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Abstract Cytosine base editing is a powerful tool for making precise single nucleotide changes in cells and model organisms like zebrafish, which are valuable for studying human diseases. However, current base editors struggle to edit cytosines in certain DNA contexts, particularly those with GC and CC pairs, limiting their use in modelling disease-related mutations. Here we show the development of zevoCDA1, an optimized cytosine base editor for zebrafish that improves editing efficiency across various DNA contexts and reduces restrictions imposed by the protospacer adjacent motif. We also create zevoCDA1-198, a more precise editor with a narrower editing window of five nucleotides, minimizing off-target effects. Using these advanced tools, we successfully generate zebrafish models of diseases that were previously challenging to create due to sequence limitations. This work enhances the ability to introduce human pathogenic mutations in zebrafish, broadening the scope for genomic research with improved precision and efficiency.

The angioedema risk may vary among stroke patients receiving different thrombolytic agents. This study aimed to investigate the angioedema risk associated with different thrombolytic agents and to identify associated risk factors. We conducted a large-scale retrospective pharmacovigilance study using the FDA Adverse Event Reporting System (FAERS) database. Stroke patients receiving thrombolytic therapy (i.e., alteplase or tenecteplase) were identified, and the associations with angioedema were explored using disproportionality analysis and time-to-onset analysis. Additionally, we used adapted Bradford Hill criteria to confirm these associations. Risk factors for angioedema were explored using stepwise logistic regression. A total of 17,776 stroke patients were included, with 2973 receiving alteplase and 278 receiving tenecteplase. Disproportionality analysis revealed that angioedema might be associated with alteplase (adjusted ROR [aROR] 5.13 [95 ​% CI, 4.55–5.79]) or tenecteplase (aROR 2.72 [95 ​% CI, 1.98–3.67]). The adapted Bradford Hill criteria suggested a probable causal relationship between alteplase and angioedema, whereas there was insufficient evidence of a probable causal relationship with tenecteplase. Multivariate analysis revealed that ACE-inhibitors use (aROR 9.73 [95 ​% CI, 7.29–12.98]), female sex (aROR 1.38 [95 ​% CI, 1.13–1.67]) and hypertension (aROR 2.11 [95 ​% CI, 1.52–2.92]) were significant risk factors for angioedema among alteplase-treated stroke patients. Our study suggested that alteplase is associated with a greater risk of angioedema among stroke patients, but there is insufficient evidence to support an association between tenecteplase and angioedema. Clinicians should be vigilant for this potentially life-threatening complication, particularly in patients with identified risk factors. It is also prudent to consider tenecteplase as an alternative, if available.

Summary: Background: Surgical interventions for spontaneous supratentorial intracerebral haemorrhage (ICH) include conventional craniotomy (CC), decompressive craniectomy (DC), and minimally invasive surgery (MIS), with the latter encompassing endoscopic surgery (ES) and minimally invasive puncture surgery (MIPS). However, the superiority of surgery over conservative medical treatment (CMT) and the comparative benefits of different surgical procedures remain unclear. We aimed to evaluate the efficacy and safety of various surgical interventions for treating ICH. Methods: In this systematic review and network meta-analysis, we searched PubMed, Cochrane Central Register of Controlled Trials, Embase, and ClinicalTrials.gov from inception to June 16, 2024. Eligible studies were randomised controlled trials (RCTs) comparing surgery (i.e., CC, ES, MIPS, or DC) with CMT or comparing different types of surgeries in patients with spontaneous supratentorial ICH. Paired reviewers independently screened citations, assessed the risk of bias of included trials, and extracted data. Primary outcomes were good functional outcome and mortality at 6 months. Secondary outcomes were good functional outcome and mortality at different follow-up times, complications (rebleeding, brain infection, pulmonary infection), and hematoma evacuation rate. The frequentist pairwise and network meta-analysis (NMA) were performed. The GRADE approach was used to evaluate the certainty of evidence. This study is registered with PROSPERO, CRD42024518961. Findings: Of the 8573 total records identified by our searches, 31 studies (6448 patients) were eligible for the systematic review and network analysis. Compared with CMT, moderate certainty evidence showed that surgery improved good functional outcome (risk ratio [RR] 1.31, 95% CI 1.13–1.52; risk difference [RD] 9.1%, 95% CI 3.8 to 15.3; I2 = 36%) and reduced mortality (RR 0.82, 95% CI 0.71–0.95; RD −5.1%, 95% CI −8.2 to −1.4; I2 = 14%). Moderate certainty evidence from NMA suggested that compared with CMT, both ES (RR 1.51, 95% CI 1.18–1.93; RD 9.4%, 95% CI 3.3–17.1) and MIPS (RR 1.48, 95% CI 1.24–1.76; RD 15.7%, 95% CI 7.9–24.9) improved good functional outcome at 6 months, and both ES (RR 0.66, 95% CI 0.52–0.85; RD −17.0%, 95% CI −24.0 to −7.5) and CC (RR 0.75, 95% CI 0.60–0.94; RD −6.3%, 95% CI −10.1 to −1.5) reduced mortality at 6 months, whereas MIPS and DC showed a trend, although not statistically significant, towards a reduction in mortality. ES and MIPS also reduced pulmonary infection risk (ES RR 0.39, 95% CI 0.23–0.69; MIPS RR 0.35, 95% CI 0.20–0.60; RD −5.3%, 95% CI −6.6 to −3.3). ES showed higher hematoma evacuation than CC (MD: 7.03, 95% CI: 3.42–10.65; I2 = 94%). No difference in rebleeding or brain infection was found between CC and MIS. Interpretation: Current moderate certainty evidence suggested that surgical intervention of spontaneous supratentorial ICH, may be associated with improved functional outcomes and a reduced risk of death at 6 months. The advantages of surgical haematoma removal are particularly pronounced when MIS including ES and MIPS are employed. ES could improve functional outcomes, reduce the risk of mortality and pulmonary infection, and have a high hematoma evacuation rate, suggesting that it might be an optimal surgical treatment. Funding: National Natural Science Foundation of China, National Science Fund for Distinguished Young Scholars, Fundamental Research Funds for the Central Public Welfare Research Institutes, and 1·3·5 project for disciplines of excellence, West China Hospital, Sichuan University.

Objective To explore the effectiveness of intraovarian injection of platelet-rich plasma(PRP) in the treatment of patients with diminished ovarian reserve(DOR), aiming to provide new diagnostic and therapeutic ideas for the treatment. Methods A total of 22 patients with DOR who underwent autologous PRP ovarian injection at the Reproductive Medical and Genetic Center of Qinzhou Maternal and Child Health Hospital from January 2021 to December 2023 were collected. Among them, 12 patients underwent assisted reproductive technology for pregnancy. The patient′s anti-Müllerian hormone (AMH), antral follicle count (AFC), basal follicle-stimulating hormone (FSH), basal luteinizing hormone (LH) and basal estradiol (E2) levels were observed. Results The levels of AMH, AFC, basal FSH, basal LH and basal E2 in 22 patients improved after treatment compared with those before treatment. Of the 12 patients who received assisted reproduction, 2 had IVF cycle canceled due to poor ovarian reaction. Ten patients obtained embryos, of which 5 obtained high-quality embryos. Conclusion Intraovarian injection of autologous PRP can effectively improve ovarian reserve function in patients with DOR.

