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Abstract Background Chronic graft-versus-host disease (cGVHD) is an immune-related disorder that is the most common complication post-allogenic hematopoietic stem cell transplant. Corticosteroids with or without calcineurin inhibitors (CNIs) remain the mainstay of cGVHD treatment for first-line therapy. However, for many patients, cGVHD symptoms cannot be effectively managed and thus require second-line therapy. Currently, there is no approved treatment for second-line cGVHD treatment in China. In this study, belumosudil, a highly selective and potent rho-associated coiled-coil-containing protein kinase-2 inhibitor demonstrated to be effective for cGVHD in the United States and other Western countries, is investigated in patients with cGVHD in China for its overall benefit–risk balance. Methods This multicenter, open-label phase II study evaluated the safety, efficacy, and pharmacokinetics of oral belumosudil 200 mg once daily in cGVHD patients who had been treated with at least one line of systemic therapy in China. The primary endpoint was overall response rate (ORR); each individual patient’s response was assessed by the investigator using the 2014 National Institutes of Health consensus criteria. Secondary endpoints were duration of response (DOR), time to response (TTR), changes in Lee Symptom Scale (LSS) score, organ response rate, corticosteroid dose change, CNI dose change, failure-free survival, time-to-next-treatment, overall survival, and safety. Results Thirty patients were enrolled in the study with a median follow-up time of 12.9 months. ORR was 73.3% (95% confidence interval: 54.1–87.7%) and all responders achieved partial response. Median DOR among responders was not reached and median TTR was 4.3 weeks (range: 3.9–48.1). Fifteen patients (50.0%) achieved clinically meaningful response in terms of reduction in LSS score by ≥ 7 points from baseline. Corticosteroid and CNI dose reductions were reported in 56.7% (17/30) and 35.0% (7/20) of patients, respectively. Most treatment-emergent adverse events (TEAEs) were mild to moderate in severity, with 11 patients (36.7%) experiencing grade ≥ 3 TEAEs. The most common grade ≥ 3 TEAE was pneumonia (n = 5, 16.7%). Conclusions Belumosudil treatment demonstrated a favorable benefit–risk balance in treating cGVHD patients who previously have had standard corticosteroid therapy in China where approved second-line setting is absent. Trial registration ClinicalTrials.gov identifier NCT04930562.

Sleep can affect nonalcoholic fatty liver disease (NAFLD). We investigated the association between sleep duration, sleep quality, and NAFLD. From January to December 2018, 1,073 patients (age: 37.94 ± 10.88, Body Mass Index (BMI): 22.85 ± 3.27) were enrolled. Pittsburgh Sleep Quality Index Questionnaire and Munich Chronotype Questionnaire were used to assess sleep duration, quality, and habits. Ultrasonography was used to diagnose NAFLD. Multivariate logistic regression models were used to calculate the odds ratio (OR) and 95% confidence interval (CI) of the risk of NAFLD by different types of sleep duration and sleep quality. No significant differences in sleep time, sleep quality, and sleep habits between the NAFLD and the non-NAFLD groups were observed (P > 0.05). There was no correlation between sleep duration and NAFLD in the whole cohort. After adjusting for age, exercise, fasting plasma glucose, and BMI, the group with long sleep duration showed a decreased risk of NAFLD in men (OR = 0.01, 95% CI: 0.001–0.27, P = 0.032). However, in all four adjusted models, no correlation between sleep duration, quality, and NAFLD was found in women. In conclusion, sleep duration was significantly and negatively associated with NAFLD in men but not women. Prospective studies are required to confirm this association.

