Search

Regulatory T (Treg) cells prevent autoimmunity and facilitate cancer immune evasion. Depletion of Tregs is a promising cancer therapy, but risks of autoimmune reactions hamper its clinical translation. Here, we demonstrate that temporally induced deletion of Ube2n in Tregs (Ube2n Treg-KO ) of adult mice results in a robust expansion and activation of cytotoxic CD8 + T-cells in response to cancer cell challenges, producing a long-lasting survival benefit without autoimmune complications. The anti-tumor effect persists following adoptive T-cell transfer to T-cell-deficient Rag1-knockout mice. Single-cell transcriptomic analysis revealed that UBE2N deletion shifted immunosuppressive Tregs to effector-like T-cells. This shift is characterized by the downregulation of c-Myc target genes, resembling that observed in tumor-infiltrating Tregs of melanoma patients. Further analyses confirm that UBE2N maintains c-Myc protein stability via suppression of K48-Ubiquitin-mediated proteasomal degradation. Taken together, our studies uncover a hitherto unexplored and potentially druggable UBE2N/c-Myc signaling axis to eradicate Treg-enabled cancer immune escape.

Mitochondria play an important role in pressure overload-induced cardiac hypertrophy. The present study aimed to investigate the role of mitochondrial transient receptor potential vanilloid 3 (TRPV3) in myocardial hypertrophy. A 0.7 mm diameter U-shaped silver clip was used to clamp the abdominal aorta of Sprague Dawley (SD) rats and establish an animal model of abdominal aortic constriction (AAC). Rat H9C2 myocardial cells were treated with angiotensin II (Ang II) to establish a hypertrophic myocardial cell model, and TRPV3 expression was knocked down using TRPV3 small interfering RNA (siRNA). JC-1 probe was used to detect mitochondrial membrane potential (MMP). DHE probe was used to detect ROS generation. Enzyme activities of mitochondrial respiratory chain complex I and III and ATP production were detected by assay kits. Immunofluorescence staining was used to detect TRPV3 expression in H9C2 cells. Western blot was used to detect the protein expression levels of β-myosin heavy chain (β-MHC), mitochondrial TRPV3 and mitochondrial NOX4. The results showed that, in the rat AAC model heart tissue and H9C2 cells treated with Ang II, the protein expression levels of β-MHC, mitochondrial TRPV3 and mitochondrial NOX4 were up-regulated, MMP was decreased, ROS generation was increased, mitochondrial respiratory chain complex I and III enzyme activities were decreased, and ATP production was reduced. After knocking down mitochondrial TRPV3 in H9C2 cells, the protein expression levels of β-MHC and mitochondrial NOX4 were down-regulated, MMP was increased, ROS generation was decreased, mitochondrial respiratory chain complex I and III enzyme activities were increased, and ATP production was increased. These results suggest that mitochondrial TRPV3 in cardiomyocytes exacerbates mitochondrial dysfunction by up-regulating NOX4, thereby participating in the process of pressure overload-induced myocardial hypertrophy.

Background: Exosomes derived from endometrial regenerative cells (ERC-Exos) can inherit the immunomodulatory function from ERCs, however, whether ERC-Exos exhibit such effect on inflammatory bowel diseases with mucosal immune dysregulation has not been explored. Insulin-like growth factor-Ⅱ (IGF2) is considered to possess the potential to induce an anti-inflammatory phenotype in immune cells. In this study, the contribution of IGF2 in mediating the protective efficacy of ERC-Exos on colitis was investigated., Methods: Lentiviral transfection was employed to obtain IGF2-specific knockout ERC-Exos (IGF2 -/- -ERC-Exos). Experimental colitis mice induced by dextran sulfate sodium (DSS) were divided into the phosphate-buffered saline (untreated), ERC-Exos-treated and IGF2 -/- -ERC-Exos-treated groups. Colonic histopathological analysis and intestinal barrier function were explored. The infiltration of CD4 + T cells and dendritic cells (DCs) were analyzed by immunofluorescence staining and flow cytometry. The maturation and function of bone marrow-derived dendritic cells (BMDCs) in different exosome administrations were evaluated by flow cytometry, ELISA and the coculture system, respectively., Results: Compared with the untreated group, ERC-Exos treatment significantly attenuated DSS-induced weight loss, bloody stools, shortened colon length, pathological damage, as well as repaired the weakened intestinal mucosal barrier, including promoting the goblet cells retention, restoring the intestinal barrier integrity and enhancing the expression of tight junction proteins, while the protective effect of exosomes was impaired with the knockout of IGF2 in ERC-Exos. Additionally, IGF2-expressing ERC-Exos decreased the proportions of Th1 and Th17, increased the proportions of Treg, as well as attenuated DC infiltration and maturation in mesenteric lymph nodes and lamina propria of the colitis mice. ERC-Exos were also observed to be phagocytosed by BMDCs and IGF2 is responsible for the modulating effect of ERC-Exos on BMDCs in vitro., Conclusions: Exosomes derived from ERCs can exert a therapeutic effect on experimental colitis with remarkable alleviation of the intestinal barrier damage and the abnormal mucosal immune responses. We emphasized that IGF2 plays a critical role for ERC-Exos mediated immunomodulatory function and protection against colitis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Morphology is a cardinal feature of a neuron that mediates its functions, but profiling neuronal morphologies at scale remains a formidable challenge. Here we describe a generalizable pipeline for large-scale brainwide study of dendritic morphology of genetically-defined single neurons in the mouse brain. We generated a dataset of 3,762 3D-reconstructed and reference-atlas mapped striatal D1- and D2- medium spiny neurons (MSNs). Integrative morphometric analyses reveal distinct impacts of anatomical locations and D1/D2 genetic types on MSN morphologies. To analyze striatal regional features of MSN dendrites without prior anatomical constraints, we assigned MSNs to a lattice of cubic boxes in the reference brain atlas, and summarized morphometric representation ("eigen-morph") for each box and clustered boxes with shared morphometry. This analysis reveals 6 modules with characteristic dendritic features and spanning contiguous striatal territories, each receiving distinct corticostriatal inputs. Finally, we found aging confers robust dendritic length and branching defects in MSNs, while Huntington's disease (HD) mice exhibit selective length-related defects. Together, our study demonstrates a systems-biology approach to profile dendritic morphology of genetically-defined single-neurons; and defines novel striatal D1/D2-MSN morphological territories and aging- or HD-associated pathologies.

Background: Postoperative pain management remains a significant challenge for patients undergoing posterior urethroplasty (PU). In a previous study, we proposed a novel technique of combined pudendal nerve (PN) and spermatic cord (SC) block to manage pain after PU. The present trial was conducted to test the hypothesis that this technique is effective for pain control after PU and provides longer-lasting analgesia than caudal epidural block (CB)., Methods: Sixty patients undergoing PU were randomized into two groups: Group NB received combined PN and SC block, and Group CB received CB. General anesthesia with a laryngeal mask was performed. The primary outcome was the postoperative analgesic duration, and the secondary outcomes included the Numeric Rating Scale (NRS) scores for pain and the number of patients with different motor scores of the lower limb at 3, 6, 12, and 24 h postoperatively., Results: Two patients in Group CB were withdrawn due to block failure. The postoperative analgesic duration was statistically longer in Group NB compared with Group CB (mean difference [95% confidence interval], 115.78 min [17.80, 213.75]; P = 0.021). The NRS scores for pain at 12 and 24 h after surgery were statistically lower in Group NB compared with Group CB. Group NB had statistically more patients with motor score 0 at 3 h postoperatively than Group CB., Conclusions: PN combined with SC block is an effective technique for postoperative analgesia in PU. This technique can achieve a longer duration of analgesia and lower pain scores, especially 12 h after surgery, than a CB., Trial Registration: This study was registered in the Chinese Clinical Trial Register (registration no. ChiCTR2100042971, registration date on 2/2/2021)., (© 2024. The Author(s).)

