Broad scale functional connectivity for Asian elephants in the Nepal-India transboundary region.

The Nepal-India transboundary region hosts one of Asia's most complex large mammal assemblages, including a small (but growing) population of Asian elephants (Elephas maximus). These elephants occur in four widespread and geographically disjunct subpopulations, and some of them undergo seasonal transboundary movements. We conducted a broad-scale evaluation of the amount and quality of elephant habitat available in the region and of functional landscape connectivity between and within subpopulations using Maxent, circuit theory, and least-cost path analysis. Habitat suitability was highly influenced by abiotic geographical factors (altitude and precipitation) and less by ecological factors (habitat heterogeneity, plant productivity) and human disturbance (distance to settlements). The region had a relatively small amount of high and optimal suitability habitat (12.6% out of 93,700 km2) but all subpopulations seem to be far from carrying capacity, suggesting ample potential for further population growth. Landscape connectivity was higher between and within the west and far-west subpopulations, which should be considered a single subpopulation. The central and ea st subpopulations, however, had low to very low between-subpopulation connectivity. Conservation priorities include maintaining the current connectivity in the west subpopulation and across the border in the east, and protecting high-quality habitats in eastern Nepal. Restoring connectivity between the central and other subpopulations is possible if the number of elephants continues growing, and it should be a long-term conservation aspiration. Maintaining and enhancing landscape connectivity in this region requires transboundary cooperation and coordination between Nepali and Indian authorities. If successful, it will bring considerable benefits for the conservation of elephants and other wildlife.

Identifying the environmental and anthropogenic causes, distribution, and intensity of human rhesus macaque conflict in Nepal.

Reducing conflict between humans and wildlife is considered a top conservation priority. However, increasingly human-induced disturbances across natural landscapes have escalated encounters between humans and wildlife. In Nepal, forests have been destroyed, fragmented, and developed for human settlements, agricultural production, and urban centers for decades. As a result, human-wildlife conflict, in the form of crop-raiding, livestock predation, and injuries to humans and wildlife, is common throughout the country. In particular, crop-raiding by macaques is an increasingly common form of human-wildlife conflict. Rhesus macaques (Macaca mulatta) have been identified as a top ten crop-raiding wildlife species in Nepal. In order to better understand the nationwide distribution and intensity of human-rhesus macaque conflict (HRMC), we conducted an extensive literature review of reported incidences of HRMC during the period 2000 to 2021 in Nepal. We also created an online survey to obtain nationwide data on the location and severity of HRMC, and modeled the set of ecological factors that affect habitat suitability for rhesus macaques. An ensemble of three different species distribution model (SDM) algorithms were used to analyze these data. We found that almost 44% of Nepal's land area contains suitable habitat for rhesus macaques, with less than 8% of all suitable habitat located in protected national parks. As humans continue to alter and fragment natural landscapes, HRMC in Nepal has intensified. At present, nearly 15% of the country's land area in which human settlements are permitted, is characterized by moderate or high rates of HRMC. We argue that prioritizing programs of forest restoration, strategic management plans designed to connect isolated forest fragments with high rhesus macaque population densities, creating government programs that compensate farmers for income lost due to crop-raiding, and educational outreach that informs local villagers of the importance of conservation and protecting biodiversity, offer the most effective solutions to reduce HRMC in Nepal.

P2Y12 Promotes Migration of Vascular Smooth Muscle Cells Through Cofilin Dephosphorylation During Atherogenesis.

OBJECTIVE: P2Y12 is a well-recognized receptor expressed on platelets and the target of thienopyridine-type antiplatelet drugs. However, recent evidence suggests that P2Y12 expressed in vessel wall plays a role in atherogenesis, but the mechanisms remain elusive. In this study, we examined the molecular mechanisms of how vessel wall P2Y12 mediates vascular smooth muscle cells (VSMCs) migration and promotes the progression of atherosclerosis. APPROACH AND RESULTS: Using a high-fat diet-fed apolipoprotein E-deficient mice model, we found that the expression of P2Y12 in VSMCs increased in a time-dependent manner and had a linear relationship with the plaque area. Moreover, administration of P2Y12 receptor antagonist for 12 weeks caused significant reduction in atheroma and decreased the abundance of VSMCs in plaque. In cultured VSMCs, we found that activation of P2Y12 receptor inhibited cAMP/protein kinase A signaling pathway, which induced cofilin dephosphorylation and filamentous actin disassembly, thereby enhancing VSMCs motility and migration. In addition, the number of P2Y12-positive VSMCs was decreased in the carotid artery plaque from patients receiving clopidogrel. CONCLUSIONS: Vessel wall P2Y12 receptor, which promotes VSMCs migration through cofilin dephosphorylation, plays a critical role in the development of atherosclerotic lesion and may be used as a therapeutic target for atherosclerosis.

