophysical properties of ENaC. To this end, we expressed various combinations of α-, β-, and γ-subunits of ENaC in Xenopusoocytes and studied ENaC currents by the two-electrode voltage-clamp and patch-clamp techniques. In addition, the effect of pH on the α-ENaC subunit was examined in planar lipid bilayers. We report that α,β,γ-ENaC currents were regulated by changes in intracellular pH (pHi) but not by changes in extracellular pH (pHo). Acidification reduced and alkalization increased channel activity by a voltage-independent mechanism. Moreover, a reduction of pHi reduced single-channel open probability, reduced single-channel open time, and increased single-channel closed time without altering single-channel conductance. Acidification of the cytoplasmic solution also inhibited α,β-ENaC, α,γ-ENaC, and α-ENaC currents. We conclude that pHi but not pHo regulates ENaC and that the α-ENaC subunit is regulated directly by pHi.
Linking genetic and ecological differentiation in an ungulate with a circumpolar distribution

Genetic differentiation among populations may arise from the disruption of gene flow due to local adaptation to distinct environments and/or neutral accumulation of mutations and genetic drift resulted from geographical isolation. Quantifying the role of these processes in determining the genetic structure of natural populations remains challenging. Here, we analyze the relative contribution of isolation-by-resistance (IBR), isolation-by-environment (IBE), genetic drift and historical isolation in allopatry during Pleistocene glacial cycles on shaping patterns of genetic differentiation in caribou/reindeer populations (Rangifer tarandus) across the entire distribution range of the species. Our study integrates analyses at range-wide and regional scales to partial out the effects of historical and contemporary isolation mechanisms. At the circumpolar scale, our results indicate that genetic differentiation is predominantly explained by IBR and historical isolation. At a regional scale, we found that environmental dissimilarity and population size significantly explained the spatial distribution of genetic variation among populations belonging to the Euro-Beringian lineage within North America. In contrast, genetic differentiation among populations within the North American lineage was predominantly explained by IBR and population size, but not IBE. We also found discrepancies between genetic and ecotype designation across the Holarctic species distribution range. Overall, these results indicate that multiple isolating mechanisms have played roles in shaping the spatial distribution of genetic variation across the distribution range of a large mammal with high potential for gene flow. Considering multiple spatial scales and simultaneously testing a comprehensive suite of potential isolating mechanisms, our study contributes to understand the ecological and evolutionary processes underlying organism–landscape interactions. This article is protected by copyright. All rights reserved.
Genome-Wide Analyses of the NAC Transcription Factor Gene Family in Pepper (Capsicum annuum L.): Chromosome Location, Phylogeny, Structure, Expression Patterns, Cis-Elements in the Promoter, and Interaction Network

The NAM, ATAF1/2, and CUC2 (NAC) transcription factors form a large plant-specific gene family, which is involved in the regulation of tissue development in response to biotic and abiotic stress. To date, there have been no comprehensive studies investigating chromosomal location, gene structure, gene phylogeny, conserved motifs, or gene expression of NAC in pepper (Capsicum annuum L.). The recent release of the complete genome sequence of pepper allowed us to perform a genome-wide investigation of Capsicum annuum L. NAC (CaNAC) proteins. In the present study, a comprehensive analysis of the CaNAC gene family in pepper was performed, and a total of 104 CaNAC genes were identified. Genome mapping analysis revealed that CaNAC genes were enriched on four chromosomes (chromosomes 1, 2, 3, and 6). In addition, phylogenetic analysis of the NAC domains from pepper, potato, Arabidopsis, and rice showed that CaNAC genes could be clustered into three groups (I, II, and III). Group III, which contained 24 CaNAC genes, was exclusive to the Solanaceae plant family. Gene structure and protein motif analyses showed that these genes were relatively conserved within each subgroup. The number of introns in CaNAC genes varied from 0 to 8, with 83 (78.9%) of CaNAC genes containing two or less introns. Promoter analysis confirmed that CaNAC genes are involved in pepper growth, development, and biotic or abiotic stress responses. Further, the expression of 22 selected CaNAC genes in response to seven different biotic and abiotic stresses [salt, heat shock, drought, Phytophthora capsici, abscisic acid, salicylic acid (SA), and methyl jasmonate (MeJA)] was evaluated by quantitative RT-PCR to determine their stress-related expression patterns. Several putative stress-responsive CaNAC genes, including CaNAC72 and CaNAC27, which are orthologs of the known stress-responsive Arabidopsis gene ANAC055 and potato gene StNAC30, respectively, were highly regulated by treatment with different types of stress. Our results also showed that CaNAC36 plays an important role in the interaction network, interacting with 48 genes. Most of these genes are in the mitogen-activated protein kinase (MAPK) family. Taken together, our results provide a platform for further studies to identify the biological functions of CaNAC genes.
Paracellular glucose transport plays a minor role in the unanesthetized dog.