Aim: This analysis compared the impact of laparoscopic appendicectomy (LA) and open appendicectomy (OA) on treating adult perforated appendicitis (PA). Methods: Articles relating to LA and OA in treating PA were retrieved from databases including PubMed, Cochrane Library and Embase since their founding to January 2022. These articles were independently filtered based on the inclusion and exclusion criteria by two investigators. The quality of these articles was assessed and article data were extracted. Dichotomous data were presented in the form of odd's ratio (OR), whereas continuous data were in the form of weighted mean difference (WMD). The included articles reported at least one of the following outcomes: intra-abdominal abscess (IAA), wound infection, operative time, hospital stay and complications. Results: Three randomised control trials (198 LA cases vs. 205 OA cases) and 12 case − control trials (914 LA cases vs. 2192 OA cases) were included. This analysis revealed that although the IAA formation rate was similar in the LA and OA groups (OR: 1.28, 95% confidence interval [CI]: 0.87–1.88), the wound infection rate was lower in the LA group (OR: 0.38, 95% CI: 0.28–0.51). Furthermore, LA was associated with shorter hospital stay (WMD: −1.43 days, 95% CI: −2.33–−0.52) and fewer complications than OA (OR: 0.40, 95% CI: 0.28–0.57). Conclusion: LA has significant benefits in treating PA and is associated with better post-operative outcomes such as shorter hospital stay, lower incidence of wound infection and other complications. However, more studies with randomised and large-sample populations are still required to determine the clinical benefit of LA in treating PA.

Explosive emission cathodes are extensively used in high power microwave sources. Growing requirements are highlighted in the performance of the explosive emission cathode with the development of the high power microwave technology. In order to improve the emission properties of the graphite cathode, modifications using SiC particles or whiskers are carried out by the in situ chemical vapor reaction method. The experiments demonstrate that SiC whiskers accelerate the explosive emission turn-on speed of the graphite cathode for large field enhancement factors and improve the emission uniformity due to the surface flashover plasma generation mechanism. SiC particles increase the emission capability of the graphite cathode, possibly corresponding to the dielectric properties of SiC particles. These results suggest that the SiC whiskers modified graphite cathode is suitable for applications under low magnetic field and large emission area conditions, while the SiC particles modified graphite cathode has a brighter application prospect in the long-time stable operation.

Abstract Background The therapeutic value of targeted therapies in patients with lung cancer is reduced when tumours acquire secondary resistance after an initial period of successful treatment. However, the molecular events behind the resistance to targeted therapies in lung cancer remain largely unknown. Aims To discover the important role and mechanism of lncRNA BC in promoting tumor metastasis and influencing clinical prognosis of LUAD. Materials & Methods: Microarrays were used to screen a comprehensive set of lncRNAs with differential expression profiles in lung cancer cells. The functional role and mechanism of lncRNA were further investigated by gain‐ and loss‐of‐function assays. RNA pull‐down, protein assays, and mass spectrometry were used to identify proteins that interacted with lncRNA. TaqMan PCR was used to measure lncRNA in lung adenocarcinoma and adjacent nontumor tissues from 428 patients. The clinical significance of lncRNA identified was statistically confirmed in this cohort of patients. Results In this study, we show that the long non‐coding RNA BC009639 (BC) is involved in acquired resistance to EGFR‐targeted therapies. Among the 235 long non‐coding RNAs that were differentially expressed in lung cancer cell lines, with different metastatic potentials, BC promoted growth, invasion, metastasis, and resistance to EGFR‐tyrosine kinase inhibitors (EGFR‐TKIs), both in vitro and in vivo. BC was highly expressed in 428 patients with lung adenocarcinoma (LUAD) and high BC expression correlated with reduced efficacy of EGFR‐TKI therapy. To uncover the molecular mechanism of BC‐mediated EGFR‐TKI resistance in lung cancer, we screened and identified nucleolin and hnRNPK that interact with BC. BC formed the splicing complex with nucleolin and hnRNPK to facilitate the production of a non‐protein‐coding inositol monophosphatase domain containing 1 (IMPAD1) splice variant, instead of the protein‐coding variant. The BC‐mediated alternative splicing (AS) of IMPAD1 resulted in the induction of the epithelial–mesenchymal transition and resistance to EGFR‐TKI in lung cancer. High BC expression correlated with clinical progress and poor survival among 402 patients with LUAD. Disscussion Through alternative splicing, BC boosted the non‐coding IMPAD1‐203 transcript variant while suppressing the IMPAD1‐201 variant. In order to control the processing of pre‐mRNA, BC not only attracted RNA binding proteins (NCL, IGF2BP1) or splicing factors (hnRNPK), but also controlled the formation of the splicing‐regulator complex by creating RNA‐RNA‐duplexes. Conclusion Our results reveal an important role for BC in mediating resistance to EGFR‐targeted therapy in LUAD through IMPAD1 AS and in implication for the targeted therapy resistance.

