Loss-of-function mutation of REV1 (p.R704Q) mediates cetuximab primary resistance by activating autophagy in RAS-wild type metastatic colorectal cancer.

Cetuximab in combination with FOLFIRI/FOLFOX is the standard first-line treatment for patients with RAS wild-type metastatic colorectal cancer (mCRC). However, some patients experience rapid tumor progression after treatment with cetuximab (primary resistance). Our previous research identified a gene mutation, REV1 p.R704Q, which may be a key biomarker for primary cetuximab resistance. This study aimed to study the mechanism of cetuximab resistance caused by REV1 p.R704Q mutation and reveal a novel mechanism to induce cetuximab resistance. Sanger sequencing and multivariate clinical prognostic analysis of 208 patients with mCRC showed that REV1 p.R704Q mutation is an independent risk factor for tumor progression after treatment with cetuximab in patients with RAS wild-type mCRC (Hazard ratio=2.481, 95% Confidence interval: 1.389-4.431, P = 0.002). The sensitivity of REV1 p.R704Q mutant cell lines to cetuximab decreased in vitro Cell Counting Kit-8 assay and in vivo subcutaneous tumor model. In vitro, we observed that decreased stability and accelerated degradation of REV1 mutant protein results in REV1 dysfunction, which activated autophagy and mediated cetuximab resistance. These findings suggested that REV1 p.R704Q mutation could predict cetuximab primary resistance in mCRC. REV1 p.R704Q mutation caused decreased stability and degradation of REV1 protein, as well as dysfunction of p.R704Q protein. REV1 p.R704Q mutation activates autophagy and mediates cetuximab resistance; further, inhibition of autophagy could reverse cetuximab resistance.

Measurement and spatio-temporal heterogeneity analysis of coupling coordination between development of digital economy and agricultural carbon emission performance.

The new development pattern has identified two key avenues for the sustained advancement of high-quality agricultural and rural development: digitalisation and low-carbon development. The measurement of the digital economy and the agricultural carbon emission performance, and their spatial and temporal heterogeneity, is a crucial step in promoting the spatial coordination and sustainable development of digitalisation and low-carbon agriculture. This paper employs the entropy value method, SBM model, and coupling coordination degree model to investigate the coupling coordination measurement and spatial-temporal heterogeneity of the performance of the digital economy and agricultural carbon emissions. The data used are provincial panel data from 2013 to 2021. The simulation results demonstrate that, between 2013 and 2021, the digital economy of all provinces exhibited varying degrees of growth, yet the development of the digital economy between provinces exhibited a more pronounced tendency to diverge. Concurrently, the agricultural carbon emission efficiency in China exhibited a fluctuating upward trend. The development of the digital economy and the efficiency of agricultural carbon emission were found to be highly coupled. Their coupling and coordination relationship showed a downward trend followed by an upward trend. In general, it is suggested that we should increase investment in digital economy infrastructure and technology, promote digital agricultural applications, strengthen policy guidance and financial support, establish a coupling coordination mechanism and strengthen farmers' digital literacy and environmental awareness.

Association between blood pressure control during aneurysm clipping and functional outcomes in patients with aneurysmal subarachnoid hemorrhage.

Objectives: We explored the relationship between blood pressure variability (BPV) during craniotomy aneurysm clipping and short-term prognosis in patients with aneurysmal subarachnoid hemorrhage to provide a new method to improve prognosis of these patients. Methods: We retrospectively analyzed the differences between patient groups with favorable modified Rankin Scale (mRS ≤ 2) and unfavorable (mRS > 2) prognosis, and examined the association between intraoperative BPV and short-term prognosis. Results: The intraoperative maximum systolic blood pressure (SBPmax, p = 0.005) and the coefficient of variation of diastolic blood pressure (DBPCV, p = 0.029) were significantly higher in the favorable prognosis group. SBPmax (OR 0.88, 95%CI 0.80-0.98) and Neu% (OR 1.22, 95%CI 1.03-1.46) were independent influence factors on prognosis. Patients with higher standard deviations of SBP (82.7% vs. 56.7%; p = 0.030), DBP (82.7% vs. 56.7%; p = 0.030), and DBPCV (82.7% vs. 56.7%; p = 0.030) had more favorable prognosis. Conclusion: Higher SBPmax (≤180 mmHg) during the clipping is an independent protective factor for a 90-day prognosis. These results highlight the importance of blood pressure (BP) control for improved prognosis; higher short-term BPV during clipping may be a precondition for a favorable prognosis.

