ADAMTS4 Enhances Oligodendrocyte Differentiation and Remyelination by Cleaving NG2 Proteoglycan and Attenuating PDGFRα Signaling.

Although NG2 is known to be selectively expressed in oligodendrocyte precursor cells (OPCs) for many years, its expressional regulation and functional involvement in oligodendrocyte differentiation have remained elusive. Here, we report that the surface-bound NG2 proteoglycan can physically bind to PDGF-AA and enhances PDGF receptor alpha (PDGFRα) activation of downstream signaling. During differentiation stage, NG2 protein is cleaved by A disintegrin and metalloproteinase with thrombospondin motifs type 4 (Adamts4), which is highly upregulated in differentiating OPCs but gradually downregulated in mature myelinating oligodendrocytes. Genetic ablation of Adamts4 gene impedes NG2 proteolysis, leading to elevated PDGFRα signaling but impaired oligodendrocyte differentiation and axonal myelination in both sexes of mice. Moreover, Adamts4 deficiency also lessens myelin repair in adult brain tissue following Lysophosphatidylcholine-induced demyelination. Thus, Adamts4 could be a potential therapeutic target for enhancing oligodendrocyte differentiation and axonal remyelination in demyelinating diseases.SIGNIFICANCE STATEMENT NG2 is selectively expressed in OPCs and downregulated during differentiation stage. To date, the molecular mechanism underlying the progressive removal of NG2 surface proteoglycan in differentiating OPCs has been unknown. In this study, we demonstrate that ADAMTS4 released by differentiating OPCs cleaves surface NG2 proteoglycan, attenuates PDGFRα signaling, and accelerates oligodendrocyte differentiation. In addition, our study also suggests ADAMTS4 as a potential therapeutic target for promoting myelin recovery in demyelinating diseases.

Silicon induces ROS scavengers, hormone signalling, antifungal metabolites, and silicon deposition against brown stripe disease in sugarcane.

Bipolaris setariae is known to cause brown stripe disease in sugarcane, resulting in significant yield losses. Silicon (Si) has the potential to enhance plant growth and biotic resistance. In this study, the impact of Si on brown stripe disease was investigated across susceptible and resistant sugarcane varieties, utilizing four Si concentrations (0, 15, 30, and 45 g per barrel of Na2SiO3·5H2O). Si significantly reduced the incidence of brown stripe disease (7.41-59.23%) and alleviated damage to sugarcane growth parameters, photosynthetic parameters, and photosynthetic pigments. Submicroscopic observations revealed that Si induced the accumulation of silicified cells in leaves, reduced spore accumulation, decreased stomatal size, and protected organelles from B. setariae damage. In addition, Si increased the activity of antioxidant enzymes (superoxide dismutase, peroxidase, and catalase), reduced reactive oxygen species production (malondialdehyde and hydrogen peroxide) and modulated the expression of genes associated with hormone signalling (PR1, TGA, AOS, AOC, LOX, PYL8, and SnRK2), leading to the accumulation of abscisic acid and jasmonic acid and inhibiting SA synthesis. Si also activated the activity of metabolism-related enzymes (polyphenol oxidase and phenylalanine ammonia lyase) and the gene expression of PAL-dependent genes (PAL, C4H, and 4CL), regulating the accumulation of metabolites, such as chlorogenic acid and lignin. The antifungal test showed that chlorogenic acid (15ug µL-1) had a significant inhibitory effect on the growth of B. setariae. This study is the first to demonstrate the inhibitory effect of Si on B. setariae in sugarcane, highlighting Si as a promising and environmentally friendly strategy for managing brown stripe disease.

Comparative Impact of Various Fasting Periods on the Welfare of Sprague-Dawley Rats With or Without Supplementation.

