Sporoderm-broken spores of Ganoderma lucidum modulate hepatoblastoma malignancy by regulating RACK1-mediated autophagy and tumour immunity.

Hepatoblastoma (HB), a primary liver tumour, is notorious for its high metastatic potential and poor prognosis. Ganoderma lucidum, an edible mushroom species utilized in traditional Chinese medicine for addressing various tumour types, presents an intriguing avenue for HB treatment. However, the effectiveness of G. lucidum in managing HB and its underlying molecular mechanism necessitates further exploration. Standard in vitro assays were conducted to evaluate the impact of sporoderm-broken spores of G. lucidum (SBSGL) on the malignant characteristics of HB cells. The mechanism of SBSGL in treating HB and its tumour immunomodulatory effects were explored and validated by various experiments, including immunoprecipitation, Western blotting, mRFP-GFP-LC3 adenovirus transfection and co-localization analysis, as well as verified with in vivo experiments in this regard. The results showed that SBSGL effectively inhibited the malignant traits of HB cells and suppressed the O-GlcNAcylation of RACK1, thereby reducing its expression. In addition, SBSGL inhibited immune checkpoints and regulated cytokines. In conclusion, SBSGL had immunomodulatory effects and regulated the malignancy and autophagy of HB by regulating the O-GlcNAcylation of RACK1. These findings suggest that SBSGL holds promise as a potential anticancer drug for HB treatment.

Ternary Eutectic Electrolyte-Assisted Formation and Dynamic Breathing Effect of the Solid-Electrolyte Interphase for High-Stability Aqueous Magnesium-Ion Full Batteries.

Aqueous rechargeable magnesium batteries hold immense potential for intrinsically safe, cost-effective, and sustainable energy storage. However, their viability is constrained by a narrow voltage range and suboptimal compatibility between the electrolyte and electrodes. Herein, we introduce an innovative ternary deep eutectic Mg-ion electrolyte composed of MgCl2·6H2O, acetamide, and urea in a precisely balanced 1:1:7 molar ratio. This formulation was optimized by leveraging competitive solvation effects between Mg2+ ions and two organic components. The full batteries based on this ternary eutectic electrolyte, Mn-doped sodium vanadate (Mn-NVO) anode, and copper hexacyanoferrate cathode exhibited an elevated voltage plateau and high rate capability and showcased stable cycling performance. Ex-situ characterizations unveiled the Mg2+ storage mechanism of Mn-NVO involving initial extraction of Na+ followed by subsequent Mg2+ intercalation/deintercalation. Detailed spectroscopic analyses illuminated the formation of a pivotal solid-electrolyte interphase on the anode surface. Moreover, the solid-electrolyte interphase demonstrated a dynamic adsorption/desorption behavior, referred to as the "breathing effect", which substantially mitigated undesired dissolution and side reactions of electrode materials. These findings underscore the crucial role of rational electrolyte design in fostering the development of a favorable solid-electrolyte interphase that can significantly enhance compatibility between electrode materials and electrolytes, thus propelling advancements in aqueous multivalent-ion batteries.

GGT5: a potential immunotherapy response inhibitor in gastric cancer by modulating GSH metabolism and sustaining memory CD8+ T cell infiltration.