Atomic force microscope generally works by manipulating the absolute magnitude of the van der Waals force between tip and specimen. This force is, however, less sensitive to atom species than to tip-sample separations, making compositional identification difficult, even under multi-modal strategies or other atomic force microscopy variations. Here, we report the phenomenon of a light-modulated tip-sample van der Waals force whose magnitude is found to be material specific, which can be employed to discriminate heterogeneous compositions of materials. We thus establish a near-field microscopic method, named light-modulated van der Waals force microscopy. Experiments discriminating heterogeneous crystalline phases or compositions in typical materials demonstrate a high compositional resolving capability, represented by a 20 dB signal-to-noise ratio on a MoTe 2 film under the excitation of a 633 nm laser of 1.2 mW, alongside a sub-10 nm lateral spatial resolution, smaller than the tip size of 20 nm. The simplicity of the light modulation mechanism, minute excitation light power, broadband excitation wavelength, and diversity of the applicable materials imply broad applications of this method on material characterization, particularly on two-dimensional materials that are promising candidates for next-generation chips., (© 2024. The Author(s).)

Thrombocytopenia is one of the common complications with the hematologic system in patients with chronic liver disease, which often causes poor quality of life and high risk of bleeding, thereby affecting their diagnosis, treatment, and prognosis. Platelet transfusion can improve the patient's declining platelet count to a certain extent, but it has problems such as high price and being easy to cause immune rejection. Thrombopoietin (TPO), as an important cytokine that affects platelet production, can bind to TPO receptors and activate megakaryocytes to produce platelets. Lusutrombopag is a newly developed small-molecule TPO receptor agonist that can induce bone marrow progenitor cells to differentiate into megakaryocytes and increase platelet production, posing characteristics of oral convenience, safety and effectiveness; thus, it has been used in many countries and regions for the treatment of patients with chronic liver diseases concurrent with thrombocytopenia. Herein, the pharmacological features and clinical research are reviewed.

Inorganic semiconductor materials are crucial for modern technologies, but their brittleness and limited processability hinder the development of flexible, wearable, and miniaturized electronics. The recent discovery of room-temperature plasticity in some inorganic semiconductors offers a promising solution, but the deformation mechanisms remain controversial. Here, we investigate the deformation of indium selenide, a two-dimensional van der Waals semiconductor with substantial plasticity. By developing a machine-learned deep potential, we perform atomistic simulations that capture the deformation features of hexagonal indium selenide upon out-of-plane compression. Unexpectedly, we find that indium selenide plastifies through a martensitic transformation; that is, the layered hexagonal structure is converted to a tetragonal lattice with specific orientation relationship. This observation is corroborated by high-resolution experimental observations and theory. It suggests a change of paradigm, where the design of new plastically deformable inorganic semiconductors can focus on compositions and structures that facilitate phase transformations, going beyond the conventional dislocation slip.

Background: Neurosurgery demands exceptional precision due to the brain's complex and delicate structures, necessitating precise targeting of pathological targets. Achieving optimal outcomes depends on the surgeon's ability to accurately differentiate between healthy and pathological tissues during operations. Raman spectroscopy (RS) has emerged as a promising innovation, offering real-time, in vivo non-invasive biochemical tissue characterization. This literature review evaluates the current research on RS applications in intraoperative neurosurgery, emphasizing its potential to enhance surgical precision and patient outcomes., Methods: Following PRISMA guidelines, a comprehensive systematic review was conducted using PubMed to extract relevant peer-reviewed articles. The inclusion criteria focused on original research discussing real-time RS applications with human tissue samples in or near the operating room, excluding retrospective studies, reviews, non-human research, and other non-relevant publications., Results: Our findings demonstrate that RS significantly improves tumor margin delineation, with handheld devices achieving high sensitivity and specificity. Stimulated Raman Histology (SRH) provides rapid, high-resolution tissue images comparable to traditional histopathology but with reduced time to diagnosis. Additionally, RS shows promise in identifying tumor types and grades, aiding precise surgical decision-making. RS techniques have been particularly beneficial in enhancing the accuracy of glioma surgeries, where distinguishing between tumor and healthy tissue is critical. By providing real-time molecular data, RS aids neurosurgeons in maximizing the extent of resection (EOR) while minimizing damage to normal brain tissue, potentially improving patient outcomes and reducing recurrence rates., Conclusions: This review underscores the transformative potential of RS in neurosurgery, advocating for continued innovation and research to fully realize its benefits. Despite its substantial potential, further research is needed to validate RS's clinical utility and cost-effectiveness.

Multivalvulidan myxosporeans (Multivalvulida) of the genera Unicapsula Davis, 1924 and Kudoa Meglitsch, 1947 are mostly causative agents of latent and imperceptible infection in marine fishes. However, they are sometimes incriminated in causing post-mortem myoliquefaction or unsightly cyst formation in commercial fish. Despite the great commercial impacts of multivalvulidan infection, the biodiversity, host range and epidemiology of multivalvulidan species remain to be explored further, including infection of alternative annelid hosts. Therefore, this study aimed to identify multivalvulidan species and their host and/or distribution records in commercial fishes in China. Multivalvulidan infection was detected in ten commercial fish species of seven families from the South and East China Seas (Northwest Pacific Ocean) and the Eastern Central Atlantic Ocean (an imported Dagetichthys lusitanicus [de Brito Capello]). Based on morphological and molecular-genetic analyses of their small and large subunit of ribosomal RNA genes, five new host and/or geographical distribution records for five fish species are presented, and three new species in five fish species are described, namely Kudoa neoscomberomori sp. n. in Scomberomorus commerson (Lacépède); Kudoa pilosa sp. n. in Helicolenus hilgendorfi (Döderlein) (type host) and Sebastiscus tertius (Barsukov et Chen); and Kudoa tumidisporica sp. n. in Photopectoralis bindus (Valenciennes) (type host) and Nuchequula nuchalis (Temminck et Schlegel). This study provides new data on multivalvulidan diversity in the ocean ecosystem.

The burgeoning global mushroom industry has precipitated challenges related to the efficient and sustainable utilization of spent mushroom substrate (SMS). Composting is regarded as an efficient way for the ecological utilization of SMS. The addition of microbial inoculants can promote the composting process and improve the quality of compost products. This study introduced two bacterial inoculants, Bacillus paralicheniformis HL-05 (BP) and Streptomyces thermoviolaceus LC-10 (ST), into the composting process of SMS. The impact of these inoculants was evaluated through analyses of physicochemical properties, lignocellulose degradation, and high-throughput sequencing to elucidate their ecological roles and optimize the composting process. The results suggest that inoculation with BP and ST significantly prolonged the thermophilic stage by 2-3 days, representing an increase of 22.22-33.33%. Moreover, it boosted the degradation rates of cellulose, hemicellulose, and lignin by 18.37-29.77%, 35.74-50.43%, and 40.32-40.83%, respectively, compared to the control. Furthermore, inoculation rapidly altered the microbial community structure during the rapid temperature-rising stage and strengthened interconnections among composting microorganisms. The microbial inoculation substantially enhanced the proliferation of thermophilic lignocellulose-degrading microorganisms during the thermophilic stage, thereby facilitating the utilization of lignocellulose. This study proposes a novel and effective strategy for SMS composting using microbial inoculants., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Guo-Qing Zhang reports financial support was provided by Beijing University of Agricultur. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Approximately 20% of patients living with colorectal cancer (CRC) have activating mutations in their tumors in the PIK3CA oncogene. Two or more activating mutations (multi-hit) for the PIK3CA allele increase PI3K⍺ signaling compared to single-point mutations, resulting in exceptional response to PI3K⍺ inhibition. We aimed to identify the prevalence of PIK3CA multi-hit mutations in metastatic CRC to identify patients who may benefit from PI3K inhibitors., Methods: The Foundation Medicine database (Boston, MA, USA) was analyzed for patients with CRC who underwent genomic profiling on tumor DNA isolated during routine clinical care from 2013 to 2021. Molecular and clinical variables were abstracted for patients with PIK3CA mutations., Results: We identified 49 051 patients with CRC who underwent Foundation Medicine testing. 710/41154 (1.7%) patients had multi-hit PIK3CA mutations, of which 53% were male (n = 448) with a median age of 60. Microsatellite status was available for 697 patients with multi-hit PIK3CA and 17.6% (123/697) were microsatellite instability-high. Clinically relevant mutations in KRAS and BRAFV600E were seen in 459/710 (64.7%) and 65/710 (9.1%), respectively. The 4 most common PIK3CA variants were H1047R (9.8%), E545K (9.2%), E542K (9.0%), and R88Q (7.1%). The most common variant pair was E542K-E545K (4.7%)., Conclusions: Multi-hit mutations in PIK3CA are seen in 1.7% of advanced CRC, a meaningful prevalence given the high burden of CRC worldwide, and may represent a subset of patients that have enhanced sensitivity to PI3K inhibition. Future investigation regarding the clinical utility of PI3K inhibitors is warranted in multi-hit PIK3CA CRC., (© The Author(s) 2024. Published by Oxford University Press.)

