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Background. Vagus nerve stimulation therapy is proven to produce neuroprotective effects against central nervous system diseases and reduce neurological injury, having a positive effect on the recovery of neurological functions in mouse model of stroke. Objective. This study was aimed at exploring a wider time window for VNS treatment, investigating the long-term behavioral improvement of long-term VNS in mice after pMCAO, and exploring the antiapoptotic properties of VNS and its role in autophagy, all of which may be a permanent deficiency potential mechanism of neuroprotection in hemorrhagic stroke. Methods. Permanent focal cerebral ischemia and implantation of vagus nerve stimulator were performed through intracavitary occlusion of the right middle cerebral artery (MCA). The vagus nerve stimulation group received five times vagus nerve stimulation from 6 h after surgery for 5 days. Adhesive removal test and NSS neurological score were used to evaluate the neurological deficit of mice. TTC staining of mouse brain tissue was performed one week after surgery in order to assess the area of cerebral infarction. Additionally, frozen sections were stained with Fluoro-Jade B to observe the apoptotic cells in the ischemic penumbra of brain tissue. Finally, Western blot was used to detect the changes in the levels of apoptosis-related proteins such as cleaved-caspase3 and Bcl-2 and autophagy-related proteins such as mTOR, Beclin-1, and LC3-II in brain tissue. Results. VNS can effectively reduce the behavioral score of pMCAO mice; TTC results showed that VNS could effectively reduce the infarct area after pMCAO ( P < 0.05 ). After VNS intervention of the pMCAO group compared with the pMCAO+VNI group, the FJB-positive cells in the VNS group were significantly decreased ( P < 0.05 ); Western Blot analysis showed that the expression of cleaved-caspase3 in the brain tissue of mice increased after pMCAO ( P < 0.05 ), and the expression of Bcl-2 decreased ( P < 0.05 ). This change could be effectively reversed after VNS intervention ( P < 0.05 ). Conclusion. VNS could effectively improve the behavioral performance of mice after permanent stroke in addition to significantly reducing the infarct size of the brain tissue. The mechanism may be related to the effective reduction of cell apoptosis and excessive autophagy after pMCAO by VNS.

OBJECTIVE: To investigate feasibility of the quantitative parameters of dual-energy computed tomography (DECT) to assess therapy response in advanced non-small cell lung cancer (NSCLC) compared with the traditional enhanced CT parameters based on the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. METHODS: Forty-five patients with unresectable locally advanced NSCLC who underwent DECT before and after chemotherapy or concurrent chemoradiotherapy (cCRT) were prospectively enrolled. By comparing baseline studies with follow-up, patients were divided into two groups according to RECIST guidelines as follows: disease control (DC, including partial response and stable disease) and progressive disease (PD). The diameter (D), attenuation, iodine concentration and normalized iodine concentration of arterial and venous phases (ICA, ICv, NICA, NICv) and the percentage of these changes pre- and post-therapy were measured and calculated. The Pearson correlation was used to analyze correlation between various quantitative parameters. The receiver operating characteristic (ROC) curves were used to evaluate accuracy of therapy response prediction. RESULTS: The change percentages of Attenuation (Δ-Attenuation-A and Δ-Attenuation-V), IC (ΔICA and ΔICV) and NIC (ΔNICA and ΔNICV) pre- and post-therapy correlate with the change percentage of D (ΔD). Among these, ΔICA strongly correlates with ΔD (r = 0.793, P

Transient receptor potential canonical 3 (TRPC3) is a nonselective cation channel, and its dysfunction is the basis of many clinical diseases. However, little is known about its possible role in the bladder. The purpose of this study was to explore the function and mechanism of TRPC3 in partial bladder outlet obstruction (PBOO)-induced detrusor overactivity (DO). We studied 31 adult female rats with DO induced by PBOO (the DO group) and 40 sham-operated rats (the control group). Here we report that the expression of TRPC3 in the bladder of DO rats increased significantly. Furthermore, PYR10, which can selectively inhibit the TRPC3 channel, significantly reduced bladder excitability in DO and control rats, but the decrease of the bladder excitability of DO rats was more obvious. PYR10 significantly reduced the intracellular calcium concentration in smooth muscle cells (SMCs) in DO and control rats. Finally, Na+/Ca2+ exchanger 1 (NCX1) colocalizes with TRPC3 and affects its expression and function. Collectively, these results indicate that TRPC3 plays an important role in the pathogenesis of DO through a synergistic effect with NCX1. TRPC3 and NCX1 may be new therapeutic targets for DO. The expression and functional levels of TRPC3, a nonselective cation channel, and NCX1, a Na+/Ca2+ exchanger, are increased in the bladders of rats with partial bladder outlet obstruction-induced detrusor overactivity. The synergistic effects of TRPC3 and NCX1 significantly increase the concentration of Ca2+i in smooth muscle cells, which induces bladder hyperactivity in this animal model of overactive bladder. TRPC3 and NCX1 may be new therapeutic targets for detrusor overactivity.

The aim of this study was to compare the efficacy and safety of surgical resection (RES) and radiofrequency ablation (RFA) in hepatocellular carcinoma (HCC) patients with cirrhosis and to evaluate short- and long-term clinical outcomes.The EMBASE, Cochrane Central Register of Control Trials and Medline databases were searched for comparative studies of RES and RFA in HCC patients with cirrhosis from inception until 30 April 2021. Overall survival (OS), disease-free survival (DFS), local recurrence rate, complication rate, hospitalization duration and operation time were compared between the 2 groups. Begg's funnel plot and Egger's test were performed to assess publication bias.A total of 16 studies met our inclusion criteria, including 1 randomized controlled trial. A total of 3760 patients were included, of which 2007 received RES and 1753 received RFA. The results showed that the 3-year OS rate, 5-year OS rate, 1-year DFS rate and 3-year DFS rate in the RFA group compared with the RES treatment group were significantly lower, and the local recurrence rate in the RFA group was significantly higher than that in the RES group. Compared with the RES group, the RFA group had lower postoperative complication rates, shorter operative times, and no significant difference in hospitalization duration. Subgroup analysis of laparoscopic RFA showed that there was no significant difference in 1- and 5-year OS rates and 3-year and 5-year DFS rates between the 2 groups, while the 3-year OS rates and 1-year DFS rates in the RES group were better than those in the laparoscopic RFA group.Surgery is widely applied among HCC patients with cirrhosis, providing acceptable short- and long-term results.