In nonclinical toxicology studies, lab animals are fasted typically overnight, to reduce variability in some clinical pathology parameters. However, fasting adds undue stress, and this is particularly concerning in rodents given their fast metabolic rates. Furthermore, as rodents are nocturnal animals, an overnight fasting may cause a protracted negative metabolic state even when the fasting has technically ended, given their minimal activity and food consumption during the day. Therefore, to evaluate the impacts of different fasting durations (±DietGel supplementation) on rats' welfare, we assessed the traditional and ancillary clinical pathology parameters in Sprague-Dawley rats, along with body weight, organ weight, and histopathology. Although most endpoints were comparable between the different fasting durations (±DietGel supplementation), the long fasting times (≥8 hr) without DietGel supplementation caused significant decreases in body weight, liver weight, liver glycogen content, serum glucose, triglyceride, and creatinine concentrations-all findings suggestive of a negative energy balance that could impact animal welfare and consequently, data quality; while the short fasting time (4 hr) and DietGel supplementation were associated with higher triglycerides variability. Hence, we propose that short fasting time should be adequate for most toxicology studies in rats, and long fasting times should only be accommodated with scientific justification.

Migrating pyramidal neurons require DSCAM to bypass the border of the developing cortical plate.

During mammalian neocortex development, nascent pyramidal neurons migrate along radial glial cells and overtake earlier-born neurons to terminate at the front of the developing cortical plate (CP), leading to the outward expansion of the CP border. While much has been learned about the cellular and molecular mechanisms that underlie the migration of pyramidal neurons, how migrating neurons bypass the preceding neurons at the end of migration to reach their final positions remains poorly understood. Here, we report that Down syndrome cell adhesion molecule (DSCAM) is required for migrating neurons to bypass their post-migratory predecessors during the expansion of the upper cortical layers. DSCAM is a type I transmembrane cell adhesion molecule. It has been linked to Down syndrome through its location in the Down syndrome critical region of Chromosome 21 trisomy and to autism spectrum disorders through loss-of-function mutations. Ex vivo time-lapse imaging demonstrates that DSCAM is required for migrating neurons to bypass their post-migratory predecessors, crossing the CP border to expand the upper cortical layers. In DSCAM-deficient cortices, migrating neurons stop prematurely under the CP border, leading to thinner and denser upper cortical layers. We further show that DSCAM weakens cell adhesion mediated by N-cadherin in the upper cortical plate, allowing migrating neurons to traverse the CP border and expand the CP. These findings suggest that DSCAM is required for proper migratory termination and final positioning of nascent pyramidal neurons, which may provide insight into brain disorders that exhibit thinner upper layers of the cerebral cortex without neuronal loss.SIGNIFICANCE STATEMENTNewly born neurons in the developing mammalian neocortex migrate outward towards the cortical surface, bypassing earlier born neurons to expand the developing cortex. How migrating neurons bypass the preceding neurons and terminate at the front of the expanding cortex remains poorly understood. We demonstrate that Down syndrome cell adhesion molecule (DSCAM), linked to Down syndrome and autism spectrum disorder, is required by migrating neurons to bypass their post-migratory predecessors and terminate migration in the outwardly expanding cortical layer. Migrating neurons deficient in DSCAM stop prematurely, failing to expand the cortex. We further show that DSCAM likely mediates migratory termination by weakening cell-adhesion mediated by N-cadherin.

The landscape of the long non-coding RNAs in developing mouse retinas.

BACKGROUND: The long non-coding RNAs (lncRNAs) are critical regulators of diverse biological processes. Nevertheless, a global view of its expression and function in the mouse retina, a crucial model for neurogenesis study, still needs to be made available. RESULTS: Herein, by integrating the established gene models and the result from ab initio prediction using short- and long-read sequencing, we characterized 4,523 lncRNA genes (MRLGs) in developing mouse retinas (from the embryonic day of 12.5 to the neonatal day of P28), which was so far the most comprehensive collection of retinal lncRNAs. Next, derived from transcriptomics analyses of different tissues and developing retinas, we found that the MRLGs were highly spatiotemporal specific in expression and played essential roles in regulating the genesis and function of mouse retinas. In addition, we investigated the expression of MRLGs in some mouse mutants and revealed that 97 intergenic MRLGs might be involved in regulating differentiation and development of retinal neurons through Math5, Isl1, Brn3b, NRL, Onecut1, or Onecut2 mediated pathways. CONCLUSIONS: In summary, this work significantly enhanced our knowledge of lncRNA genes in mouse retina development and provided valuable clues for future exploration of their biological roles.

