Search

Abstract Background Centella Asiatica has been shown to have beneficial value for the treatment of tumors. However, its active ingredients and molecular mechanisms of action have not been fully elucidated. Pectic polysaccharides are the primary active components from medicinal plants. Moreover, these polysaccharides are regarded as potential inhibitors of galectins, such as galectin-1, -3, -7, that generally promote tumor growth. Nevertheless, detailed structural analysis of pectic polysaccharides from Centella Asiatica is sorely lacking, as is knowledge of their interactions with galectins. Methods Water-soluble pectic polysaccharides (WCAP) isolated from Centella Asiatica were purified into two homogeneous fractions (WCAP-A2b and WCAP-A5b) by a combination of anion-exchange and gel-permeation chromatography. Monosaccharide composition, FT-IR, NMR and enzymatic analyses were used to characterize their structural features. Furthermore, the interactions between galectin-1, -3, -7 and a series of these polysaccharides, including two pectin fractions and their structural domains produced by enzymatic hydrolysis, were evaluated by using hemagglutination and biolayer interferometry. Results WCAP-A2b and WCAP-A5b have weight averaged molecular weights of 30.0 kDa and 34.0 kDa, respectively, and both polysaccharides consist of rhamnogalacturonan I (RG-I), rhamnogalacturonan II (RG-II) and homogalacturonan (HG) domains, with mass ratios of 1.3: 1.0: 1.4 and 1.1: 1.0: 2.4, respectively. Their RG-I domains contain arabinan, galactan, and/or arabinogalactan, along with neutral sugar side chains that are more prevalent in WCAP-A2b than in WCAP-A5b. Hemagglutination and biolayer interferometry binding assays indicate that galectin-3 vis-à-vis galectin-1 and -7, binds strongly to the RG-I domain (likely via its neutral side chains) in WCAP-A5b, thereby inhibiting galectin-3-mediated cell–cell interactions. Conclusions Our study provides structural information on pectin polysaccharides from Centella Asiatica. Results suggest that RG-I domains from WCAP-A5b and WCAP-A2b may be developed as potential inhibitors of galectin-3-mediated cell–cell adhesion and tumor growth. Graphical Abstract

Abstract Background At present, heat stress (HS) has become a key factor that impairs broiler breeding industry, which causes growth restriction and poor meat quality of broilers. Selenium (Se) is an excellent antioxidant and plays a unique role in meat quality improvement. Recent years, nano-selenium (NanoSe) has received tremendous attention in livestock production, due to its characteristic and good antibacterial performance in vitro. Here, we developed the heat stressed-broiler model to investigate the protective effects of NanoSe on growth performance and meat quality of broilers and compare whether there are differences with that of other Se sources (Sodium selenite, SS; Selenoyeast, SeY; Selenomethionine, SeMet). Results HS jeopardized the growth performance and caused poor meat quality of breast muscle in broilers, which were accompanied by lowered antioxidant capacity, increased glycolysis, increased anaerobic metabolism of pyruvate, mitochondrial stress and abnormal mitochondrial tricarboxylic acid (TCA) cycle. All Se sources supplementation exhibited protective effects, which increased the Se concentration and promoted the expression of selenoproteins, improved the mitochondrial homeostasis and the antioxidant capacity, and promoted the TCA cycle and the aerobic metabolism of pyruvate, thus improved the breast muscle meat quality of broilers exposed to HS. However, unlike the other three Se sources, the protective effect of NanoSe on meat quality of heat stressed-broilers was not ideal, which exhibited limited impact on the pH value, drip loss and cooking loss of the breast muscle. Compared with the other Se sources, broilers received NanoSe showed the lowest levels of slow MyHC, the highest levels of fast MyHC and glycogen, the highest mRNA levels of glycolysis-related genes (PFKM and PKM), the highest protein expression of HSP60 and CLPP, and the lowest enzyme activities of GSH-Px, citroyl synthetase (CS) and isocitrate dehydrogenase (ICD) in breast muscle. Consistent with the SS, the Se deposition in breast muscle of broilers received NanoSe was lower than that of broilers received SeY or SeMet. Besides, the regulatory efficiency of NanoSe on the expression of key selenoproteins (such as SELENOS) in breast muscle of heat stressed-broilers was also worse than that of other Se sources. Conclusion Through comparing the meat quality, Se deposition, muscle fiber type conversion, glycolysis, mitochondrial homeostasis, and mitochondrial TCA cycle-related indicators of breast muscle in heat stressed broilers, we found that the protective effects of organic Se (SeY and SeMet) are better than that of inorganic Se (SS) and NanoSe. As a new Se source, though NanoSe showed some protective effect on breast muscle meat quality of heat stressed broilers, the protective effect of NanoSe is not ideal, compared with other Se sources.

Abstract Accumulating evidences are challenging the paradigm that methane in surface water primarily stems from the anaerobic transformation of organic matters. Yet, the contribution of oxygenic photosynthetic bacteria, a dominant species in surface water, to methane production remains unclear. Here we show methanogenesis triggered by the interaction between oxygenic photosynthetic bacteria and anaerobic methanogenic archaea. By introducing cyanobacterium Synechocystis PCC6803 and methanogenic archaea Methanosarcina barkeri with the redox cycling of iron, CH4 production was induced in coculture biofilms through both syntrophic methanogenesis (under anoxic conditions in darkness) and abiotic methanogenesis (under oxic conditions in illumination) during the periodic dark-light cycles. We have further demonstrated CH4 production by other model oxygenic photosynthetic bacteria from various phyla, in conjunction with different anaerobic methanogenic archaea exhibiting diverse energy conservation modes, as well as various common Fe-species. These findings have revealed an unexpected link between oxygenic photosynthesis and methanogenesis and would advance our understanding of photosynthetic bacteria’s ecological role in the global CH4 cycle. Such light-driven methanogenesis may be widely present in nature.

Malignant mesothelioma is a rare highly invasive tumour originating from the mesothelial cells of the pleura, peritoneum and pericardium. Malignant pleural mesothelioma (MPM) is the most common type in all malignant mesothelioma. The onset of MPM is associated with exposure to asbestos and it can have an incubation period of up to 40 years. The incidence of MPM has been increasing worldwide in recent years, so more attention has been focused on its diagnosis, treatment and prognosis. Activating mutations, amplifications and fusions/rearrangements of the anaplastic lymphoma kinase receptor tyrosine kinase ( ALK ) gene are commonly seen in patients with non-small cell lung cancer. However, it is rare in MPM. This current case report describes a female patient with advanced MPM with an ALK gene fusion mutation. In this particular case, treatment with crizotinib demonstrated some initial efficacy, which suggests that this might be a promising strategy for patients with advanced MPM with an ALK gene mutation. This required further research and evaluation in the future.

Electrochemical chlorination is promising for direct potable reuse (DPR) with zero-chemical-input and was investigated in this study for its application potential in reverse osmosis (RO)-based and non-RO-based DPR processes. Treatment of the simulated reclaimed water from non-RO-based trains showed satisfactory chlorine evolution compared to that from the RO-based trains. Under an applied current of 100 mA, a desired free chlorine concentration of 2 mg Cl2 L−1 was obtained within a short reaction time of 3.5 s. Consistent chlorine evolution performance was achieved in continuous experiments for 500 cycles, and the effluent pH was within the range of potable water guidelines (6.5 – 8.5). Electrochemical chlorination showed competitive disinfection performance compared to conventional chemical chlorination (7 log inactivation of E. coli within 60 s) at a low energy demand of ∼ 0.05 kWh m−3. The results of this preliminary investigation encourage the further exploration of electrochemical chlorination for DPR through the use of noble-metal-free anodes, utilization of renewable energy sources, removing persistent organic contaminants, and examining the synergy with RO-based DPR.

