Explore the vast range of titles available.

Among 88,902 participants followed over a period of 22 years in the Nurses' Health Study and the Health Professionals Follow-up Study, colon cancer mortality was reduced after screening sigmoidoscopy (hazard ratio, 0.59) and screening colonoscopy (hazard ratio, 0.32). Randomized, controlled trials have shown that screening with flexible sigmoidoscopy reduces the incidence of colorectal cancer and associated mortality, albeit with diminished effectiveness for cancers of the proximal colon. 1 – 3 Although comparable data from randomized, controlled trials of screening colonoscopy are not yet available, 4 colonoscopy is also widely endorsed by expert bodies for population-based screening, largely on the basis of case–control studies that show associations with reduced colorectal-cancer incidence and mortality. 5 – 9 However, as with flexible sigmoidoscopy, there is uncertainty about the effectiveness of colonoscopy in reducing the incidence of and mortality associated with proximal colon cancer 10 – 19 and about . . .

In this study, mortality from colorectal cancer was reduced by about 80% in a subgroup of patients with tumors that expressed a mutated, activated form of phosphatidylinositol 3-kinase (17% of all tumors) when the patients took aspirin regularly after the diagnosis. Numerous observational and randomized, controlled studies have suggested a protective effect of regular use of aspirin on colorectal neoplasias. 1 – 7 The favorable outcome that has been associated with aspirin use after colorectal cancer is diagnosed 8 – 10 suggests that aspirin is a promising agent for adjuvant therapy. Accumulating data suggest that colorectal cancers are a heterogeneous group of diseases that potentially have differential responses to treatment. 11 The effect of postdiagnosis aspirin use on survival appears to differ according to tumor expression of PTGS2 (HGNC:9605, the official symbol for prostaglandin-endoperoxide synthase 2, also known as cyclooxygenase-2) as assessed by immunohistochemical techniques. 8 Considering . . .

Mesenchymal’ stem cells (MSC) are widely used for transplantation to treat various diseases due to their strong immune regulatory and tissue repair abilities. Magnetic nanoparticles (MNPs) can be used to track transplanted MSC. However, the potential impact of the MNPs we developed on MSC function remains unclear. In this study, we treated MSC with poly-L-lysine (PLL)-modified MNPs (MSC-MNPs) at a concentration of 0.1 µg/µL to assess their effects on MSC. The results showed that there were no significant effects on cell morphology, differentiation potential, proliferation, apoptosis, or the cell cycle after MSC were treated with MNPs. Interestingly, further experiments revealed that MNPs significantly enhanced the migratory capacity of MSC. Bio-Plex analysis revealed that MNPs promoted the expression of anti-inflammatory cytokines while inhibiting the secretion of pro-inflammatory factors. Flow cytometry also detected a significant increase in the number of MSC subpopulations, including CD184⁺MSC, CD106⁺MSC, and CD55⁺MSC, after MNPs labeling, which was further supported by proteomic analysis. Moreover, MSC-MNPs promoted the phenotypic transition of reactive astrocytes from A1 to A2 after coculture with activated astrocytes. In conclusion, MNPs have no cytotoxic effects on MSC labeling and significantly enhance their anti-inflammatory functions, offering new possibilities for the clinical application of MSC.

Total synthesis of the proposed noursamycin A has been accomplished, which disproves the original structural assignments. The synthetic strategy described herein has also been employed in the first total synthesis of nicrophorusamide A, a cyclopeptide that is structurally related to noursamycin A.

ObjectiveColorectal cancer is typically classified into proximal colon, distal colon and rectal cancer. Tumour genetic and epigenetic features differ by tumour location. Considering a possible role of bowel contents (including microbiome) in carcinogenesis, this study hypothesised that tumour molecular features might gradually change along bowel subsites, rather than change abruptly at splenic flexure.DesignUtilising 1443 colorectal cancers in two US nationwide prospective cohort studies, the frequencies of molecular features (CpG island methylator phenotype (CIMP), microsatellite instability (MSI), LINE-1 methylation and BRAF, KRAS and PIK3CA mutations) were examined along bowel subsites (rectum, rectosigmoid junction, sigmoid, descending colon, splenic flexure, transverse colon, hepatic flexure, ascending colon and caecum). The linearity and non-linearity of molecular relations along subsites were statistically tested by multivariate logistic or linear regression analysis.ResultsThe frequencies of CIMP-high, MSI-high and BRAF mutations gradually increased from the rectum (<2.3%) to ascending colon (36–40%), followed by falls in the caecum (12–22%). By linearity tests, these molecular relations were significantly linear from rectum to ascending colon (p<0.0001), and there was little evidence of non-linearity (p>0.09). Caecal cancers exhibited the highest frequency of KRAS mutations (52% vs 27–35% in other sites; p<0.0001).ConclusionsThe frequencies of CIMP-high, MSI-high and BRAF mutations in cancer increased gradually along colorectum subsites from the rectum to ascending colon. These novel data challenge the common conception of discrete molecular features of proximal versus distal colorectal cancers, and have a substantial impact on clinical, translational and epidemiology research, which has typically been performed with the dichotomous classification of proximal versus distal tumours.