PURPOSE: The variable responses to immunotherapy observed in gastric cancer (GC) patients can be attributed to the intricate nature of the tumor microenvironment. Glutathione (GSH) metabolism significantly influences the initiation and progression of gastric cancer. Consequently, targeting GSH metabolism holds promise for improving the effectiveness of Immune checkpoints inhibitors (ICIs). METHODS: We investigated 16 genes related to GSH metabolism, sourced from the MSigDB database, using pan-cancer datasets from TCGA. The most representative prognosis-related gene was identified for further analysis. ScRNA-sequencing analysis was used to explore the tumor heterogeneity of GC, and the results were confirmed by  Multiplex immunohistochemistry (mIHC). RESULTS: Through DEGs, LASSO, univariate and multivariate Cox regression analyses, and survival analysis, we identified GGT5 as the hub gene in GSH metabolism with the potential to promote GC. Combining CIBERSORT, ssGSEA, and scRNA analysis, we constructed the immune architecture of GC. The subpopulations of T cells were isolated, revealing a strong association between GGT5 and memory CD8+ T cells. Furthermore, specimens from 10 GC patients receiving immunotherapy were collected. mIHC was used to assess the expression levels of GGT5 and memory CD8+ T cell markers. Our results established a positive correlation between GGT5 expression, the enrichment of memory CD8+ T cells, and a suboptimal response to immunotherapy. CONCLUSIONS: Our study identifies GGT5, a hub gene in GSH metabolism, as a potential therapeutic target for inhibiting the response to immunotherapy in GC patients. These findings offer new insights into strategies for optimizing immunotherapy of GC.

Heat stress reprograms herbivory-induced defense responses in potato plants.

Climate change is predicted to increase the occurrence of extreme weather events such as heatwaves, which may thereby impact the outcome of plant-herbivore interactions. While elevated temperature is known to directly affect herbivore growth, it remains largely unclear if it indirectly influences herbivore performance by affecting the host plant they feed on. In this study, we investigated how transient exposure to high temperature influences plant herbivory-induced defenses at the transcript and metabolic level. To this end, we studied the interaction between potato (Solanum tuberosum) plants and the larvae of the potato tuber moth (Phthorimaea operculella) under different temperature regimes. We found that P. operculella larvae grew heavier on leaves co-stressed by high temperature and insect herbivory than on leaves pre-stressed by herbivory alone. We also observed that high temperature treatments altered phylotranscriptomic patterns upon herbivory, which changed from an evolutionary hourglass pattern, in which transcriptomic responses at early and late time points after elicitation are more variable than the ones in the middle, to a vase pattern. Specifically, transcripts of many herbivory-induced genes in the early and late defense stage were suppressed by HT treatment, whereas those in the intermediate stage peaked earlier. Additionally, we observed that high temperature impaired the induction of jasmonates and defense compounds upon herbivory. Moreover, using jasmonate-reduced (JA-reduced, irAOC) and -elevated (JA-Ile-elevated, irCYP94B3s) potato plants, we showed that high temperature suppresses JA signaling mediated plant-induced defense to herbivore attack. Thus, our study provides evidences on how temperature reprograms plant-induced defense to herbivores.

Low-temperature plasma jet suppresses bacterial colonisation and affects wound healing through reactive species.

An argon-based low-temperature plasma jet (LTPJ) was used to treat chronically infected wounds in Staphylococcus aureus-laden mice. Based on physicochemical property analysis and in vitro antibacterial experiments, the effects of plasma parameters on the reactive nitrogen and oxygen species (RNOS) content and antibacterial capacity were determined, and the optimal treatment parameters were determined to be 4 standard litre per minute and 35 W. Additionally, the plasma-treated activation solution had a bactericidal effect. Although RNOS are related to the antimicrobial effect of plasma, excess RNOS may be detrimental to wound remodelling. In vivo studies demonstrated that medium-dose LTPJ promoted MMP-9 expression and inhibited bacterial growth during the early stages of healing. Moreover, LTPJ increased collagen deposition, reduced inflammation, and restored blood vessel density and TGF-ß levels to normal in the later stages of wound healing. Therefore, when treating chronically infected wounds with LTPJ, selecting the medium dose of plasma is more advantageous for wound recovery. Overall, our study demonstrated that low-temperature plasma jets may be a potential tool for the treatment of chronically infected wounds.

Off the Shelf Multibranched Endograft for Thoraco-Abdominal and Pararenal Abdominal Aortic Aneurysms: a Prospective, Single Centre Study of the G-Branch Endograft.

