Assessing Hydropower Potential in Nepal's Sunkoshi River Basin: An Integrated GIS and SWAT Hydrological Modeling Approach.

This study assessed the hydropower potential of a mountain watershed within the Sunkoshi River basin in Sindhupalchok, Nepal, utilizing geographic information systems (GIS) and the soil and water assessment tool (SWAT) hydrological model. Topographical, soil, land use, meteorological, and discharge data were employed to assess the study area for the appropriateness of hydropower generation. SWAT was utilized to delineate the Sunkoshi basin into 23 distinct subbasins and involved the creation of a detailed river network, incorporating various hydrological attributes including stream links, stream order, stream length, and slope gradient. After that, it was employed to simulate river discharges within these subbasins. The Sequential Uncertainty Fitting Version 2 (SUFI-2) algorithm, integrated within the SWAT Calibration and Uncertainty Program (SWAT-CUP), was employed to calibrate and validate the model. This step involved the adjustment of 25 selected parameters to enhance the model's accuracy and reliability in representing the hydrological processes of the Sunkoshi basin. Model performance was assessed utilizing three well-established efficiency criteria: coefficient of determination (R2 = 0.79), Nash-Sutcliffe efficiency (NSE = 0.73), and percent bias (PBIAS = 17.59). The study identified 36 sites across streams of order 3, 4, and 5 as having potential for hydropower generation. The hydropower potential at each identified site was evaluated using estimated stream flow and topographical head at various probability of exceedance (PoE) levels (40%, 45%, 50%, and 60%). The aggregate hydropower potential of the basin was quantified, yielding a potential of 371.30 MW at a 40% PoE. The findings suggest that an integrated approach combining SWAT-based hydrological modeling within a GIS can accurately assess a river basin's hydropower potential and provide insights into further evaluation of the comprehensive environmental assessment of the fragile Himalayan watersheds.

Plasmin improves blood-gas barrier function in oedematous lungs by cleaving epithelial sodium channels.

BACKGROUND AND PURPOSE: Lung oedema in association with suppressed fibrinolysis is a hallmark of lung injury. Here, we have tested whether plasmin cleaves epithelial sodium channels (ENaC) to resolve lung oedema fluid. EXPERIMENTAL APPROACH: Human lungs and airway acid-instilled mice were used for analysing fluid resolution. In silico prediction, mutagenesis, Xenopus oocytes, immunoblotting, voltage clamp, mass spectrometry, and protein docking were combined for identifying plasmin cleavage sites. KEY RESULTS: Plasmin improved lung fluid resolution in both human lungs ex vivo and injured mice. Plasmin activated αßγENaC channels in oocytes in a time-dependent manner. Deletion of four consensus proteolysis tracts (αΔ432-444, γΔ131-138, γΔ178-193, and γΔ410-422) eliminated plasmin-induced activation significantly. Further, immunoblotting assays identified 7 cleavage sites (K126, R135, K136, R153, K168, R178, K179) for plasmin to trim both furin-cleaved C-terminal fragments and full-length human γENaC proteins. In addition, 9 new sites (R122, R137, R138, K150, K170, R172, R180, K181, K189) in synthesized peptides were found to be cleaved by plasmin. These cleavage sites were located in the finger and the thumb, particularly the GRIP domain of human ENaC 3D model composed of two proteolytic centres for plasmin. Novel uncleaved sites beyond the GRIP domain in both α and γ subunits were identified to interrupt the plasmin cleavage-induced conformational change in ENaC channel complexes. Additionally, plasmin could regulate ENaC activity via the G protein signal. CONCLUSION AND IMPLICATIONS: Plasmin can cleave ENaC to improve blood-gas exchange by resolving oedema fluid and could be a potent therapy for oedematous lungs.

Gastrointestinal vascular permeability changes following spinal cord injury.

