Simulation of climate change effect on the global distribution of Rosa multiflora.

Rosa multiflora, originated from East Asia, is one of the original ancestors of modern roses. It is also an important genetic resource and rootstock for rose cultivation. Due to its high resistance and vigorous growth, R. multiflora has become an invasive species in some introduction sites, such as North America. To explore the correlation between the suitable habitat of R. multiflora and climate change, we predicted its potential geographic distribution with an optimized MaxEnt model based on 1246 distribution records and nine bioclimatic variables. The results showed that the mean temperature of the coldest quarter, minimum temperature of the coldest month, precipitation of the warmest quarter, and isothermality were significant bioclimatic variables affecting the potential geographic distribution of R. multiflora. Under current climate conditions, R. multiflora naturally distributed in the plains and hilly areas to the east and south of the Loess Plateau. The distribution pattern in the mid-holocene was similar to its current distribution, but the highly suitable distribution area was in the south of North China Plain, the Sichuan Basin, and parts of the Middle-Lower Yangtze Plain. During the last interglacial, the suitable areas generally contrac-ted southward, while the highly suitable areas significantly expanded and mainly located in the Sichuan Basin, the Middle-Lower Yangtze Plains, the Yunnan-Guizhou Plateau, and the Southeast Hills. Beyond its natural distribution in East Asia, R. multiflora had been introduced and spread to most parts of Europe and the central and eastern United States. The distribution area of R. multiflora would expand under three warming scenarios of different shared socioeconomic pathways (SSP1-2.6, SSP2-4.5, and SSP5-8.5) during 2041-2060 and 2081-2100. Its average distribution center (centroid) would shift towards higher latitude, indicating that the distribution of R. multiflora was closely related to climate change and that global warming might lead to an expansion of its distribution area. These results would improve our understanding of the ecological adaptability of R. multiflora, facilitate the predicting of its future distribution, and provide a theoretical basis for monitoring and early warning measures following its introduction.

The genetic architecture of age at menarche and its causal effects on other traits.

Age at menarche (AAM) is a sign of puberty of females. It is a heritable trait associated with various adult diseases. However, the genetic mechanism that determines AAM and links it to disease risk is poorly understood. Aiming to uncover the genetic basis for AAM, we conducted a joint association study in up to 438,089 women from 3 genome-wide association studies of European and East Asian ancestries. A series of bioinformatical analyses and causal inference were then followed to explore in-depth annotations at the associated loci and infer the causal relationship between AAM and other complex traits/diseases. This largest meta-analysis identified a total of 21 novel AAM associated loci at the genome wide significance level (P < 5.0 × 10-8), 4 of which were European ancestry-specific loci. Functional annotations prioritized 33 candidate genes at newly identified loci. Significant genetic correlations were observed between AAM and 67 complex traits. Further causal inference demonstrated the effects of AAM on 13 traits, including forced vital capacity (FVC), high blood pressure, age at first live birth, etc, indicating that earlier AAM causes lower FVC, worse lung function, hypertension and earlier age at first (last) live birth. Enrichment analysis identified 5 enriched tissues, including the hypothalamus middle, hypothalamo hypophyseal system, neurosecretory systems, hypothalamus and retina. Our findings may provide useful insights that elucidate the mechanisms determining AAM and the genetic interplay between AAM and some traits of women.

Astrocyte involvement in metabolic regulation and disease.

Astrocytes, the predominant glial cell type in the mammalian brain, influence a wide variety of brain parameters including neuronal energy metabolism. Exciting recent studies have shown that obesity and diabetes can impact on astrocyte function. We review evidence that dysregulation of astrocytic lipid metabolism and glucose sensing contributes to dysregulation of whole-body energy balance, thermoregulation, and insulin sensitivity. In addition, we consider the overlooked topic of the sex-specific roles of astrocytes and their response to hormonal fluctuations that provide insights into sex differences in metabolic regulation. Finally, we provide an update on potential ways to manipulate astrocyte function, including genetic targeting, optogenetic and chemogenetic techniques, transplantation, and tailored exosome-based therapies, which may lead to improved treatments for metabolic disease.