Glucocorticoids disrupt longitudinal advance of cortical bone basic multicellular units in the rabbit distal tibia.

Glucocorticoids (GCs) are the leading cause of secondary osteoporosis. The emerging perspective, derived primarily from 2D histological study of trabecular bone, is that GC-induced bone loss arises through the uncoupling of bone formation and resorption at the level of the basic multicellular units (BMUs), which carry out bone remodeling. Here we explore the impact of GCs on cortical bone remodeling in the rabbit model. Based upon the rapid reduction of bone formation and initial elevation of resorption caused by GCs, we hypothesized that the rate of advance (longitudinal erosion rate; LER) of cortical BMUs would be increased. To test this hypothesis we divided 20 female New Zealand White rabbits into four experimental groups: ovariohysterectomy (OVH), glucocorticoid (GC), OVH + GC and SHAM controls (n = 5 animals each). Ten weeks post-surgery (OVH or sham), and two weeks after the initiation of dosing (daily subcutaneous injections of 1.5 mg/kg of methylprednisolone sodium succinate in the GC-treated groups and 1 ml of saline for the others), the right tibiae were scanned in vivo using Synchrotron Radiation (SR) in-line phase contrast micro-CT at the Canadian Light Source. After an additional 2 weeks of dosing, the rabbits were euthanized and ex vivo images were collected using desktop micro-CT. The datasets were co-registered in 3D and LER was calculated as the distance traversed by BMU cutting-cones in the 14-day interval between scans. Counter to our hypothesis, LER was greatly reduced in GC-treated rabbits. Mean LER was lower in GC (4.27 µm/d; p < 0.001) and OVH + GC (4.19 µm/d; p < 0.001), while similar in OVH (40.13 µm/d; p = 0.990), compared to SHAM (40.44 µm/d). This approximately 90 % reduction in LER with GCs was also associated with an overall disruption of BMU progression, with radial expansion of the remodeling space occurring in all directions. This unexpected outcome suggests that GCs do not simply uncouple formation and resorption within cortical BMUs and highlights the value of the time-lapsed 4D approach employed.

Magnetic covalent organic frameworks as sorbents in the chromatographic analysis of environmental organic pollutants.

Covalent organic frameworks (COFs) are featured with large specific surface areas, good thermal stability, and abundant pores. These properties are exactly what the sorbents used for extraction or adsorption of interest substances are desired with. While, the low density and hydrophobicity of COFs often makes them difficult to be dispersed evenly and recovered from the aqueous solution. Magnetic covalent organic frameworks (MCOFs) inherit magnetic property of the magnetic particles and porous structure of COFs. They have improved dispersity in aqueous solution and phase separation can be rapidly achieved via external magnetic fields. This review summarized the synthesis strategies for MCOFs, and their application in trace environmental organic pollutants analysis by chromatography techniques. The selection of COFs types and modification with active groups for a certain adsorption purpose is discussed, along with the exploration of adsorption mechanisms, which is beneficial for the design and synthesis of MCOFs.

Exploratory analysis on the association of dietary live microbe and non-dietary prebiotic/probiotic intake with serum cotinine levels in the general adult population.

Background: Previous research has indicated the potential involvement of the microbiota in smoking-related processes. The present study seeks to examine the relationship between dietary live microbes, as well as probiotic or prebiotic consumption, and serum cotinine levels. Methods: This study used data from the National Health and Nutrition Examination Survey 1999-2018. Dietary intake information and probiotic/prebiotic intake data was collected through self-reported questionnaires. Participants were stratified into low, medium, and high intake groups according to their consumption of foods with varying microbial content. Multiple linear models were applied to explore the relationships of dietary live microbes, probiotic or prebiotic use with the serum cotinine level. Results: A total of 42,000 eligible participants were included in the final analysis. The weighted median serum cotinine level was 0.05 (0.01, 10.90) ng/ml. Participants with low, medium, and high dietary microbe intake represented 35.4, 43.6, and 21.0% of the cohort, respectively. Furthermore, participants were stratified into three groups based on their overall consumption of foods with variable microbe contents. The association between dietary live microbe intake and serum cotinine levels remained robust across all models, with medium intake as the reference (Model 2: ß = -0.14, 95% CI: -0.20, -0.07; High: ß = -0.31, 95% CI: -0.39, -0.22). Moreover, both prebiotic and probiotic use exhibited an inverse relationship with serum cotinine levels (Prebiotic: ß = -0.19, 95% CI: -0.37, -0.01; Probiotic: ß = -0.47, 95% CI: -0.64, -0.30). Subgroup analyses revealed no discernible interactions between dietary live microbe, prebiotic, probiotic use, and serum cotinine levels. Conclusion: Our findings suggest a negative correlation between dietary live microbe intake, as well as non-dietary prebiotic/probiotic consumption, and serum cotinine levels.

