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Abstract X-ray imaging with a large field of view (FOV) and high resolution is extremely important for Rayleigh–Taylor instability measurement with a small amplitude and high spatial frequency in laser inertial confinement fusion. We developed an advanced Kirkpatrick–Baez (AKB) microscope based on the quadratic-aberration theory to realize a large FOV and high resolution. This microscope was assembled and tested in a laboratory, and it was then successfully applied for imaging the hydrodynamic instability of a perturbation target in implosion experiments at the Shenguang-III prototype laser facility. Imaging results demonstrate that the AKB microscope can achieve an optimal resolution of ~ 0.53 μm and ~ 0.40 μm and a spatial resolution of

Abstract Under the condition of weak grid, the phase‐locked loop (PLL) is one of the main reasons for the sub‐synchronous oscillation of the grid‐connected inverter. Therefore, it is necessary to identify the PLL parameters of the grid‐connected inverter for the analysis of the inverter operating performance. This paper uses the sequence impedance model and measured impedance data of grid‐connected inverter to construct the identification function for parameter identification of PLL, and the function is calculated by particle swarm optimization algorithm to overcome the nonlinear problem of sequence impedance model. In addition, the identification frequency band is selected based on PLL parameter sensitivity to improve the parameter identification accuracy under the same impedance measurement error. At different frequencies, the positive correlation between the sensitivity of the PLL parameters and the identification accuracy is proven to determine the definite frequency band for PLL parameter identification of grid‐connected inverter. Finally, the feasibility and effectiveness of the above research are verified by simulation and semi‐physical experiments.

Abstract To evaluate the impact of the CD4 count on ESAT6-CFP10 (EC) skin test, QuantiFERON-TB Gold In-tube test (QFT) and tuberculin skin test (TST) in a large prison and communities in Jiangsu Province among people living with HIV (PLHIV). Participants in communities were tested with the QFT and EC skin test and in prison were tested with the QFT, TST and EC skin test. A 4-knotted restricted cubic spline fitted for Logistic models was used to explore the cutoff point of CD4 count and the associations between changes in CD4 count and Mycobacterium tuberculosis (M.tb) infection. Among 1,815 PLHIV included, 19.3% (350) were from prisons and 80.7% (1465) were identified through community screenings. M.tb infection rates were 12.2% and 8.3% through QFT and EC tests, respectively. Odd Ratios (ORs) for infection increased with CD4 counts, peaking at 618 cells/mm3 for EC, 392 cells/mm3 for QFT, then plateaued. However, the pattern differed for EC between prison and screening scenarios. In prison settings, M.tb infection increased with CD4 count from 0 to 350 cells/mm3, plateaued until 500 cells/mm3, and then persistently increased. Conversely, for community, ORs decreased until 300 cells/mm3, followed by an increase between 300 and 729 cells/mm3, after which they continued to rise persistently. Our cross-sectional study among PLHIV revealed a higher rate of M.tb infection in prison compared to the community. The relationship between CD4 count and infection became negative after a certain threshold. This pivotal point differed with detection methods, with QFT showing lower CD4 thresholds than EC.

Abstract The objective of this research was to establish a rat model for cardiopulmonary bypass (CPB) with cardiac arrest and resuscitation that is both practical and economical and simulates clinical cardiac surgery. Concurrently, the study aimed to evaluate the myocardial protective effects conferred by histidine–tryptophan–ketoglutarate (HTK) cardioplegia. Thirty rats were randomly assigned to three groups: the histidine–tryptophan–ketoglutarate (HTK), 4:1 blood cardioplegia (BC) and del Nido cardioplegia (DN) groups. The cardiopulmonary bypass (CPB) procedure was implemented and sustained for a duration of one hour. Subsequent to the cessation of CPB, the rats were subjected to monitoring and observation for an additional two hours. Following this observation period, the heart and blood samples were procured for subsequent analysis. During CPB, the average hematocrit level was significantly below the typical physiological range (P

Programmed cell death ligand-1 (PD-L1) is a T cell inhibitory immune checkpoint molecule that interacts with programmed cell death-1 (PD-1) to promote immune escape of tumor cells. Compared with antibody therapies, small molecule drugs show better prospects due to their advantages such as higher bioavailability, better tissue penetration, and reduced risk of immunogenicity. Here, we found that the small molecule demethylzeylasteral (Dem) can significantly downregulate the expression of PD-L1 in colorectal cancer cells and enhance the killing effect of T cells on tumor cells. Mechanistically, Dem binds to the deubiquitinating enzyme USP22 and promotes its degradation, resulting in increased ubiquitination and degradation of PD-L1 through the proteasome pathway. In addition, Dem increased the activity of cytotoxic T cells and reduced the number of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in tumor-infiltrating lymphocytes (TILs), thereby activating the tumor immune microenvironment and inhibiting the growth of subcutaneous MC38 tumors in C57BL/6 mice. Moreover, we also found that the combination of Dem and CTLA4 antibodies can further improve the efficacy of antitumor therapy. Our study reveals the mechanism by which Dem promotes PD-L1 degradation and suggests that the combination of Dem and CTLA4 antibodies may improve the efficacy of immunotherapy.

Ferroelectric phase transition has been identified as a promising avenue for designing high-performance electrocaloric materials for zero-emission and solid-state refrigeration. However, extensive research has been limited to developing ferroelectric materials with large electrocaloric effects near room temperature, preventing them from meeting diverse refrigeration requirements. In this study, by leveraging the room-temperature phase diagram of the (PbLa)(ZrTi)O3 solution, we prepared a series of Pb0.775La0.15ZrxTi1−xO3 bulk ceramics spanning the ferroelectric and relaxor ferroelectric phase regions. This enabled the attainment of various phase transition features and temperatures. Finally, large electrocaloric effects, coupled with adjustable operation temperatures ranging from 150 to −45 °C, are successfully achieved through manipulation of the Zr/Ti ratio. This comprehensive range of operation temperatures effectively addresses diverse refrigeration application requirements, ranging from industrial equipment to freezer cabinets. This work not only underscores the expansion of the electrocaloric refrigeration application domain but also proposes a material design strategy tailored to meet these evolving demands.

Abstract Internal combustion engine fueled by carbon-free hydrogen (H2-ICE) offers a promising alternative for sustainable transportation. Herein, we report a facile and universal strategy through the physical mixing of Pt catalyst with zeolites to significantly improve the catalytic performance in the selective catalytic reduction of nitrogen oxides (NO x ) with H2 (H2-SCR), a process aiming at NO x removal from H2-ICE. Via the physical mixing of Pt/TiO2 with Y zeolite (Pt/TiO2 + Y), a remarkable enhancement of NO x reduction activity and N2 selectivity was simultaneously achieved. The incorporation of Y zeolite effectively captured the in-situ generated water, fostering a water-rich environment surrounding the Pt active sites. This environment weakened the NO adsorption while concurrently promoting the H2 activation, leading to the strikingly elevated H2-SCR activity and N2 selectivity on Pt/TiO2 + Y catalyst. This study provides a unique, easy and sustainable physical mixing approach to achieve proficient heterogeneous catalysis for environmental applications.