Abstract Recently, hydrogels have been widely applied as draw agents in forward osmosis (FO) desalination. This work aims to synthesize bioartificial hydrogel from a blend of sodium alginate (SA) and polyvinyl alcohol (PVA) using epichlorohydrin (ECH) as a crosslinker. Then this prepared hydrogel was applied as a draw agent with cellulose triacetate membrane in a batch (FO) cell. The effects of the PVA content in the polymer blend and the crosslinker dose on the hydrogel’s swelling capacity were investigated to optimize the hydrogel’s composition. Furthermore, the water flux and the reverse solute flux of the optimum SA/PVA hydrogel were evaluated in a batch (FO) unit under the effect of the hydrogel’s particle size, feed solution (FS) temperature, FS concentration, and membrane orientation. Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), X-ray diffraction (XRD) and compression strength tests were used to characterize the prepared hydrogel. Results revealed that the equilibrium swelling ratio (%) of 5228 was achieved with a hydrogel that had 25% PVA and a crosslinking ratio of 0.8. FO experiments revealed that the maximum water flux of 0.845 LMH achieved, when distilled water was used as FS, average hydrogel’s particle size was 60 µm, and the FS temperature was 40 °C.

Abstract Investigations of one-dimensional segmented heteronanostructures (1D-SHs) have recently attracted much attention due to their potentials for applications resulting from their structure and synergistic effects between compositions and interfaces. Unfortunately, developing a simple, versatile and controlled synthetic method to fabricate 1D-SHs is still a challenge. Here we demonstrate a stress-induced axial ordering mechanism to describe the synthesis of 1D-SHs by a general under-stoichiometric reaction strategy. Using the continuum phase-field simulations, we elaborate a three-stage evolution process of the regular segment alternations. This strategy, accompanied by easy chemical post-transformations, enables to synthesize 25 1D-SHs, including 17 nanowire-nanowire and 8 nanowire-nanotube nanostructures with 13 elements (Ag, Te, Cu, Pt, Pb, Cd, Sb, Se, Bi, Rh, Ir, Ru, Zn) involved. This ordering evolution-driven synthesis will help to investigate the ordering reconstruction and potential applications of 1D-SHs.

Abstract Background Poultry feather waste has a potential for bioenergy production because of its high protein content. This research explored the use of chicken feather hydrolysate for methane and hydrogen production via anaerobic digestion and bioelectrochemical systems, respectively. Solid state fermentation of chicken waste was conducted using a recombinant strain of Bacillus subtilis DB100 (p5.2). Results In the anaerobic digestion, feather hydrolysate produced maximally 0.67 Nm3 CH4/kg feathers and 0.85 mmol H2/day.L concomitant to COD removal of 86% and 93%, respectively. The bioelectrochemical systems used were microbial fuel and electrolysis cells. In the first using a microbial fuel cell, feather hydrolysate produced electricity with a maximum cell potential of 375 mV and a current of 0.52 mA. In the microbial electrolysis cell, the hydrolysate enhanced the hydrogen production rate to 7.5 mmol/day.L, with a current density of 11.5 A/m2 and a power density of 9.26 W/m2. Conclusions The data indicated that the sustainable utilization of keratin hydrolysate to produce electricity and biohydrogen via bioelectrical chemical systems is feasible. Keratin hydrolysate can produce electricity and biofuels through an integrated aerobic-anaerobic fermentation system. Graphical Abstract

Background: Panax ginseng Meyer polysaccharides exhibit various biological functions, like antagonizing galectin-3-mediated cell adhesion and migration. Galectin-8 (Gal-8), with its linker-joined N- and C-terminal carbohydrate recognition domains (CRDs), is also crucial to these biological processes, and thus plays a role in various pathological disorders. Yet the effect of ginseng-derived polysaccharides in modulating Gal-8 function has remained unclear. Methods: P. ginseng-derived pectin was chromatographically isolated and enzymatically digested to obtain a series of polysaccharides. Biolayer Interferometry (BLI) quantified their binding affinity to Gal-8, and their inhibitory effects on Gal-8 was assessed by hemagglutination, cell migration and T-cell apoptosis. Results: Our ginseng-derived pectin polysaccharides consist mostly of rhamnogalacturonan-I (RG-I) and homogalacturonan (HG). BLI shows that Gal-8 binding rests primarily in RG-I and its β-1,4-galactan side chains, with sub-micromolar KD values. Both N- and C-terminal Gal-8 CRDs bind RG-I, with binding correlated with Gal-8-mediated function. Conclusion: P. ginseng RG-I pectin β-1,4-galactan side chains are crucial to binding Gal-8 and antagonizing its function. This study enhances our understanding of galectin-sugar interactions, information that may be used in the development of pharmaceutical agents targeting Gal-8.

ABSTRACTThe gut microbiota has been shown to influence the efficacy and toxicity of chemotherapy, thereby affecting treatment outcomes. Understanding the mechanism by which microbiota affects chemotherapeutic toxicity would have a profound impact on cancer management. In this study, we report that fecal microbiota transplantation from oxaliplatin-exposed mice promotes toxicity in recipient mice. Splenic RNA sequencing and macrophage depletion experiment showed that the microbiota-induced toxicity of oxaliplatin in mice was dependent on macrophages. Furthermore, oxaliplatin-mediated toxicity was exacerbated in Il10-/- mice, but not attenuated in Rag1-/- mice. Adoptive transfer of macrophage into Il10-/- mice confirmed the role of macrophage-derived IL-10 in the improvement of oxaliplatin-induced toxicity. Depletion of fecal Lactobacillus and Bifidobacterium was associated with the exacerbation of oxaliplatin-mediated toxicity, whereas supplementation with these probiotics alleviated chemotherapy-induced toxicity. Importantly, IL-10 administration and probiotics supplementation did not attenuate the antitumor efficacy of chemotherapy. Clinically, patients with colorectal cancer exposed to oxaliplatin exhibited downregulation of peripheral CD45+IL-10+ cells. Collectively, our findings indicate that microbiota-mediated IL-10 production influences tolerance to chemotherapy, and thus represents a potential clinical target.

Abstract Background Spermatogonial stem cells (SSCs) are the foundation cells for continual spermatogenesis and germline regeneration in mammals. SSC activities reside in the undifferentiated spermatogonial population, and currently, the molecular identities of SSCs and their committed progenitors remain unclear. Results We performed single-cell transcriptome analysis on isolated undifferentiated spermatogonia from mice to decipher the molecular signatures of SSC fate transitions. Through comprehensive analysis, we delineated the developmental trajectory and identified candidate transcription factors (TFs) involved in the fate transitions of SSCs and their progenitors in distinct states. Specifically, we characterized the Asingle spermatogonial subtype marked by the expression of Eomes. Eomes+ cells contained enriched transplantable SSCs, and more than 90% of the cells remained in the quiescent state. Conditional deletion of Eomes in the germline did not impact steady-state spermatogenesis but enhanced SSC regeneration. Forced expression of Eomes in spermatogenic cells disrupted spermatogenesis mainly by affecting the cell cycle progression of undifferentiated spermatogonia. After injury, Eomes+ cells re-enter the cell cycle and divide to expand the SSC pool. Eomes+ cells consisted of 7 different subsets of cells at single-cell resolution, and genes enriched in glycolysis/gluconeogenesis and the PI3/Akt signaling pathway participated in the SSC regeneration process. Conclusions In this study, we explored the molecular characteristics and critical regulators of subpopulations of undifferentiated spermatogonia. The findings of the present study described a quiescent SSC subpopulation, Eomes+ spermatogonia, and provided a dynamic transcriptional map of SSC fate determination.