Styrene-butadiene-styrene (SBS) is currently the most widely used asphalt modifier. However, high-SBS-concentration high-viscosity modified asphalts (HVMA) are characterized by poor flow and storage instability. To make up for the lack of performance of traditional SBS-HVMA, a nano-based high-viscosity composite modified asphalt with excellent performance was developed. Since carbon nanotubes (CNTs) are nanomaterials, they are prone to agglomeration when added to the modified asphalt, and the dispersion effect is poor, which affects the modifier’s contribution rate. To better disperse CNTs in the modified asphalt, the nanomaterials were modified, and two new CNT additives were prepared by combining two polymers with CNTs. The appropriate ratio of these two new additives was selected to be further combined with SBS to obtain CNTs/SBS-HVMA. The flow characteristics and anti-aging properties of the three kinds of bitumen in different temperature ranges were studied by taking the common SBS-HVMA and Tafpack super (TPS) high-viscosity modified asphalts (TPS/SBS-HVMA) as comparison samples and by evaluating the road performance of a stone mastic asphalt (SMA-13) mixture. The storage stability, workable performance, rheological characteristics, and aging resistance of three high-viscosity asphalts were analyzed through a segregation test, dynamic viscosity analysis, Brookfield viscosity measurements, bending beam rheometer (BBR) tests, dynamic shear rheometer (DSR), and multiple stress creep recovery (MSCR) before and after short-term aging. The experimental results showed that CNT/SBS-HVMA exhibited good storage stability and workability. DSR measurements and other rheological tests revealed that TPS/SBS-HVMA had higher low-temperature flexibility than the other modified asphalts, while CNT/SBS-HVMA exhibited good high-temperature resistance, aging resistance, and deformation resistance. Through the verification of asphalt mixture performance, it was found that the high-temperature rutting resistance of CNTs/SBS-HVMA prepared by new CNT additives was 7% and 28% higher than those of SBS-HVMA and TPS/SBS-HVMA, respectively, but the low-temperature performance of CNT/SBS-HVMA was 5% lower than that of SBS-HVMA. This showed that CNT/SBS addition improved the high-temperature performance of the asphalt without a significant negative impact on the low-temperature performance of the asphalt.

Qudong Lu,1 Yang Yang,1 Hengshuai Zhang,1 Cheng Chen,2 Jiang Zhao,1 Zhenxing Yang,1 Yi Fan,1 Longkun Li,1 Huan Feng,1 Jingzhen Zhu,1 Shanhong Yi1 1Department of Urology, Second Affiliated Hospital, Army Medical University, Chongqing, 400037, People’s Republic of China; 2Department of Burns, First Affiliated Hospital, Army Medical University, Chongqing, 400037, People’s Republic of ChinaCorrespondence: Jingzhen Zhu; Shanhong YiDepartment of Urology, Second Affiliated Hospital, Army Medical University, Chongqing, People’s Republic of ChinaTel +86 23-68774453Email zhujz1114@163.com; 2644057844@qq.comPurpose: Hyperalgesia and bladder overactivity are two main symptoms of interstitial cystitis/bladder pain syndrome (IC/BPS). Cannabinoid receptors participate in the modulation of pain and bladder function. GPR18, a member of the cannabinoid receptor family, also participates in the regulation of pain and bladder function, but its underlying mechanisms are unknown. In this work, we sought to study the role of GPR18 in IC/BPS.Methods: A rat model of IC/BPS was established with cyclophosphamide (CYP). Paw withdrawal threshold (PWT) measurement and cystometry were used to evaluate pain and bladder function, respectively. RT-PCR, Western blotting and immunofluorescence were used to assess the expression and distribution of GPR18. The role of GPR18 in pain and bladder function was studied by intrathecal injection of resolvin D2 (RvD2, a GPR18 agonist) and O-1918 (a GPR18 antagonist). Calcium imaging was used to study the relationship between GPR18 and TRPV1.Results: A rat model of IC/BPS, which exhibited a decreased PWT and micturition interval, was successfully established with CYP. The mRNA and protein expression of GPR18 was reduced in the bladder and dorsal root ganglia (DRG) in rats with CYP-induced cystitis. Intrathecal injection of RvD2 increased the PWT and micturition interval. However, O-1918 blocked the therapeutic effect of RvD2. GPR18 was present in bladder afferent nerves and colocalized with TRPV1 in DRG, and RvD2 decreased capsaicin-induced calcium influx in DRG.Conclusion: Activation of GPR18 by RvD2 alleviated hyperalgesia and improved bladder function, possibly by inhibiting TRPV1 in rats with CYP-induced cystitis.Keywords: interstitial cystitis/bladder pain syndrome, GPR18, TRPV1, hyperalgesia, bladder overactivity, resolvin D2, O-1918

The previous study using Sertoli cells cultured in vitro has shown that the protective effects of astragaloside IV (AsIV) on cadmium (Cd)-induced damage to Sertoli cells and its membrane proteins. Yet, it is not known if AsIV has an equivalent effect on Cd-induced damage to the spermatogenesis microenvironment in rats. Using an in vivo model, Cd-induced damage to the spermatogenesis microenvironment and the protective effects of AsIV were studied. Eighteen male Sprague Dawley (SD) rats were randomly divided into three groups (n = 6/group): Cd group, CdA Cd: cadmium; SD: Sprague Dawley; ZO-1: zonal occludin-1; Cx43: connexin 43; BTB: blood-testis barrier; MAPKs: mitogen-activated protein kinases; OSP: oligodendrocyte-specific protein; Cxs: connexins; GJIC: gap junctional intercellular communication; ROS: reactive oxygen species; MDA: malondialdehyde; TGF: tumor growth factor; PBS: phosphate buffer saline; BSA: bovine serum albumin.