OBJECTIVE: To investigate outcomes of a novel, off the shelf multibranched endovascular stent graft for the treatment of thoraco-abdominal aortic aneurysm (TAAA) and pararenal abdominal aortic aneurysm (PAAA). METHODS: A prospective, single centre study including 15 patients (mean age, 63.4 ± 10.7 years; 13 male) with TAAA or PAAA treated from October 2019 to March 2021 with a G-Branch endograft (Lifetech Scientific, Shenzhen, China) featuring a mixed multibranch design with two inner and two outer branches for reconstruction of the visceral and bilateral renal arteries, respectively. Follow up assessments were scheduled before discharge and at 30 days, six and 12 months after the index procedure. Annual telephone interviews were performed beyond the initial 12 months. The Kaplan-Meier method was used to estimate cumulative mortality and morbidity rates after endovascular repair. RESULTS: Technical success was achieved in all 15 patients. Nine patients (60%) had TAAA and six (40%) had PAAA (mean maximum aneurysm diameter, 73.7 ± 15.8 mm). The median follow up was 31.4 months (range, 10.1 - 44.0 months). At 30 days, there was no death and 7% morbidity (one case of temporary spinal cord ischaemia on Day 4). At one year, the mortality rate was 7% (one death from stroke at 10 months) and morbidity was 13% (one other case of renal function decline at six months). There were no aneurysm dilatations, re-interventions, or access related complications, and two (13%) persistent type II endoleaks. The one year primary branch patency rate was 100% for the four renovisceral arteries in all 13 patients who underwent computed tomography examinations. One patient died of hepatocellular carcinoma 29 months post-operatively, resulting in an estimated three year mortality rate of 13%. CONCLUSION: The G-Branch endograft yielded high technical success with good early and midterm outcomes for the treatment of TAAA and PAAA. A large multicentre study is warranted.

Downregulation of MYBL1 in endothelial cells contributes to atherosclerosis by repressing PLEKHM1-inducing autophagy.

MYBL1 is a strong transcriptional activator involved in the cell signaling. However, there is no systematic study on the role of MYBL1 in atherosclerosis. The aim of this study is to elucidate the role and mechanism of MYBL1 in atherosclerosis. GSE28829, GSE43292 and GSE41571 were downloaded from NCBI for differentially expressed analysis. The expression levels of MYBL1 in atherosclerotic plaque tissue and normal vessels were detected by qRT-PCR, Western blot and Immunohistochemistry. Transwell and CCK-8 were used to detect the migration and proliferation of HUVECs after silencing MYBL1. RNA-seq, Western blot, qRT-PCR, Luciferase reporter system, Immunofluorescence, Flow cytometry, ChIP and CO-IP were used to study the role and mechanism of MYBL1 in atherosclerosis. The microarray data of GSE28829, GSE43292, and GSE41571 were analyzed and intersected, and then MYBL1 were verified. MYBL1 was down-regulated in atherosclerotic plaque tissue. After silencing of MYBL1, HUVECs were damaged, and their migration and proliferation abilities were weakened. Overexpression of MYBL1 significantly enhanced the migration and proliferation of HUVECs. MYBL1 knockdown induced abnormal autophagy in HUVEC cells, suggesting that MYBL1 was involved in the regulation of HUVECs through autophagy. Mechanistic studies showed that MYBL1 knockdown inhibited autophagosome and lysosomal fusion in HUVECs by inhibiting PLEKHM1, thereby exacerbating atherosclerosis. Furthermore, MYBL1 was found to repress lipid accumulation in HUVECs after oxLDL treatment. MYBL1 knockdown in HUVECs was involved in atherosclerosis by inhibiting PLEKHM1-induced autophagy, which provided a novel target of therapy for atherosclerosis.

Development of a Serum-Based MicroRNA Signature for Early Detection of Pancreatic Cancer: A Multicenter Cohort Study.