Secure optical communication system based on polarization regulation of the data fragmentation multipath transmission technology.

We propose and demonstrate a data fragment multipath transmission scheme to achieve a secure optical communication based on polarization regulation. A dual-polarization Mach-Zehnder modulator (DPMZM) is driven by digital signals which are scattered by field-programmable gate array (FPGA) and transmitted in multiple paths. By utilizing two orthogonal polarization states, we have achieved a signal transmission under different optical parameters, and the transmission rate of the two paths can reach over 10 Gbps through a 20 km fiber with 2.5 Gbps hopping rate. In addition, we establish a theoretical model to analyze the security of the system and simulate brute force cracking; the probability of cracking the minimum information unit is 1.53 × 10-53. This proves that it is difficult to obtain a user data even using the fastest computers. Our scheme has provided, to our knowledge, a new approach for physical layer security.

Non-uniform line-of-sight measurements of nitric oxide using mid-infrared Faraday rotation spectroscopy.

Traditional absorption spectroscopy relies on detecting intensity variations along the line-of-sight to gauge average concentration and temperature. While methods like profile fitting and temperature binning offer insights into the non-uniformity of the path, they fall short of accurately capturing the precise spatial distribution with a single line-of-sight measurement. We propose a novel measurement scheme for non-uniformly distributed concentration of nitric oxide (NO) along the line-of-sight utilizing a single laser and path, by incorporating Faraday rotation spectroscopy with magnetic fields changing over time and space. We validate the proposed scheme by measuring a path of two regions in series with different NO concentrations, and comparing the measurement results with direct absorption spectroscopy of each respective region. In this work, the tuning range of the interband cascade laser used is from 1899.42 to 1900.97 cm-1, encompassing two sets of spectral lines corresponding to the 2Π1/2 and 2Π3/2 transitions of NO's R(6.5). The average relative uncertainty in the concentration measurement for each region is estimated to be within 1.5%, with the concentration for individual absorption cells ranging from 0.2% to 0.8%.

Soil Organic Matter and Total Nitrogen Reshaped Root-Associated Bacteria Community and Synergistic Change the Stress Resistance of Codonopsis pilosula.

The stress resistance of medicinal plants is essential to the accumulation of pharmacological active ingredients, but the regulation mechanism of biological factors and abiotic factors on medicinal plants is still unclear. To investigate the mechanism of soil nutrient and microecology on the stress resistance of C. pilosula, rhizosphere soil and roots were collected across the four seasons in Minxian, Gansu, and their physicochemical properties, as well as root-associated microorganisms, were examined. The results showed that the bacterial α-diversity indexes increased in the endosphere and rhizosphere from summer to autumn. At the same time, the community composition and function changed considerably. The stability of the endophytic bacterial community was higher than that rhizospheric bacteria, and the complexity of the endophytic bacterial community was lower than rhizospheric bacteria. Soil organic matter (OM), water content (WC), total potassium (TK), and total nitrogen (TN) have been identified as the key factors affecting bacterial community diversity and stress resistance of C. pilosula. WC, TN, and OM showed significant differences from summer to autumn (P < 0.5). Four key soil physiochemical factors changed significantly between seasons (P < 0.01). TN and OM change the stress resistance of C. pilosula mainly by changing the activity of antioxidant enzymes. Changes of OM and endophytic bacterial diversity affect the accumulation of soluble sugars to alter stress resistance. These four key soil physicochemical factors significantly influenced the diversity of endophytic bacteria. WC and OM were identified as the most important factors for endophytic and rhizospheric bacteria, respectively. This study provided the research basis for the scientific planting of C. pilosula.

Role of cspA on the Preparation of Escherichia coli Competent Cells by Calcium Chloride Method.

One of the fundamental techniques in genetic engineering is the creation of Escherichia coli competent cells using the CaCl2 method. However, little is known about the mechanism of E. coli competence formation. We have previously found that the cspA gene may play an indispensable role in the preparation of E. coli DH5α competent cells through multiomics analysis. In the present study, the cellular localization, physicochemical properties, and function of the protein expressed by the cspA gene were analyzed. To investigate the role of the cspA gene in E. coli transformation, cspA-deficient mutant was constructed by red homologous recombination. The growth, transformation efficiency, and cell morphology of the cspA-deficient strain and E. coli were compared. It was found that there were no noticeable differences in growth and morphology between E. coli and the cspA-deficient strain cultured at 37°C, but the mutant exhibited increased transformation efficiencies compared to E. coli DH5α for plasmids pUC19, pET-32a, and p1304, with enhancements of 2.23, 2.24, and 3.46 times, respectively. It was proved that cspA gene is an important negative regulatory gene in the CaCl2 preparation of competent cells.