MicroRNA-150 regulates blood-brain barrier permeability via Tie-2 after permanent middle cerebral artery occlusion in rats.

The mechanism of blood-brain barrier (BBB) disruption, involved in poststroke edema and hemorrhagic transformation, is important but elusive. We investigated microRNA-150 (miR-150)-mediated mechanism in the disruption of BBB after stroke in rats. We found that up-regulation of miR-150 increased permeability of BBB as detected by MRI after permanent middle cerebral artery occlusion in vivo as well as increased permeability of brain microvascular endothelial cells after oxygen-glucose deprivation in vitro. The expression of claudin-5, a key tight junction protein, was decreased in the ischemic boundary zone after up-regulation of miR-150. We found in brain microvascular endothelial cells that overexpression of miR-150 decreased not only cell survival rate but also the expression levels of claudin-5 after oxygen-glucose deprivation. With dual-luciferase assay, we confirmed that miR-150 could directly regulate the angiopoietin receptor Tie-2. Moreover, silencing Tie-2 with lentivirus-delivered small interfering RNA reversed the effect of miR-150 on endothelial permeability, cell survival, and claudin-5 expression. Furthermore, poststroke treatment with antagomir-150, a specific miR-150 antagonist, contributed to BBB protection, infarct volume reduction, and amelioration of neurologic deficits. Collectively, our findings suggested that miR-150 could regulate claudin-5 expression and endothelial cell survival by targeting Tie-2, thus affecting the permeability of BBB after permanent middle cerebral artery occlusion in rats, and that miR-150 might be a potential alternative target for the treatment of stroke.-Fang, Z., He, Q.-W., Li, Q., Chen, X.-L., Baral, S., Jin, H.-J., Zhu, Y.-Y., Li, M., Xia, Y.-P., Mao, L., Hu, B. MicroRNA-150 regulates blood-brain barrier permeability via Tie-2 after permanent middle cerebral artery occlusion in rats.

CYP2C19 polymorphism and clinical outcomes among patients of different races treated with clopidogrel: A systematic review and meta-analysis.

Several studies have investigated the association between CYP2C19 polymorphism and clinical outcomes of patients treated with clopidogrel, but few have noticed the difference in association between Westerners and Asians. We searched MEDLINE, EMBASE and Cochrane Library database and conducted a systematic review and meta-analysis. Thirty-six studies involving 44 655 patients with coronary artery disease (CAD) treated with clopidogrel were included, of which more than 68% had undergone percutaneous coronary intervention (PCI). The primary outcome of our interest was the recurrence of major adverse cardiovascular events (MACE) in those CAD patients. Firstly, we found that the distribution of reduced-function CYP2C19 allele varied between Westerners and Asians. Among Asians, 1 and 2 reduced-function CYP2C19 mutant allele carriers accounted for 42.5% and 10%, respectively. While among Westerners, 1 and 2 reduced-function CYP2C19 mutant allele carriers accounted for 25.5% and 2.4%, respectively. Secondly, the impact of CYP2C19 polymorphism on clinical outcomes of patients treated with clopidogrel varied with races. Among Asians, only 2 reduced-function CYP2C19 mutant allele carriers had the reduced effect of clopidogrel. And the reduced effect was significant only after the 30th day of treatment. While among Westerners, both 1 and 2 reduced-function CYP2C19 allele carriers had the reduced effect, and it mainly occurred within the first 30 days. Thirdly, the safety of clopidogrel was almost the same among races. Reduced-function allele non-carriers had higher risk for total bleeding but did not have higher risk for major bleeding. It is suggested that CYP2C19 polymorphism affects the efficacy of clopidogrel differently among Westerners and Asians.

Landscape-level habitat connectivity of large mammals in Chitwan Annapurna Landscape, Nepal.

The populations of many species of large mammals occur in small isolated and fragmented habitat patches in the human-dominated landscape. Maintenance of habitat connectivity in the fragmented landscapes is important for maintaining a healthy population of large mammal. This study evaluated the landscape patches and their linkages on two carnivores (leopard and Himalayan black bear) and seven prey species (northern red muntjac, chital, sambar, wild pig, Himalayan goral, rhesus macaque, and langur) between Chitwan National Park (CNP) and Annapurna Conservation Area (ACA) by using the least-cost path (LCP) approach and the Linkage Mapper tool in ArcGIS. A total of 15 habitat patches (average area 26.67 ± 12.70 km2) were identified that had more than 50% of the total studied mammals. A weak relation among the habitat patches was found for chital and sambar (Cost-weighted distance [CWD]: Euclidean distance EucD >100), showed poor connectivity between the habitat patches, while ratio of CWD and EucD was low (i.e., low LCP) between majority of the patches for muntjac, wild pig and leopard hence had potential functional connectivity along the landscape. Similarly, low LCP between the habitat patches located in the mid-hills was observed for Himalayan goral and Himalayan black bear. Furthermore, the multi-species connectivity analysis identified the potential structural connectivity between the isolated populations and habitat patches. Therefore, these sites need to be considered connectivity hotspots and be prioritized for the conservation of large mammals in the landscape.

