Search

Abstract Interleukin-18, a member of the interleukin − 1 family of cytokines, is upregulated in glioma. However, its effects on glioma remain unclear. This study aimed to explore the role and underlying mechanisms of interleukin-18 expression in glioma. Here, we demonstrated that interleukin-18 enhanced resistance to temozolomide by increasing proliferation and inhibiting apoptosis in cultured glioma cells. Further in vivo studies revealed that interleukin-18 promoted temozolomide resistance in BALB/c nude mice bearing tumor. Mechanical exploration indicated that interleukin-18 stimulation could activate the PI3K/AKT signaling pathway in glioma cells, and PI3K inhibition could reduce the temozolomide resistance promoted by interleukin-18. We found that interleukin-18 upregulated CD274 expression in glioma, revealing its potential effects on the microenvironment. Furthermore, we established a tumor xenograft model and explored the therapeutic efficacy of anti-interleukin-18 monoclonal antibody. Targeting interleukin-18 prolonged survival and attenuated CD274 expression in the mice bearing tumor. Combined treatment with anti-interleukin-18 and anti-PD-1 monoclonal antibody showed better efficacy in suppressing tumor growth than either treatment alone in mice bearing tumor. Collectively, these data present that interleukin-18 promotes temozolomide chemoresistance in glioma cells via PI3K/Akt activation and establishes an immunosuppressive milieu by modulating CD274. This study highlights the therapeutic value of interleukin-18 in glioma.

Abstract Background Innovative attempt to explore the feasibility and accuracy of using indocyanine green fluorescence (ICGF) to identify the intersegmental plane by the target segmental veins preferential ligation during thoracoscopic segmentectomy. Methods A retrospective analysis was conducted on clinical data of 32 consecutive patients who underwent thoracoscopic segmentectomy with intersegmental plane identification using both ICGF and inflation-deflation method after target segmental veins prioritized blocking at Nanjing Chest Hospital from December 2022 to June 2023. Preoperative three-dimensional reconstruction was used to identify the target segment and the anatomical structure of the arteries, veins, and bronchi. After ligating the target segmental veins during surgery, the first intersegmental plane was immediately identified and marked with an electrocoagulation device using an inflation-deflation method. Subsequently, the second intersegmental plane was determined using the ICGF method. Finally, the consistency of the two intersegmental planes was evaluated. Results All the 32 patients successfully completed thoracoscopic segmentectomy without ICG-related complications and perioperative death. The average operation time was (98.59 ± 20.72) min, the average intraoperative blood loss was (45.31 ± 35.65) ml, and the average postoperative chest tube removal time was (3.5 ± 1.16) days. The average postoperative hospital stay was (4.66 ± 1.29) days, and the average tumor margin width was (26.96 ± 5.86) mm. The intersegmental plane determined by ICGF method was basically consistent with inflation-deflation method in all patients. Conclusion The ICGF can safely and accurately identify the intersegmental plane by target segmental veins preferential ligation during thoracoscopic segmentectomy, which is a beneficial exploration and important supplement to the simplified thoracoscopic anatomical segmentectomy.

Abstract Background Controversy exists regarding the origin of femoral torsion, and specific treatment rules regarding the optimal position of femoral osteotomy in patients with recurrent patellar subluxation and excessive femoral torsion are scarce. Purpose To establish a novel classification system for such patients, and to compare clinical and radiological outcomes after distal derotational femoral osteotomy (DDFO) between femoral torsion at proximal (neck and shaft) and distal levels. Methods Between January 2014 and June 2019, patients who underwent DDFO were retrospectively reviewed. The segmental torsion analysis was performed to establish a novel classification system, and classify included patients into two groups: 35 patients in proximal torsion group and 38 patients in distal torsion group. These patients were followed-up for at least 3 years. Clinical evaluations included functional outcomes, physical examinations, quality of life, activity level, satisfaction, and complications. Radiological outcomes included patellofemoral osteoarthritis, congruence, and alignment. Results Type I was defined as the proximal torsion. Type II was defined as the distal torsion. Proximal torsion group had lower postoperative femoral torsion (12.6 ± 2.6° vs. 14.8 ± 3.6°; P = .004) and higher surgical correction angle (21.6 ± 5.0° vs. 19.1 ± 3.0°; P = .009). All clinical and radiological outcomes improved significantly in both groups, but proximal torsion group had significantly higher quality of life (EQ-5D-5L: 0.96 ± 0.06 vs. 0.91 ± 0.07; P = .003. EQ-VAS: 92.0 ± 6.0 vs. 88.7 ± 5.8; P = .021) and Tegner activity score (5.2 ± 1.5 vs. 4.5 ± 1.4; P = .040), and fewer patellofemoral osteoarthritis (8.6% vs. 26.3%; P = .048). Two patients in the distal torsion group had subjective patellar instability. The percentage of patients with anterior knee pain was higher in the distal torsion group. Conclusion A novel classification system for patients with recurrent patellar subluxation and excessive femoral torsion based on segmental femoral torsion analysis was established. DDFO was more appropriate for patients with proximal torsion, yielding higher surgical correction angle, and better clinical and radiological outcomes. Study design Cohort study; Level of evidence, 3.

In this study, Hypermesh and LS-DYNA numerical simulation software are used to build a multi domain coupling model of natural gas pipeline, including soil, pipeline, TNT explosive and air domain, and the non-reflection boundary conditions are set for the model. The TNT equivalent method is used to convert the physical explosion amount of natural gas pipeline into 1387.38 kg TNT explosive amount. The simulation results show that the physical explosion of pipeline forms an approximate elliptical crater with a width of 12.68 m and a depth of 4.12 m; the TNT equivalent of the model is corrected by comparing the crater simulation value and the size value of the crater calculated by the PRCI empirical formula under the same laying condition, and the correction coefficient is selected as 0.9, and the corrected TNT equivalent is 1248.64 kg; the modified model crater size is 3.72 m deep and 12.66 m wide, compared with the crater size obtained from the field test, the error of crater depth and width calculated by the modified model simulation is 5.7% and 15.5% respectively.

Abstract Background Perioperative reflux aspiration presents a grave concern during sedation or general anesthesia, particularly when solid gastric contents prompt acute upper respiratory obstruction, potentially resulting in fatal consequences for patients. Currently, there are limited means for promptly assessing solid gastric contents in clinical settings. Therefore, this study examined the efficacy of ultrasound assessment for solid gastric contents, offering a rapid and non-invasive approach for early detection and decision-making regarding interventions. Methods The study included 400 patients scheduled for upper endoscopy procedures, which encompassed both gastroscope and gastroscope combined colonoscopy examinations with sedation. Ultrasound scanning of the antrum was performed while patients were positioned semi-sitting or in the right lateral decubitus (RLD) posture. The evaluation of solid gastric contents relied on direct visual observation during endoscopy. Gastric volume measurement occurred subsequent to endoscopic suction of gastric contents. Receiver operating characteristic curves were utilized to assess the effectiveness of ultrasonography in discerning solid contents. Result Seven patients undergoing gastroscope with sedation were found to have solid gastric contents. The sensitivity, specificity, positive predictive value, and negative predictive value of the ultrasound qualitative evaluation of solid contents were 85.7%, 99%, 60%, and 99.7%, respectively. Conclusion Solid stomach contents can be evaluated qualitatively with reasonable accuracy using ultrasonography. Additionally, in patients undergoing upper endoscopy and assessed to have solid gastric contents with ultrasound, administration of mild sedation is recommended. Trial registration www.chictr.org.cn (ChiCTR2100048994); registered 19/07/2021.