Impact of Baduanjin exercise combined with rational emotive behavior therapy on sleep and mood in patients with poststroke depression: A randomized controlled trial.

BACKGROUND: Poststroke depression (PSD) is one of the most common stroke complications. It not only leads to a decline in patients' quality of life but also increases the mortality of patients. In this study, the method of combining Chinese traditional exercise Baduanjin with psychotherapy was used to intervene in patients with PSD and to explore the improvement of sleep, mood, and serum levels of brain-derived neurotrophic factor (BDNF), 5-hydroxytryptamine (5-HT), and interleukin-6 (IL-6) levels in patients with PSD by combined treatment. METHODS: A total of 100 patients with PSD who met the inclusion criteria were randomly assigned to Baduanjin group (n = 50) or control group (n = 50). The control group received treatment with escitalopram oxalate and rational emotive behavior therapy, while the experimental group received Baduanjin training in addition to the treatment given to the control group. Changes in sleep efficiency, sleep total time, sleep latency, arousal index, Hamilton Anxiety Rating Scale, Hamilton Depression Scale score, serum BDNF, 5-HT, IL-6 levels, and Modified Barthel Index were measured at baseline, 4 weeks and 8 weeks after intervention, and the results were compared between the 2 groups. RESULTS: Significantly improvements in the sleep efficiency, sleep total time, serum 5-HT, BDNF levels, and Modified Barthel Index score were detected at week 4 in the Baduanjin group than in the control group (P < .05). Additionally, the sleep latency, arousal index, Hamilton Anxiety Rating Scale, Hamilton Depression Scale scores and IL-6 levels in the Baduanjin group were lower than those in the control group (P < .05). After 8 weeks of treatment, the above indexes in the Baduanjin group were further improved compared with the control group (P < .05), and the above indexes of the 2 groups were significantly improved compared with the baseline (P < .001). CONCLUSION: Baduanjin exercise combined with rational emotive behavior therapy effectively improves the mood and sleep status of patients with PSD; It increases the serum levels of 5-HT and BDNF while reducing the level of serum proinflammatory factor IL-6; additionally, the intervention alleviates the degree of neurological impairment, upgrades the ability of daily living, and improves the quality of life.

Biomechanical role of bone grafting for calcaneal fracture fixation in the presence of bone defect: A finite element analysis.

BACKGROUND: The purpose of this study was to compare the biomechanical stress and stability of calcaneal fixations with and without bone defect, before and after bone grafting, through a computational approach. METHODS: A finite element model of foot-ankle complex was reconstructed, impoverished with a Sanders III calcaneal fracture without bone defect and with moderate and severe bone defects. Plate fixations with and without bone grafting were introduced with walking stance simulated. The stress and fragment displacement of the calcaneus were evaluated. FINDINGS: Moderate and severe defect increased the calcaneus stress by 16.11% and 32.51%, respectively and subsequently decreased by 10.76% and 20.78% after bone grafting. The total displacement was increased by 3.99% and 24.26%, respectively by moderate and severe defect, while that of posterior joint facet displacement was 86.66% and 104.44%. The former was decreased by 25.73% and 35.96% after grafting, while that of the latter was reduced by 88.09% and 84.78% for moderate and severe defect, respectively. INTERPRETATION: Our finite element prediction supported that bone grafting for fixation could enhance the stability and reduce the risk of secondary stress fracture in cases of bone defect in calcaneal fracture.

HighFold: accurately predicting structures of cyclic peptides and complexes with head-to-tail and disulfide bridge constraints.

In recent years, cyclic peptides have emerged as a promising therapeutic modality due to their diverse biological activities. Understanding the structures of these cyclic peptides and their complexes is crucial for unlocking invaluable insights about protein target-cyclic peptide interaction, which can facilitate the development of novel-related drugs. However, conducting experimental observations is time-consuming and expensive. Computer-aided drug design methods are not practical enough in real-world applications. To tackles this challenge, we introduce HighFold, an AlphaFold-derived model in this study. By integrating specific details about the head-to-tail circle and disulfide bridge structures, the HighFold model can accurately predict the structures of cyclic peptides and their complexes. Our model demonstrates superior predictive performance compared to other existing approaches, representing a significant advancement in structure-activity research. The HighFold model is openly accessible at https://github.com/hongliangduan/HighFold.