Abstract Transcriptional Co-Activator with PDZ-Binding Motif (TAZ, also known as WWTR1) is a downstream effector of the Hippo pathway, involved in the regulation of organ regeneration and cell differentiation in processes such as development and regeneration. TAZ has been shown to play a tumor-promoting role in various cancers. Currently, many studies focus on the role of TAZ in the process of mitophagy. However, the molecular mechanism and biological function of TAZ in renal clear cell carcinoma (KIRC) are still unclear. Therefore, we systematically analyzed the mRNA expression profile and clinical data of KIRC in The Cancer Genome Atlas (TCGA) dataset. We found that TAZ expression was significantly upregulated in KIRC compared with normal kidney tissue and was closely associated with poor prognosis of patients. Combined with the joint analysis of 36 mitophagy genes, it was found that TAZ was significantly negatively correlated with the positive regulators of mitophagy. Finally, our results confirmed that high expression of TAZ in KIRC inhibits mitophagy and promotes KIRC cell proliferation. In conclusion, our findings reveal the important role of TAZ in KIRC and have the potential to be a new target for KIRC therapy.

Abstract Background Pulmonary arterial hypertension (PAH) is a severe cardiopulmonary disease characterized by complement dependent and proinflammatory activation of macrophages. However, effective treatment for complement activation in PAH is lacking. We aimed to explore the effect and mechanism of CP40-KK (a newly identified analog of selective complement C3 inhibitor CP40) in the PAH model. Methods We used western blotting, immunohistochemistry, and immunofluorescence staining of lung tissues from the monocrotaline (MCT)-induced rat PAH model to study macrophage infiltration, NLPR3 inflammasome activation, and proinflammatory cytokines (IL-1β and IL-18) release. Surface plasmon resonance (SPR), ELISA, and CH50 assays were used to test the affinity between CP40-KK and rat/human complement C3. CP40-KK group rats only received CP40-KK (2 mg/kg) by subcutaneous injection at day 15 to day 28 continuously. Results C3a was significantly upregulated in the plasma of MCT-treated rats. SPR, ELISA, and CH50 assays revealed that CP40-KK displayed similar affinity binding to human and rat complement C3. Pharmacological inhibition of complement C3 cleavage (CP40-KK) could ameliorate MCT-induced NLRP3 inflammasome activity, pulmonary vascular remodeling, and right ventricular hypertrophy. Mechanistically, increased proliferation of pulmonary arterial smooth muscle cells is closely associated with macrophage infiltration, NLPR3 inflammasome activation, and proinflammatory cytokines (IL-1β and IL-18) release. Besides, C3a enhanced IL-1β activity in macrophages and promoted pulmonary arterial smooth muscle cell proliferation in vitro. Conclusion Our findings suggest that CP40-KK treatment was protective in the MCT-induced rat PAH model, which might serve as a therapeutic option for PAH.

Modular multilevel converter (MMC) based fault ride through (FRT) control is a promising solution to deal with the pole-to-ground (PTG) fault in high voltage direct current (HVDC) system. However, when MMC switches to the FRT control, capacitor voltage imbalance between upper and lower arms will occur, resulting in the deterioration of FRT performance. This letter provides a comprehensive analysis for the imbalance issue from the perspective of fundamental frequency circulating current (FFCC). It is found the imbalance during FRT stage will not expand continuously, but converge to a certain value gradually. The specific imbalance degree is closely associated with the amplitude of FFCC. In order to solve the imbalance issue, an open-loop balancing control is proposed. By introducing a fundamental frequency feedforward item to the inherent circulating current control, the proposed method can not only balance the capacitor voltages, but also minimize the amplitude of FFCC, and consequently the power loss of MMC during FRT process can be reduced. Finally, simulation results of PSCAD/ EMTDC verify the validity of theoretical analysis.

Abstract As the latest and most anticipated method of tumor immunotherapy, CAR-NK therapy has received increasing attention in recent years, and its safety and high efficiency have irreplaceable advantages over CAR-T. Current research focuses on the application of CAR-NK in hematological tumors, while there are fewer studies on solid tumor. This article reviews the process of constructing CAR-NK, the effects of hypoxia and metabolic factors, NK cell surface receptors, cytokines, and exosomes on the efficacy of CAR-NK in solid tumor, and the role of CAR-NK in various solid tumor. The mechanism of action and the research status of the potential of CAR-NK in the treatment of solid tumor in clinical practice, and put forward the advantages, limitations and future problems of CAR-NK in the treatment of solid tumor.

Abstract Water dropwort (Oenanthe javanica (Blume) DC), an aquatic perennial plant from the Apiaceae family, rich in dietary fibert, vitamins, and minerals. It usually grows in wet soils and water. Despite accumulating the transcriptomic data, gene function research on water dropwort is still far behind than that of the other crops. The cucumber mosaic virus (CMV) induced gene silencing was established to study the functions of gene and microRNA (miRNA) in the water dropwort. CMV Fast New York strain (CMV-Fny) genomic RNAs 1, 2, and 3 were individually cloned into pCB301 vectors. We deleted part of the ORF 2b region and introduced recognition sites. A CMV-induced gene silencing vector was employed to suppress the expression of endogenous genes, including phytoene desaturase (PDS). In order to assess the efficacy of gene silencing, we also cloned conserved sequence of gibberellin insensitive dwarf (GID1) cDNA sequences into the vector and inoculated the water dropwort. The height of CMV-GID1-infected plants was marginally reduced as a result of GID1 gene silencing, and their leaves were noticeably longer and thinner. Additionally, we also used a CMV-induced silencing vector to analyze the roles of endogenous miRNAs. We used a short tandem target mimic approach to clone miR319 and miR396 from water dropwort into the CMV vector. Plants with CMV-miRNA infection were driven to exhibit the distinctive phenotypes. We anticipate that functional genomic research on water dropwort will be facilitated by the CMV-induced gene silencing technique.

Abstract Recently, fresh water resources have been limited globally. Thus, desalination has been the most recommended solution to overcome this issue. Forward osmosis (FO) is an affordable and developing desalination technique. In this current study, a cutting-edge green hydrogel was prepared from a polymer blend of flaxseed gum (FG) and sodium alginate using epichlorohydrin (ECH) as a crosslinker and polyethylene glycol (PEG) as a semi-interpenetrating network polymer. The impact of PEG incorporation on the hydrogel’s response was investigated, and the influence of different mass contents of FG and ECH on the swelling measurements of the hydrogel was studied to optimize the composition of the hydrogel. The optimum hydrogel was characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, and X-ray diffraction and the compressive strength test. Furthermore, the behavior of the present hydrogel was examined as a draw agent in a batch FO unit. The water flux and the reverse solute flux were measured at various values of average hydrogel particle size and feed solution (FS) temperature and concentration. The optimal hydrogel of 0.3 PEG/polymer blend mass ratio, 12% FG, and 0.95 ECH/polymer blend mass ratio exhibits a swelling ratio (%) of 1800 after an hour and an equilibrium swelling ratio (ESR) (%) of 5300. The results of the FO experiments revealed that raising FS temperature and reducing FS concentration and average hydrogel particle size enhance water flux.

A clear understanding of customer needs is key to the success of new product development and customer-centric product design. Online reviews, particularly initial reviews, are commonly used as effective sources for mining customer requirements. Although customers may post truer and more objective supplementary reviews after a period of product use, such reviews are often overlooked when identifying customer requirements for product design improvement. In this study, we proposed a framework for identifying customer requirements by combining initial and supplementary reviews based on text mining. We categorized the identified customer needs into five product attribute categories using the Kano model. Two case studies were conducted in the laptop and cell phone industries to demonstrate the effectiveness of our method. Thus, dynamic customer requirements and satisfaction can be accurately mined and captured when considering supplementary reviews. In practice, the appropriate use of supplementary reviews may provide valuable guidance for product design and development strategies.