Human brain proteome-wide association study provides insights into the genetic components of protein abundance in obesity.

BACKGROUNDS: Genome-wide association studies have identified multiple genetic variants associated with obesity. However, most obesity-associated loci were waiting to be translated into new biological insights. Given the critical role of brain in obesity development, we sought to explore whether obesity-associated genetic variants could be mapped to brain protein abundances. METHODS: We performed proteome-wide association studies (PWAS) and colocalization analyses to identify genes whose cis-regulated brain protein abundances were associated with obesity-related traits, including body fat percentage, trunk fat percentage, body mass index, visceral adipose tissue, waist circumference, and waist-to-hip ratio. We then assessed the druggability of the identified genes and conducted pathway enrichment analysis to explore their functional relevance. Finally, we evaluated the effects of the significant PWAS genes at the brain transcriptional level. RESULTS: By integrating human brain proteomes from discovery (ROSMAP, N = 376) and validation datasets (BANNER, N = 198) with genome-wide summary statistics of obesity-related phenotypes (N ranged from 325,153 to 806,834), we identified 51 genes whose cis-regulated brain protein abundance was associated with obesity. These 51 genes were enriched in 11 metabolic processes, e.g., small molecule metabolic process and metabolic pathways. Fourteen of the 51 genes had high drug repurposing value. Ten of the 51 genes were also associated with obesity at the transcriptome level, suggesting that genetic variants likely confer risk of obesity by regulating mRNA expression and protein abundance of these genes. CONCLUSIONS: Our study provides new insights into the genetic component of human brain protein abundance in obesity. The identified proteins represent promising therapeutic targets for future drug development.

Causal relationships between vitamin E and multiple kidney diseases: evidence from trans-ethnic Mendelian randomization study.

PURPOSE: The association between vitamin E and the risk of kidney disease is well documented in observational studies, but the role of vitamin E in kidney disease remain inconclusive. Here, we evaluated the causal effect of vitamin E on the risk of multiple kidney diseases, including chronic kidney disease, membranous nephropathy, diabetic nephropathy, IgA nephropathy, and dialysis. METHODS: We conducted a two-sample Mendelian randomization analysis from large-scale trans-ancestry genome-wide association studies to determine whether there was a significant causal relationship between vitamin E and multiple kidney diseases in European, American, and Asian ancestry. Instrumental genetic variants associated with vitamin E were selected, and summary statistic-based methods of inverse variance weighted, MR Egger, weighted median, simple mode, and weighted mode methods were conducted. Pleiotropy and sensitivity were assessed. RESULTS: We obtained 87 instrumental genetic variants in European ancestry and found no causal relationship between vitamin E and chronic kidney disease, membranous nephropathy, diabetic nephropathy, IgA nephropathy, and dialysis with no heterogeneity and pleiotropy. We obtained 18 instrumental genetic variants in Asian ancestry and vitamin E had no causal relationship with membranous nephropathy, diabetic nephropathy, and IgA nephropathy with no heterogeneity and pleiotropy. In African ancestry, 25 instrumental genetic variants were obtained and no causal relationship was identified with no heterogeneity and pleiotropy. CONCLUSION: Our study first suggested plausible non-causal associations between vitamin E and multiple kidney diseases among different ancestry.

Improving cellular uptake and synergetic anti-tumor effects of magnolol and Brucea javanica oil through self-microemulsion.