Whistler waves are believed to have close relationship with the dynamics of the magnetic flux ropes (FRs) in the Earth's magnetotail. Previous studies about whistler waves in FRs were mainly based on event analysis. However, several key issues should be investigated from a statistical perspective, such as the spatial distributions of whistler waves in FRs with different motion directions, the frequency ranges of whistler waves, as well as the magnetic field power spectral densities (PSDs) and the excitation mechanisms of whistler waves. In this study, using the unprecedented high-resolution data from the magnetospheric multiscale (MMS) mission during the periods of magnetotail crossing between May and August in 2017, we perform a detailed statistical study on the whistler waves in the Earth's magnetotail FRs. Based on the magnetic field variation characteristics, the FRs are divided into three regions: the leading draping region, the core region, and the trailing draping region. Moreover, whistler waves are categorized into two types: low-band whistler waves with a frequency range between 0.1fce (fce is the local electron cyclotron frequency) and 0.5fce, and upper-band whistler waves with a frequency range from 0.5fce to fce. We separately investigate the spatial distribution characteristics, the magnetic-field PSDs, and excitation mechanisms of low-band whistler waves and upper-band whistler waves in earthward and tailward FRs. Finally, our research findings can be summarized as follows: (1) Whistler waves in the Earth’s magnetotail FRs are primarily lower-band ones; (2) More whistler waves along with more intense magnetic-field PSDs in the two frequency ranges both tend to occur in the trailing draping region; (3) The electron temperature with a dominant perpendicular anisotropy can account for the generation of low-band and upper-band whistler waves in the center region of core region of earthward FRs and low-band whistler waves in the center region of core region of tailward FRs; (4) In addition, the electron beams may provide free energy for upper-band whistler waves in the trailing draping region of earthward and tailward FRs. Our results may contribute to the interpretation of the impact of whistler waves on the evolution of Earth's magnetotail FRs and the magnetotail dynamics.

Abstract Stem cell-derived exosomes exert comparable therapeutic effects to those of their parental stem cells without causing immunogenic, tumorigenic, and ethical disadvantages. Their therapeutic advantages are manifested in the management of a broad spectrum of diseases, and their dosing versatility are exemplified by systemic administration and local delivery. Furthermore, the activation and regulation of various signaling cascades have provided foundation for the claimed curative effects of exosomal therapy. Unlike other relevant reviews focusing on the upstream aspects (e.g., yield, isolation, modification), and downstream aspects (e.g. phenotypic changes, tissue response, cellular behavior) of stem cell-derived exosome therapy, this unique review endeavors to focus on various affected signaling pathways. After meticulous dissection of relevant literature from the past five years, we present this comprehensive, up-to-date, disease-specific, and pathway-oriented review. Exosomes sourced from various types of stem cells can regulate major signaling pathways (e.g., the PTEN/PI3K/Akt/mTOR, NF-κB, TGF-β, HIF-1α, Wnt, MAPK, JAK-STAT, Hippo, and Notch signaling cascades) and minor pathways during the treatment of numerous diseases encountered in orthopedic surgery, neurosurgery, cardiothoracic surgery, plastic surgery, general surgery, and other specialties. We provide a novel perspective in future exosome research through bridging the gap between signaling pathways and surgical indications when designing further preclinical studies and clinical trials.

Abstract The high-intactness and ultraclean fabrication of suspended 2D materials has always been a challenge due to their atomically thin nature. Here, we present a universal polymer-free transfer approach for fabricating suspended 2D materials by using volatile micro-molecule cyclododecane as the transfer medium, thus ensuring the ultraclean and intact surface of suspended 2D materials. For the fabricated monolayer suspended graphene, the intactness reaches 99% for size below 10 µm and suspended size reaches 36 µm. Owing to the advantages of ultra-cleanness and large size, the thermal conductivity reaches 4914 $${\rm{W}}\,{{\rm{m}}}^{-1}{{\rm{K}}}^{-1}$$ W m − 1 K − 1 at 338 K. Moreover, this strategy can also realize efficient batch transfer of suspended graphene and is applicable for fabricating other 2D suspended materials such as MoS2. Our research not only establishes foundation for potential applications and investigations of intrinsic properties of large-area suspended 2D materials, but also accelerates the wide applications of suspended graphene grid in ultrahigh-resolution TEM characterization.

Abstract On-chip optical power monitors are indispensable for functional implementation and stabilization of large-scale and complex photonic integrated circuits (PICs). Traditional on-chip optical monitoring is implemented by tapping a small portion of optical power from the waveguide, which leads to significant loss. Due to its advantages like non-invasive nature, miniaturization, and complementary metal-oxide-semiconductor (CMOS) process compatibility, a transparent monitor named the contactless integrated photonic probe (CLIPP), has been attracting great attention in recent years. The CLIPP indirectly monitors the optical power in the waveguide by detecting the conductance variation of the local optical waveguide caused by the surface state absorption (SSA) effect. In this review, we first introduce the fundamentals of the CLIPP including the concept, the equivalent electric model and the impedance read-out method, and then summarize some characteristics of the CLIPP. Finally, the functional applications of the CLIPP on the identification and feedback control of optical signal are discussed, followed by a brief outlook on the prospects of the CLIPP. Graphical Abstract

Abstract Particle migration in oil and gas reservoirs is a common phenomenon in the process of oil and gas development, and is considered to be an important reason for the damage of reservoir permeability and the reduction of oil and gas productivity. The mechanism of this phenomenon includes the desorption, migration, and precipitation of particles, which eventually clogs the throat and causes reservoir damage. Therefore, it is necessary to accurately characterize the complex mechanism of particle migration and identify the main controlling factors of particle migration, which is very important for efficient oilfield development and plugging solution. First, the reservoir types are divided into three types and the pore structure models of different types of reservoirs are established. Then, computational fluid dynamics and discrete element coupling method numerical simulation and microscopic visualization of pore throat structure model were combined, to characterize the rules of particles and migration, and analyze the main controlling factors. Finally, a typical model of particle migration and clogging is established. The results show that particle size/throat and particle concentration are the key factors affecting particle plugging, and particle migration has the least effect on the permeability of Type I reservoir and the greatest damage to Type III reservoir. According to the mechanical and hydrodynamic behavior of particles in porous media, three mechanisms and six modes of particle plugging are proposed.

Hepatitis E virus (HEV) is the major pathogen of viral hepatitis. Immunocompromised individuals infected by HEV are prone to chronic hepatitis and increase the risk of hepato-cellular carcinoma (HCC). Inhibitor of growth family member 5 (ING5) is a tumor suppressor that is expressed at low levels in cancer tumors or cells. However, the underlying relationship between ING5 and HEV infection is unclear. In the present study, acute and chronic HEV animal models are used to explore the interaction between ING5 and HEV. Notably, the expression of ING5 is significantly increased in both the livers of acute HEV-infected BALB/c mice and chronic HEV-infected rhesus macaques. In addition, the relationship between HEV infection and ING5 expression is further identified in human hepatoma (HepG-2) cells. In conclusion, HEV infection strongly upregulates ING5 expression both in vivo and in vitro, which has significant implications for further understanding the pathogenic mechanism of HEV infection.

Maize seedling blight caused by Fusarium verticillioides is a widely occurring maize disease, but the genetics and mechanisms of resistance are not well understood. In this study, GWAS performed by MLM and 3VmrMLM identified 40 and 20 QTNs, associated with seedling blight resistance. These methods identified 49 and 36 genes, respectively. Functional verification of candidate gene ZmSBR1 identified by both methods showed that the resistance of a mutant line to seedling blight decreased by 0.37 grade points after inoculation with F. verticillioides, compared with the WT. The length of the stem rot lesion caused by F. verticillioides increased by 86% in mutant seedlings, and the relative length of the adult plant stalk rot increased by 35% in mutant plants compared to the wild type after inoculation with Fusarium graminearum. Transcriptome analysis showed that expression of defense-related genes after inoculation was down-regulated in the mutant compared to the wild type, synthesis of secondary metabolites associated with resistance was reduced, and the immune response triggered by PAMP decreased, resulting in decreased resistance of mutant maize seedlings. Candidate gene association analysis showed that most maize inbred lines carried the susceptible haplotype. A functional PCR marker was developed. The results demonstrated that ZmSBR1 conferred resistance to multiple Fusarium diseases at the seedling and adult growth stages and had important application value in breeding.