In this study we aimed to understand and summarize the clinical and pathological characteristics of cutaneous mixed tumors. A retrospective analysis was conducted on the clinical and pathological data of 20 patients diagnosed with cutaneous mixed tumors in our outpatient department between January 2014 and April 2024. The study comprised 20 patients with a male-to-female ratio of 3:2. The mean age of onset was 52.10 ± 15.46 years. All patients presented with solitary cutaneous lesions ranging from 2 to 30 mm in diameter. Notably, none of the patients received a preoperative diagnosis of cutaneous mixed tumor. The clinical manifestations of cutaneous mixed tumors are nonspecific, necessitating histopathological examination for a definitive diagnosis., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: This research aimed to evaluate the impact of grading and zoning nursing management on traumatic brain injury (TBI) patients' emergency treatment outcomes., Methods: This randomized controlled trial included 200 TBI patients. They were treated with a conventional care (control group, n  = 100) and a novel grading and zoning approach (study group, n  = 100), respectively. This innovative model organized care into levels based on urgency and complexity, facilitating targeted medical response and resource allocation. Key metrics compared included demographic profiles, consultation efficiency (time metrics and emergency treatment rates), physiological parameters (HR, RR, MAP, SpO 2 , RBS), and patient outcomes (hospital and ICU stays, complication rates, and emergency outcomes)., Results: The study group demonstrated significantly improved consultation efficiency, with reduced times for physician visits, examinations, emergency stays, and specialist referrals (all p  < 0.001), alongside a higher emergency treatment rate (93% vs. 79%, p  = 0.004), notably better physiological stability, improved HR, RR, MAP, SpO 2 and RBS ( p  < 0.001), shorter hospital and ICU stays, fewer complications, and superior emergency outcomes., Conclusion: Grading and zoning nursing management substantially enhances TBI patients' emergency care efficiency and clinical outcomes, suggesting a viable model for improving emergency treatment protocols.

Gastrochilusbalangshanensis , a new orchid species from the Balang Mountain, Sichuan Province, Southwest China, is described and illustrated. It morphologically resembles G.affinis , but differs in having shorter stems, a reniform epichile and a sub-hemispherical hypochile (spur), obtuse-rounded at the apex. The results of molecular phylogenetic analyses based on nuclear ribosome internal transcribed spacer (nrITS) and four chloroplast DNA markers ( mat K, psb A- trn H, psb M- trn D and trn L-F) from 50 Gastrochilus species indicate that G.balangshanensis is closely related to G.heminii and G.bernhardtianus , also endemic to the Hengduan Mountains. The novelty is a branch and trunk epiphyte in mixed coniferous forest., Competing Interests: The authors have declared that no competing interests exist., (Jun-Yi Zhang, Yue-Hong Cheng, Min Liao, Sen-Long Jin, Hong-Qiang Lin, Pan-Yan Yang, Hai He, Bo Xu.)

IgA vasculitis (IgAV) is a pediatric disease with skin and systemic manifestations. Here, we conducted genome, transcriptome, and proteome-wide association studies in 2,170 IgAV cases and 5,928 controls, generated IgAV-specific maps of gene expression and splicing from blood of 255 pediatric cases, and reconstructed myeloid-specific regulatory networks to define disease master regulators modulated by the newly identified disease driver genes. We observed significant association at the HLA - DRB1 (OR=1.55, P=1.1×10 -25 ) and fine-mapped specific amino-acid risk substitutions in DRβ1. We discovered two novel non-HLA loci: FCAR (OR=1.51, P=1.0×10 -20 ) encoding a myeloid IgA receptor FcαR, and INPP5D (OR=1.34, P=2.2×10 -9 ) encoding a known inhibitor of FcαR signaling. The FCAR risk locus co-localized with a cis-eQTL increasing FCAR expression; the risk alleles disrupted a PRDM1 binding motif within a myeloid enhancer of FCAR . Another risk locus was associated with a higher genetically predicted levels of plasma IL6R. The IL6R risk haplotype carried a missense variant contributing to accelerated cleavage of IL6R into a soluble form. Using systems biology approaches, we prioritized IgAV master regulators co-modulated by FCAR , INPP5D and IL6R in myeloid cells. We additionally identified 21 shared loci in a cross-phenotype analysis of IgAV with IgA nephropathy, including novel loci PAID4, WLS , and ANKRD55 .

Phanerozoic orogenic gold mineralization at craton margins is related to the metasomatism of the lithospheric mantle by crustal material. Slab subduction transfers Au from the crust to the metasomatized mantle and oxidizes the latter to facilitate the mobilization of Au into mantle melts. The role of volatiles in the mobilization of Au in the mantle is unclear because of the absence of direct geochemical evidence relating the mantle source of Au to Au mineralization in the overlying crust. This study uses lithium isotopes from a large suite of lamprophyres to characterize the mantle beneath the eastern North China Craton, which hosts giant Mesozoic gold deposits. Our results indicate a strong genetic link between carbonate metasomatism in the mantle and Au mineralization in the overlying crust. Although pre-enrichment of Au in the mantle is critical for forming giant Au provinces, the oxidation of the lithospheric mantle controls the mobilization of Au.

Introduction: The course of maternal antiviral prophylaxis to prevent mother-to-child transmission of hepatitis B virus (HBV-MTCT) varies greatly, and it has not been demonstrated in a randomized controlled study., Methods: In this multicenter, open-label, randomized controlled trial, eligible pregnant women with HBV DNA of 5.3-9.0 log 10 IU/mL who received tenofovir alafenamide fumarate (TAF) from the first day of 33 gestational weeks to delivery (expected 8 week) or to 4 weeks postpartum (expected 12 week) were randomly enrolled at a 1:1 ratio and followed until 6 months postpartum. All infants received standard immunoprophylaxis (hepatitis B immunoglobulin and vaccine). The primary end point was the safety of mothers and infants. The secondary end point was the HBV-MTCT rate of infants at the age of 7 months., Results: Among 119 and 120 intention-to-treat pregnant women, 115 and 116 women were followed until delivery, and 110 and 112 per-protocol mother-infant dyads in 2 groups completed the study. Overall, TAF was well tolerated, no one discontinued the therapy due to adverse events (0/239, 0%, 95% confidence interval [CI] 0%-1.6%), and no infant had congenital defects or malformations at delivery (0/231, 0%, 95% CI 0%-1.6%). The infants' physical development at birth (n = 231) and at 7 months (n = 222) was normal. Furthermore, 97.0% (224/231, 95% CI 93.9%-98.5%) of women achieved HBV DNA <5.3 log 10 IU/mL at delivery. The intention-to-treat and per-protocol infants' HBV-MTCT rates were 7.1% (17/239, 95% CI 4.5%-11.1%) and 0% (0/222, 95% CI 0%-1.7%) at the age of 7 months. Comparatively, 15.1% (18/119, 95% CI 9.8%-22.7%) vs 18.3% (22/120, 95% CI 12.4%-26.2%) of women in the 2 groups had mildly elevated alanine aminotransferase levels at 3 months and 6 months postpartum, respectively ( P = 0.507); notably, no one experienced alanine aminotransferase flare (0% [0/119, 95% CI 0%-3.1%] vs 0% [0/120, 0%-3.1%])., Discussion: Maternal TAF prophylaxis to prevent HBV-MTCT is generally safe and effective, and expected 8-week prenatal duration is feasible. ClinicalTrials.gov , NCT04850950., (Copyright © 2024 by The American College of Gastroenterology.)