Abstract Background This study aimed to investigate the relationship between childhood physical activity enjoyment and current kinesiophobia among individuals with chronic low back pain (CLBP), considering the mediating influence of adult physical activity. Methods We recruited 648 adults (474 males, 174 females) with CLBP through an online platform. Of these, 99.1% (n = 642) were aged 18–60 years, and 0.9% (n = 6) were older than 60 years. Childhood physical activity enjoyment was retrospectively assessed using a single-item question to gauge participants’ enjoyment during primary school. Kinesiophobia was measured with the 11-item Tampa Scale for Kinesiophobia (TSK-11), and physical activity was assessed focusing on walking, moderate, and vigorous physical activities. Age, sex, education, and income served as control variables in the analysis. Results A significant negative association was found between childhood physical activity enjoyment and adult kinesiophobia. Additionally, childhood physical activity enjoyment was positively associated with adult physical activity across the three types of physical activities. In the adjusted mediation model, walking was identified as the only statistically significant partial mediator. Conclusion The findings highlight the long-term protective role of childhood physical activity enjoyment against the development of kinesiophobia in adulthood. Walking, in particular, holds unique therapeutic potential, emphasizing the importance of fostering physical activity enjoyment early in life for sustained physical activity and reduced risk of kinesiophobia among CLBP patients.

Abstract The interplay between the insect immune system and entomopathogenic fungi during cuticle penetration is not yet fully understood. Here, we show that a secretory protein COA1 (coat of appressorium 1) from Metarhizium robertsii, an entomopathogenic fungus causing diseases in a wide range of insects, is required to avoid host immune recognition during cuticle penetration. COA1 is highly expressed on the cuticle and translocated to the cell surface, where it directly binds with and masks carbohydrates of the fungal cell wall to avoid provoking the host’s intense immune response. Deletion of Coa1 results in a robust immune response, leading to a reduction in bacterial load in both the gut and hemocoel and ultimately attenuating fungal virulence. Our work reveals a novel cell surface protein indispensable for fungal pathogenicity via masking cell wall carbohydrates to avert a hypersensitive response from the host.

Abstract Thermoelectrics converting heat and electricity directly attract broad attentions. To enhance the thermoelectric figure of merit, zT, one of the key points is to decouple the carrier-phonon transport. Here, we propose an entropy engineering strategy to realize the carrier-phonon decoupling in the typical SrTiO3-based perovskite thermoelectrics. By high-entropy design, the lattice thermal conductivity could be reduced nearly to the amorphous limit, 1.25 W m−1 K−1. Simultaneously, entropy engineering can tune the Ti displacement, improving the weighted mobility to 65 cm2 V−1 s−1. Such carrier-phonon decoupling behaviors enable the greatly enhanced μ W/κ L of ~5.2 × 103 cm3 K J−1 V−1. The measured maximum zT of 0.24 at 488 K and the estimated zT of ~0.8 at 1173 K in (Sr0.2Ba0.2Ca0.2Pb0.2La0.2)TiO3 film are among the best of n-type thermoelectric oxides. These results reveal that the entropy engineering may be a promising strategy to decouple the carrier-phonon transport and achieve higher zT in thermoelectrics.

Abstract Background Insulin resistance (IR) is prevalent in individuals undergoing peritoneal dialysis (PD) and is related to increased susceptibility to coronary artery disease and initial peritonitis. In recent investigations, correlations have been found between indices of IR and the incidence of all-cause mortality in various populations. However, such correlations have not been detected among individuals undergoing PD. Hence, the present study’s aim was to explore the connections between IR indices and the incidence of all-cause mortality in PD patients. Methods Peritoneal dialysis patients (n = 1736) were recruited from multiple PD centres between January 2010 and December 2021. Cox proportional hazards and restricted cubic spline regression models were used to evaluate the connections between the triglyceride–glucose (TyG) index, triglyceride–glucose/body mass index (TyG–BMI), and triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) ratio and the occurrence of all-cause mortality. All three IR indices were integrated into the same model to assess the predictive stability. Furthermore, a forest plot was employed to display the findings of the subgroup analysis of PD patients. Results Overall, 378 mortality events were recorded during a median follow-up time of 2098 days. Among PD patients, a higher TyG index, TyG–BMI, and TG/HDL-C ratio were identified as independent risk factors for all-cause mortality according to Cox proportional hazards analyses (hazard ratio (HR) 1.588, 95% confidence interval (CI) 1.261–2.000; HR 1.428, 95% CI 1.067–1.910; HR 1.431, 95% CI 1.105–1.853, respectively). In a model integrating the three IR indices, the TyG index showed the highest predictive stability. According to the forest plot for the TyG index, no significant interactions were observed among the subgroups. Conclusion Significant associations were found between the TyG index, TyG–BMI, and TG/HDL-C ratio and the incidence of all-cause mortality among PD patients. The TyG index may be the most stable of the three surrogate IR markers. Finally, a correlation was identified between IR and the risk of all-cause mortality in patients undergoing PD.

Abstract Patients carrying mutations in polymerase epsilon/polymerase delta have shown positive responses to immune checkpoint inhibitors. Yet, prospective trials exploring the efficacy in those with polymerase epsilon/polymerase delta mutations are still lacking. A phase II clinical trial was initiated to evaluate the efficacy of toripalimab, a humanized IgG4K monoclonal antibody to human PD-1, in patients with advanced solid tumors with unselected polymerase epsilon/polymerase delta mutations but without microsatellite instability-high. A total of 15 patients were enrolled, 14 of whom were assessed for treatment efficacy. There was a 21.4% overall response rate, with a disease control rate of 57.1%. The median overall survival and median progression-free survival were 17.9 (95% CI 13.5-not reach) months and 2.5 (95% CI 1.4-not reach) months, respectively. For patients with exonuclease domain mutations, the objective response rate was 66.7% (2/3), with a disease control rate of 66.7% (2/3). For those with non-exonuclease domain mutations, the rates were 9.1% (1/11) and 54.5% (6/11), respectively. Notably, patients with PBRM1 gene mutations exhibited a high response rate to toripalimab at 75.0% (3/4). This study showed that neither the exonuclease domain mutations nor non-exonuclease domain mutations could fully predict the efficacy of immunotherapy, urging the need for more investigations to clarify potential immune sensitization differences within polymerase epsilon/polymerase delta mutation variants.

Abstract Converting solar energy into fuels is pursued as an attractive route to reduce dependence on fossil fuel. In this context, photothermal catalysis is a very promising approach through converting photons into heat to drive catalytic reactions. There are mainly three key factors that govern the photothermal catalysis performance: maximized solar absorption, minimized thermal emission and excellent catalytic property of catalyst. However, the previous research has focused on improving solar absorption and catalytic performance of catalyst, largely neglected the optimization of thermal emission. Here, we demonstrate an optically selective catalyst based Ti3C2Tx Janus design, that enables minimized thermal emission, maximized solar absorption and good catalytic activity simultaneously, thereby achieving excellent photothermal catalytic performance. When applied to Sabatier reaction and reverse water-gas shift (RWGS) as demonstrations, we obtain an approximately 300% increase in catalytic yield through reducing the thermal emission of catalyst by ~70% under the same irradiation intensity. It is worth noting that the CO2 methanation yield reaches 3317.2 mmol gRu −1 h−1 at light power of 2 W cm−2, setting a performance record among catalysts without active supports. We expect that this design opens up a new pathway for the development of high-performance photothermal catalysts.