Novel insights into molecular signatures and pathogenic cell populations shared by systemic lupus erythematosus and vascular dementia.

Although vascular dementia (VD) and systemic lupus erythematosus (SLE) may share immune-mediated pathophysiologic processes, the underlying mechanisms are unclear. This study investigated shared gene signatures in SLE versus VD, as well as their potential molecular mechanisms. Bulk RNA sequencing (RNAseq) and single-cell or single-nucleus RNAseq (sc/snRNAseq) datasets from SLE blood samples and VD brain samples were obtained from Gene Expression Omnibus. The identification of genes associated with both SLE and VD was performed using the weighted gene co-expression network analysis (WGCNA) and machine learning algorithms. For the sc/snRNAseq data, an unbiased clustering pipeline based on Seurat and CellChat was used to determine the cellular landscape profile and examine intracellular communication, respectively. The results were subsequently validated using a mice model of SLE with cognitive dysfunction (female MRL/lpr mice). WGCNA and machine learning identified C1QA, LY96, CD163, and MS4A4A as key genes for SLE and VD. sc/snRNAseq analyses revealed that CD163 and MS4A4A were upregulated in mononuclear phagocytes (MPs) from SLE and VD samples and were associated with monocyte-macrophage differentiation. Intriguingly, LGALS9-associated molecular pathway, as the only signaling pathway common between SLE and VD via CellChat analysis, exhibited significant upregulation in cortical microglia of MRL/lpr mice. Our analyses identified C1QA, LY96, CD163, and MS4A4A as potential biomarkers for SLE and VD. Moreover, the upregulation of CD163/MS4A4A and activation of LGALS9 signaling in MPs may contribute to the pathogenesis of VD with SLE. These findings offer novel insight into the mechanisms underlying VD in SLE patients.

Characterization of Elimination Pathways and the Feasibility of Endogenous Metabolites as Biomarkers of Organic Anion Transporter 1/3 Inhibition in Cynomolgus Monkeys.

Organic anion transporters 1 and 3 (OAT1/3) occupy a key role in mediating renal elimination. Kynurenic acid (KYNA) was previously discovered as an effective endogenous biomarker to assess drug-drug interaction (DDI) for OAT inhibitors. Here, further in vitro and in vivo investigation was performed to characterize the elimination routes and feasibility of KYNA, along with other reported endogenous metabolites, as biomarkers of Oat1/3 inhibition in bile duct-cannulated (BDC) cynomolgus monkeys. Our results suggested that KYNA is a substrate of OAT1/3 and OAT2, but not OCT2, MATE1/2K, or NTCP, and that it shares comparable affinities between OAT1 and OAT3. Renal and biliary excretions and plasma concentration-time profiles of KYNA, pyridoxic acid (PDA), homovanillic acid (HVA), and coproporphyrin I (CP-I) were assessed in BDC monkeys dosed with either probenecid (PROB) at 100 mg/kg or the control vehicle. Renal excretion of KYNA, PDA, and HVA was determined to be the major elimination route. The maximum concentration and the area under the plasma concentration-time curve (Cmax and AUC0-24h) of KYNA were about 11.6- and 3.7-fold higher in the PROB group than in the vehicle group. Renal clearance of KYNA decreased by 3.2-fold, but biliary clearance (CLbile) was not altered after PROB administration. A similar trend was observed for PDA and HVA. Interestingly, an elevation of plasma concentration and reduction of CP-I CLbile were observed after PROB treatment, which suggested inhibition of the CP-I Oatp-Mrp2 transport axis by PROB. Overall, our results indicated that KYNA could potentially facilitate early and reliable assessment of DDI liabilities of Oat inhibition in monkeys. SIGNIFICANCE STATEMENT: This work reported renal excretion as the major elimination pathway for kynurenic acid, pyridoxic acid, and homovanillic acid. Administration of probenecid reduced renal clearance and increased plasma exposure of these biomarkers in monkeys, consistent with the observation in humans. These endogenous biomarkers discovered in monkeys could be potentially used to evaluate the clinical drug-drug interactions in the early phase of drug development.