Unlike sequencing-based methods, which require cell lysis, optical pooled genetic screens enable investigation of spatial phenotypes, including cell morphology, protein subcellular localization, cell-cell interactions and tissue organization, in response to targeted CRISPR perturbations. Here we report a multimodal optical pooled CRISPR screening method, which we call CRISPRmap. CRISPRmap combines in situ CRISPR guide-identifying barcode readout with multiplexed immunofluorescence and RNA detection. Barcodes are detected and read out through combinatorial hybridization of DNA oligos, enhancing barcode detection efficiency. CRISPRmap enables in situ barcode readout in cell types and contexts that were elusive to conventional optical pooled screening, including cultured primary cells, embryonic stem cells, induced pluripotent stem cells, derived neurons and in vivo cells in a tissue context. We conducted a screen in a breast cancer cell line of the effects of DNA damage repair gene variants on cellular responses to commonly used cancer therapies, and we show that optical phenotyping pinpoints likely pathogenic patient-derived mutations that were previously classified as variants of unknown clinical significance., (© 2024. The Author(s).)

Astrocytes play significant roles in regulating the central stress response. Chronic stress impairs the structure and function of astrocytes in many brain regions such as media prefrontal cortex (mPFC) in multiple neuropsychiatric conditions, but the astrocytic dynamics on the timescale of behavior remains unclear. Here, we recorded mPFC astrocytic activity in freely behaving mice and found that astrocytes are activated immediately by different aversive stimuli. Astrocyte specific GCaMP6s calcium indicator were virally expressed in mPFC astrocytes and fiber photometry experiments revealed that astrocytes are activated by tail-restraint (TRT), foot shock (FS), open arm exploration, stressor of height, predator odor and social defeat (SD) stress. ΔF/F analyses demonstrated that an unpredictable stimulus such as elevated platform stress (EPS) at the initial encounter induced the most intense and rapid changes in astrocytic calcium activity, while a predictable 2,5-dihydro-2,4,5-trimethylthiazoline (TMT) stimulus resulted in the weakest response with a longer peak latency. In TRT, FS or SD test, a somatic stimulus led to higher average calcium activity level and faster average peak latency in repeated trails. Similar to TMT stimulus, astrocytic calcium activity in elevated plus maze (EPM) test exhibited a smaller average change in amplitude and the longest peak latency during open arm exploration. Moreover, astrocytic calcium activity exhibited different changes across behavioral states in SD tests. Our findings show that mPFC astrocytes exhibit distinct patterns of calcium activity in response to various negative stimuli, indicating that the dynamic activity of astrocytes may reflect the stress-related behavioral state under different stimulus conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 The Authors. Published by Elsevier Inc.)

Background: Despite sharing common pathophysiological risk factors, the relationship between gallstones and depression requires further evidence for a clearer understanding. This study combines the National Health and Nutrition Examination Survey 2017 - 2020 observational data and Mendelian randomization (MR) analysis to shed light on the potential correlation between these conditions., Methods: By analyzing the National Health and Nutrition Examination Survey 2017 - 2020 data through weighted multivariable-adjusted logistic regression, we examined the association between depression and gallstone risk. MR was subsequently applied, utilizing genetic instruments from a large genome-wide association study on depression (excluding 23andMe, 500,199 participants) and gallstone data (28,627 cases, 348,373 controls), employing the main inverse variance-weighted method alongside other MR methods to explore the causal relationship. Sensitivity analyses validated the study's conclusions., Results: Among the 5,303 National Health and Nutrition Examination Survey participants, a significant association was found between depressive symptoms and increased gallstone risk (initial odds ratio (OR) = 2.001; 95% confidence interval (CI) = 1.523 - 2.598; P < 0.001), with the association persisting after comprehensive adjustments (final OR = 1.687; 95% CI = 1.261 - 2.234; P < 0.001). MR findings also indicated a causal link between genetically predicted depression and higher gallstone risk (OR = 1.164; 95% CI = 1.053 - 1.286; P = 0.003)., Conclusions: Depression is significantly associated with a higher risk of gallstones, supported by genetic evidence suggesting a causal link. These findings highlight the importance of considering depression in gallstone risk assessments and management strategies., Competing Interests: No potential conflict of interest was reported by the authors., (Copyright 2024, Wang et al.)

The high heterogeneity within and between breast cancer patients complicates treatment determination and prognosis assessment. Treatment decision-making is influenced by various factors, such as tumor subtype, histological grade, and genotype, necessitating personalized treatment strategies. Prognostic outcomes vary significantly depending on patient-specific conditions. As a critical branch of artificial intelligence, machine learning efficiently handles large datasets and automates decision-making processes. The introduction of machine learning offers new solutions for breast cancer treatment selection and prognosis assessment. In the field of cancer therapy, traditional methods for predicting treatment and survival outcomes often rely on single or few biomarkers, limiting their ability to capture the complexity of biological processes comprehensively. Machine learning analyzes patients' multi-omic data and the intricate patterns of variations during cancer initiation and progression to predict patients' survival and treatment outcomes. Consequently, it facilitates the selection of appropriate therapeutic interventions to implement early intervention and improve treatment efficacy for patients. Here, we first introduce common machine learning methods, and then elaborate on the application of machine learning in the field of survival prediction and prognosis from two aspects: evaluating survival and predicting treatment outcomes for breast cancer patients. The aim is to provide breast cancer patients with precise treatment strategies to improve therapeutic outcomes and quality of life.

Objective: This study aimed to evaluate and compare the effectiveness of knowledge base-optimized and unoptimized large language models (LLMs) in the field of orthopedics to explore optimization strategies for the application of LLMs in specific fields., Methods: This research constructed a specialized knowledge base using clinical guidelines from the American Academy of Orthopaedic Surgeons (AAOS) and authoritative orthopedic publications. A total of 30 orthopedic-related questions covering aspects such as anatomical knowledge, disease diagnosis, fracture classification, treatment options, and surgical techniques were input into both the knowledge base-optimized and unoptimized versions of the GPT-4, ChatGLM, and Spark LLM, with their generated responses recorded. The overall quality, accuracy, and comprehensiveness of these responses were evaluated by 3 experienced orthopedic surgeons., Results: Compared with their unoptimized LLMs, the optimized version of GPT-4 showed improvements of 15.3% in overall quality, 12.5% in accuracy, and 12.8% in comprehensiveness; ChatGLM showed improvements of 24.8%, 16.1%, and 19.6%, respectively; and Spark LLM showed improvements of 6.5%, 14.5%, and 24.7%, respectively., Conclusion: The optimization of knowledge bases significantly enhances the quality, accuracy, and comprehensiveness of the responses provided by the 3 models in the orthopedic field. Therefore, knowledge base optimization is an effective method for improving the performance of LLMs in specific fields., (© 2024. Huazhong University of Science and Technology.)