Background In patients with untreated CD20-positive diffuse large B-cell lymphoma (DLBCL), a phase 3 trial was carried out to evaluate the efficacy and safety of zuberitamab plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone; Hi-CHOP) versus rituximab plus CHOP (R-CHOP) treatment regimens.Methods In a 2:1 ratio, eligible patients were assigned randomly to receive treatment of six cycles of either 375 mg/m2 zuberitamab or rituximab together with conventional CHOP chemotherapy. The objective response rate (ORR) at C6D50 served as the primary endpoint, and a non-inferiority margin of 10% was established. The secondary endpoints included the complete response (CR) rate at C6D50, duration of response (DOR), progression-free survival (PFS) and event-free survival (EFS) judged by blinded-independent review committee (BIRC), overall survival (OS) and safety outcomes.Results Of the 487 randomized patients, 423 patients including 287 in the Hi-CHOP and 136 in the R-CHOP groups completed the C6D50 assessment. For the full analysis set (FAS) and per-protocol set (PPS), BIRC-assessed ORR at C6D50 for the Hi-CHOP and R-CHOP groups were 83.5% versus 81.4% and 95.3% versus 93.7%, respectively. The non-inferiority was confirmed as the lower limit of the two-sided 95% CI for the intergroup differences of −5.2% and −3.3%; both were >−10% in the FAS and PPS. The BIRC-assessed CR rate of Hi-CHOP was significantly higher in PPS (85.7% vs 77.3%, p=0.038), but comparable in FAS (75.2% vs 67.9%, p=0.092). After a median follow-up of 29.6 months, patients in the Hi-CHOP group had a slight advantage with regard to the DOR (HR 0.74, p=0.173), PFS (HR 0.67, p=0.057), EFS (HR 0.90, p=0.517) and OS (HR 0.60, p=0.059). Patients with the germinal-center B cell-like subtype who received Hi-CHOP exhibited statistically significant improvements in ORR (p=0.034) and CR rate (p=0.038) at C6D50, EFS (p=0.046) and OS (p=0.014). Treatment-emergent adverse event occurrence rates were comparable across groups (all p>0.05). Infusion-related responses occurred more often in the Hi-CHOP group (32.1% vs 19.9%, p=0.006), all of grade 1–3 severity.Conclusions Zuberitamab (375 mg/m2) plus CHOP was non-inferior to R-CHOP regarding ORR but exhibited a higher CR rate and was well tolerated in CD20-positive, previously untreated Chinese patients with DLBCL.Trial registration number Chinese Clinical Trial Registry, ChiCTR2000040602, retrospectively registered.

Efficaciously assessing product quality remains time- and resource-intensive. Online Process Analytical Technologies (PATs), encompassing real-time monitoring tools and soft-sensor models, are indispensable for understanding process effects and real-time product quality. This research study evaluated three modeling approaches for predicting CHO cell growth and production, metabolites (extracellular, nucleotide sugar donors (NSD) and glycan profiles): Mechanistic based on first principle Michaelis-Menten kinetics (MMK), data-driven orthogonal partial least square (OPLS) and neural network machine learning (NN). Our experimental design involved galactose-fed batch cultures. MMK excelled in predicting growth and production, demonstrating its reliability in these aspects and reducing the data burden by requiring fewer inputs. However, it was less precise in simulating glycan profiles and intracellular metabolite trends. In contrast, NN and OPLS performed better for predicting precise glycan compositions but displayed shortcomings in accurately predicting growth and production. We utilized time in the training set to address NN and OPLS extrapolation challenges. OPLS and NN models demanded more extensive inputs with similar intracellular metabolite trend prediction. However, there was a significant reduction in time required to develop these two models. The guidance presented here can provide valuable insight into rapid development and application of soft-sensor models with PATs for ipurposes. Therefore, we examined three model typesmproving real-time product CHO therapeutic product quality. Coupled with emerging -omics technologies, NN and OPLS will benefit from massive data availability, and we foresee more robust prediction models that can be advantageous to kinetic or partial-kinetic (hybrid) models.

BackgroundA previous investigation reported that an abnormal P-wave terminal force in lead V1 (PTFV1) is a marker for electrical remodeling of the left atrium (LA). We aimed to assess the relationship of PTFV1 with LA tachyarrhythmia (LATA) recurrence after radiofrequency catheter ablation (RFCA) in patients with paroxysmal atrial fibrillation (PAF) and normal LA size.MethodsPatients with PAF and normal LA size (LA volume index 4,000 μV*ms were 1.22 (1.13–1.32, p

Scientific risk assessment of exogenous and endogenous toxic substances in traditional Chinese medicine (TCM) is of great significance. The present review comprises a comprehensive summary of progress in the health risk assessment of harmful exogenous substances in TCMs. Such substances include heavy metals, pesticide residues, biotoxins, and endogenous toxic components involving pyrrolizidine alkaloids. The review also discusses the strengths and weaknesses of various bioaccessibility and bioavailability models, and their applications in risk assessment. Future avenues of risk assessment research are highlighted, including further exploration of risk assessment parameters, innovation of bioaccessibility and bioavailability techniques, enhancement of probabilistic risk assessment combined with bioavailability, improvement of cumulative risk assessment strategies, and formulation of strategies for reducing relative bioavailability (RBA) values in TCMs. Such efforts represent an attempt to develop a risk assessment system that is capable of evaluating the exogenous and endogenous toxic substances in TCMs to ensure its safe use in clinics, and to promote the sustainable development of the TCM industry.

IntroductionIschemic stroke is a leading cause of morbidity and mortality in older adults. Therefore, in this study, we sought to understand the interplay between the microbiota, gut, and brain in the context of stroke in older adults.ObjectiveTo determine whether gut microbiota from younger individuals promotes recovery through angiogenesis in both elderly stroke patients and aged stroke mice, we explored the changes in gut microbiota and the correlation between short-chain fatty acids (SCFAs) and angiogenesis in the aged stroke population. Then, we altered the gut microbiome in aged mice by transplanting microbiota from younger donors before inducing experimental stroke to explore the mechanism by which gut microbiota-derived SCFAs promote angiogenesis.MethodsPart I: We conducted a single-center, double-blind trial to compare gut microbiota diversity and SCFA levels in fecal samples from older stroke patients with those from younger stroke patients. Additionally, we measured levels of vascular endothelial growth factor (VEGF) and VEGFC levels in plasma to assess their correlation with SCFA levels. Part II: We performed fecal microbiota transplantation (FMT) 3 days before inducing ischemic stroke in aged male mice (16–18) via distal middle cerebral artery occlusion (dMCAO). The FMT was conducted using gut microbiomes from either young donors (2–3 months) or aged donors (16–18 months).ResultsIn older stroke patients, gut microbiota diversity was significantly reduced compared to that in younger stroke patients. Furthermore, levels of acetate, a bacterially derived SCFA, were lower and positively correlated with angiogenesis markers (VEGF and VEGF-C). In aged stroke mice, transplantation of young microbiota improved stroke outcomes by promoting angiogenesis, which was facilitated by lymphatic ingrowth into the cortex. This protective effect was linked to gut microbiota-derived acetate, which enhanced lymphangiogenesis by replenishing acetyl coenzyme A.Conclusions(a) Gut microbiota-derived acetate promotes angiogenesis post-stroke and (b) lymphatic ingrowth into the cerebral cortex was observed in post-dMCAO mice. These findings suggest that selectively promoting SCFA-producing bacteria, particularly acetate-producers, could be a promising therapeutic strategy to reduce functional impairments in older stroke subjects.

IntroductionHemophagocytic lymphohistiocytosis (HLH) is a rare, complicated and life threatening hyperinflammatory syndrome that maybe triggered by various infectious agents, malignancies and rheumatologic disorders. Early diagnosis and identification of the cause is essential to initiate appropriate treatment and improve the quality of life and survival of patients. The recently developed Onco-mNGS technology can be successfully used for simultaneous detection of infections and tumors.MethodsIn the present study, 92 patients with clinically confirmed HLH were etiologically subtyped for infection, tumor and autoimmunity based on CNV and microbial data generated by Onco-mNGS technology, and a predictive model was developed and validated for the differential diagnosis of the underlying disease leading to secondary HLH. Furthermore, the treatment outcomes of patients with HLH triggered by EBV infection and non-EBV infection were evaluated, respectively.ResultsThe current study demonstrated that the novel Onco-mNGS can identify the infection and malignancy- related triggers among patients with secondary HLH. A random forest classification model based on CNV profile, infectious pathogen spectrum and blood microbial community was developed to better identify the different HLH subtypes and determine the underlying triggers. The prognosis for treatment of HLH patients is not only associated with CNV, but also with the presence of pathogens and non- pathogens in peripheral blood. Higher CNV burden along with frequent deletions on chromosome 19, higher pathogen burden and lower non-pathogenic microbes were prognosis factors that significantly related with unfavorable treatment outcomes.DiscussionOur study provided comprehensive knowledge in the triggers and prognostic predictors of patients with secondary HLH, which may help early diagnosis and appropriate targeted therapy, thus improving the survival and prognosis of the patients.

