Plexin B3 guides axons to cross the midline in vivo.

During the development of neural circuits, axons are guided by a variety of molecular cues to navigate through the brain and establish precise connections with correct partners at the right time and place. Many axon guidance cues have been identified and they play pleiotropic roles in not only axon guidance but also axon fasciculation, axon pruning, and synaptogenesis as well as cell migration, angiogenesis, and bone formation. In search of receptors for Sema3E in axon guidance, we unexpectedly found that Plexin B3 is highly expressed in retinal ganglion cells of zebrafish embryos when retinal axons are crossing the midline to form the chiasm. Plexin B3 has been characterized to be related to neurodevelopmental disorders. However, the investigation of its pathological mechanisms is hampered by the lack of appropriate animal model. We provide evidence that Plexin B3 is critical for axon guidance in vivo. Plexin B3 might function as a receptor for Sema3E while Neuropilin1 could be a co-receptor. The intracellular domain of Plexin B3 is required for Semaphorin signaling transduction. Our data suggest that zebrafish could be an ideal animal model for investigating the role and mechanisms of Sema3E and Plexin B3 in vivo.

A randomized, double-blind, placebo-controlled, phase IIa, clinical study on investigating the efficacy and safety of SPH3127 tablet in patients with essential hypertension.

Around 70% of patients diagnosed with hypertension exhibit increased levels of renin. SPH3127, an inventive renin inhibitor, has shown favorable tolerability and sustained pharmacodynamic inhibitory impact on plasma renin activity (PRA) during previous phase I trials. This phase II study was conducted to investigate the efficacy and safety of SPH3127 in patients with essential hypertension. This study was conducted in patients with mild to moderate essential hypertension, utilizing a randomized, double-blind, placebo-controlled design. The patients were administered either tablet of SPH3127 at doses of 50 mg, 100 mg, or 200 mg, or a placebo. A total of 122 patients were included in the study, with 121 patients included in the full analysis set. Among these patients, there were 30 individuals in each subgroup receiving different dosage regimens of SPH3127, and 31 patients in the placebo group. The reductions in mean sitting diastolic blood pressure (msDBP) after 8 weeks compared to baseline were 5.7 ± 9.5, 8.6 ± 8.8, and 3.8 ± 10.6 mmHg in the SPH3127 50-, 100-, and 200 mg groups, respectively. In the placebo group, the reduction was 3.1 ± 8.4 mmHg. The corresponding reductions in mean sitting systolic blood pressure (msSBP) were 11.8 ± 13.0, 13.8 ± 11.2, 11.1 ± 13.1, and 7.7 ± 9.7 mmHg in each respective group. SPH3127 is a promising drug for the treatment of patients with essential hypertension. The recommended dosage is 100 mg daily.Clinical trial registration: This study was registered in ClinicalTrials.gov (NCT03756103).

Nrf2-mediated ferroptosis of spermatogenic cells involved in male reproductive toxicity induced by polystyrene nanoplastics in mice. / Nrf2ä»‹å¯¼çš„ç”Ÿç²¾ç»†èƒžé“æ­»äº¡å‚ä¸Žäº†èšè‹¯ä¹™çƒ¯çº³ç±³å¡‘æ–™å¯¼è‡´çš„å°é¼ é›„æ€§ç”Ÿæ®–æ¯’æ€§.

Microplastics (MPs) and nanoplastics (NPs) have become hazardous materials due to the massive amount of plastic waste and disposable masks, but their specific health effects remain uncertain. In this study, fluorescence-labeled polystyrene NPs (PS-NPs) were injected into the circulatory systems of mice to determine the distribution and potential toxic effects of NPs in vivo. Interestingly, whole-body imaging found that PS-NPs accumulated in the testes of mice. Therefore, the toxic effects of PS-NPs on the reproduction systems and the spermatocytes cell line of male mice, and their mechanisms, were investigated. After oral exposure to PS-NPs, their spermatogenesis was affected and the spermatogenic cells were damaged. The spermatocyte cell line GC-2 was exposed to PS-NPs and analyzed using RNA sequencing (RNA-seq) to determine the toxic mechanisms; a ferroptosis pathway was found after PS-NP exposure. The phenomena and indicators of ferroptosis were then determined and verified by ferroptosis inhibitor ferrostatin-1 (Fer-1), and it was also found that nuclear factor erythroid 2-related factor 2 (Nrf2) played an important role in spermatogenic cell ferroptosis induced by PS-NPs. Finally, it was confirmed in vivo that this mechanism of Nrf2 played a protective role in PS-NPs-induced male reproductive toxicity. This study demonstrated that PS-NPs induce male reproductive dysfunction in mice by causing spermatogenic cell ferroptosis dependent on Nrf2.