Cerium oxide nanoparticles (CeO2 NPs), as the oxides of the most abundant elements in rare earths, have been widely used in biomedical and industrial production and other fields that are closely related to human life. China is a large country in resources and production of rare earth, and the impact of CeO2 NPs on human health has been increasingly concerned. In response to the possible health risks of CeO2 NPs, researchers begin to focus on their toxic effects on living organisms, especially on the reproductive system. The male reproductive system is not only responsible for producing sperm and regulating the secretion of testosterone, but also plays a key role in maintaining male sexual characters and function. Any adverse effects on the male reproductive system may lead to reduced fertility and reproductive dysfunction. Some studies have shown that long-term exposure to CeO2 NPs may lead to gonadal damage, sex hormone disorders, and other problems in male animals. Therefore, an in-depth study of the potential effects of CeO2 NPs on the male reproductive system is of great scientific significance and practical value. In this study, we reviewed the male reproductive toxicity of CeO2 NPs in terms of spermatogenic cells, spermatozoa structure, blood-testis barrier, hypothalamic-pituitary-gonadal axis, and functional changes in epididymis, and analyzed the effects of the size and shape of physicochemical parameters of CeO2 NPs on the toxicity to male reproductive system. The findings will provide a theoretical basis and scientific evidence for the rational use of CeO2 NPs.

Abstract Background Intestinal obstruction represents a severe intestinal disease associated with higher mortality rates. However, the determinants of mortality in patients with intestinal obstruction remain inadequately understood. This study sought to elucidate the potential risk factors associated with mortality in the context of intestinal obstruction during the COVID-19 pandemic. Methods A retrospective analysis was performed on a cohort of 227 patients diagnosed with intestinal obstruction at the First Hospital of Hebei Medical University, spanning the period from September 7, 2022, to January 7, 2023. The primary endpoint of the study was mortality within four weeks following discharge. Univariate and multivariable logistic regression models were utilized to evaluate the risk factors associated with mortality outcomes. Results A cohort of 227 patients diagnosed with intestinal obstruction (median age, 59.02 years [IQR, 48.95–70.85 years]) was included in our study. Malignant bowel obstruction (MBO) and COVID-19 were identified as independent risk factors for mortality among these patients. Notably, the mortality rate increased significantly to 38.46% when MBO was concomitant with COVID-19. Furthermore, postoperative pulmonary complications (PPC) (OR, 54.21 [death]; 95% CI, 3.17-926.31), gastric cancer (OR, 9.71 [death]; 95% CI, 1.38–68.18), VTE (Caprini Score ≥ 5) (OR, 7.64 [death]; 95% CI, 1.37–42.51), and COVID-19 (OR, 5.72 [death]; 95% CI, 1.01–32.29) were all determined to be independent risk factors for postoperative mortality. Additionally, gastric cancer could have emerged as one of the most severe risk factors for mortality in individuals with intestinal obstruction within the cohort of cancer patients, of which gastric cancer exhibited higher mortality rates compared to individuals with other forms of cancer. Conclusion The study identifies MBO, gastric cancer, COVID-19, PPC, and VTE as potential risk factors for mortality in cases of intestinal obstruction. These findings highlight the necessity for continuous monitoring of indicators related to these mortality risk factors and their associated complications, thereby offering valuable insights for the management and treatment of intestinal obstruction.

Abstract Photosynthesis converting solar energy to chemical energy is one of the most important chemical reactions on earth. In cyanobacteria, light energy is captured by antenna system phycobilisomes (PBSs) and transferred to photosynthetic reaction centers of photosystem II (PSII) and photosystem I (PSI). While most of the protein complexes involved in photosynthesis have been characterized by in vitro structural analyses, how these protein complexes function together in vivo is not well understood. Here we implemented STAgSPA, an in situ structural analysis strategy, to solve the native structure of PBS–PSII supercomplex from the cyanobacteria Arthrospira sp. FACHB439 at resolution of ~3.5 Å. The structure reveals coupling details among adjacent PBSs and PSII dimers, and the collaborative energy transfer mechanism mediated by multiple super-PBS in cyanobacteria. Our results provide insights into the diversity of photosynthesis-related systems between prokaryotic cyanobacteria and eukaryotic red algae but are also a methodological demonstration for high-resolution structural analysis in cellular or tissue samples.

Abstract Background Limited data exists on the efficacy of immune checkpoint inhibitor (ICI) combinations in non-small-cell lung cancer (NSCLC) with uncommon driver alterations in genes such as ERBB2, BRAF, RET, and MET. This study retrospectively assessed ICI-combination therapy outcomes in this molecular subset of NSCLC. Methods We retrospectively analyzed patients with advanced NSCLC confirmed with driver alterations in genes including ERBB2, BRAF, RET or MET, and received ICI combined with chemotherapy (ICI + chemo) and/or targeted therapy (ICI + chemo/TT) as first-line (1L) or second- or third-line (≥ 2L) treatment at Hunan Cancer Hospital between January 2018 and May 2024. Results Of the 181 patients included in the study, 131 patients received 1L-ICI + chemo (ERBB2, n = 64; BRAF, n = 34; RET, n = 23; and MET, n = 10), and 50 patients received ≥ 2L-ICI + chemo/TT (ERBB2, n = 16; BRAF, n = 7; RET, n = 14; MET, n = 13). The full cohort had an overall response rate (ORR) of 45.9% and disease control rate of 84.0%. Among patients who received 1L-ICI + chemo, ORR ranged between 51.6% and 60.0%, with the median progression-free survival (mPFS) and overall survival (mOS) of 8.2 and 21.0 months for those with ERBB2-altered tumors, 10.0 and 15.0 months for BRAF-altered tumors, 12.1 months and OS not reached for RET-altered tumors, and 6.2 and 28.0 months for MET-altered tumors, respectively. Additionally, ORR ranged between 14.3% and 30.8% for ≥ 2L-ICI + chemo/TT; mPFS and mOS were 5.4 and 16.2 months for patients with ERBB2-altered tumors, 2.7 and 5.0 months for BRAF-altered tumors, 6.2 and 14.3 months for RET-altered tumors, and 5.7 and 11.5 months for MET-altered tumors, respectively. Conclusion ICI-based combination therapies, regardless of treatment line, were effective in treating patients with advanced NSCLC harboring driver alterations in ERBB2, BRAF, RET, or MET. This suggests their potential as alternative treatment options in this patient population.

The mechanism of phenol degradation by micro-electrolytic systems can be fully understood by evaluating the oxidation of active substances from the two aspects of phenol bond-breaking and mineralization, and the direction of promoting the generation of active substances is pointed out. In this article, the effects of H2O2, O2-•, ·OH and 1O2 in the degradation of phenol were analyzed using phenol and chemical oxygen demand (COD) removal rates as judgment indicators, respectively. And the addition of C6O8H6 to the micro-electrolysis system was adopted to promote the generation of active substances. The experimental results showed that the active substances which played a dominant effect in the process of phenol bond-breaking and mineralization were changed. While 1O2 is dominant in the bond-breaking of phenol, •OH is dominant in the mineralization of phenol. After adding C6O8H6 (1 mmol/L), the removal rates of phenol and COD were increased by 7.35 and 4.85%, respectively. This was attributed to the autoxidation reaction of C6O8H6 and the continuous supply of H+ while reducing Fe3+ to Fe2+. Additionally, the C6O8H6 regulated the reaction pathway to improve the utilization of H2O2. This study provides a new perspective for the understanding of active substances in micro-electrolysis systems. HIGHLIGHTS The main active substances in the bond-breaking and mineralization are different.; is the main active substance in the phenol bond-breaking process.; •OH is the main active substance in the phenol mineralization process.; C6O8H6 can promote the formation of active substances in the system.; C6O8H6 can promote the Fe2+/Fe3+ cycle and improve the utilization of •OH.;