Since the first Industrial Revolution in the 18th century, the gap for technical talent began to widen, and the concept of large-scale technical and vocational education and training (TVET) began to be advocated [...]

Ticks are parasitic organisms that can transmit a wide range of pathogenic microorganisms. They are the second most common vectors of diseases affecting humans and animals. The occurrence and transmission of tick-borne diseases has recently shown increasing or fluctuating trends. DNA was extracted after the collection of tick samples. A library targeting the V4 hypervariable region of the 16S rRNA gene was constructed. After quality control, next-generation sequencing was performed with the Illumina NextSeq platform to analyze microbial diversity within the ticks. Samples were gathered between May 2023 and July 2023. A total of 77 ticks from five distinct regions were selected for next-generation sequencing. Molecular identification confirmed that all sequenced samples belonged to Haemaphysalis longicornis . The most abundant bacteria belonged to the phylum Proteobacteria , which was present in all samples. Variations in sample richness and evenness were observed among sampling sites (Shannon index, P = 0.019). The bacterial diversity in LT exhibited the highest value, with an average of 2.449. Rickettsia and Coxiella were the predominant bacterial species, both of which are classified as tick-borne pathogens. The linear discriminant analysis effect size revealed significant differences in microbial composition among groups, except for the PC and LY groups, and identified distinct biomarkers for each group. Our findings indicated the high relative abundance of both pathogenic bacteria and non-pathogenic endosymbionts in H. longicornis and the potential for pathogen transmission to residents. However, further validation through human case studies is necessary. Health care providers should be aware of the possibility of the occurrence of these diseases.

Summary: Background: Treatment options remain rather limited for extensive disease small cell lung cancer (ED-SCLC) patients in second or further-line setting. Methods: The phase 2 investigator-initiated non-randomized study enrolled patients who had disease progression on at least one line of platinum-based chemotherapy. Participants received intravenous sintilimab 200 mg on day one and oral daily anlotinib 12 mg on days 1–14 once every three weeks per cycle. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. This study is registered with ClinicalTrials.gov (NCT04055792). Findings: Forty-two patients were enrolled between August 29, 2019 and December 26, 2021 at Henan Cancer Hospital in China. 37 patients were evaluable for efficacy. The median follow-up was 24.8 months (IQR: 16.9–28.2). The median PFS was 6.1 months (95% CI: 5.0–7.3). The OS was 12.7 months (95% CI: 7.1–18.2). The ORR was 56.8% (21/37, 95% CI: 40.0–73.5) and the DCR was 89.2% (33/37, 95% CI: 78.7–99.7). Forty patients (40/42, 95%) had at least one treatment-related adverse event (TRAE). Immune-related adverse events (irAEs) were reported in 39 patients (39/42, 93%), while grade 3 or higher irAEs occurred in 11 patients (11/42, 26%). The most frequent irAEs were hypothyroidism (16/42, 38%), elevated gamma-glutamyl transpeptidase (15/42, 36%) and elevated creatine kinase MB (15/42, 36%). The most frequent grade 3 or higher irAEs were elevated gamma-glutamyl transpeptidase (5/42, 12%) and increased aspartate aminotransferase (3/42, 7%). Interpretation: Sintilimab plus anlotinib demonstrated promising antitumor activities as second or further-line therapy for ED-SCLC and had manageable toxicities. The findings support further randomized controlled trials of this combination regimen for ED-SCLC. Funding: Henan Province Health and Youth Subject Leader Training Project, Henan Health Science and Technology Innovation Talents, ZHONGYUAN QIANREN JIHUA, Henan International Joint Laboratory of drug resistance and reversal of targeted therapy for lung cancer, Tumor Research Fund of Anti-Angiogenesis Targeted Therapy of China Anti-Cancer Association.

Summary: Iron overload is closely associated with metabolic dysfunction. However, the role of iron in the hypothalamus remains unclear. Here, we find that hypothalamic iron levels are increased, particularly in agouti-related peptide (AgRP)-expressing neurons in high-fat-diet-fed mice. Using pharmacological or genetic approaches, we reduce iron overload in AgRP neurons by central deferoxamine administration or transferrin receptor 1 (Tfrc) deletion, ameliorating diet-induced obesity and related metabolic dysfunction. Conversely, Tfrc-mediated iron overload in AgRP neurons leads to overeating and adiposity. Mechanistically, the reduction of iron overload in AgRP neurons inhibits AgRP neuron activity; improves insulin and leptin sensitivity; and inhibits iron-induced oxidative stress, endoplasmic reticulum stress, nuclear factor κB signaling, and suppression of cytokine signaling 3 expression. These results highlight the critical role of hypothalamic iron in obesity development and suggest targets for treating obesity and related metabolic disorders.

Background: In this study, we present a case of Japanese spotted fever (JSF) caused by Rickettsia japonica and use this case to investigate the process of diagnosing and reintegrating traceability of infectious diseases via metagenomic next-generation sequencing (mNGS). Methods: From data relating to epidemiological history, clinical and laboratory examinations, and mNGS sequencing, a diagnosis of severe JSF was concluded. Results: A detailed field epidemiological investigation discovered parasitic Haemaphysalis longicornis from a host animal (dog) in the domicile of the patient, within which R. japonica was detected, along with a diverse array of other potentially pathogenic microorganisms that could cause other infectious diseases. Conclusion: The mNGS provided an efficient method to diagnose JSF infection. This methodology could also be applied to field epidemiological investigations to establish the traceability of infectious diseases.

ObjectiveTo genetically characterize microbial community and Anaplasma – a major pathogen harbored by Haemaphysalis tibetensis collected in Yadong county, Tibet Autonomous Region. MethodsTotally 141 ticks parasitizing on yaks were collected in Yadong county in May 2022 and the species of the ticks were identified according to amplified sequences of mitochondrial 16s rDNA of Ixodes. High-throughput sequencing was carried on the identified Haemaphysalis tibetensis using the Illumina Novaseq 6000 platform. The resulting raw data underwent processing for assembly, gene prediction, abundance analysis, and taxonomic prediction. The 16S rDNA gene fragment of Anaplasma was amplified and sequenced with nested PCR for phylogenetic analysis. ResultsOut of 141 adult tick samples collected, 121 were positively identified as Haemaphysalis tibetensis. According to species annotation with the National Center for Biotechnology Information (NCBI)-NR database, the most prevalent microorganisms were eukaryotes (19.78%) and bacteria (13.54%), with the dominant genera of Anaplasma, Trypanosoma, Psychrobacter, and Rickettsia and the dominant species of phagocytophilum group, Trypanosoma theileri, and spotted fever group rickettsia. Among the bacterial florae, the dominant phyla were Proteobacteria, Bacteroidetes, and Firmicutes. The phylogenetic analysis revealed a high homology of the tick-born Anaplasma and Anaplasma ovis. ConclusionIn the research area, the dominant tick species parasitizing on yaks in this region is the Haemaphysalis tibetensis and the major genotype of the tick-born Anaplasma is Anaplasma ovis. The results suggest that local residents and livestock could be exposed to various tick-borne pathogens and targeted surveillance and preventive measures against tick-borne diseases should be enhanced.