BACKGROUND: A grim prognosis of pancreatic cancer (PCa) was attributed to the difficulty in early diagnosis of the disease. AIMS: Identifying novel biomarkers for early detection of PCa is thus urgent to improve the overall survival rates of patients. METHODS: The study was performed firstly by identification of candidate microRNAs (miRNAs) in formalin-fixed, paraffin-embedded tissues using microarray profiles, and followed by validation in a serum-based cohort study to assess clinical utility of the candidates. In the cohorts, a total of 1273 participants from four centers were retrospectively recruited as two cohorts including training and validation cohort. The collected serum specimens were analyzed by real-time polymerase chain reaction. RESULTS: We identified 27 miRNAs expressed differentially in PCa tissues as compared to the benign. Of which, the top-four was selected as a panel whose diagnostic efficacy was fully assessed in the serum specimens. The panel exhibited superior to CA19-9, CA125, CEA and CA242 in discriminating patients with early stage PCa from healthy controls or non-PCa including chronic pancreatitis as well as pancreatic cystic neoplasms, with the area under the curves (AUC) of 0.971 (95% CI 0.956-0.987) and 0.924 (95% CI 0.899-0.949), respectively. Moreover, the panel eliminated interference from other digestive tumors with a specificity of 90.2%. CONCLUSIONS: A panel of four serum miRNAs was developed showing remarkably discriminative ability of early stage PCa from either healthy controls or other pancreatic diseases, suggesting it may be developed as a novel, noninvasive approach for early screening of PCa in clinic.

The relevance of the superior cervical ganglion for cardiac autonomic innervation in health and disease: a systematic review.

PURPOSE: The heart receives cervical and thoracic sympathetic contributions. Although the stellate ganglion is considered the main contributor to cardiac sympathetic innervation, the superior cervical ganglia (SCG) is used in many experimental studies. The clinical relevance of the SCG to cardiac innervation is controversial. We investigated current morphological and functional evidence as well as controversies on the contribution of the SCG to cardiac innervation. METHODS: A systematic literature review was conducted in PubMed, Embase, Web of Science, and COCHRANE Library. Included studies received a full/text review and quality appraisal. RESULTS: Seventy-six eligible studies performed between 1976 and 2023 were identified. In all species studied, morphological evidence of direct or indirect SCG contribution to cardiac innervation was found, but its contribution was limited. Morphologically, SCG sidedness may be relevant. There is indirect functional evidence that the SCG contributes to cardiac innervation as shown by its involvement in sympathetic overdrive reactions in cardiac disease states. A direct functional contribution was not found. Functional data on SCG sidedness was largely unavailable. Information about sex differences and pre- and postnatal differences was lacking. CONCLUSION: Current literature mainly supports an indirect involvement of the SCG in cardiac innervation, via other structures and plexuses or via sympathetic overdrive in response to cardiac diseases. Morphological evidence of a direct involvement was found, but its contribution seems limited. The relevance of SCG sidedness, sex, and developmental stage in health and disease remains unclear and warrants further exploration.

High-Voltage Electrostatic Field Hydrogel Microsphere 3D Culture System Improves Viability and Liver-like Properties of HepG2 Cells.

Three-dimensional (3D) hepatocyte models have become a research hotspot for evaluating drug metabolism and hepatotoxicity. Compared to two-dimensional (2D) cultures, 3D cultures are better at mimicking the morphology and microenvironment of hepatocytes in vivo. However, commonly used 3D culture techniques are not suitable for high-throughput drug screening (HTS) due to their high cost, complex handling, and inability to simulate cell-extracellular matrix (ECM) interactions. This article describes a method for rapid and reproducible 3D cell cultures with ECM-cell interactions based on 3D culture instrumentation to provide more efficient HTS. We developed a microsphere preparation based on a high-voltage electrostatic (HVE) field and used sodium alginate- and collagen-based hydrogels as scaffolds for 3D cultures of HepG2 cells. The microsphere-generating device enables the rapid and reproducible preparation of bioactive hydrogel microspheres. This 3D culture system exhibited better cell viability, heterogeneity, and drug-metabolizing activity than 2D and other 3D culture models, and the long-term culture characteristics of this system make it suitable for predicting long-term liver toxicity. This system improves the overall applicability of HepG2 spheroids in safety assessment studies, and this simple and controllable high-throughput-compatible method shows potential for use in drug toxicity screening assays and mechanistic studies.