Abstract Background Promoting the work adaptation of nurses returning to work after childbirth is key to improving their physical and mental health and ensuring the quality of nursing care. Although postpartum nurses have reported high work stress and poor adaptation after returning to work, little is known regarding the experiences, problems and further needs. This study aimed to explore the adaptation experiences of postpartum nurses returning to work. Methods This was a qualitative study with descriptive phenomenological approach. Individual semi-structured interviews were conducted between March and May 2023 in four tertiary hospitals in Changsha, mainland China, which were selected using convenience sampling. A total of 16 postpartum nurses returning to work within one year were recruited using purposive sampling and maximum variation sampling. The interviews were analysed using the Colaizzi’s 7-step method. Results ‘Breakdown and healing’ is a strong thread in postpartum nurses’ work adaptation. It links 13 subthemes in the interview data, which can be grouped under three overarching themes: (a) changes and challenges of multiple roles; (b) self-coping and social support; and (c) further needs after returning to work. The phrase ‘breakdown and healing’ reflects the mutual relationship between stress and coping among postpartum nurses. The changes and challenges associated with being required to fulfil multiple roles of mothers, wives and nurses make the subjects feel on the verge of ‘breakdown’. When returning to work, most of them move slowly towards ‘healing’ through positive self-management and support from their partners, families, supervisors and colleagues. Moreover, their ongoing demands and unsolved problems – such as their desire for a workplace that is friendly and serves their needs – were generated by the constant process of ‘breakdown and healing’. Conclusions Understanding how postpartum nurses returning to work perceive adaptation experiences is essential for nursing managers, who can use the findings to implement targeted measures to shorten postpartum nurses’ maladaptation period after returning to work and promote their work adaptation. This study underscores the critical importance of personalized return-to-work training, flexible work arrangements, support from colleagues and managers, well-established maternal facilities and services, and targeted policy efforts in enhancing postpartum nurses’ work adaptation.

Abstract Background Extranodal natural killer/T-cell lymphoma (ENKTL) with tonsil involvement is not common, especially in children. Case presentation A 13-year-old girl presented with an unexplained sore throat for more than 2 months, together with intermittent fever and suppurative tonsilitis. Nasopharyngoscopy revealed a pharyngeal mass. Enhanced computed tomography (CT) scan showed tonsillar hypertrophy and punctate calcification. Chronic pyogenic granulomatous inflammation with pseudoepithelial squamous epithelial hyperplasia was observed in left tonsil, and pyogenic granulomatous inflammation and a small number of T-lymphoid cells were detected in the right tonsil. The immunohistochemical results showed CD2+, CD3+, CD4+, CD5+, CD8+, granzyme B+, and TIA-1+. The Ki-67 proliferation index was 20%. The case showed T cell receptor gene rearrangement. Finally, the case was diagnosed as ENKTL of stage II with tonsil involvement. The patient received 6 cycles of chemotherapy with SMILE regimen, and showed complete response with no recurrence in the follow-up. Conclusion We presented a rare case of ENKTL with tonsil involvement in a child. The patient showed complete response to the SMILE chemotherapy with no recurrence.

Abstract Aim Tumor budding (TB) has excellent prognostic value in many solid tumors, but there is little research on it in hepatocellular carcinoma (HCC). This study assessed the prognostic value of TB in patients with HCC who received hepatectomy. Methods This retrospective study included 210 patients with HCC who received curative hepatectomy at the First Affiliated Hospital of Xi'an Jiaotong University, between 2016 and 2018. TB was evaluated on hematoxylin‐ and eosin‐stained slides according to the criteria established by the 2016 International Tumor Budding Consensus Conference. t‐tests, Chi‐squared tests, and rank‐sum tests were used to correlate the extent of TB with clinicopathological parameters. Prognostic analysis was performed using Cox regression models and the Kaplan–Meier method. Results The positive detection rate of TB was 45.2% (95/210) in 210 patients with HCC. Patients positive for TB always exhibit lower tumor differentiation, higher hepatitis B virus DNA levels, and more severe liver fibrosis. Multivariate Cox analysis identified TB (hazard ratio [HR]: 2.232, 95% confidence interval [CI]: 1.479–3.368, p

Abstract Background Several core breeding and supporting lines of the Qingyuan partridge chicken, a representative local chicken breed in China, have been developed over 20 years. Consequently, its economic traits related to growth and reproduction have been significantly improved by breeding selection and commercial utilization, but some characteristic traits, such as partridge feathers, high meat quality and sufficient flavor, have always been retained. However, effective methods for genetic assessment and functional gene exploration of similar trait groups are lacking. The presence of identical haplotype fragments transmitted from parent to offspring results in runs of homozygosity (ROH), which offer an efficient solution. In this study, genomes of 134 Qingyuan partridge chickens representing two breeding populations and one preserved population were re-sequenced to evaluate the genetic diversity and explore functional genes by analyzing the diversity, distribution, and frequency of ROH. Results The results showed a low level of genomic linkage and degree of inbreeding within both the bred and preserved populations, suggesting abundant genetic diversity and an adequate genetic potential of the Qingyuan partridge chicken. Throughout the long-term selection process, 21 genes, including GLI3, ANO5, BLVRA, EFNB2, SLC5A12, and SVIP, associated with breed-specific characteristics were accumulated within three ROH islands, whereas another 21 genes associated with growth traits including IRX1, IRX2, EGFR, TPK1, NOVA1, BDNF and so on were accumulated within five ROH islands. Conclusions These findings provide new insights into the genetic assessment and identification of genes with breed-specific and selective characteristics, offering a solid genetic basis for breeding and protection of Qingyuan partridge chickens.

Abstract With the rapid proliferation of climate policies in both number and scope, there is an increasing demand for a global-level dataset that provides multi-indicator information on policy elements and their implementation contexts. To address this need, we developed the Global Climate Change Mitigation Policy Dataset (GCCMPD) using a semisupervised hybrid machine learning approach, drawing upon policy information from global, regional, and sector-specific sources. Differing from existing climate policy datasets, the GCCMPD covers a large range of policies, amounting to 73,625 policies of 216 entities. Through the integration of expert knowledge-based dictionary mapping, probability statistics methods, and advanced natural language processing technology, the GCCMPD offers detailed classification of multiple indicators and consistent information on sectoral policy instruments. This includes insights into objectives, target sectors, instruments, legal compulsion, administrative entities, etc. By aligning with the sector classification of the Intergovernmental Panel on Climate Change (IPCC) emission datasets, the GCCMPD serves to help policy-makers, researchers, and social organizations gain a deeper understanding of the similarities and distinctions among climate activities across countries, sectors, and entities.

Abstract Immune-related GTPase M (IRGM) induces autophagy and suppresses inflammation, but its putative role and signaling mechanism remain undefined in the pathogenesis of liver failure. This study aimed to address how IRGM attenuates inflammatory injury by regulating autophagy in liver failure. In this study, a total of 10 patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) and 10 healthy controls were prospectively enrolled. Intrahepatic expression of IRGM/Irgm1, NLRP3 inflammasome (NLRP3, ASC, and caspase-1), autophagy-related proteins (LC3II, P62), and inflammatory cytokines (IL-1β, TNF-α) were measured. Autophagy was activated by rapamycin (4 mg/kg) in an acute liver failure (ALF) mouse model, which was used to further study the expression of Irgm1, NLRP3 inflammasome, autophagy-related proteins, and inflammatory cytokines using both qRT-PCR and Western blot analyses. Irgm1 expression was knocked down using Irgm1 short hairpin RNA (shRNA) in lipopolysaccharide (LPS)-induced AML12 cells to investigate the effects of Irgm1 deletion on autophagy and inflammation. We found that the expression of IRGM and autophagy-related proteins was significantly downregulated while the NLRP3 inflammasome was significantly upregulated in the livers of HBV-ACLF patients and the ALF mouse model (all P

