Incorporating Social Determinants of Health in Infectious Disease Models: A Systematic Review of Guidelines.

BACKGROUND: Infectious disease (ID) models have been the backbone of policy decisions during the COVID-19 pandemic. However, models often overlook variation in disease risk, health burden, and policy impact across social groups. Nonetheless, social determinants are becoming increasingly recognized as fundamental to the success of control strategies overall and to the mitigation of disparities. METHODS: To underscore the importance of considering social heterogeneity in epidemiological modeling, we systematically reviewed ID modeling guidelines to identify reasons and recommendations for incorporating social determinants of health into models in relation to the conceptualization, implementation, and interpretations of models. RESULTS: After identifying 1,372 citations, we found 19 guidelines, of which 14 directly referenced at least 1 social determinant. Age (n = 11), sex and gender (n = 5), and socioeconomic status (n = 5) were the most commonly discussed social determinants. Specific recommendations were identified to consider social determinants to 1) improve the predictive accuracy of models, 2) understand heterogeneity of disease burden and policy impact, 3) contextualize decision making, 4) address inequalities, and 5) assess implementation challenges. CONCLUSION: This study can support modelers and policy makers in taking into account social heterogeneity, to consider the distributional impact of infectious disease outbreaks across social groups as well as to tailor approaches to improve equitable access to prevention, diagnostics, and therapeutics. HIGHLIGHTS: Infectious disease (ID) models often overlook the role of social determinants of health (SDH) in understanding variation in disease risk, health burden, and policy impact across social groups.In this study, we systematically review ID guidelines and identify key areas to consider SDH in relation to the conceptualization, implementation, and interpretations of models.We identify specific recommendations to consider SDH to improve model accuracy, understand heterogeneity, estimate policy impact, address inequalities, and assess implementation challenges.

Solution-processing induced H-aggregate of Perylene-Diimide Zwitterion Exhibiting Compact Molecular Stacking toward Efficient Cathode Modification in Organic Solar Cells.

High-performance organic cathode interlayers (CILs) play a crucial role in the advance of organic solar cells (OSCs). However, organic CILs have exhibited inferior performances to their inorganic counterparts over a long time, due to the inherent shortcoming of poor charge transporting capability. Here, we designed and synthesized a perylene-diimide (PDI) zwitterion PDI-B as high-performance organic CIL for OSCs. We revealed that an obvious H-aggregate of PDI-B was formed during the solution processing, thereby significantly enhancing the charge transporting capability of the CIL. Compared to the classic PDINN, the π-π stacking distance of PDI-B was reduced from 4.2 Å to 3.9 Å, which further facilitated the charge transport. Consequently, PDI-B showed a high conductivity of 1.81×10-3S/m; this is comparable to that of inorganic CILs. The binary OSC showed an elevated PCE of 19.23%, which is among the highest PCE values for binary OSCs. Benefitting from improved solvent resistance and good compatibility with large-area processing method of PDI-B, the photovoltaic performances of inverted and 1-cm2 OSC were significantly improved. The results from this work provide a new approach of optimizing the condensed structure of PDI film to boost the charge conductivity, opening an avenue to develop high-performance PDI-based CILs.

ProT-Diff: A Modularized and Efficient Strategy for De Novo Generation of Antimicrobial Peptide Sequences by Integrating Protein Language and Diffusion Models.

Antimicrobial peptides (AMPs) are a promising solution for treating antibiotic-resistant pathogens. However, efficient generation of diverse AMPs without prior knowledge of peptide structures or sequence alignments remains a challenge. Here, ProT-Diff is introduced, a modularized deep generative approach that combines a pretrained protein language model with a diffusion model for the de novo generation of AMPs sequences. ProT-Diff generates thousands of AMPs with diverse lengths and structures within a few hours. After silico physicochemical screening, 45 peptides are selected for experimental validation. Forty-four peptides showed antimicrobial activity against both gram-positive or gram-negative bacteria. Among broad-spectrum peptides, AMP_2 exhibited potent antimicrobial activity, low hemolysis, and minimal cytotoxicity. An in vivo assessment demonstrated its effectiveness against a drug-resistant E. coli strain in acute peritonitis. This study not only introduces a viable and user-friendly strategy for de novo generation of antimicrobial peptides, but also provides potential antimicrobial drug candidates with excellent activity. It is believed that this study will facilitate the development of other peptide-based drug candidates in the future, as well as proteins with tailored characteristics.