Abstract Background We concurrently developed a prospective study to assess clinical outcomes among patients receiving 9-month bedaquiline (BDQ)-containing regimens, aiming to provide valuable data on the use of this short-course regimen in China. Methods This open-label, randomized, controlled, multicenter, non-inferiority trial was conducted at sixteen hospitals, and enrolled participants aged 18 years and older with pulmonary rifampicin/multidrug tuberculosis. Participants were randomly assigned, in a 1:1 ratio. Individuals within the standard-regimen group received 6 months of BDQ, linezolid, levofloxacin, clofazimine, and cycloserine plus 12 months of levofloxacin, and any three potentially effective drugs from clofazimine, cycloserine pyrazinamide, ethambutol and protionamide, whereas individuals within shorter-regimen group received 9 months of BDQ, linezolid, levofloxacin, clofazimine and cycloserine. The primary outcome was the percentage of participants with a composite unfavorable outcome (treatment failure, death, treatment discontinuation, or loss to follow-up) by the end of the treatment course after randomization in the modified intention-to-treat population. The noninferiority margin was 10%. This trial was registered with www.chictr.org.cn , ChiCTR2000029012. Results Between Jan 1, 2020, and Dec 31, 2023, 264 were screened and randomly assigned, 132 of 264 participants were assigned to the standard-regimen group and 132 were assigned to the shorter-regimen. Thirty-three (12.55%) of 264 participants were excluded from the modified intention-to-treat analysis. As a result, 231 participants were included in the modified intention-to-treat analysis (116 in the standard-regimen group and 115 in the shorter-regimen group).In the modified intention-to-treat population, unfavorable outcomes were reported in 19 (16.5%) of 115 participants for whom the outcome was assessable in the shorter-regimen group and 26 (22.4%) of 116 participants in the standard care group (risk difference 5.9 percentage points (97.5% CI − 5.8 to 17.5)). One death was reported in the standard-regimen group. The incidence of QTcF prolongation in the shorter-regimen group (22.6%, 26/115) was similar to the standard-regimen group (24.1%, 28/116). Conclusions The 9-month, all-oral regimen is safe and efficacious for the treatment of pulmonary rifampicin/multidrug-resistant tuberculosis. The high incidence of QTc prolongation associated with the use of BDQ highlights the urgent need of routine electrocardiogram monitoring under treatment with BDQ-containing regimens in the Chinese population.

Abstract Advancements in CRISPR technology, particularly the development of base editors, revolutionize genetic variant research. When combined with model organisms like zebrafish, base editors significantly accelerate and refine in vivo analysis of genetic variations. However, base editors are restricted by protospacer adjacent motif (PAM) sequences and specific editing windows, hindering their applicability to a broad spectrum of genetic variants. Additionally, base editors can introduce unintended mutations and often exhibit reduced efficiency in living organisms compared to cultured cell lines. Here, we engineer a suite of adenine base editors (ABEs) called ABE-Ultramax (Umax), demonstrating high editing efficiency and low rates of insertions and deletions (indels) in zebrafish. The ABE-Umax suite of editors includes ABEs with shifted, narrowed, or broadened editing windows, reduced bystander mutation frequency, and highly flexible PAM sequence requirements. These advancements have the potential to address previous challenges in disease modeling and advance gene therapy applications.

Abstract Remarkable advances in protocol development have been achieved to manufacture insulin-secreting islets from human pluripotent stem cells (hPSCs). Distinct from current approaches, we devised a tunable strategy to generate islet spheroids enriched for major islet cell types by incorporating PDX1+ cell budding morphogenesis into staged differentiation. In this process that appears to mimic normal islet morphogenesis, the differentiating islet spheroids organize with endocrine cells that are intermingled or arranged in a core-mantle architecture, accompanied with functional heterogeneity. Through in vitro modelling of human pancreas development, we illustrate the importance of PDX1 and the requirement for EphB3/4 signaling in eliciting cell budding morphogenesis. Using this new approach, we model Mitchell-Riley syndrome with RFX6 knockout hPSCs illustrating unexpected morphogenesis defects in the differentiation towards islet cells. The tunable differentiation system and stem cell-derived islet models described in this work may facilitate addressing fundamental questions in islet biology and probing human pancreas diseases.

Abstract Background Faced with the high cost and limited efficiency of classical randomized controlled trials, researchers are increasingly applying adaptive designs to speed up the development of new drugs. However, the application of adaptive design to drug randomized controlled trials (RCTs) and whether the reporting is adequate are unclear. Thus, this study aimed to summarize the epidemiological characteristics of the relevant trials and assess their reporting quality by the Adaptive designs CONSORT Extension (ACE) checklist. Methods We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL) and ClinicalTrials.gov from inception to January 2020. We included drug RCTs that explicitly claimed to be adaptive trials or used any type of adaptative design. We extracted the epidemiological characteristics of included studies to summarize their adaptive design application. We assessed the reporting quality of the trials by Adaptive designs CONSORT Extension (ACE) checklist. Univariable and multivariable linear regression models were used to the association of four prespecified factors with the quality of reporting. Results Our survey included 108 adaptive trials. We found that adaptive design has been increasingly applied over the years, and was commonly used in phase II trials (n = 45, 41.7%). The primary reasons for using adaptive design were to speed the trial and facilitate decision-making (n = 24, 22.2%), maximize the benefit of participants (n = 21, 19.4%), and reduce the total sample size (n = 15, 13.9%). Group sequential design (n = 63, 58.3%) was the most frequently applied method, followed by adaptive randomization design (n = 26, 24.1%), and adaptive dose-finding design (n = 24, 22.2%). The proportion of adherence to the ACE checklist of 26 topics ranged from 7.4 to 99.1%, with eight topics being adequately reported (i.e., level of adherence ≥ 80%), and eight others being poorly reported (i.e., level of adherence ≤ 30%). In addition, among the seven items specific for adaptive trials, three were poorly reported: accessibility to statistical analysis plan (n = 8, 7.4%), measures for confidentiality (n = 14, 13.0%), and assessments of similarity between interim stages (n = 25, 23.1%). The mean score of the ACE checklist was 13.9 (standard deviation [SD], 3.5) out of 26. According to our multivariable regression analysis, later published trials (estimated β = 0.14, p

Abstract Salamanders possess remarkable regenerative capacities for organ regeneration among tetrapod vertebrates. Previous research has primarily focused on studying the regeneration of canonical tissues or organs such as limbs, tail, brain, spinal cord, heart, and lens. The advancements made in these areas have broader implications for understanding regeneration and developing therapeutic approaches for these organs, not only in salamanders but also in other vertebrates. In recent years, there has been an increasing interest in studying the regeneration of non‐canonical organs in salamanders, such as the liver, lungs, kidneys, and pancreas. This diversification of research has opened up new avenues and provided potential solutions to challenging clinical problems. This review aims to summarize the progress made in the field of non‐canonical organ regeneration in salamanders and provides an outlook on future research directions.

Abstract Unified visual perception requires integration of bottom-up and top-down inputs in the primary visual cortex (V1), yet the organization of top-down inputs in V1 remains unclear. Here, we used optogenetics-assisted circuit mapping to identify how multiple top-down inputs from higher-order cortical and thalamic areas engage V1 excitatory and inhibitory neurons. Top-down inputs overlap in superficial layers yet segregate in deep layers. Inputs from the medial secondary visual cortex (V2M) and anterior cingulate cortex (ACA) converge on L6 Pyrs, whereas ventrolateral orbitofrontal cortex (ORBvl) and lateral posterior thalamic nucleus (LP) inputs are processed in parallel in Pyr-type-specific subnetworks (Pyr←ORBvl and Pyr←LP) and drive mutual inhibition between them via local interneurons. Our study deepens understanding of the top-down modulation mechanisms of visual processing and establishes that V2M and ACA inputs in L6 employ integrated processing distinct from the parallel processing of LP and ORBvl inputs in L5.

ObjectivesTo analyze the costs and medication patterns of patients with chronic kidney disease (CKD) and comorbidities in Xuzhou, China, using a large electronic medical records database.MethodsData were obtained from an electronic medical records database. The annual per-person and per-visit cost of hospitalization, as well as the proportions of those costs, are presented.ResultsThe majority of the participants were middle-aged men, and had medical insurance. Glomerulonephritis was the primary cause of CKD in patients with an identified etiology. The average per-visit cost of hospitalization for the CKD-renal anemia and CKD-mineral and bone disorder groups was 8,674.5 (5,154.3–13,949.6) and 8,182.6 (4,798.2–12,844.7) Yuan, respectively, which was greater than that of the other groups. The major expenses incurred were for diagnostics, drug usage, surgical procedures, laboratory tests and material costs.ConclusionThe substantial burden imposed by CKD with comorbidities indicates the importance of implementing public health strategies aimed at detecting and preventing these conditions in the general population. With the aging population, our nation may experience a greater CKD-related economic burden.