Abstract Metastatic pancreatic cancer (mPC) has a dismal prognosis. Herein, we conducted a prospective, multicentre, single-arm, phase II trial evaluating the efficacy and safety of penpulimab and anlotinib in combination with nab-paclitaxel/gemcitabine (PAAG) in patients with first-line mPC (NCT05493995). The primary endpoints included the objective response rate (ORR) and disease control rate (DCR), while secondary endpoints encompassed progression-free survival (PFS), overall survival (OS), and safety. In 66 patients analysed for efficacy, the best response, indicated by the ORR, was recorded at 50.0% (33/66) (95% CI, 37.4–62.6%), with 33 patients achieving partial response (PR). Notably, the DCR was 95.5% (63/66, 95% CI, 87.3–99.1%). The median PFS (mPFS) and OS (mOS) were 8.8 (95% CI, 8.1–11.6), and 13.7 (95% CI, 12.4 to not reached) months, respectively. Grade 3/4 treatment-related adverse events (TRAEs) were reported in 39.4% of patients (26/66). In prespecified exploratory analysis, patients with altered SWI/SNF complex had a poorer PFS. Additionally, low serum CA724 level, high T-cell recruitment, low Th17 cell recruitment, and high NK CD56dim cell scores at baseline were potential predicative biomarkers for more favourable efficacy. In conclusion, PAAG as a first-line therapy demonstrated tolerability with promising clinical efficacy for mPC. The biomolecular findings identified in this study possess the potential to guide the precise clinical application of the triple-combo regimen.

We evaluate the cytotoxicity, intracellular redox conditions, apoptosis, and methylation of DNMTs/TETs upon exposure to LiTFSI, a novel Per and Polyfluoroalkyl Substances (PFAS) commonly found in lithium-ion batteries, on human renal carcinoma cells (A498) and hepatoma cells (HepG2). The MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay showed both Perfluorooctane sulfonate (PFOS) and Lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) had a dose-dependent effect on A498 and HepG2, with LiTFSI being less toxic. Intracellular redox conditions were assessed with a microplate reader and confocal, which showed a significant decrease in Reactive Oxygen Species (ROS) levels and an increase in Superoxide dismutase (SOD) content in both cells. Exposure to LiTFSI enhanced cell apoptosis, with HepG2 being more susceptible than A498. Quantitative analysis of mRNA expression levels of 19 genes associated with kidney injury, methylation, lipid metabolism and transportation was performed. LiTFSI exposure impacted kidney function by downregulating smooth muscle alpha-actin (Acta2) and upregulating transforming growth factor beta 1 (Tgfb1), B-cell lymphoma 2-like 1) Bcl2l1, hepatitis A virus cellular receptor 1 (Harvcr1), nuclear factor erythroid 2-like 2 (Nfe2l2), and hairy and enhancer of split 1 (Hes1) expression. LiTFSI exposure also affected the abundance of transcripts associated with DNA methylation by the expression of ten-eleven translocation (TET) and DNA methyltransferase (DNMT) genes. Furthermore, LiTFSI exposure induced an increase in lipid anabolism and alterations in lipid catabolism in HepG2. Our results provide new insight on the potential role of a new contaminant, LiTFSI in the regulation of oxidative stress, apoptosis and methylation in human renal carcinoma and hepatoma cells.

BackgroundPolytrauma and hemorrhagic shock can lead to direct and indirect liver damage involving intricate pathophysiologic mechanisms. While hepatic function has been frequently highlighted, there is minimal research on how the receptor activator of the NF-κB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system is regulated in the liver following trauma. Furthermore, cross-talking complement and toll-like-receptor (TLR) systems can contribute to the posttraumatic response. Therefore, we investigated the hepatic consequences of polytrauma focusing on the RANK-RANKL-OPG axis, and evaluated the effects of a dual blockade of complement factor C5 and TLR-cofactor CD14 on hepatic features.MethodsThe established pig model of polytrauma (PT) and hemorrhagic shock included pulmonary contusion, hepatic dissection, and bilateral femur fractures, surgically addressed either by external fixation (Fix ex) or intramedullary nailing (Nail). Four groups were investigated: 1) sham animals; 2) PT treated by Fix ex (Fix ex); 3) PT by Nail (Nail); or 4) PT by Nail plus combined C5/CD14 inhibition (Nail+Therapy). Serum samples were obtained between 0 - 72 h, and liver samples at 72 h after PT. Liver tissues were histologically scored and subjected to RT-qPCR-analyses, immunohistochemistry and ELISAs to evaluate the posttraumatic hepatic response with a focus on the RANK-RANKL-OPG system.ResultsFollowing PT, the liver injury score of the Nail+Therapy group was significantly lower than in the Fix ex or Nail group without immunomodulation (p

Studying key leaf functional traits is crucial for understanding plant resource utilization strategies and growth. To explore the patterns and driving factors of key leaf functional traits in forests along elevational gradients under global change, we collected survey data from 697 forests across China from 2008 to 2020. This study examined the elevational patterns of Specific Leaf Area (SLA, m²/kg), Leaf Dry Matter Content (LDMC, g/g), Leaf Nitrogen (LN, mg/g), and Leaf Phosphorus (LP, mg/g), and their responses to climate, soil nutrients, and stand factors. The results showed distinct differences in these key leaf traits at different elevational gradients. Generally, as elevation increased, SLA decreased, while LDMC significantly increased (P < 0.001), and LN first increase and then decreased (P < 0.001). The direct influence of elevation on the spatial variation of key leaf traits was greater than its indirect effects (through environmental and stand factors). The elevational patterns of leaf traits related to resource utilization strategies (SLA and LDMC) were mainly influenced by climate (temperature and precipitation) and soil nutrient factors, showing opposite trends in response to environmental changes. The patterns of leaf nutrient traits (LN and LP) along elevational gradients were primarily influenced by climatic factors, with LN exhibiting greater environmental plasticity. Compared to other stand factors, forest age predominantly influenced the spatial variation of key leaf traits, especially SLA. These findings have significant theoretical implications for revealing how plants adapt to global change.

ABSTRACT Bombyx mori cypovirus (BmCPV), a member of the Reoviridae family, is a well-established research model for double-stranded RNA (dsRNA) viruses with segmented genomes. Despite its small genome size, the coding potential of BmCPV remains largely unexplored. In this study, we identified a novel small open reading frame within the S10 dsRNA genome, encoding a small viral peptide (VSP59) with 59 amino acid residues. Functional characterization revealed that VSP59 acts as a negative regulator of viral replication. VSP59 predominantly localizes to the cytoplasm, where it interacts with prohibitin 2 (PHB2), an inner membrane mitophagy receptor. This interaction targets mitochondria and triggers caspase 3-dependent apoptosis. Transient expression of vsp59 in BmN cells suppressed viral replication, an effect that was reversed by silencing PHB2 expression. Moreover, recombinant BmCPV with a mutated vsp59 exhibited reduced replication. Our findings demonstrate that VSP59 interacts with PHB2 on mitochondria, inducing apoptosis and thereby diminishing viral replication. This study expands our understanding of the genetic information encoded by the BmCPV genome and highlights the role of novel small peptides in host-virus interactions.IMPORTANCEA novel small open reading frame (sORF) from the viral genome was identified and characterized. The sORF could encode a small viral peptide (VSP59) that targeted mitochondria and induced prohibitin 2-related apoptosis, further attenuating Bombyx mori cypovirus replication.