BACKGROUND: Gastrointestinal (GI) dysfunction is observed clinically after spinal cord injury (SCI) and contributes to the diminished long-term quality of life. Our study examined the acute and chronic GI vascular changes that occur following SCI. We demonstrated that the GI vascular tract in SCI mice becomes compromised during the acute phase of injury and persists into the chronic phase of injury. METHODS: Gastrointestinal vasculature permeability was measured using dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) at 48 hours, and 2 and 4 weeks following contusion spinal cord injury. Angiopoietin-1, a vascular stabilizing protein, was administered intravenously following injury. Intestinal contractile activity assessments were performed following the last imaging session. KEY RESULTS: Our results indicated that a single administration of Ang-1 reduced vascular permeability at 48 hours but the effect was only transient. However, when the treatment paradigm was changed from a single administration to multiple administrations of Ang-1 following contusion injury, our DCE MRI data indicated a significant decrease in GI vascular permeability 4 weeks after injury compared with vehicle control treated animals. This improved GI vascular permeability was associated with improved sustained intestinal contractile activity. We also demonstrated that Ang-1 reduced the expression of sICAM-1 in the ileum compared with the saline-treated group. CONCLUSIONS AND INFERENCES: We show that the GI vasculature is compromised in the acute and chronic phase of injury following spinal contusion. Our results also indicate that multiple administrations of Ang-1 can attenuate GI vascular permeability, possibly reduce inflammation, and improve sustained agonist-induced contraction compared with saline treatment.

Prevalence and factors associated with depression among higher secondary school adolescents of Pokhara Metropolitan, Nepal: a cross-sectional study.

OBJECTIVE: This study examined the prevalence and factors associated with depression among adolescents attending higher secondary schools in the Pokhara Metropolitan City of Nepal. DESIGN: A cross-sectional study design was adopted. SETTING: Four randomly selected higher secondary schools of Pokhara Metropolitan, Nepal. PARTICIPANTS: 312 randomly sampled higher secondary school students. METHODS: The Center for Epidemiologic Studies Depression Scale was used to assess the level of depression among students. The data collected through a self-administered questionnaire were analysed using descriptive statistical methods such as frequency and percentage. χ2 test and unadjusted OR (UOR) were calculated to assess the statistical relationship between depression and various variables at 95% CI, with level of significance at p<0.05. RESULTS: The study found a high prevalence of depression among high school students, with more than two-fifths (44.2%) of students having depression. Furthermore, almost a quarter (25.3%) of the students were noted to have mild depression and 18.9% of the students expressed major depression. Students who had low perceived social support (UOR: 3.604; 95% CI 2.088 to 6.220), did not share their problems with anyone (UOR: 1.931; 95% CI 1.228 to 3.038) and had low self-esteem (UOR: 5.282; 95% CI 2.994 to 9.319) were at higher odds of being depressed. CONCLUSION: A high prevalence of depression was observed among high school students. It was also observed that students' level of perceived social support, self-esteem and help-seeking behaviour are somehow related to their mental well-being. Hence, improving social support and self-esteem may alleviate depression and mental distress among these adolescents.

CXCL1 is upregulated during the development of ileus resulting in decreased intestinal contractile activity.

BACKGROUND: Although the development of ileus is widespread and negatively impacts patient outcomes, the mechanism by which ileus develops remains unclear. The purpose of our study was to examine the contribution of myogenic mechanisms to postoperative ileus development and the involvement of inflammation in mediating intestinal smooth muscle dysfunction. METHODS: Contractile activity and the effects of CXCL1 were studied in a gut manipulation model. KEY RESULTS: Contraction amplitude in the ileum decreased significantly, while tone increased significantly in response to gut manipulation. Differences in contraction amplitude were affected by tetrodotoxin at earlier time points, but not at later time points. Agonist-induced contractions in the small intestine decreased significantly with ileus development. Intestinal transit slowed significantly after the induction of ileus. Myosin light chain phosphorylation was significantly decreased and edema increased significantly in the intestinal wall. Conditioned media from mechanically activated macrophages depressed intestinal contractile activity. CXCL1 (GroA) was significantly increased in the mechanically activated macrophages and intestinal smooth muscle within 1 hour after induction of ileus compared with control cells and sham animals, respectively. Treatment with CXCL1 significantly decreased contraction amplitude and agonist-induced contractile activity and increased tone in the small intestine. In the gut manipulation model, treatment with a CXCR2 antagonist prevented the decrease in agonist-induced contractile activity but not contraction amplitude. CONCLUSIONS & INFERENCES: These data suggest that CXCL1, released from macrophages during intestinal wall stress, can suppress intestinal contractile activity. CXCL1 is a potential target for preventing or treating ileus in trauma patients.

