The effects of grassland degradation on the genetic structure of a small mammal.

Grassland degradation is challenging the health of grassland ecosystems globally and causing biodiversity decline. Previous studies have demonstrated the impact of grassland degradation on the abundance and behavior of small mammals. Little is known about how it affects the genetic structure of gregarious mammals in the wild. This study explores the effects of grassland degradation on the genetic structure of a small burrowing mammal, plateau pika (Ochotona curzoniae). We used nine microsatellite loci to analyze the genetic diversity and genetic differentiation between colonies and genetic relatedness between individuals within the colony. We found that pikas in severely degraded grasslands had a significantly higher genetic diversity within colonies, a higher level of gene flow between colonies, and a lower genetic differentiation between colonies compared to pikas in less degraded grasslands. Individuals within colonies had a significantly lower genetic relatedness in severely degraded grasslands than in less degraded grasslands. This study has provided potential evidence of a significant impact of grassland degradation on the genetic structure of pikas, which has caused a breakdown of their kin-selected colony structure.

Prey selection by leopards (Panthera pardus fusca) in the mid-hill region of Nepal.

Information on prey selection and the diet of the leopard (Panthera pardus fusca) is essential for leopard conservation. We conducted an investigation into the prey species and the proportion of each species in the leopard's diet in a human-dominated mid-hill region of Nepal. The analysis of 96 leopard scats collected between August 2020 and March 2021 revealed that leopards consumed 15 prey species, including small- and medium-sized mammals and livestock. In addition to these prey species, we also found plastic materials, bird feathers, and some unidentified items in the leopard scats. Wild ungulates (such as barking deer, Muntiacus muntjak and wild boar, Sus scrofa) constituted only 10% of the biomass in the scats, while livestock contributed 27%, and other wild prey contributed 50%. Among all species, domestic goats had the highest relative biomass in the scats, followed by the jungle cat (Felis chaus), domestic dog (Canis familiaris), and large Indian civet (Viverra zibetha). Similarly, the Indian hare (Lepus nigricollis) had the highest proportion of relative individuals present in the scat samples, followed by the jungle cat and the large Indian civet. A lower proportion of biomass from wild ungulates in the leopard's diet and a higher dependency of the leopard on domestic prey and other wild prey indicate a shortage of medium-sized wild prey, such as barking deer and wild boar, in leopard habitats. Therefore, the conservation of wild prey species, especially medium-sized prey, is crucial for reducing the leopard's dependence on livestock and mitigating human-leopard conflicts in the future.

Alpine grassland degradation intensifies the burrowing behavior of small mammals: evidence for a negative feedback loop.

Globally, grassland degradation is an acute ecological problem. In alpine grassland on the Tibetan Plateau, increased densities of various small mammals in degraded grassland are assumed to intensify the degradation process and these mammals are subject to lethal control. However, whether the negative impact of small mammals is solely a result of population size or also a result of activity and behavior has not been tested. In this study, we use plateau pika as a model to compare population size, core area of colony, and the number of burrow entrances and latrines between lightly and severely degraded grassland. We test whether the alleged contribution of pika to grassland degradation is a result of increased population size or increased burrowing activities of individuals in response to lower food abundance. We found that grassland degradation resulted in lower plant species richness, plant height, and biomass. Furthermore, the overall population size of pika was not significantly affected by location in lightly and severely degraded grassland. However, pika core areas in severely grassland degradation were significantly larger and had significantly higher densities of burrows and latrines. Our study provides convincing evidence that habitat-induced changes in the behavior of small, burrowing mammals, such as pika, can exacerbate grassland degradation. This finding has significant implications for managing small mammals and restoring degraded grassland ecosystems.

Possibility of Wild Boar Harm Occurring in Five Provinces of Northwest China.

With the implementation of ecological engineering projects and related policies in China, wild boar (Sus scrofa) populations have surged, leading to increasingly serious conflicts with humans. We evaluated their potential habitat changes from the perspective of environmental suitability. To elucidate the suitable habitat characteristics for wild boars, we obtained data from 79 sites in five provinces in northwest China using database retrieval, human-wildlife conflict (HWC) incident questionnaires, and document retrieval. Thus, 10 environmental variables with lower correlation were selected, and potentially suitable distribution areas for wild boars under the current climate scenario were predicted based on the maximum entropy model. These areas were superimposed with different land use types in different periods to explore habitat selection. Precipitation seasonality (26.40%), human footprint index (16.50%), and elevation (11.90%) were the main environmental factors affecting wild boar distribution. The areas with high potential suitability for wild boars were mainly in the southeast and northwest of the region (total area of 2.63 × 105 km2). The land use types in the high-suitability zones are mainly woodland and grassland with high coverage, canopy density, and cultivated land borders. This study provides a reference for the effective prevention of HWC and management of wild boars.