Climate change is one of the foremost challenges confronting the contemporary world. Carbon and water cycles and their interconnections of ecosystems are playing a pivotal role in assessing the impacts of climate change on ecosystems. The Qinling Mountains of China represent a focal area for research on global climate change and regional adaptation strategies. Based on historical and CMIP6 (Coupled Model Intercomparison Project Phase 6) future climatic data, the Biome-BGC model, which was sufficiently optimized with the Biome-BGC-PEST package, was used to simulate the historical and future trends of GPP (Gross primary productivity), ET (Evapotranspiration), and WUE (Ecosystem water use efficiency) in the Qinling Mountains, so as to elucidate the dynamics and spatiotemporal variations of carbon and water fluxes amidst climate change. The results showed that the GPP, ET, and WUE of the Qinling Mountains heterogeneously distributed in space, due to the dramatic disparities in carbon and water fluxes among different vegetation types in the Qinling Mountains. Among the various vegetation types, evergreen needle-leaved forest had the highest annual mean value of WUE. In the historical period of 1979-2018, deciduous broad-leaved forest had the highest annual mean value of GPP and ET, while evergreen needle-leaved forest would dominate in the future (2021-2100). For the annual GPP and ET flux variations, different vegetation cover types followed varying peak patterns in the Qinling Mountains. Deciduous broad-leaved forest, evergreen needle-leaved forest, and shrub meadow showed ’single-peak’ pattern annually, whereas the crop area displayed ’double-peak’ pattern due to the different growing seasons of crops. There also were temporal variations for the carbon and water fluxes within the same vegetation type. Future projections suggested a continuous increase in GPP and ET fluxes, underscoring the consistent role of the Qinling Mountains in water resource conservation and carbon sink amid evolving climatic conditions.

Hills and mountains cover approximately 25 % of Earth’s landmass; therefore, investigating landscape ecological risk (LER) in these regions is imperative for ecosystem management. Hilly and mountainous regions susceptible to influences such as desertification and erosion include the Southern Hill and Mountainous Belt (SHMB) in southern China. Over the past 30 years, the SHMB has undergone significant changes, offering an excellent research case. A comprehensive assessment of the ecological status of this region is crucial for the protection and management of the ecosystems in the SHMB. This study assessed the LER of the SHMB, identified influencing factors over the past 30 years, and utilized a patch-generating land-use simulation model (PLUS) to project future land use and LER. Accounting for more than 90 % of the total area, cropland and forestland were the two most common land use types in the SHMB. From 1990 to 2020, impervious surface and water area saw obvious increases, rising by 154 % (from 1209.37 km2 to 3073.59 km2) and 21 % (from 1584.78 km2 to 1924.8 km2), respectively. Grasslands and shrublands decreased by 54 % and 34 %. It is anticipated that there will be little change in land-use types by 2030 compared to 2020. Additionally, the overall LER in the SHMB was low, with low- and medium–low-risk representing around 70 % of the overall risk. The general state of LER improved during the research period but did not converge. Specifically, the LER intensity did not decrease although the total LER showed a declining trend. In the western portion of the research region, the karst area displayed an increasing LER, and the severity of the high-risk area increased. Furthermore, natural factors promote the restoration of LER. For example, the abundance of hydrothermal conditions (i.e., increased temperature and precipitation) promotes the recovery of vegetation growth and reduces the LER. Human activities, such as the construction of stations, highways, and an increasing population, exacerbate LER, contributing to an increase in LER. This study offers helpful guidance for formulating ecological conservation strategies to maintain the ecological balance and sustainability of hilly and mountainous regions.

[Nd2(C6H5N2O2)6(H2O)4]n, monoclinic, P21/c (no. 14), a = 9.383(3) Å, b = 22.741(6) Å, c = 18.775(5) Å, β = 90.231(5)°, V = 4006(2) Å3, Z = 4, Rgt (F) = 0.0427, wRref (F 2) = 0.0862, T = 296 K.

Purposes The strain tolerance of Ba(Mg1/3Ta2/3)O3 (BMT) thermal barrier coating prepared by conventional atmospheric plasma spraying is low. Methods With suspension plasma spraying (SPS), BMT suspensions with different compositions are prepared by mechanical ball grinding with ethanol as the dispersion medium and polyacrylic acid (PAA), polyethyleneimine (PEI), and polyethylene glycol (PEG) as dispersants. The dispersion behavior of BMT suspension was studied through gravity sedimentation observation method, UV-Vis spectrophotometry, and Zeta potentiometry. The effects of dispersant type and content on the stability of BMT suspension were analyzed. The BMT coating was deposited by SPS, and the phase structure, surface morphology, and cross-section microstructure of the BMT coating were characterized and analyzed. Findings The results show that the adsorption of the dispersant PEI on the surface of the BMT particles improves their Zeta potential, enhances the repulsive force between particles, and provides a steric hindrance, which results the better dispersion of BMT suspension with PEI dispersant than that with PAA and PEG. In addition, the BMT suspension with PEI has a low viscosity (1.5-2 mPa·s), making it appropriate for SPS. The coating prepared by SPS essentially preserves the BMT phase structure, and shows a clear columnar-crystal microstructure. With the increases of the solid content in the suspension, the deposition efficiency of the BMT coating increase, and the volume of columnar crystals formed becomes larger, which conforms to the microstructural characteristics of high strain tolerance coatings.

Abstract The time difference of arrival is a common method to find the leakage point of water pipeline. The leakage point localization is achieved by calculating the time delay between the signals reaching different sensors. Mainstream time delay estimation algorithms based on signal correlation analysis are susceptible to the introduction of noise signals, low sampling rates, and signal clipping, resulting in inaccurate localization results. The article analyzed the impact of different interference factors and proposed a new time delay estimation algorithm based on signal cross-zero information modulation (CZIM) to address these problems. By normalizing the amplitude of the two signals at the detection points on both sides of the pipeline leakage position, two sets of sparse signal sequences with only two eigenvalues of 0 and 1 are obtained. The error coefficient function is calculated by a similar traversal method to finally index the time delay. In this paper, the principle and characteristics of the algorithm are analyzed and compared with the most commonly used GCC method. In both numerical simulations and actual pipe leakage localization experiments, the CZIM algorithm has shown its wide applicability, low impact by low sampling rate, and adaptability to low signal-to-noise ratios, etc. At the same time, the algorithm is simple in design and has a small amount of calculation and can meet the demand for real-time data processing, providing a new idea for the development of acoustic localization technology.

Abstract Background Haemophagocytic lymphohistiocytosis (HLH) is a syndrome that occurs in patients with severe systemic hyperinflammation. GATA binding protein 2 (GATA2) is a transcription factor and key component in haematopoiesis and stem cell biology. Case presentation Three patients with HLH, one with Mycobacterium avium infection, one with Epstein–Barr virus (EBV) infection, and one with Mycobacterium kansasii infection, were all subsequently found to have a defect in the GATA2 gene through genetic testing. Conclusions GATA2 deficiency syndrome should be considered in patients with myelodysplastic syndrome, nontuberculous mycobacterium infection and HLH. In addition, the GATA2 gene variant may be a genetic defect that could be the cause of the primary HLH. However, further studies are needed to confirm the role of GATA2 pathogenic variants in the pathogenesis of HLH.