A 70-day experiment was conducted to investigate the effects of mulberry leaf extract (MLE) on growth, proximate compositions, antioxidant and plasma biochemical parameters, and indices of non-specific immunity of largemouth bass (Micropterus salmoides) fed a high-starch diet. Two hundred eighty largemouth bass (initial body weight, 68.00 ± 0.19 g) were randomly fed seven diets: basal-starch diet (BSD; 8.88% starch), high-starch diet (HSD; 11.42% starch), and HSD diets supplemented with 0.05%, 0.10%, 0.20%, 0.50%, and 1.00% MLE (MLE1, MLE2, MLE3, MLE4, and MLE5, respectively). The results indicated that HSD and MLE did not significantly affect the growth performance of largemouth bass during the experimental period compared with that of the BSD, but the supplementation with more than 0.20% (MLE3, MLE4, and MLE5) MLE significantly decreased the hepatosomatic index (HSI) values, and 1.00% (MLE5) MLE significantly decreased the viscerosomatic index (VSI) values. The whole-body moisture of fish fed an HSD decreased significantly, while the whole-body lipid content increased significantly in the HSD group compared with the BSD group. Compared with HSD, MLE supplementation significantly decreased the moisture and lipid contents in the whole body. Supplementation with more than 0.20% MLE (MLE3, MLE4, and MLE5) significantly decreased the moisture content in the muscle. Supplementation with 1.00% MLE significantly decreased the content of hepatic and muscle glycogen. The malondialdehyde (MDA) content of the HSD group was significantly increased compared to that of the BSD group, whereas more than 0.10% (MLE2, MLE3, MLE4, and MLE5) MLE significantly decreased the MDA content. Additionally, the total antioxidant capacity (T-AOC), catalase (CAT), and glutathione peroxidase (GSH-Px) activities of MLE5 were significantly higher than those of the HSD group. The complement-3 (C3) content and globulin (GLB) in the plasma of the HSD group were significantly lower than those of the BSD group. Plasma C3 levels in the MLE3, MLE4, and MLE5 groups were significantly higher than those in the HSD group. In addition, glucose (GLU) levels in the MLE3, MLE4, and MLE5 groups were significantly lower than those in the HSD group. Supplementation with 0.50% (MLE4) MLE significantly increased the lysozyme (LYZ) content and decreased the activities of alanine transaminase (ALT) and aspartate transaminase (AST). Supplementation with 1.00% MLE significantly increased complement-4 (C4) and GLB contents and alkaline phosphatase (ALP) activity. Overall, these findings suggest that MLE could improve antioxidant capacity, immune function, and glycolipid metabolism, thereby alleviating the negative effects of a high-starch diet in M. salmoides.

Post-stroke cognitive impairment (PSCI) refers to a series of syndromes that meet the diagnostic criteria of cognitive impairment 6 months after stroke. PSCI seriously affects patients'ability of daily life activities and quality of life, hinders the comprehensive rehabilitation of stroke patients, and brings heavy burden to society and families. The clinical practice guidelines of PSCI rehabilitation based on evidence-based medicine are of great significance to standardize clinical diagnosis and treatment and optimize the clinical effects. The guidelines focus on the development of traditional Chinese medicine (TCM) standards of PSCI, give full play to the advantages of TCM, and devote themselves to the development of integrated traditional Chinese and western medicine rehabilitation measures to optimize the outcome of rehabilitation, so as to provide certain reference basis for the formulation of integrated traditional Chinese and western medicine diagnosis and treatment strategies for cognitive rehabilitation. The guidelines regulate PSCI in terms of terminology and definitions, clinical diagnostic criteria, rehabilitation evaluation criteria, rehabilitation treatment, etc., aiming to help clinicians and therapists determine the optimal intervention measures, synthesize relevant information, and maximize clinical efficacy. The guidelines consist of traditional rehabilitation, western rehabilitation and rehabilitation treatment of integrated traditional Chinese and western medicine, which explain concrete practice content and levels of evidence of various methods. The guidelines are of importance for scientific, systematic, validity and clinical applicability.