Efficacy of resveratrol supplementation on lipid profile parameters: An umbrella of meta-analysis.

Several studies have evaluated the effects of resveratrol supplementation on lipid profile parameters in humans and have demonstrated varying results. We systematically evaluated the literature and performed an umbrella meta-analysis of the effects of resveratrol supplementation on lipid profile. A comprehensive literature search was conducted in the following databases; PubMed, Embase, Scopus, and Web of Science for studies published up to November 2023. According to the standardized mean difference (SMD) analysis, resveratrol supplementation was effective in reducing serum triglyceride (TG) (SMD = -0.14 mg/dl, 95 % CI: -0.24, -0.03; p = 0.001), total cholesterol (TC) (SMD = -0.20, 95 % CI: -0.31, -0.08; p= 0.001), but not high-density lipoprotein cholesterol (HDL-c) (SMD = 0.00, 95 % CI: -0.04, 0.05; p =0.92), and low-density lipoprotein-cholesterol (LDL-c) (SMD = -0.16 mg/dl, 95 % CI: -0.40, 0.07; p =0.17). In the weighted mean difference analysis, resveratrol did not significantly decrease lipid profile parameters. Resveratrol supplementation reduces TC and TG (based on SMD analysis), but it does not significantly affect other indices. However, these significant decreases are not clinically important. Therefore, resveratrol only can be considered as an adjunctive therapeutic approach in managing dyslipidemia.

Use of trimethoprim- sulfamethoxazole for treating Pneumocystis jirovecii pneumonia in a patient with glucose-6-phosphate dehydrogenase deficiency: a case report.

Background: Pneumocystis jirovecii pneumonia (PJP) is an opportunistic infection caused by the yeast-like fungus P. jirovecii. As recommended by some guidelines, the first-line treatment for this infection is trimethoprim-sulfamethoxazole (TMP-SMX), and the second-line treatment includes drugs such as dapsone, pentamidine, primaquine, Atovaquone, clindamycin, and caspofungin. Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked gene disorder in which treatment with oxidizing drugs, such as sulfonamides, dapsone, primaquine, can directly destroy hemoglobin present in red blood cells (RBCs), thereby inducing methemoglobin and hemolysis. Case presentation: Here, we present the case of a lymphoma patient with previous G6PD deficiency who was admitted to ICU for the treatment of severe pneumonia combined with respiratory failure. PJP was detected by the next-generation sequencing of the bronchoalveolar lavage fluid. The patient was initially treated with the antifungal drug caspofungin; however, this treatment showed poor therapeutic effect. Based on the evaluation of G6PD enzyme activity and the patient's previous history of G6PD deficiency, we finally treated the patient with low-dose TMP-SMX combined with caspofungin and provided rigorous medical care to the patient. Following this treatment, the patient's clinical symptoms improved, lung computed tomography showed reduced pulmonary inflammation, and the fungal ß-(1,3)-D-glucan test (G test) showed decreased levels of fungal D-glucan. After 57 days, the TMP-SMX treatment was discontinued. No symptoms related to G6PD deficiency, such as hemolysis, hematuria, and anemia, occurred during the treatment course. Conclusion: This is the first report mentioning the successful treatment of Pneumocystis jirovecii pneumonia with a double-drug regimen with low-dose TMP-SMX and caspofungin in a T-lymphoblastic leukemia/lymphoma patient with previous G6PD deficiency. Enzyme activity detection is the first step for anti-PJP treatment in patients with G6PD deficiency. Although patients with mild enzyme deficiency may not show any adverse reactions, we still recommend the regular monitoring of the levels of RBCs, hemoglobin, and hematocrit before and after the use of sulfonamides or sulfoxides and other oxidizing drugs in patients with G6PD deficiency. Among other things, early and correct diagnosis of Pneumocystis jirovecii pneumonia in hematological malignancies patients is very important. Relevant oncologists should be alert to the risk of Pneumocystis jirovecii pneumonia in these patients.

Biologic activity and treatment resistance to gastrointestinal cancer: the role of circular RNA in autophagy regulation.