Yield and Efficiency of a Population-Based Mass Tuberculosis Screening Intervention Among Persons With Diabetes in Jiangsu Province, China.

BACKGROUND: The evidence-base for mass tuberculosis screening among persons with diabetes (PWD) is poor. We evaluated the yield and costs of mass screening among PWD in eastern China. METHODS: We included individuals with type 2 diabetes from 38 townships in Jiangsu Province. Screening comprised of physical examinations, symptom screening, and chest X-rays; smear and culture testing were performed through clinical triage. We assessed the yield and number needed to screen (NNS) to detect 1 tuberculosis case among all PWD, those with symptoms, and with suggestive chest X-rays. Unit costing was collected to estimate screening costs and to calculate cost per case detected. We performed a systematic review of other mass tuberculosis screening programs concentrated on PWD. RESULTS: Of 89 549 screened PWD, 160 were diagnosed with tuberculosis (179 cases per 100 000 persons; 95% confidence interval [CI]: 153-205). The NNS was 560 (95% CI: 513-606), 248 (95% CI: 217-279), and 36 (95% CI: 24-48) among all participants, with abnormal chest X-rays, and symptoms. The cost per case was high overall (US$13 930) but lower with symptoms (US$1037) and high fasting blood glucose levels (US$6807). From systematic review, the pooled NNS to detect one case among all PWD (regardless of symptoms or chest X-ray results) in high- versus low-burden settings was 93 (95% CI: 70-141) versus 395 (95% CI: 283-649). CONCLUSIONS: A mass tuberculosis screening program focused on PWD was feasible however, the overall yield was low and not cost-efficient. Risk-stratified approaches may be practical among PWD in low- and medium tuberculosis burden settings.

Targeting DCLK1 attenuates tumor stemness and evokes antitumor immunity in triple-negative breast cancer by inhibiting IL-6/STAT3 signaling.

Triple-negative breast cancer (TNBC) exhibits the poorest outcomes among breast cancer subtypes due to the high heterogeneity and a lasting scarcity of effectual treatments. Targeted therapies based on molecular subtypes of TNBC are critical step toward tailoring treatments to improve clinical outcomes. Gastrointestinal cancer stem cell (CSC) marker DCLK1 was reported to be highly expressed in stem cell-rich subtype of TNBC. Here, we firstly explored the impacts of DCLK1 on tumor cells as well as their immune microenvironment in TNBC and potential therapeutic strategies for TNBC patients with high DCLK1 expression. Our results disclosed that DCLK1 overexpression promoted, while knockout of DCLK1 suppressed the CSC-like traits of TNBC cells and resistance to chemotherapeutics. Besides, DCLK1 supported immune escape by inhibiting intratumoral cytotoxic T cell infiltration in TNBC and hence limited immune checkpoint inhibitors efficacy. Mechanistically, bioinformatics analysis revealed that IL-6/STAT3 signaling was significantly enriched in high DCLK1-expressing patients, and our results further revealed that DCLK1 enhanced IL-6 expression and STAT3 activation in TNBC cells, which finally gave rise to upregulated CSC traits and suppressed CD8+ T-cell activity. Inhibiting IL-6/STAT3 pathway by IL-6R antagonist, Tocilizumab or STAT3 inhibitor, S31-201 could abolish DCLK1-promoted malignant phenotypes of TNBC cells. Finally, DCLK1 was identified to be specifically and highly expressed in the mesenchymal-like subtype of TNBC and targeting DCLK1 could improve chemotherapy efficacy and activate antitumor immunity. Overall, our study revealed the potential clinical benefits of targeting DCLK1 in TNBC treatment.

Effect of Norovirus Inoculum Dose on Virus Kinetics, Shedding, and Symptoms.