Incorporation of Th4+ and Sr2+ into Rhabdophane/Monazite by Wet Chemistry: Structure and Phase Stability.

Rhabdophane is an important permeable reactive barrier to enrich radionuclides from groundwater and has been envisaged to host radionuclides in the backend of the nuclear fuel cycle. However, understanding of how An4+ and Sr2+ precipitate into rhabdophane by wet chemistry has not been resolved. In this work, Th4+ and Sr2+ incorporation in the rhabdophane/monazite structure as La1-2xSrxThxPO4·nH2O solid solutions is successfully achieved in the acid solution at 90 °C. Some specific issues such as lattice occupation of Th4+ and Sr2+, precipitation reaction kinetics, and crystal growth affected by starting stoichiometry are discussed in detail, along with investigating the chemical stability of La1-2xSrxThxPO4·nH2O precipitations and associated La1-2xSrxThxPO4 monazite. The results reveal that the excess of Sr2+ appears to be a prevailing factor with a suggested initial Sr: Th ≥ 2 to obtain the stability domain of La1-2xSrxThxPO4·nH2O (x = 0∼ 0.1). A rapid ion removal associated with a nucleation process has been observed within 8 h, and Th4+ can be removed more than 98% after 24 h in 0.01 mol/L solutions. From structural energetics based on density functional theory, the lattice occupation of Th4+ and Sr2+ is energetically favorable in nonhydrated lattice sites of [LaO8], although two-thirds of lattice sites are associated with [LaO8·H2O] hydrated sites. Intriguingly, the crystal transformation from rhabdophane to monazite associated with the transformation from [SrO8] to [SrO9] polyhedra can greatly improve the leaching stability of Sr2+.

Study on the mechanism of nitrapyrin microcapsule suspension effectively improving nitrification inhibition rate in black soil.

Nitrification inhibitors (NIs) have been widely applied to inhibit nitrification and reduce N2O emissions in agriculture. However, there are still some shortcomings, e.g. short effective periods, large applying amounts, low effectiveness, easy deactivation and different effect. Thus, a nitrapyrin microcapsule suspension (CPCS) was used as a new experimental material to elaborate its effects on nitrogen transformation and microbial response mechanisms in black soil by cultivation experiments with six treatments of no fertilization (CK), urea, urea+ 0.2 % CPES, urea+ 0.1 % CPCS, urea+ 0.2 % CPCS, and urea+ 0.3 % CPCS. The content of ammonium, nitrate nitrogen, functional microbial activity, degradation rate and adsorption characteristics of CPCS in the soil at different incubating times were determine. Compared with the nitrapyrin emulsifiable concentrate (CPEC) treatment, the degradation rate of CPCS decreased by 21.54 %, the half-life increased by 10.2 days, and the adsorption rate of nitrapyrin on black soil decreased more than 6-fold. CPCS effectively inhibited the transformation of ammonium nitrogen to nitrate nitrogen within more than 42 days. CPCS had a negative effect on amoA gene abundance and a positive effect on nrfA gene abundance. The research results provide a basic theoretical support for the application of CPCS on black soil.

Bilateral medial sacrospinous ligament suture for apical suspension through natural spaces: A single-center study with low perioperative complications.

Sacrospinous ligament fixation (SSLF) is one of the most used native tissue approaches for apical suspension with a high rate of perioperative complications. This study aimed to review cases undergoing a modified SSLF and assess its perioperative adverse events. It was a retrospective study of 168 consecutive patients undergoing modified transvaginal SSLF at a single tertiary center from 2017 to 2021. The sutures were placed on the sacrospinous ligament (SSL) approaching the sacrum through natural spaces under direct vision. Moreover, it was performed bilaterally. Patient demographics and perioperative complications were reviewed. The median age was 65 years, and 85.7% (144/168) had stage III-IV prolapse. Among the 168 patients undergoing this modified SSLF, 161 were for uterovaginal prolapse, and seven were for posthysterectomy vaginal vault prolapse. 83.9% (135/161) patients were concomitant with hysterectomy, and 70.2% (118/168) were with anteroposterior colporrhaphy. The median operation time was 82 min (interquartile range [IQR], 61-100 min), and the median intraoperative blood loss was 50 ml (IQR, 30-50 ml). Two cases had pelvic hematoma, and both were cured after expectant treatment. No patient required a homologous blood transfusion, and none complained about buttock or lower limb pain 2 weeks postoperatively. Nor did injury of the ureters, bladder, or rectum occur intraoperatively. This modified transvaginal SSLF procedure was safe and had no severe perioperative complications.