A novel perspective on di-hexyl phthalate (2-ethylhexyl)-induced reproductive toxicity in females: Lipopolysaccharide synergizes with mono-2-ethylhexyl ester to cause inflammatory apoptosis rather than autophagy in ovarian granulosa cells.

Di-hexyl phthalate (2-ethylhexyl) (DEHP) has been confirmed to cause female reproductive toxicity in humans and model animals by affecting the survival of ovarian granulosa cells (GCs), but the interrelationships between DEHP's on autophagy, apoptosis, and inflammation in GCs are not clear. Our previous study demonstrated that DEHP exposure resulted in the disturbance of intestinal flora associated with serum LPS release, which in turn led to impaired ovarian function. LPS has also been shown to determine cell fate by modulating cellular autophagy, apoptosis, and inflammation. Therefore, this study investigated the role and link between LPS and autophagy, apoptosis, and inflammation of GCs in DEHP-induced ovarian injury. Here, we constructed an in vivo injury model by continuous gavage of 0-1500 mg/kg of DEHP in female mice for 30 days and an in vitro injury model by treatment of human ovarian granulosa cells (KGN) cells with mono-2- ethylhexyl ester (MEHP, an active metabolite of DEHP in vivo). In addition, the expression of relevant pathway molecules was detected by immunohistochemistry, immunofluorescence, qRT-PCR, and Western blotting after the addition of the autophagy inhibitor 3-methyladenine (3-MA), the apoptosis inhibitor Z-VAD- FMK and the NF-κB inhibitor BAY11-7082. The current study found that autophagy and apoptosis were significantly activated in GCs of DEHP-induced atretic follicles in vivo and found that MEHP-induced KGN cells autophagy and apoptosis were independent and potentially cytotoxic of each other in vitro. Further studies confirmed that DEHP exposure resulted in LPS release from the intestinal tract and entering the ovary, thereby participating in DEHP-induced inflammation of GCs. In addition, we found that exogenous LPS synergized with MEHP could activate the NF-κB signaling pathway to induce inflammation and apoptosis of GCs in a relatively prolonged exposure condition. Meanwhile, inhibition of inflammatory activation could rescue apoptosis and estrogen secretion function of GCs induced by MEHP combined with LPS. These results indicated that the increased LPS influenced by DEHP might cooperate with MEHP to induce inflammatory apoptosis of GCs, an important cause of ovarian injury in mice.

In Vivo Toxicology of Metabolizable Atomically Precise Au25 Clusters at Ultrahigh Doses.

Ultrasmall Au25(MPA)18 clusters show great potential in biocatalysts and bioimaging due to their well-defined, tunable structure and properties. Hence, in vivo pharmacokinetics and toxicity of Au nanoclusters (Au NCs) are very important for clinical translation, especially at high dosages. Herein, the in vivo hematological, tissue, and neurological effects following exposure to Au NCs (300 and 500 mg kg-1) were investigated, in which the concentration is 10 times higher than in therapeutic use. The biochemical and hematological parameters of the injected Au NCs were within normal limits, even at the ultrahigh level of 500 mg kg-1. Meanwhile, no histopathological changes were observed in the Au NC group, and immunofluorescence staining showed no obvious lesions in the major organs. Furthermore, real-time near-infrared-II (NIR-II) imaging showed that most of the Au25(MPA)18 and Au24Zn1(MPA)18 can be metabolized via the kidney. The results demonstrated that Au NCs exhibit good biosafety by evaluating the manifestation of toxic effects on major organs at ultrahigh doses, providing reliable data for their application in biomedicine.