Circular RNAs (circRNAs) lack the 5'-end methylated guanine cap structure and 3' polyadenylate tail structure, classifying it as a non-coding RNA. With the extensive investigation of circRNA, its role in regulating cell death has garnered significant attention in recent years, establishing it as a recognized participant in cancer's biological processes. Autophagy, an essential pathway in programmed cell death (PCD), involves the formation of autophagosomes using lysosomes to degrade cellular contents under the regulation of various autophagy-related (ATG) genes. Numerous studies have demonstrated that circRNA can modulate the biological activity of cancer cells by influencing the autophagy pathway, exhibiting a dualistic role in suppressing or promoting carcinogenesis. In this review, we comprehensively analyze how autophagy-related circRNA impacts the progression of gastrointestinal cancer (GIC). Additionally, we discuss drug resistance phenomena associated with autophagy regulation in GIC. This review offers valuable insights into exploring potential biological targets for prognosis and treatment strategies related to GIC.

Correlation of unobserved factors of old town street walkability using SEM: Case study of old southern area, Nanjing.

Contemporary research on the walking environment focuses closely on the construction logic and internal correlation. Walkability is one of the vital characteristics of the old town street space. To understand how to improve the old town street space effectively, the investigation of the correlation mechanism of street walkability is essential. This study utilizes structural equation model (SEM) to construct a street walkability measurement model composed of four unobserved factors. Then, take Old Southern Area in Nanjing as an example, integrate Depthmap, ArcGIS and Python to obtain multi-source data, and establish a database of observed factors on street space. Finally, the matrix of the observed factors is set by SEM to calculate the correlation of the unobserved factors. This paper provides a novel technical approach for the correlation study of spatial construction logic as well as a reference for strengthening the spatial quality of the contemporary built environment.

The effect of oral probiotics in the last trimester on the human milk and infant gut microbiotas at six months postpartum: A randomized controlled trial.

Objective: The main aim of this study was to evaluate the effect of oral probiotics on the human milk microbiota and determine whether that influenced infant microbiota development. Methods: A total of 27 pregnant women were recruited; 14 were assigned to the probiotic group, and the rest were assigned to the control group. Their infants were likewise assigned to the probiotic group or the control group. Pregnant women in the probiotic group received probiotic supplementation from 32 weeks of gestation until delivery. Human milk samples and infant fecal samples were collected at 6 months after delivery, and 16S rRNA sequencing was used to analyze the composition of the human milk and infant gut microbiota (NCT06241222). Results: In the control group, bacterial microbiota were detected in 8 out of 13 milk samples, whereas in the probiotic group, only 6 out of 14 milk samples contained bacterial microbiota. We examined the composition of the human milk and infant gut microbiota in both the control and probiotic groups. Spearman correlation analysis revealed that various genera in human milk were correlated with the infant gut microbiota. The Linear discriminant analysis effect size (LEfSe) showed that 6 bacteria in the human milk microbiota in the control group were significantly more abundant than those in the probiotic group. Nine bacteria were significantly more abundant in the human milk microbiota in the probiotic group than the control group. According to the LEfSe results, 11 bacteria in the infant gut microbiota in the control group were significantly more abundant than those in the probiotic group. Fourteen bacteria were significantly more abundant in the infant gut microbiota in the probiotic group than in the control group. Conclusion: The infant gut microbiota at 6 months has a complicated relationship with the maternal human milk microbiota. Oral probiotic supplementation can change the composition of the human milk microbiota and the infant gut microbiota.

COL12A1 Promotes Osteosarcoma Progression via the FAK/PI3K/AKT/mTOR Pathway.

BACKGROUND: Osteosarcoma (OS) is a common malignancy among adolescents and children, characterized by a high propensity for metastasis and resistance to chemotherapy. AIMS: This study aimed to investigate the role of COL12A1, a gene often overexpressed in various cancers and associated with poor prognosis, in the progression of OS and explore the underlying mechanisms. METHODS: The expression pattern and potential function of COL12A1 in OS were evaluated using bioinformatics analyses, clinical sample examination, and OS cell lines. Various assays, including transwell, CCK-8, flow cytometry, and wound healing, were performed to assess the impact of COL12A1 on OS cell growth, cell cycle progression, apoptosis, invasion, and migration. Western blot analysis was conducted to investigate markers associated with the FAK/PI3K/AKT/mTOR pathway. RESULTS: COL12A1 expression was significantly elevated in OS tissues and cells. Upregulation of COL12A1 promoted cell growth, accelerated cell cycle progression, and enhanced migration and invasion while inhibiting apoptosis. Conversely, the knockdown of COL12A1 had the opposite effect. Additionally, COL12A1 overexpression increased the phosphorylation of components in the FAK/PI3K/AKT/mTOR pathway. The FAK inhibitor Y15 mitigated the effects of COL12A1 overexpression on cell apoptosis, invasion, proliferation, and the FAK/PI3K/AKT/mTOR pathway in OS. CONCLUSION: Our findings indicated that COL12A1 enhanced OS development by activating the FAK/PI3K/AKT/mTOR pathway, suggesting that COL12A1 could serve as a valuable biomarker for the prediction and identification of OS patients.