Distance learning has been expanding. Learner engagement is particularly important in project-based learning (PBL), but the interaction between teacher and learner and the understanding of learner status, including engagement, is not easy. This study aims to support teacher-learner communication based on learner engagement for remote PBL. In this paper, we propose the use of video activity reports by learners to estimate and understand learner engagement and to demonstrate its feasibility on the basis of the relationship between verbal and nonverbal information that can be obtained from video activity reports and learner engagement. Analysis of 232 video activity reports submitted by eight graduate students while working on remote research-based PBLs reveals that learner engagement decreases (1) when the report contained negative words, (2) when filled pauses were frequent or long, and (3) when silent pauses were infrequent or short. Furthermore, the feasibility of an AI-based support system is demonstrated through the design and implementation of a prototype.

This study developed a series of lightweight composite films with adjustable reflectivity and superior mechanical properties. Carbon fiber (CF) was electroplated with both conventional and nanocone-shaped Ni coatings to create Ni-plated carbon fiber (CF@Ni), which was then further classified into conventional Ni carbon fiber (CF@CN) and nanocone-shaped Ni carbon fiber (CF@NN). CF@Ni fibers were sheared and filtered to produce Ni-plated carbon fiber fabric (CFF@Ni), which was then encapsulated in polyimide resin (PI) to form the final thin film materials (CF@Ni/PI). The shielding performance and mechanical properties of these CF@Ni/PI thin films have been comprehensively investigated. The study found that the nanocone-shaped Ni-plated samples exhibited superior performance. Absorption loss was dominant when a relatively low amount of Ni-plated carbon fiber was added, while reflection loss dominated when a relatively high amount was added. Adding 0.3 g of nanocone-shaped Ni carbon fiber created a 1.2 mm thin film with a shielding effectiveness of 71 dB and a tensile strength of 22.4 MPa. Additionally, the thin film demonstrated excellent flexibility and durability. Due to its exceptional mechanical properties and flexibility, this composite film holds significant potential in the fields of microelectronics and intelligent electronic devices.

Abstract Background Spermatogonial stem cells (SSCs) provide a foundation for robust and continual spermatogenesis in mammals. SSCs self-renew to maintain a functional stem cell pool and differentiate to supply committed progenitors. Metabolism acts as a crucial determinant of stem cell fates; however, factors linking metabolic programs to SSC development and maintenance are poorly understood. Results We analyzed the chromatin accessibility of undifferentiated spermatogonia at the single-cell level and identified 37 positive TF regulators that may have potential roles in dictating SSC fates. The transcription factor E4F1 is expressed in spermatogonia, and its conditional deletion in mouse germ cells results in progressive loss of the entire undifferentiated spermatogonial pool. Single-cell RNA-seq analysis of control and E4f1-deficient spermatogonia revealed that E4F1 acts as a key regulator of mitochondrial function. E4F1 binds to promotors of genes that encode components of the mitochondrial respiratory chain, including Ndufs5, Cox7a2, Cox6c, and Dnajc19. Loss of E4f1 function caused abnormal mitochondrial morphology and defects in fatty acid metabolism; as a result, undifferentiated spermatogonia were gradually lost due to cell cycle arrest and elevated apoptosis. Deletion of p53 in E4f1-deficient germ cells only temporarily prevented spermatogonial loss but did not rescue the defects in SSC maintenance. Conclusions Emerging evidence indicates that metabolic signals dictate stem cell fate decisions. In this study, we identified a list of transcription regulators that have potential roles in the fate transitions of undifferentiated spermatogonia in mice. Functional experiments demonstrated that the E4F1-mediated transcription program is a crucial regulator of metabolism and SSC fate decisions in mammals. Graphical Abstract

Designing suitable surface structures is crucial to achieving long-lasting superhydrophobic properties. In this study, laser marking was utilized to fabricate micron groove arrays, creating the LM sample, which was then coated with a nickel nanocone-shaped structure through electrodeposition, forming the LME sample. Organic modifications were applied to both samples to increase their hydrophobicity. The surface morphology and cross-section structure of the coatings were analyzed in detail, and contact angle measurements indicated the presence of an air layer. A thorough analysis was conducted to compare the hydrophobicity of the laser marked and LME samples, revealing that the LME sample demonstrated exceptional wear-resistant superhydrophobicity. This was validated by various friction wear tests, which were performed using a well-designed testing setup. Moreover, the coating adhesion was assessed through a peeling test, revealing a strong adherence to the substrate. The corrosion resistance of the LME sample was also superior to that of the LM sample, as demonstrated by the results of the corrosion tests. The cost-effective and controllable method of laser marking and electrodeposition used in this study provides a feasible way to develop durable and resistant superhydrophobic coatings on light alloy surfaces.

With the rapid development of the renewable energy vehicles, pursuing the power converters with high efficiency and high reliability has caught more attention recently. In order to solve those problem with low cost, this paper proposes a sensor-less synchronous rectification method for the CLLLC resonant converters. The precise conduction time of the synchronous switches is obtained based on the analysis of the working principle of CLLLC resonant converter, and the relationship between the SRs switching time and the inverter switching time can be derived as well. To achieve the wide output voltage range, the converter requires wide working frequency. And the correct turn-on and turn-off time for the synchronous switches can be obtained respectively by calculation and piecewise linear function fitting methods within full working frequency range. Compared with traditional synchronous rectification control for CLLLC, which require additional high bandwidth voltage sensors or current sensors, the method proposed in this paper is realized by only one low-cost output voltage sensor. And the proposed method is suitable for high-power applications with a wide voltage and load variation. Moreover, because of the symmetrical topology, this method is valid in bidirectional power transfer. Additionally, the exist analog synchronous rectification control chips suffer from losing accuracy with wide bus voltage variation, however, this method can overcome this shortcoming. Thus, the proposed synchronous rectification method is a low-cost and suitable for high-power, high power density, high efficiency application which benefit from its simple algorithm. Finally, the proposed sensor-less synchronous rectification method is validated by the simulation results and experimental results. The results of simulation and experimental have shown the proposed method offers significant benefits which increases the efficiency of the whole CLLLC system by about 3%, and the reliability of the converter are greatly increased, due to the cooler SRs.

Graphene oxide-silver poly(vinylidene fluoride) membranes (PVDF@GO-Ag) were successfully synthesized by the electrospinning method, which exhibited a high catalytic activity using the hydrogenation of 4-nitrophenol (4-NP) as a model reaction in a batch reaction study. The hybrid membranes doped with 1 wt% GO and 2 wt% Ag (PVDF-1-2) exhibited the most desired performance for the catalytic reduction of 4-NP. Importantly, PVDF-1-2 exhibited excellent cycling stability in 10 catalytic cycle tests and was highly amenable to separation. This property effectively addresses the significant challenges associated with the practical application of nanocatalysts. Furthermore, density-functional theory (DFT) calculations have demonstrated that the GO-Ag nanocomposites exhibit the strongest adsorption capacity for 4-NP− when a specific ratio of GO and Ag is achieved, accompanied by the loading of Ag nanoclusters onto GO. Additionally, the study demonstrated that an increase in temperature significantly accelerated the reaction rate, in line with the van’t Hoff rule. This study provides an effective and environmentally friendly solution for the treatment of 4-NP in wastewater.

