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Many studies indicate that climate change impacts on water availability and extreme events will be on both global and local scales. The humid tropical basin of Upper Bernam River, Malaysia is taken as case study to evaluate the impact of climate change on water availability on local scale by using Downscaled Global Climate Change Model (DGCM) data with a distributed hydrologic model. DGCM data was downscaled by using a Regional Climate Model called "Providing Regional Climates for Impacts Studies" (PRECIS). The study area is important since it is the main source of irrigation water using run-of-the-river irrigation system serving 20,000 ha of rice cultivation. The study answers the question of whether any trend in the annual and monthly series of temperature and rainfall can be detected at the local scale. DGCM temperature and rainfall data were compared with the actual observed data. The results of the comparison indicate that DGCM temperature data for specific grids were close to the actual temperature data unlike the rainfall data. The actual data and DGCM data were then used with SWAT model to simulate stream flow. The results show that stream flows were more accurately simulated by using actual observed data than using DGCM data. For average monthly flows using weather station data, Nash and Sutcliffe Efficiency (ENS) and coefficient of determination (R2) were found to be 0.79 and 0.80 respectively while ENS and R2 for average monthly flows using DGCM data were found to be -3.273, 0.085 respectively. The average monthly flows during the study period with data from weather station and DGCM were 45.5 and 73.3 m3/s respectively. The Mann--Kendall test was then used to examine the presence of trend for temperature, rainfall and flow time series of actual data and DGCM. Mann--Kendall test results show that there is an increasing trend for temperature in all cases. However, there is no trend detected for rainfall in all cases. The flow trend analysis by SWAT using weather station inputs resulted in increasing trend with more than 90% probability level of significance, whereas no flow trend was detected by SWAT using DGCM data. [ABSTRACT FROM AUTHOR]

Large-conductance Ca2+-dependent K+ (BKCa) channels are activated by intracellular Ca2+ and membrane depolarization in an allosteric manner. We investigated the pharmacological and biophysical characteristics of a BKCa-type K+ channel in androgen-dependent LNCaP (lymph node carcinoma of the prostate) cells with novel functional properties, here termed BKL. K+ selectivity, high conductance, activation by Mg2+ or NS1619, and inhibition by paxilline and penitrem A largely resembled the properties of recombinant BKCa channels. However, unlike conventional BKCa channels, BKL channels activated in the absence of free cytosolic Ca2+ at physiological membrane potentials; the half-maximal activation voltage was shifted by about −100 mV compared with BKCa channels. Half-maximal Ca2+-dependent activation was observed at 0.4 μ M for BKL (at −20 mV) and at 4.1 μ M for BKCa channels (at +50 mV). Heterologous expression of hSlo1 in LNCaP cells increased the BKL conductance. Expression of hSlo-β 1 in LNCaP cells shifted voltage-dependent activation to values between that of BKL and BKCa channels and reduced the slope of the P open (open probability)-voltage curve. We propose that LNCaP cells harbor a so far unknown type of BKCa subunit, which is responsible for the BKL phenotype in a dominant manner. BKL-like channels are also expressed in the human breast cancer cell line T47D. In addition, functional expression of BKL in LNCaP cells is regulated by serum-derived factors, however not by androgens. [ABSTRACT FROM AUTHOR]

Introduction: Increasing the effectiveness of eradication therapy is an important task in gastroenterology. The aim of this study was to evaluate the efficacy and safety of postbiotic containing inactivated (nonviable) Limosilactobacillus (Lactobacillus) reuteri DSM 17648 (Pylopass) as adjuvant treatment of Helicobacter pylori eradication in patients with functional dyspepsia (FD)., Methods: This randomized, double-blind, placebo-controlled, multicenter, parallel study included H. pylori -positive patients with FD. The postbiotic group received Pylopass 200 mg bid for 14 days in combination with eradication therapy (esomeprazole 20 mg bid + amoxicillin 1,000 mg bid + clarithromycin 500 mg bid for 14 days) and another 14 days after the completion of eradication therapy. The study was registered in the ISRCTN registry (ISRCTN20716052)., Results: Eradication efficiency was 96.7% for the postbiotic group vs 86.0% for the placebo group ( P = 0.039). Both groups showed significant improvements in quality of life and reduction of most gastrointestinal symptoms with no significant differences between groups. The overall number of digestive adverse effects in the postbiotic group was lower than in the placebo group. Serious adverse effects were not registered., Discussion: The postbiotic containing inactivated L. reuteri DSM 17648 significantly improves the effectiveness of H. pylori eradication therapy in FD and decreases overall number of digestive adverse effects of this therapy., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Steady-state vowels are vowels that are uttered with a momentarily fixed vocal tract configuration and with steady vibration of the vocal folds. In this steady-state, the vowel waveform appears as a quasi-periodic string of elementary units called pitch periods. Humans perceive this quasi-periodic regularity as a definite pitch. Likewise, so-called pitch-synchronous methods exploit this regularity by using the duration of the pitch periods as a natural time scale for their analysis. In this work, we present a simple pitch-synchronous method using a Bayesian approach for estimating formants that slightly generalizes the basic approach of modeling the pitch periods as a superposition of decaying sinusoids, one for each vowel formant, by explicitly taking into account the additional low-frequency content in the waveform which arises not from formants but rather from the glottal pulse. We model this low-frequency content in the time domain as a polynomial trend function that is added to the decaying sinusoids. The problem then reduces to a rather familiar one in macroeconomics: estimate the cycles (our decaying sinusoids) independently from the trend (our polynomial trend function); in other words, detrend the waveform of steady-state waveforms. We show how to do this efficiently.