Nature-inspired nanocarriers for improving drug therapy of atherosclerosis.

Atherosclerosis (AS) has emerged as one of the prevalent arterial vascular diseases characterized by plaque and inflammation, primarily causing disability and mortality globally. Drug therapy remains the main treatment for AS. However, a series of obstacles hinder effective drug delivery. Nature, from natural micro-/nano-structural biological particles like natural cells and extracellular vesicles to the distinctions between the normal and pathological microenvironment, offers compelling solutions for efficient drug delivery. Nature-inspired nanocarriers of synthetic stimulus-responsive materials and natural components, such as lipids, proteins and membrane structures, have emerged as promising candidates for fulfilling drug delivery needs. These nanocarriers offer several advantages, including prolonged blood circulation, targeted plaque delivery, targeted specific cells delivery and controlled drug release at the action site. In this review, we discuss the nature-inspired nanocarriers which leverage the natural properties of cells or the microenvironment to improve atherosclerotic drug therapy. Finally, we provide an overview of the challenges and opportunities of applying these innovative nature-inspired nanocarriers.

Adaptations to a cold climate promoted social evolution in Asian colobine primates.

The biological mechanisms that underpin primate social evolution remain poorly understood. Asian colobines display a range of social organizations, which makes them good models for investigating social evolution. By integrating ecological, geological, fossil, behavioral, and genomic analyses, we found that colobine primates that inhabit colder environments tend to live in larger, more complex groups. Specifically, glacial periods during the past 6 million years promoted the selection of genes involved in cold-related energy metabolism and neurohormonal regulation. More-efficient dopamine and oxytocin pathways developed in odd-nosed monkeys, which may have favored the prolongation of maternal care and lactation, increasing infant survival in cold environments. These adaptive changes appear to have strengthened interindividual affiliation, increased male-male tolerance, and facilitated the stepwise aggregation from independent one-male groups to large multilevel societies.

Advances in surface-modified nanometal-organic frameworks for drug delivery.

Nanometal-organic frameworks (NMOFs) are porous network structures composed of metal ions or metal clusters through self-assembly. NMOFs have been considered as a promising nano-drug delivery system due to their unique properties such as pore and flexible structures, large specific surface areas, surface modifiability, non-toxic and degradable properties. However, NMOFs face a series complex environment during in vivo delivery. Therefore, surface functionalization of NMOFs is vital to ensure that the structure of NMOFs remain stable during delivery, and can overcome physiological barriers to deliver drugs more accurately to specific sites, and achieve controllable release. In this review, the first part summarizes the physiological barriers that NMOFs faced during drug delivery after intravenous injection and oral administration. The second part summarizes the current main ways to load drugs into NMOFs, mainly including pore adsorption, surface attachment, formation of covalent/coordination bonds between drug molecules and NMOFs, and in situ encapsulation. The third part is the main review part of this paper, which summarizes the surface modification methods of NMOFs used in recent years to overcome the physiological barriers and achieve effective drug delivery and disease therapy, which are mainly divided into physical modifications and chemical modifications. Finally, the full text is summarized and prospected, with the hope to provide ideas for the future development of NMOFs as drug delivery.

Impact of climate change on distribution of common leopard (Panthera pardus) and its implication on conservation and conflict in Nepal.

