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Abstract Background Efgartigimod, a human immunoglobulin G (IgG)1-derived Fc fragment targeting the neonatal Fc receptor, has been developed into intravenous (IV) and subcutaneous (SC) formulations for treating generalized myasthenia gravis (gMG) and other autoimmune diseases. Data in the Chinese population were not available to date, and while both formulations have been approved in the USA, the EU, Japan and China for the treatment of gMG. Objective We present the pharmacokinetic, pharmacodynamic, and safety of IV and SC PH20 efgartigimod in healthy Chinese participants. Methods In two independent, double-blinded, placebo-controlled, phase I studies of the IV and SC formulations of efgartigimod, healthy Chinese adults were randomized 3:1 to receive active treatment or matching placebo once every 7 days for four doses. Primary endpoints were pharmacokinetic parameters. Results After the fourth IV infusion, a mean maximum observed concentration (C max) of 194 µg/mL was reached at the end of the 1 h infusion; the mean area under concentration–time curve from time zero to 168 h (AUC0–168h) was 5300 µg × h/mL. After the fourth SC injection, a mean C max of 42.1 µg/mL was achieved with a median T max of 47.74 h; the mean AUC0–168h was 4790 µg × h/mL. Maximal mean reductions from baseline in total IgG levels were reached approximately 24 days after the first dose (60.7%, IV formulation; 66.4%, SC formulation). Treatment-related adverse events (TRAEs) were reported in seven (58.3%) participants receiving SC efgartigimod, mostly injection-site reactions. No TRAEs or AEs of special interest were reported in the IV study. Conclusions The efgartigimod IV and SC pharmacokinetic, pharmacodynamic, and safety profiles in Chinese participants were similar to the known profiles in non-Chinese participants. Both formulations effectively reduced total IgG levels by a similar percentage. Clinical Trial Registration CTR20211952 and CTR20211805.

Abstract Background TG103, a glucagon-like peptide-1 analog, is being investigated as an option for weight management. We aimed to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of TG103 injection in participants who are overweight or obese without diabetes. Methods In this randomized, double-blind, placebo-controlled, multiple-dose phase 1b study, participants aged 18–75 years with a body-mass index (BMI) ≥ 26.0 kg/m2 and body weight ≥ 60 kg were enrolled from three centers in China. The study included three cohorts, and in each cohort, eligible participants were randomly assigned (3:1) to one of three once-weekly subcutaneous TG103 groups (15.0, 22.5 and 30.0 mg) or matched placebo, without lifestyle interventions. In each cohort, the doses of TG103 were escalated in 1-week intervals to the desired dose over 1 to 4 weeks. Then participants were treated at the target dose until week 12 and then followed up for 2 weeks. The primary endpoint was safety and tolerability assessed by the incidence and severity of adverse events (AEs) from baseline to the end of the follow-up period. Secondary endpoints included pharmacokinetic and pharmacodynamic profiles of TG103 and the occurrence of anti-drug antibodies to TG103. Results A total of 147 participants were screened, and 48 participants were randomly assigned to TG103 (15.0, 22.5 and 30.0 mg groups, n = 12 per group) or placebo (n = 12). The mean (standard deviation, SD) age of the participants was 33.9 (10.0) years; the mean bodyweight was 81.65 (10.50) kg, and the mean BMI was 29.8 (2.5) kg/m2. A total of 466 AEs occurred in 45 of the 48 participants, with 35 (97.2%) in the TG103 group and 10 (83.3%) in the pooled placebo group. Most AEs were grade 1 or 2 in severity, and there were no serious adverse events (SAEs), AEs leading to death, or AEs leading to discontinuation of treatment. The steady-state exposure of TG103 increased with increasing dose and was proportional to Cmax,ss, AUCss, AUC0-t and AUC0-inf. The mean values of Cmax,ss ranged from 951 to 1690 ng/mL, AUC0-t ranged from 150 to 321 μg*h/mL, and AUC0-inf ranged from 159 to 340 μg*h/mL. TG103 had a half-life of 110–116 h, with a median Tmax of 36–48 h. After treatment for 12 weeks, the mean (SD) values of weight loss from baseline in the TG103 15.0 mg, 22.5 mg and 30.0 mg groups were 5.65 (3.30) kg, 5.35 (3.39) kg and 5.13 (2.56) kg, respectively, and that in the placebo group was 1.37 (2.13) kg. The least square mean percent weight loss from baseline to D85 in all the TG103 groups was more than 5% with p