Objectives: The primary objective of this study was to describe the accuracy of pneumonia diagnosis, both community-acquired pneumonia (CAP) and hospitalacquired pneumonia (HAP). Secondary objectives were describing the choice of antibiotics used, pathogens isolated, and predictive parameters in diagnosing pneumonia., Methods: This was a prospective cross-sectional study to determine the accuracy of the diagnosis of CAP and HAP admitted to Hospital Tuanku Ja'afar. All patients aged ≥12 years admitted to the general medical ward with the diagnosis of CAP or HAP were included in the study. Chest radiograph interpretation was done by certified radiologists. An accurate diagnosis of pneumonia was defined by clinical signs and symptoms of pneumonia supported by radiographical evidence., Results: A total of 159 patients were enrolled into the study from January 2018 to February 2018. Of these only 59(37.1%) cases were accurately diagnosed as pneumonia. Amongst those with pneumonia diagnosis made by the emergency department, medical officers and specialists of medical department; 65.4%, 60% and 47.3% respectively were not pneumonia. Amoxicillin with clavulanate and azithromycin were amongst the most common first choice of antibiotic used (46.5%). In this study, pathogens were isolated either by blood culture or sputum culture in only 20 (12.6%) patients. There was no significant predictive parameter identified in this study, which included white cell counts, Creactive protein (CRP) levels, erythrocyte sedimentation rate (ESR), and Pao2/FiO2 ratio., Conclusion: About two-thirds of patients diagnosed with pneumonia did not have a compatible radiological finding. Better tools and systems are needed to aid in the diagnosis of pneumonia.

Since the 2007-2009 financial crisis, substantial academic effort has been dedicated to improving our understanding of interbank lending networks (ILNs). Because of data limitations or by choice, the literature largely lacks multiple loan maturities. We employ a complete interbank loan contract dataset to investigate whether maturity details are informative of the network structure. Applying the layered stochastic block model of Peixoto (2015) and other tools from network science on a time series of bilateral loans with multiple maturity layers in the Russian ILN, we find that collapsing all such layers consistently obscures mesoscale structure. The optimal maturity granularity lies between completely collapsing and completely separating the maturity layers and depends on the development phase of the interbank market, with a more developed market requiring more layers for optimal description. Closer inspection of the inferred maturity bins associated with the optimal maturity granularity reveals specific economic functions, from liquidity intermediation to financing. Collapsing a network with multiple underlying maturity layers or extracting one such layer, common in economic research, is therefore not only an incomplete representation of the ILN's mesoscale structure, but also conceals existing economic functions. This holds important insights and opportunities for theoretical and empirical studies on interbank market functioning, contagion, stability, and on the desirable level of regulatory data disclosure.