Obeticholic acid (OCA), a semisynthetic bile acid derivative, was approved for its therapeutic use in primary biliary cirrhosis. OCA has a enterohepatic circulation and host-gut microbiota metabolic interaction, which produce various metabolites. Such metabolites, especially structural isomers of OCA, together with the need to achieve idea lower limit of quantitation (LLOQ) with minimum matrix interference, bring about significant difficulties to the bioanalysis of OCA. Herein, by applying a combination of solid-phase extraction (SPE) and ultra-high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS), we introduced an approach for the bioanalysis of OCA along with its two major metabolites-glyco-OCA (GOA) and tauro-OCA (TOA) in human plasma, the full validation results of which showed excellent performance. The quantitative range is 0.2506 ∼ 100.2 ng/mL for OCA, 0.2500 ∼ 100.0 ng/mL for GOA, as well as 0.1250 ∼ 50.00 ng/mL for TOA, respectively. This method was successfully applied to the pharmacokinetic studies in healthy subjects following administration of OCA tablets., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Interventions targeting the gut microbiota, such as fecal microbiota transplantation, prove effective in repairing the intestinal barrier and facilitating the recovery of its function and metabolism. However, the regulatory mechanisms governing the remodeling of rumen epithelial morphology and function, rumen metabolism, and host metabolism in cows of SARA remain poorly understood. Here, we explored the changes in rumen epithelial morphology and transcriptome, rumen metabolome, and blood biochemical parameters in SARA cows following rumen content transplantation (RCT). The entire experiment consisted of 2 periods: the SARA induction period and the RCT period. During the SARA induction period, 12 ruminally cannulated lactating Holstein cows were randomly allocated into 2 groups, fed either a conventional diet (CON; n = 4; 40% concentrate, DM basis) or a high-grain diet (HG; n = 8; 60% concentrate, DM basis). Following the SARA induction period, the RCT period started. The HG cows were randomly assigned to 2 groups: the donor-recipient (DR) group and the self-recipient (SR) group. Rumen contents were entirely removed from both groups before RCT. For the DR group, cows were administered 70% rumen content from the CON cows, paired based on comparable BW; for the SR group, each cow received 70% self-derived rumen content. The results revealed no significant differences in the thicknesses of the stratum corneum, granulosum, and spinosum or basale layers, as well as the total depth of the epithelium between the SR and DR groups. All these measurements exhibited a decreasing trend and fluctuations over time after the transfer. Notably, these fluctuations tended to stabilize at 13 or 16 d after RCT in the SR group, whereas they tended to stabilize after 8 or 13 d of transfer for the DR group. Transcriptome sequencing revealed that a total of 277 differentially expressed genes (DEG) were identified between the 2 groups. Enrichment analysis showed that the DEG were significantly enriched in 11 Gene Ontology biological processes and 14 Kyoto Encyclopedia of Genes and Genomes pathways. The DEG corresponding to almost any of these 11 biological process terms and 14 pathways showed mixed up- or downregulation following RCT. Metabolomics analysis indicated that a total of 33 differential metabolites were detected between the SR and DR groups, mainly enriched in 5 key metabolic pathways, including plant polysaccharides and starch degradation, lipid metabolism, amino-sugar and nucleotide-sugar metabolism, purine metabolism, and Krebs cycle. Among them, the levels of differential metabolites associated with the degradation of plant polysaccharides and starches, metabolism of amino sugars and nucleotides, and purine metabolism pathways were significantly elevated in the DR cows. The results of blood biochemical parameters showed that the triglyceride concentration of the DR cows was increased than that of the SR cows, comparable to the level observed in the CON cows during the SARA induction period. Generally, our findings indicated that RCT facilitated the recovery of rumen epithelial morphological structure but did not promote its function recovery. Moreover, RCT enhanced rumen plant polysaccharide and starch degradation, amino-sugar and nucleotide-sugar metabolism, as well as purine metabolism. Additionally, it further promoted the recovery of plasma metabolites related to lipid metabolism., (The Authors. Published by Elsevier Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Cypripedioideae (slipper orchids; Orchidaceae) currently consist of ∼200 herbaceous species with a strikingly disjunctive distribution in tropical and temperate regions of both hemispheres. In this study, an updated phylogeny with representatives from all five cypripedioid genera was presented based on maximum likelihood and Bayesian inference of plastome and low-copy nuclear genes. Phylogenomic analyses indicated that each genus is monophyletic, but some relationships (e.g., those among Cypripedium sects. Acaulia, Arietinum, Bifolia, Flabellinervia, Obtusipetala and Palangshanensia) conflict with those in previous studies based on Sanger data. Cypripedioideae appeared to have arisen in South America and/or the adjacent Qinghai-Tibet Plateau and Hengduan Mountains ∼35 Mya. We inferred multiple dispersal events between East Asia and North America in Cypripedium, and between mainland Southeast Asia and the Malay Archipelago in Paphiopedilum. In the Americas, divergences among four genera (except Cypripedium) occurred around 31-20 Mya, long before the closure of the Isthmus of Panama, indicating the importance of long-distance dispersal. Evolutionary patterns between morphological and plastome character evolution suggested several traits, genome size and NDH genes, which are likely to have contributed to the success of slipper orchids in alpine floras and low-elevation forests. Species diversification rates were notably higher in epiphytic clades of Paphiopedilum than in other, terrestrial cypripedioids, paralleling similar accelerations associated with epiphytism in other groups. This study also suggested that sea-level fluctuations and mountain-building processes promoted the diversification of the largest genera, Paphiopedilum and Cypripedium., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Self-supervised learning (SSL) has recently achieved impressive performance on various time series tasks. The most prominent advantage of SSL is that it reduces the dependence on labeled data. Based on the pre-training and fine-tuning strategy, even a small amount of labeled data can achieve high performance. Compared with many published self-supervised surveys on computer vision and natural language processing, a comprehensive survey for time series SSL is still missing. To fill this gap, we review current state-of-the-art SSL methods for time series data in this article. To this end, we first comprehensively review existing surveys related to SSL and time series, and then provide a new taxonomy of existing time series SSL methods by summarizing them from three perspectives: generative-based, contrastive-based, and adversarial-based. These methods are further divided into ten subcategories with detailed reviews and discussions about their key intuitions, main frameworks, advantages and disadvantages. To facilitate the experiments and validation of time series SSL methods, we also summarize datasets commonly used in time series forecasting, classification, anomaly detection, and clustering tasks. Finally, we present the future directions of SSL for time series analysis.

Maintaining intracellular redox balance is essential for the survival, antibody secretion, and mucosal immune homeostasis of immunoglobulin A (IgA) antibody-secreting cells (ASCs). However, the relationship between mitochondrial metabolic enzymes and the redox balance in ASCs has yet to be comprehensively studied. Our study unveils the pivotal role of mitochondrial enzyme PCK2 in regulating ASCs' redox balance and intestinal homeostasis. We discover that PCK2 loss, whether globally or in B cells, exacerbates dextran sodium sulphate (DSS)-induced colitis due to increased IgA ASC cell death and diminished antibody production. Mechanistically, the absence of PCK2 diverts glutamine into the TCA cycle, leading to heightened TCA flux and excessive mitochondrial reactive oxygen species (mtROS) production. In addition, PCK2 loss reduces glutamine availability for glutathione (GSH) synthesis, resulting in a decrease of total glutathione level. The elevated mtROS and reduced GSH expose ASCs to overwhelming oxidative stress, culminating in cell apoptosis. Crucially, we found that the mitochondria-targeted antioxidant Mitoquinone (Mito-Q) can mitigate the detrimental effects of PCK2 deficiency in IgA ASCs, thereby alleviating colitis in mice. Our findings highlight PCK2 as a key player in IgA ASC survival and provide a potential new target for colitis treatment., (© 2024 John Wiley & Sons Ltd.)

The brain-computer interface (BCI) system serves as a critical link between external output devices and the human brain. A monitored object's mental state, sensory cognition, and even higher cognition are reflected in its electroencephalography (EEG) signal. Nevertheless, unprocessed EEG signals are frequently contaminated with a variety of artifacts, rendering the analysis and elimination of impurities from the collected EEG data exceedingly challenging, not to mention the manual adjustment thereof. Over the last few decades, the rapid advancement of artificial intelligence (AI) technology has contributed to the development of BCI technology. Algorithms derived from AI and machine learning have significantly enhanced the ability to analyze and process EEG electrical signals, thereby expanding the range of potential interactions between the human brain and computers. As a result, the present BCI technology with the help of AI can assist physicians in gaining a more comprehensive understanding of their patients' physical and psychological status, thereby contributing to improvements in their health and quality of life., (© 2024. Huazhong University of Science and Technology.)

Background: This retrospective study aimed to analyze the evolution of primary indications and surgical techniques for corneal transplantation in Southern China from 2012 to 2021., Methods: The medical charts of all patients who underwent keratoplasty between January 2012 and December 2021 at Zhongshan Ophthalmic Centre, Sun Yat-Sen University, Guangzhou, Southern China were reviewed. We collected and analyzed the primary indications for corneal transplantation and the surgical methods used in each keratoplasty., Results: The total number of corneal transplantations was 7,286 during this decade, increasing from 210 cases in 2012 to 1054 cases in 2021. The primary indications for keratoplasty included acquired nontraumatic corneal diseases (56.2%), congenital corneal abnormalities (16.4%), acquired traumatic corneal diseases (14.0%), and regraft (13.4%). Infectious keratitis was the leading indication among all keratoplasties (18.5%), followed by regraft (13.4%). Over the decade, the proportion of infectious keratitis gradually decreased (P = 0.013), while the proportion of regraft increased (P = 0.019). The predominant surgical technique was penetrating keratoplasty (PKP), accounting for 56.7%. However, the number of deep anterior lamellar keratoplasty (DALK) and endothelial keratoplasty (EK) significantly increased from 2012 to 2021 (P = 0.007 and P = 0.002)., Conclusions: The annual number of corneal transplants significantly increased from 2012 to 2021. In the past decade, infectious keratitis and regraft have become the leading primary indications for corneal transplantation. Although the use of customized lamellar techniques has dramatically increased, PKP remains the predominant surgical technique for keratoplasty., (© 2024. The Author(s).)