Abstract Interhemispheric communication through the corpus callosum is required for both sensory and cognitive processes. Impaired transcallosal inhibition causing interhemispheric imbalance is believed to underlie visuospatial bias after frontoparietal cortical damage, but the synaptic circuits involved remain largely unknown. Here, we show that lesions in the mouse anterior cingulate area (ACA) cause severe visuospatial bias mediated by a transcallosal inhibition loop. In a visual-change-detection task, ACA callosal-projection neurons (CPNs) were more active with contralateral visual field changes than with ipsilateral changes. Unilateral CPN inactivation impaired contralateral change detection but improved ipsilateral detection by altering interhemispheric interaction through callosal projections. CPNs strongly activated contralateral parvalbumin-positive (PV+) neurons, and callosal-input-driven PV+ neurons preferentially inhibited ipsilateral CPNs, thus mediating transcallosal inhibition. Unilateral PV+ neuron activation caused a similar behavioral bias to contralateral CPN activation and ipsilateral CPN inactivation, and bilateral PV+ neuron activation eliminated this bias. Notably, restoring interhemispheric balance by activating contralesional PV+ neurons significantly improved contralesional detection in ACA-lesioned animals. Thus, a frontal transcallosal inhibition loop comprising CPNs and callosal-input-driven PV+ neurons mediates interhemispheric balance in visuospatial processing, and enhancing contralesional transcallosal inhibition restores interhemispheric balance while also reversing lesion-induced bias.

The southern catfish (Silurus meridionalis) is an economically important carnivorous freshwater fish in China. In this study, we compared the properties of skin collagen from southern catfish fed with raw food (RF) and cooked food (CF). The skin collagen yield in the RF group (8.66 ± 0.11%) was significantly higher than that of the CF group (8.00 ± 0.27%). SDS-PAGE, circular dichroism spectroscopy, and FTIR analyses revealed that the collagen extracted from southern catfish skin in both groups was type I collagen, with a unique triple helix structure and high purity. The thermal denaturation temperature of collagen in the RF group (35.20 ± 0.11 °C) was significantly higher than that of the CF group (34.51 ± 0.25 °C). The DPPH free radical scavenging rates were 68.30 ± 2.41% in the RF collagen and 61.78 ± 3.91% in the CF collagen, which was higher than that found in most fish collagen. Both the RF and CF groups had high ability to form fibrils in vitro. Under the same conditions, the CF group exhibited faster fibril formation and a thicker fibril diameter (p < 0.05). In addition, the RF group exhibited significantly higher expression of col1a1 compared to the CF group. These results indicated that feeding southern catfish raw food contributed to collagen production, and the collagen from these fish may have potential in biomaterial applications.

In a highly competitive electricity spot market, virtual power plants (VPPs) that aggregate dispersed resources face various uncertainties during market transactions. These uncertainties directly impact the economic benefits of VPPs. To address the uncertainties in the economic optimization of VPPs, scenario analysis is employed to transform the uncertainties of wind turbines (WTs), photovoltaic (PV) system outputs, and electricity prices into deterministic problems. The objective is to maximize the VPP’s profits in day-ahead and intra-day markets (real-time balancing market) by constructing an economic optimization decision model based on two-stage stochastic programming. Gas turbines and electric vehicles (EVs) are scheduled and traded in the day-ahead market, while flexible energy storage systems (ESS) are deployed in the real-time balancing market. Based on simulation analysis, under the uncertainty of WTs and PV system outputs, as well as electricity prices, the proposed model demonstrates that orderly charging of EVs in the day-ahead stage can increase the revenue of the VPP by 6.1%. Additionally, since the ESS can adjust the deviations in day-ahead bid output during the intra-day stage, the day-ahead bidding strategy becomes more proactive, resulting in an additional 3.1% increase in the VPP revenue. Overall, this model can enhance the total revenue of the VPP by 9.2%.

Additive/subtractive hybrid manufacturing (ASHM) based on laser powder bed fusion (LPBF) enables to achieve high precision and good surface quality of complex structures such as small holes with overhanging features. However, the rapid heating and cooling rates during the ASHM results in sinkage at the alternating interface of additive manufacturing and subtractive milling, which degrades the surface quality of the components. This study employs shielding height at the alternating interface to solve this problem and improve the surface quality. The effect of internal diameters and shielding heights on the surface quality were studied experimentally for overhanging holes fabricated by ASHM of Ti6Al4V. The results show that the Ti6Al4V samples prepared by LPBF possessed high density and uniformly distributed microstructure. For overhanging holes without shielding height, the largest depth value of sinkage and surface roughness were obtained, indicating a worse surface quality; when the shielding height was increased to 0.5 mm, the smallest sinkage value and surface roughness were obtained, indicating a better surface quality. With the same shielding height, the overhanging holes with different diameters had a similar surface roughness. This study reveals that an appropriate shielding height can improve the surface quality, which provides guidance to the improvement of the surface quality for complex structures in ASHM.

Abstract Objectives The purpose of this study was to explore the influence of individual patient factors, such as volume of the planning target volume (PTV) (VPTV), cardiothoracic ratio (CTR), central lung distance (CLD), and maximal heart distance (MHD), on the design of treatment plans in terms of target dose coverage, integral dose, and dose to organs at risk (OAR) in early breast cancer. Methods Ninety-six patients were selected for this study. Radiation doses of 50 Gy and a simultaneous dose of 60 Gy in 25 fractions were administered to the whole breast and tumor bed, respectively. The intensity modulation plan (IMRT) of each patient uses both physical parameters and an equivalent uniform dose (EUD) to optimize the target function. Univariate and multivariate linear regression were used to analyze the relationship between predictive impact factors and OAR percent dose volume, conformity index (CI), and homogeneity index (HI). Results The average CI and HI values of the left breast cancer plan were 0.595 ± 0.071 (0.3–0.72) and 1.095 ± 0.023 (1.06–1.18), respectively. The CTR (B = 0.21, P = 0.045), VPTV (B = 0.63, P = 0.000), volume of the lung (Vlung) (B = − 0.29, P = 0.005), and MHD (B = 0.22, P = 0.041) were identified as factors influencing the CI index of the left breast cancer intensity modulation plan. VPTV (B = 1.087, P = 0.022) was identified as the influencing factor of the HI index of the left breast cancer intensity modulation plan. volume of the heart (Vheart) (B = − 0.43, P = 0.001) and CLD (B = 0.28, P = 0.008) were influencing factors of the volume of lung (Vlung20) of the lung. The prediction formulas for left-sided breast cancer are noted as follows: CI = 0.459 + 0.19CTR-0.16CLD, Vlung10 = 35.5–0.02Vheart; and Vlung20 = 21.48 + 2.8CLD-0.018Vheart. Conclusions CTR, CLD, and MHD can predict the rationality of the parameters of the left breast cancer IMRT. The calculation formula generated based on this information can help the physicist choose the optimal radiation field setting method and improve the quality of the treatment plan.

Abstract Background The rock cut slope (RCS) could cause damage to regional ecological functions and landscapes and requires recovery. Biological soil crusts (BSCs) are pioneer and dominant colonizers during the initial recovery stage. To accelerate the natural recovery of RCS, the development process and influencing agents of BSC should be revealed. Thus, the area index of crevices (I R), BSC coverage (COV) and biomass (BM), soil weight (SW), and major soil nutrients [organic carbon (OC), total nitrogen (TN) and total phosphorus (TP)] content, collected from 164 quadrats on 13 RCSs in the mountainous area of west Sichuan Province, China, were measured, to explore the effect of crevice of RCS on BSC development. Results Soil OC, TN and TP on RCSs ranged from 18.61 to 123.03 g kg−1, 0.96 to 6.02 g kg−1 and 0.52 to 2.46 g kg−1, respectively, and were approximately to or higher than those on natural slopes. The OC, TN and TP contents in soils elevated unsystematically with recovery time of RCSs. BSCs on RCS distributed along crevices generally and firstly. During the first 13 years of natural recovery, COV, BM and SW ranged from 6.5 to 28.2%, 14.43 to 67.25 g m−2, and 127.69 to 1277.74 g m−2, respectively. COV, BM and SW increased linearly with I R on RCSs. The positive correlation between COV and BM and I R was insignificantly impacted by bedrock, slope aspect and altitude within the recovery time less than 13 years. COV and BM on RCSs increased significantly when the recovery time is more than 27 years. Conclusions Crevice on RCSs could be a major environmental factor which is conducive to BSC development and soil accumulation through creating a space for water and soil particle. Furthermore, with the increase of recovery time of RCSs, BSCs may grow and reach a stable state with the promotion of soil nutrients, plant growth and microbial activity. These results provide a development process of BSC that from inside to outside the crevices on RCSs. In the areas with stable rock strata and a low risk of geological disasters, purposeful improvement in crevice density on RCS may effectively accelerate BSC development.