Copper(I) thiocyanate (CuSCN) is a p-type semiconductor with exceptional properties for optoelectronic devices such as solar cells, thin-film transistors , organic light-emitting diodes, etc. Understanding the structure-optical property relationships in CuSCN is critical for its optoelectronic applications. Herein, high-pressure techniques combined with theoretical calculations are used to thoroughly investigate the structural and optical changes of CuSCN upon compression. Under high pressure, CuSCN exhibits a progressive decrease of the band gap with different rates, which is relevant to the β to α phase transition in CuSCN and the subsequent amorphization through polymerization. UV-vis spectra measurements reveal a reduction in band gap from 3.4 to 1.3 eV upon decompression to ambient conditions. Such transitions could be attributed to the pressure-induced rotation of CuNS

The protein corona on nano drug carriers is an important well-known biological issue that often induce biological incompatibility and screens the targeting molecules on the surfaces of carriers, therefore, the design of NPs with good protein corona-free property is highly desired and challenged. The natural polysaccharide has been demonstrated as one types of stealth materials after the functional group modification process, but the types and structures of their chains has never been considered. Here, we have designed five types of core-shell starch-coated poly (methyl methacrylate) nanoparticles and we found the starch coated NPs with low amylose content (

Tibet orbivirus (TIBOV), a new candidate of Orbivirus genus, was initially isolated from mosquitoes in Tibet in 2009 and subsequently from both Culicoides and mosquitoes in several provinces of China and Japan. Little is known about the origin, genetic diversity, dissemination and pathogenicity of TIBOV, although its potential threat to animal health has been acknowledged. In this study, two viruses, V290/YNSZ and V298/YNJH, were isolated from the Culicoides and sentinel cattle in Yunnan Province. Their genome sequences, cell tropism in mammalian and insect cell lines along with pathogenicity in suckling mice were determined. Genome phylogenetic analyses confirmed their classification as TIBOV species; however, OC1 proteins of the V290/YNSZ and V298/YNJH shared maximum sequence identities of 31.5% and 33.9% with other recognized TIBOV serotypes (TIBOV-1 to TIBOV-4) and formed two monophyletic branches in phylogenetic tree, indicating they represented two novel TIBOV serotypes which were tentatively designated as TIBOV-5 and TIBOV-6. The viruses replicated robustly in BHK, Vero and C6/36 cells and triggered overt clinical symptoms in suckling mice after intracerebral inoculation, causing mortality of 100% and 25%. Cross-sectional epidemiology analysis revealed silent circulation of TIBOV in Yunnan Province with overall prevalence of 16.4% (18/110) in cattle, 10.8% (13/120) in goats and 5.5% (6/110) in swine. The prevalence patterns of four investigated TIBOV serotypes (TIBOV-1, -2, -5 and 6) differed from each one another, with their positive rates ranging from 8.2% (9/110) for TIBOV-2 in cattle to 0.9% (1/110) for TIBOV-1 and TIBOV-5 in cattle and swine. Our findings provided new insights for diversity, pathogenicity and epidemiology of TIBOV and formed a basis for future studies addressing the geographical distribution and the zoonotic potential of TIBOV.

Objective: In this study vagus nerve stimulation (VNS) was used in mouse ischemic stroke model to observe its effects on the proliferation of vascular endothelial cells and gliogenesis, and to explore the potential protective mechanism of VNS on ischemic stroke angiogenesis. Methods: 80 male C57BL/6J mice were randomly divided into four groups: A: Sham+VNS group; B: pMCAO+VNS group; C: pMCAO +VNI group D: Sham group. The behavioral changes of mice were monitored after operation. Laser speckle Doppler imager was used to detect the cerebral blood flow and blood vessel density of mice at 6 hours, 3 days, 7 days and 14 days after operation. Evans Blue method was used to measure blood-brain barrier integrity, the ratio of dry and wet weight of brain tissue was measured to measure the degree of edema in the brain tissue of mice in each group, CD31/Ki67, GFAP/Ki67, and Ibal/Ki67 were identified by immunofluorescence method to label new vascular endothelial cells and new glial cells, The expressions of angiogenic factors such as endothelial nitric oxide synthase (eNOS), brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) were detected by Elisa Kits.Results: 1. VNS treatment can effectively improve neurological deficit scores of the stroke mice after VNS treatment at 7 days, 14 days and 21 days (PConclusion: VNS can improve the nerve injury of ischemic stroke by regulating vascular endothelial cell regeneration and glial cell remodeling, and provide guidance for further exploration of stroke neuroprotection.

In July 2019, a novel viral strain (JH2019C603) was isolated from sentinel cattle in Jinghong City, in the subtropical region of Yunnan Province, China. The virus replicated and caused cytopathological effects in both Aedes albopictus (C6/36) and Baby Hamster Syrian Kidney (BHK-21) cells. Agarose gel electrophoresis analysis revealed a viral genome comprised of 10 segments of double-stranded RNA, with a 1-2-2-1-1-1-1-1 migration pattern. Complete genome sequences of the JH2019C603 virus were determined through full-length cDNA amplification. Phylogenetic analysis based on the amino acid (aa) sequences of RNA-dependent RNA Polymerase (Pol), Major subcore (T2) and Major core-surface (T13) showed that JH2019C603 clustered with Yonaguni orbivirus (YONOV) from Japan, with aa identities relative to YONOV of 97.7% (Pol), 99.0% (T2) and 98.5% (T13). However, phylogenetic analysis based on the aa sequences of the outer capsid protein one and two (OC1 and OC2) showed that JH2019C603 formed an independent branch in the phylogenetic tree, and its aa identity with YONOV was only 55.4% (OC1) and 80.8% (OC2), respectively. Compared with the prototype of YONOV, a notable sequence deletion was observed in the 3' non-coding region of NS1, with the NS1 of JH2019C603 encoded within segment 7 (Seg-7), in contrast to YONOV, which contains NS1 in Seg-6. These results indicate that JH2019C603 belongs to the YONOV lineage and might be a novel serotype or a highly variant strain of YONOV. These findings will facilitate the identification of new isolates and clarify their geographical distribution, epidemiology, genetic diversity and possible disease associations.