OBJECTIVE: Magnolol (MG) and Brucea javanica (L.) Merr. oil (BJO) possess synergetic anti-tumor effects, but have poor water solubility and stability, which results in low oral bioavailability. SIGNIFICANCE: The MG loaded self-microemulsion drug delivery system (MG-SMDDS) with BJO as oil phase component was utilized to improve the cellular uptake and synergetic anti-tumor effects. METHODS: Compatibility study and pseudoternary phase diagram (PTPD) were respectively employed to screen for the composition and proportion of oil phase in the formulation. Central composite design-effect surface method was applied to optimize proportion of each formulation condition. The droplet size, ζ-potential, colloid stability, encapsulation rate (ER) and in vitro dissolution rate of MG-SMDDS were evaluated. Furthermore, cellular uptake and cytotoxicity of the microemulsion on HepG2 cells were assessed. RESULTS: The optimal composition of MG-SMDDS was: MG (9.09%), castor oil (7.40%), BJO (2.47%), Cremophor EL 35 (54.04%) and 1, 2-propanediol (27.01%). The MG-SMDDS exhibited satisfactory droplet size, ζ-potential, colloid stability and ER, as well as faster dissolution rate than free MG. More importantly, SMEDDS containing BJO could enhance the cellular uptake and cytotoxicity of free BJO and free MG on tumor cells. CONCLUSIONS: The BJO self-microemulsion delivery technique can provide an idea for design of oral delivery vehicles based on BJO.

Bone morphogenetic protein 10 and atrial fibrillation.

Background: The association between bone morphogenetic protein 10 (BMP10) and atrial fibrillation (AF) has been widely investigated by observational studies, but their causal relationships remain inconclusive. Here, we aimed to evaluate the causal effect of BMP10 on the risk of AF through single-nucleotide polymorphisms. Methods: A Mendelian randomization (MR) analytic framework was applied to data from two BMP10-specific genome-wide association studies comprising a total of 11,036,163 single-nucleotide polymorphisms of European ancestry. Instrument genetic variants associated with BMP10 were selected. A total of 12 AF-specific genome-wide association studies comprising a total of 5,095,117 European participants were included. Summary statistic-based methods of inverse variance weighted, MR Egger, weighted median, simple mode, and weighted mode methods were used. Pleiotropy and sensitivity were assessed. Results: Specific to AF-specific genome-wide association studies, we found that BMP10 was not associated with AF among different methods (all P > 0.05). We further identified no significant horizontal pleiotropy (all P > 0.05) and no fundamental impact among various data. Conclusions: This large-scale population study upon data from BMP10- and AF-specific genome-wide association studies and a longitudinal biobank cohort indicates plausible non-causal associations between BMP10 and AF in the European populations. Further studies regarding ancestral diversity are warranted to validate such causal associations.

Influence of Different Ratios of DSPE-PEG2k on Ester Prodrug Self-Assembly Nanoparticles for Cell Migration and Proliferation Suppression.

Background: Bufalin (BFL, an active anti-tumor compound derived from toad venom) is limited in its application due to high toxicity and rapid metabolism of the cardiotonic steroid. Ester prodrug self-assembly nanoparticles have shown significant improved effects in addressing the above-mentioned issues. Methods: An ester bond was formed between linoleic acid and bufalin to synthesize linoleic acid-bufalin prodrug (LeB). The self-assembly nanoparticles (LeB-PSNs) containing different mass ratios of DSPE-PEG2k and prodrug (6:4, 7:3, 8:2, 9:1 and 10:0) were prepared via co-precipitation method and defined as 6:4-PSNs, 7:3-PSNs, 8:2-PSNs, 9:1-PSNs and LeB-PSNs, respectively. Further, the characterization (particle size, zeta potential, surface morphology and stability) of the nanoparticles was carried out. Finally, we evaluated the impact of different ratios of DSPE-PEG2k on the hydrolysis rate, cytotoxicity, cellular uptake, cell migration and proliferation suppression potential of the prodrug nanoparticles. Results: The linoleic acid-bufalin prodrug (LeB) was successfully synthesized. Upon the addition of DSPE-PEG2k at different weight ratios, both particle size and polydispersity index (PDI) significantly decreased, while the zeta potential increased remarkably. No significant differences in particle size, PDI and Zeta potential were observed among the 9:1, 8:2 and 7:3 PSNs. Notably, the 8:2 (w/w) DSPE-PEG2k nanoparticles exhibited superior stability, hydrolysis and cellular uptake rates, along with efficient cell cytotoxicity, cell migration and proliferation suppression. Conclusion: These findings indicate that DSPE-PEG2k could improve the performance of BFL prodrug nanoparticles, namely enhancing stability and achieving adaptive drug release by modulating the hydrolysis rate of esterase. This study therefore provides more opportunities for the development of BFL application.