Sodium butyrate improves cognitive dysfunction in high-fat diet/ streptozotocin-induced type 2 diabetic mice by ameliorating hippocampal mitochondrial damage through regulating AMPK/PGC-1α pathway.

Cognitive dysfunction is an important comorbidity of type 2 diabetes mellitus (T2DM). Sodium butyrate (NaB) is a short-chain fatty acid and has an effect improving T2DM-associated cognitive dysfunction. Using a high-fat diet (HFD)/streptozotocin (STZ)-induced T2DM mouse model, the present study investigated the mechanism involved in the beneficial effect of butyrate on diabetic cognitive dysfunction, with a focus on ameliorating mitochondrial damage through regulating the adenosine monophosphate-activated protein kinase/peroxisome proliferator-activated receptor gamma coactivator 1α (AMPK/PGC-1α) pathway considering the important role of mitochondrial impairments in the occurrence of T2DM-associated cognitive dysfunction. We found, based on reconfirmation of the improvement of NaB on cognitive impairment, that NaB treatment improved damaged synaptic structural plasticity including the decrease in dendritic spine density and downregulation in the expression of postsynaptic density protein 95 and synaptophysin in the hippocampus in the model mice. NaB treatment also ameliorated mitochondrial ultrastructural damage, increased mitochondrial membrane potential and adenosine 5'-triphosphate content, and improved mitochondrial biogenesis and dynamics in the model mice. Furthermore, the expression of phosphorylated AMPK and PGC-1α was upregulated after NaB treatment in the model mice. In particular, the above beneficial effects of NaB were blocked by the inhibition of either AMPK or PGC-1α. In conclusion, NaB treatment improved cognitive impairment and damaged synaptic structural plasticity in the hippocampus by ameliorating damage to mitochondrial morphology and function through regulating the AMPK/PGC-1α pathway in HFD/STZ-induced T2DM mice.

Convergence-Adaptive Roundtrip Method Enables Rapid and Accurate FEP Calculations.

The free energy perturbation (FEP) method is a powerful technique for accurate binding free energy calculations, which is crucial for identifying potent ligands with a high affinity in drug discovery. However, the widespread application of FEP is limited by the high computational cost required to achieve equilibrium sampling and the challenges in obtaining converged predictions. In this study, we present the convergence-adaptive roundtrip (CAR) method, which is an enhanced adaptive sampling approach, to address the key challenges in FEP calculations, including the precision-efficiency tradeoff, sampling efficiency, and convergence assessment. By employing on-the-fly convergence analysis to automatically adjust simulation times, enabling efficient traversal of the important phase space through rapid propagation of conformations between different states and eliminating the need for multiple parallel simulations, the CAR method increases convergence and minimizes computational overhead while maintaining calculation accuracy. The performance of the CAR method was evaluated through relative binding free energy (RBFE) calculations on benchmarks comprising four diverse protein-ligand systems. The results demonstrated a significant speedup of over 8-fold compared to conventional FEP methods while maintaining high accuracy. The overall R2 values of 0.65 and 0.56 were obtained using the combined-structure FEP approach and the single-step FEP approach, respectively, in conjunction with the CAR method. In-depth case studies further highlighted the superior performance of the CAR method in terms of convergence acceleration, improved predicted correlations, and reduced computational costs. The advancement of the CAR method makes it a highly effective approach, enhancing the applicability of FEP in drug discovery.

Simulation of the bone remodelling microenvironment by calcium compound-loaded hydrogel fibrous membranes for in situ bone regeneration.