No detailed quantitative global, regional, or national estimates of the disability-adjusted life years (DALYs) of type 2 diabetes mellitus (T2DM) are available.We used data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 to estimate the global, regional, and national incidence rates and DALYs of T2DM, as well as the associated risk factors, in all 194 countries and territories by age, sex, and sociodemographic status during the period from 2007 to 2017.Globally, the age-standardized incidence and DALY rates increased by 3.23% and 5.07% during 2007 to 2017, respectively. The age-standardized incidence and DALY rates in 2017 and the corresponding percentage changes during 2007 to 2017 were highest in the low-middle sociodemographic index (SDI) quintile. Regionally, the highest 2017 age-standardized incidence and DALY rates were observed in Oceania, whereas the largest percentage increases in both rates during 2007 to 2017 were observed in Southeast Asia. Nationally, Iran, the United Kingdom, and Indonesia reported the largest percentage increases in the age-standardized incidence rates, whereas Georgia, Czech Republic, and Iran showed the largest percentage increases in the age-standardized DALY rates. Globally, the largest percentage increases in risk-attributable DALYs were associated with a high body mass index, low physical activity level, high fasting plasma glucose level, and high sugar-sweetened beverage and red meat consumption.The global T2DM age-standardized incidence and DALY rates increased globally between 2007 and 2017, especially in the low-middle SDI quintile, Southeast Asia.背景: 目前尚无关于2型糖尿病 (T2DM) 的残疾调整生命年 (DALY) 的详细的全球、区域或国家定量估计值。 方法: 我们使用 2017 年全球疾病负担、伤害和风险因素研究 (GBD) 的数据来估计所有 194个国家的 T2DM 发病率和 DALYs 以及 2007 年至 2017 年期间按年龄、性别和社会人口状况划分的地区相关的风险因素。 结果: 在全球范围内, 2007年至 2017年的年龄标准化发病率和 DALY 率分别增加了 3.23% 和 5.07%。 2017 年的年龄标准化发病率和 DALY 率以及 2007 年至 2017 年期间的相应百分比变化在中低收入国家中最高。从区域来看, 2017 年年龄标准化发病率和 DALY 率最高的是大洋洲, 而 2007 年至 2017 年期间, 东南亚的百分比增幅最大。在全国范围内, 伊朗、英国和印度尼西亚的年龄标准化发病率百分比增幅最大, 而格鲁吉亚、捷克共和国和伊朗的年龄标准化 DALY 比率增幅最大。在全球范围内, 可归因于风险的 DALY 的最大百分比增加与高体重指数、低体力活动水平、高空腹血糖水平以及高含糖饮料和红肉消费相关。 结论: 2007 年至 2017 年间, T2DM 年龄标准化发病率和 DALY 率在全球范围内增加, 尤其是在东南亚中低收入国家。.

This article presents an analytical and coherent design method for the generalized high-efficiency broadband parallel-circuit (PC) Class-E/F 3 power amplifier (PA). By importing the initial phase shift of the third harmonic and adding series reactive element to the load network, a free design parameter can be defined and the design space of the load network parameters are expanded. The design equations of the idealized waveforms and the optimum values of the load network components are derived in detail, and the performance of the peak drain voltage, maximum operating frequency, and power output capability can be improved. In addition, with the expanding space of load network, the generalized PC Class-E/F 3 structure exhibits broadband capability. A matching method with the real frequency technique (RFT) and the de-embedding technique is presented to design the optimal broadband matching network. To verify the validity of the proposed method, a broadband high-efficiency PA working from 1.7 to 2.6 GHz (fractional bandwidth of 42%) is designed. The experimental results of the fabricated PA present high-efficiency characteristics of 68.5%-81% drain efficiency and 62%-75.8% power-added efficiency with 38.8-40.5 dBm output power over the whole operation bandwidth.

According to the laws of thermodynamics, materials normally exhibit contraction or expansion along the directions of the applied pressure or tension. Here, we show that a man-made cocrystal of a me ...

Summary We studied the efficacy and safety of humanized CAR‐T therapy following intensive chemotherapy for refractory/relapsed (R/R) acute lymphoblastic leukaemia (B‐ALL). Twenty‐three patients with R/R B‐ALL were pretreated with intensive chemotherapy (fludarabine combined with medium‐dose cytarabine) 12 days before CAR‐T therapy. Adverse events (AEs), curative effects, infection indicators and cytokine release syndrome (CRS) were monitored. Each of the 23 patients received a dose of 1·0 × 106 cells/kg CAR‐T cell infusion on day 0. After 14 days, 19 patients (82·61%) achieved complete response (CR) or CR with incomplete count recovery. No survival benefit was achieved with consolidative haematopoietic stem‐cell transplantation (HSCT), with a median follow‐up of 14·0 months (range, 1·5–21·0 months). The notable AEs were grade 1–2 CRS in 18 patients, while the other five patients were grade 3 CRS. No patients died of CRS. Only one patient died of respiratory failure due to cytomegalovirus infection 24 days after infusion. The proportion of leukaemic cells in bone marrow on infusion day and the peaks of IL‐6, TNF‐α and IL‐8 levels were correlated with CRS levels. A lower disease burden was achieved by intensive lymphodepleting chemotherapy, and the subsequent CAR‐T therapy had a high response and manageable toxicity. Trial registration: The patients were enrolled in a clinical trial of ChiCTR‐ONN‐16009862, and ChiCTR1800019622.

Purpose Fractures of the humeral shaft, especially the treatment of extraarticular fractures of the distal third of the humerus, which is a challenge. We hypothesize that a new feasibility and safety minimally invasive surgical approach can be used for the treatment of middle-and distal-third humeral fractures. The main purpose of this study was to evaluate this new approach and develop it.Methods In 13 adult cadaver arms, a minimally invasive surgical approach to the anteromedial humerus was simulated, followed by fixation with a locking compression plate and the measurement of several sets of anatomical data to clarify the possible risk of iatrogenic vascular and nerve injury in this surgical approach. Between 2017 and 2019 in 18 patients with humeral fractures who were treated with this surgical approach.Results Patients were followed for average 20.1 months (range, 15 – 34 months). The distance from the vertex of the medial epicondyle to the median nerve was 2.96 cm (range, 2.30 – 3.40 cm). The distance from the tip of the distal end of the screw in the medial epicondyle to the ulnar nerve was 1.7 mm (range, 0.00 – 4.00 mm). The shortest distance between the Olecranon Fossa and the tip of the screws at the distal end of the plate in the medial humeral epicondyle was 0.69 mm (range, 0.00 – 7.00 mm). The distance from the vertex of the epicondyle to the intersection of the median nerve and the distal end of the underlying steel plate was 6.28 cm (range, 5.70 – 6.90 cm).Conclusions This approach does not cause iatrogenic neurovascular injury and provides sufficient strength for the fixation of fractures of the middle and distal thirds of the humerus. This approach can be used as an alternative in the treatment of extraarticular fractures of the middle and distal thirds of the humerus.Type of study/level of evidence Therapeutic Level IV.