Neutrophils, known as an important part of the immune system, are the most abundant leukocyte population in peripheral blood, but excessive recruitment will lead to tissue/organ injury. RNA sequencing showed that ionizing radiation significantly increased the expression of characteristic genes of neutrophils in intestinal tissues compared with liver and lung tissues. By clearing neutrophils with an anti-Ly6G antibody, we found that neutrophil infiltration is critical for irradiation-induced intestinal injury. CXCR2 is a G-protein-coupled receptor that mediates the migration of neutrophils by combining with its ligands. Compared with observations in liver and lung tissues, we found that CXCR2 and its ligands, including CXCL1, CXCL2, CXCL3, and CXCL5, were all significantly upregulated in irradiated intestinal tissues. Further studies showed that SB225002, an inhibitor of CXCR2, could effectively inhibit the chemotaxis of neutrophils and tissue damage mediated by the CXCL-CXCR2 signalling pathway.

It has been widely assumed and proven that a firm’s research and development (R&D) investment is limited if the availability of cash flow is constrained. The purpose of this study is to verify the opposite proposition: whether firms invest heavily in R&D when more cash flow is available. This paper discusses the heterogeneous relationship between cash flow from different sources and the R&D investment of firms. The study divides the firm’s cash flow into three categories according to the business activities that generate firm finance: cash flow from operating activities (CFO), cash flow from investing activities (CFI), and cash flow from financing activities (CFF). On this basis, a dynamic R&D investment model is constructed, and the relevant data for Chinese listed firms are used for the empirical research. The study finds that Chinese listed firms do not necessarily spend more cash on R&D investment, even if the availability of cash flow is not constrained. For young firms, CFO and CFI do not significantly correlate with R&D investment, and CFF significantly negatively correlates with R&D investment. For mature firms, the correlations between cash flow generated from different activities and R&D investment are nonsignificant.

Radio frequency Ohmic loss due to non-ideal conductor boundaries seriously limits the performance of electronic devices. In this paper, the Ohmic losses of two simple models are calculated by particle-in-cell (PIC) simulation, which is also verified by theoretical calculation. Thereafter, based on PIC simulation, we have studied the variation of the Ohmic losses of relativistic backward wave oscillators (RBWOs) with operating frequency and material conductivity. The PIC simulation results show that as the frequency advances, the Ohmic losses of RBWOs deteriorate sharply. The power loss becomes non-negligible when compared with the output power. The loss-power ratio of a V-band RBWO made of stainless steel is over 25%. The non-negligible Ohmic loss can explain to some extent that the difference between the simulated and the experimental output power of the RBWO becomes apparent as the working frequency increases.

Drought is a major factor that influences the productivity of crops including wheat. However, drought tolerance is a complex trait involving many genes and cellular pathways. To help understand the complex regulatory mechanisms governing drought tolerance in wheat, we performed small RNA sequencing analysis in a highly drought-tolerant wheat variety (Triticum aestivum L. cv. XF 20). Experimental plants were cultivated in the presence of PEG6000 to induce drought stress, while control plants were grown in the absence of PEG6000. Sequencing results confirmed the expression of 199 previously reported miRNAs. We also identified 32 novel miRNAs in this species. The expression of 37 miRNAs was significantly affected by PEG6000-induced drought stress (27 upregulated, 10 downregulated), including 5 novel miRNAs. Degradome sequencing showed that 222 target gene mRNAs were cleaved by these miRNAs. The target genes identified by psRNATarget and degradome were all enriched in gene ontology categories. There were significant differences in the number of target genes regulated by differentially expressed miRNAs, especially in signal transducer, response to stress and antioxidant pathways. MiRNA targets that are known to be related to drought and/or stress response in plants included 6-phosphogluconate dehydrogenase, epoxide hydrolase, sucrose synthase and phytochrome and flowering time regulatory protein. Our results shed light on the molecular mechanisms of drought tolerance in wheat, and identify drought-responsive miRNAs and their targets in a drought-resistant variety. These results could be exploited to improve wheat and related plants, which is expected to be vital as agriculture addresses the consequences of climate change.