Evidence That DDR1 Promotes Oligodendrocyte Differentiation during Development and Myelin Repair after Injury.

Oligodendrocytes generate myelin sheaths vital for the formation, health, and function of the central nervous system. Mounting evidence suggests that receptor tyrosine kinases (RTKs) are crucial for oligodendrocyte differentiation and myelination in the CNS. It was recently reported that discoidin domain receptor 1 (Ddr1), a collagen-activated RTK, is expressed in oligodendrocyte lineage. However, its specific expression stage and functional role in oligodendrocyte development in the CNS remain to be determined. In this study, we report that Ddr1 is selectively upregulated in newly differentiated oligodendrocytes in the early postnatal CNS and regulates oligodendrocyte differentiation and myelination. Ddr1 knock-out mice of both sexes displayed compromised axonal myelination and apparent motor dysfunction. Ddr1 deficiency alerted the ERK pathway, but not the AKT pathway in the CNS. In addition, Ddr1 function is important for myelin repair after lysolecithin-induced demyelination. Taken together, the current study described, for the first time, the role of Ddr1 in myelin development and repair in the CNS, providing a novel molecule target for the treatment of demyelinating diseases.

Hsa-circ-0006091 modulates the proliferation of hepatocellular carcinoma via the miR-622/CCNB1 axis.

Background/aim: Hepatocellular carcinoma (HCC) is a common type of cancer. We hypothesize that circular RNA-0006091 (circ-0006091) affects the progression of HCC. The study aims to investigate the effect of circ-0006091 in HCC cells. Materials and methods: The levels of circ-0006091, microRNA-622 (miR-622), and cyclin B1 (CCNB1) were assayed using qRT-PCR and western blotting. The metastasis of the HCC cells was measured with wound healing and transwell assays. The protein expression levels of MMP-2 and MMP-9 were assayed with western blotting. Dual-luciferase reporter and RNA-pulldown assays were used to determine the link between miR-622 and circ-0006091 or CCNB1. Mice-based tests were used to determine the effect of circ-0006091 on the proliferation of HCC cells. Results: The levels of circ-0006091 and CCNB1 were increased in the HCC cells, but miR-622 was down-regulated. Deficiency of circ-0006091 reduced the metastasis of the HCC cells, and silencing of circ-0006091 decreased the activities of MMP-2 and MMP-9 in the same cells. Circ-0006091 modulated the CCNB1 level in the HCC cells via miR-622. Silencing of circ-0006091 suppressed the proliferation of the HCC cells in vivo. Conclusion: Circ-0006091 regulated HCC cell metastasis via the miR-622/CCNB1 axis, a possible therapeutic target in managing HCC.

EGF signaling promotes the lineage conversion of astrocytes into oligodendrocytes.

BACKGROUND: The conversion of astrocytes activated by nerve injuries to oligodendrocytes is not only beneficial to axonal remyelination, but also helpful for reversal of glial scar. Recent studies have shown that pathological niche promoted the Sox10-mediated astrocytic transdifferentiation to oligodendrocytes. The extracellular factors underlying the cell fate switching are not known. METHODS: Astrocytes were obtained from mouse spinal cord dissociation culture and purified by differential adherent properties. The lineage conversion of astrocytes into oligodendrocyte lineage cells was carried out by Sox10-expressing virus infection both in vitro and in vivo, meanwhile, epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR) inhibitor Gefitinib were adopted to investigate the function of EGF signaling in this fate transition process. Pharmacological inhibition analyses were performed to examine the pathway connecting the EGF with the expression of oligodendrogenic genes and cell fate transdifferentiation. RESULTS: EGF treatment facilitated the Sox10-induced transformation of astrocytes to O4+ induced oligodendrocyte precursor cells (iOPCs) in vitro. The transdifferentiation of astrocytes to iOPCs went through two distinct but interconnected processes: (1) dedifferentiation of astrocytes to astrocyte precursor cells (APCs); (2) transformation of APCs to iOPCs, EGF signaling was involved in both processes. And EGF triggered astrocytes to express oligodendrogenic genes Olig1 and Olig2 by activating extracellular signal-regulated kinase 1 and 2 (Erk1/2) pathway. In addition, we discovered that EGF can enhance astrocyte transdifferentiation in injured spinal cord tissues. CONCLUSIONS: These findings provide strong evidence that EGF facilitates the transdifferentiation of astrocytes to oligodendrocytes, and suggest that targeting the EGF-EGFR-Erk1/2 signaling axis may represent a novel therapeutic strategy for myelin repair in injured central nervous system (CNS) tissues.