TERT mediates the U-shape of glucocorticoids effects in modulation of hippocampal neural stem cells and associated brain function.

BACKGROUND: Glucocorticoids (GCs) are steroidal hormones produced by the adrenal cortex. A physiological-level GCs have a crucial function in maintaining many cognitive processes, like cognition, memory, and mood, however, both insufficient and excessive GCs impair these functions. Although this phenomenon could be explained by the U-shape of GC effects, the underlying mechanisms are still not clear. Therefore, understanding the underlying mechanisms of GCs may provide insight into the treatments for cognitive and mood-related disorders. METHODS: Consecutive administration of corticosterone (CORT, 10 mg/kg, i.g.) proceeded for 28 days to mimic excessive GCs condition. Adrenalectomy (ADX) surgery was performed to ablate endogenous GCs in mice. Microinjection of 1 µL of Ad-mTERT-GFP virus into mouse hippocampus dentate gyrus (DG) and behavioral alterations in mice were observed 4 weeks later. RESULTS: Different concentrations of GCs were shown to affect the cell growth and development of neural stem cells (NSCs) in a U-shaped manner. The physiological level of GCs (0.01 µM) promoted NSC proliferation in vitro, while the stress level of GCs (10 µM) inhibited it. The glucocorticoid synthesis blocker metyrapone (100 mg/kg, i.p.) and ADX surgery both decreased the quantity and morphological development of doublecortin (DCX)-positive immature cells in the DG. The physiological level of GCs activated mineralocorticoid receptor and then promoted the production of telomerase reverse transcriptase (TERT); in contrast, the stress level of GCs activated glucocorticoid receptor and then reduced the expression of TERT. Overexpression of TERT by AD-mTERT-GFP reversed both chronic stresses- and ADX-induced deficiency of TERT and the proliferation and development of NSCs, chronic stresses-associated depressive symptoms, and ADX-associated learning and memory impairment. CONCLUSION: The bidirectional regulation of TERT by different GCs concentrations is a key mechanism mediating the U-shape of GC effects in modulation of hippocampal NSCs and associated brain function. Replenishment of TERT could be a common treatment strategy for GC dysfunction-associated diseases.

Exome-Wide Sequencing Study Identified Genetic Variants Associated With Sarcopenic Obesity.

Sarcopenic obesity (SO) is an age-related disease characterized by the coexistence of excessive adiposity and low muscle mass or function. Although obesity and sarcopenia are heritable conditions, the genetic determinants of SO have not been fully understood. We conducted a large-scale exome-wide association analysis of SO in a sequenced sample of 2 887 cases and 113 284 controls and an imputed sample of 4 003 cases and 161 990 controls in the UK Biobank cohort. Single-variant association analysis identified one locus 1q41 (lead SNP rs1417066, LYPLAL1-AS1, odds ratio [OR] = 1.15, 95% confidence interval [CI] = [1.11-1.19], p = 1.75 × 10-14) that was significantly associated with SO at the exome-wide significance level (p < 1 × 10-8). Colocalization analysis in the Genotype-Tissue Expression expression quantitative trait locus database showed that LYPLAL1-AS1 was colocalized with SO in multiple musculoskeletal-related tissues. Gene-based burden test of rare loss-of-function variants identified 5 genes at the gene-wise significance level (p < 4.3 × 10-6): PDE3B (OR = 2.48, p = 1.10 × 10-6), MYOZ3 (OR = 25.49, p = 1.41 × 10-7), SLC15A3 (OR = 4.75, p = 6.82 × 10-7), RNF130 (OR = 25.83, p = 4.07 × 10-6), and TNK2 (OR = 4.25, p = 8.75 × 10-8). Overall, our study uncovered the genetic effects of both common and rare variants on SO susceptibility, expanded existing knowledge of the genetic architecture of SO, and improved understanding of the genetic mechanisms underlying SO.

Construction of 1,3,4-oxadiazolines bearing CF3-quaternary centers via amino-assisted [3 + 2] cycloadditions.