Climate change is projected to create alterations in species distributions over the planet. The common leopard (Panthera pardus) serves an important ecological function as a member of the big carnivore guild, but little is known about how climate change may affect their distribution. In this study, we use MaxEnt to simulate the geographic distributions by illustrating potential present and future ranges of common leopard by utilizing presence records alongside important topographic and bioclimatic variables based on two shared socioeconomic pathways (SSP2-4.5 and SSP5-8.5) scenarios. The goals of this study was to look into possible distribution ranges of common leopards due to climate change, as well as explore the implications for conservation and potential conflict with humans. At present, 4% of Nepal was found to be highly suitable for common leopards, 43% suitable, 19% marginally suitable, and 34% unsuitable. A large portion of the climatically suitable habitat was confined to non-protected areas, and the majority of the highly suitable habitat was encompassed by forest land, followed by agricultural areas. Elevation, mean temperature of driest quarter, annual precipitation, and precipitation seasonality were the variables influencing habitat suitability for the common leopard. A significant increase in marginally suitable habitat was observed in the high mountain region, indicating a shift of habitat in upper elevation areas due to the effects of climate change. We recommend timely management of these potential habitats to expand the range of this vulnerable species. At the same time, a combination of expanding new habitats and poor management practices could escalate human-leopard conflict. Therefore, further study on the impact of climate change on the distribution of prey species and proper habitat management techniques should be prioritized to mitigate conflicts.

Effects of different management practices on soil microbial community structure and function in alpine grassland.

Management practices, such as grazing exclusion and reseeding, have been implemented to mitigate the degradation of grassland. Low grazing intensities and reseeding increase grass production. Nevertheless, few studies have investigated the effects of these measures on the soil microbial community structure and function in the Qinghai Tibetan Plateau (QTP). To reveal the effects of management practices on soil microbes and give a reference to assess and improve ecosystems functions, we here evaluated the impact of various types of grazing (exclusion, seasonal, and traditional), reseeding (annual oat (Avena fatua) grassland (RO) and perennial artificial grassland cultivated >10 y), and integrated restoration (weed control and no-tillage reseeding) measures on soil microbial community structure and function in the QTP. The Shannon-Wiener diversity indices were highest for prokaryotes under RO and for fungi under integrated grassland restoration. Relative Actinobacteria abundance was higher under seasonal grazing than that under integrated grassland restoration. The latter had relatively higher abundances of Betaproteobacteria, Alphaproteobacteria, and Deltaproteobacteria and comparatively lower abundance of Thermoleophilia. There were significantly higher abundances of plant pathogens under seasonal grazing than those under other managements. There were significantly high proportions of pathotrophs and saprotrophs (10.0%) under seasonal and traditional grazing, respectively. The proportion of pathotrophs under integrated restoration (10.0%) was about seven-fold greater than that under grazing exclusion (1.5%). The relative differences among treatments in terms of soil water content, plant biomass, and soil C:N partially explained the differences in their prokaryotic community compositions. Increases in soil organic carbon and C:N may explain the observed changes in the soil fungal communities. The management practices affected soil microorganisms mainly by altering the soil nutrient profile. Grazing attracted specific pathotrophs and saprotrophs while repelling certain plant pathogens. Hence, modulations in soil microbial community structure and function must be considered in the process of planning for the implementation of grassland degradation management measures.

Anthropogenic mortality of large mammals and trends of conflict over two decades in Nepal.

Wildlife conservation in human-dominated landscapes faces increased challenges due to rising conflicts between humans and wildlife. We investigated the human and wildlife loss rates due to human-wildlife conflict between 2000 and 2020 in Nepal. We concentrated on Asian elephant (Elephas maximus), greater one-horned rhino (Rhinoceros unicornis), tiger (Panthera tigirs), and leopard (Panthera pardus) mortality, as well as human mortality caused by these species. Over the 21-year period, we recorded 1139 cases of wildlife mortality and 887 cases of human mortality. Leopard mortality was the highest, followed by that of greater one-horned rhinos, tigers, and Asian elephants. Overall, the rate of wildlife mortality has been increasing over the years. Asian elephants were found to be more responsible for crop damage than greater one-horned rhinos, while leopards were found to be more responsible for livestock depredation than tigers. The generalized linear model indicated that the mortality of wildlife in the districts is best predicted by the additive effect of human mortality, the proportion of agricultural land, and the literacy rate of the districts. Retaliatory wildlife mortality was the most challenging issue for wildlife conservation, especially for the large mammals. Findings from this study are important for mitigation of human-wildlife conflicts, controlling retaliatory killing, and conserving these threatened large mammals.

"Cascaded Rocket" Nanosystems with Spatiotemporal Separation for Triple-Synergistic Therapy of Alzheimer's Disease.