Misfolding and abnormal aggregation of α-synuclein (αSyn) have been shown to increase the risk of developing Parkinson's disease (PD). Finding some way to reduce the aggregation of αSyn is particularly important for the treatment of PD. The main route in prion-like αSyn spreading is the cholinergic innervated vagus nervous system and central cholinergic neurons. Since the degenerative changes and death of cholinergic neurons also run through the pathological process of PD, we hypothesize an involvement of the cholinergic system in αSyn aggregation. The α7 nicotinic acetylcholine receptors (α7-nAChRs) are one of the most abundant nAChRs in the mammalian brain. Using nicotine and a selective α7-nAChRs agonist PNU-282987, we found a protective effect of α7-nAChRs on the cell damage induced by αSyn-PFF (preformed fibrils) through inhibiting apoptotic cell death. We further discovered an additive effect of α7-nAChRs on the clearance of αSyn in normal and αSyn stably transduced SH-SY5Y cells. Moreover, using α7-nAChRs knockout mice, we noticed that α7-nAChRs deficiency increased the deposition of αSyn and aggravated the loss of dopaminergic neurons in a chronic MPTP mouse model of PD. Our findings for the first time indicated that α7-nAChRs activation exhibited a neuroprotective effect on αSyn pathology and aggregation by promoting the clearance of αSyn.

In the study of breakdown in high power microwave (HPM) devices, researchers pay attention to the plasma effects caused by material ablation under electron bombardment. In this paper, the destruction of material under the bombardment of electrons with a range of energies around 100 keV is investigated. The simulation results reveal that low-energy electrons are more likely to cause ablation damage to the material, with the location of maximal energy deposition density close to the material’s surface. The experiment has a good agreement with the simulation results. Compared with high-energy electrons, the damage traces bombarded by low-energy electrons are more serious, possessing the characteristics of large size and shallow depth. This abnormal physics phenomenon provides a reference for the breakdown of HPM devices and the surface treatment of materials by pulsed electron beams.

Intracellular adenosine monophosphate (AMP) is indispensable for cellular metabolic processes, and it is interconverted to ADP and/or ATP or activates AMP-activated protein kinase (AMPK). However, the specific biological function of extracellular AMP has not been identified. We evaluated the effect of extracellular AMP using in vivo and in vitro models of endotoxemia. We found that AMP inhibited inflammation and neutrophil activation in lipopolysaccharide (LPS)-induced endotoxemic mice. The effects of extracellular AMP were abolished by an adenosine 1 receptor (A1R) antagonist but were not influenced by inhibiting the conversion of AMP to adenosine (ADO), indicating that AMP inhibited inflammation by directly activating A1R. In addition, in vitro experiments using LPS-stimulated mouse neutrophils showed that AMP inhibited LPS-induced reactive oxygen species (ROS) production, degranulation, and cytokine production, while the effects were reversed by an A1R antagonist. Further research showed that AMP regulated LPS-stimulated neutrophil functions by inhibiting the p38 MAPK pathway. These findings were also confirmed in primary neutrophils derived from healthy human blood. Moreover, we collected serum samples from septic patients. We found that AMP levels were increased compared with those of healthy volunteers and that AMP levels were negatively correlated with disease severity. Together, these data provide evidence that extracellular AMP acts on A1R to suppress endotoxemia-induced inflammation by inhibiting neutrophil overactivation and that the p38 MAPK signaling pathway is involved.

The incidence of multiple myeloma in Asia has risen in the past 30 years. Lenalidomide, an IMiD immunomodulatory agent, has improved the overall survival in patients with relapsed/refractory multiple myeloma (RRMM) when used with dexamethasone versus dexamethasone alone. This observational registry (T-CC-MM-009; NCT01752075) assessed the safety and efficacy of lenalidomide plus dexamethasone in a large Chinese population of patients with RRMM. Methods: This registry followed the first 100 patients treated with lenalidomide plus dexamethasone in Taiwan. Patients were ≥18 years old and had ≥1 prior treatment. The recommended starting dose for the first four 28-day cycles was 25 mg lenalidomide on days 1–21 and 40 mg dexamethasone on days 1–4, 9–12, and 17–20. Thereafter, dexamethasone was given on days 1–4 only. The primary objective was safety; secondary objectives were efficacy, lenalidomide dosage, and reasons for discontinuation. Results: The median duration of treatment was 34.6 weeks, and 75.5% completed ≥3 cycles. Most patients (82.7%) experienced ≥1 treatment-related adverse event; the most commonly reported were neutropenia (23.5%), thrombocytopenia (19.4%), anemia (16.3%), fatigue (16.3%), and hypoesthesia (15.3%). Bleeding events (25.5% of patients) were mostly grade 1/2 (80%). Three patients (3%) had venous thromboembolic events. Two invasive second primary malignancies were reported; however, time to onset was