Hengshuai Zhang, Xingyou Dong, Zhenxing Yang, Jiang Zhao, Qudong Lu, Jingzhen Zhu, Longkun Li, Shanhong Yi, Jie Xu Department of Urology, Second Affiliated Hospital, Army Medical University, Chongqing, 400037, People’s Republic of ChinaCorrespondence: Jie Xu; Shanhong YiDepartment of Urology, Second Affiliated Hospital, Army Medical University, Chongqing, 400037, People’s Republic of ChinaEmail xujie1981@tmmu.edu.cn; 2644057844@qq.comBackground: Cross-sensitization of pelvic organs is one theory for why symptoms of gut sickness and interstitial cystitis/bladder pain syndrome overlap. Experimental colitis has been shown to trigger bladder hyperactivity and hyperalgesia in rats. The chemokine receptor CXCR4 plays a key role in bladder function and central sensitization. We aim to study the role of CXCR4 and its inhibitor AMD3100 in colon-bladder cross-organ sensitization.Methods: The colitis model was established by rectal infusion of trinitrobenzene sulfonic acid. Western blot and immunofluorescence were used to assess the expression and distribution of CXCR4. Intrathecal injection of AMD3100 (a CXCR4 inhibitor) and PD98059 (an ERK inhibitor) were used to inhibit CXCR4 and downstream extracellular signal-regulated kinase (ERK) in the spinal cord and dorsal root ganglion (DRG). Intravesical perfusion of resiniferatoxin was performed to measure the pain behavior counts of rats, and continuous cystometry was performed to evaluate bladder voiding function.Results: Compared to the control group, CXCR4 was expressed more in bladder mucosa and colon mucosa, L6-S1 dorsal root ganglion (DRG), and the corresponding segment of the spinal dorsal horn (SDH) in rats with colitis. Moreover, intrathecal injection of the AMD3100 suppressed bladder overactivity, bladder hyperalgesia, and mastocytosis symptoms caused by colitis. Furthermore, AMD3100 effectively inhibited ERK activation in the spinal cord induced by experimental colitis. Finally, treatment with PD98059 alleviated bladder overactivity and hyperalgesia caused by colitis.Conclusion: Increased CXCR4 in the DRG and SDH contributes to colon inflammation-induced bladder overactivity and hyperalgesia partly via the phosphorylation of spinal ERK. Treatment targeting the CXCR4/ERK pathway might provide a potential new approach for the comorbidity between the digestive system and the urinary system.Keywords: pain, visceral hypersensitivity, sensory afferents, urgency, colitis, ERK

Epizootic hemorrhagic disease virus (EHDV) is a member of the genus Orbivirus, family Sedoreoviridae. It was firstly recognized in 1955 to cause a highly fatal disease of wild white-tailed deer in America. So far, EHDV was detected and isolated in many wild or domestic ruminants, and widely distributed all over the world. Although the domestic cattle and sheep infected by EHDV were usually asymptomatic or subclinical, several outbreaks of epizootic hemorrhagic disease (EHD) in deer and cattle had been reported. Many EHDV strains were isolated and sequenced in last two decades in China, which promoted a general serologic investigation of EHDV in China. In this study, 18,122 sera were collected from asymptomatic or subclinical domestic ruminants (cattle, cow, yaks, sheep, goats, and deer) in 116 regions belonging to 15 provinces in China. All the sera were tested by EHDV C-ELISA, and the results were obtained by big data analysis. EHDV infections were detected in the 14 of 15 provinces, and only Tibet (average altitude ≥ 4000 ​m) which was the highest province in China was free of EHDV. The numbers of seropositive collections in both bovine and goat/sheep were in an inverse proportion to the latitude. However, the seropositive rates in bovine were ranged from 0% to 100%, while the seropositive rates in goat/sheep were no more than 50%. The results suggested that bovine was obviously more susceptive for EHDV infection than goat and sheep, therefore might be a major reservoir of EHDV in China. The prevalence of EHDV was consistent with the distribution of Culicoides which were known as the sole insect vectors of EHDV. In particular, the seropositive rates of EHDV were very high in the southern provinces, which required the enhanced surveillance in the future.

This study aimed to investigate whether histopathological confirmed extramural vascular invasion (EMVI) is associated with quantitative parameters derived from dual-energy computed tomography (DECT) of rectal cancer.This retrospective study included patients with rectal cancer who underwent rectal cancer surgery and DECT (including arterial-, venous-, and delay-phase scanning) between November 2019 and November 2020. The EMVI of rectal cancer was confirmed via postoperative pathological results. Iodine concentration (IC), IC normalized to the aorta (NIC), and CT attenuation values of the three phases were measured and compared between patients with and without EMVI. Receiver operating characteristic (ROC) curves were generated to determine the diagnostic performance of these DECT quantitative parameters.Herein, 36 patients (22 men and 14 women) with a mean age of 62 [range, 43-77] years) with (n = 13) and without (n = 23) EMVI were included. Patients with EMVI exhibited significantly higher IC in the venous and delay phases (venous-phase: 2.92 ± 0.6 vs 2.34 ± 0.48; delay-phase: 2.46 ± 0.47 vs 1.88 ± 0.35) and NIC in all the three phases (arterial-phase: 0.31 ± 0.12 vs 0.24 ± 0.06; venous-phase: 0.58 ± 0.11 vs 0.41 ± 0.07; delay-phase: 0.68 ± 0.10 vs 0.46 ± 0.08) than patients without EMVI. Among them, the highest area under the ROC curve (AUC) was obtained in the delay-phase NIC (AUC = 0.983). IC in the arterial-phase and CT attenuation in all the three phases did not significantly differ between patients with and without EMVI (p = 0.205-0.869).Iodine quantification using dual-energy CT, especially the NIC of the tumor, differs between the EMVI-positive and EMVI-negative groups and seems to help predict the EMVI of rectal cancer in this preliminary study; however, a larger sample size study is warranted in the future.