Heptageniidae are known for their flat heads and bodies and are divided into three subfamilies. Despite the extensive diversity within this group and considerable efforts made to understand their evolutionary history, the internal classifications and origin time of Heptageniidae remains controversial. In this study, we newly sequenced 17 complete mitogenomes of Heptageniidae to reconstruct their phylogenetic positions within this family. Because of the ambiguous time of origin, our study also estimated the divergence time within Heptageniidae based on five fossil calibration points. The results of BI and ML trees all highly supported the monophyly of Heptageniidae and three subfamilies. The phylogenetic relationship of Rhithrogeninae + (Ecdyonurinae + Heptageniinae) was also recovered. The divergence time showed that Heptageniidae originated from 164.38 Mya (95% HPD, 150.23-181.53 Mya) in the mid-Jurassic, and Rhithrogeninae originated from 95.54 Mya (95% HPD, 73.86-120.19 Mya) in the mid-Cretaceous. Ecdyonurinae and Heptageniinae began to diverge at 90.08 Mya (95% HPD, 68.81-113.16 Mya) in the middle Cretaceous. After morphological identification, analysis of the mitogenome's composition, genetic distance calculation, phylogenetic analysis, and divergence time calculation, we suggest that two different populations of Epeorus montanus collected from Aksu, Xinjiang Uygur Autonomous Region (40°16' N, 80°26' E) and Xinyuan, Xinjiang Uygur Autonomous Region (43°20' N, 83°43' E) in China are cryptic species of E. montanus , but further detailed information on their morphological characteristics is needed to fully identify them.

Background: The development mechanisms of Lynch syndrome (LS)-related breast cancer (BC) and rectal cancer are complex and variable, leading to personalized variations in diagnosis and treatment plans., Case Summary: This paper presents a comprehensive review of clinical diagnosis and treatment data from a patient with LS-associated BC and rectal cancer. Moreover, screening data and management guidelines, as well as relevant literature on LS, are included in this report. This study summarizes the molecular pathogenesis, clinicopathological features, and screening and management protocols for LS-associated BC and rectal cancer., Conclusion: Implementing early screening, prevention, and timely diagnosis and treatment measures is expected to reduce mitigate the incidence and mortality of LS-related BC and rectal cancer., Competing Interests: Conflict-of-interest statement: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Using 7.33  fb^{-1} of e^{+}e^{-} collision data collected by the BESIII detector at center-of-mass energies in the range of sqrt[s]=4.128-4.226  GeV, we search for the rare decays D&#95;{s}^{+}→h^{+}(h^{0})e^{+}e^{-}, where h represents a kaon or pion. By requiring the e^{+}e^{-} invariant mass to be consistent with a ϕ(1020), 0.98

Natural plant-derived compounds with broad-spectrum antimicrobial activity have become an effective strategy against multidrug-resistant bacteria. The present study was designed to compare the antibacterial activity of six chlorogenic acid (CA) isomers extracted from stevia and investigated the underlying antibacterial mechanisms involved. The results indicated that isochlorogenic acid C (ICAC) exhibited the strongest antibacterial activity against the tested bacteria, especially E. coli , at a 2 mg/mL minimum inhibitory concentration (MIC) and 8 mg/mL minimum bactericidal concentration (MBC). At the MBC, ICAC inhibited 72.66% of the clinical multidrug-resistant strains. Scanning electron microscopy (SEM) revealed that ICAC induced considerable morphological alterations in E. coli ATCC25922 and C4E2. The significant increase in the activity of extracellular alkaline phosphatase (AKP) indicated that ICAC damages the permeability of the bacterial cell wall. Additionally, the intracellular membrane (IM) permeability and the content of lipopolysaccharide (LPS), a main component of the outer membrane (OM), were determined. The significant decrease in LPS content and increased leakage of intracellular proteins and K + from E. coli indicated that ICAC could induce the exfoliation of OM and disrupt IM permeability, resulting in the loss of barrier function. The uptake of propidium iodide (PI), a compromised cell membrane nucleic acid stain, and confocal laser scanning microscopy (CLSM) further demonstrated that ICAC disrupted IM integrity. Moreover, the bactericidal effect and damage to bacterial microstructural function occurred in a dose-dependent manner. These data demonstrate that ICAC has excellent antibacterial activity and is a promising approach for overcoming the antibiotic resistance of pathogenic bacteria., Competing Interests: M-LX and L-FW were employed by Chenguang Biological Technology Group Co, Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Yi, Bai, Cao, Wang, Shang, Li, Xu, Wu, Zhu and Zhang.)

Lilium saccatum is a species of ornamental plant found in southeastern Xizang, China. In the present study, the complete chloroplast (cp) genome of L. saccatum was sequenced using next-generation sequencing (NGS). The de novo assembled cp genome was 151,839 bp in length, including a pair of inverted repeat regions (IRs; 26,421 bp), a small single-copy region (SSC; 17,528 bp), and a large single-copy region (LSC; 81,469 bp). The cp genome encodes 113 unique genes, including 79 protein-coding genes (PCGs), 30 tRNA genes, and four rRNA genes. The total GC content of the cp genome was 37.0%. Phylogenetic analysis of 24 cp genomes revealed that L. saccatum was closely related to L. souliei . This study could provide fundamental information for the phylogenomics and utilization of Lilium ., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

To determine the low-carbon development path of Ordos, three scenarios （baseline scenario, low carbon scenario, and enhanced low carbon scenario） were constructed based on the LEAP model to forecast the energy demand and carbon emission in Ordos from 2020 to 2050 and to analyze the contribution of various policy initiatives to reduce carbon emission. The results showed that under the enhanced low carbon scenario, the energy demand in Ordos peaked at 52 million tons of standard coal equivalent in 2025 and decreased to 40 million tons of standard coal equivalent in 2050, and carbon emissions peaked at 163 million tons in 2025 and decreased to 16 million tons in 2050, which was 88% lower than that in 2020. Regarding emission reduction contribution, comparing the baseline scenario and the enhanced low-carbon scenario, the increase in renewable energy power generation installation, the reduction in energy consumption of terminal energy use, and the increase in terminal electrification rate contributed to the emission reductions of 43%, 25%, and 24%, respectively. The Ordos should vigorously develop renewable energy and make full use of the rich endowment of wind and light resources； at the same time, it should promote economic transformation and gradually increase the proportion of high-value-added and low-energy-consuming industries in the industrial structure. For the power sector, the power generation structure should be adjusted. Traditional thermal power generation should be replaced by zero-carbon and low-carbon power generation technologies. For the industrial and transportation sectors, the terminal electrification rate should be increased, and the energy intensity should be reduced.

The J/ψ, ψ(3686)→Σ^{0}Σ[over ¯]^{0} processes and subsequent decays are studied using the world's largest J/ψ and ψ(3686) data samples collected with the BESIII detector. The parity-violating decay parameters of the decays Σ^{0}→Λγ and Σ[over ¯]^{0}→Λ[over ¯]γ, α&#95;{Σ^{0}}=-0.0017±0.0021±0.0018 and α[over ¯]&#95;{Σ^{0}}=0.0021±0.0020±0.0022, are measured for the first time. The strong CP symmetry is tested in the decays of the Σ^{0} hyperons for the first time by measuring the asymmetry A&#95;{CP}^{Σ}=α&#95;{Σ^{0}}+α[over ¯]&#95;{Σ^{0}}=(0.4±2.9±1.3)×10^{-3}. The weak CP test is performed in the subsequent decays of their daughter particles Λ and Λ[over ¯]. Also for the first time, the transverse polarizations of the Σ^{0} hyperons in J/ψ and ψ(3686) decays are observed with opposite directions, and the ratios between the S-wave and D-wave contributions of the J/ψ, ψ(3686)→Σ^{0}Σ[over ¯]^{0} decays are obtained. These results are crucial to understand the decay dynamics of the charmonium states and the production mechanism of the Σ^{0}-Σ[over ¯]^{0} pairs.