Alzheimer's disease (AD) remains an incurable disease due to the intricate pathogenesis. The neuropathological hallmarks include extracellular amyloid-ß (Aß) plaques, tau phosphorylation and extensive oxidative stress in neurons, which facilitate the progression of AD. Based on the complex etiology, a spatiotemporally "cascaded rocket" delivery system (DPH/TPGAS NPs) with metal ion/enzyme responses is established in this study for triple-synergistic AD treatment. After targeting and permeating the blood-brain barrier (BBB), the histidine units in the DPH chelate excess metal ions at the extracellular microenvironment, restraining the formation of Aß aggregates, inducing the first-stage separation. Then, the remanent system targets neuronal cells and triggers the second separation with cathepsin B for reducing the level of phosphorylated tau and oxidative stress. Accordingly, the DPH/TPGAS NPs can achieve spatiotemporal drug release, which results in enhanced synergistic therapeutic effects both in the extracellular and intracellular region of the AD brain. After treating with DPH/TPGAS NPs, the memory deficits, levels of Aß and phosphorylated tau, inflammation and neuron damages are remarkably ameliorated in 3 × Tg-AD mice. Therefore, this "cascaded rocket" delivery system has great potential to serve as a powerful platform and provides a new horizon to the therapeutic strategy for AD and other brain diseases' treatments.

Intranasal Administration of Self-Oriented Nanocarriers Based on Therapeutic Exosomes for Synergistic Treatment of Parkinson's Disease.

The treatment of Parkinson's disease (PD) has been hindered by the complex pathologies and multiple membrane barriers during drug delivery. Although exosomes derived from mesenchymal stem cells (MSCs) have great potential for PD, MSC-derived exosomes alone could not fully meet the therapeutic requirements due to their limitation in therapy and delivery. Here, we develop a self-oriented nanocarrier called PR-EXO/PP@Cur that combines therapeutic MSC-derived exosomes with curcumin. PR-EXO/PP@Cur can be self-oriented across the multiple membrane barriers and directly release drugs into the cytoplasm of target cells after intranasal administration. With enhanced accumulation of drugs in the action site, PR-EXO/PP@Cur achieves three-pronged synergistic treatment to deal with the complex pathologies of PD by reducing α-synuclein aggregates, promoting neuron function recovery, and alleviating the neuroinflammation. After treatment with PR-EXO/PP@Cur, the movement and coordination ability of PD model mice are significantly improved. These results show that PR-EXO/PP@Cur has great prospects in treatment of PD or other neurodegenerative diseases.

Self-Catalytic Small Interfering RNA Nanocarriers for Synergistic Treatment of Neurodegenerative Diseases.

Gene therapy has shown great potential for neurodegenerative diseases with complex pathology. However, its therapeutic effect is limited due to the delivery barriers and its own single function. Herein, self-catalytic small interfering RNA (siRNA) nanocarriers (S/Ce-PABMS) are developed to catalyze delivery process and treatment process for synergistic treatment of neurodegenerative diseases. On the one hand, the rough surface of the S/Ce-PABMS mediated by ceria (CeO2 ) nanozymes can catalyze cellular uptake in the delivery process, so that S/Ce-PABMS with acetylcholine analogs penetrate the blood-brain barrier and enter neurons more effectively. On the other hand, the CeO2 nanozymes can catalyze the treatment process by scavenging excess reactive oxygen species, and cooperate with siRNA-targeting SNCA to decrease the α-synuclein (α-syn) aggregation and alleviate the Parkinsonian pathology. Moreover, the S/Ce-PABMS treatment reduces the number of activated microglia and regulates the release of inflammatory cytokine, thereby relieving neuroinflammation. After treatment with S/Ce-PABMS, dyskinesia in Parkinson's disease model mice is significantly alleviated. The finding shows that the self-catalytic nanocarriers, S/Ce-PABMS, have great potential in the treatment of neurodegenerative diseases.

Nature-inspired dynamic gene-loaded nanoassemblies for the treatment of brain diseases.