Systematic profiling of Taxol resistance and sensitivity to tubulin missence mutations at molecular and cellular levels.

Taxol (paclitaxel) is the first approved microtubule-stabilizing agent (MSA) by binding stoichiometrically to tubulin, which is considered to be one of the most significant advances in first-line chemotherapy against diverse tumors. However, a large number of residue missence mutations harboring in the tubulin have been observed to cause acquired drug resistance, largely limiting the clinical application of Taxol and its analogs in chemotherapy. A systematic investigation of the intermolecular interactions between the Taxol and various tubulin mutants would help to establish a comprehensive picture of drug response to tubulin mutations in clinical treatment of cancer, and to design new MSA agents with high potency and selectivity to overcome drug resistance. In this study, we described an integration of in silico analysis and in vitro assay (iSiV) to profile Taxol against a panel of 149 clinically observed, cancer-associated missence mutations in ß-tubulin at molecular and cellular levels, aiming to a systematic understanding of molecular mechanism and biological implication underlying drug resistance and sensitivity conferring from tubulin mutations. It is revealed that the Taxol-resistant mutations can be classified into three types: (I) nonbonded interaction broken due to mutation, (II) steric hindrance caused by mutation, and (III) conformational change upon mutation. In addition, we identified three new Taxol-resistant mutations (C239Y, T274I, and R320P) that can largely reduce the binding affinity of Taxol to tubulin at molecular level, in which the T274I and R320P were observed to considerably impair the antitumor activity of Taxol at cellular level. Moreover, a novel drug-susceptible mutation (M363T) was also identified, which improves Taxol affinity by 2.6-fold and decreases Taxol antitumor EC50 values from 29.4 to 18.7 µM.

Are children with IgA nephropathy different from adult patients?

BACKGROUND: Previously, several studies have indicated that pediatric IgA nephropathy (IgAN) might be different from adult IgAN, and treatment strategies might be also different between pediatric IgAN and adult IgAN. METHODS: We analyzed two prospective cohorts established by pediatric and adult nephrologists, respectively. A comprehensive analysis was performed investigating the difference in clinical and pathological characteristics, treatment, and prognosis between children and adults with IgAN. RESULTS: A total of 1015 children and 1911 adults with IgAN were eligible for analysis. More frequent gross hematuria (88% vs. 20%, p < 0.0001) and higher proteinuria (1.8 vs. 1.3 g/d, p < 0.0001) were seen in children compared to adults. In comparison, the estimated glomerular filtration rate (eGFR) was lower in adults (80.4 vs. 163 ml/min/1.73 m2, p < 0.0001). Hypertension was more prevalent in adult patients. Pathologically, a higher proportion of M1 was revealed (62% vs. 39%, p < 0.0001) in children than in adults. S1 (62% vs. 28%, p < 0.0001) and T1-2 (34% vs. 8%, p < 0.0001) were more frequent in adults. Adjusted by proteinuria, eGFR, and hypertension, children were more likely to be treated with glucocorticoids than adults (87% vs. 45%, p < 0.0001). After propensity score matching, in IgAN with proteinuria > 1 g/d, children treated with steroids were 1.87 (95% CI 1.16-3.02, p = 0.01) times more likely to reach complete remission of proteinuria compared with adults treated with steroids. CONCLUSIONS: Children present significantly differently from adults with IgAN in clinical and pathological manifestations and disease progression. Steroid response might be better in children.

Optimal dose of fenfluramine in adjuvant treatment of drug-resistant epilepsy: evidence from randomized controlled trials.