MiR-181b Antagonizes Atherosclerotic Plaque Vulnerability Through Modulating Macrophage Polarization by Directly Targeting Notch1.

Atherosclerotic plaque vulnerability is the major cause for acute stroke and could be regulated by macrophage polarization. MicroRNA-181b (miR-181b) was involved in macrophage differential. Here, we explore whether miR-181b could regulate atherosclerotic plaque vulnerability by modulating macrophage polarization and the underline mechanisms. In acute stroke patients with atherosclerotic plaque, we found that the serum level of miR-181b was decreased. Eight-week apolipoprotein E knockout (ApoE-/-) mice were randomly divided into three groups (N = 10): mice fed with normal saline (Ctrl), mice fed with high-fat diet, and tail vein injection with miRNA agomir negative control (AG-NC)/miR-181b agomir (181b-AG, a synthetic miR-181b agonist). We found that the serum level of miR-181b in AG-NC group was lower than that in Ctrl group. Moreover, 181b-AG could upregulate miR-181b expression, reduce artery burden and attenuate atherosclerotic plaque vulnerability by modulating macrophage polarization. In RAW264.7 cells treated with oxidized low-density lipoprotein (ox-LDL), we found miR-181b could reverse the function of ox-LDL on M1/M2 markers at both mRNA and protein levels. Furthermore, by employing luciferase reporter assay, we found that Notch1 was a direct target of miR-181b and could be regulated by miR-181b in vivo and in vitro. Finally, inhibition of Notch1 could abolish the function of downregulating miR-181b on increasing M2 phenotype macrophages. Our study demonstrates that administration of miR-181b could reduce atherosclerotic plaque vulnerability partially through modulating macrophage phenotype by directly targeting Notch1.

MicroRNA-493 regulates angiogenesis in a rat model of ischemic stroke by targeting MIF.

MicroRNA-493 (miR-493) is known to suppress tumour metastasis and angiogenesis and its expression is decreased in stroke patients. In the present study, we investigated a role for miR-493 in regulating post-stroke angiogenesis. We found decreased expression of miR-493 in the ischemic boundary zone (IBZ) of rats subjected to middle cerebral artery occlusion (MCAO), and in rat brain microvascular endothelial cells (RBMECs) exposed to oxygen glucose deprivation. Down-regulating miR-493 with a lateral ventricular injection of antagomir-493, a synthetic miR-493 inhibitor, increased capillary density in the IBZ, decreased focal infarct volume and ameliorated neurologic deficits in rats subjected to MCAO. Intriguingly, MCAO also increased the expression of macrophage migration inhibitory factor (MIF) in the IBZ of rats; MIF expression was also increased in RBMECs exposed to oxygen glucose deprivation. We found that miR-493 directly targeted MIF, and that the protective effect of miR-493 inhibition in angiogenesis was attenuated by knocking down MIF. This effect could then be rescued by administration of recombinant MIF. Our findings highlight the importance of miR-493 in regulating angiogenesis after MCAO, and indicate that miR-493 is a potential therapeutic target in the treatment of stroke.

MicroRNA-107 contributes to post-stroke angiogenesis by targeting Dicer-1.

Previous studies have suggested that microRNA-107 (miR-107) regulates cell migration in tumor and promotes Hypoxia Inducible Factor 1α (HIF1α) regulated angiogenesis under hypoxia. We found that miR-107 was strongly expressed in ischemic boundary zone (IBZ) after permanent middle cerebral artery occlusion (pMCAO) in rats and inhibition of miR-107 could reduce capillary density in the IBZ after stroke. Such finding led us to hypothesize that miR-107 might regulate post-stroke angiogenesis and therefore serve as a therapeutic target. We also found that antagomir-107, a synthetic miR-107 inhibitor, decreased the number of capillaries in IBZ and increased overall infarct volume after pMCAO in rats. We demonstrated that miR-107 could directly down-regulate Dicer-1, a gene that encodes an enzyme essential for processing microRNA (miRNA) precursors. This resulted in translational desupression of VEGF (vascular endothelial growth factor) mRNA, thereby increasing expression of endothelial cell-derived VEGF (VEGF165/VEGF164), leading to angiogenesis after stroke. This process might be a protective mechanism for ischemia-induced cerebral injury and miR-107 might be used as a novel tool in stroke treatment.