The present study aimed to compare the differences between the humanized CD19 chimeric antigen receptor (CAR)-T cell therapy and the murine CD19 CAR-T therapy in recurrent B-acute lymphoblastic leukemia (B-ALL). A 62-year-old male patient who had B-ALL (BCR/ABL+) for 4 years was diagnosed with relapsed central nervous system leukemia (CNSL). After several courses of high dose methotrexate combined with intrathecal chemotherapy, the patient received murine CD19 CAR-T therapy and achieved complete response (CR). The patient was diagnosed with relapsed CNSL again 15 months after his murine CD19 CAR-T therapy, and was therefore enrolled in the humanized CD19 CAR-T therapy. Subsequently, the present study aimed to compare murine and humanized CD19 CAR-T cells against Nalm-6 cells in vitro and in mice. The patient initially achieved CR from his murine CD19 CAR-T therapy with Grade 1 cytokine-release syndrome (CRS) and Grade 1 CAR-T cell-related encephalopathy syndrome (CRES). The patient then achieved CR again from his humanized CD19 CAR-T therapy with Grade 1 CRS and Grade 2 CRES. Peak levels of CD19 CAR-T cells were higher in humanized CD19 CAR-T therapy than those in murine CD19 CAR-T therapy 7 days after infusion in the peripheral blood, in bone marrow and in cerebrospinal fluid (CSF). The cytokine levels were higher in humanized CD19 CAR-T therapy than those in murine CD19 CAR-T therapy in the peripheral blood and in CSF. The cytotoxicity to Nalm-6 cells was higher in humanized CD19 CAR-T cells than that in murine CD19 CAR-T cells in vitro. In Nalm-6 BALB/c mice, the median survival time of mice in the murine CD19 CAR-T group was 35 days, while it was 43 days in the humanized CD19 CAR-T group. In conclusion, humanized CD19 CAR-T cell therapy had a better curative effect than that of murine CD19 CAR-T therapy, and may be used as a salvage treatment for recurrent B-ALL after treatment with murine CD19 CAR-T therapy.

Human urine-derived stem cells (hUSCs) show multipotential differentiation ability and can differentiate into mesodermal cell lineages. Interstitial cells of Cajal-like cells (ICC-LCs) are crucial for the pace-making function of spontaneous contraction in the bladder. However, the mechanisms by which hUSCs generate ICC-LCs have not been elucidated. In this study, we developed a strategy for directional differentiation of hUSCs into ICC-LCs. hUSCs were transfected with lentiviral vectors encoding c-Kit, stem cell factor (SCF), hyperpolarization activated cyclic nucleotide gated potassium channel 4 (HCN4), and 5-azacytidine induced 2 (AZI2) genes, and the cells were cultured for an additional 7 days in specific medium. The expression of the surface marker c-Kit on ICC-LCs was determined at 7 days after transfection. hUSCs were successfully expanded and transfected with the four lentiviral vectors. hUSCs transfected with lentiviral-c-Kit, lentiviral-HCN4, and lentiviral-AZI2 showed higher expression of c-Kit 7 days after transfection, but only the lentiviral-HCN4-transfected cells showed morphological alterations in ICC-LCs. These cells also displayed visible HCN current amplitude and density. This approach may provide a new strategy for the treatment of underactive bladder.

The protein corona on nano drug carriers is an important well-known biological issue that often induces biological incompatibility and screens the targeting molecules on the surfaces of carriers, thus causing a loss of targeting specificity. Although polyethylene glycol (PEG) and zwitterionic polymers have been widely used as anti-fouling materials, there still remain critical challenges for their use as protein-corona agents for drug delivery and targeting. Here, we have designed novel amphoteric natural starch-stabilized core-shell colloidal nanoparticles with more efficient protein corona-free properties, under long term circulation, at different protein concentrations and in different protein charge environments, compared to typical anti-fouling materials such as PEG and zwitterionic polymers. More importantly, the starch-coated polymer nanoparticles can be further functionalized by antibodies to achieve additional excellent targeting and cell internalization capabilities for their use in photodynamic therapy. Our findings demonstrate a novel protein-free or anti-fouling natural material that is very promising for use as highly efficient nano drug carriers and marine coatings.

We show that the photoluminescence (PL) emission color of few layered g-C3N4 (FL-CN) can be tuned from blue to yellow by applying pressure. FL-CN also exhibits an anomalous PL enhancement and obvious change in the light absorption at very low pressure. Further studies reveal that the increase of pressure-induced interlayer interactions affects the charge separation of photo-induced electrons and holes and thus leads to PL enhancement. An obvious decrease in interlayer compressibility probably due to interlayer stacking transition in FL-CN has been observed at above 3 GPa, which becomes less compressible than that of graphite, accompanied by obvious PL intensity weakening and emission band broadening. The results suggest that interlayer interactions may play dominant roles in the optical properties of FL-CN, shedding new insights into our understanding on PL engineering in g-C3N4.

Crystallized black phosphorus-graphite (BP-G) composites with tunable phosphorus carbon (P C) bonds have been prepared by a facile high pressure and high temperature (HPHT) method. It is found that P C bonds were formed between phosphorus and graphene layers, and their concentration can be tuned by controlling the ratio of the two precursors (i.e., red phosphorus and graphitic carbon nitride). The maximum content of P C bond is ∼13.3% in the obtained composites by HPHT treatment, which reaches the highest record reported previously by other methods. Meanwhile, by combining theoretical calculation with experiment, we studied the bonding sites of P C bonds, and also the effect of P C bonds on the cycling performance of crystallized BP-G composites, which sheds new insights into our understanding on the electrochemical performance of phosphorus/carbon materials.