Objective: Several clinical trials have suggested that fenfluramine (FFA) is effective for the treatment of epilepsy in Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). However, the exploration of its optimal target dose is ongoing. This study aimed to summarize the best evidence to inform this clinical issue. Materials and methods: We searched PubMed, Embase (via Ovid), and Web of Science for relevant literature published before December 1st, 2023. Randomized, double-blind, placebo-controlled studies that evaluated the efficacy, safety, and tolerability of FFA in DS and LGS were identified and meta-analysis was performed according to doses. The study was registered with PROSPERO (CRD42023392454). Results: Six hundred and twelve patients from four randomized controlled trials were enrolled. The results demonstrated that FFA at 0.2, 0.4, or 0.7 mg/kg/d showed significantly greater efficacy compared to placebo in terms of at least 50% reduction (p < 0.001, p < 0.001, p < 0.001) and at least 75% reduction (p < 0.001, p = 0.007, p < 0.001) in monthly seizure frequency from baseline. Moreover, significantly more patients receiving FFA than placebo were rated as much improved or very much improved in CGI-I by both caregivers/parents and investigators (p < 0.001). The most common treatment-emergent adverse events were decreased appetite, diarrhea, fatigue, and weight loss, with no valvular heart disease or pulmonary hypertension observed in any participant. For dose comparison, 0.7 mg/kg/d group presented higher efficacy on at least 75% reduction in seizure (p = 0.006) but not on at least 50% reduction. Weight loss (p = 0.002), decreased appetite (p = 0.04), and all-cause withdrawal (p = 0.036) were more common in 0.7 mg/kg/d group than 0.2 mg/kg/d. There was no statistical difference in other safety parameters between these two groups. Conclusion: The higher range of the licensed dose achieves the optimal balance between efficacy, safety, and tolerability in patients with DS and LGS. Clinical trial registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023392454.

Triglyceride glucose index is associated with functional coronary artery stenosis in hypertensive patients.

Background: The triglyceride glucose (TyG) index is an effective method for determining insulin resistance (IR). Limited research has explored the connection between the TyG index and functionally significant stenosis in hypertensive patients. Furthermore, the connections between the TyG index, fat attenuation index (FAI) and atherosclerotic plaque characteristics are also worth exploring. Methods: The study screened 1622 hypertensive participants without coronary artery disease history who underwent coronary computed tomography angiography. The TyG index was calculated as ln (fasting glucose [mg/dL] * fasting TG [mg/dL]/2). Adverse plaque characteristics (HRPCs), high-risk plaques (HRPs), FAI, and CT-derived fractional flow reserve (FFRCT) were analyzed and measured for all patients. Functionally significant stenosis causing ischemia is defined as FFRCT ≤ 0.80. Two patient groups were created based on the FFRCT: the FFRCT < 0.80 group and the FFRCT > 0.80 group. In hypertensive patients, the association between the TyG index and FFRCT was examined applying a logistic regression model. Results: The TyG index was higher for people with FFRCT ≤ 0.80 contrast to those with FFRCT > 0.80. After controlling for additional confounding factors, the logistic regression model revealed a clear connection between the TyG index and FFRCT ≤ 0.80 (OR = 1.718, 95% CI 1.097-2.690, p = 0.018). The restricted cubic spline analysis displayed a nonlinear connection between the TyG index and FFRCT ≤ 0.80 (p for nonlinear = 0.001). The TyG index increased the fraction of individuals with HRPs and HRPCs, FAI raised, and FFRCT decreased (p < 0.05). The multivariate linear regression analysis illustrated a powerfulcorrelation between high TyG index levels and FAI, FFRCT, positive remodeling (PR), and low-attenuation plaque (LAPs) (standardized regression coefficients: 0.029 [p = 0.007], -0.051 [p < 0.001], 0.029 [p = 0.027], and 0.026 [p = 0.046], separately). Conclusion: In hypertensive patients, the TyG index showed an excellent association with a risk of FFRCT ≤ 0.80. Additionally, the TyG index was also linked to FAI, FFRCT, PR, and LAPs.

Spatio-temporal variation and drivers of blue carbon sequestration in Hainan Island, China.