Purpose: HSK16149 is a novel, potent gamma-aminobutyric acid (GABA) analog for the treatment of neuropathic pain. This study aimed to evaluate the safety, tolerability, and pharmacokinetics of HSK16149 after single and multiple doses in healthy Chinese subjects.Methods: The randomized, double-blind, placebo-controlled study comprised two parts: SAD (single ascending-dose study) and MAD (multiple ascending-dose study). A total of 122 healthy subjects were enrolled in this study. HSK16149 capsule or placebo was administered as the protocol required. The safety of the drug was evaluated through clinical examinations and adverse events. Blood and urine samples were collected at the designated time intervals for pharmacokinetic analysis.Results: Subjects were generally well tolerated after HSK16149 administration and the most common treatment-emergent adverse event (TEAEs) was dizziness, which was expected based on the mechanism of action of HSK16149. In SAD, AUC and Cmax were shown to have a dose-proportional relationship in the dose range of 5-120 mg. The t1/2 of HSK16149 is 3.7-6.4 h. In MAD, after a single and multiple administration of 15-80 mg, AUC and Cmax are proportional to the increased dose of HSK16149, and the accumulative ratios of AUC and Cmax at steady-state were 1.05–1.44 and 1.07–1.36, respectively, indicating that HSK16149 only accumulated slightly after repeated administration.Conclusion: HSK16149 was well tolerated in healthy Chinese subjects. Based on the safety and pharmacokinetic data, 80 mg twice daily (BID) was suggested as the highest target dose for further clinical development.Clinical Trial Registration:http://www.chinadrugtrials.org.cn, identifier CTR20182535 and CTR20191317

Previous studies exhibited reproductive and neurodevelopmental toxicity in rats exposed to Di-n-butyl phthalate (DBP). However, the effects of DBP exposure on the other endocrine organ are still unclear. This study aimed to assess the impact of DBP exposure on the thyroid of male rats and the associated mechanisms. Here, rats were respectively treated with DBP at 0 (control), 50 (low dose), 250 (medium dose), or 500 (high dose) mg/kg/day dissolved in 1 ml quantity of corn oil by intragastrical administration for two weeks. The results demonstrated that the proliferation and inflammatory response changes were significantly different compared to the control. In vivo DBP is mainly converted to mono-n-butyl phthalate (MBP), an active form producing untoward reactions of DBP exposure. Therefore, for in vitro experiments, we treated the thyroid follicular epithelial cell line (Nthy-ori 3–1) in a temporal gradient using 1 mM MBP. Further in vitro studies showed that MBP exposure upregulated tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), as well as interleukin-1β (IL-1β) by activating AKT/NF-κB/NLRP3 signaling. Meanwhile, we detected that Pellino2 (Peli2) played an essential role in promoting the activation of NLRP3 inflammasome. Briefly speaking, this study confirmed that DBP exposure caused impaired thyroid structure and thyroid inflammation in male rats, which offered new views into the harm of DBP exposure on the endocrine organ.

Objectives: Dual specificity phosphatase 1 (DUSP1) is high-expressed in various cancers and plays an important role in the cellular response to agents that damage DNA. We aimed to investigate the expressions and mechanisms of DUSP1 signaling pathway regulating cytarabine (Ara-C) resistance in acute myeloid leukemia (AML). Methods: Immunohistochemistry was performed on bone marrow biopsy specimens from AML and controls to explore the expression of DUSP1. Western blot and Q-PCR were used to detect the protein and mRNA expression levels. MTT assay was used to detect the proliferation of cells. Cell apoptosis was detected by flow cytometry. The immune protein-protein interaction (PPI) network of DUSP1 was analyzed in the platform of Pathway Commons, and immune infiltration analysis was used to study the immune microenvironment of AML. Results: We found that the expression levels of DUSP1 in AML patients exceeded that in controls. Survival analysis in public datasets showed that AML patients with higher levels of DUSP1 had poor clinical outcomes. Further public data analysis indicated that DUSP1 was overexpressed in NRAS mutated AML. DUSP1 knockdown by siRNA could sensitize AML cells to Ara-C treatments. The phosphorylation level of mitogen-activated protein kinase (MAPK) pathway was significantly elevated in DUSP1 down-regulated NRAS G13D mutated AML cells. The PPI analysis showed DUSP1 correlated with immune gene CREB1 and CXCL8 in NRAS mutated AML. We also revealed a correlation between tumor-infiltrating immune cells in RAS mutated AML microenvironment. Conclusion : Our findings suggest that DUSP1 signaling pathways may regulate Ara-C sensitivity in AML.

Abstract Switchgrass is a promising energy crop has the potential to mitigate global warming and energy security, improve local ecology and generate profit. Its quantitative traits, such as biomass productivity and environmental adaptability, are determined by genotype‐by‐environment interaction (GEI) or response of genotypes grown across different target environments. To simulate the yield of switchgrass outside its original habitat, a genotype‐specific growth model, SwitchFor that captures GEI was developed by parameterising the MiscanFor model. Input parameters were used to describe genotype‐specific characteristics under different soil and climate conditions, which enables the model to predict the yield in a wide range of environmental and climate conditions. The model was validated using global field trail data and applied to estimate the switchgrass yield potentials on the marginal land of the Loess Plateau in China. The results suggest that upland and lowland switchgrass have significant differences in the spatial distribution of the adaptation zone and site‐specific biomass yield. The area of the adaption zone of upland switchgrass was 4.5 times of the lowland ecotype's. The yield difference between upland and lowland ecotypes ranges from 0 to 34 Mg ha−1. The weighted average yield of the lowland ecotype (20 Mg ha−1) is significantly higher than the upland type (5 Mg ha−1). The optimal yield map, generated by comparing the yield of upland and lowland ecotypes based on 1 km2 grid locations, illustrates that the total yield potential of the optimal switchgrass is 61.6–106.4 Tg on the marginal land of the Loess Plateau, which is approximately twice that of the individual ecotypes. Compared with the existing models, the accuracy of the yield prediction of switchgrass is significantly improved by using the SwitchFor model. This spatially explicit and cultivar‐specific model provides valuable information on land management and crop breeding and a robust and extendable framework for yield mapping of other cultivars.

Abstract Background The aim of this study was to construct a nomogram model for discriminating the risk of delirium in patients undergoing cardiovascular surgery. Methods From January 2017 to June 2020, we collected data from 838 patients who underwent cardiovascular surgery at the Affiliated Hospital of Nantong University. Patients were randomly divided into a training set and a validation set at a 5:5 ratio. A nomogram model was established based on logistic regression. Discrimination and calibration were used to evaluate the predictive performance of the model. Results The incidence of delirium was 48.3%. A total of 389 patients were in the modelling group, and 449 patients were in the verification group. Logistic regression analysis showed that CPB duration (OR $$=$$ = 1.004, 95% CI: 1.001–1.008, $$P=$$ P = 0.018), postoperative serum sodium (OR $$=$$ = 1.112, 95% CI: 1.049–1.178, $$P

Abstract This study aimed to evaluate the pharmacokinetics (PKs), safety, and immunogenicity of the biosimilar (RD12014) compared to reference liraglutide (Victoza) in healthy Chinese male subjects, so as to provide the basis for the similarity evaluation of the two drugs. Eligible subjects were randomized 1:1 to two sequences (RD12014‐Victoza or Victoza‐RD12014). Subjects received a single 0.6 mg dose of Victoza or RD12014 by abdominal subcutaneous injection during the first period. After a 7‐day washout period, subjects received the alternative drug during the second period. Blood samples were collected at predefined timepoints for PKs and immunogenicity assessment. The primary PK end points were maximum plasma concentration (Cmax) and area under the concentration‐time curve from time zero to the time of the last quantifiable concentration (AUC0−last). PK bioequivalence was achieved, if the 90% confidence intervals (CIs) of the geometric mean ratio (GMR) of Cmax and AUC0−last were within the range of 80.00–125.00%. Safety was assessed throughout the study. The 90% CIs of the GMR of RD12014 to Victoza for Cmax and AUC0−last were completely within the range of 80.00–125.00%. Thirteen treatment‐related adverse events (TRAEs) were reported in 11 subjects (22.4%) in the RD12014 group, compared to 12 TRAEs reported in 12 subjects (24.5%) in the Victoza group. The blood samples of 49 subjects were negative for anti‐drug antibody and the neutralizing antibody was not further detected. This study demonstrated PK similarity of RD12014 to Victoza in healthy Chinese male subjects. Safety and immunogenicity profiles were comparable between the two groups.