Abstract Background To assess the efficacy and safety of fruquintinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, in metastatic colorectal cancer (mCRC) patients. Methods A phase Ib open-label study and phase II randomized, placebo-controlled trial compared the efficacy of fruquintinib plus best supportive care (BSC) with placebo plus BSC in mCRC patients with ≥2 lines of prior therapies. The primary endpoint was progression-free survival (PFS). Results In the phase Ib study, 42 patients took fruquintinib 5 mg for 3 weeks on/1 week off. The median PFS was 5.80 months, and the median overall survival (OS) was 8.88 months. In the phase II study, 71 patients were randomized (47 to fruquintinib, 24 to placebo). PFS was significantly improved with fruquintinib plus BSC (4.73 months; 95% confidence interval [CI] 2.86–5.59) versus placebo plus BSC (0.99 months; 95% CI 0.95–1.58); (hazard ratio [HR] 0.30; 95% CI 0.15–0.59; P

Astrocytes, as the largest population of glial subtype, play crucial roles in normal brain function and pathological conditions, such as Parkinson’s disease (PD). Restoring the functions of astrocyte is a promising new therapeutic target for PD. Astrocytes can express multiple types of neurotransmitter receptors, including functional α7 nicotinic acetylcholine receptor (α7nAChR). Previously, we found that a non-selective α7nAChR agonist nicotine exerted a protective effect against H2O2-induced astrocyte apoptosis via an α7nAChR-dependent pathway. However, the molecular mechanism of the antiapoptotic response of astroglial α7nAChR has not been studied. In the present study, using pharmacological inhibition and genetic knockout of α7nAChR, we assessed the antiapoptotic effects of an α7nAChR agonist PNU-282987 in primary cultured astrocytes treated with 1-methyl-4-phenylpyridinium (MPP+). PNU-282987 promoted the viability of astrocytes, alleviated MPP+ induced apoptosis, and decreased the number of GFAP+/TUNEL+ cells. Meanwhile, PNU-282987 upregulated the expression of the antiapoptotic protein Bcl-2 and downregulated the expression of the apoptotic protein Bax and cleaved-caspase-3. Moreover, the suppression of the JNK-p53-caspase-3 signaling may underlie the neuroprotective property of PNU-282987. Therefore, PNU-282987 ameliorates astroglial apoptosis induced by MPP+ through α7nAChR-JNK-p53 signaling. Our findings suggest that PNU-282987 may be a potential drug for restoring astroglial functions in the treatment of PD.

Background and Objective: Inhibition of thrombosis and platelet aggregation through a thromboxane synthetase inhibitor proved to be an effective and promising treatment for cardiovascular and/or cerebrovascular disease (CCVD) patients. This phase I study evaluated the safety, tolerability, and pharmacokinetics of sodium pyragrel, a novel thromboxane A2 synthetase inhibitor, in healthy volunteers.Methods: A total of 84 healthy Chinese volunteers were enrolled in the study and randomized into one of five dosing regimens of intravenous pyragrel, which were single ascending dose (30 to 300 mg), multiple doses (pyragrel 180 mg once daily on Day 1 and Day 6, twice daily from Day 2 to Day 5), 3×3 Latin square crossover (60, 120, 240 mg), and a continuous dose (360 mg in 24 h), respectively. Plasma concentrations were determined using HPLC-MS/MS. Pharmacokinetics parameters were calculated with non-compartment analysis.Results: The maximum plasma concentrations of pyragrel were essentially reached at the end of the 3 h infusion. The pharmacokinetic process of pyragrel and two main metabolites (BBS and BJS) is linear over the 30–300 mg dose range, with no significant accumulation on multiple doses. The urinary excretion of pyragrel accounted for more than 70% of the total drug amount. Preliminary pharmacodynamic results demonstrated that the production of urinary 11-D-HTXB2 was time- and dose-dependently inhibited by single i.v. dose of pyragrel.Conclusions: Pyragrel was well tolerated after single ascending doses up to 300 mg, multiple doses of 180 mg, and continuous administration of 360 mg within 24 h. No drug-related, serious adverse drug reactions occurred during the five-part study. The most common pyragrel-related adverse events (AEs) were total bilirubin (TB)/direct bilirubin (DB) elevations with a relatively low incidence rate and seemed to be dose independent. Given the acceptable safety and appropriate pharmacokinetic properties of sodium pyragrel proven in this study, continued clinical development is warranted. The study was registered at http://www.chictr.org.cn (ChiCTR-IID-16010159).