Large-conductance voltage- and Ca(2+)-activated K(+) (Slo1 BK) channels serve numerous cellular functions, and their dysregulation is implicated in various diseases. Drugs activating BK channels therefore bear substantial therapeutic potential, but their deployment has been hindered in part because the mode of action remains obscure. Here we provide mechanistic insight into how the dehydroabietic acid derivative Cym04 activates BK channels. As a representative of NS1619-like BK openers, Cym04 reversibly left-shifts the half-activation voltage of Slo1 BK channels. Using an established allosteric BK gating model, the Cym04 effect can be simulated by a shift of the voltage sensor and the ion conduction gate equilibria toward the activated and open state, respectively. BK activation by Cym04 occurs in a splice variant-specific manner; it does not occur in such Slo1 BK channels using an alternative neuronal exon 9, which codes for the linker connecting the transmembrane segment S6 and the cytosolic RCK1 domain--the S6/RCK linker. In addition, Cym04 does not affect Slo1 BK channels with a two-residue deletion within this linker. Mutagenesis and model-based gating analysis revealed that BK openers, such as Cym04 and NS1619 but not mallotoxin, activate BK channels by functionally interacting with the S6/RCK linker, mimicking site-specific shortening of this purported passive spring, which transmits force from the cytosolic gating ring structure to open the channel's gate.

The Notch signaling pathway is an important regulation system for the development and self-renewal of different tissues. A specific feature of this signaling cascade is the function of Notch as a surface receptor and regulator of gene expression. Hence, Notch activation and signal transduction requires the proteolytic release of the Notch intracellular domain (NICD), which activates the transcription of cell-specific genes after its transport into the nucleus. To date, little is known about the mechanisms that mediate NICD nuclear import. We here show that transport of NICD into the nucleus is mediated by the canonical importin alpha/beta1 pathway. GST pull-down experiments revealed that NICD binds via one of its four potential nuclear localization signals to importins alpha3, alpha4, and alpha7, but not to alpha1 and alpha5. siRNA-mediated knockdown experiments showed that importins alpha3, alpha4 (and to a lesser extent, alpha7) mediate nuclear import of NICD and thus are directly involved in Notch signaling.

The formation of extracellular amyloid plaques is a common patho-biochemical event underlying several debilitating human conditions, including Alzheimer's disease (AD). Considerable evidence implies that AD damage arises primarily from small oligomeric amyloid forms of Abeta peptide, but the precise mechanism of pathogenicity remains to be established. Using a cell culture system that reproducibly leads to the formation of Alzheimer's Abeta amyloid plaques, we show here that the formation of a single amyloid plaque represents a template-dependent process that critically involves the presence of endocytosis- or phagocytosis-competent cells. Internalized Abeta peptide becomes sorted to multivesicular bodies where fibrils grow out, thus penetrating the vesicular membrane. Upon plaque formation, cells undergo cell death and intracellular amyloid structures become released into the extracellular space. These data imply a mechanism where the pathogenic activity of Abeta is attributed, at least in part, to intracellular aggregates.

Inactivation of voltage-gated Kv1 channels can be altered by Kvbeta subunits, which block the ion-conducting pore to induce a rapid ('N-type') inactivation. Here, we investigate the mechanisms and structural basis of Kvbeta1.3 interaction with the pore domain of Kv1.5 channels. Inactivation induced by Kvbeta1.3 was antagonized by intracellular PIP(2). Mutations of R5 or T6 in Kvbeta1.3 enhanced Kv1.5 inactivation and markedly reduced the effects of PIP(2). R5C or T6C Kvbeta1.3 also exhibited diminished binding of PIP(2) compared with wild-type channels in an in vitro lipid-binding assay. Further, scanning mutagenesis of the N terminus of Kvbeta1.3 revealed that mutations of L2 and A3 eliminated N-type inactivation. Double-mutant cycle analysis indicates that R5 interacts with A501 and T480 of Kv1.5, residues located deep within the pore of the channel. These interactions indicate that Kvbeta1.3, in contrast to Kvbeta1.1, assumes a hairpin structure to inactivate Kv1 channels. Taken together, our findings indicate that inactivation of Kv1.5 is mediated by an equilibrium binding of the N terminus of Kvbeta1.3 between phosphoinositides (PIPs) and the inner pore region of the channel.

Large-conductance Ca(2+)- and voltage-activated K(+) (BK) channels are comprised of four pore-forming -subunits (Slo1), whose mRNA is alternatively spliced in a cell-specific manner. Here we report the first case of a correctly spliced mutually exclusive exon in a mammalian (human and mouse) BK channel; an exon coding for the region from S6 to the RCK1 domain is exchanged for an alternative exon of the same length. The slo1 transcript with this novel exon is present in native brain tissues and inclusion of the alternative exon profoundly alters the channel's gating characteristics: faster activation at low Ca(2+) concentrations and greater open probability at resting membrane potential at high Ca(2+) concentrations. The novel gating features conferred by the alternative exon are dominant over those of the commonly described Slo1 variant when coexpressed. The evolutionarily preserved splicing of the Slo1 S6-RCK1 linker segment possess great potential to fine-tune neuronal excitability.