The tetrapod salamander species axolotl ( Ambystoma mexicanum ) is capable of regenerating injured brain. For better understanding the mechanisms of brain regeneration, it is very necessary to establish a rapid and efficient gain-of-function and loss-of-function approaches to study gene function in the axolotl brain. Here, we establish and optimize an electroporation-based method to overexpress or knockout/knockdown target gene in ependymal glial cells (EGCs) in the axolotl telencephalon. By orientating the electrodes, we were able to achieve specific expression of EGFP in EGCs located in dorsal, ventral, medial, or lateral ventricular zones. We then studied the role of Cdc42 in brain regeneration by introducing Cdc42 into EGCs through electroporation, followed by brain injury. Our findings showed that overexpression of Cdc42 in EGCs did not significantly affect EGC proliferation and production of newly born neurons, but it disrupted their apical polarity, as indicated by the loss of the ZO-1 tight junction marker. This disruption led to a ventricular accumulation of newly born neurons, which are failed to migrate into the neuronal layer where they could mature, thus resulted in a delayed brain regeneration phenotype. Furthermore, when electroporating CAS9-gRNA protein complexes against TnC ( Tenascin-C ) into EGCs of the brain, we achieved an efficient knockdown of TnC . In the electroporation-targeted area, TnC expression is dramatically reduced at both mRNA and protein levels. Overall, this study established a rapid and efficient electroporation-based gene manipulation approach allowing for investigation of gene function in the process of axolotl brain regeneration.

Abstract Introduction : Parkinson's disease (PD) is a neurodegenerative disorder that affects millions of people worldwide. Subthalamic nucleus (STN) deep brain stimulation (DBS) has been shown to be an effective treatment for PD; however, the effects of this surgery on cerebral metabolism and presynaptic dopamine transporter (DAT) distribution are still being studied. Methods : In this study, we included 12 PD patients (6 male and 6 female) who underwent STN‐DBS surgery and had both 18F‐FDG and 11C‐CFT PET/CT imaging before and 1 year after the surgery. We used paired t‐tests to identify changes in cerebral metabolism and calculated PD‐related metabolic covariance pattern (PDRP) scores. We also assessed the uptake of 11C‐CFT in the striatum using striatal‐to‐occipital ratios (SORs). Results : One year after surgery, we observed significant reductions in tremor, rigidity, akinesia, postural instability/gait disturbance, and Unified Parkinson's Disease Rating Scale Part III scores (p

Abstract Background Circadian rhythm disorders (CRDs) are closely associated with the occurrence and development of various diseases, such as inflammatory and cardiovascular diseases, as well as tumors. The impact of a CRD on bodily health is a complex and comprehensive process, and its molecular mechanisms and signaling pathways are still unclear. We therefore aimed to investigate the molecular mechanism variation and adverse outcomes associated with CRDs in a prospective cohort of CRD cases and controls at term using multiomics data. The study has been tasked with developing a precise health promotion model for the prevention and management of CRDs. Methods This will be a 5-year prospective cohort study centered on the health management of individuals with CRDs. One hundred volunteers were recruited and had undergone baseline specimen collection, health examination, and health assessment. All of them will be followed up every year using the same protocol, and their biological specimens will be subjected to multiomics analysis after standardized processing. Discussion Longitudinal health examination, health assessment, and multiomics data will be analyzed to study the impact of CRDs on the volunteers’ health status. The results of this study will promote the development of targeted health management programs based on precision medicine. Trial registration The clinical study registration has been completed (Trial Registration No. ChiCTR2100047242 ).

Phages provide a potential therapy for multi-drug-resistant (MDR) bacteria. However, a significant portion of viral genes often remains unknown, posing potential dangers. The identification of non-essential genes helps dissect and simplify phage genomes, but current methods have various limitations. In this study, we present an in vivo two-plasmid transposon insertion system to assess the importance of phage genes, which is based on the V. cholerae transposon Tn6677, encoding a nuclease-deficient type I-F CRISPR–Cas system. We first validated the system in Pseudomonas aeruginosa PAO1 and its phage S1. We then used the selection marker AcrVA1 to protect transposon-inserted phages from CRISPR-Cas12a and enriched the transposon-inserted phages. For a pool of selected 10 open-reading frames (2 known functional protein genes and 8 hypothetical protein genes) of phage S1, we identified 5 (2 known functional protein genes and 3 hypothetical protein genes) as indispensable genes and the remaining 5 (all hypothetical protein genes) as dispensable genes. This approach offers a convenient, site-specific method that does not depend on homologous arms and double-strand breaks (DSBs), holding promise for future applications across a broader range of phages and facilitating the identification of the importance of phage genes and the insertion of genetic cargos.

Abstract Background The acupoint selections impact the effects of acupuncture, and preliminary evidence showed potential connection between pain threshold (PT) and acupuncture response. This study examined whether acupuncture at acupoints with lower PT versus higher PT would yield different effects in patients with knee osteoarthritis (KOA). Methods In this multicenter randomized clinical trial, patients were randomly assigned (1:1:1) to receive acupuncture at acupoints with lower PT (LPT group), acupuncture at acupoints with higher PT (HPT group), and no acupuncture (waiting-list group). PT was measured with electronic von Frey detector. The primary outcome was the change in WOMAC total score from baseline to 16 weeks, and the secondary outcomes were SF-12 score, and active knee range of motion (ROM). Intention-to-treat analysis was conducted with linear mixed-effect model. Results Among 666 randomized patients, 625 (93.84%) completed the study. From baseline to 16 weeks, patients in the LPT group versus HPT group had similar effects in reducing WOMAC total score (adjusted mean difference (MD) 2.21, 95% confidence interval (CI) −2.51 to 6.92, P = 0.36), while a greater reduction in WOMAC total score was observed in LPT group (−9.77, 95% CI −14.47 to −5.07, P

The recent development of PAM-less base editors makes it possible to assess the functional impact and pathogenicity of nucleotide mutations in animals. Here the authors show that SpG and SpRY could edit NGN and NNN PAMs in zebrafish using the purified protein with synthetically modified gRNA, respectively.

Abstract Baloxavir marboxil is an endonuclease inhibitor indicated for the treatment of influenza in patients ≥12 years. No data exist for Chinese patients in global studies. This randomized, open‐label, phase I study evaluated the pharmacokinetics (PK) and safety of baloxavir marboxil in healthy Chinese volunteers and was used to anticipate efficacy in Chinese patients. Patients received a single oral dose of baloxavir marboxil (40 or 80 mg [1:1]). Serial blood samples were collected predose and at various timepoints up to 14 days postdose. Baloxavir marboxil and acid plasma concentrations were determined by liquid chromatography tandem mass spectrometry. PK parameters of baloxavir acid were estimated by noncompartmental analysis. Adverse events (AEs) were recorded. Time to alleviation of symptoms (TTAS) was simulated for otherwise healthy (OwH) and high‐risk (HR) Chinese and Asian patients. Thirty‐two male patients received baloxavir marboxil. Baloxavir acid plasma concentration peaked 4 h postdose. Mean maximum concentration (Cmax) was 107.6 and 206.9 ng/ml, and mean area under the plasma concentration‐time curve from zero to infinity (AUC0–inf) was 6955 and 9643 ng·h/ml in the 40 and 80 mg cohorts, respectively. AEs were mild and transient; no new safety signals were identified. Simulated median TTAS for OwH and HR Chinese patients agreed with simulated values in Asian patients. PK parameters were similar to Asian populations in other studies. The globally adopted baloxavir marboxil dosing strategy was consistent with the established safety profile of baloxavir marboxil in this population. Simulated efficacy indicated Chinese patients could benefit from similar efficacy to Asian patients.

Abstract HSK16149 is a novel, potent gamma‐aminobutyric acid (GABA) analog for the treatment of neuropathic pain. The purpose of this study was to assess the effect of a high‐fat and high‐calorie meal on the pharmacokinetics of HSK16149 in healthy Chinese subjects. An open‐label, two‐period crossover design was applied in this study. Twenty‐six subjects were enrolled and were randomly divided into two groups: a fasted‐fed group and a fed‐fasted group, with 13 subjects in each group. Subjects took a single oral dose of 45 mg of HSK16149 under fasted or fed conditions on Day 1 and Day 4. A series of blood samples were collected for PK analysis. Safety was evaluated throughout the study by physical examinations, clinical laboratory tests, 12‐lead ECGs, vital signs, and adverse events (AEs). The parameters AUC0‐∞, AUC0‐t, and Cmax of HSK16149 were compared to assess the bioequivalence of HSK16149 under fasted and fed conditions. The geometric mean ratios (GMRs) and their 90% confidence intervals (CIs) of AUC0‐t and AUC0‐∞ under the fed condition compared with the fasted condition were 95.84% (91.94–99.90%) and 95.79% (91.89–99.84%), respectively, which were all within the bioequivalent interval (80.00–125.00%). The GMR (90% CI) of Cmax under the fed condition compared with the fasted condition was 66.04% (59.45–73.36%), which was not within the bioequivalent range (80.00–125.00%). All adverse events were transient and resolved. This study demonstrated that HSK16149 can be administered with or without food.