The effect of norovirus dose on outcomes such as virus shedding and symptoms after initial infection is not well understood. We performed a secondary analysis of a human challenge study by using Bayesian mixed-effects models. As the dose increased from 4.8 to 4,800 reverse transcription PCR units, the total amount of shed virus in feces increased from 4.5 × 1011 to 3.4 × 1012 genomic equivalent copies; in vomit, virus increased from 6.4 × 105 to 3.0 × 107 genomic equivalent copies. Onset time of viral shedding in feces decreased from 1.4 to 0.8 days, and time of peak viral shedding decreased from 2.3 to 1.5 days. Time to symptom onset decreased from 1.5 to 0.8 days. One type of symptom score increased. An increase in norovirus dose was associated with more rapid shedding and symptom onset and possibly increased severity. However, the effect on virus load and shedding was inconclusive.

A mechanical HSA biosensor based on multi-field-coupling-mediated magnetic sensitization strategy.

The conventional mechanical biosensor based on stress and electrical conversion can be an effective method to detect key human biomarkers for clinical diagnosis and early disease prevention. However, the applications of this type of biosensor are greatly limited due to their unsatisfactory sensitivity. In this work, a magnetic-sensitized (MS) mechanical biosensor based on multi-field coupling was developed for higher sensitivity, giving access to detect human serum albumin (HSA). Via introducing secondary magnetic antibodies labeled with magnetized Fe2O3 nanoparticles to the stress and electrical conversion element of the MS-biosensor, the multi-field coupling was realized based on stress, electricity, and magnetism. Under the action of the magnetic field, the magnetic force of the secondary magnetic antibody and the stress of antigen-antibody binding jointly drove and enhanced the deformation of the MS-biosensor, amplifying the electrical signal, and realizing magnetic sensitization. The HSA was detected by the MS-biosensor at a range of 0-80 µg/mL with a limit of detection (LOD) of 0.14 µg/mL, demonstrating the high performance of the MS-biosensor. Moreover, the MS-biosensor showed high selectivity, specificity, and stability, indicating that the magnetic sensitization strategy of the MS-biosensor was significant for the clinical application of mechanical biosensors.

Age-related model for estimating the symptomatic and asymptomatic transmissibility of COVID-19 patients.

Estimation of age-dependent transmissibility of COVID-19 patients is critical for effective policymaking. Although the transmissibility of symptomatic cases has been extensively studied, asymptomatic infection is understudied due to limited data. Using a dataset with reliably distinguished symptomatic and asymptomatic statuses of COVID-19 cases, we propose an ordinary differential equation model that considers age-dependent transmissibility in transmission dynamics. Under a Bayesian framework, multi-source information is synthesized in our model for identifying transmissibility. A shrinkage prior among age groups is also adopted to improve the estimation behavior of transmissibility from age-structured data. The added values of accounting for age-dependent transmissibility are further evaluated through simulation studies. In real-data analysis, we compare our approach with two basic models using the deviance information criterion (DIC) and its extension. We find that the proposed model is more flexible for our epidemic data. Our results also suggest that the transmissibility of asymptomatic infections is significantly lower (on average, 76.45% with a credible interval (27.38%, 88.65%)) than that of symptomatic cases. In both symptomatic and asymptomatic patients, the transmissibility mainly increases with age. Patients older than 30 years are more likely to develop symptoms with higher transmissibility. We also find that the transmission burden of asymptomatic cases is lower than that of symptomatic patients.

Identification and validation of novel signature associated with hepatocellular carcinoma prognosis using Single-cell and WGCNA analysis.