Gene therapy has great potential to treat brain diseases. However, genetic drugs need to overcome a cascade of barriers for their full potential. The conventional delivery systems often struggle to meet expectations. Natural biological particles that are highly optimized for specific functions in body, can inspire optimization of dynamic gene-loaded nanoassemblies (DGN). The DGN refer to gene loaded nanoassemblies whose functions and structures are changeable in response to the biological microenvironments or can dynamically interact with tissues or cells. The nature-inspired DGN can meet the needs in brain diseases treatment, including i) Non-elimination in blood (N), ii) Across the blood-brain barrier (A), iii) Targeting cells (T), iv) Efficient uptake (U), v) Controllable release (R), vi) Eyeable (E)-abbreviated as the "NATURE". In this Review, from nature to "NATURE", we mainly summarize the specific application of nature-inspired DGN in the "NATURE" cascade process. Furthermore, the Review provides an outlook for this field.

Characterization and management of human-wildlife conflicts in mid-hills outside protected areas of Gandaki province, Nepal.

With the intent to better management human wildlife conflict (HWC) and wildlife conservation in mid-hills outside protected areas of Gandaki province, Nepal, we analyzed the patterns and drivers of HWC. Using data collected from literature, government records and questionnaire survey, we investigated temporal, seasonal and spatial distribution of human casualties caused by wildlife attacks. We also appraised the perception of local people towards wildlife conservation. We have recorded 77 cases (69 human injuries and 8 mortalities) during the period of nine year between 2011 and 2019. The number of wildlife attacks increased over this period. Wildlife attacks were more frequent in winter with 50% (42) of attacks occurred between September and December. Common leopard (Panthera pardus) and Himalayan black bear (Ursus thibetanus laniger) were the major species involved in these conflicts. Common leopard was the most feared species that causes highest number of human mortalities (87%, n = 67); the most severe type of HWC outcome. Forty-eight percent (n = 37) attacks were reported at human settlement areas followed by 27% attacks in agriculture land (n = 21) and 24% (n = 19) in forest. Generalized linear model analysis on spatial variables showed that the probability of human attacks increases with decreasing elevation (ß = -0.0021, Z = -1.762, p = 0.078) and distance from the forest (ß = -0.608, Z = -0.789, p = 0.429). We recommend to decrease habitat degradation / fragmentation, carry out habitat management program within forest to increase prey availability to decrease the wildlife invasion into human settlement area, and decrease dependency of people on forest resources by providing alternative livelihood opportunities. Simplified relief fund distribution mechanism at local level also helps alleviate the impact of HWC. The knowledge obtained by this study and management measures are important for better human-wildlife co-existence.

Synaptic vesicle-inspired nanoparticles with spatiotemporally controlled release ability as a "nanoguard" for synergistic treatment of synucleinopathies.

Synaptic vesicle-inspired nanoparticles (RT-PPB NPs) as a "nanoguard" were designed for clearing the toxic α-synuclein aggregates in diseased neurons and preventing the culprits from escaping to affect other normal cells. The NPs could overcome a series of tissue and cellular barriers and controllably release drugs in the diseased neurons, which ensured the optimization of synergistic treatment. This study indicates that the synaptic vesicle-inspired NPs may have the potential to open up a new avenue for the treatment of synucleinopathies, as well as other neurodegenerative diseases.

Traceable Nano-Biohybrid Complexes by One-Step Synthesis as CRISPR-Chem Vectors for Neurodegenerative Diseases Synergistic Treatment.

Abnormal protein aggregations are essential pathological features of neurodegenerative diseases. Eliminating while inhibiting the regeneration of these protein aggregates is considered an effective treatment strategy. Herein, the CRISPR/Cas9 gene-editing tool is employed to inhibit the regeneration of disease-related proteins, while chemical drugs are applied to eliminate the proteins that are produced. To efficiently deliver CRISPR-chem drugs into brain lesions, traceable nano-biohybrid complexes (F-TBIO) are constructed by one-step synthesis and CRISPR/Cas9 plasmids (CF-TBIO) are loaded in a controllable manner. CF-TBIO can knock out the BACE1 gene and reduce the burden of amyloid-ß, and thereby significantly improve the cognitive abilities of 2xTg-AD mice. In particular, by prolonging the dosing interval, the pathological damage and behavioral abilities of 2xTg-AD mice are still significantly improved. During the therapeutic process, CF-TBIO with a high relaxation rate provides accurate imaging signals in the complex brain physiological environment. The finding shows that CF-TBIO has great potential to serve as a CRISPR-chem drug-delivery platform for neurodegenerative diseases therapy.