Therapeutic time window of multipotent adult progenitor therapy after traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is a major cause of death and disability. TBI results in a prolonged secondary central neuro-inflammatory response. Previously, we have demonstrated that multiple doses (2 and 24 h after TBI) of multipotent adult progenitor cells (MAPC) delivered intravenously preserve the blood-brain barrier (BBB), improve spatial learning, and decrease activated microglia/macrophages in the dentate gyrus of the hippocampus. In order to determine if there is an optimum treatment window to preserve the BBB, improve cognitive behavior, and attenuate the activated microglia/macrophages, we administered MAPC at various clinically relevant intervals. METHODS: We administered two injections intravenously of MAPC treatment at hours 2 and 24 (2/24), 6 and 24 (6/24), 12 and 36 (12/36), or 36 and 72 (36/72) post cortical contusion injury (CCI) at a concentration of 10 million/kg. For BBB experiments, animals that received MAPC at 2/24, 6/24, and 12/36 were euthanized 72 h post injury. The 36/72 treated group was harvested at 96 h post injury. RESULTS: Administration of MAPC resulted in a significant decrease in BBB permeability when administered at 2/24 h after TBI only. For behavior experiments, animals were harvested post behavior paradigm. There was a significant improvement in spatial learning (120 days post injury) when compared to cortical contusion injury (CCI) in groups when MAPC was administered at or before 24 h. In addition, there was a significant decrease in activated microglia/macrophages in the dentate gyrus of hippocampus of the treated group (2/24) only when compared to CCI. CONCLUSIONS: Intravenous injections of MAPC at or before 24 h after CCI resulted in improvement of the BBB, improved cognitive behavior, and attenuated activated microglia/macrophages in the dentate gyrus.

Prostaglandin E2 Indicates Therapeutic Efficacy of Mesenchymal Stem Cells in Experimental Traumatic Brain Injury.

Traumatic brain injury (TBI) is soon predicted to become the third leading cause of death and disability worldwide. After the primary injury, a complex set of secondary injuries develops hours and days later with prolonged neuroinflammation playing a key role. TBI and other inflammatory conditions are currently being treated in preclinical and clinical trials by a number of cellular therapies. Mesenchymal stem cells (MSC) are of great interest due to their widespread usage, safety, and relative ease to isolate and culture. However, there has been a wide range in efficacy reported using MSC clinically and in preclinical models, likely due to differences in cell preparations and a significant amount of donor variability. In this study, we seek to find a correlation between in vitro activity and in vivo efficacy. We designed assays to explore the responsiveness of MSC to immunological cues to address the immunomodulatory properties of MSC, one of their primary modes of therapeutic activity in TBI. Our results showed intrinsic differences in the immunomodulatory capacity of MSC preparations from different bone marrow and amniotic fluid donors. This difference mirrored the therapeutic capacity of the MSC in an experimental model of TBI, an effect confirmed using siRNA knockdown of COX2 followed by overexpressing COX2. Among the immunomodulatory factors assessed, the therapeutic benefit correlated with the secretion of prostaglandin E2 (PGE2 ) by MSC prior to treatment, suggesting that measurement of PGE2 could be a very useful potency marker to create an index of predicted efficacy for preparations of MSC to treat TBI. Stem Cells 2017;35:1416-1430.