An amino-assisted [3 + 2] cycloaddition strategy of nitrile imines with o-aminotrifluoroacetophenones has been explored, thus providing functionalized 1,3,4-oxadiazolines bearing CF3-quaternary centers in good to excellent yields in the presence of K2CO3 under mild conditions. The amino groups located at the ortho-position of trifluoroacetophenone might play a crucial role in the present cyclization. The MTT assay shows that the 1,3,4-oxadiazoline derivatives could be potential candidates for the treatment of head and neck cancers.

Feasibility of applying a noninvasive method for sleep monitoring based on mouse behaviors.

INTRODUCTION: Currently, electroencephalogram (EEG)/electromyogram (EMG) system is widely regarded as the "golden standard" for sleep monitoring. Imperfectly, its invasive monitoring may somehow interfere with the natural state of sleep. Up to now, noninvasive methods for sleep monitoring have developed, which could preserve the undisturbed and naïve sleep state of mice to the greatest extent, but the feasibility of their application under different conditions should be extensive validated. METHODS: Based on existing research, we verified the feasibility of a sleep monitoring system based on mouse behaviors under different conditions. The experimental mice were exposed to various stresses and placed into a combined device comprising noninvasive sleep monitoring equipment and an EEG/EMG system, and the sleep status was recorded under different physiological, pharmacological, and pathophysiological conditions. The consistency of the parameters obtained from the different systems was calculated using the Bland-Altman statistical method. RESULTS: The results demonstrated that the physiological sleep times determined by noninvasive sleep monitoring system were highly consistent with those obtained from the EEG/EMG system, and the coefficients were 94.4% and 95.1% in C57BL/6J and CD-1 mice, respectively. The noninvasive sleep monitoring system exhibited high sensitivity under the sleep-promoting effect of diazepam and caffeine-induced wakefulness, which was indicated by its ability to detect the effect of dosage on sleep times, and accurate determination of the sleep/wakeful status of mice under different pathophysiological conditions. After combining the data obtained from all the mice, the coefficient between the sleep times detected by behavior-based sleep monitoring system and those obtained from the EEG/EMG equipment was determined to .94. CONCLUSION: The results suggested that behavior-based sleep monitoring system could accurately evaluate the sleep/wakeful states of mice under different conditions.

Clinical application of a novel stent-assisted in situ intestinal bypass in preventing postoperative anastomotic leakage for low-mid rectal cancer: A retrospective study.

This study aimed to investigate the safety and feasibility of a novel stent-assisted in situ intestinal bypass for low-mid rectal cancer patients. Patients who were diagnosed with rectal cancer and received laparoscopic low anterior rectal resection plus a novel stent-assisted in situ intestinal bypass were respectively included from March 2022 to June 2022. Biofragmentable intestinal stent with a protective sleeve was placed in the proximal colon before anastomosis, and feces could be discharged through the protective sleeve without touching the anastomosis, which achieved an in situ bypass of feces. Perioperative characteristics and short-term outcomes were collected. Rectal imaging was performed each week after surgery for the first 3 weeks to surveil the stent and feces delivery. Follow-ups were conducted for more than 3 months. Thirty patients who successfully received surgery were included in this study. There were 18 (60.0%) males and 12 (40.0%) females. As for perioperative characteristics, operation time was 213.8 ± 43.0 minutes, blood loss was 53.3 ± 24.6 mL, time to first flatus via protective sleeve after surgery was 3.2 ± 1.1 days, postoperative hospital stay was 11.8 ± 1.6 days, and time to discharge stent was 22.4 ± 3.2 days. As for short-term outcomes, 6 patients suffered from pneumonia, urinary tract infection or incision infection. During the follow-up, there was no anastomotic leakage or mortality. This novel stent-assisted in situ intestinal bypass is safe and feasible, it might be an applicable way to prevent postoperative anastomotic leakage for patients with low-mid rectal cancer.

Screening Plasma Proteins for the Putative Drug Targets for Carpal Tunnel Syndrome.