Background: Loss of chromosome 9p is an important biomarker in the malignant transformation of oral leukoplakia (OLK) to head and neck squamous cell carcinoma (HNSCC), and is associated with the prognosis of HNSCC patients. However, various challenges have prevented 9p loss from being assessed in clinical practice. The objective of this study was to develop a pathomics-based artificial intelligence (AI) model for the rapid and cost-effective prediction of 9p loss (9PLP)., Materials and Methods: 333 OLK cases were retrospectively collected with hematoxylin and eosin (H&E)-stained whole slide images and genomic alteration data from multicenter cohorts to develop the genomic alteration prediction AI model. They were divided into a training dataset (n=217), a validation dataset (n=93), and an external testing dataset (n=23). The latest Transformer method and XGBoost algorithm were combined to develop the 9PLP model. The AI model was further applied and validated in two multicenter HNSCC datasets (n=42, n=365, respectively). Moreover, the combination of 9PLP with clinicopathological parameters was used to develop a nomogram model for assessing HNSCC patient prognosis., Results: 9PLP could predict chromosome 9p loss rapidly and effectively using both OLK and HNSCC images, with the area under the curve achieving 0.890 and 0.825, respectively. Furthermore, the predictive model showed high accuracy in HNSCC patient prognosis assessment (the area under the curve was 0.739 for 1-year prediction, 0.705 for 3-year prediction, and 0.691 for 5-year prediction)., Conclusion: To the best of our knowledge, this study developed the first genomic alteration prediction deep learning model in OLK and HNSCC. This novel AI model could predict 9p loss and assess patient prognosis by identifying pathomics features in H&E-stained images with good performance. In the future, the 9PLP model may potentially contribute to better clinical management of OLK and HNSCC., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Liver fibrosis is a serious global health issue for which effective treatment remains elusive. Chemical-induced hepatocyte-like cells (ciHeps) have emerged as an appealing source for cell transplantation therapy, although they present several challenges such as the risk of lung thromboembolism or hemorrhage. Apoptotic vesicles (apoVs), small membrane vesicles generated during the apoptosis process, have gained attention for their role in regulating various physiological and pathological processes. In this study, we generated ciHep-derived apoVs (ciHep-apoVs) and investigated their therapeutic potential in alleviating liver fibrosis. Our findings revealed that ciHep-apoVs induced the transformation of macrophages into an anti-inflammatory phenotype, effectively suppressed the activity of activated hepatic stellate cells (aHSCs), and enhanced the survival of hepatocytes. When intravenously administered to mice with liver fibrosis, ciHep-apoVs were primarily engulfed by macrophages and myofibroblasts, leading to a reduction in liver inflammation and fibrosis. Proteomic and miRNA analyses showed that ciHep-apoVs were enriched in various functional molecules that modulate crucial cellular processes, including metabolism, signaling transduction, and ECM-receptor interactions. ciHep-apoVs effectively suppressed aHSCs activity through the synergistic inhibition of glycolysis, the PI3K/AKT/mTOR pathway, and epithelial-to-mesenchymal transition (EMT) cascades. These findings highlight the potential of ciHep-apoVs as multifunctional nanotherapeutics for liver fibrosis and provide insights into the treatment of other liver diseases and fibrosis in other organs., (© 2024. The Author(s).)

Background: NUP98 rearrangements (NUP98-r) are rare but overrepresented mutations in pediatric acute myeloid leukemia (AML) patients. NUP98-r is often associated with chemotherapy resistance and a particularly poor prognosis. Therefore, characterizing pediatric AML with NUP98-r to identify aberrations is critically important., Methods: Here, we retrospectively analyzed the clinicopathological features, genomic and transcriptomic landscapes, treatments, and outcomes of pediatric patients with AML., Results: Nine patients with NUP98-r mutations were identified in our cohort of 142 patients. Ten mutated genes were detected in patients with NUP98-r. The frequency of FLT3-ITD mutations differed significantly between the groups harboring NUP98-r and those without NUP98-r (P = 0.035). Unsupervised hierarchical clustering via RNA sequencing data from 21 AML patients revealed that NUP98-r samples clustered together, strongly suggesting a distinct subtype. Compared with that in the non-NUP98-r fusion and no fusion groups, CMAHP expression was significantly upregulated in the NUP98-r samples (P < 0.001 and P = 0.001, respectively). Multivariate Cox regression analyses demonstrated that patients harboring NUP98-r (P < 0.001) and WT1 mutations (P = 0.030) had worse relapse-free survival, and patients harboring NUP98-r (P < 0.008) presented lower overall survival., Conclusions: These investigations contribute to the understanding of the molecular characteristics, risk stratification, and prognostic evaluation of pediatric AML patients., (© 2024. The Author(s).)

Tumor-associated macrophages (TAMs) constitute the largest number of immune cells in the tumor microenvironment (TME). They play an essential role in promoting tumor progression and metastasis, which makes them a potential therapeutic target for cancer treatment. TAMs are usually divided into two categories: pro-tumoral M2-like TAMs and antitumoral M1 phenotypes at either extreme. The reprogramming of M2-like TAMs toward a tumoricidal M1 phenotype is of particular interest for the restoration of antitumor immunity in cancer immunotherapy. Notably, nanomedicines have shown great potential for cancer therapy due to their unique structures and properties. This review will briefly describe the biological features and roles of TAMs in tumor, and then discuss recent advances in nanomedicine-mediated repolarization of TAMs for cancer immunotherapy. Finally, perspectives on nanomedicine-mediated repolarization of TAMs for effective cancer immunotherapy are also presented., (© 2024 Wiley Periodicals LLC.)

Background and Aim: The incidence of rectal neuroendocrine tumors (R-NETs) has increased in recent years. However, the predictors of lymph node (LN) metastasis and clinical outcomes, particularly following endoscopic treatment, remain unclear. Our study aims to elucidate the potential risk factors for LN metastasis and the clinical outcomes of patients undergoing endoscopic resection in R-NETs., Methods: A total of 128 patients with R-NETs were retrospectively identified from a single center between June 2012 and December 2021. Risk factors for LN metastasis in R-NETs were analyzed using multivariate analysis. Additionally, the clinical outcomes of endoscopic resections in patients with R-NETs were assessed., Results: In our study, 128 patients with R-NETs were retrospectively analyzed. The risk factors for LN metastasis determined by multivariate analysis were tumor size and patient age at diagnosis. Among the 111 patients treated with endoscopic resection and with tumor margin records available, 92 underwent endoscopic submucosal dissection (ESD) and 19 underwent conventional endoscopic mucosal resection (EMR). There was no significant difference between the two groups regarding the positive rates of basal tumor margin and lateral tumor margin. Furthermore, 64 patients who underwent endoscopic resection for R-NETs were successfully followed up (range, 1.64-76.71 months), during which only one patient developed local recurrence., Conclusion: Tumor size and age at diagnosis were predictors for LN metastasis of R-NETs. Both ESD and EMR are alternative techniques with a favorable prognosis for R-NETs, even in cases with positive resection margins. However, due to the relatively small number of patients undergoing EMR and missing data in follow-up protocols, definitive conclusions require further large-scale studies., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Incorporating ultralow loading of nanoparticles into polymers has realized increases in dielectric constant and breakdown strength for excellent energy storage. However, there are still a series of tough issues to be dealt with, such as organic solvent uses, which face enormous challenges in scalable preparation. Here, a new strategy of dual in situ synthesis is proposed, namely polymerization of polyethylene terephthalate (PET) synchronizes with growth of calcium borate nanoparticles, making polyester nanocomposites from monomers directly. Importantly, this route is free of organic solvents and surface modification of nanoparticles, which is readily accessible to scalable synthesis of polyester nanocomposites. Meanwhile, uniform dispersion of as ultralow as 0.1 wt% nanoparticles and intense bonding at interfaces have been observed. Furthermore, the PET-based nanocomposite displays obvious increases in both dielectric constant and breakdown strength as compared to the neat PET. Its maximum discharged energy density reaches 15 J cm -3 at 690 MV m -1 and power density attains 218 MW cm -3 under 150 Ω resistance at 300 MV m -1 , which is far superior to the current dielectric polymers that can be produced at large scales. This work presents a scalable, safe, low-cost, and environment-friendly route toward polymer nanocomposites with superior capacitive performance., (© 2024 Wiley‐VCH GmbH.)