Abstract Recent years have witnessed the remarkable progress in wireless communication systems due to the escalating demand for higher data rates, improved reliability, and increased energy efficiency. In this regard, Non-Orthogonal Multiple Access (NOMA) has emerged as a promising technology, enhancing spectral efficiency and accommodating multiple users concurrently within the same time and frequency resources. Simultaneously, the energy harvesting has surfaced as a sustainable solution, converting ambient environmental energy into usable electrical power for operating communication nodes. This paper proposes a cooperative NOMA transmission scheme integrating energy harvesting and utilizing Least Squares (LS) channel estimation for precise Channel State Information (CSI) acquisition. The objective is to establish an optimal communication path from source to destination. Relay selection methods: Optimal Relay Selection (ORS) and Max-Min Relay Selection (MMRS), are compared, focusing on their impact on the system performance. The analysis considers the influence of the number of relays and power allocation factor on the system, with a specific emphasis on the outage probability expressions. Comparative analysis between the cooperative-NOMA and the traditional cooperative relaying without NOMA reveals the superior performance of the cooperative-NOMA. Additionally, the ORS scheme outperforms MMRS in terms of the outage performance.

Abstract Background Advanced unresectable gastric cancer (GC) patients were previously treated with chemotherapy alone as the first-line therapy. However, with the Food and Drug Administration’s (FDA) 2022 approval of programmed cell death protein 1 (PD-1) inhibitor combined with chemotherapy as the first-li ne treatment for advanced unresectable GC, patients have significantly benefited. However, the significant costs and potential adverse effects necessitate precise patient selection. In recent years, the advent of deep learning (DL) has revolutionized the medical field, particularly in predicting tumor treatment responses. Our study utilizes DL to analyze pathological images, aiming to predict first-line PD-1 combined chemotherapy response for advanced-stage GC. Methods In this multicenter retrospective analysis, Hematoxylin and Eosin (H&E)-stained slides were collected from advanced GC patients across four medical centers. Treatment response was evaluated according to iRECIST 1.1 criteria after a comprehensive first-line PD-1 immunotherapy combined with chemotherapy. Three DL models were employed in an ensemble approach to create the immune checkpoint inhibitors Response Score (ICIsRS) as a novel histopathological biomarker derived from Whole Slide Images (WSIs). Results Analyzing 148,181 patches from 313 WSIs of 264 advanced GC patients, the ensemble model exhibited superior predictive accuracy, leading to the creation of ICIsNet. The model demonstrated robust performance across four testing datasets, achieving AUC values of 0.92, 0.95, 0.96, and 1 respectively. The boxplot, constructed from the ICIsRS, reveals statistically significant disparities between the well response and poor response (all p-values

Abstract Background The coexistence of cardiac arrhythmias in patients with acute myocardial infarction (AMI) usually exhibits poor prognosis. However, there are few contemporary data available on the burden of cardiac arrhythmias in AMI patients and their impact on in-hospital outcomes. Methods The present study analyzed data from the China Acute Myocardial Infarction (CAMI) registry involving 23,825 consecutive AMI patients admitted to 108 hospitals from January 2013 to February 2018. Cardiac arrhythmias were defined as the presence of bradyarrhythmias, sustained atrial tachyarrhythmias, and sustained ventricular tachyarrhythmias that occurred during hospitalization. In-hospital outcome was defined as a composite of all-cause mortality, cardiogenic shock, re-infarction, stroke, or heart failure. Results Cardiac arrhythmia was presented in 1991 (8.35%) AMI patients, including 3.4% ventricular tachyarrhythmias, 2.44% bradyarrhythmias, 1.78% atrial tachyarrhythmias, and 0.73% ≥2 kinds of arrhythmias. Patients with arrhythmias were more common with ST-segment elevation myocardial infarction (83.3% vs. 75.5%, P

Abstract Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of hematological malignancies with poor survival, while treatment options for relapsed or refractory (R/R) disease remain quite limited, with a median progression-free survival of only 3–4 months. Notably, the emergence of innovative therapeutic agents and regimens holds promise for durable responses and improved survival for patients with R/R PTCL. We summarize recent advances in the treatment of R/R PTCL from the 2023 ASH Annual Meeting, highlighting novel agents targeting EZH1/2, JAK1, PI3K, KIR3DL2, CD38/CD3xCD28, or CDK9, as well as therapeutic regimens in combination with stem cell transplantation, immunomodulators, epigenetic modifying agents, or CD30/CD16A bispecific antibodies.

Abstract Diphthamide is a modified histidine residue unique for eukaryotic translation elongation factor 2 (eEF2), a key ribosomal protein. Loss of this evolutionarily conserved modification causes developmental defects through unknown mechanisms. In a patient with compound heterozygous mutations in Diphthamide Biosynthesis 1 (DPH1) and impaired eEF2 diphthamide modification, we observe multiple defects in neural crest (NC)-derived tissues. Knockin mice harboring the patient’s mutations and Xenopus embryos with Dph1 depleted also display NC defects, which can be attributed to reduced proliferation in the neuroepithelium. DPH1 depletion facilitates dissociation of eEF2 from ribosomes and association with p53 to promote transcription of the cell cycle inhibitor p21, resulting in inhibited proliferation. Knockout of one p21 allele rescues the NC phenotypes in the knockin mice carrying the patient’s mutations. These findings uncover an unexpected role for eEF2 as a transcriptional coactivator for p53 to induce p21 expression and NC defects, which is regulated by diphthamide modification.

Abstract Durability is one of the technical bottlenecks restricting fuel cell electric vehicle development. As a result, significant time and resources have been invested in research related to this area worldwide. Current durability research mainly focuses on the single cell and stack levels, which is quite different from the usage scenarios of actual vehicles. There is almost no research on developing durability test cycles on the fuel cell system level. This paper proposes a universal model for developing a durability test cycle for fuel cell system based on the China automotive test cycle. Large-scale comparison tests of the fuel cell systems are conducted. After 1000 h test, the output performance degradation of three mass-produced fuel cell system is 14.49%, 9.59%, and 4.21%, respectively. The test results show that the durability test cycle proposed in this paper can effectively accelerate the durability test of the fuel cell system and evaluate the durability performance of the fuel cell system. Moreover, the methodology proposed in this paper could be used in any other test cycles such as NEDC (New European Driving Cycle), WLTC (Worldwide Harmonized Light Vehicles Test Procedure), etc. And it has comprehensive application value and are significant for reducing the cost of durability testing of fuel cell systems and promoting the industrialization of fuel cell electric vehicles.

Abstract Background Natural killer/T cell lymphoma (NKTCL) is a clinically and genetically heterogeneous disease with poor prognosis. Genome sequencing and mutation characterization provides a powerful approach for patient stratification, treatment target discovery, and etiology identification. However, previous studies mostly concentrated on base-level mutations in primary NKTCL, whereas the large-scale genomic alterations in NKTCL and the mutational landscapes in relapsed/refractory NKTCL remain largely unexplored. Methods Here, we assembled whole-genome sequencing and whole-exome sequencing data from 163 patients with primary or relapsed/refractory NKTCL and compared their somatic mutational landscapes at both nucleotide and structure levels. Results Our study not only confirmed previously reported common NKTCL mutational targets like STAT3, TP53, and DDX3X but also unveiled several novel high-frequency mutational targets such as PRDM9, DST, and RBMX. In terms of the overall mutational landscape, we observed striking differences between primary and relapsed/refractory NKTCL patient groups, with the latter exhibits higher levels of tumor mutation burden, copy number variants (CNVs), and structural variants (SVs), indicating a strong signal of genomic instability. Complex structural rearrangements such as chromothripsis and focal amplification are also significantly enriched in relapsed/refractory NKTCL patients, exerting a substantial impact on prognosis. Accordingly, we devised a novel molecular subtyping system (i.e., C0–C4) with distinct prognosis by integrating potential driver mutations at both nucleotide and structural levels, which further provides an informative guidance for novel treatments that target these specific driver mutations and genome instability as a whole. Conclusions The striking differences underlying the mutational landscapes between the primary and relapsed/refractory NKTCL patients highlight the importance of genomic instability in driving the progression of NKTCL. Our newly proposed molecular subtyping system is valuable in assisting patient stratification and novel treatment design towards a better prognosis in the age of precision medicine.