Abstract Background The protein tyrosine phosphatase H receptor (PTPRH) is known to regulate the occurrence and development of pancreatic and colorectal cancer. However, its association with glycolysis in non-small cell lung cancer (NSCLC) is still unclear. In this study, we aimed to investigate the relationship between PTPRH expression and glucose metabolism and the underlying mechanism of action. Methods The expression of PTPRH in NSCLC cells was evaluated by IHC staining, qRT‒PCR and Western blotting. The effect of PTPRH on cell biological behavior was evaluated by colony assays, EdU experiments, Transwell assays, wound healing assays and flow cytometry. Changes in F-18-fluorodeoxyglucose (18F‐FDG) uptake and glucose metabolite levels after altering PTPRH expression were detected via a gamma counter and lactic acid tests. The expression of glycolysis-related proteins in NSCLC cells was detected by Western blotting after altering PTPRH expression. Results The results showed that PTPRH was highly expressed in clinical patient tissue samples and closely related to tumor diameter and clinical stage. In addition, PTPRH expression was associated with glycometabolism indexes on 18F-FDG positron emission tomography/computed tomography (PET/CT) imaging, the expression level of Ki67 and the expression levels of glycolysis-related proteins. PTPRH altered cell behavior, inhibited apoptosis, and promoted 18F-FDG uptake, lactate production, and the expression of glycolysis-related proteins. In addition, PTPRH modulated the glycometabolism of NSCLC cells via the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway, as assessed using LY294002 and 740Y-P (an inhibitor and agonist of PI3K, respectively). The same results were validated in vivo using a xenograft tumor model in nude mice. Protein expression levels of PTPRH, glycolysis-related proteins, p-PI3K/PI3K and p-AKT/AKT were measured by IHC staining using a subcutaneous xenograft model in nude mice. Conclusions In summary, we report that PTPRH promotes glycolysis, proliferation, migration, and invasion via the PI3K/AKT/mTOR signaling pathway in NSCLC and ultimately promotes tumor progression, which can be regulated by LY294002 and 740Y-P. These results suggest that PTPRH is a potential therapeutic target for NSCLC. Graphical Abstract

Abstract Introduction Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, blocks cytokine signaling involved in psoriasis pathogenesis. This ethnic-bridging study evaluated deucravacitinib pharmacokinetics, tolerability, and safety in healthy Chinese subjects. Methods This phase I, double-blind, single-/multiple-dose study randomized healthy Chinese subjects 4:1 to a single dose of deucravacitinib 6 mg or placebo (group 1) or deucravacitinib 12 mg or placebo (group 2) on day 1; groups 1 and 2 received deucravacitinib 6 mg and 12 mg once daily, respectively, or placebo on days 5–19. Blood samples were collected on days 1–5 (0 predose–96 h postdose), day 5 (0–24 h postdose), days 9 and 12 (0 h), and day 19 (0–24 h postdose). Deucravacitinib and metabolite (BMT-153261, BMT-158170) concentrations were determined using liquid chromatography/mass spectrometry; pharmacokinetic parameters were calculated using noncompartmental analysis. Urine was collected on days 1–4 (4 h predose–96 h postdose). Safety was monitored throughout. Results Forty healthy Chinese subjects (groups 1 and 2: deucravacitinib, n = 32; placebo, n = 8) were enrolled. Deucravacitinib was rapidly absorbed after single-/multiple-dose administration, with median time to maximal plasma concentration of 1.5–2.3 h. Systemic exposure after single or multiple doses increased approximately twofold with twofold dose increase. Modest deucravacitinib accumulation was observed after multiple-dose administration (1.3- to 1.4-fold increase in area under the curve [AUC] under one dosing interval). Metabolite-to-parent ratios for maximal plasma concentration and AUC remained consistent in each dose group. Mean urinary percent recovery and renal clearance were similar between dose groups. Most adverse events (AEs) were mild/moderate, with no serious treatment-related AEs, deaths, or discontinuations due to AEs. Conclusion Deucravacitinib was safe and well tolerated in healthy Chinese subjects. Deucravacitinib exhibited rapid absorption, dose-related increases in exposure, comparable half-life, and no evidence of time-dependent pharmacokinetics, suggesting minimal effect of Chinese ethnicity on deucravacitinib pharmacokinetics. Clinical Trial Registration NCT03956953.