Blue carbon ecosystems, such as mangrove, seagrass bed and salt marsh, have attracted increasing attention due to their remarkable capacity for efficient carbon sequestration. However, the current threat posed by human activities to these ecosystems necessitates the characterization of their changes and identification of the primary driving factors in order to facilitate the gradual restoration of blue carbon ecosystems. In this study, we present an analysis of the spatio-temporal characteristics and primary influencing factors governing carbon sequestration in mangrove and seagrass beds located in Hainan Island. The findings revealed a 40% decline in carbon sequestration by mangroves from 1976 to 2017, while seagrass beds exhibited a 13% decrease in carbon sequestering between 2009 and 2016. The decline in carbon sequestration was primarily concentrated in Wenchang city, with aquaculture and population growth identified as the primary driving factors. Despite the implementation of measures aimed at reducing aquaculture in Hainan Island to promote blue carbon sequestration over the past two decades, the resulting recovery remains insufficient in achieving macro-level goals for carbon sequestration. This study emphasizes the necessity of safeguarding blue carbon ecosystems in Hainan Island by effectively mitigating anthropogenic disturbances.

Genome-wide analysis of in vivo-evolved Candida auris reveals multidrug-resistance mechanisms.

Candida auris, an emerging and multidrug-resistant fungal pathogen, has led to numerous outbreaks in China. While the resistance mechanisms against azole and amphotericin B have been studied, the development of drug resistance in this pathogen remains poorly understood, particularly in in vivo-generated drug-resistant strains. This study employed pathogen whole-genome sequencing to investigate the epidemiology and drug-resistance mutations of C. auris using 16 strains isolated from two patients. Identification was conducted through Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and antimicrobial susceptibilities were assessed using broth microdilution and Sensititre YeastOne YO10. Whole-genome sequencing revealed that all isolates belonged to the South Asian lineage, displaying genetic heterogeneity. Despite low genetic variability among patient isolates, notable mutations were identified, including Y132F in ERG11 and A585S in TAC1b, likely linked to increased fluconazole resistance. Strains from patient B also carried F214L in TAC1b, resulting in a consistent voriconazole minimum inhibitory concentration of 4 µg/mL across all isolates. Furthermore, a novel frameshift mutation in the SNG1 gene was observed in amphotericin B-resistant isolates compared to susceptible ones. Our findings suggest the potential transmission of C. auris and emphasize the need to explore variations related to antifungal resistance. This involves analyzing genomic mutations and karyotypes, especially in vivo, to compare sensitive and resistant strains. Further monitoring and validation efforts are crucial for a comprehensive understanding of the mechanisms of drug resistance in C. auris.

Reducing target binding affinity improves the therapeutic index of anti-MET antibody-drug conjugate in tumor bearing animals.

Many oncology antibody-drug conjugates (ADCs) have failed to demonstrate efficacy in clinic because of dose-limiting toxicity caused by uptake into healthy tissues. We developed an approach that harnesses ADC affinity to broaden the therapeutic index (TI) using two anti-mesenchymal-epithelial transition factor (MET) monoclonal antibodies (mAbs) with high affinity (HAV) or low affinity (LAV) conjugated to monomethyl auristatin E (MMAE). The estimated TI for LAV-ADC was at least 3 times greater than the HAV-ADC. The LAV- and HAV-ADCs showed similar levels of anti-tumor activity in the xenograft model, while the 111In-DTPA studies showed similar amounts of the ADCs in HT29 tumors. Although the LAV-ADC has ~2-fold slower blood clearance than the HAV-ADC, higher liver toxicity was observed with HAV-ADC. While the SPECT/CT 111In- and 124I- DTPA findings showed HAV-ADC has higher accumulation and rapid clearance in normal tissues, intravital microscopy (IVM) studies confirmed HAV mAb accumulates within hepatic sinusoidal endothelial cells while the LAV mAb does not. These results demonstrated that lowering the MET binding affinity provides a larger TI for MET-ADC. Decreasing the affinity of the ADC reduces the target mediated drug disposition (TMDD) to MET expressed in normal tissues while maintaining uptake/delivery to the tumor. This approach can be applied to multiple ADCs to improve the clinical outcomes.

SIRT3 regulates cardiolipin biosynthesis in pressure overload-induced cardiac remodeling by PPARγ-mediated mechanism.