Abstract Exposure to alcohol content in media increases alcohol consumption and related harm. With exponential growth of media content, it is important to use algorithms to automatically detect and quantify alcohol exposure. Foundation models such as Contrastive Language-Image Pretraining (CLIP) can detect alcohol exposure through Zero-Shot Learning (ZSL) without any additional training. In this paper, we evaluated the ZSL performance of CLIP against a supervised algorithm called Alcoholic Beverage Identification Deep Learning Algorithm Version-2 (ABIDLA2), which is specifically trained to recognise alcoholic beverages in images, across three tasks. We found ZSL achieved similar performance compared to ABIDLA2 in two out of three tasks. However, ABIDLA2 outperformed ZSL in a fine-grained classification task in which determining subtle differences among alcoholic beverages (including containers) are essential. We also found that phrase engineering is essential for improving the performance of ZSL. To conclude, like ABIDLA2, ZSL with little phrase engineering can achieve promising performance in identifying alcohol exposure in images. This makes it easier for researchers, with little or no programming background, to implement ZSL effectively to obtain insightful analytics from digital media. Such analytics can assist researchers and policy makers to propose regulations that can prevent alcohol exposure and eventually prevent alcohol consumption.

Abstract Smart window is an attractive option for efficient heat management to minimize energy consumption and improve indoor living comfort owing to their optical properties of adjusting sunlight. To effectively improve the sunlight modulation and heat management capability of smart windows, here, we propose a co-assembly strategy to fabricate the electrochromic and thermochromic smart windows with tunable components and ordered structures for the dynamic regulation of solar radiation. Firstly, to enhance both illumination and cooling efficiency in electrochromic windows, the aspect ratio and mixed type of Au nanorods are tuned to selectively absorb the near-infrared wavelength range of 760 to 1360 nm. Furthermore, when assembled with electrochromic W18O49 nanowires in the colored state, the Au nanorods exhibit a synergistic effect, resulting in a 90% reduction of near-infrared light and a corresponding 5 °C cooling effect under 1-sun irradiation. Secondly, to extend the fixed response temperature value to a wider range of 30–50 °C in thermochromic windows, the doping amount and mixed type of W-VO2 nanowires are carefully regulated. Last but not the least, the ordered assembly structure of the nanowires can greatly reduce the level of haze and enhance visibility in the windows.

In order to further meet the requirements of weight, volume, and dose minimization for new nuclear energy devices, the bare-bones multi-objective particle swarm optimization algorithm is used to automatically and iteratively optimize the design parameters of radiation shielding system material, thickness, and structure. The radiation shielding optimization program based on the bare-bones particle swarm optimization algorithm is developed and coupled into the reactor radiation shielding multi-objective intelligent optimization platform, and the code is verified by using the Savannah benchmark model. The material type and thickness of Savannah model were optimized by using the BBMOPSO algorithm to call the dose calculation code, the integrated optimized data showed that the weight decreased by 78.77%, the volume decreased by 23.10% and the dose rate decreased by 72.41% compared with the initial solution. The results show that the method can get the best radiation shielding solution that meets a lot of different goals. This shows that the method is both effective and feasible, and it makes up for the lack of manual optimization.

ObjectiveTo reveal the safety and efficacy of clipping and coiling in patients with ruptured distal anterior cerebral artery aneurysms (DACAA) and to calculate the risk factors affecting the two-year survival rate in follow-up patients.MethodsA retrospective study was conducted on the data of 140 patients (21 were lost to follow-up) with DACAA rupture who were treated by neurosurgery at 12 medical centers over a 2-year period, from January 2017 to December 2020. Univariate analysis was used to examine factors contributing to poor patient prognosis and to compare the prognosis of coiling and clipping treatments. Survival analysis was employed to compare survival rates between coiling and clipping, and risk factors affecting patient survival were analyzed using multivariate Cox regression analysis.ResultsOut of 140 patients with ruptured DACAA, 80 (57.1%) were male, and 60 (42.9%) were female. A total of 111 (79.3%) patients were classified under Hunt-Hess scale grades I-III, while 95 (67.9%) were graded I-III according to the WFNs classification. Among them, 63 (45%) were treated with clipping, and 77 (55%) underwent coiling. Within 2 years of discharge from the hospital, 31 (59.6%) patients who underwent clipping and 54 (80.6%) who underwent coiling had a good prognosis. Multivariate Cox regression analysis revealed that only WFNs classification (I-III) was a protective factor influencing the 2-year survival of patients with ruptured DACAA.ConclusionIn the reality of medical practice, neurosurgeons are more likely to choose clipping as the treatment for cases with WFNs classification than or equal to III. There was no difference between clipping and coiling in the two-year prognosis at discharge. High priority should be given to DACAA cases with WFNs grading (I-III), as better outcomes can be achieved. The sample size will continue to be enlarged in the future to obtain more accurate findings. Abstracts for reviews, technical notes, and historical vignettes do not need to be separated into sections. They should begin with a clear statement of the paper’s purpose followed by appropriate details that support the authors’ conclusion(s).

Summary: Background: Exclusive enteral nutrition (EEN) is an important alternative strategy for patients with Crohn’s disease (CD), and during this process, microbiota alterations have been observed. However, the underlying mechanisms by which EEN reduces intestinal inflammation are currently unclear. Methods: The therapeutic potential of enteral nutrition (EN) was assessed using various mouse models. Fecal full-length 16S rDNA sequencing analysis and several CD metagenome datasets were used to identify the candidate therapeutic bacteria Faecalibaculum rodentium (F. rodentium). Whole genome sequencing of F. rodentium and widely-targeted metabolome analysis of the supernatant showed that EN-induced F. rodentium accumulation protected against colitis via histidine biosynthesis. Findings: The therapeutic potential of EN therapy was observed in both dextran sulfate sodium (DSS)-induced colitis and Il10−/− spontaneous colitis mouse models. Accumulation of F. rodentium after EN therapy was determined using full-length 16S rDNA sequencing and verified with several metagenome datasets from patients with CD. Colonization of an isolated F. rodentium could reduce colitis in Il10−/− mice. Significant histidine enrichment was observed in the F. rodentium culture supernatant, and a series of histidine biosynthesis genes were observed in the F. rodentium genome. Engineered Escherichia coli Nissle 1917 (EcN), encoding the heterologous hisG of F. rodentium (EcN-hisG), which was a key driver of histidine biosynthesis in F. rodentium, was found to protect against colitis. Interpretation: This study suggests that EN-induced F. rodentium accumulation protects against colitis in mice via gut bacteria-mediated histidine biosynthesis. Funding: A full list of funding bodies can be found in the Acknowledgements section.

BackgroundHepatocellular carcinoma (HCC) is the most common type of liver cancer, accounting for ~90% of the total cases. DnaJ heat shock protein family member C8 (DNAJC8), belonging to the heat shock protein 40 (HSP40) family, is known to regulate cancer biology function. However, the role of DNAJC8 on HCC development remains unknown.MethodsThe Cancer Genome Atlas, GTEx, cBioPortal, and Human Protein Atlas were used to analyze the expression and clinical significance of DNAJC8 in HCC. Two HCC cell lines, MHCC-97H and Huh-7, were utilized to determine the biological function of DNAJC8.ResultsDNAJC8 expression was upregulated in HCC tissues and correlated with poor clinical prognosis. It was closely related to spliceosome, nucleocytoplasmic transport, and cell cycle and might be involved in the formation of tumor immunosuppressive microenvironment. Knockdown of DNAJC8 severely inhibited HCC cell proliferation and induced apoptosis.ConclusionOur study demonstrate that DNAJC8 functions as an oncogene in HCC and hence may be used as a potential therapeutic target and prognostic marker for HCC.