Traditionally, intestinal glucose absorption was thought to occur through active, carrier-mediated transport. However, proponents of paracellular transport have argued that previous experiments neglected effects of solvent drag coming from high local concentrations of glucose at the brush-border membrane. The purpose of this study was to evaluate glucose absorption in the awake dog under conditions that would maximize any contribution of paracellular transport. Jejunal Thiry-Vella loops were constructed in six female mongrel dogs. After surgical recovery, isotonic buffers containingl-glucose as the probe for paracellular permeability were given over 2-h periods by constant infusion pump. At physiological concentrations ofd-glucose (1-50 mM), the fractional absorption ofl-glucose was only 4-7% of total glucose absorption. Infusion of supraphysiological concentrations (150 mM) of d-glucose,d-maltose, ord-mannitol yielded low-fractional absorptions ofl-glucose (2-5%), so too did complex or nonabsorbable carbohydrates. In all experiments, there was significant fractional water absorption (5-19%), a prerequisite for solvent drag. Therefore, with even up to high concentrations of luminal carbohydrates in the presence of significant water absorption, the relative contribution of paracellular glucose absorption remained low.
S-nitrosoglutathione enhances neutrophil DNA fragmentation and cell death.

Enhancing the clearance of neutrophils by enhancing apoptotic cell death and macrophage recognition may be beneficial in acute lung injury. Exogenous nitric oxide gas depresses neutrophil oxidative functions and accelerates cell death (A. H. Daher, J. D. Fortenberry, M. L. Owens, and L. A. Brown. Am. J. Respir. Cell Mol. Biol. 16: 407-412, 1997). We hypothesized that S-nitrosoglutathione (GSNO), a physiologically relevant nitric oxide donor, could also enhance neutrophil DNA fragmentation. Neutrophils were incubated for 2-24 h in the absence and presence of GSNO (dose range 0.1-5 mM) and evaluated for cell death by a fluorescent viability/cytotoxicity assay. Neutrophil DNA fragmentation was assessed by cell death detection ELISA and by terminal deoxynucleotidyltransferase-mediated fluorescence-labeled dUTP nick end labeling assay. Neutrophil oxidative function was also determined. Incubation with GSNO increased cell death at 2, 4, and 24 h. GSNO incubation for 24 h significantly increased DNA fragmentation in a dose-dependent fashion at 0.5 (median 126% of control value; P = 0.002) and 5 mM (185% of control value; P = 0.002) by terminal deoxynucleotidyltransferase-mediated fluorescence-labeled dUTP nick end labeling and at 0.5 mM by ELISA (164% of control value; P = 0.03). The apoptosis-to-total cell death ratio increased with increasing GSNO concentration ( P < 0.05). Effects were mitigated by coincubation with superoxide dismutase. Five millimolar GSNO decreased overall superoxide generation and O2 consumption but not when adjusted for dead neutrophils. GSNO significantly enhances cell death and neutrophil DNA fragmentation in a dose-dependent fashion.