Large-conductance Ca2+-dependent K+ (BK(Ca)) channels are activated by intracellular Ca2+ and membrane depolarization in an allosteric manner. We investigated the pharmacological and biophysical characteristics of a BK(Ca)-type K+ channel in androgen-dependent LNCaP (lymph node carcinoma of the prostate) cells with novel functional properties, here termed BK(L). K+ selectivity, high conductance, activation by Mg2+ or NS1619, and inhibition by paxilline and penitrem A largely resembled the properties of recombinant BK(Ca) channels. However, unlike conventional BK(Ca) channels, BK(L) channels activated in the absence of free cytosolic Ca2+ at physiological membrane potentials; the half-maximal activation voltage was shifted by about -100 mV compared with BK(Ca) channels. Half-maximal Ca2+-dependent activation was observed at 0.4 microM: for BK(L) (at -20 mV) and at 4.1 microM: for BK(Ca) channels (at +50 mV). Heterologous expression of hSlo1 in LNCaP cells increased the BK(L) conductance. Expression of hSlo-beta1 in LNCaP cells shifted voltage-dependent activation to values between that of BK(L) and BK(Ca) channels and reduced the slope of the P (open) (open probability)-voltage curve. We propose that LNCaP cells harbor a so far unknown type of BK(Ca) subunit, which is responsible for the BK(L) phenotype in a dominant manner. BK(L)-like channels are also expressed in the human breast cancer cell line T47D. In addition, functional expression of BK(L) in LNCaP cells is regulated by serum-derived factors, however not by androgens.

Long chain fatty acid esters of coenzyme A (LC-CoA) are potent activators of ATP-sensitive (K(ATP)) channels, and elevated levels have been implicated in the pathophysiology of type 2 diabetes. This stimulatory effect is thought to involve a mechanism similar to phosphatidylinositol 4,5-bisphosphate (PIP2), which activates all known inwardly rectifying potassium (Kir) channels. However, the effect of LC-CoA on other Kir channels has not been well characterized. In this study, we show that in contrast to their stimulatory effect on K(ATP) channels, LC-CoA (e.g. oleoyl-CoA) potently and reversibly inhibits all other Kir channels tested (Kir1.1, Kir2.1, Kir3.4, Kir7.1). We also demonstrate that the inhibitory potency of the LC-CoA increases with the chain length of the fatty acid chain, while both its activatory and inhibitory effects critically depend on the presence of the 3'-ribose phosphate on the CoA group. Biochemical studies also demonstrate that PIP2 and LC-CoA bind with similar affinity to the C-terminal domains of Kir2.1 and Kir6.2 and that PIP2 binding can be competitively antagonized by LC-CoA, suggesting that the mechanism of LC-CoA inhibition involves displacement of PIP2. Furthermore, we demonstrate that in contrast to its stimulatory effect on K(ATP) channels, phosphatidylinositol 3,4-bisphosphate has an inhibitory effect on Kir1.1 and Kir2.1. These results demonstrate a bi-directional modulation of Kir channel activity by LC-CoA and phosphoinositides and suggest that changes in fatty acid metabolism (e.g. LC-CoA production) could have profound and widespread effects on cellular electrical activity.

Butyrate, formed by bacterial fermentation of plant foods, has been suggested to reduce colon cancer risks by suppressing the proliferation of tumor cells. In addition, butyrate has been shown to induce glutathione S-transferases (GSTs) in tumor cell lines, which may contribute to the detoxification of dietary carcinogens. We hypothesize that butyrate also affects biotransformation in non-transformed colon cells. Thus, we have investigated the gene expression of drug metabolism genes in primary human colon tissue, premalignant LT97 adenoma and HT29 tumor cells cultured in an appropriate medium+/-butyrate. A total of 96 drug metabolism genes (including 12 GSTs) spotted on cDNA macroarrays (Superarray; n = 3) were hybridized with biotin-labeled cDNA probes. To validate the expression detected with Superarray, samples of LT97 cells were also analyzed with high density microarrays (Affymetrix U133A), which include biotransformation genes that overlap with the set of genes represented on the Superarray. Relative expression levels were compared across colon samples and for each colon sample+/-butyrate. Compared with fresh tissue, 13 genes were downregulated in primary cells cultivated ex vivo, whereas 8 genes were upregulated. Several genes were less expressed in LT97 (40 genes) or in HT29 (41 and 17 genes, grown for 72 and 48 h, respectively) compared with primary colon tissue. Butyrate induced GSTP1, GSTM2, and GSTA4 in HT29 as previously confirmed by other methods (northern blot/qPCR). We detected an upregulation of GSTs (GSTA2, GSTT2) that are known to be involved in the defence against oxidative stress in primary cells upon incubation with butyrate. The changes in expression detected in LT97 by Superarray and Affymetrix were similar, confirming the validity of the results. We conclude that low GST expression levels were favourably altered by butyrate. An induction of the toxicological defence system possibly contributes to reported chemopreventive properties of butyrate, a product of dietary fibre fermentation in the gut.