Cardiac remodeling is the primary pathological feature of chronic heart failure (HF). Exploring the characteristics of cardiac remodeling in the very early stages of HF and identifying targets for intervention are essential for discovering novel mechanisms and therapeutic strategies. Silent mating type information regulation 2 homolog 3 (SIRT3), as a major mitochondrial nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, is required for mitochondrial metabolism. However, whether SIRT3 plays a role in cardiac remodeling by regulating the biosynthesis of mitochondrial cardiolipin (CL) is unknown. In this study, we induced pressure overload in wild-type (WT) and SIRT3 knockout (SIRT3-/-) mice via transverse aortic constriction (TAC). Compared with WT mouse hearts, the hearts of SIRT3-/- mice exhibited more-pronounced cardiac remodeling and fibrosis, greater reactive oxygen species (ROS) production, decreased mitochondrial-membrane potential (ΔΨm), and abnormal mitochondrial morphology after TAC. Furthermore, SIRT3 deletion aggravated TAC-induced decrease in total CL content, which might be associated with the downregulation of the CL synthesis related enzymes cardiolipin synthase 1 (CRLS1) and phospholipid-lysophospholipid transacylase (TAFAZZIN). In our in vitro experiments, SIRT3 overexpression prevented angiotensin II (AngII)- induced aberrant mitochondrial function, CL biosynthesis disorder, and peroxisome proliferator-activated receptor gamma (PPARγ) downregulation in cardiomyocytes; meanwhile, SIRT3 knockdown exacerbated these effects. Moreover, the addition of GW9662, a PPARγ antagonist, partially counteracted the beneficial effects of SIRT3 overexpression. In conclusion, SIRT3 regulated PPARγ-mediated CL biosynthesis, maintained the structure and function of mitochondria, and thereby protected the myocardium against cardiac remodeling.

Quercetin of huoxuehuayu tongluo decoction and azithromycin combination therapy effectively improves rat tubal factor infertility by inhibiting inflammation.

Objectives: Tubal factor infertility (TFI) is common female infertility responsible for a large portion of female factor infertility. This study reveals the effect of the quercetin of Huoxuehuayu Tongluo Decoction with azithromycin on the pregnancy rate and inflammation of TFI female rats. Materials and Methods: Female Sprague Dawley rats were constructed into the TFI model and treated with quercetin, Huoxuehuayu Tongluo Decoction, and combination therapy (quercetin and azithromycin). Pregnancy rate and litter size were measured. Network pharmacology was applied to analyze the interaction between Huoxuehuayu Tongluo Decoction and TFI. The combination of quercetin and IL-6 was analyzed by molecular docking. HE staining and electron microscopy were used to observe the histopathology and ultrastructure of fallopian tube tissues. The TNF-α, IL-1ß, IL-6, IL-8, and MPO levels were detected by ELISA. The activation of JAK/STAT, MAPK, and NF-κB p65 pathways was detected by western blot or immunohistochemistry. Results: Quercetin was the main active component of Huoxuehuayu Tongluo Decoction, and could bind to IL-6 in TFI. Target genes were enriched in the IL-17 signaling pathway, JAK-STAT signaling pathway, inflammatory disease, etc. Under the quercetin and azithromycin combination therapy, both rat pregnancy rates and litter sizes increased significantly. quercetin and azithromycin alleviated the symptoms of hydrosalpinx and inflammatory damage in fallopian tube tissues. The phosphorylation of JAK/STAT and MAPK pathways and NF-κB p65 translocation to the nucleus were significantly inhibited by the quercetin and azithromycin therapy. Conclusion: Quercetin and azithromycin combination therapy inhibited inflammation and phosphorylation of JAK/STAT and MAPK pathways to improve TFI inflammation and pregnancy function.

Cough symptoms in children following COVID-19: a single-center retrospective study.