Background: Hepatocellular carcinoma is a rapidly advancing malignancy with a poor prognosis. Therefore, further research is needed on its potential pathogenesis and therapeutic targets. Methods: In this study, the relevant datasets were downloaded from the TCGA database and the key modules were identified using WGCNA in the necroptosis-related gene set, while single-cell datasets were scored using the necroptosis gene set. Differential genes in the high- and low-expression groups were determined using the WGCNA module genes as intersection sets to identify key genes involved in necroptosis in liver cancer. Then, prognostic models were constructed using LASSO COX regression followed by multi-faceted validation. Finally, model genes were found to be correlated with key proteins of the necroptosis pathway and used to identify the most relevant genes, followed by their experimental validation. Subsequently, on the basis of the analysis results, the most relevant SFPQ was selected for cell-level verification. Results: We constructed a prognosis model that included five necroptosis-related genes (EHD1, RAC1, SFPQ, DAB2 and PABPC4) to predict the prognosis and survival of HCC patients. The results showed that the prognosis was more unfavorable in the high-risk group compared to the low-risk group, which was corroborated using ROC curves and risk factor plots. In addition, we further checked the differential genes using GO and KEGG analyses and found that they were predominantly enriched in the neuroactive ligand-receptor interaction pathway. The results of the GSVA analysis demonstrated that the high-risk group was mainly enriched in DNA replication, regulation of the mitotic cycle, and regulation of various cancer pathways, while the low-risk group was predominantly enriched in the metabolism of drugs and xenobiotics using cytochrome P450. SFPQ was found to be the main gene that affects the prognosis and SFPQ expression was positively correlated with the expression of RIPK1, RIPK3 and MLKL. Furthermore, the suppression of SFPQ could inhibit hyper-malignant phenotype HCC cells, while the WB results showed that inhibition of SFPQ expression also resulted in lower expression of necroptosis proteins, compared to the sh-NC group. Conclusions: Our prognostic model could accurately predict the prognosis of patients with HCC to further identify novel molecular candidates and interventions that can be used as alternative methods of treatment for HCC.

Landscape context affects the sustainability of organic farming systems.

Organic agriculture promotes sustainability compared to conventional agriculture. However, the multifunctional sustainability benefits of organic farms might be mediated by landscape context. Assessing how landscape context affects sustainability may aid in targeting organic production to landscapes that promote high biodiversity, crop yields, and profitability. We addressed this using a meta-analysis spanning 60 crop types on six continents that assessed whether landscape context affected biodiversity, yield, and profitability of organic vs. conventional agroecosystems. We considered landscape metrics reflecting landscape composition (percent cropland), compositional heterogeneity (number and diversity of cover types), and configurational heterogeneity (spatial arrangement of cover types) across our study systems. Organic sites had greater biodiversity (34%) and profits (50%) than conventional sites, despite lower yields (18%). Biodiversity gains increased as average crop field size in the landscape increased, suggesting organic farms provide a "refuge" in intensive landscapes. In contrast, as crop field size increased, yield gaps between organic and conventional farms increased and profitability benefits of organic farming decreased. Profitability of organic systems, which we were only able to measure for studies conducted in the United States, varied across landscapes in conjunction with production costs and price premiums, suggesting socioeconomic factors mediated profitability. Our results show biodiversity benefits of organic farming respond differently to landscape context compared to yield and profitability benefits, suggesting these sustainability metrics are decoupled. More broadly, our results show that the ecological, but not the economic, sustainability benefits of organic agriculture are most pronounced in more intensive agricultural landscapes.

[Effect of Family Environment on Non-Suicidal Self-Injury Among Middle School Students During the COVID-19 Epidemic: The Mediating Role of Depression].

Objective: To study the current status of non-suicidal self-injury (NSSI) incidents among middle school students in Chengdu during the COVID-19 epidemic and to explore the mechanism of action of depression on the relationship between family environment and NSSI. Methods: Data were obtained from the Chengdu Positive Child Development (CDPD) cohort. In June and July 2020, after primary and secondary schools were reopened after the closure due to the COVID-19 epidemic, on-site questionnaire surveys were conducted with the Deliberate Self-Harm Inventory (DSHI), the Chinese Family Assessment Instrument (C-FAI), and Center for Epidemiologic Studies Depression Scale for Children (CES-DC), thereby obtaining the data of 3595 middle school students. Two-sample t-test and χ 2 test were used to compare the incidence of NSSI among middle school students of different grades and genders, and the Model 58 test of the SPSS PROCESS component was used to analyze the mediating effect of gender-mediated depression. Results: 1) The incidence of NSSI among middle school students in Chengdu during the COVID-19 epidemic was 49.67%. The incidence of NSSI among ninth-graders (80.70%) was significantly higher than those of the eighth graders (33.82%) and seventh graders (32.32%), and the incidence of NSSI among female middle school students (54.75%) was significantly higher than that of male students (44.52%). 2) Family environment ( r=0.34, P<0.001) and depression ( r=0.50, P<0.001) were positively correlated with NSSI. 3) Depression partially mediated the effect of family environment on NSSI, with the mediating effect accounting for 64.64% of the total effect. Compared with that of male students, the positive predictive effect between family environment and depression and that between depression and NSSI in female middle school students were more significant. Conclusion: During the COVID-19 pandemic, middle school students in Chengdu had a high incidence of NSSI, which indicates that the family environment should be improved, more attention should be given to gender differences, and early screening and intervention for depression should be strengthened to reduce the incidence of NSSI.