Suppression of contractile activity in the small intestine by indomethacin and omeprazole.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to treat a number of conditions, and proton pump inhibitors (PPIs) are often used to prevent NSAID-induced gastric mucosal damage; however, the effects of NSAIDs on intestinal motility are poorly understood. The purpose of the present study is to determine the effects of a prototypical NSAID, indomethacin, either alone or in conjunction with the PPI omeprazole, on intestinal motility. Rats were randomly divided into four groups treated with vehicle, omeprazole, indomethacin, or a combination of indomethacin and omeprazole. Intestinal motility and transit were measured along with inflammatory mediators in the intestinal smooth muscle, markers of mucosal damage, and bacterial counts in the intestinal wall. Indomethacin, but not omeprazole, caused mucosal injury indicated by lower gut bleeding; however, both omeprazole and indomethacin suppressed contractile activity and frequency in the distal part of the small intestine. Cotreatment with omeprazole did not reduce indomethacin-induced intestinal bleeding. Furthermore, although indomethacin caused increased inflammation as indicated by increased edema development and inflammatory mediators, cotreatment with omeprazole did not reduce inflammation in the intestinal smooth muscle or prevent the increased bacterial count in the intestinal wall induced by indomethacin. We conclude that both NSAID and PPI treatment suppressed contractile activity in the distal regions of the small intestine. The suppression of intestinal contractility was associated with increased inflammation in both cases; however, indomethacin and omeprazole appear to affect intestinal motility by different mechanisms.

Regulation of epithelial sodium channels in urokinase plasminogen activator deficiency.

Epithelial sodium channels (ENaC) govern transepithelial salt and fluid homeostasis. ENaC contributes to polarization, apoptosis, epithelial-mesenchymal transformation, etc. Fibrinolytic proteases play a crucial role in virtually all of these processes and are elaborated by the airway epithelium. We hypothesized that urokinase-like plasminogen activator (uPA) regulates ENaC function in airway epithelial cells and tested that possibility in primary murine tracheal epithelial cells (MTE). Both basal and cAMP-activated Na(+) flow through ENaC were significantly reduced in monolayers of uPA-deficient cells. The reduction in ENaC activity was further confirmed in basolateral membrane-permeabilized cells. A decrease in the Na(+)-K(+)-ATPase activity in the basolateral membrane could contribute to the attenuation of ENaC function in intact monolayer cells. Dysfunctional fluid resolution was seen in uPA-disrupted cells. Administration of uPA and plasmin partially restores ENaC activity and fluid reabsorption by MTEs. ERK1/2, but not Akt, phosphorylation was observed in the cells and lungs of uPA-deficient mice. On the other hand, cleavage of γ ENaC is significantly depressed in the lungs of uPA knockout mice vs. those of wild-type controls. Expression of caspase 8, however, did not differ between wild-type and uPA(-/-) mice. In addition, uPA deficiency did not alter transepithelial resistance. Taken together, the mechanisms for the regulation of ENaC by uPA in MTEs include augmentation of Na(+)-K(+)-ATPase, proteolysis, and restriction of ERK1/2 phosphorylation. We demonstrate for the first time that ENaC may serve as a downstream signaling target by which uPA controls the biophysical profiles of airway fluid and epithelial function.

8-(4-chlorophenylthio)-guanosine-3',5'-cyclic monophosphate-Na stimulates human alveolar fluid clearance by releasing external Na+ self-inhibition of epithelial Na+ channels.

Salt absorption via alveolar epithelial Na(+) channels (ENaC) is a critical step for maintaining an airspace free of flooding. Previously, we found that 8-(4-chlorophenylthio)-guanosine-3',5'-cyclic monophosphate-Na (CPT-cGMP) activated native and heterologous ENaC. To investigate the potential pharmacological relevance, we applied this compound intratracheally to human lungs and found that ex vivo alveolar fluid clearance was increased significantly. Furthermore, this compound eliminated self-inhibition in human lung H441 cells and in oocytes expressing human αßγ but not δßγ channels. To further elucidate this novel mechanism, we constructed mutants abolishing (ß(ΔV348) and γ(H233R)) or augmenting (α(Y458A) and γ(M432G)) self-inhibition. The mutants eliminating self-inhibition lost their responses to CPT-cGMP, whereas those enhancing self-inhibition facilitated the stimulatory effects of this compound. CPT-cGMP was unable to activate a high P(o) mutant (ß(S520C)) and plasmin proteolytically cleaved channels. Our data suggest that elimination of self-inhibition of αßγ ENaC may be a novel mechanism for CPT-cGMP to stimulate salt reabsorption in human lungs.