The endowment of guided bone regeneration (GBR) membranes with the ability to activate the endogenous regenerative capability of bone to regenerate bone defects is of clinical significance. Herein we explored the preparation of the calcium compound (CC) (calcium sulfate (CaSL), calcium hydrophosphate (CaHP), or tricalcium phosphate (TCaP)) loaded ultrathin silk fibroin (SF)/gelatin (G) fibre membranes via electrospinning as the GBR membranes to regenerate the calvarial bone defects. The in vitro experiments demonstrated that the CaSL-loaded ultrathin fibrous membranes could simulate optimally the bone remodelling microenvironment in comparison with the CaHP- and TCaP-loaded fibrous membranes, displaying the highest activity to regulate the migration, proliferation, and differentiation of mesenchymal stem cells (MSCs). Also, the in vivo experiments demonstrated that the CaSL-loaded fibrous membranes presented the highest intrinsic osteoinduction to guide in situ regeneration of bone. Furthermore, the in vivo experiments demonstrated that the as-prepared composite fibrous membranes possessed good degradability. In summary, our results suggested that the CaSL-loaded fibrous membranes with high intrinsic osteoinduction and good degradability have potential to translate into clinical practice.

Immunotherapy for colorectal cancer.

Colorectal cancer is the third most common cancer and the second most lethal cancer in the world. The main cause of the disease is due to dietary and behavioral factors. The treatment of this complex disease is mainly based on traditional treatments, including surgery, radiotherapy, and chemotherapy. Due to its high prevalence and high morbidity, more effective treatments with fewer side effects are urgently needed. In recent years, immunotherapy has become a potential therapeutic alternative and one of the fastest-developing treatments. Immunotherapy inhibits tumor growth by activating or enhancing the immune system to recognize and attack cancer cells. This review presents the latest immunotherapies for immune checkpoint inhibitors, cell therapy, tumor-infiltrating lymphocytes, and oncolytic viruses. Some of these have shown promising results in clinical trials and are used in clinical treatment.

Optimal management of breast cancer with physical exam negative/radiological abnormal axilla.

For breast cancer patients with physical exam node negative but radiological finding node abnormal (cN0/rNa), the NCCN and ASCO guidelines recommend sentinel lymph node biopsy (SLNB) as the first-line axillary staging. However, patients who undergo surgery firstly may be upstaged to pathological II-III status, and these patients happen to be the adaptive population of neoadjuvant therapy (NAT). There is no consensus on the optimal management of cN0/rNa patients. The aim is to explore the optimal management strategy of these patients. We performed a retrospective real-world study of 1414 cN0/rNa patients from June 2014 to October 2022. There were 1003 patients underwent surgery first and 411 patients underwent surgery after NAT. We analyzed the real-world conditions of these patients, compared axilla tumor burden between these two groups. In addition, we compared benefit ratio of axillary surgery and regional nodal irradiation (RNI) de-escalation under the two strategies. Among 1003 patients underwent surgery first, the positive and negative rates of fine needle aspiration (FNA) were 18.5% and 81.5%, respectively. There were 66.1% had ≤ 2 lymph nodes+. There were 40.8% of FNA+ patients could be exempted from ALND underwent surgery first. In 411 patients underwent surgery after NAT, the FNA positive and negative rates were 60.8% and 49.2%, respectively. There were 54.4% of FNA+ patients achieved axilla pathologic complete response (apCR) and could omit ALND after NAT. The apCR was 67.3% in HER2+/TNBC subtypes. According to the NSABP-B51 trial, there were 0 and 54.4% of FNA+ patients could omit RNI among surgery first and after NAT, respectively. Among 1-2 sentinel lymph node (SLN)-positive patients underwent surgery first, with a median follow-up 49 months, there was no difference of survival benefit between SLNB-only and SLNB-ALND. Compared with 1-2 SLN+ patients without RNI, RNI could bring better invasive disease-free survival (97.38% vs. 89.36%, P = 0.046) and breast cancer special survival (100% vs. 94.68%, P = 0.020). It is safe to perform SLNB omitting ALND when detected 1-2 positive SLNs in cN0/rNa patients. Patients with HER2+/TNBC subtypes underwent surgery after NAT had more chance to benefit from dual de-escalation, including axillary surgery and RNI de-escalation.