Transition metals exhibit high reactivity for Fenton-like catalysis in environmental remediation, but how to save consumption and reduce pollution is of great interest. In this study, rationally designed defect-engineered Fe@MoS 2 (Fe@D-MoS 2 ) was prepared by incorporating reactive iron onto structural defects generated from the chemical acid-etching, aiming to improve the energetic consumption of the catalyst in Fenton-like applications. Morphological and structural properties were elucidated in details, the Fenton-like reactivity was evaluated with five phenolic contaminants for oxidant activation, radical generation and environmental remediation. Compared to Fe@MoS 2 , Fe@D-MoS 2 exhibited a 18.9-fold increase in phenol degradation (0.09 versus 1.79 min -1 ). Quenching experiments, electron paramagnetic resonance tests and electrochemical measurements revealed the dominant sulfate and superoxide radicals. Rendered by strong metal-substrate surface and electronic interactions from regulated chemical environment and coordination structure, the inert ≡ Fe(III) was reduced to the reactive ≡ Fe(II) accompanied by the ≡ Mo(IV) oxidation to ≡ Mo(V) in MoS 2 lattice, with adjacent sulfur serving as the key electron transfer bridge. Therefore, this work shows that the incorporation of reactive centers is able to boost two-dimensional sulfide materials for environmental catalysis applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Osteoarthritis (OA) is the most prevalent joint disease in the elderly population and its substantial morbidity and disability impose a heavy economic burden on patients and society. Knee osteoarthritis (KOA) is the most common subtype of OA, which is characterized by damage to progressive articular cartilage, synovitis, and subchondral bone sclerosis. Most current treatments for OA are palliative, primarily aim at symptom management, and do not prevent the progression of the disease or restore degraded cartilage. The activation of α-granules in platelets releases various growth factors that are involved in multiple stages of tissue repair, suggesting potential for disease modification. In recent years, platelet-based therapies, such as platelet-rich plasma, platelet-rich fibrin, and platelet lysates, have emerged as promising regenerative treatments for KOA, but their related effects and mechanisms are still unclear. Therefore, this review aims to summarize the biological characteristics and functions of platelets, classify the products of platelet-based therapy and related preparation methods. Moreover, we summarize the basic research of platelet-based regeneration strategies for KOA and discuss the cellular effects and molecular mechanisms. Further, we describe the general clinical application of platelet-based therapy in the treatment of KOA and the results of the meta-analysis of randomized controlled trials., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Three undescribed phenols, mandshusica C-E (1-3) and a new lignan, mandshusica F (5), along with six known compounds (4, 6-10) were isolated from the roots and rhizomes of Clematis terniflora var. manshurica (Rupr.) Ohwi. Their structures were elucidated by extensive spectroscopic analysis as well as NMR and ECD calculations. Moreover, the possible biosynthetic pathways of compounds 1-3 were also discussed. All compounds were evaluated for their anti-inflammatory activities in LPS-induced RAW 264.7 cells. Compounds 1, 3, 4 significantly reduced the levels of NO and TNF-α, while compounds 2 and 8 significantly inhibited NO production in LPS-induced RAW264.7 cells., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

The utilization of lignocellulosic substrates for microbial oil production by oleaginous yeasts has been evidenced as an economically viable process for industrial-scale biodiesel preparation. Efficient sugar utilization and tolerance to inhibitors are critical for lipid production from lignocellulosic substrates. This study investigated the lignocellulosic sugar utilization and inhibitor tolerance characteristics of Rhodotorula toruloides C23. The results demonstrated that C23 exhibited robust glucose and xylose assimilation irrespective of their ratios, yielding over 21 g/L of lipids and 11 mg/L of carotenoids. Furthermore, C23 exhibited high resistance and efficiently degradation towards toxic inhibitors commonly found in lignocellulosic hydrolysates. The potential molecular mechanism underlying xylose metabolism in C23 was explored, with several key enzymes and signal regulation pathways identified as potentially contributing to its superior lipid synthesis performance. The study highlights R. toruloides C23 as a promising candidate for robust biofuel and carotenoid production through direct utilization of non-detoxified lignocellulosic hydrolysates., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background: The brown planthopper (BPH), Nilaparvata lugens, is one of the most destructive pests of rice. Owing to the rapid adaptation of BPH to many pesticides and resistant varieties, identifying putative gene targets for developing RNA interference (RNAi)-based pest management strategies has received much attention for this pest. The glucoprotein papilin is the most abundant component in the basement membranes of many organisms, and its function is closely linked to development., Results: In this study, we identified a papilin homologous gene in BPH (NlPpn). Quantitative Real-time PCR analysis showed that the transcript of NlPpn was highly accumulated in the egg stage. RNAi of NlPpn in newly emerged BPH females caused nonhatching phenotypes of their eggs, which may be a consequence of the maldevelopment of their embryos. Moreover, the transcriptomic analysis identified 583 differentially expressed genes between eggs from the dsGFP- and dsNlPpn-treated insects. Among them, the 'structural constituent of cuticle' cluster ranked first among the top 15 enriched GO terms. Consistently, ultrastructural analysis unveiled that dsNlPpn-treated eggs displayed a discrete and distorted serosal endocuticle lamellar structure. Furthermore, the hatchability of BPH eggs was also successfully reduced by the topical application of NlPpn-dsRNA-layered double hydroxide nanosheets onto the adults., Conclusion: Our findings demonstrate that NlPpn is essential to maintaining the regular structure of the serosal cuticle and the embryonic development in BPH, indicating NlPpn could be a potential target for pest control during the egg stage. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Intermittent hypoxia (IH), a major pathophysiologic alteration in obstructive sleep apnea syndrome (OSAS), is an important contributor to cognitive impairment. Increasing research suggests that melatonin has anti-inflammatory properties and improves functions related to synaptic plasticity. However, it is unclear whether melatonin has a protective effect against OSAS-induced cognitive dysfunction in aged individuals and the involved mechanisms are also unclear. Therefore, in the study, the effects of exposure to IH alone and IH in combination with daily melatonin treatment were investigated in C57BL/6 J mice aged 18 months. Assessment of the cognitive ability of mice in a Morris water maze showed that melatonin attenuated IH-induced impairment of learning and memory in aged mice. Enzyme-linked immunosorbent assay, polymerase chain reaction, and western blotting molecular techniques showed that melatonin treatment reduced the levels of the proinflammatory cytokines, interleukin-1β, interleukin-6, and tumor necrosis factor-α, decreased the levels of NOD-like receptor thermal protein domain associated protein 3 and nuclear factor kappa-B, lowered the levels of ionized calcium-binding adapter molecule 1 and glial fibrillary acidic protein, and increased the levels of the synaptic proteins, activity-regulated cytoskeleton-associated protein, growth-associated protein-43, postsynaptic density protein 95, and synaptophysin in IH-exposed mice. Moreover, electrophysiological results showed that melatonin ameliorated the decline in long-term potentiation induced by IH. The results suggest that melatonin can ameliorate IH-induced cognitive deficits by inhibiting neuroinflammation and improving synaptic plasticity in aged mice., Competing Interests: Declaration of Competing Interest All authors declare no competing financial interests or potential conflicts of interest., (Copyright © 2024. Published by Elsevier Ltd.)

A 66-year-old female patient presenting with dysphagia was diagnosed with stage IV unresectable gastric cancer (cTxN+M1). Multiple liver metastases were identified. The patient subsequently underwent five courses of chemotherapy and immunotherapy, including the capecitabine plus oxaliplatin (XELOX) regimen combined with tislelizumab. After fifth course treatment, it was confirmed that the liver metastases had completely disappeared and the primary tumor had significantly reduced in size. Consequently, a laparoscopy was performed, revealing a retraction-like response in the primary tumor and no obvious metastases in the abdominal cavity. Subsequently, a radical total gastrectomy was carried out through open abdominal surgery. Pathological analysis showed no remaining cancer or lymph node metastases, and the tumor regression was classified as grade 0. The patient has been now receiving additional chemotherapy and immunotherapy to manage any potential residual metastases. This case illustrated the rare and significant impact of combining chemotherapy with tislelizumab, transitioning the treatment approach from palliative to curative. It highlighted the critical role of immunotherapy in managing advanced gastric cancer with liver metastases.