Yunnan snub-nosed monkeys (Rhinopithecus bieti) are the highest elevation lived non-human primate, and their survival has been threatened for decades. To promote their population growth, a reserve provides a typical monkey population with supplemental food. However, the influences of this food provisioning on their gut microbiota and antibiotic resistance genes (ARGs) were unknown. Therefore, we investigated the gut microbiota and ARGs of the food-provisioned monkey population compared with another wild foraging population. We found that food provisioning significantly increased the gut microbiota diversity and changed the community composition, particularly increased both the Firmicutes abundance and Firmicutes/Bacteroidetes ratio. Meanwhile, the food provisioning decreased the complex and stable gut microbiota network. KEGG functions were also influenced by food provisioning, with wild foraging monkeys showing higher functions of metabolism and genetic information processing, especially the carbohydrate metabolism, while food-provisioned monkeys exhibited increased environmental information processing, cellular processes, and organismal systems, including valine, leucine, and isoleucine degradation. In addition, food provisioning increased the abundance of ARGs in the gut microbiota, with most increasing the abundance of bacA gene and changing the correlations between specific ARGs and bacterial phyla in each population. Our study highlights that even food provisioning could promote wildlife nutrient intake, and it is necessary to pay attention to the increased ARGs and potential effects on gut microbiota stability and functions for this human conservation measure.

Abstract CSPCHA115 is a highly selective and potent antagonist of chemoattractant receptor‐homologous molecule expressed on TH2 cells (CRTH2). This study aimed to evaluate the pharmacokinetics (PKs), safety, and tolerability of single and multiple ascending doses of CSPCHA115 in Chinese healthy subjects. Two phase I studies both adopted a randomized, double‐blind, placebo‐controlled, single‐center, and ascending‐dose design. In the single ascending dose (SAD) study, subjects were randomly allocated to receive a single dose of CSPCHA115 (25–1000 mg) or a placebo. In the multiple ascending dose (MAD) study, 100, 200, 400, or 600 mg of CSPCHA115 or placebo were given to subjects once daily for 7 days. PK parameters were estimated by noncompartmental analysis. Safety was assessed by monitoring treatment‐emergent adverse events (TEAEs), clinical laboratory tests, electrocardiograms, vital signs, and physical examinations throughout the study period. Forty‐eight healthy subjects were enrolled in the SAD study, and 40 healthy subjects were in the MAD study. Following single and multiple administrations, CSPCHA115 was rapidly absorbed with a median time to maximum concentration of ~0.5–3.5 h; and the systemic exposure of CSPCHA115 generally increased dose‐proportionally within the dose range studied. Steady‐state was approximately achieved by day 5, and

Abstract Background This study introduces a novel retrograde precision shaping elastic stable intramedullary nailing (ESIN-RPS) technique and reports clinical outcomes in pediatric distal radius metaphyseal diaphysis junction (DRMDJ) fracture. Methods Data about DRMDJs were collected from February 1, 2020, to April 31, 2022 at two hospitals, retrospectively. All patients were treated with closed reduction and ESIN-RPS fixation. The operation time, blood loss, fluoroscopy times, alignment, and residual angulation on X-ray were recorded. At the last follow-up, the function of wrist and forearm rotation were evaluated. Results Totally, 23 patients were recruited. The mean time of follow-up was 11 months and the minimum was 6 months. The mean operation time was 52 min, and the mean fluoroscopies pulses were 6 times. The postoperative anterioposterior (AP) alignment was 93 ± 4% and the lateral alignment was 95 ± 3%. The postoperative AP angulation was (4 ± 1)°, and the lateral angulation was (3 ± 1)°. At the last follow-up, the evaluation of the Gartland and Werley demerit criteria of wrist revealed 22 excellent cases and 1 good case. The forearm rotation and thumb dorsiflexion functions were not limited. Conclusion The ESIN-RPS is a novel, safe, and effective method for the treatment of pediatric DRMDJ fracture.