Atherosclerotic diseases are systemic and patient outcomes depend on comprehensive imaging evaluation. Computed tomography angiography (CTA) is a powerful tool used to assess atherosclerosis. However, the scanning protocol is designed for cardiovascular and cerebrovascular imaging, which require considerations into the radiation dose, contrast agent and image quality. The purpose of the present study was to evaluate ultra-low dose one-step CTA for coronary, carotid and cerebral arteries with a low concentration contrast agent. A total of 78 patients were enrolled and randomly divided into two groups: Group A (n=38) and B (n=40). High-pitch CTA for coronary, carotid and cerebral arteries with a tube voltage of 70 or 80 kVp and 40 ml contrast agent (270 mgI/ml) was performed by a 128-slice dual-source CT scanner for group A. Standard high-pitch CTA with a tube voltage of 100 kVp and 60 ml contrast agent (370 mgI/ml) was conducted for group B. The image quality, radiation dose and amount of contrast agent in group A were evaluated and compared with group B. The dose length product for groups A and B was 62.95±21.54 vs. 160.15±15.13 mGy cm, respectively (t=-23.157, P

Background Epizootic haemorrhagic disease virus (EHDV) and the Palyam serogroup viruses (PALV) have led to significant economic losses associated with livestock production globally. A rapid, sensitive and specific method for the detection of EHDV and PALV is critical for virus detection, monitoring, and successful control and elimination of related diseases. Results In the present study, a recombinase polymerase amplification combined with lateral flow dipstick (RPA-LFD) assay for the co-detection of genome segment 1 (Seg-1) of EHDV and PALV was developed and evaluated. The analytical sensitivities of the established RPA-LFD assay in the detection of EHDV and PALV were 7.1 copies/µL and 6.8 copies/µL, respectively. No cross-reaction with other members of the genus Orbivirus, including African horse sickness virus, bluetongue virus, Guangxi orbivirus, Tibet orbivirus and Yunnan orbivirus was observed. The established RPA-LFD assay accurately detected 39 EHDV strains belonging to 5 serotypes and 29 PALV strains belonging to 3 serotypes. The trace back results of quantitative real-time polymerase chain reaction (qRT-PCR) and the established RPA-LFD assay on sentinel cattle were consistent. The coincidence rates of qRT-PCR and the established RPA-LFD assay in 56 blood samples from which EHDV or PALV had been isolated and 96 blood samples collected from cattle farms were more than 94.8 %. The results demonstrated that the established RPR-LFD assay is specific, sensitive and reliable, and could be applied in early clinical diagnosis of EHDV and PALV. Conclusions This study highlights the development and application of the RPA-LFD assay in the co-detection of EHDV and PALV for the first time. The assay could be used as a potential optional rapid, reliable, sensitive and low-cost method for field diagnosis of EHDV and PALV.

Hemorrhagic cystitis is an important complication of cyclophosphamide chemotherapy, and current therapies for the disease are limited. The natural flavonoid luteolin (LUT) has significant anti-inflammatory and antioxidant properties, but its protective effect on cyclophosphamide (CYP)-induced bladder toxicity has yet to be evaluated. This study aims to explore the protective effect of LUT on CYP-induced acute cystitis in rats. Female Sprague-Dawley rats were randomly assigned to the control (CON) group, CON + LUT group, CYP group, and CYP + LUT group. A single intraperitoneal injection of CYP was administered to establish an acute hemorrhagic cystitis model. HE staining was performed to detect the degree of bladder tissue damage, and TUNEL staining was performed to count apoptotic cells. Oxidative stress indicators were measured using commercial kits, and bladder surgery was performed to assess urinary function. The levels of inflammatory cytokines, apoptosis-related indicators, TXNIP/NLRP3 pathway, and NF-κB pathway were detected by western blot. We found that LUT treatment reduced bladder bleeding, congestion, and edema caused by CYP. Compared with the CYP + LUT group, the level of apoptosis was more highly expressed in the CYP group. We also found that caspase-3, caspase-8, and Bax were significantly upregulated and Bcl-2 was downregulated after LUT treatment. In addition, LUT inhibited the activation of NF-κB signal pathway in the rat bladder tissue after CYP exposure. LUT treatment can also reduce the NLRP3 inflammasome (NLRP3, ASC, and caspase-1) and TXNIP in the bladder. Finally, LUT can reduce the increase in the urination frequency and maximum urination pressure caused by cystitis. These results indicate that LUT displays effective anti-inflammatory, antioxidant, and antiapoptotic properties in CYP-induced acute hemorrhagic cystitis rats by inhibiting the TXNIP/NLRP3 and NF-κB pathways. LUT may be a potent therapeutic agent for the prevention and treatment of hemorrhagic cystitis.

We consider the dynamics of point particles which are confined to a bounded, possibly nonconvex domain $\Omega$. Collisions with the boundary are described as purely elastic collisions. This turns the description of the particle dynamics into a coupled system of second order ODEs with discontinuous right-hand side. The main contribution of this paper is to develop a precise solution concept for this particle system, and to prove existence of solutions. In this proof we construct a solution by passing to the limit in an auxiliary problem based on the Yosida approximation. In addition to existence of solutions, we establish a partial uniqueness theorem, and show by means of a counterexample that uniqueness of solutions cannot hold in general., Comment: 21 pages

The congenital intellectual disability (ID)-causing gene mutations remain largely unclear, although many genetic variations might relate to ID. We screened gene mutations in Chinese Han children suffering from severe ID and found a single-nucleotide polymorphism (SNP) in the 5′-untranslated region (5′-UTR) of fibroblast growth factor 13 (FGF13) mRNA (NM_001139500.1:c.-32c>G) shared by three male children. In both HEK293 cells and patient-derived induced pluripotent stem cells, this SNP reduced the translation of FGF13, which stabilizes microtubules in developing neurons. Mice carrying the homologous point mutation in 5′-UTR of Fgf13 showed delayed neuronal migration during cortical development, and weakened learning and memory. Furthermore, this SNP reduced the interaction between FGF13 5′-UTR and polypyrimidine-tract-binding protein 2 (PTBP2), which was required for FGF13 translation in cortical neurons. Thus, this 5′-UTR SNP of FGF13 interferes with the translational process of FGF13 and causes deficits in brain development and cognitive functions.