Nanoparticles (NPs) have achieved extensive utilization across diverse domains, highlighting their unavoidable impact on health. The internalization of NPs carries the potential to trigger inflammation and instigate ailments by selectively targeting lysosomes, thereby posing significant public health concern. Lysosomes, essential organelles responsible for the degradation of biological macromolecules within cells, are crucial for cellular homeostasis and participate in key biological processes, including inter-organelle communication, signal transduction, plasma membrane repair, and immune responses. Consequently, a thorough understanding of lysosomal function is essential for elucidating the mechanisms underlying NPs-mediated toxicity. NPs-induced lysosomal dysfunction primarily involves disruptions in the acidic microenvironment of lysosomes, lysosomal membrane rupture, and membrane permeabilization. Additionally, potential molecular mechanisms contributing to the increased risk of lysosomal damage caused by NPs have been described, particularly concerning ion channel proteins such as V-ATPase, TRPM2, CLC-7, and LAMPs. This review aims to detail the alterations in lysosomal functionality induced by NPs and their associated mechanisms. By providing a theoretical framework, this review aims to support the potential application of NPs in biomedical fields.

Summary: This retrospective study demonstrated that patients with advanced non-small cell lung cancer who experienced any-grade or grade 1–2 immune-related adverse events (irAEs) with immune checkpoint inhibitor plus chemotherapy (ICI+Chemo) as first-line treatment regimen had significantly longer progression-free survival (PFS; p

IntroductionKawasaki disease (KD), a common cause of acquired heart disease in children in developed countries, is primarily treated with intravenous immunoglobulin (IVIG), but some children demonstrate IVIG resistance with increased coronary artery injury risk. T cells have been demonstrated to be involved in the pathogenesis of KD and its treatment with IVIG. However, the role and mechanism of dual TCR T lymphocytes in the occurrence of KD and IVIG therapy remain unclear.MethodsThis study, based on scRNA-seq combined with TCR-seq technology, clustered the peripheral blood mononuclear cells of 3 healthy controls and 6 KD patients before and after IVIG treatment. Comparative analysis was conducted to investigate the differences in the proportion of single/dual receptor T cells, the characteristics of CDR3 repertoires, cell types, and the expression of transcription factors among the three groups. The study aimed to explore the correlation between dual TCR T cells and KD as well as IVIG treatment.ResultsIn our experimental results, we observed the presence of dual TCR T cells in all three groups. However, compared to the healthy control group and the IVIG-treated group, the KD patients before IVIG treatment exhibited a lower proportion of dual TCR T cells, with variability between samples, ranging from 4% to 15%. Notably, after IVIG treatment, the proportion of dual TCR T cells significantly increased, stabilizing above 12%, and these T cells also exhibited clonal expansion and a preference for V gene usage. In addition we found differences in dual TCR T cell subsets among the three groups, for example, IVIG treatment increases the proportion of dual TCR Treg cells, but it still remains below that of healthy control groups, significantly higher proportions of both dual TCR CD8 central and effector memory T cells in IVIG-treated KD patients, and differences in the expression of transcription factors between single and dual TCR T cells. These results suggest dual TCR T cells correlate with KD and IVIG treatment.ConclusionDual TCR T lymphocytes, especially dual TCR CD8 T cells and Treg cells, play crucial roles in the pathogenesis of KD and during IVIG treatment, providing strong support for further elucidating KD pathogenesis and optimizing treatment strategies.

Reduction of the driving range under either cold temperature or real-world running condition has become the biggest challenge for battery electric vehicle (BEV). In this paper, a simulation platform that combines a kinematics model, a thermal management model, and extracted typical running conditions has been established to estimate the energy flows inside the electric vehicle under cold temperature and real-world running condition. Three vehicles have been selected to validate the accuracy of the simulation platform, giving an accuracy between 90.6% and 96.6% according to different running conditions. Under highway running condition, the driving range could be reduced by 54%. Under urban running condition, when the environment temperature drops down to −20°C, the driving range is only 49.1% of that under 20°C. In addition, there could be a 4.4% increase in driving range if the target cabin temperature could be decreased from 28°C to 20°C. According to simulation, the application of motor waste heat recovery, internal gas recirculation, and heat pump, could increase the driving range at −7°C under urban running condition by 3.5%, 2.9%, and 3.9%, indicating a 10.3% improvement in total. This has been validated via experimental test after implementing these three approaches onto the test vehicle.

Land use types, land development and utilization intensity within watersheds have changed based on intensifying human activities and climate change, thereby inducing spatiotemporal variations in non-point source pollution (NPS), significantly impacting soil and water quality. This study performed a case study on an ecological environment functional zone at the northern foot of Qinling Mountains, an area strongly affected by human activities and land use changes. It employed an improved potential non-point pollution index (PNPI) model to analyze potential non-point source pollution (PNPS) and associated risk evolution characteristics in watershed over the past 30 years. The results indicate that from 1990 to 2020, the dominant land use categories were forest and arable land, making up 95 % of the entire watershed area. Notably, urban residential land presented the most significant expansion rates and nearly doubled in area between 1990 and 2020, whereas shrubland, grassland, and unused land showed a decreasing trend. With the application of the quantile classification method, PNPS risk values were divided into five categories: very low, low, moderate, high, and very high. A polarized trend in risk was observed, with increases in areas influenced by human activities and rapid expansion of very high-risk regions. Concurrently, the pollution risk in the upstream water source area decreased. In recent years, accelerated urbanization has been the main driver causing expansion of high PNPS risk regions. This study explores the spatial and temporal evolution of PNPS risk in the Heihe Basin by using an improved PNPI model. The improved model is more accurate in calculations and provides a better understanding of the distribution of PNPS, which is an important reference for watershed management and water resource governance.

Melt electrospinning writing (MEW) combines the fundamental principles of electrospinning, a fiber forming technology, and 3D printing. The process, however, is highly complex and the quality of the fabricated structures strongly depends on the interplay of key printing parameter settings including processing temperature, applied voltage, collection speed, and applied pressure. These parameters act in unison, comprising the principal forces on the electrified jet: pushing the viscous polymer out of the nozzle and mechanically and electrostatically dragging it for deposition towards the collector. This article will reveal the correlation between the printing process parameters and the fiber morphology for curved printing fibers below the critical translation speed (CTS), and prepare controllable curved scaffolds by adjusting the electric field strength, which have fully interconnected pores and allow cells to migrate and proliferate. Furthermore, the study verified the advantages of these scaffolds through mechanical and in vitro culture experiments. The results showed that compared with the linearly printed scaffolds, the curved printed scaffolds exhibited better mechanical properties and enhanced cell attachment and proliferation.

In July 2022, regions with elevations exceeding 5 000 m on the inner Tibetan Plateau (TP) witnessed a record-breaking heatwave. But how the atmospheric circulation and soil moisture play roles in the occurrence and maintenance of the heatwave in such high elevation climate sensitive region remains unknown. Here, by using the flow analogue method, we find that negative soil moisture anomalies explain more than half of the extreme high temperature during the heatwave, while atmospheric circulation explains less than half. The high soil moisture-temperature coupling metric and the increased correlation between latent heat flux and soil moisture during heatwave revealed strong land-atmosphere feedback in the Qiangtang Plateau which has amplified the heatwave. Analyses of numerical experiments confirm that the presence of interaction between soil moisture and the atmosphere has increased the intensity of hot extreme event under the same atmospheric circulation conditions. Under the warming background, land-atmosphere coupling leads to a faster increase in extreme high temperatures compared to the global mean warming rate, and it is twice as fast as the increase in extreme high temperatures without coupling. We highlight the increased probability of extreme high temperature over the TP in the future due to soil moisture feedback and the results are hoped to inform policymakers in making decisions for climate adaptation activities.