Human serum albumin (HSA) is an intrinsic protein and important carrier that transports endogenous as well as exogenous substances. It is demonstrated in this study that the regional accumulation of albumin in the ischemia-reperfusion (I/R) brain may lead in the application of HSA based nanoparticles in the study of cerebral I/R injury. Resveratrol (RES) is potential in the treatment of cerebral I/R injury but is restricted for its water insolubility and short half-life in vivo. In our study, RES loaded HSA nanoparticles (RES-HSA-NPs) were prepared to facilitate the application of RES in protection from cerebral I/R injury. RES-HSA-NPs demonstrated spherical shape, a diameter about 100 nm, a highest RES encapsulation efficiency of 60.9 ± 5.07%, and controlled release pattern with the maximum release ratio of 50.2 ± 4.91% [in pH = 5.0 phosphate buffered saline (PBS)] and 26. 2 ± 2.73% (in pH = 7.4 PBS), respectively, after 90 h incubation at 37°C. After intravenous injection into transient middle cerebral artery occlusion (tMCAO) rats, RES-HSA-NPs improved neurological score and decreased infarct volume at 24 h after tMCAO in a dose dependent manner. A single dose of 20 mg/kg RES-HSA-NPs via tail vein improved neurological outcomes and decreased infarct volume at 24 and 72 h in tMCAO rats. I/R increased oxidative stress (indicated by products of lipid peroxidation, MDA) and neuronal apoptosis (indicated by yellow-brown TUNEL-positive cells), RES-HSA-NPs significantly attenuated oxidative stress and neuronal apoptosis. These results demonstrated the potential of RES-HSA-NPs in the therapy of cerebral I/R injury.

On March 25th 2019, the Belle II detector recorded the first collisions delivered by the SuperKEKB accelerator. This marked the beginning of the physics run with vertex detector. The vertex detector was aligned initially with cosmic ray tracks without magnetic field simultaneously with the drift chamber. The alignment method is based on Millepede II and the General Broken Lines track model and includes also the muon system or primary vertex position alignment. To control weak modes, we employ sensitive validation tools and various track samples can be used as alignment input, from straight cosmic tracks to mass-constrained decays. With increasing luminosity and experience, the alignment is approaching the target performance, crucial for the first physics analyses in the era of Super-BFactories. We will present the software framework for the detector calibration and alignment, the results from the first physics run and the prospects in view of the experience with the first data.

The Belle II experiment features a substantial upgrade of the Belle detector and will operate at the SuperKEKB energy-asymmetric e+e− collider at KEK in Tsukuba, Japan. The accelerator completed its first phase of commissioning in 2016, and the Belle II detector saw its first electron-positron collisions in April 2018. Belle II features a newly designed silicon vertex detector based on double-sided strip layers and DEPFET pixel layers. A subset of the vertex detector was operated in 2018 to determine background conditions (Phase 2 operation). The collaboration completed full detector installation in January 2019, and the experiment started full data taking. This paper will report on the final arrangement of the silicon vertex detector part of Belle II with a focus on online monitoring of detector conditions and data quality, on the design and use of diagnostic and reference plots, and on integration with the software framework of Belle II. Data quality monitoring plots will be discussed with a focus on simulation and acquired cosmic and collision data.