The evolution of sterile worker castes in eusocial insects was a major problem in evolutionary theory until Hamilton developed a method called inclusive fitness. He used it to show that sterile castes could evolve via kin selection, in which a gene for altruistic sterility is favored when the altruism sufficiently benefits relatives carrying the gene. Inclusive fitness theory is well supported empirically and has been applied to many other areas, but a recent paper argued that the general method of inclusive fitness was wrong and advocated an alternative population genetic method. The claim of these authors was bolstered by a new model of the evolution of eusociality with novel conclusions that appeared to overturn some major results from inclusive fitness. Here we report an expanded examination of this kind of model for the evolution of eusociality and show that all three of its apparently novel conclusions are essentially false. Contrary to their claims, genetic relatedness is important and causal, workers are agents that can evolve to be in conflict with the queen, and eusociality is not so difficult to evolve. The misleading conclusions all resulted not from incorrect math but from overgeneralizing from narrow assumptions or parameter values. For example, all of their models implicitly assumed high relatedness, but modifying the model to allow lower relatedness shows that relatedness is essential and causal in the evolution of eusociality. Their modeling strategy, properly applied, actually confirms major insights of inclusive fitness studies of kin selection. This broad agreement of different models shows that social evolution theory, rather than being in turmoil, is supported by multiple theoretical approaches. It also suggests that extensive prior work using inclusive fitness, from microbial interactions to human evolution, should be considered robust unless shown otherwise.

Following spinal cord injury (SCI), multiple signaling cascades are activated instantaneously in the injured segments of the spinal cord to create a complex and pathogenic microenvironment, making it difficult to treat SCI. Nevertheless, the significance of the integrated stress response (ISR) to the series of physiological and pathological changes that occur after SCI remains unclear. Through western blotting (WB), we determined that the autophosphorylation of stress receptors (GCN2, PERK, PKR, and HRI) was enhanced after SCI, leading to increased phosphorylation of eIF2α at Ser51. Strikingly, we found that eIF2α was highly phosphorylated at 1 day post injury (dpi) and that this hypophosphorylation was maintained thereafter in the spinal cord, especially in neurons, which suggests that intervening with eIF2α phosphorylation may be a treatment strategy for SCI. Therefore, we employed the small molecule ISRIB, which inhibits eIF2α phosphorylation when the ISR is activated at moderate or low levels but not when the ISR is highly activated. Daily intraperitoneal injection of ISRIB significantly inhibited ISR signaling after SCI, reduced the cytosolic localization of RNA-binding proteins, and decreased neuronal apoptosis. Histological and functional experiments further demonstrated that treatment with ISRIB after SCI effectively curbed morphological deterioration and promoted the recovery of locomotor function. In summary, the ISR plays an important role in SCI, and ISRIB is a promising drug for the treatment of SCI.