Background: Cough is the most common respiratory symptom in children with mild coronavirus disease 2019 (COVID-19); however, evidence regarding the duration and severity of COVID-19-related cough is sparse. Herein, we investigated the correlation between cough severity/duration and disease duration in children with allergic diseases following COVID-19. Methods: This single-center, retrospective case-control study was conducted at the Department of Pediatrics, Peking University Third Hospital, from February 6-13, 2023. Children aged 0-16 completed a questionnaire survey collecting basic information and weekly cough scores for 8 consecutive weeks after COVID-19 in December 2022. The Kaplan-Meier method was used to draw event curves, and the log-rank method was used to compare inter-group differences. Stepwise regression was applied for multivariate analysis of correlations between age, sex, allergic diseases, and the degree and duration of cough following COVID-19. Results: Overall, 686 children were included, of whom 183 (26.7%) had allergic diseases and 503 (73.3%) did not. Kaplan-Meier analysis identified significant differences between patients with and without allergic disease (log-rank test, P = 0.002) and between patients with no allergic disease and those with one and more than one allergic disease (log-rank test, P = 0.003). Multivariate regression identified a link between the presence of more than one allergic disease and coughing for >4 weeks after infection (P < 0.001). Allergic disease was the primary factor linked to cough symptoms lasting 8 weeks and cough severity (P < 0.001). Conclusions: Allergic disease contributes to the prolonged duration and severity of coughing in children with mild COVID-19.

Mechanosensitive protein polycystin-1 promotes periosteal stem/progenitor cells osteochondral differentiation in fracture healing.

Background: Mechanical forces are indispensable for bone healing, disruption of which is recognized as a contributing cause to nonunion or delayed union. However, the underlying mechanism of mechanical regulation of fracture healing is elusive. Methods: We used the lineage-tracing mouse model, conditional knockout depletion mouse model, hindlimb unloading model and single-cell RNA sequencing to analyze the crucial roles of mechanosensitive protein polycystin-1 (PC1, Pkd1) promotes periosteal stem/progenitor cells (PSPCs) osteochondral differentiation in fracture healing. Results: Our results showed that cathepsin (Ctsk)-positive PSPCs are fracture-responsive and mechanosensitive and can differentiate into osteoblasts and chondrocytes during fracture repair. We found that polycystin-1 declines markedly in PSPCs with mechanical unloading while increasing in response to mechanical stimulus. Mice with conditional depletion of Pkd1 in Ctsk+ PSPCs show impaired osteochondrogenesis, reduced cortical bone formation, delayed fracture healing, and diminished responsiveness to mechanical unloading. Mechanistically, PC1 facilitates nuclear translocation of transcriptional coactivator TAZ via PC1 C-terminal tail cleavage, enhancing osteochondral differentiation potential of PSPCs. Pharmacological intervention of the PC1-TAZ axis and promotion of TAZ nuclear translocation using Zinc01442821 enhances fracture healing and alleviates delayed union or nonunion induced by mechanical unloading. Conclusion: Our study reveals that Ctsk+ PSPCs within the callus can sense mechanical forces through the PC1-TAZ axis, targeting which represents great therapeutic potential for delayed fracture union or nonunion.

Evaluation of ecotourism suitability based on AHP-GIS: Taking Xiaoxiangling area of the Giant Panda National Park and the surrounding communities as an example.

The primary goal of national parks is to protect ecological environment, but also with the functions of scientific research, education, and recreation. Aiming for the realization of universal sharing, we used the analytic hierarchy process (AHP) to construct an ecotourism suitability evaluation system by selecting four factors, including landscape resources, ecological environment carrying capacity, recreation utilization capacity and social condition, taking Xiaoxiangling area of Giant Panda National Park and the surrounding communities as an example. We evaluated the ecotourism suitability based on GIS, and conducted a questionnaire survey of tourists, to propose suggestions on the functional zoning in terms of ecotourism suitability and subjective choice preferences of tourists. The results showed that the ecotourism suitability of the evaluation area could be classified into five levels. The most suitable areas were located nearby the natural landscape resources and far away from the core conservation area, and the least suitable areas distributed at the edge of the core conservation area. According to the results of suitability analysis, the evaluation area was divided into suitable development area, moderate development area, and restricted development area. Combined with the tourist preferences, we divided the recreational activities in the evaluation area into seven activities, namely, ecotourism, eco-camping, science education, leisure vacation, agricultural and animal husbandry culture experience, eco-education, and mountain adventure. These findings could help provide suitable services for different tourists and offer reference for the ecotourism developmental planning of the Xiaoxiangling area of the Giant Panda National Park.