Charge-switchable zwitterionic polycarboxybetaine particle as an intestinal permeation enhancer for efficient oral insulin delivery.

Insulin, a peptide hormone, is one of the most common and effective antidiabetic drugs. Although oral administration is considered to be the most convenient and safe choice for patients, the oral bioavailability of insulin is very low due to the poor oral absorption into blood circulation. Intestinal epithelium is a major barrier for the oral absorption of insulin. Therefore, it is vital to develop intestinal permeation enhancer to increase the antidiabetic efficacy of insulin after oral administration. Methods: Charge-switchable zwitterionic polycarboxybetaine (PCB) was used to load insulin to form PCB/insulin (PCB/INS) particles through the electrostatic interaction between positively charged PCB in pH 5.0 and negatively charged insulin in 0.01 M NaOH. The opening effect of PCB/INS particles on intestinal epithelium was evaluated by detecting the changes of claudin-4 (CLDN4) protein and transepithelial electrical resistance (TEER) after incubation or removal. The mechanism was further elucidated based on the results of Western blot and fluorescence images. The PCB/INS particles were then used for type 1 diabetes mellitus therapy after oral administration. Results: PCB could load insulin with the loading efficiency above 86% at weight ratio of 8:1. PCB/INS particles achieved sustained release of insulin at pH 7.4 due to their charge-switchable ability. Surprisingly, PCB/INS particles induced the open of the tight junctions of intestinal epithelium in endocytosis-mediated lysosomal degradation pathway, which resulted in increased intestinal permeability of insulin. Additionally, the opening effect of PCB/INS particles was reversible, and the decreased expression of CLDN4 protein and TEER values were gradually recovered after particles removal. In streptozotocin-induced type 1 diabetic rats, oral administration of PCB/INS particles with diameter sub-200 nm, especially in capsules, significantly enhanced the bioavailability of insulin and achieved longer duration of hypoglycemic effect than the subcutaneously injected insulin. Importantly, there was no endotoxin and pathological change during treatment, indicating that PCB/INS particles were safe enough for in vivo application. Conclusion: These findings indicate that this system can provide a platform for oral insulin and other protein drugs delivery.

Targeted exosome coating gene-chem nanocomplex as "nanoscavenger" for clearing α-synuclein and immune activation of Parkinson's disease.

The most critical problem in the treatment of neurodegenerative diseases is brain neuronal protection, which can be overcome by clearing pathological substances and regulating the immune environment. In the above treatment strategies, the traditional poor drug delivery problem is inevitable. Here, we show an engineering core-shell hybrid system named rabies virus glycoprotein (RVG) peptide-modified exosome (EXO) curcumin/phenylboronic acid-poly(2-(dimethylamino)ethyl acrylate) nanoparticle/small interfering RNA targeting SNCA (REXO-C/ANP/S). It is a nanoscavenger for clearing α-synuclein aggregates and reducing their cytotoxicity in Parkinson's disease neurons. The motor behavior of Parkinson's disease mice is substantially improved after REXO-C/ANP/S treatment. In particular, we demonstrate that REXO-C/ANP/S is also a nanoscavenger for clearing immune activation due to its natural immature dendritic cell EXO coating. Our findings show that REXO-C/ANP/S may serve as a platform for neurodegenerative diseases treatment.

A Reactive Oxygen Species-Responsive Poly(amino acids) Nanoparticle Loading Doxorubicin for Glioblastoma Multiforme Treatment.

Amino acids are significant for human life and therefore considered as the crucial nutrients for human body with high biosafety. Due to their high biocompatibilities and various physicochemical properties, their polymers can be applied to construct drug delivery systems for various diseases' treatments. Among them, glioblastoma multiforme received special attention and numerous efforts regarding to nanotechnology were developed to treat such tumor. However, the biosafety of the delivering materials in those efforts arises as a critical issue in consideration of the weak patients. Therefore, a ROSresponsive nanoparticle (DOX@PLSPL) with poly(amino acids) encapsulating doxorubicin was developed for glioblastoma multiforme treatment. DOX@PLSPL was constructed by poly-lysine and poly-leucine with high biocompatibility. The high doxorubicin encapsulation efficiency and the controlled release manner of DOX@PLSPL ensured its high anti-tumor effect. Totally, this DOX@PLSPL can be used as a promising drug delivery system for glioblastoma multiforme treatments.