With the acceleration of population aging and the increasingly prominent problem of insufficient physical activity among older adults, how to effectively promote physical activity participation among older adults has become an important issue in the field of public health. Neighborhood environment, as the primary setting for daily living among older adults, exerts considerable influence on their physical activity engagement; however, the underlying mechanisms remain inadequately understood. Grounded in Social Cognitive Theory, this study aimed to examine the impact of neighborhood environment on physical activity among older adults and to test the chain mediating effects of self-efficacy and outcome expectations.BackgroundWith the acceleration of population aging and the increasingly prominent problem of insufficient physical activity among older adults, how to effectively promote physical activity participation among older adults has become an important issue in the field of public health. Neighborhood environment, as the primary setting for daily living among older adults, exerts considerable influence on their physical activity engagement; however, the underlying mechanisms remain inadequately understood. Grounded in Social Cognitive Theory, this study aimed to examine the impact of neighborhood environment on physical activity among older adults and to test the chain mediating effects of self-efficacy and outcome expectations.This study employed a cross-sectional design to collect data on physical activity participation from 937 older adults residing in 12 communities across Chengdu, Sichuan Province, China, through questionnaire surveys. Assessment instruments included the Neighborhood Environment Scale, International Physical Activity Questionnaire, Self-Efficacy Scale, and Physical Activity Outcome Expectations Scale to comprehensively evaluate participants' environmental perceptions, physical activity levels, and psychological cognitive characteristics. Following data collection, statistical analyses were conducted using SPSS 26.0, with structural equation modeling (AMOS) and Bootstrap methods employed to test potential mediating effects and ensure the reliability of results.MethodsThis study employed a cross-sectional design to collect data on physical activity participation from 937 older adults residing in 12 communities across Chengdu, Sichuan Province, China, through questionnaire surveys. Assessment instruments included the Neighborhood Environment Scale, International Physical Activity Questionnaire, Self-Efficacy Scale, and Physical Activity Outcome Expectations Scale to comprehensively evaluate participants' environmental perceptions, physical activity levels, and psychological cognitive characteristics. Following data collection, statistical analyses were conducted using SPSS 26.0, with structural equation modeling (AMOS) and Bootstrap methods employed to test potential mediating effects and ensure the reliability of results.The analyses revealed significant positive correlations among neighborhood environment, physical activity, self-efficacy, and outcome expectations. Specifically, neighborhood environment demonstrated a significant direct effect on physical activity among older adults, indicating that favorable neighborhood environments directly facilitate physical activity participation. Furthermore, self-efficacy and outcome expectations exhibited a chain mediating effect between neighborhood environment and physical activity, whereby neighborhood environment indirectly influenced physical activity levels through enhancing individual exercise self-efficacy and outcome expectations.ResultsThe analyses revealed significant positive correlations among neighborhood environment, physical activity, self-efficacy, and outcome expectations. Specifically, neighborhood environment demonstrated a significant direct effect on physical activity among older adults, indicating that favorable neighborhood environments directly facilitate physical activity participation. Furthermore, self-efficacy and outcome expectations exhibited a chain mediating effect between neighborhood environment and physical activity, whereby neighborhood environment indirectly influenced physical activity levels through enhancing individual exercise self-efficacy and outcome expectations.This study elucidates the underlying mechanisms between neighborhood environment and physical activity among older adults, Neighborhood environment is not only directly associated with physical activity levels among older adults but also indirectly influences physical activity through two psychological cognitive mediators: self-efficacy and outcome expectations.ConclusionThis study elucidates the underlying mechanisms between neighborhood environment and physical activity among older adults, Neighborhood environment is not only directly associated with physical activity levels among older adults but also indirectly influences physical activity through two psychological cognitive mediators: self-efficacy and outcome expectations.

T-cell engagers (TCEs) are a growing class of biotherapeutics being investigated in the clinic for treatment of a variety of hematological and solid tumor indications. However, preclinical evaluation of TCEs in vivo has been mostly limited to xenograft tumor models in human T-cell reconstituted immunodeficient mice, which have a number of limitations. To explore the efficacy of human TCEs in fully immunocompetent hosts, we developed a knock-in mouse model (hCD3E-epi) in which a 5-residue N-terminal fragment of murine CD3-epsilon was replaced with an 11-residue stretch from the human sequence that encodes for a common epitope recognized by anti-human CD3E antibodies in the clinic. T cells from hCD3E-epi mice underwent normal thymic development and could be efficiently activated upon crosslinking of the T-cell receptor with anti-human CD3E antibodies in vitro. Furthermore, a TCE targeting human CD3E and murine CD20 induced robust T-cell redirected killing of murine CD20-positive B cells in ex vivo hCD3E-epi splenocyte cultures, and also depleted nearly 100% of peripheral B cells for up to 7 days following in vivo administration. These results highlight the utility of this novel mouse model for exploring the efficacy of human TCEs in vivo, and suggest a useful tool for evaluating TCEs in combination with immuno-oncology/non-immuno-oncology agents against heme and solid tumor targets in hosts with a fully intact immune system.

In traditional power networks, security protection models primarily rely on perimeter-based defenses, utilizing firewalls, virtual private networks (VPNs), and identity authentication to block external threats. However, once a node within the power system is compromised, attackers can exploit it as a pivot to launch lateral movement attacks from within the system, posing serious threats to the core operations of the power grid. To address the increasingly complex cybersecurity landscape, this paper proposes a security defense approach that integrates an improved trust evaluation model based on the Practical Byzantine Fault Tolerance (PBFT) algorithm with a zero-trust architecture, leveraging the structural and functional symmetry among network nodes. The PBFT algorithm’s fault tolerance and consensus mechanisms are leveraged to ensure dynamic trust scoring across multiple nodes. This approach guarantees that each node has an equal role in the system’s operations, maintaining fairness and security across the network. Furthermore, the primary node in the PBFT consensus process is redefined as the arbitration node in the zero-trust framework, and faulty nodes can be automatically replaced through the view change protocol, thereby mitigating the centralization risk inherent in traditional zero-trust models. Experimental results demonstrate that the proposed approach achieves high accuracy and robustness in defending against both internal and external attacks in power network scenarios, highlighting the role of symmetry in enhancing secure and balanced system operations.