Curcumin restrains hepatocellular carcinoma progression depending on the regulation of the circ_0078710/miR-378b/PRIM2 axis.

PURPOSE: Curcumin has shown anti-tumor activity in multiple malignancies. The aim of our study was to explore the molecular mechanism behind the anti-tumor activity of curcumin in hepatocellular carcinoma (HCC). METHODS: The proliferation, migration, invasion, and apoptosis were analyzed by 5-ethynyl-2'-deoxyuridine (EDU) assay, transwell migration assay, transwell invasion assay, and flow cytometry. Western blot assay and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were conducted to analyze protein and RNA expression. Dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay, and RNA-pull down assay were performed to confirm the interaction between microRNA-378b (miR-378b) and circular RNA_0078710 (circ_0078710) or DNA primase, polypeptide 2 (PRIM2). Tumor xenograft assay was conducted to assess the roles of curcumin and circ_0078710 in vivo. RESULTS: Curcumin stimulation restrained the proliferation, migration, and invasion, and triggered the apoptosis of HCC cells. Curcumin down-regulated the expression of circ_0078710 in HCC cells in a dose-dependent manner. Circ_0078710 knockdown aggravated curcumin-mediated anti-tumor effects in HCC cells. Circ_0078710 acted as a molecular sponge for miR-378b. Circ_0078710 interference-induced effects in curcumin-stimulated HCC cells were partly abolished by the silence of miR-378b. MiR-378b bound to the 3' untranslated region (3'UTR) of PRIM2. PRIM2 overexpression partly reversed circ_0078710 interference-mediated influences in curcumin-treated HCC cells. Circ_0078710 silencing aggravated curcumin-mediated suppressive effect in tumor growth in vivo. CONCLUSIONS: Circ_0078710 silencing aggravated curcumin-mediated anti-tumor effects through mediating the miR-378b/PRIM2 signaling in HCC cells.

Ternary Flash Memory with a Carbazole-Based Conjugated Copolymer: WS2 Composites as Active Layers.

For nonvolatile memory devices, the design and synthesis of their substrate materials are very important. Due to the versatility and large-area fabrication of the low-temperature spin coating process, organic/inorganic nanomaterials as active layers of memory devices have been deeply studied. Inorganic nanoparticles can engage in interactions with polymers via external voltage. WS2 NPs have a large specific surface area and good conductivity. They can be used as the charge trap center in the active layer, which is conducive to the charge transfer in the active layer. Poly[2,7-9-(9-heptadecanyl)-9H-carbazole-co-benzo[4,5] imidazole[2,1-α] isoindol-11-one] (PIIO) was synthesized via the Suzuki coupling reaction. ITO/PIIO/Al and ITO/PIIO:WS2 NP/Al devices were prepared by the spin coating method and vacuum evaporation technology. All devices showed tristable switching behavior. The influence of the WS2 mass fraction on memory performance was studied. The device composite with 6 wt % WS2 NPs showed the best storage features. The OFF/ON1/ON2 current ratio was 1: 1.11 × 101: 2.03 × 104, and the threshold voltage Vth1/Vth2 was -0.60 V/-1.05 V. The device is steady for 12,000 s in three states-high-resistance state (HRS), intermediate state (IRS), and low-resistance state (LRS). After reading 3500 times, the switch-state current displayed no obvious attenuation. This work shows that the polymer and its composites have broad prospects in next-generation nonvolatile storage.