IntroductionAs tick-borne diseases rise to become the second most prevalent arthropod-transmitted disease globally, the increasing investigations focus on ticks correspondingly. Factors contributed to this increase include anthropogenic influences, changes in vertebrate faunal composition, social-recreational shifts, and climatic variation. Employing the 16S gene sequence method in next-generation sequencing (NGS) allows comprehensive pathogen identification in samples, facilitating the development of refined approaches to tick research omnidirectionally.MethodsIn our survey, we compared the microbial richness and biological diversity of ticks in Wuwei City, Gansu province, differentiating between questing ticks found in grass and parasitic ticks collected from sheep based on 16S NGS method.ResultsThe results show Rickettsia, Coxiella, and Francisella were detected in all 50 Dermacentor nuttalli samples, suggesting that the co-infection may be linked to specific symbiotic bacteria in ticks. Our findings reveal significant differences in the composition and diversity of microorganisms, with the Friedmanniella and Bordetella genera existing more prevalent in parasitic ticks than in questing ticks (p 0.6. For instance, Francisella restrains the development of 10 other bacteria in parasitic ticks, whereas Phyllobacterium and Arthrobacter enhance colonization across all tick species.DiscussionBy leveraging NGS techniques, our study reveals a high degree of species and phylogenetic diversity within the tick microbiome. It further highlights the potential to investigate the interplay between bacterial genera in both parasitic and questing ticks residing in identical habitat environments.

Oceanic emissions are a major source of atmospheric, very short-lived, ozone-depleting, brominated substances. These substances can be produced by marine microalgae, estimates of their current and future emissions are imperfect, because the processes by which marine microalgae respond to environmental changes are rarely account for environmental pollutants. Here, concurrent measurements of the potential effects of polystyrene (PS) microplastics with concentrations of 25–100 mg/L on the growth of Phaeodactylum tricornutum and their volatile halocarbons (VHCs) production were made over a 20-day culture period. The maximum inhibition rates (IR) due to 0.1 µm and 0.5 µm PS microplastics on cell density were 40.11 % and 32.87 %, on Chl a content were 25.89 % and 20.73 %, and on Fv/Fm were 9.74 % and 9.00 %, respectively. All IR showed dose-dependent effects with maxima occurring in the logarithmic phase. However, in the stationary phase, P. tricornutum exposed to PS microplastics exhibited improved attributes. Enhanced biogenesis of VHCs was induced by the excess reactive oxygen species in algal cells due to microplastics exposure, and their production rates were higher in the logarithmic phase than stationary phase. This represents that oxidative stress to cells plays a dominant role in determining the release of CHBrCl2, CHBr2Cl, and CHBr3. Hence, we suggest that the widespread microplastics in the ocean may be partly responsible for the increase in the emission of VHCs by marine phytoplankton, thereby affecting the ozone layer recovery in the future.

ABSTRACTDietary iron intake is closely related to the incidence of colorectal cancer. However, the interactions among dietary iron, gut microbiota, and epithelial cells in promoting tumorigenesis have rarely been discussed. Here, we report that gut microbiota plays a crucial role in promoting colorectal tumorigenesis in multiple mice models under excessive dietary iron intake. Gut microbiota modulated by excessive dietary iron are pathogenic, irritating the permeability of the gut barrier and causing leakage of lumen bacteria. Mechanistically, epithelial cells released more secretory leukocyte protease inhibitor (SLPI) to combat the leaked bacteria and limit inflammation. The upregulated SLPI acted as a pro-tumorigenic factor and promoted colorectal tumorigenesis by activating the MAPK signaling pathway. Moreover, excessive dietary iron significantly depleted Akkermansiaceae in the gut microbiota; while supplementation with Akkermansia muciniphila could successfully attenuate the tumorigenic effect from excessive dietary iron. Overall, excessive dietary iron perturbs diet – microbiome–epithelium interactions, which contributes to intestinal tumor initiation.

ABSTRACTObjectives Primary mediastinal large B-cel l lymphoma (PMBCL) is a rare subtype of B-cell lymphoma that is not yet fully understood. This population-based study aimed to assess the latest survival and treatment strategies for patients with PMBCL.Methods The study used the dataset from the Surveillance, Epidemiology, and End Results Program registry to retrospectively analyze adult patients diagnosed with PMBCL between 2001 and 2018. The primary outcome measures included overall survival (OS) and disease-specific survival (DSS).Results Among the 814 identified cases, the study revealed a 5-year OS rate of 86.7% and a 5-year DSS rate of 88.2% after a median follow-up of 54 months. Cox regression analysis indicated that age over 60 years, pre-2010 diagnosis, non-White ethnicity, advanced stage, and absence of chemotherapy significantly reduced both OS and DSS. It also found that chemotherapy has remained the primary therapeutic protocol for PMBCL over the last 20 years, whereas the utilization of surgery and radiation declined significantly. Patients diagnosed with PMBCL between 2010 and 2018 had a significantly reduced mortality risk (∼50%) compared to those diagnosed between 2001 and 2009. Notably, in the era of rituximab’s widespread usage, recipients of radiotherapy exhibited a poorer OS rate than non-recipients.Conclusion Survival outcomes for patients with PMBCL have significantly improved in the current era, possibly due to the evolving treatment paradigm. The value of radiotherapy in PMBCL is still debated and requires further prospective evaluation.

Abstract Probabilistic predictions for regression problems are more popular than point predictions and interval predictions, since they contain more information for test labels. Conformal predictive system is a recently proposed non-parametric method to do reliable probabilistic predictions, which is computationally inefficient due to its learning process. To build faster conformal predictive system and make full use of training data, this paper proposes the predictive system based on locally weighted jackknife prediction approach. The theoretical property of our proposed method is proved with some regularity assumptions in the asymptotic setting, which extends our earlier theoretical researches from interval predictions to probabilistic predictions. In the experimental section, our method is implemented based on our theoretical analysis and its comparison with other predictive systems is conducted using 20 public data sets. The continuous ranked probability scores of the predictive distributions and the performance of the derived prediction intervals are compared. The better performance of our proposed method is confirmed with Wilcoxon tests. The experimental results demonstrate that the predictive system we proposed is not only empirically valid, but also provides more information than the other comparison predictive systems.

Abstract Metabolic reprogramming is a hallmark of cancer. However, it is not well known how metabolism affects cancer progression. We identified that metabolic enzyme acyl-CoA oxidase 1 (ACOX1) suppresses colorectal cancer (CRC) progression by regulating palmitic acid (PA) reprogramming. ACOX1 is highly downregulated in CRC, which predicts poor clinical outcome in CRC patients. Functionally, ACOX1 depletion promotes CRC cell proliferation in vitro and colorectal tumorigenesis in mouse models, whereas ACOX1 overexpression inhibits patient-derived xenograft growth. Mechanistically, DUSP14 dephosphorylates ACOX1 at serine 26, promoting its polyubiquitination and proteasomal degradation, thereby leading to an increase of the ACOX1 substrate PA. Accumulated PA promotes β-catenin cysteine 466 palmitoylation, which inhibits CK1- and GSK3-directed phosphorylation of β-catenin and subsequent β-Trcp-mediated proteasomal degradation. In return, stabilized β-catenin directly represses ACOX1 transcription and indirectly activates DUSP14 transcription by upregulating c-Myc, a typical target of β-catenin. Finally, we confirmed that the DUSP14-ACOX1-PA-β-catenin axis is dysregulated in clinical CRC samples. Together, these results identify ACOX1 as a tumor suppressor, the downregulation of which increases PA-mediated β-catenin palmitoylation and stabilization and hyperactivates β-catenin signaling thus promoting CRC progression. Particularly, targeting β-catenin palmitoylation by 2-bromopalmitate (2-BP) can efficiently inhibit β-catenin-dependent tumor growth in vivo, and pharmacological inhibition of DUSP14-ACOX1-β-catenin axis by Nu-7441 reduced the viability of CRC cells. Our results reveal an unexpected role of PA reprogramming induced by dephosphorylation of ACOX1 in activating β-catenin signaling and promoting cancer progression, and propose the inhibition of the dephosphorylation of ACOX1 by DUSP14 or β-catenin palmitoylation as a viable option for CRC treatment.