IntroductionTraditional DBS is usually conducted under local anesthesia (LA) which is intolerable to some patients, DBS under general anesthesia (GA) was opted to extended surgical indication. This study aimed to compare the efficacy and safety of bilateral subthalamic deep brain stimulation (STN-DBS) for Parkinson’s disease (PD) under asleep and awake anesthesia state in 1-year postoperative follow-up.MethodsTwenty-one PD patients were assigned to asleep group and 25 patients to awake group. Patients received bilateral STN-DBS under different anesthesia state. The PD participants were interviewed and assessed preoperatively and at 1-year postoperative follow-up.ResultsAt 1-year follow-up, compared surgical coordinate in two groups, the left-side Y of asleep group showed more posterior than awake group (Y was-2.39 ± 0.23 in asleep group, −1.46 ± 0.22 in awake group, p = 0.007). Compared with preoperative OFF MED state, MDS-UPDRS III scores in OFF MED/OFF STIM state remained unchanged, while in OFF MED/ON STIM state were significantly improved in awake and asleep groups, yet without significant difference. Compared with preoperative ON MED state, MDS-UPDRS III scores in ON MED/OFF STIM, and ON MED/ON STIM state remained unchanged in both groups. In non-motor outcomes, PSQI, HAMD, and HAMA score significantly improved in asleep group compared to awake group at 1-year follow-up (PSQI, HAMD, and HAMA score in 1-year follow-up were 9.81 ± 4.43; 10.00 ± 5.80; 5.71 ± 4.75 in awake group, 6.64 ± 4.14; 5.32 ± 3.78; 3.76 ± 3.87 in asleep group, p = 0.009; 0.008; 0.015, respectively), while there was no significant difference in PDQ-39, NMSS, ESS, PDSS score, and cognitive function. Anesthesia methods was significantly associated with improvement of HAMA and HAMD score (p = 0.029; 0.002, respectively). No difference in LEDD, stimulation parameters and adverse events was observed between two groups.DiscussionAsleep STN-DBS may be considered a good alternative method for PD patients. It is largely consistent with awake STN-DBS in motor symptoms and safety. Yet, it showed higher improvement in terms of mood and sleep compared to awake group at 1-year follow-up.

ABSTRACT Infection by fungal pathogens is the main factor leading to postharvest rot and quality deterioration of fruit and vegetables. Rotting caused by Alternaria alternata is a concerning disease for numerous crops in both production and postharvest stages, especially tomato black spots. In this study, the double Petri dish assay showed that the VOCs of Ceratocystis fimbriata WJSK-1 and Mby inhibited the mycelial growth of fungal pathogen A. alternata, with a percentage inhibition of 52.2% and 42.9%. Then, HS-SPME-GC-MS technology was used to analyze the volatiles produced by two strains of C. fimbriata (WJSK-1, Mby), a total of 42 volatile single components were obtained, the main volatiles compounds identified include nine esters, 10 ketones, five alcohols, four aldehydes, three aromatic hydrocarbons, three heterocycles, four alkenes, three alkanes, and one acid. After that, the antifungal activity of a single volatile component was evaluated both in vitro and in vivo, four single components with antifungal effects were screened out, namely, benzaldehyde, nonanal, 2-Phenylethanol and isoamyl acetate, with IC50 values show the smallest values for benzaldehyde and nonanal at 0.11 μL mL−1, 0.04 μL mL−1. A. alternata exposed to VOCs had abnormal morphology for hyphae, delayed sporulation, and inhibited spore germination. In vivo experiment shows that the four volatile components can effectively suppress disease incidence on fungal-inoculated fruit; the two aldehydes (benzaldehyde and nonanal) have more prominent effect on delaying fruit onset of disease. The results showed that VOCs produced by C. fimbriata have potential as a fumigant for controlling black rot in cherry tomatoes. IMPORTANCE In this research, the volatile organic compounds (VOCs) produced based on C. fimbriata exhibited strong antifungal activity against the fungal pathogen A. alternata. Our aim is to explore their bacteriostatic components. HS-SPME-GC-MS technology was used to analyze the volatiles produced by the C. fimbriata strain (WJSK-1, Mby). Postharvest cherry tomato fruit black rot caused by A. alternata was treated both in vitro and in vivo, with pure individual components produced by C. fimbriata. The benzaldehyde, nonanal, 2-Phenylethanol, and isoamyl acetate from C. fimbriata can effectively inhibit growth of A. alternata, and delay disease. It has the potential to be developed as a new type of fumigant, a potential replacement for fungicides in the future.

Abstract It is well known that the main forms of innervation are synapses and free nerve endings, while other forms of innervation have not been reported. Here, we explore a new way of innervating lymphoid organs. Male Sprague‐Dawley rats were used for studying the innervation of sympathetic nerve fibers in lymph nodes by means of anterograde tracking, immunoelectron microscopy, three‐dimension reconstruction analysis, and immunofluorescence labeling. The results showed that the Fluoro‐Ruby labeled nerve endings targeted only a group of cells in the lymph nodes and entered the cells through the plasma membrane. The electron microscopy showed that the biotinylated glucan amine reaction elements were distributed in the cytoplasm, and most of the biotinylated glucan amine active elements were concentrated on the microtubule and microfilament walls. Birbeck particles with rod‐shaped and/or tennis racket like structures can be seen in the labeled cells at high magnification, and Birbeck particles contain biotinylated glucan amine‐reactive elements. The immunofluoresence results showed that the Fluoro‐Ruby‐labeled nerve innervating cells expressed CD207 and CD1a protein. This result confirmed that the labeled cells were Langerhans cells. Our findings suggested that Langerhans cells might serve as a “bridge cell” for neuroimmune cross‐talking in lymph organs, which play an important role in transmitting signals of the nervous system to immune system. This study also opened up a new way for further study of immune regulation mechanism.

Previous studies have revealed nephrotoxicity, hepatotoxicity, subchronic developmental and reproductive toxicity in rats exposed to fluorotelomer alcohol (FTOH). However, the effects of embryonic 6:2 FTOH exposure on the reproductive system of offspring mice remain unclear. The purpose of this study is to explore the reproductive toxic effects of embryonic 6:2 FTOH exposure on offspring male mice and the related molecular mechanisms. Therefore, the pregnant mice were given corn oil or 6:2 FTOH by gavage from gestational days 12.5–21.5. The results demonstrated that embryonic 6:2 FTOH exposure resulted in disrupted testicular structure, low expression of tight junction protein between Sertoli cells (SCs), impaired blood-testis barrier (BTB) formation and maturation, reduced sperm viability and increased malformation, and induced testicular inflammation in the offspring of mice. Further in vitro studies showed that 6:2 FTOH treatment upregulated MMP-8 expression by activating AKT/NF-κB signaling pathway, which in turn enhanced occludin cleavage leading to the disruption of SCs barrier integrity. In summary, this study demonstrated that 6:2 FTOH exposure caused reproductive dysfunction in male offspring through disruption of BTB, which provided new insights into the effects of 6:2 FTOH exposure on the offspring.