Helicobacter pylori (H. pylori) often play an important role in the pathogenesis of gastritis, peptic ulcer, and probably also gastric cancer. Reactive oxygen species (ROS) produced by this bacterium may be one of the crucial factors whereby oxidative stress can play a role in the pathogenesis of ulcer disease. The aim of this study was to assess ROS activity and glutathione redox status, a principal cellular redox sensor, in H. pylori-associated indomethacin-induced gastric ulcers in rats. Gastric lesion was produced by intragastric administration of indomethacin (7 mg/kg) for three days followed by administration of H. pylori suspension (density 10(9) colony forming units). Animals receiving indomethacin only or followed by administration of H. pylori suspension were sacrificed after 11 and 18 days. ROS activity was assessed by the level of lipid peroxidation (LPO) and the glutathione redox status by the ratio between oxidized and reduced glutathione (GSSG/GSH). Indomethacin did not significantly increase the level of LPO and the GSSG/GSH ratio. When H. pylori suspension was given together with indomethacin the LPO was increased both on days 11 and 18 and GSSG/GSH on day 18. H. pylori, thus, substantially increases glutathione redox ratio and lipid peroxidation in gastric mucosa, which may play an important role in the pathological mechanisms of this bacterium. The findings support the idea that dietary antioxidants could be beneficial in combination therapy for eradication of H. pylori.

Collection of missense mutations in the SUP45 gene of Saccharomyces cerevisiae encoding translation termination factor eRF1 has been obtained by different approaches. It has been shown that most of isolated mutations cause amino acid substitutions in the N-terminal part of eRF1 and do not decrease the eRF1 amount. Most of mutations studied do not abolish eRF1-eRF3 interaction. The role of the N-terminal part of eRF1 in stop codon recognition is discussed.

Voltage-gated potassium (Kv) channels control action potential repolarization, interspike membrane potential, and action potential frequency in excitable cells. It is thought that the combinatorial association between distinct alpha and beta subunits determines whether Kv channels function as non-inactivating delayed rectifiers or as rapidly inactivating A-type channels. We show that membrane lipids can convert A-type channels into delayed rectifiers and vice versa. Phosphoinositides remove N-type inactivation from A-type channels by immobilizing the inactivation domains. Conversely, arachidonic acid and its amide anandamide endow delayed rectifiers with rapid voltage-dependent inactivation. The bidirectional control of Kv channel gating by lipids may provide a mechanism for the dynamic regulation of electrical signaling in the nervous system.

Phosphatidylinositol polyphosphates (PIPs) are potent modulators of Kir channels. Previous studies have implicated basic residues in the C terminus of Kir6.2 channels as interaction sites for the PIPs. Here we examined the role of the N terminus and identified an arginine (Arg-54) as a major determinant for PIP(2) modulation of ATP sensitivity in K(ATP) channels. Mutation of Arg-54 to the neutral glutamine (R54Q) and, in particular, to the negatively charged glutamate (R54E) impaired PIP(2) modulation of ATP inhibition, while mutation to lysine (R54K) had no effect. These data suggest that electrostatic interactions between PIP(2) and Arg-54 are an essential step for the modulation of ATP sensitivity. This N-terminal PIP(2) site is highly conserved in Kir channels with the exception of the pH-gated channels Kir1.1, Kir4.1, and Kir5.1 that contain a neutral residue at the corresponding positions. Introduction of an arginine at this position in Kir1.1 channels rendered the N-terminal PIP(2) site functional largely increasing the PIP(2) affinity. Moreover, Kir1.1 channels lose the ability to respond to physiological changes of the intracellular pH. These results explain the need of a silent N-terminal PIP(2) site in pH-gated channels and highlight the N terminus as an important region for PIP(2) modulation of Kir channel gating.