Illuminating the fight against breast cancer: Preparation and visualized photothermal therapy of hyaluronic acid coated ZIF-8 loading with indocyanine green and cryptotanshinone for triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is characterized by higher recurrence rate and mortality. Thermally-mediated ablation via photothermal therapy (PTT) demonstrates considerable promise for the eradication of breast cancer. Nonetheless, the efficacy of PTT is impeded by the thermal tolerance of tumor cells, which is attributed to the augmented expression of heat shock proteins (HSPs). These proteins, which function as ATP-dependent molecular chaperones, confer protection to cancer cells against the cytotoxic heat generated during PTT. Glycolysis is an important way for breast cancer cells to produce ATP, which can promote the occurrence and development of lung metastasis of breast cancer. Therefore, inhibiting glycolysis may diminish the expression of HSPs, curtail the growth of breast cancer, and prevent its metastasis. Glycolytic metabolism plays a pivotal role in the ATP biosynthesis within breast cancer cells, facilitating the progression and dissemination of pulmonary metastases. Consequently, targeting glycolysis presents a strategic approach to HSP expression, the proliferation of breast cancer, and impede its metastatic spread. Herein, we designed an indocyanine green (ICG) and cryptotanshinone (CTS) loaded hyaluronic acid (HA) coated Zeolitic Imidazolate Framework-8 (ZIF-8) drug delivery system. The drug delivery system had excellent photothermal properties, which could reach temperature sufficient for photothermal ablation of tumor cells. (ICG + CTS)@HA-ZIF-8 also showed pH-responsive drug release, enhancing the sustained release of ICG and CTS to extend their systemic circulation duration. Moreover, the HA modification of ZIF-8 served to augment its targeting capabilities both in vitro and in vivo, leveraging the enhanced permeation and retention (EPR) effect, as well as active tumor targeting via the CD44 receptor pathway, resulting in a higher drug concentration and a better therapeutic effect in tumor. (ICG + CTS)@HA-ZIF-8 could downregulate the expression of glycolysis-related protein pyruvate kinase-M2 (PKM2), thereby inhibiting the glycolysis process, further suppressing tumor cell energy metabolism, downregulating the expression of HSPs, overcoming tumor cell heat resistance, and improving PTT effect. It exhibited a notable suppressive impact on both the proliferation and migration of breast cancer cells, potentially offering innovative insights for the visualized PTT in breast cancer treatment.

53BP1 loss elicits cGAS-STING-dependent antitumor immunity in ovarian and pancreatic cancer.

53BP1 nucleates the anti-end resection machinery at DNA double-strand breaks, thereby countering BRCA1 activity. Loss of 53BP1 leads to DNA end processing and homologous recombination in BRCA1-deficient cells. Consequently, BRCA1-mutant tumors, typically sensitive to PARP inhibitors (PARPi), become resistant in the absence of 53BP1. Here, we demonstrate that the 'leaky' DNA end resection in the absence of 53BP1 results in increased micronuclei and cytoplasmic double-stranded DNA, leading to activation of the cGAS-STING pathway and pro-inflammatory signaling. This enhances CD8+ T cell infiltration, activates macrophages and natural killer cells, and impedes tumor growth. Loss of 53BP1 correlates with a response to immune checkpoint blockade (ICB) and improved overall survival. Immunohistochemical assessment of 53BP1 in two malignancies, high grade serous ovarian cancer and pancreatic ductal adenocarcinoma, which are refractory to ICBs, reveals that lower 53BP1 levels correlate with an increased adaptive and innate immune response. Finally, BRCA1-deficient tumors that develop resistance to PARPi due to the loss of 53BP1 are susceptible to ICB. Therefore, we conclude that 53BP1 is critical for tumor immunogenicity and underpins the response to ICB. Our results support including 53BP1 expression as an exploratory biomarker in ICB trials for malignancies typically refractory to immunotherapy.

RAD21 promotes oncogenesis and lethal progression of prostate cancer.