ObjectivesTo compare the rate and extent of absorption of a launched generic calcium dobesilate capsule versus the branded reference formulation under fasting and fed conditions in healthy Chinese subjects, and to assess their bioequivalence and tolerability.MethodsThis single-dose, open-label, randomized-sequence, 2-period crossover bioequivalence study was conducted on healthy Chinese volunteers aged 18 to 45 years. Subjects received a single 0.5 g dose of calcium dobesilate capsule under fasting or fed conditions, with a 3-day washout period between doses of the test (T) and reference (R) formulations. Blood samples were collected before and up to 24 hours after administration. The plasma concentration of calcium dobesilate was determined by a validated Liquid chromatography-tandem mass spectrometry method. Non-compartmental analysis was applied to identify the pharmacokinetic (PK) properties. The primary PK parameters including the maximal plasma concentration (Cmax), the area under the plasma concentration-time curve (AUC0-t), and the AUC extrapolated to infinity (AUC0-inf) were used for bioequivalence evaluation.ResultsThe mean of PK parameters for T and R capsules under fasting (fed) condition were: Cmax, 13.57 (6.71) and 12.59 (7.25) μg/mL; AUC0-t, 97.32 (79.74) and 96.97 (80.71) h*μg/mL; AUC0-inf, 101.68 (88.01) and 101.64 (87.81) h*μg/mL. The 90% confidence intervals (CIs) of GMRs under fasting (fed) condition were: Cmax, 97.91%-116.62% (88.63%-96.53%); AUC0-t, 97.15%-104.00% (96.58%-101.39%); and AUC0-inf, 97.19%-102.89% (98.67%-103.99%). These 90% CIs were all within the bioequivalence range of 80%-125%. All adverse events were mild.ConclusionIn this study, the T calcium dobesilate 0.5 g capsule was bioequivalent to the reference product under both fasting and fed conditions. Taking food would slow down its rate and reduce its amount of absorption. Both formulations were generally well tolerated.

Halosulfuron-methyl (HSM) is a new and highly effective sulfonylurea herbicide widely used in weed control, but its residue in the environment poses a potential risk to soybean. Soybean–rhizobium symbiotic nitrogen fixation is crucial for sustainable agricultural development and ecological environment health. However, the impact of HSM on the symbiosis between soybean and rhizobium is unclear. In this study, the effects of HSM on the soybean–rhizobium symbiotic process and nitrogen fixation were investigated by means of transcriptomic and physiological analyses. Treatment with a concentration of HSM less than 0.5 mg L−1 had no effect on rhizobium growth, but significantly reduced nodules number, the biomass of soybean nodules, and nitrogenase activity in root nodules (P

Regeneration of a complex appendage structure such as limb requires upstream and downstream coordination of multiple types of cells. Given type of cell may sit at higher upstream position to control the activities of other cells. Muscles are one of the major cell masses in limbs. However, the subtle functional relationship between muscle and other cells in vertebrate complex tissue regeneration are still not well established. Here, we use Pax7 mutant axolotls, in which the limb muscle is developmentally lost, to investigate limb regeneration in the absence of skeletal muscle. We find that the pattern of regenerated limbs is relative normal in Pax7 mutants compared to the controls, but the joint is malformed in the Pax7 mutants. Lack of muscles do not affect the early regeneration responses, specifically the recruitment of macrophages to the wound, as well as the proliferation of fibroblasts, another major population in limbs. Furthermore, using single cell RNA-sequencing, we show that, other than muscle lineage that is mostly missing in Pax7 mutants, the composition and the status of other cell types in completely regenerated limbs of Pax7 mutants are similar to that in the controls. Our study reveals skeletal muscle is barely required for the guidance of other cells, as well the patterning in complex tissue regeneration in axolotls, and provides refined views of the roles of muscle cell in vertebrate appendage regeneration.

Abstract With a large marginal land area, the Loess Plateau in China holds great potential for biomass production and environmental improvement. Identifying suitable locations for biomass production on marginal land is important for decision‐makers from the viewpoint of land‐use planning. However, there is limited information on the suitability of marginal land within the Loess Plateau for biomass production. Therefore, this study aims to evaluate the suitability of the promising perennial energy crop switchgrass (Panicum virgatum L.) on marginal land across the Loess Plateau. A fuzzy logical model was developed and validated based on field trials on the Loess Plateau and applied to the marginal land of this region, owing to its ability of dealing with the continuous nature of soil, landscape variations, and uncertainties of the input data. This study identified that approximately 12.8–20.8 Mha of the Loess Plateau as available marginal land, of which 2.8–4.7 Mha is theoretically suitable for switchgrass cultivation. These parts of the total marginal land are mainly distributed in northeast and southwest of the Loess Plateau. The potential yield of switchgrass ranges between 44 and 77 Tg. This study showed that switchgrass can grow on a large proportion of the marginal land of the Loess Plateau and therefore offers great potential for biomass provision. The spatial suitability maps produced in this study provide information to farmers and policymakers to enable a more sustainable development of biomass production on the Loess Plateau. In addition, the fuzzy‐theory‐based model developed in this study provided a good framework for evaluating the suitability of marginal land.

AlCrSiN coatings are promising protective candidates for cutting and forming tools. During the coating deposition process, the microstructure and properties of the coatings were dramatically affected by bias voltages. To further optimize and enhance the AlCrSiN coating, a series of coatings were deposited at different pulse bias voltages using arc ion plating technology. By virtue of scanning electron microscopy, X-ray diffraction, scratch method, OCP, EIS, and other analytical methods, the effects of the pulse bias voltage on the crystal structure, microstructure, and mechanical, tribological, and electrochemical properties of the AlCrSiN coatings were analyzed. The study revealed that the pulse bias voltage exerted a slight influence on the aluminum and nitrogen content of the coatings. As the pulse bias voltage increased, the hardness, critical load, and tribological performance of the AlCrSiN coatings first increased gradually, and then were impaired slightly. When the pulse bias voltage was −100 V, the resulting AlCrSiN coating exhibited the densest structure, the highest hardness, the strongest adhesion, and the best wear resistance. In this case, the coating hardness and critical load reached 2668 HV and 72.7 N, respectively. The friction coefficient and wear rate were 0.35 and 1.02 × 10−3 μm3/N·μm, respectively. Simultaneously, the AlCrSiN coating demonstrated exceptional corrosion resistance in 3.5 wt.% NaCl solutions, surpassing uncoated 304 steel by 3~4 times.

Antimony (Sb) is a potential candidate anode for potassium-ion batteries (PIBs) owing to its high theoretical capacity. However; in the process of potassium alloying reaction; the huge volume expansion (about 407%) leads to pulverization of active substance as well as loss of electrical contact resulting in rapidly declining capacity. Herein; uniformly dispersed Sb-Nanodot in carbon frameworks (Sb-ND@C) were constructed by in situ confined polymerization of ionic liquids. Attributed to the uniformly dispersed Sb-ND and confinement effect of carbon frameworks; as anode for PIBs; Sb-ND@C delivered a superior rate capability (320.1 mA h g−1 at 5 A g−1) and an outstanding cycling stability (486 mA h g−1 after 1000 cycles; achieving 89.8% capacity retention). This work offers a facile route to prepare highly dispersed metal-Nanodot via the in situ polymerization of ionic liquid for high-performance metal-ion batteries

The Loess Plateau, with a large area of marginal land, holds the potential to produce 62–106 Tg per year of switchgrass biomass; however, the economic feasibility of producing bioenergy in the region is unclear. The farm-gate feedstock production (FGFP) cost of switchgrass was calculated in a spatially explicit way by taking the geographic variation in crop yield, soil properties, land quality, and input costs into consideration in order to evaluate the economic performance of bioenergy production. Cost–supply curves were constructed to explore the energy supply potential of switchgrass feedstock. The calculations were conducted using ArcGIS in a 1 km grid and all the evaluations were conducted under different agricultural management practice (AMP) scenarios in parallel. The FGFP costs showed significant spatial variation ranging from 95 to 7373 CNY (Chinese Yuan) per tonne−1 and that the most economically desirable areas are scattered in the south and southeast region. The weighted average FGFP costs are 710, 1125, and 1596 CNY per tonne−1 for small bale (SB), large bale (LB), and chipping (CP) harvest methods, respectively. The projected energy supply potential is 1927 PJ (Petajoules) per year−1, of which 30–93% can be supplied below the market prices of different fossil fuels according to feedstock formats. Compared to current biomass residual pricing, 50–66 Tg (Teragrams) switchgrass feedstock is competitive. The results demonstrated that the Loess Plateau holds the potential to produce bioenergy that is economically feasible. This study provides a methodological framework for spatially explicit evaluation of the economic performance of perennial energy crops. Detailed information obtained from this study can be used to select the optimal locations and AMPs to produce feedstock production at minimum cost.

Abstract A successful tissue regeneration is a very complex process that requires a precise coordination of many molecular, cellular and physiological events. One of the critical steps is to convert the injury signals into regeneration signals to initiate tissue regeneration. Although many efforts have been made to investigate the mechanisms triggering tissue regeneration, the fundamental questions remain unresolved. One of the major obstacles is that the injury and the initiation of regeneration are two highly coupled processes and hard to separate from one another. In this article, we review the major events occurring at the early injury/regeneration stage in a range of species, and discuss the possible common mechanisms during initiation of tissue regeneration.