Anatomic identification of laparoscopic uterosacral ligament suspension: A step-by-step procedure.

INTRODUCTION AND HYPOSTHESIS: The uterosacral ligament (USL) is the main structure of physiological apical support, and USL suspension is one of the most commonly used methods for native tissue apical suspension. Structures surrounding the USL are complex, and the USL itself is difficult to identify, especially the sacral portion of the USL. Laparoscopy improves visualization, but exposure of the USL is still unsatisfactory. METHODS: In this study, we report a simple method for exposing and suturing the USL laparoscopically, with step-by-step instructions, well-presented figures and videos. The key techniques are shown as follows: keeping tension on the USL with a uterine manipulator, dissecting the space medial to the USL, exposing the portion of the USL near the sacrum through the natural space, and then suturing it medially and connecting it directly to the posterior cervix. RESULTS: 95 consecutive patients have undergone this modified USLS and none had serious perioperative complication. CONCLUSION: In this way, the USL anatomy is exposed well, which may make placement of sutures in USL suspension safe and effective.

A New Potential Antidepressant: Dexmedetomidine Alleviates Neuropathic Pain-Induced Depression by Increasing Neurogenesis in the Hippocampus.

INTRODUCTION: Studies have suggested dexmedetomidine (DEX) as a potential antidepressant. However, no relevant research exists on its effects and mechanisms in curing depression caused by chronic pain. Therefore, an understanding of DEX's role in depressive disorders proposes new approaches for antidepressant treatment. METHODS: In this study, C57Bl/6 mice (n = 80) were divided into sham (n = 8) and chronic constrictive injury (CCI, n = 72) groups. The CCI group was further divided into six subgroups: CCI + normal saline (NS), CCI + DEX6.25, CCI + DEX12.5, CCI + DEX25, CCI + DEX50, and CCI + DEX100. Fourteen days after CCI, mice that did not develop a depressive phenotype were excluded through sucrose preference test (SPT), forced swimming test (FST), paw thermal withdrawal latency (PTWL), and serum corticosterone (CORT). Subsequently, mice in the sham group were administered 0.1 mL/10 g NS once daily. However, mice in the CCI subgroups were administered NS (0.1 mL/10 g), DEX (6.25 µg/kg), DEX (12.5 µg/kg), DEX (25 µg/kg), DEX (50 µg/kg), and DEX (100 µg/kg) intraperitoneally once daily for 1 week, respectively. Afterward, bromodeoxyuridine (BrdU) was injected intraperitoneally once daily as well for 3 consecutive days before sampling, following BrdU- and doublecortex (DCX)-positive cell detection in the hippocampus through immunofluorescence. RESULTS: The success rate of the chronic pain-depression (CPD) model was 62.5%. As observed, DEX dose-dependently affected sucrose preferences during the SPT and immobility time during FST. Results also showed that 25 µg/kg DEX had the best promotion effect during increased sucrose preference and reduced immobility time. Moreover, although DEX improved PTWL and serum CORT, no improvement over the DEX 25 µg/kg treatment was observed. Compared to the sham group, the percentage of BrdU+ and DCX+ cells was also significantly lower in the CCI + NS group. Besides, DEX dose-dependently affected cell proliferation and neuronal differentiation. Additionally, the percentage of BrdU+ and DCX+ cells in the dentate gyrus (DG) region of the hippocampus was highest in the CCI + DEX25 group. CONCLUSION: Therefore, DEX dose-dependently alleviates depression induced by chronic pain through neurogenesis promotion in the DG region of the hippocampus.

The Nucleoside/Nucleotide Analogs Tenofovir and Emtricitabine Are Inactive against SARS-CoV-2.