Arbuscular mycorrhizal fungi (AMF) and plants form a symbiotic relationship that promotes plant growth and development. However, the regulatory mechanisms through which AMF promote plant growth and development are largely unexplored. In this study, the apple rootstock M26 was assessed physiologically, transcriptionally and metabolically when grown with and without AMF inoculation. AMF significantly promoted the number of lateral root (LR) increase and shoot elongation. Root transcriptomic and metabolic data showed that AMF promoted lateral root development mainly by affecting glucose metabolism, fatty acid metabolism, and hormone metabolism. Shoot transcriptomic and metabolic data showed that AMF promoted shoot elongation mainly by affecting hormone metabolism and the expression of genes associated with cell morphogenesis. To investigate whether shoot elongation is caused by root development, we analyzed the root/shoot dry weight ratio. There was a correlation between shoot growth and root development, but analysis of root and shoot metabolites showed that the regulation of AMF on plant shoot metabolites is independent of root growth. Our study bridged the gap in the field of growth and development related to AMF.

ObjectiveTo explore the immune change of lung injury of Ulcerative colitis (UC) by observing the changes of inherent immunity and adaptive immunity of the lung and bowel in UC rat models after the treatment of Sodium Houttuyfonate combined with Matrine. MethodUC rat models were established with the mucous membrane of colon allergize combined with TNBS-alcohol enteroclysis for 1 week and 5 weeks. 1-week experimental rats were divided into normal group and model group, 5/each group. 5-weeks experimental rats were divided into normal group, model group, Sodium Houttuyfonate (2.9mg/ml) combined with Matrine (1.47mg/ml), and positive control sulfasalazine (10mg/ml), 5/each group. All rats were administered by gavage for 5 weeks. The histopathological and fibrotic changes in the lung and bowel were observed, and the expressions of Tumor Necrosis Factor (TNF)- α, interleukin (IL)-8 in the lung, bowel, and serum were detected by radio-immunity and immunohistochemistry, and the mRNA expressions of Toll-like receptor (TLR)-4, nuclear factor kappa (NF-κB), Macrophage migration inhibitory factor (MIF), Mucosal addressing cell adhesion molecule-1 (MadCAM1) and Pulmonary surfactant protein-A (SP-A) in the lung and bowel were detected by Real time-PCR.ResultCompared with the normal group, the model rats had significant histopathological and fibrotic changes both in the lung and bowel, and all treatment groups were improved. After treatment, TLR4, IL-8, MIF, and TNF-α in the lung decreased (P

Abstract Background The major fleshy tissues of the apple fruit are spatially separable into cortex and pith. These tissues display differential growth during development. Key features of such differential growth, and sink metabolic programs supporting it have not been investigated previously. We hypothesized that differential growth between these fruit tissues is supported by differential sink metabolic programs, particularly during early development. Growth, metabolite concentrations, and transcript abundance of metabolism-related genes were measured to determine characteristics of differential growth and their underlying metabolic programs. Results The cortex displayed > 5-fold higher growth than the pith during early fruit development, indicating that differential growth was established during this period. Further, when resource availability was increased through sink-removal, cortex growth was preferentially enhanced. Greatest diversity in metabolic programs between these tissues was evident during early fruit development. Higher cortex growth during early development was facilitated by increased catabolism of imported carbon (C) resources, sorbitol and sucrose, and the nitrogen (N) resource, asparagine. It was also associated with enhanced primary C metabolism, and C storage as malate and quinate. The pith metabolic program during this period involved limited allocation of C and N to growth, but greater allocation to storage, and enhanced sucrose-sucrose cycling. Conclusions Together, these data indicate that the fruit cortex tissue displays a resource intensive metabolic program during early fruit development. This provides the C backbones, proteins, energy and osmolytes to support its higher growth.

Crystals undergoing tandem reactions where the first transformation enables the second one are rare. Using photoreactive Dewar benzene 3,4,5,6-tetramethyl-1,2-dicarboxylic diacid (DB) as a hydrogen-bonding template for the [2π+2π] photodimerization of trans-4,4-bipyridyl-ethenes (BPE), we obtained crystals DB-BPE-NT with a DB:BPE = 2:1 stoichiometry with double bonds at a nonreactive distance of 5.957 Å. Exposure to UV light resulted in valence bond isomerization to Hückel benzene 3,4,5,6-tetramethyl-1,2-dicarboxylic acid (HB) by a quantum chain reaction that triggered the sought-after topochemical [2π+2π] photodimerization reaction. Notably, crystals HB:BPE-T with the Hückel benzene isomer and BPE adopted a 2:2 stoichiometry and displayed an efficient topochemically templated photodimerization reaction.