Identification of potential cerebrovascular disorder in the patient with traumatic subarachnoid hemorrhage (tSAH) is a key element to decrease the complication occurrence and mortality rate. In this study, we aim to compare the diagnostic values between dual-source computed tomography angiography (DSCTA) and traditional tomography angiography (CTA) in identification of potential cerebrovascular disorder among tSAH patients. A total of 113 tSAH patients with the hemorrhage involving more than 2 cisterns were recruited. Among that, 42 patients received DSCTA scans, and another 71 patients received traditional CTA scans. Subsequently, all patients received digital subtraction angiography (DSA) tests to confirm the presence of the cerebrovascular disorder. In DSCTA scan group, 21.4 % (9/42) patients were reported to have cerebrovascular disorders: seven patients had intracranial aneurysms; a patient had pseudoaneurysm with carotid artery cavernous sinus fistula; and a patient had Moyamoya disease. DSA tests had the same results with that with DSCTA scans. In the cohort receiving CTA scans, 19.7 % (14/71) patients were reported to had intracranial aneurysms. However, the positive results of DSA tests for this cohort were 22.5 % (16/71). Two inconsistent results between the CTA scan and DSA test were found, including an arteriovenous malformation and an arteriovenous fistula. In summary, DSCTA and CTA had similar positive rates but differ in diagnostic accuracy for identification of cerebrovascular disorders in tSAH patients.

Objective: Glioblastomas are highly vascularized malignant tumors. We determined the efficacy and safety of the anti-angiogenic multi-kinase inhibitor, anlotinib, for a newly diagnosed glioblastoma. Methods: This multicenter, single-arm trial (NCT04119674) enrolled 33 treatment-naïve patients with histologically proven glioblastomas between March 2019 and November 2020. Patients underwent treatment with the standard STUPP regimen [fractionated focal irradiation in daily fractions of 1.8-2 Gy given 5 d/w × 6 w (total = 54-60 Gy)] or radiotherapy plus continuous daily temozolomide (TMZ) (75 mg/m2 of body surface area/d, 7 d/w from the first to the last day of radiotherapy), followed by 6 cycles of adjuvant TMZ (150–200 mg/m2 × 5 d during each 28-d cycle) plus anlotinib (8 mg/d on d 1–14 of each 3-w cycle for 2 cycles during concomitant chemoradiotherapy, 8 maximal cycles as adjuvant therapy, followed by maintenance at 8 mg/d. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS) and adverse events (AEs). Results: Thirty-three patients received the planned treatment. The median PFS was 10.9 months (95% CI, 9.9–18.7 months) and the 12-month PFS rate was 48.5%. The median OS was 17.4 months (95% CI, 14.5–21.1 months) and the 12-month OS rate was 81.8%. The most common AEs included hypertriglyceridemia [58% (n = 19)], hypoalbuminemia [46% (n = 15)], and hypercholesterolemia [46% (n = 15)] during concurrent chemoradiotherapy and leukopenia [73% (n = 24)], hypertriglyceridemia [67% (n = 22)], and neutropenia [52% (n = 17)] during adjuvant therapy. Five patients discontinued treatment due to AEs. HEG1 (HR, 5.6; 95% CI, 1.3–23.7; P = 0.021) and RP1L1 alterations (HR, 11.1; 95% CI, 2.2–57.2; P = 0.004) were associated with a significantly shorter PFS. Conclusions: Anlotinib plus the STUPP regimen has promising anti-tumor activity against glioblastoma and manageable toxicity. HEG1 and RP1L1 alterations might be novel predictive biomarkers of the response to anlotinib.

Abstract With the rapid development of modern medical technology and the dramatic increase in the amount of medical data, traditional centralized medical information management is facing many challenges. In recent years blockchain, which is a peer-to-peer distributed database, has been increasingly accepted and adopted by different industries and use cases. Key areas of healthcare blockchain applications include electronic medical record (EMR) management, medical device supply chain management, remote condition monitoring, insurance claims and personal health data (PHD) management, among others. Even so, there are a number of challenges in applying blockchain concepts to healthcare and its data, including interoperability, data security privacy, scalability, TPS and so on. While these challenges may hinder the development of blockchain in healthcare scenarios, they can be improved with existing technologies In this paper, we propose a blockchain-based healthcare operations management framework that is combined with the Interplanetary File System (IPFS) for managing EMRs, protects data privacy through a distributed approach while ensuring that this medical ledger is tamper-proof. Doctors act as full nodes, patients can participate in network maintenance either as light nodes or as full nodes, and the hospital acts as the endpoint database of data, i.e., the IPFS node, which saves the arithmetic power of nodes and allows the data stored in the hospitals and departments to be shared with the other organizations that have uploaded the data. Therefore, the integration of blockchain and zero-knowledge proof proposed in this paper helps to protect data privacy and is efficient, better scalable, and more throughput.

Abstract Background Proteolysis-targeting chimeras (PROTACs) are being developed for therapeutic use. However, they have poor pharmacokinetic profiles and their tissue distribution kinetics are not known. Methods A typical von Hippel-Lindau tumor suppressor (VHL)—PROTAC 14C-A947 (BRM degrader)—was synthesized and its tissue distribution kinetics was studied by quantitative whole-body autoradiography (QWBA) and tissue excision in rats following IV dosing. Bile duct-cannulated (BDC) rats allowed the elucidation of in vivo clearance pathways. Distribution kinetics was evaluated in the tissues and tumors of mice to support PK-PD correlation. In vitro studies enabled the evaluation of cell uptake mechanisms and cell retention properties. Results Here, we show that A947 quickly distributes into rat tissues after IV dosing, where it accumulates and is retained in tissues such as the lung and liver although it undergoes fast clearance from circulation. Similar uptake/retention kinetics enable tumor growth inhibition over 2–3 weeks in a lung cancer model. A947 quickly excretes in the bile of rats. Solute carrier (SLC) transporters are involved in hepatocyte uptake of PROTACs. Sustained BRM protein degradation is seen after extensive washout that supports prolonged cell retention of A947 in NCI-H1944 cells. A947 tissue exposure and pharmacodynamics are inversely correlated in tumors. Conclusions Plasma sampling for VHL-PROTAC does not represent the tissue concentrations necessary for efficacy. Understanding of tissue uptake and retention could enable less frequent IV administration to be used for therapeutic dosing.

Abstract By incompletely understood mechanisms, type 2 (T2) inflammation present in the airways of severe asthmatics drives the formation of pathologic mucus which leads to airway mucus plugging. Here we investigate the molecular role and clinical significance of intelectin-1 (ITLN-1) in the development of pathologic airway mucus in asthma. Through analyses of human airway epithelial cells we find that ITLN1 gene expression is highly induced by interleukin-13 (IL-13) in a subset of metaplastic MUC5AC+ mucus secretory cells, and that ITLN-1 protein is a secreted component of IL-13-induced mucus. Additionally, we find ITLN-1 protein binds the C-terminus of the MUC5AC mucin and that its deletion in airway epithelial cells partially reverses IL-13-induced mucostasis. Through analysis of nasal airway epithelial brushings, we find that ITLN1 is highly expressed in T2-high asthmatics, when compared to T2-low children. Furthermore, we demonstrate that both ITLN-1 gene expression and protein levels are significantly reduced by a common genetic variant that is associated with protection from the formation of mucus plugs in T2-high asthma. This work identifies an important biomarker and targetable pathways for the treatment of mucus obstruction in asthma.