Real-world outcomes of regorafenib combined with immune checkpoint inhibitors in patients with advanced or metastatic microsatellite stable colorectal cancer: A multicenter study.

BACKGROUND: Treatment strategies are limited for patients with chemotherapy refractory microsatellite stable (MSS) colorectal cancer. We aim to evaluate the efficacy and safety of immune checkpoint inhibitors (ICIs) combined with regorafenib in this population in routine clinical practice. METHODS: We retrospectively analyzed patients with advanced or metastatic colorectal cancer who received at least one dose of ICIs combined with regorafenib in 14 Chinese medical centers. The primary outcome was objective response rate (ORR). This study was registered at ClinicalTrials.gov on February 2020 (NCT04771715). RESULTS: Eighty-four patients received ICIs combined with regorafenib from January 2019 to January 2021. Most patients (91%) received two or more systemic treatment lines before the study treatment. Seventy-six patients (90%) had confirmed MSS status. At a median follow-up of 5.5 months, four patients achieved partial response (5%) and 37 patients achieved stable disease (45%) as the best response. The median progression-free survival (PFS) was 3.1 months, and the median overall survival was 17.3 months. Eleven patients (13%) remained progression-free for more than 6 months. Baseline liver metastasis (HR 1.98, 95%CI 1.07-3.69, P = 0.03) and neutrophil-lymphocyte ratio (NLR) of ≥ 1.5 (HR 2.83, 95%CI 1.00-7.98, P = 0.05) were associated with shorter PFS in multivariate analysis. Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 16 patients (19%). CONCLUSION: The combination of ICIs with regorafenib can be a valuable treatment option for a proportion of patients with chemotherapy refractory MSS colorectal cancer. Patients with no liver metastasis and a low NLR at baseline may derive most benefit from this strategy.

Few shot domain adaptation for in situ macromolecule structural classification in cryoelectron tomograms.

MOTIVATION: Cryoelectron tomography (cryo-ET) visualizes structure and spatial organization of macromolecules and their interactions with other subcellular components inside single cells in the close-to-native state at submolecular resolution. Such information is critical for the accurate understanding of cellular processes. However, subtomogram classification remains one of the major challenges for the systematic recognition and recovery of the macromolecule structures in cryo-ET because of imaging limits and data quantity. Recently, deep learning has significantly improved the throughput and accuracy of large-scale subtomogram classification. However, often it is difficult to get enough high-quality annotated subtomogram data for supervised training due to the enormous expense of labeling. To tackle this problem, it is beneficial to utilize another already annotated dataset to assist the training process. However, due to the discrepancy of image intensity distribution between source domain and target domain, the model trained on subtomograms in source domain may perform poorly in predicting subtomogram classes in the target domain. RESULTS: In this article, we adapt a few shot domain adaptation method for deep learning-based cross-domain subtomogram classification. The essential idea of our method consists of two parts: (i) take full advantage of the distribution of plentiful unlabeled target domain data, and (ii) exploit the correlation between the whole source domain dataset and few labeled target domain data. Experiments conducted on simulated and real datasets show that our method achieves significant improvement on cross domain subtomogram classification compared with baseline methods. AVAILABILITY AND IMPLEMENTATION: Software is available online https://github.com/xulabs/aitom. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.