BackgroundThe accurate assessment of patients with disorders of consciousness (DOC) is a challenge to most experienced clinicians. As a potential clinical tool, functional magnetic resonance imaging (fMRI) could detect residual awareness without the need for the patients’ actual motor responses.MethodsWe adopted a simple active fMRI motor paradigm (hand raising) to detect residual awareness in these patients. Twenty-nine patients were recruited. They met the diagnosis of minimally conscious state (MCS) (male = 6, female = 2; n = 8), vegetative state/unresponsive wakefulness syndrome (VS/UWS) (male = 17, female = 4; n = 21).ResultsWe analyzed the command-following responses for robust evidence of statistically reliable markers of motor execution, similar to those found in 15 healthy controls. Of the 29 patients, four (two MCS, two VS/UWS) could adjust their brain activity to the “hand-raising” command, and they showed activation in motor-related regions (which could not be discovered in the own-name task).ConclusionLongitudinal behavioral assessments showed that, of these four patients, two in a VS/UWS recovered to MCS and one from MCS recovered to MCS+ (i.e., showed command following). In patients with no response to hand raising task, six VS/UWS and three MCS ones showed recovery in follow-up procedure. The simple active fMRI “hand-raising” task can elicit brain activation in patients with DOC, similar to those observed in healthy volunteers. Activity of the motor-related network may be taken as an indicator of high-level cognition that cannot be discerned through conventional behavioral assessment.

The utilization of modeling tools has gained significant attention recently. These models typically involve a series of partial differential equations, which can be challenging for novice modelers. This paper presented an approach in practical teaching of modeling tools for ion-exchange chromatography with three parts: model introduction, model calibration through group learning using different calibration strategies, and model applications. This approach was integrated into the traditional bioseparation engineering curriculum as an activity, using the separation of monomer-dimer mixtures of monoclonal antibodies as an example. Results of competitive group learning and the Wilcoxon test revealed that the parameter-by-parameter method was more user-friendly than the Yamamoto method for novice modelers to obtain reasonable model parameters quickly. Then, students used the well-fitted model for process optimization and explored the effects of process parameters and material input variation on the chromatography process, which helped students appreciate the critical role of time and material savings achieved through modeling tools. Finally, the student questionnaire results revealed that over two-thirds of the students gave positive feedback on the activity. Through this practical teaching, students became familiar with chromatography modeling tools, moving away from the tedious formulaic descriptions found in traditional modeling courses. This well-designed activity can be expanded from academia to industry, transforming the novice modelers into experienced modelers who can meet the high demands of the modern biopharmaceutical industry.

Background. To investigate the link and mechanisms between intestine and lung in the ulcerative colitis (UC) rat model. Materials and Methods. We used the UC rat model by immunological sensitization combined with local 2, 4, 6-trinitrobenzene sulfonic acid (TNBS) in 50% ethanol enema, observed dynamically animal general state and body weight, examined the histological and functional changes in the colon, lung, liver, and kidney tissues, and detected microvascular endothelium response towards inflammation characterized with the expression of iNOS, TXB2, P-selectin, ICAM-1, and vascular endothelial growth factor A (VEGF-A) in the colon and lung tissue. Results. Pulmonary function results suggested ventilator disorder, and pathological findings showed interstitial pneumonia. There were no significant changes in the liver and kidney function and histopathology. The colon and lung tissue iNOS, TXB2, P-selectin, ICAM-1, and VEGF-A expression of the model rats was significantly higher than the normal rats at both time points. Conclusions. Our study is the first to demonstrate the close association between the large intestine and lung in the immune-TNBS-ethanol-induced UC rat model. Different organs and tissues with the same embryonic origin may share the same pathological specificities in a disease. The present study provided a new way of thinking for pathological changes in clinical complex diseases manifested with multiorgan damage.

Due to the irregular management, the effluent water of some waste water treatment plants (WWPT) of Liaoning province didn’t meet the demand of the National Discharge Standard. Meanwhile, excessive of dosage and discharge of sludge made the results of operation costs increasing and environmental pollution during the processes. The use of mathematical models for the simulationof wastewater treatment processes has gained widespread acceptance as a tool to aid the design of newworks and the optimization of existing facilities. STOAT developed by the Water Research Center is the most widely used model for simulating the WWST processes. This paper invited the STOAT as simulation model for the design and optimization of Liaoning waste water treatment plant.