Higher levels of aneuploidy, characterized by imbalanced chromosome numbers, are associated with lethal progression in prostate cancer. However, how aneuploidy contributes to prostate cancer aggressiveness remains poorly understood. In this study, we assessed in patients which genes on chromosome 8q, one of the most frequently gained chromosome arms in prostate tumors, were most strongly associated with long-term risk of cancer progression to metastases and death from prostate cancer (lethal disease) in 403 patients and found the strongest candidate was cohesin subunit gene, RAD21, with an odds ratio of 3.7 (95% CI 1.8, 7.6) comparing the highest vs. lowest tertiles of mRNA expression and adjusting for overall aneuploidy burden and Gleason score, both strong prognostic factors in primary prostate cancer. Studying prostate cancer driven by the TMPRSS2-ERG oncogenic fusion, found in about half of all prostate tumors, we found that increased RAD21 alleviated toxic oncogenic stress and DNA damage caused by oncogene expression. Data from both organoids and patients indicate that increased RAD21 thereby enables aggressive tumors to sustain tumor proliferation, and more broadly suggests one path through which tumors benefit from aneuploidy.

An Attacker-Defender Game Model with Constrained Strategies.

Recently, research interest in the field of infrastructure attack and defense scenarios has increased. Numerous methods have been proposed for studying strategy interactions that combine complex network theory and game theory. However, the unavoidable effect of constrained strategies in complex situations has not been considered in previous studies. This study introduces a novel approach to analyzing these interactions by including the effects of constrained strategies, a factor often neglected in traditional analyses. First, we introduce the rule of constraints on strategies, which depends on the average distance between selected nodes. As the average distance increases, the probability of choosing the corresponding strategy decreases. Second, we establish an attacker-defender game model with constrained strategies based on the above rule and using information theory to evaluate the uncertainty of these strategies. Finally, we present a method for solving this problem and conduct experiments based on a target network. The results highlight the unique characteristics of the Nash equilibrium when setting constraints, as these constraints influence decision makers' Nash equilibria. When considering the constrained strategies, both the attacker and the defender tend to select strategies with lower average distances. The effect of the constraints on their strategies becomes less apparent as the number of attackable or defendable nodes increases. This research advances the field by introducing a novel framework for examining strategic interactions in infrastructure defense and attack scenarios. By incorporating strategy constraints, our work offers a new perspective on the critical area of infrastructure security.

Operando chemo-mechanical evolution in LiNi0.8Co0.1Mn0.1O2 cathodes.

Ni-rich LiNi x Co y Mn z O2 (NCMxyz, x + y + z = 1, x ≥ 0.8) layered oxide materials are considered the main cathode materials for high-energy-density Li-ion batteries. However, the endless cracking of polycrystalline NCM materials caused by stress accelerates the loss of active materials and electrolyte decomposition, limiting the cycle life. Hence, understanding the chemo-mechanical evolution during (de)lithiation of NCM materials is crucial to performance improvement. In this work, an optical fiber with µÎµ resolution is designed to in operando detect the stress evolution of a polycrystalline LiNi0.8Co0.1Mn0.1O2 (P-NCM811) cathode during cycling. By integrating the sensor inside the cathode, the stress variation of P-NCM811 is completely transferred to the optical fiber. We find that the anisotropy of primary particles leads to the appearance of structural stress, inducing the formation of microcracks in polycrystalline particles, which is the main reason for capacity decay. The isotropy of primary particles reduces the structural stress of polycrystalline particles, eliminating the generation of microcracks. Accordingly, the P-NCM811 with an ordered arrangement structure delivered high electrochemical performance with capacity retention of 82% over 500 cycles. This work provides a brand-new perspective with regard to understanding the operando chemo-mechanical evolution of NCM materials during battery operation, and guides the design of electrode materials for rechargeable batteries.

Affinity-independent memory B cell origin of the early antibody-secreting cell response in naive individuals upon SARS-CoV-2 vaccination.

Memory B cells (MBCs) formed over the individual's lifetime constitute nearly half of the circulating B cell repertoire in humans. These pre-existing MBCs dominate recall responses to their cognate antigens, but how they respond to recognition of novel antigens is not well understood. Here, we tracked the origin and followed the differentiation paths of MBCs in the early anti-spike (S) response to mRNA vaccination in SARS-CoV-2-naive individuals on single-cell and monoclonal antibody levels. Pre-existing, highly mutated MBCs showed no signs of germinal center re-entry and rapidly developed into mature antibody-secreting cells (ASCs). By contrast, and despite similar levels of S reactivity, naive B cells showed strong signs of antibody affinity maturation before differentiating into MBCs and ASCs. Thus, pre-existing human MBCs differentiate into ASCs in response to novel antigens, but the quality of the humoral and cellular anti-S response improved through the clonal selection and affinity maturation of naive precursors.