The urgent response to the COVID-19 pandemic required accelerated evaluation of many approved drugs as potential antiviral agents against the causative pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Using cell-based, biochemical, and modeling approaches, we studied the approved HIV-1 nucleoside/tide reverse transcriptase inhibitors (NRTIs) tenofovir (TFV) and emtricitabine (FTC), as well as prodrugs tenofovir alafenamide (TAF) and tenofovir disoproxilfumarate (TDF) for their antiviral effect against SARS-CoV-2. A comprehensive set of in vitro data indicates that TFV, TAF, TDF, and FTC are inactive against SARS-CoV-2. None of the NRTIs showed antiviral activity in SARS-CoV-2 infected A549-hACE2 cells or in primary normal human lung bronchial epithelial (NHBE) cells at concentrations up to 50 µM TAF, TDF, FTC, or 500 µM TFV. These results are corroborated by the low incorporation efficiency of respective NTP analogs by the SARS-CoV-2 RNA-dependent-RNA polymerase (RdRp), and lack of the RdRp inhibition. Structural modeling further demonstrated poor fitting of these NRTI active metabolites at the SARS-CoV-2 RdRp active site. Our data indicate that the HIV-1 NRTIs are unlikely direct-antivirals against SARS-CoV-2, and clinicians and researchers should exercise caution when exploring ideas of using these and other NRTIs to treat or prevent COVID-19.

Assessment and dynamic mechanisms of the land-use dominant morphology transition: a case study of Hainan Province, China.

This paper was aimed at providing a perspective on the assessment of land-use dominant transition. Based on the transfer matrix of land-use type, the dynamic degree of dominant morphology transition was measured, and an active degree index was proposed. The spatiotemporal differentiation characteristics were assessed and analyzed by land use change characteristics in different phases. Our assessment resulted in three types of spatiotemporal differentiation of Hainan Province in China. The whole island can be divided into three regions with two parallel lines at 45° based on spatiotemporal differentiation characteristics. The "slow-type" was distributed in four eastern counties (cities), "steady-type" was distributed in 13 central and western counties (cities), and the "active-type" was distributed in four central counties (cities). Over three phases, namely 2010-2011, 2012-2015, and 2015-2018, four levels of spatiotemporal differentiation of the 21 counties (cities) were assessed, and they were relatively stable, leaping, declining, and unstable. Areas of new construction and fixed assets investments consumed by increased construction land were the positive factors of land-use dominant transition, while output values of secondary industries and area of industrial-mining per capita were the negative factors. Based on these results, a more informative examination of LULC was proposed, and all resulting land management policies will be more targeted and effective.

Microglial mTOR is Neuronal Protective and Antiepileptogenic in the Pilocarpine Model of Temporal Lobe Epilepsy.

Excessive activation of mammalian target of rapamycin (mTOR) signaling is epileptogenic in genetic epilepsy. However, the exact role of microglial mTOR in acquired epilepsy remains to be clarified. In the present study, we found that mTOR is strongly activated in microglia following excitatory injury elicited by status epilepticus. To determine the role of microglial mTOR signaling in excitatory injury and epileptogenesis, we generated mice with restrictive deletion of mTOR in microglia. Both male and female mice were used in the present study. We found that mTOR-deficient microglia lost their typical proliferative and inflammatory responses to excitatory injury, whereas the proliferation of astrocytes was preserved. In addition, mTOR-deficient microglia did not effectively engulf injured/dying neurons. More importantly, microglial mTOR-deficient mice displayed increased neuronal loss and developed more severe spontaneous seizures. These findings suggest that microglial mTOR plays a protective role in mitigating neuronal loss and attenuating epileptogenesis in the excitatory injury model of epilepsy.SIGNIFICANCE STATEMENT The mammalian target of rapamycin (mTOR) pathway is strongly implicated in epilepsy. However, the effect of mTOR inhibitors in preclinical models of acquired epilepsy is inconsistent. The broad presence of mTOR signaling in various brain cells could prevent mTOR inhibitors from achieving a net therapeutic effect. This conundrum has spurred further investigation of the cell type-specific effects of mTOR signaling in the CNS. We found that activation of microglial mTOR is antiepileptogenic. Thus, microglial mTOR activation represents a novel antiepileptogenic route that appears to parallel the proepileptogenic route of neuronal mTOR activation. This may explain why the net effect of mTOR inhibitors is paradoxical in the acquired models of epilepsy. Our findings could better guide the use of mTOR inhibitors in preventing acquired epilepsy.