The cavity form of complex microcavity lasers predominantly relies on disordered structures, whether found in nature or artificially prepared. These structures, characterized by disorder, facilitate random lasing through the feedback effect of the cavity boundary and the internal scattering medium via various mechanisms. In this paper, we report on a random fiber laser employing a disordered scattering cladding medium affixed to the inner cladding of a hollow-core fiber. The internal flowing liquid gain establishes a stable liquid-core waveguide environment, enabling long-term directional coupling output for random laser emission. Through theoretical analysis and experimental validation, we demonstrate that controlling the disorder at the cavity boundary allows liquid-core fiber random microcavities to exhibit random lasing output with different mechanisms. This provides a broad platform for in-depth research into the generation and control of complex microcavity lasers, as well as the detection of scattered matter within micro- and nanostructures.

Debris-free and debris-covered glaciers are both extensively present in the southeastern Tibetan Plateau. High-precision and rigorous comparative observational studies on different types of glaciers help us to accurately understand the overall state of water resource variability and the underlying mechanisms. In this study, we used multi-temporal simultaneous UAV surveys to systematically explore the surface elevation change, surface velocity, and surface mass balance of two representative glaciers. Our findings indicate that the thinning rate in the debris-free Parlung No. 4 glacier UAV survey area was consistently higher than that in the debris-covered 24K glacier in 2020–2021 (−1.16 ± 0.03 cm/d vs. −0.36 ± 0.02 cm/d) and 2021–2022 (−0.69 ± 0.03 cm/d vs. −0.26 ± 0.03 cm/d). Moreover, the surface velocity of the Parlung No. 4 glacier was also consistently higher than that of the 24K glacier across the survey period, suggesting a more dynamic glacial state. The surface mass balance of the Parlung No. 4 glacier (2020–2021: −1.82 ± 0.09 cm/d; 2021–2022: −1.30 ± 0.09 cm/d) likewise outpaced that of the 24K glacier (2020–2021: −0.81 ± 0.07 cm/d; 2021–2022: −0.70 ± 0.07 cm/d) throughout the observation period, which indicates that the debris cover slowed the glacier’s melting. Additionally, we extracted the melt contribution of the ice cliff area in the 24K glacier and found that the melt ratio of this ‘hotspot’ area ranged from 10.4% to 11.6% from 2020 to 2022. This comparative analysis of two representative glaciers provides evidence to support the critical role of debris cover in controlling surface elevation changes, glacier dynamics, and surface mass balance.

Microbial electrochemical systems (MES) are studied to degrade organic contaminants with a lower energy demand, but degradation of recalcitrant compounds tends to be challenging. To enhance contaminant degradation in MES, advanced oxidation processes (AOPs) are synergistically linked to create cooperative processes such as bio-electro-Fenton (BEF) and enhanced bioanodes. BEF can achieve a high contaminant degradation efficiency with a low energy consumption due to the ability for energy recovery from the anodic organic wastes. Modifying a bioanode with catalytic oxidation materials, e.g., photocatalyst and MnO2, will achieve organic removal via the cooperation of catalysis and biodegradation. This paper has provided a concise review on the integration of AOPs with MES and identified and discussed the challenges such as deeper understanding of the electron transfer mechanisms, development of low-cost membrane, and the synergetic effects between functional materials and bacteria that are important to develop AOP-MES treatment systems.

The unfolded protein response (UPR) is a cell-designated strategy that maintains the balance of protein folding in the endoplasmic reticulum (ER). UPR features a network of signal transduction pathways that reprogram the transcription, mRNA translation, and protein post-translational modification to relieve the ER stresses from unfolded/misfolded proteins. Infection with plant viruses can induce the UPR, and activated UPR often promotes plant viral infections in turn. However, the mechanism used by plant viruses to balance UPR and achieve robust infection remain largely unknown. In this study, P1SCSMV was identified as a virus-encoded RNA silencing suppressor (VSR). Heterologous overexpression of P1SCSMV via potato virus X (PVX) was found lead to programmed cell death (PCD) in Nicotiana benthamiana. Furthermore, P1SCSMV was also found to inhibit the PVX infection-triggered UPR by downregulating UPR-related genes and directly induced the distortion and collapse of the ER polygonal meshes on PVX-P1SCSMV infected N. benthamiana. Moreover, self-interaction, VSR activity, UPR inhibition, and cell death phenotype of P1SCSMV were also found to be dependent on its bipartite nuclear localization signal (NLS) (251RKRKLFPRIPLK262). P1SCSMV was found to directly bind to the stem-loop region of NbbZIP60U via its NLS and inhibit the UPR pathways, ultimately resulting in a PCD phenotype in PVX-P1SCSMV infected N. benthamiana leaves. This study also revealed the balancing role of potyviruses encoded P1SCSMV in the UPR pathway to achieve robust viral infection. This may represent a novel virulence strategy for plant viruses.

Abstract Deep Reinforcement Learning (DRL) has been increasingly attempted in assisting clinicians for real-time treatment of sepsis. While a value function quantifies the performance of policies in such decision-making processes, most value-based DRL algorithms cannot evaluate the target value function precisely and are not as safe as clinical experts. In this study, we propose a Weighted Dueling Double Deep Q-Network with embedded human Expertise (WD3QNE). A target Q value function with adaptive dynamic weight is designed to improve the estimate accuracy and human expertise in decision-making is leveraged. In addition, the random forest algorithm is employed for feature selection to improve model interpretability. We test our algorithm against state-of-the-art value function methods in terms of expected return, survival rate, action distribution and external validation. The results demonstrate that WD3QNE obtains the highest survival rate of 97.81% in MIMIC-III dataset. Our proposed method is capable of providing reliable treatment decisions with embedded clinician expertise.

Context Yiqi Huoxue Tongluo recipe (YHTR) is a traditional Chinese medicine for the treatment of chronic kidney disease, but its exact mechanism is not clear.Objectives To monitor the potential improvement of renal mitochondrial function in unilateral ureteral obstruction (UUO) rats by regulating NR4A1 using the YHTR.Materials and methods Wistar rats were randomly divided into four groups: sham, UUO (left ureteral ligation for 14 days), eplerenone (EPL) (UUO + EPL), and YHTR (UUO + YHTR). UUO rats were established and intragastrically administered EPL (100 mg/day/kg) or YHTR (11.7 g/day/kg) for 14 days. The expression of related proteins in kidneys was detected by immunohistochemistry, western blot, RT-PCR, and chemical colorimetric assay, respectively.Results In vivo, YHTR treatment reduced the levels of BUN and Scr (by 17.9% and 23.5%) in UUO rats. Moreover, YHTR improved the renal mitochondrial function via increasing key enzymes of the tricarboxylic acid (TCA) cycle (p

Abstract This paper presents an analytical model of a dual‐stator spoke‐type permanent magnet (DSSTPM) synchronous machines accounting for tooth‐tips. Based on the two‐dimensional (2‐D) subdomain technique, the field domain of DSSTPM machine is divided into seven sub‐regions, that is, permanent magnet (PM), outer/inner air gaps, slots and slot openings. The magnetic field distribution and electromagnetic performance can be calculated via solving the governing functions based on boundary and interface conditions. The analytical predictions for DSSTPM machine under both open‐circuit and on‐load conditions are calculated and compared by the finite element (FE) method.

The genetic bases of yak adaptations to extreme conditions remains elusive. This study compares yak and cattle at a genomic and transcriptomic level, revealing a new type of endothelial cell and candidate genes related with elastic fiber formation in yak lungs that might contribute to high altitude adaptation.