Carpal tunnel syndrome (CTS) is one of the most common work-related musculoskeletal disorders. The present study sought to identify putative causal proteins for CTS. We conducted a two-sample Mendelian randomization (MR) analysis to evaluate the causal association between 2859 plasma proteins (N = 35,559) and CTS (N = 1,239,680) based on the published GWAS summary statistics. Then we replicated the significant associations using an independent plasma proteome GWAS (N = 10,708). Sensitivity analyses were conducted to validate the robustness of MR results. Multivariate MR and mediation analyses were conducted to evaluate the mediation effects of body mass index (BMI), type 2 diabetes (T2D), and arm tissue composition on the association between putative causal proteins and CTS. Colocalization analysis was used to examine whether the identified proteins and CTS shared causal variant(s). Finally, we evaluated druggability of the identified proteins. Ten plasma proteins were identified as putative causal markers for CTS, including sCD14, PVR, LTOR3, CTSS, SIGIRR, IFNL3, ASPN, TM11D, ASIP, and ITIH1. Sensitivity analyses and reverse MR analysis validated the robustness of their causal effects. Arm tissue composition, BMI, and T2D may play a fully/partial mediating role in the causal relationships of ASIP, TM11D, IFNL3, PVR, and LTOR3 with CTS. The association of ASPN and sCD14 with CTS were supported by colocalization analysis. Druggability assessment demonstrated that sCD14, CTSS, TM11D, and IFNL3 were potential drug therapeutic targets. The present study identified several potential plasma proteins that were causally associated with CTS risk, providing new insights into the pathogenesis of protein-mediated CTS and offering potential targets for new therapies.

Decreasing the memory of the discontinuous Galerkin volume integral equation method for scattering from inhomogeneous dielectric objects.

A memory-efficient implementation scheme for the discontinuous Galerkin volume integral equation method (DGVIE) using Schaubert-Wilton-Glisson (SWG) basis functions is proposed to analyze electromagnetic scattering from inhomogeneous dielectric objects. For this proposed scheme, almost no half-SWG basis functions are needed for the elements separating nonconformal meshes, while these half-SWG basis functions are indispensable for the conventional DGVIE-SWG method. This is realized by applying the divergence-free condition of the electric displacement vector explicitly for nonconformal meshes separating neighboring subdomains of an inhomogeneous dielectric body. Therefore, the number of unknowns of the conventional DGVIE method can be further reduced. As a result, the memory of the proposed DGVIE method is only about half of the conventional one for inhomogeneous dielectric problems. Meanwhile, the total solution time has been reduced by the use of the proposed scheme. Particularly, the proposed DGVIE-SWG method is efficient in memory usage not only for inhomogeneous dielectric cases with high contrast ratio but also for cases with relatively low contrast ratio.

Metagenomic next-generation sequencing in the diagnosis of neurocysticercosis: A case report.

BACKGROUND: The clinical symptoms and imaging manifestations of neurocysticercosis (NCC) are very different, and the difficulty and delay of clinical diagnoses may lead to an increase in mortality and disability. Rapid and accurate pathogen identification is important for the treatment of these patients. Metagenomic next-generation sequencing (mNGS) is a powerful tool to identify pathogens, especially in infections that are difficult to identify by conventional methods. CASE SUMMARY: A 43-year-old male patient was admitted due to a recurrent headache for a few months. Imaging examinations showed hydrocephalus and cystic lesions, which were considered to be a central nervous system infection, but no etiology was found by routine examination. mNGS of the cerebrospinal fluid revealed high Taenia solium reads, and the positive results of a cysticercosis antibody test confirmed the infection. Combined with the patient's clinical manifestations, the etiological evidence, and the imaging manifestation, the patient was finally diagnosed with NCC and he was prescribed dexamethasone, albendazole, neurotrophic drugs, and intracranial pressure reduction therapy. The headaches disappeared after anti-parasite treatment, and no associated symptoms recurred prior to the three- and six-month follow-up. CONCLUSION: As an accurate and sensitivity detection method, mNGS can be a reliable approach for the diagnosis of NCC.

[Construction of a Mouse Model for Myeloproliferative Neoplasms and an Evaluation System].