Abstract The vacuum-ultraviolet (VUV, 10–200 nm) imaging photodetector (PD) based on the wide bandgap semiconductor (WBGS) can realize a more detailed observation of solar storms than the silicon ones. Here, an 8 × 8 VUV PD array based on the semiconductor AlN with an ultra-wide bandgap is presented, exhibiting the shortest cutoff wavelength (203 nm) reported so far. The PD array with a Pt/AlN/SiC/Ti/Au photovoltaic structure shows an excellent selective response to VUV light, an extremely low dark current density of 2.85 × 10–11 A·cm−2@ -2 V, a responsivity of 0.054 A·W−1@ 0 V and an ultra-short rise time of 13 ns. Also, the clear boundaries and an obvious contrast between light and dark of the VUV image displayed in the imaging measurement indicate the good imaging ability of this PD array, which can be used for the imaging application with high signal-to-noise ratio and high response speed. These results provide rich experience for the development of VUV imaging PDs based on WBGSs both in their fabrication and the practical applications in VUV detection.

With our continuous endeavors in seeking potent anti-HIV-1 agents, we reported here the discovery, biological characterization, and druggability evaluation of a class of nonnucleoside reverse transcriptase inhibitors. To fully explore the chemical space of the NNRTI-binding pocket, novel series of dihydrothiopyrano [3,2-d]pyrimidines were developed by employing the structure-based design strategy. Most of the derivatives were endowed with prominent antiviral activities against HIV-1 wild-type and resistant strains at nanomolar levels. Among them, compound 23h featuring the aminopiperidine moiety was identified as the most potent inhibitor, with EC50 values ranging from 3.43 to 21.4 nmol/L. Especially, for the challenging double-mutants F227L + V106A and K103N + Y181C, 23h exhibited 2.3- to 14.5-fold more potent activity than the first-line drugs efavirenz and etravirine. Besides, the resistance profiles of 23h achieved remarkable improvement compared to efavirenz and etravirine. The binding target of 23h was further confirmed to be HIV-1 reverse transcriptase. Molecular modeling studies were also performed to elucidate the biological evaluation results and give guidance for the optimization campaign. Furthermore, no apparent inhibition of the major CYP450 enzymes and hERG channel was observed for 23h. Most importantly, 23h was characterized by good pharmacokinetic properties and excellent safety in vivo. Collectively, 23h holds great promise as a potential candidate for its effective antiviral efficacy and favorable drug-like profiles.

This study aimed to assess the level of knowledge regarding influenza viruses and vaccines among different professional groups to investigate the reasons for vaccine hesitancy. We collected 2190 questionnaires regarding influenza vaccines in China in 2022. The respondents were categorized into the general population (GP), foreign affairs workforce population (FAWP), and veterinary workforce population (VWP) according to their job positions. Linear regression was used to assess the association between multiple factors and influenza vaccination rates. The association between work and influenza vaccination rates was also assessed by grouping different workforce populations. The vaccination rate of the GP was higher than that of the VWP (odds ratio: 1.342, 95% confidence interval: 1.025–1.853), surpassing the rates reported in previous studies. This may be attributed to heightened concerns about infectious diseases influenced by the ongoing coronavirus disease 2019 pandemic. Despite the VWP’s more in-depth knowledge of the VWP on zoonotic diseases and their recognition of their importance, there was no significant difference in influenza knowledge among the three populations. This discrepancy contrasts with the observed differences in vaccination rates. Further investigation revealed that, compared with FAWP, the price of vaccines emerged as a primary influencing factor for vaccination rates (odds ratio:0.398, 95%CI; 0.280–0.564). General concerns regarding the protective effects and side effects of vaccines were also noted.

ABSTRACTInfluenza D virus (IDV) plays an important role in the bovine respiratory disease (BRD) complex. Its potential for the zoonotic transmission is of particular concern. In China, IDV has previously been identified in agricultural animals by molecular surveys with no live virus isolates reported. In this study, live IDVs were successfully isolated from cattle in China, which prompted us to further investigate the national prevalence, antigenic property, and infection biology of the virus. IDV RNA was detected in 11.1% (51/460) of cattle throughout the country in 2022–2023. Moreover, we conducted the first IDV serosurveillance in China, revealing a high seroprevalence (91.4%, 393/430) of IDV in cattle during the 2022–2023 winter season. Notably, all the 16 provinces from which cattle originated possessed seropositive animals, and 3 of them displayed the 100% IDV-seropositivity rate. In contrast, a very low seroprevalence of IDV was observed in pigs (3%, 3/100) and goats (1%, 1/100) during the same period of investigation. Furthermore, besides D/Yama2019 lineage-like IDVs, we discovered the D/660 lineage-like IDV in Chinese cattle, which has not been detected to date in Asia. Finally, the Chinese IDVs replicated robustly in diverse cell lines but less efficiently in the swine cell line. Considering the nationwide distribution, high seroprevalence, and appreciably genetic diversity, further studies are required to fully evaluate the risk of Chinese IDVs for both animal and human health in China, which can be evidently facilitated by IDV isolates reported in this study.

AbstractIt has become almost a stylized fact that sustainable agricultural practices (SAPs) are central to improving productivity, welfare, and food security. However, SAPs adoption rates have been perceived to be generally low in rural China. Understanding the factors influencing SAPs adoption is critical for sustainable food system development. Drawing on a survey of Chinese farmers, this study examined the determinants associated with adoption decision and intensity of multiple SAPs using a Heckman two-stage model. The findings showed that the adoption of SAPs is a multi-stage sophisticated process resulting from the interplay of several elements, such as individual characteristics, government support, and social networks. Age, education, risk attitude, cognition of SAPs, market access, services from Agricultural Science and Technology Park, policy subsidies, technical training, access to credit, and strong ties were the main determinants encouraging SAPs adoption. Adoption decision also significantly depended on farm size; whereas, adoption intensity relied on off-farm activities, town access, and information channels. This study contributes to the literature by identifying the critical determinants of farmers’ adoption behavior of SAPs in China. Furthermore, our findings are of great value to policymakers as they can target the aforementioned factors to achieve higher SAPs adoption.

The digital correlator is one of the most crucial data processing components of a radio telescope array. With the scale of radio interferometeric array growing, many efforts have been devoted to developing a cost-effective and scalable correlator in the field of radio astronomy. In this paper, a 192-input digital correlator with six CASPER ROACH2 boards and seven GPU servers has been deployed as the digital signal processing system for Tianlai cylinder pathfinder located in Hongliuxia observatory. The correlator consists of 192 input signals (96 dual-polarization), 125-MHz bandwidth, and full-Stokes output. The correlator inherits the advantages of the CASPER system, for example, low cost, high performance, modular scalability, and a heterogeneous computing architecture. With a rapidly deployable ROACH2 digital sampling system, a commercially expandable 10 Gigabit switching network system, and a flexible upgradable GPU computing system, the correlator forms a low-cost and easily-upgradable system, poised to support scalable large-scale interferometeric array in the future.

Developing eco-friendly polymeric plasticizers with excellent migration resistance is one of the research hotspots in the polyvinyl chloride (PVC) industry. A low-molecular-weight biobased polyester rubber (LMW-BPR) was synthesized from five biobased polyester monomers in a 100-L reactor and evaluated as a potential eco-friendly polymeric plasticizer for PVC. The obtained LMW-BPR is an amorphous polyester material with a low glass transition temperature of −48°C and a molecular weight of 22 kg/mol, which is lower than that of existing polyester rubber but higher than those of most polyester plasticizer commodities. Plasticized PVC composites with a total plasticizer content of 50 phr were prepared by using the mixture of LMW-BPR and di-isononyl cyclohexane-1,2-dicarboxylate (DINCH, an eco-friendly monomeric plasticizer commodity) as the plasticizer. The migration resistance test showed that the migration loss of plasticizer in plasticized PVC composite decreased significantly with the increase of LMW-BPR content. When the content of LMW-BPR reaches 30 phr, the plasticized PVC composites are almost nonmigratory. In addition, compared with PVC composite plasticized by pure DINCH, co-plasticized PVC composites containing LMW-BPR exhibit higher tensile strength and thermal stability, and their flexibility, low-temperature resistance and biocompatibility are also maintained at a similar level to the former. Overall, LMW-BPR is an effective eco-friendly polymeric plasticizer for PVC and also sustainable and scalable, thus it is worthy of wide application.

BackgroundHemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by hyperinflammation and organ failure, with a high mortality rate. Current first-line treatments for adult patients have limited efficacy and significant toxicity. The novel selective histone deacetylase inhibitor (HDACi), chidamide, has shown promise in preclinical studies for the potential treatment of HLH.MethodsAn open-label, single-center study was conducted to evaluate the efficacy and safety of chidamide in combination with etoposide and glucocorticoids for the treatment of HLH in adult patients. Seventeen patients who fulfilled at least five of the eight HLH-2004 criteria were enrolled and treated with the combination therapy. The primary outcome was overall response rate (ORR), and secondary outcomes included survival, safety and tolerability, and changes in laboratory indicators.ResultsA total of 17 HLH patients who met the inclusion criteria were enrolled in this study, with a male to female ratio of 1.8:1. The age range at enrollment was 31 to 71 years old, with a median age of 52 years old. The ORR was 76.5% (13/17 patients), with a complete response (CR) rate of 17.6% (3/17 patients) and a partial response (PR) rate of 58.8% (10/17 patients). The median overall survival (OS) was not achieved, with OS at 6 months and 12 months being 81% and 65%, respectively. The median progression free survival (PFS) was not achieved, with PFS at 6 months and 12 months being 68% and 55%, respectively. Hematologic toxicities is the most common. Safety profile was favorable, with very few cases of grade 3/4 toxicities observed. The results showed that the levels of sCD25, platelets, aspartate aminotransferase, lactate dehydrogenase, and albumin in these patients were significantly improved 3 weeks after treatment.ConclusionThe addition of chidamide to etoposide and glucocorticoids may be a promising new treatment option for patients with HLH, with a high ORR, manageable safety profile, and significant improvement in laboratory indicators. Further research is needed to confirm these findings and determine the optimal dosing and duration of therapy.

IntroductionAllergic rhinitis (AR) is an upper airway inflammatory disease of the nasal mucosa. Conventional treatments such as symptomatic pharmacotherapy and allergen-specific immunotherapy have considerable limitations and drawbacks. As an emerging therapy with regenerative potential and immunomodulatory effect, mesenchymal stem cell-derived exosomes (MSC-Exos) have recently been trialed for the treatment of various inflammatory and autoimmune diseases.MethodsIn order to achieve sustained and protected release of MSC-Exos for intranasal administration, we fabricated Poly(lactic-co-glycolic acid) (PLGA) micro and nanoparticles-encapsulated MSC-Exos (PLGA-Exos) using mechanical double emulsion for local treatment of AR. Preclinical in vivo imaging, ELISA, qPCR, flow cytometry, immunohistochemical staining, and multiomics sequencing were used for phenotypic and mechanistic evaluation of the therapeutic effect of PLGA-Exos in vitro and in vivo.ResultsThe results showed that our PLGA platform could efficiently encapsulate and release the exosomes in a sustained manner. At protein level, PLGA-Exos treatment upregulated IL-2, IL-10 and IFN-γ, and downregulated IL-4, IL-17 and antigen-specific IgE in ovalbumin (OVA)-induced AR mice. At cellular level, exosomes treatment reduced Th2 cells, increased Tregs, and reestablished Th1/Th2 balance. At tissue level, PLGA-Exos significantly attenuated the infiltration of immune cells (e.g., eosinophils and goblet cells) in nasal mucosa. Finally, multiomics analysis discovered several signaling cascades, e.g., peroxisome proliferator-activated receptor (PPAR) pathway and glycolysis pathway, that might mechanistically support the immunomodulatory effect of PLGA-Exos.DiscussionFor the first time, we present a biomaterial-facilitated local delivery system for stem cell-derived exosomes as a novel and promising strategy for AR treatment.

Precise developmental timing control is essential for organism formation and function, but its mechanisms are unclear. In C. elegans, the microRNA lin-4 critically regulates developmental timing by post-transcriptionally downregulating the larval-stage-fate controller LIN-14. However, the mechanisms triggering the activation of lin-4 expression toward the end of the first larval stage remain unknown. We demonstrate that the transmembrane transcription factor MYRF-1 is necessary for lin-4 activation. MYRF-1 is initially localized on the cell membrane, and its increased cleavage and nuclear accumulation coincide with lin-4 expression timing. MYRF-1 regulates lin-4 expression cell-autonomously and hyperactive MYRF-1 can prematurely drive lin-4 expression in embryos and young first-stage larvae. The tandem lin-4 promoter DNA recruits MYRF-1GFP to form visible loci in the nucleus, suggesting that MYRF-1 directly binds to the lin-4 promoter. Our findings identify a crucial link in understanding developmental timing regulation and establish MYRF-1 as a key regulator of lin-4 expression.

Summary: Background: MIL62, a novel glycoengineered type Ⅱ anti-CD20 monoclonal antibody, with a nearly completely afucosylated N-glycans in Fc region, has demonstrated superior activity compared with rituximab and obinutuzumab in vitro and in vivo, respectively. Methods: This multicentre, single-arm, phase 1b/2 trial aimed to explore the efficacy, pharmacokinetics, and safety of MIL62 combined with lenalidomide in patients with relapsed/refractory (R/R) follicular lymphoma (FL) or marginal zone lymphoma (MZL). Eligible patients included those who had histopathologically confirmed CD20 positive FL (grade 1–3a) or MZL and failed to be treated with rituximab. Patients received intravenously infused MIL62 1000 mg (cycle 1: day 1, 15; cycles 2–8: day 1, cycles 10 and 12: day 1) combined with oral lenalidomide (once a day, days 2–22, the initial dose was 10 mg, and the maximum dose was 20 mg) for 12 cycles, 28 days as a cycle. The primary endpoint was objective response rate (ORR) assessed by investigator per Lugano 2014 criteria every 3 cycles. This study was registered in ClinicalTrials.gov (NCT04110301). Findings: Between November 22, 2019 and December 22, 2020, 54 patients were enrolled from 11 hospitals in China and received study treatment. Fifty patients were included in the efficacy analysis set, and 43 patients (86%, 95% CI: 73, 94) achieved objective response, meeting the pre-specified primary endpoint. Disease control rate was 96% (48/50, 95% CI: 86, 100), proportion of patients with duration of response (DoR) > 6 months was 77% (33/43). The median follow-up for survival was 12.3 months (IQR 12.0–12.6). The 1-year progression-free survival rate was 72% (95% CI: 57, 83), 9-month DoR rate was 74% (95% CI: 58, 85), and 1-year overall survival rate was 98% (95% CI: 85, 100). Most common TRAEs were neutropenia (93%, 50/54), leukopenia (85% 46/54), thrombocytopenia (61% 33/54), lymphopenia (32% 17/54), and alanine aminotransferase increased (20% 11/54). Interpretation: MIL62 combined with lenalidomide showed promising efficacy in patients with R/R FL and MZL. A multicentre, randomized, open-label, phase Ⅲ trial of MIL62 combined with lenalidomide versus lenalidomide in anti-CD20 monoclonal antibody refractory FL patients is ongoing (NCT04834024). Funding: Beijing Mabworks Biotech Co. Ltd, Beijing China and the National Science and Technology Major Project for Key New Drug Development (2017ZX09304015).

In order to solve the oscillatory heat transfer problem of gas-liquid two-phase flow of cooling oil gallery of piston, a reciprocating oscillatory experimental device reformed by diesel engine was designed and established. The oscillatory flow process of gas-liquid two-phase flow in a test piece was visualized by high-speed camera technology, and the oscillatory flow patterns of gas-liquid two-phase flow in the test piece at initial and full oscillation stage under different rotation speed and liquid filling rate were analyzed respectively. The results show that at initial oscillation stage, the interface between gas and liquid is obvious, and there is no intense turbulent mixing motion. At full oscillation stage, the movement law and flow pattern of liquid change periodically. Rotational speed mainly affects the turbulence intensity of gas-liquid two-phase flow, while the liquid filling rate mainly affects the flow pattern of gas-liquid two-phase flow. The research results reveal the oscillatory flow rules of gas-liquid two-phase flow in cooling oil gallery, and also provide a reference for the structural optimization design of the highly-intensified piston in the future.