Hot torsion tests for AZ80 magnesium alloy were carried out in the temperature range of 380 °C-260 °C, with a constant decreasing temperature rate of 10 °C/s in order to weaken the basal texture and refine the grains. The results indicated that the average grain sizes were refined forming gradient structure with increasing specimen radial position from center (12.2–5.4 μm), and that the initial basal texture intensity of the extruded magnesium alloy was weakened from 46.2 to 8.3. Furthermore, the extension twins (ETs) could be disintegrated from the twins forming separated twins with smaller sizes. Interestingly, ETs with the same twin variant intersecting with each other could be coalesced forming grains with similar orientation, while ETs with different twin variants were separated by twins boundaries contributing to grain refinement. Moreover, in addition to the conventional continuous dynamic recrystallized (CDRX) grains with 30˚ orientation rotated around C-axis of the parent grains, CDRXed grains with 30˚ rotation around a-axis and random rotation axis were also discerned. Besides, the CDRX evolution induced twins were also elaborated, exhibiting the complex competition between CDRX and twining. Hot torsion deformation with constant decreasing temperatures rate is an effective way of grain refinement and texture modification.

Abstract Exercise is usually regarded to have short-term beneficial effects on immune health. Here we show that early-life regular exercise exerts long-term beneficial effects on inflammatory immunity. Swimming training for 3 months in male mice starting from 1-month-old curbs cytokine response and mitigates sepsis when exposed to lipopolysaccharide challenge, even after an 11-month interval of detraining. Metabolomics analysis of serum and liver identifies pipecolic acid, a non-encoded amino acid, as a pivotal metabolite responding to early-life regular exercise. Importantly, pipecolic acid reduces inflammatory cytokines in bone marrow-derived macrophages and alleviates sepsis via inhibiting mTOR complex 1 signaling. Moreover, early-life exercise increases histone 3 lysine 4 trimethylation at the promoter of Crym in the liver, an enzyme responsible for catalyzing pipecolic acid production. Liver-specific knockdown of Crym in adult mice abolishes this early exercise-induced protective effects. Our findings demonstrate that early-life regular exercise enhances anti-inflammatory immunity during middle-aged phase in male mice via epigenetic immunometabolic modulation, in which hepatic pipecolic acid production has a pivotal function.

Abstract In this paper, we focus on the general free scalar–tensor gravity with three free coupling functions, which in the near-field region looks like general relativity (GR) plus a fifth force of Yukawa-type induced by the scalar field. We show that the fifth force is always attractive in the theory. We investigate the effects of the attractive fifth force and calculate in detail the fifth force-induced orbital precession rate $$\delta \omega /\omega $$ δ ω / ω and the parameterized post-Newtonian parameters $$\gamma $$ γ and $$\beta $$ β , all of which depend on the fifth force parameters and the interaction distance. It turns out that, due to the attractive fifth force, $$\delta \omega /\omega $$ δ ω / ω is always greater than zero, $$\gamma $$ γ is always less than one, $$\beta $$ β is greater than one at large distances, and additionally this class of theories is ruled out as an alternative theory to dark matter. We place stringent constraints on the fifth force parameters by combining the lunar laser ranging (LLR), Cassini, and Mercury precession experiments, and derive the upper bounds on the strength ratio of the fifth force to gravitational force at different scales from the LLR observation. We find that the Mercury constraint is not competitive with the LLR and Cassini constraints and the LLR observation imposes much more stringent bounds on the strength ratio on large scales than on small scales. Our results show that this theory is sufficiently close to GR for a small enough fifth force strength and can reduce to GR with a minimally coupled scalar field in the absence of fifth force.

With the continuous expansion of satellite constellation, this paper analyzed the characteristics of mega constellation, and summarized the capability requirements of routing algorithms for mega constellation from two aspects of networking transmission and service requirements, included reducing signaling overhead, load balancing, fault recovery, and guaranteeing QoS.In addition, it introduced the routing methods, algorithms, and their performances that were applicable to mega constellation.It looked forward to the future related technology directions for mega constellation, included software defined network, area division management, artificial intelligence, and computing power routing, with the aim of providing reference for the construction of 6G satellite Internet.

Abstract In response to the issues of traditional backpropagation (BP) neural networks in state of charge (SOC) estimation, including easy convergence to local optima, slow convergence speed, and low accuracy, this paper proposes a novel adaptive crossover mutation strategy and dynamic sparrow search algorithm to optimize BP networks' initial values and thresholds (ACMSSA‐BP). The proposed method is based on the sparrow search algorithm, where the number of producers and scroungers is adjusted through an adaptive factor. This improvement effectively transitions the search process from extensive full exploration to localized fine‐tuning search. In the position update phase of the producers, crossover mutation and dynamic search strategies are introduced to increase the diversity of good populations, prevent the algorithm from converging to local optima, and maintain its local search capability in the later stage. Using real transportation data from coal mining flame‐proof tracked vehicles, we applied correlation theory to extract model feature parameters and constructed a training data set to estimate the SOC. The results of both static and dynamic validation experiments have indicated that the ACMSSA‐BP method has delivered impressive performance in predicting SOC, as reflected in the mean absolute error, root mean squared error, and mean absolute percentage error values of less than 1.5%, 1.5%, and 1.6%, respectively. Compared with BP, SSA‐BP, CMSSA‐BP, PSO‐BP, and NARX_NN methods, the ACMSSA‐BP approach demonstrates enhanced accuracy in estimation, significant robustness, and impressive generalization capabilities.

Abstract Pericardial synovial sarcomas (PSS) have a low incidence rate and are highly invasive with a dismal prognosis. Standard treatment includes surgery, radiotherapy and chemotherapy but with limited response. Here, we report the case of a 15‐year‐old nonsmoking youngster diagnosed with PSS who developed disease relapsed from surgery after 1 month. Next‐generation sequencing (NGS) using baseline tissue was performed, and BRCA2 c.968dupT was detected. Then pazopanib (a multitargeted inhibitor) plus nivolumab (an immune checkpoint inhibitor) was administered, with a partial response and progression‐free survival of 14 months. BRCA2 c.968dupT has not previously been reported in PSS and its response to targeted combination immunotherapy are not well characterized. Here, we report the efficacy of pazopanib combined with nivolumab in a PSS patient harboring BRCA2 c.968dupT and also provide the clinical evidence of the utility of NGS in exploring actionable mutations for solid tumor. Combination therapy based on immunotherapy may be a potential treatment choice for PSS harboring BRCA2 mutation.

Jointed soft-hard composite rock mass is very common in engineering. The existence of joint and the uncoordinated deformation of soft-hard layer make the failure behavior more complicated. In this study, soft-hard composite rock with three parallel joints (two coplanar joints and one out-of-plane parallel joint) were fabricated to carry out uniaxial compression experiment. With the aid of digital imagine correlation (DIC) and acoustic emission (AE) technology, the influence of joint angle, ligament angle and the location of out-of-plane joint on crack propagation behavior of specimen is analyzed. The results show that when the hard layer contains more joints, the rock mass presents more obvious brittleness. The variation of peak strength with ligament angle also depends on the rock layer where the out-of-plane crack is located. Three failure modes and ten crack coalescence modes are summarized, which are affected by joint angle and ligament angle. The transition of crack coalescence between adjacent rock layer is mainly influenced by the space of wing cracks at joint tips. The coalescence of rock bridge in the layer with double joints is affected by ligament angle and the relative strength of layer. When the out-of-plane joint is in the hard layer, the coalescence possibility is greatly reduced.