OBJECTIVE: To construct a myeloproliferative neoplasms (MPN) transplanted mouse model with JAK2-V617F, MPLW515L or CALR-Type I gene mutation, and establish a systematic evaluation system to verify the success of model construction. METHODS: The bone marrow c-kit+ cells of the mice were obtained by the following steps: The mice were killed by cervical dislocation, the femur, tibia and ilium were separated, and the bone marrow cells were collected. The c-kit+ cells were sorted after incubation with CD117 magnetic beads. The method of constructing mouse primary mutant cells is as follows: A gene mutation vector with a GFP tag was constructed by the retroviral system, and the retroviral vector was packaged into the Platinum-E cells to obtain the virus supernatant, and then used it to infect the c-kit+ cells of mice. The MPN mouse model was constructed as follows: the mouse primary c-kit+ cells containing the mutant genes were collected after infection, and then transplanted them via the tail vein into the female recipient mice of the same species which were irradiated with a lethal dose of gamma rays (8.0 Gy). The MPN mouse model was evaluated as follows: After transplantation, the peripheral blood of the mice was regularly collected from the tail vein to perform the complete blood count test, and the size of spleen and the degree of bone marrow fibrosis were estimated. RESULTS: The mouse c-kit+ cells with the mutant genes were successfully obtained from the bone marrow. MPN mouse model was successfully constructed: The peripheral blood cells of the MPN-transplanted mice carried exogenous implanted GFP-positive cells, and the white blood cells (WBC), platelet (PLT) and hematocrit (HCT) were all increased; the body weight loss, and the water and food intake were reduced in the transplanted mice; further pathological analysis showed that the transplanted mice displayed splenomegaly and bone marrow fibrosis. These results suggested that the MPN mouse model was successfully constructed. According to the common and different characteristics of the three MPN mouse model, a preliminary evaluation system for judging the success of MPN mouse model construction was summarized, which mainly included the following indicators, for example, the proportion of GFP-positive cells in the peripheral blood of mice; WBC, PLT and HCT; the degree of spleen enlargement and the bone marrow fibrosis. CONCLUSION: The MPN mouse model with JAK2-V617F, MPLW515L or CALR-Type I gene mutation is successfully established by retroviral system, which can provide an important experimental animal model for the research of MPN pathogenesis and drug-targeted therapy.

Projecting future aboveground carbon sequestration rate of alpine forest on the eastern Tibetan Plateau in response to climate change.

The aboveground carbon sequestration rate (ACSR) of forests serves as an indicator of their carbon sequestration capacity over time, providing insights into the potential carbon sequestration capacity of forest ecosystems. To explore the long-term Spatiotemporal variation of ACSR in the transitional ecotone of the eastern Tibetan Plateau under climate change scenarios, we utilized a forest landscape model that was parameterized with forest inventory data from the eastern Tibetan Plateau to simulate this ecological function changes. The study found that climate warming had significant effect on forests ACSR in different types of forests. ACSR was significantly reduced (p<0.05) in cold temperate coniferous and temperate coniferous forests, whereas it was significantly increased in deciduous broad-leaved forests. However, the impact of climate warming on evergreen broad-leaved forests was found to be negligible. At the species level, climate warming has mostly suppressed the ACSR of coniferous trees, except for Chinese hemlock. The main dominant species, spruce and fir, have been particularly affected. Conversely, the ACSR of most broad-leaved trees has increased due to climate warming. In addition, at the landscape scale, the ACSR within this region is expected to experience a steady decline after 2031s-2036s. Despite the effects of climate warming, this trend is projected to persist. In conclusion, the forests ACSR in this region will be significantly affected by future climate warming. Our research indicates that climate warming will have a noticeable suppressive effect on conifers. It is imperative that this factor be taken into account when devising forest management plans for the future in this region.

Causal associations between type 1 diabetes and COVID-19 infection and prognosis: a two-sample Mendelian randomization study.