Improved overall image quality in low-dose dual-energy computed tomography enterography using deep-learning image reconstruction.

OBJECTIVE: To demonstrate the clinical advantages of a deep-learning image reconstruction (DLIR) in low-dose dual-energy computed tomography enterography (DECTE) by comparing images with standard-dose adaptive iterative reconstruction-Veo (ASIR-V) images. METHODS: In this Institutional review board approved prospective study, 86 participants who underwent DECTE were enrolled. The early-enteric phase scan was performed using standard-dose (noise index: 8) and images were reconstructed at 5 mm and 1.25 mm slice thickness with ASIR-V at a level of 40% (ASIR-V40%). The late-enteric phase scan used low-dose (noise index: 12) and images were reconstructed at 1.25 mm slice thickness with ASIR-V40%, and DLIR at medium (DLIR-M) and high (DLIR-H). The 70 keV monochromatic images were used for image comparison and analysis. For objective assessment, image noise, artifact index, SNR and CNR were measured. For subjective assessment, subjective noise, image contrast, bowel wall sharpness, mesenteric vessel clarity, and small structure visibility were scored by two radiologists blindly. Radiation dose was compared between the early- and late-enteric phases. RESULTS: Radiation dose was reduced by 50% in the late-enteric phase [(6.31 ± 1.67) mSv] compared with the early-enteric phase [(3.01 ± 1.09) mSv]. For the 1.25 mm images, DLIR-M and DLIR-H significantly improved both objective and subjective image quality compared to those with ASIR-V40%. The low-dose 1.25 mm DLIR-H images had similar image noise, SNR, CNR values as the standard-dose 5 mm ASIR-V40% images, but significantly higher scores in image contrast [5(5-5), P < 0.05], bowel wall sharpness [5(5-5), P < 0.05], mesenteric vessel clarity [5(5-5), P < 0.05] and small structure visibility [5(5-5), P < 0.05]. CONCLUSIONS: DLIR significantly reduces image noise at the same slice thickness, but significantly improves spatial resolution and lesion conspicuity with thinner slice thickness in DECTE, compared to conventional ASIR-V40% 5 mm images, all while providing 50% radiation dose reduction.

Curcumin relieves oxaliplatin-induced neuropathic pain via reducing inflammation and activating antioxidant response.

Oxaliplatin (OXA) has shown high effectiveness in the treatment of cancers, but its anticancer clinical effects often induce neurotoxicity leading to neuropathic pain. Oxidative damage and NLRP3 inflammasome play important roles in neuropathic pain development. Here, neuropathic pain mouse model was constructed by continuous intraperitoneal injection of OXA. OXA administration induced mechanical pain, spontaneous pain, thermal hyperalgesia and motor disability in mice. The spinal cord tissues of OXA mice exhibited the suppressed antioxidative response, the activated NLRP3 inflammasome mediated inflammatory responses, and the increased GSK-3ß activity. Next, we injected curcumin (CUR) intraperitoneally in OXA mice for seven consecutive days. CUR-treated mice showed increased mechanical pain thresholds, reduced number of spontaneous flinches, increased paw withdrawal latency, and restored latency to fall. While in the spinal cord, CUR treatment inhibited the NLRP3 inflammasome mediated inflammatory response, increased Nrf2/GPX4-mediated antioxidant responses, and decreased mitochondrial oxidative generation. Additionally, CUR combined with GSK-3ß through four covalent bonds and reduced GSK-3ß activity. In conclusion, our findings suggest that CUR treatment inhibits GSK-3ß activation, increases Nrf2 mediated antioxidant responses, inhibits oxidative damage and inflammatory reaction, and alleviates OXA-induced neuropathic pain.