Transient receptor potential canonical 3 (TRPC3) is a nonselective cation channel, and its dysfunction is the basis of many clinical diseases. However, little is known about its possible role in the bladder. The purpose of this study was to explore the function and mechanism of TRPC3 in partial bladder outlet obstruction (PBOO)-induced detrusor overactivity (DO). We studied 31 adult female rats with DO induced by PBOO (the DO group) and 40 sham-operated rats (the control group). Here we report that the expression of TRPC3 in the bladder of DO rats increased significantly. Furthermore, PYR10, which can selectively inhibit the TRPC3 channel, significantly reduced bladder excitability in DO and control rats, but the decrease of the bladder excitability of DO rats was more obvious. PYR10 significantly reduced the intracellular calcium concentration in smooth muscle cells (SMCs) in DO and control rats. Finally, Na

Qing Li,1 Juan Mu,1 Jijun Yuan,2 Zhenxing Yang,2 Jia Wang,1 Qi Deng1 1Department of Hematology, Tianjin First Central Hospital, Tianjin 300192, People’s Republic of China; 2Medical Department, Shanghai Genbase Biotechnology Co., Ltd, Shanghai 201203, People’s Republic of ChinaCorrespondence: Qi Deng Email kachydeng@126.comPurpose: To investigate the donor chimerism changes and curative effects associated with the use of autologous anti-CD19 chimeric antigen receptor (CAR) T cells with B-cell acute lymphoblastic leukemia (B-ALL) presenting with a low donor chimerism level and relapse after allogeneic hematopoietic stem cell transplant (allo-HSCT).Methods: Nine patients with B-ALL showing low donor chimerism level and relapse after allo-HSCT were enrolled. Patients 1– 3 received CD19 CAR-T cell therapy using cells derived from autologous peripheral blood mononuclear cells (PBMCs) (comprising a mixture of patient and original donor cells) as their donors could not provide PBMCs. Samples from the other six patients (Patients A–F) were investigated only in vitro. The changes in the degree of donor chimerism, function of the CD19 CAR-T cells and T cells in all nine patients were analyzed in vitro. The therapeutic effects and adverse events (AEs) were also evaluated in Patients 1– 3.Results: The CAR-T cells and T cells in all nine patients showed complete donor chimerism restoration following a 12-day culture period in vitro. These CD19 CAR-T cells demonstrated strong cytotoxicity towards Nalm 6 cells in vitro except in patients 3 and D. In the latter patients, the absolute numbers of all subsets, especially the CD8 + T-cell absolute numbers in peripheral blood were very low. Patients 3 and D showed relatively short durations from transplant to recurrence and received chemotherapy after relapse. In the patients receiving CD19 CAR-T cell therapy, the most commonly observed AE was grade 1 to 2 cytokine release syndrome. None of the cases showed acute graft-versus-host disease during treatment. Patients 1 and 2 achieved complete response with complete restoration of donor chimerism. Patient 3, who received the same CD19 CAR-T cell therapy, did not respond to this therapy.Conclusion: CD19 CAR-T cells derived from patients relapsed after allo-HSCT with a low level of donor chimerism were effective for salvage therapy and could restore to complete donor chimerism after 12 days’ culture in vitro.Trial Registration: Humanized CD19 CAR-T cell therapy for relapse or refractory B-cell lymphoma or acute B lymphocytic leukemia, ChiCTR1800019622, Registered 24 November 2018, http://www.chictr.org.cn/index.aspx.Keywords: chimeric antigen receptor, acute lymphoblastic leukemia, allogeneic hematopoietic stem cell transplant, relapse, donor chimerism

Bluetongue virus (BTV) is the 'type' species of the genus Orbivirus causing bluetongue (BT) in sheep, bovine and other ruminants. Twenty-four serotypes and several atypical serotypes of BTV were identified worldwide. In present study, a novel strain of BTV (V196/XJ/2014) was isolated from an asymptomatic sentinel goat in Yuli County, Xinjiang of China. Serotype identification of this isolate exhibited uniform negative results by serotype-specific conventional RT-PCR and real-time RT-PCR for BTV-1 to BTV-27, and virus neutralization tests using reference sera of BTV-1 to BTV-24. Genomic analysis showed V196/XJ/2014 grouped with atypical serotypes of BTV-25 to BTV-28, BTV-X/XJ1407, BTV-X/ITL2015 and BTV-Y/TUN2017, while segment 2 and VP2 protein of V196/XJ/2014 shared

Backgrounds:The mechanism underlying bladder urination pathophysiologies has not been understood yet because the types of interstitial cells present in the bladder are still obscure. Results:Here, we classified the cell types in the bladder without bias using 10x genomics single-cell RNA-seq and identified 35,510 and 19,946 cells from human and rat bladder tissues, respectively. In addition to the major cell clusters including urothelial cells, smooth muscle cells, endothelial cells, neurons, and immune cells, three types of interstitial cells were identified in this study. Fibroblasts and myofibroblasts were shown to occupy large proportions of interstitial cells, located mainly between the epithelial strata and muscle strata. A new type of interstitial cell, Mki67+, which was found both in human and rat bladder tissues, may participate in bladder disease development. Conclusions:Our investigation thus lays the ground work for identifying the cell types in bladder tissues and provides potential clues to understand abnormal bladder functions.

The congenital intellectual disability (ID)-causing gene mutations remain largely unclear, although many genetic variations might relate to ID. We screened gene mutations in Chinese Han children suffering from severe ID and found a single-nucleotide polymorphism (SNP) in the 5′-untranslated region (5′-UTR) of fibroblast growth factor 13 (FGF13) mRNA (NM_001139500.1:c.-32c>G) shared by three male children. In both HEK293 cells and patient-derived induced pluripotent stem cells, this SNP reduced the translation of FGF13, which stabilizes microtubules in developing neurons. Mice carrying the homologous point mutation in 5′-UTR of Fgf13 showed delayed neuronal migration during cortical development, and weakened learning and memory. Furthermore, this SNP reduced the interaction between FGF13 5′-UTR and polypyrimidine-tract-binding protein 2 (PTBP2), which was required for FGF13 translation in cortical neurons. Thus, this 5′-UTR SNP of FGF13 interferes with the translational process of FGF13 and causes deficits in brain development and cognitive functions.