Abstract Clinically, rosacea occurs frequently in acne patients, which hints the existence of shared signals. However, the connection between the pathophysiology of rosacea and acne are not yet fully understood. This study aims to unveil molecular mechanism in the pathogenesis of rosacea and acne. We identified differentially expressed genes (DEGs) by limma and weighted gene co-expression network analysis and screened hub genes by constructing a protein–protein interaction network. The hub genes were verified in different datasets. Then, we performed a correlation analysis between the hub genes and the pathways. Finally, we predicted and verified transcription factors of hub genes, performed the immune cell infiltration analysis using CIBERSORT, and calculated the correlation between hub genes and immune cells. A total of 169 common DEGs were identified, which were mainly enriched in immune-related pathways. Finally, hub genes were identified as IL1B, PTPRC, CXCL8, MMP9, CCL4, CXCL10, CD163, CCR5, CXCR4, and TLR8. 9 transcription factors that regulated the expression of hub genes were identified. The infiltration of γδT cells was significantly increased in rosacea and acne lesions and positively linked with almost all hub genes. These identified hub genes and immune cells may play a crucial role in the development of rosacea and acne.

This study proposed the numerical simulation method of full-length prestressed anchor grouting support based on the post-grouting technology, and the modification of the embedded PILE structural unit in FLAC3D software. Specifically, we conducted the numerical simulation and made comparison in terms of the control effect of roadway surrounding rock under six types of factors: ground stress, strength grade of original rock, length of supporting members, layout spacing, grouting strengthening index and prestress, with the aim to reveal how these factors affect the deformation of surrounding rock and the evolution of plastic zone. Then, we proposed the sensitivity evaluation index of control effect under full-length prestressed anchor grouting support. The influencing factors are divided into 3 levels: strength of surrounding rock, ground stress and design of bolt-grouting support members. Suggestions for engineering are also given according to the sensitivity level of each factor. Finally, the combined high-strength grouting bolt and high-strength hollow grouting cable are developed based on a typical roadway in weak broken strata. It can effectively enhance the self-carrying capacity of weak broken surrounding rock, give full play to the supporting potential of anchoring members, and limit the deformation and failure of roadway surrounding rock. Through the field application, the full-length prestressed bolt-grouting support is verified.

To address the national mandate to enhance learner abilities and ensure continuous learning, and to overcome the challenges of inadequate quantity and low quality of teachers, the Philippine government enacted the Excellence in Teacher Education Act in April 2022, initiating teacher education reforms. Focusing on the concept of excellent teachers, the act addresses the definition of Filipino excellence in teaching and the establishment of an excellent teacher education system. The training objectives for excellent teachers aim to cultivate individuals who embody integrity, competence, and a commitment to continuous professional growth, serving as Filipino educators and school leaders. In terms of system construction, the Teacher Excellence Education Act mandates the formation of a comprehensive triangular structure comprising decision-making, management, and execution layers. Specific measures include empowering the Teacher Education Council to oversee the entire teacher education landscape, enhancing management systems to enforce the regulatory responsibilities of the National Educators Academy of the Philippines, and leveraging exemplary Centers of Excellence in Teacher Education to improve the implementation of teacher education. An analysis of the training objectives and system construction of excellent teacher education in the Philippines reveals characteristics such as modernized governance, standardized professional development, visualized growth paths, and flexible incentive mechanisms. However, challenges remain, such as the shortage of qualified teachers, a lower overall educational attainment level among teachers, and inadequate funding. Therefore, there is still a significant gap between the vision of pursuing "excellent teachers" and the current reality in the Philippines.

Abstract Background Postpartum dysfunctions and complications can occur in women. However, functional assessment should be conducted to make treatment plans before any intervention is implemented. In this context, the International Classification of Functioning, Disability and Health (ICF) may be a useful tool for women postpartum to document functional data and set rehabilitation goals. The purpose of this study was to determine the corresponding domains that should be considered in the evaluation of women’s postpartum functioning based on the International Classification of Functioning, Disability and Health (ICF) model using the Delphi method. Methods Fifteen domestic experts were invited to conduct two rounds of expert consensus survey on the ICF-based postpartum functional assessment category pool obtained through literature retrieval, clinical investigation, and reference to relevant literature. The sample was medical staff with professional knowledge of women’s health. The opinions of experts were summarized, and the positive coefficient, authority coefficient and coordination degree of experts were calculated. Results A total of 15 domestic experts participated in this expert consensus. Through two rounds of a questionnaire survey, 69 items were finally selected to form the ICF-based postpartum functional assessment tool for women. The items included 32 items of body function, 12 items of body structure, 17 items of activity and participation, and 8 items of environmental factors. In addition, we identified 8 items of personal factors. The expert positive coefficients of the two rounds of expert consensus were both 100%, the authority coefficient was 0.789, and the coefficient of variation was between 0.09 to 0.31. Conclusion A postpartum functional assessment tool for women based on the ICF model was constructed based on the Delphi method, which can provide more comprehensive health management and life intervention for postpartum women. Trial registration The Registration number of the Chinese Clinical Trial Registry is ChiCTR2200066163, 25/11/2022.

Abstract HLX01 (HanliKang®) is a rituximab biosimilar that showed bioequivalence to reference rituximab in untreated CD20-positive diffuse large B-cell lymphoma (DLBCL) in the phase 3 HLX01-NHL03 study. Here, we report the 5-year follow-up results from the open-label extension part. Patients were randomised to either rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or HLX01 plus CHOP (H-CHOP) every 21 days for up to six cycles. The primary efficacy endpoint was overall survival (OS), and secondary efficacy endpoint was progression-free survival (PFS). Of the 407 patients enrolled in HLX01-NHL03, 316 patients (H-CHOP = 157; R-CHOP = 159) were included in the 5-year follow-up for a median duration of 65.1 (range, 2.2–76.5) months. 96.5% of the patients had an International Prognostic Index (IPI) of 1 or 2, and 17.7% had bone marrow involvement. The 5-year OS rates were 81.0% (95% CI: 74.9–87.5%) and 75.4% (95% CI: 68.9–82.6%)( HR: 0.75, 95% CI 0.47–1.20; p = 0.23) while 5-year PFS rates were 77.7% (95% CI: 71.4–84.6%) and 73.0% (95% CI: 66.3–80.3%) (HR: 0.84, 95% CI 0.54–1.30; p = 0.43) in the H-CHOP and R-CHOP groups, respectively. Treatment outcomes did not differ between groups regardless of IPI score and were consistent with the primary analysis. H-CHOP and R-CHOP provided no significant difference in 5-year OS or PFS in previously untreated patients with low or low-intermediate risk DLBCL.

Abstract Although stem cell-based therapy has demonstrated considerable potential to manage certain diseases more successfully than conventional surgery, it nevertheless comes with inescapable drawbacks that might limit its clinical translation. Compared to stem cells, stem cell-derived exosomes possess numerous advantages, such as non-immunogenicity, non-infusion toxicity, easy access, effortless preservation, and freedom from tumorigenic potential and ethical issues. Exosomes can inherit similar therapeutic effects from their parental cells such as embryonic stem cells and adult stem cells through vertical delivery of their pluripotency or multipotency. After a thorough search and meticulous dissection of relevant literature from the last five years, we present this comprehensive, up-to-date, specialty-specific and disease-oriented review to highlight the surgical application and potential of stem cell-derived exosomes. Exosomes derived from stem cells (e.g., embryonic, induced pluripotent, hematopoietic, mesenchymal, neural, and endothelial stem cells) are capable of treating numerous diseases encountered in orthopedic surgery, neurosurgery, plastic surgery, general surgery, cardiothoracic surgery, urology, head and neck surgery, ophthalmology, and obstetrics and gynecology. The diverse therapeutic effects of stem cells-derived exosomes are a hierarchical translation through tissue-specific responses, and cell-specific molecular signaling pathways. In this review, we highlight stem cell-derived exosomes as a viable and potent alternative to stem cell-based therapy in managing various surgical conditions. We recommend that future research combines wisdoms from surgeons, nanomedicine practitioners, and stem cell researchers in this relevant and intriguing research area.