BackgroundFacial appearance and expressions influence social interaction. Hemifacial spasm (HFS), blepharospasm (BPS), and blepharospasm-oromandibular dystonia (BOD) are common forms of craniofacial movement disorders. Few studies have focused on the mental burden and quality of life (QoL) in patients with craniofacial movement disorders. Therefore, this study investigated mental health and QoL in these patients.MethodsThis cross-sectional study included 90 patients with craniofacial movement disorders (HFS, BPS, and BOD; 30 patients per group) and 30 healthy individuals without craniofacial movement disorders (control group) recruited from October 2019 to November 2020. All participants underwent QoL and mental health evaluations for depression, anxiety, and stigma using the 36-item Short Form Health Survey (SF-36), Hamilton Anxiety Rating Scale (HAMA), Hamilton Rating Scale for Depression-24 (HAMD-24) and a questionnaire related to stigma.ResultsDepression was diagnosed in 37 (41.11%) patients, whereas 30 patients (33.33%) had anxiety. HAMA scores were significantly higher in the BPS and BOD groups than in the control group. Nineteen patients (21.11%) experienced stigma and SF-36 scores were lower in various dimensions in the movement disorders groups compared to healthy controls. The role-physical and social function scores were significantly lower in the movement disorders groups than in the control group all p < 0.05. The vitality scores of the BPS group and mental health scores of the BPS and BOD groups were significantly lower than those of the control group. Correlation analysis showed that the eight dimensions of SF-36 correlated with education level, disease duration, HAMD score, and HAMA score (all p < 0.05). Regression analysis demonstrated that the HAMD score correlated with general health, vitality, social function, role-emotional, and mental health (all p < 0.05). The HAMA score correlated with body pain after adjusting for education level and disease duration.ConclusionThis study highlights the significant frequency of mental symptoms, including depression, anxiety, and stigma, which lower QoL in patients with craniofacial movement disorders.

Background: Danhong injection is widely used for treating ischemic stroke in China. However, its effects on ischemic stroke patients when given along with Western medicines (i.e., the add-on effect) were not well-established.Methods: We searched PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and three Chinese databases from inception to 20 July 2020 to identify randomized controlled trials (RCTs) that assessed the effects of Danhong injection as add-on therapy in patients with ischemic stroke. Pairs of trained reviewers independently screened for eligible studies, assessed risk of bias, and extracted the data. The outcomes were the National Institutes of Health Stroke Scale Score (NIHSS), Barthel index, activities of daily living (ADL), total cholesterol, and homocysteine (Hcy).Results: Sixty-seven RCTs of 6594 patients with varying risk of bias were included. Compared with Western medicine alone, the addition of Danhong injection to Western medicine significantly lowered the NIHSS score (45 RCTs with 4565 patients; MD −4.21, 95% CI −4.96 to −3.46), total cholesterol (10 trials with 1019 patients; MD −1.14 mmol/L, 95% CI −1.57 to −0.72), and Hcy (four trials with 392 patients; MD −3.54 μmol/L, 95% CI −4.38 to −2.07). The addition of Danhong also increased the Barthel index (14 trials with 1270 patients; MD 8.71, 95% CI 3.68–13.74) and ADL (12 trials with 1114 patients; MD 14.48, 95% CI 9.04–19.92) scores. Subgroup analyses showed differential effects in the average cerebral blood flow rate by mean age of patients (

Effective tiller number (ETN) is an important factor affecting plant architecture and wheat yield. The reduction of genetic diversity in common wheat breeding forces us to explore new genetic resources for ETN from wheat related species to increase wheat yield. Here, a tetraploid wheat recombinant inbred line (RIL) population developed from the cross between a durum and a wild emmer accession was used to construct a genetic map using the wheat 55 K single nucleotide polymorphism (SNP) array. The map contained 1154 SNP markers with a total length of 2452.79 cM and an average density of 2.13 cM/marker. Quantitative trait locus (QTL) analysis identified a major and stably expressed QTL, Qetn-DW-4B.1 for ENT, explaining 12.40–15.25% of the phenotypic variation. The favorable allele of this QTL was from wild emmer wheat and physically mapped in a 2.25 Mbp interval of 4BL containing 23 genes among which several were likely related to tiller development. Further comparison with previous studies showed that Qetn-DW-4B.1 is likely a novel QTL. Genetic associations between ETN and other agronomic traits were also analyzed. Collectively, this study reported a major QTL for ENT from related species and lays a foundation to fine mapping and further wheat molecular breeding. Supplemental data for this article is available online at https://doi.org/10.1080/13102818.2021.1996271 .

The human oral cavity provides a habitat for oral microbial communities. The complexity of its anatomical structure, its connectivity to the outside, and its moist environment contribute to the complexity and ecological site specificity of the microbiome colonized therein. Complex endogenous and exogenous factors affect the occurrence and development of the oral microbiota, and maintain it in a dynamic balance. The dysbiotic state, in which the microbial composition is altered and the microecological balance between host and microorganisms is disturbed, can lead to oral and even systemic diseases. In this review, we discuss the current research on the composition of the oral microbiota, the factors influencing it, and its relationships with common oral diseases. We focus on the specificity of the microbiota at different niches in the oral cavity, the communities of the oral microbiome, the mycobiome, and the virome within oral biofilms, and interventions targeting oral pathogens associated with disease. With these data, we aim to extend our understanding of oral microorganisms and provide new ideas for the clinical management of infectious oral diseases.

Atmospheric nitrogen deposition is an important contributor to global and regional nitrogen cycles, and atmospheric nitrogen could be a critical limit nutrient for remote areas. In this study, nitrogen species compositions, deposition fluxes, and historical records in the mountains of Western China, including the Tibetan Plateau, were determined from snowpit and ice core samples collected from mountain glaciers. The mean concentration of total dissolved nitrogen (TDN) in the snowpit samples was 12.6 μmol L−1 (8.0–17.8 μmol L−1) and comprised 59% ammonium nitrogen, 35% nitrate nitrogen, and ∼6% dissolved organic nitrogen. The deposition of nitrogen species, except organic nitrogen (likely due to its low concentrations and/or different origination), varied seasonally in a similar way based on the records of the snowpit profile. Based on monthly surface sample collection in one of the glaciers, the mass concentration and composition of nitrogen species varied monthly, mainly because of melting processes. During melting, the inorganic nitrogen content could be lost significantly, whereas the dissolved organic nitrogen concentration could be enriched because of microbial activity. For the historical records, the nitrogen deposition in mountain areas of Western China after 1960s was increased by about one time of that during 1900–1950 and was dominated by ammonium-N. From the snowpit data, we estimated the total dissolved nitrogen deposition flux at 0.56–1.3 (mean 0.88) kg ha−1 a−1 in the mountain area of Western China. These results could improve our understanding of nitrogen deposition and cycle in the mountain areas of Western China.

Tumour vascular mimicry (VM) is the process by which new blood vessels are formed by tumour cells rather than endothelial cells. An increasing number of studies have revealed that the VM process is associated with cancer progression and metastasis. MiR-138-5p has been reported to act as a tumour suppressor in many cancers. However, the role and underlying mechanism of miR-138-5p in hepatocellular carcinoma (HCC) VM remain unclear. In this study, VM density was detected by CD31/periodic acid-Schiff double staining in HCC clinical specimens. We found that miR-138-5p expression correlated strongly and negatively with microvessel density. Additionally, the miR-138-5p mimic or inhibitor decreased or increased, respectively, tube formation capacity in HepG2 and Hep3B cells. Consistent with this finding, miR-138-5p repressed vessel density in vivo. Moreover, miR-138-5p targeted hypoxia-inducible factor 1α (HIF-1α) and regulated the expression of HIF-1α and vascular endothelial growth factor A (VEGFA), which are established classical master regulators for angiogenesis. Consistent with these findings, the HIF-1α inhibitor CAY10585 effectively blocked HCC cell VM and VEGFA expression. In conclusion, miR-138-5p inhibits HepG2 and Hep3B cell VM by blocking the HIF-1α/VEGFA pathway. Therefore, miR-138-5p may serve as a useful therapeutic target for miRNA-based HCC therapy.