INTRODUCTION: It has been suggested that type 1 diabetes was associated with increased COVID-19 morbidity and mortality. However, their causal relationship is still unclear. Herein, we performed a two-sample Mendelian randomization (MR) to investigate the causal effect of type 1 diabetes on COVID-19 infection and prognosis. RESEARCH DESIGN AND METHODS: The summary statistics of type 1 diabetes were obtained from two published genome-wide association studies of European population, one as a discovery sample including 15 573 cases and 158 408 controls, and the other data as a replication sample consisting of 5913 cases and 8828 controls. We first performed a two-sample MR analysis to evaluate the causal effect of type 1 diabetes on COVID-19 infection and prognosis. Then, reverse MR analysis was conducted to determine whether reverse causality exists. RESULTS: MR analysis results showed that the genetically predicted type 1 diabetes was associated with higher risk of severe COVID-19 (OR=1.073, 95% CI: 1.034 to 1.114, pFDR=1.15×10-3) and COVID-19 death (OR=1.075, 95% CI: 1.033 to 1.119, pFDR=1.15×10-3). Analysis of replication dataset showed similar results, namely a positive association between type 1 diabetes and severe COVID-19 (OR=1.055, 95% CI: 1.029 to 1.081, pFDR=1.59×10-4), and a positively correlated association with COVID-19 death (OR=1.053, 95% CI: 1.026 to 1.081, pFDR=3.50×10-4). No causal association was observed between type 1 diabetes and COVID-19 positive, hospitalized COVID-19, the time to the end of COVID-19 symptoms in the colchicine treatment group and placebo treatment group. Reverse MR analysis showed no reverse causality. CONCLUSIONS: Type 1 diabetes had a causal effect on severe COVID-19 and death after COVID-19 infection. Further mechanistic studies are needed to explore the relationship between type 1 diabetes and COVID-19 infection and prognosis.

Effects of gestational inflammation on age-related cognitive decline and hippocampal Gdnf-GFRα1 levels in F1 and F2 generations of CD-1 Mice.

BACKGROUND: It has been reported that age-associated cognitive decline (AACD) accelerated by maternal lipopolysaccharide (LPS) insult during late pregnancy can be transmitted to the second generation in a sex-specificity manner. In turn, recent studies indicated that glial cell line-derived neurotrophic factor (GDNF) and its cognate receptor (GFRα1) are critical for normal cognitive function. Based on this evidence, we aimed to explore whether Gdnf-GFRα1 expression contributes to cognitive decline in the F1 and F2 generations of mouse dams exposed to lipopolysaccharide (LPS) during late gestation, and to evaluate also the potential interference effect of pro-inflammatory cytokines. METHODS: During gestational days 15-17, pregnant CD-1 mice (8-10 weeks old) received a daily intraperitoneal injection of LPS (50 µg/kg) or saline (control). In utero LPS-exposed F1 generation mice were selectively mated to produce F2 generation mice. In F1 and F2 mice aged 3 and 15 months, the Morris water maze (MWM) was used to evaluated the spatial learning and memory ability, the western blotting and RT-PCR were used for analyses of hippocampal Gdnf and GFRα1 expression, and ELISA was used to analyse IL-1ß, IL-6 and TNF-α levels in serum. RESULTS: Middle-aged F1 offspring from LPS-treated mothers exhibited longer swimming latency and distance during the learning phase, lower percentage swimming time and distance in targe quadrant during memory phase, and lower hippocampal levels of Gdnf and GFRα1 gene products compared to age-matched controls. Similarly, the middle-aged F2 offspring from the Parents-LPS group had longer swimming latency and distance in the learning phase, and lower percentage swimming time and distance in memory phase than the F2-CON group. Moreover, the 3-month-old Parents-LPS and 15-month-old Parents- and Father-LPS groups had lower GDNF and GFRα1 protein and mRNAs levels compared to the age-matched F2-CON group. Furthermore, hippocampal levels of Gdnf and GFRα1 were correlated with impaired cognitive performance in the Morris water maze after controlling for circulating pro-inflammatory cytokine levels. CONCLUSIONS: Our findings indicate that accelerated AACD by maternal LPS exposure can be transmitted across at least two generations through declined Gdnf and GFRα1 expression, mainly via paternal linage.