Exploring the mechanisms underlying effects of bisphenol a on cardiovascular disease by network toxicology and molecular docking.

Background: Globally, cardiovascular disease (CVD) has emerged as a leading cause of mortality. Bisphenol A (BPA), recognized as one of the most prevalent and widely distributed endocrine-disrupting chemicals (EDCs), has been consistently linked to the progression of CVD. This research centers on unraveling the molecular mechanisms responsible for the toxic effects of BPA exposure on CVD. Key targets and pathways involved in action of BPA on CVD were investigated by network toxicology. Binding abilities of BPA to core targets were evaluated by molecular docking. Methods and results: Based on information retrieved from ChEMBL, DrugBank, and OMIM databases, a total of 27 potential targets were found to be associated with the influence of BPA on CVD. Furthermore, the STRING and Cytoscape software were employed to identify three central genes-ESR1, PPARG, and PTGS2-and to construct both the protein-protein interaction network and an interaction diagram of potential targets. Gene ontology (GO) and KEGG (Kyoto Encyclopedia of Genes and Genomes, KEGG) pathway enrichment analyses via WebGestalt revealed key biological processes (BP), cellular components (CC), molecular functions (MF), and pathways, such as the calcium signaling pathway, inflammatory mediator regulation of TRP channels, gap junction, adrenergic signaling in cardiomyocytes, cGMP-PKG signaling pathway, and cAMP signaling pathway, predominantly involved in BPA-induced CVD toxicity. By using molecular docking investigations, it proved that BPA binds to ESR1, PPARG, and PTGS2 steadily and strongly. Conclusion: This study not only establishes a theoretical framework for understanding the molecular toxicity mechanism of BPA in cardiovascular disease (CVD) but also introduces an innovative network toxicology approach to methodically investigate the influence of environmental contaminants on CVD. This methodology sets the stage for drug discovery efforts targeting CVD linked to exposure to endocrine-disrupting chemicals (EDCs).

DCTPep, the data of cancer therapy peptides.

With the discovery of the therapeutic activity of peptides, they have emerged as a promising class of anti-cancer agents due to their specific targeting, low toxicity, and potential for high selectivity. In particular, as peptide-drug conjugates enter clinical, the coupling of targeted peptides with traditional chemotherapy drugs or cytotoxic agents will become a new direction in cancer treatment. To facilitate the drug development of cancer therapy peptides, we have constructed DCTPep, a novel, open, and comprehensive database for cancer therapy peptides. In addition to traditional anticancer peptides (ACPs), the peptide library also includes peptides related to cancer therapy. These data were collected manually from published research articles, patents, and other protein or peptide databases. Data on drug library include clinically investigated and/or approved peptide drugs related to cancer therapy, which mainly come from the portal websites of drug regulatory authorities and organisations in different countries and regions. DCTPep has a total of 6214 entries, we believe that DCTPep will contribute to the design and screening of future cancer therapy peptides.

Degradation of petroleum hydrocarbon contaminants by Rhodococcus erythropolis KB1 synergistic with alfalfa (Medicago sativa L.).

Petroleum hydrocarbons are a stubborn pollutant that is difficult to degrade globally, and plant-microbial degradation is the main way to solve this type of pollutant. In this study, the physiological and ecological responses of alfalfa to petroleum hydrocarbons in different concentrations of petroleum hydrocarbon-contaminated soil with KB1 (Rhodococcus erythropolis) were analyzed and determined by laboratory potting techniques. The growth of alfalfa (CK) and alfalfa with KB1 (JZ) in different concentrations of petroleum hydrocarbons contaminated soil was compared and analyzed. The results of the CK group showed that petroleum hydrocarbons could significantly affect the activity of alfalfa antioxidant enzyme system, inhibit the development of alfalfa roots and the normal growth of plants, especially in the high-concentration group. KB1 strain had the ability to produce IAA, form biofilm, fix nitrogen, produce betaine and ACC deaminase, and the addition of KB1 could improve the growth traits of alfalfa in the soil contaminated with different concentrations of petroleum hydrocarbons, the content of soluble sugars in roots, and the stress resistance and antioxidant enzyme activities of alfalfa. In addition, the degradation kinetics of the strain showed that the degradation rate of petroleum could reach 75.2% after soaking with KB1. Furthermore, KB1 can efficiently degrade petroleum hydrocarbons in advance and significantly alleviate the damage of high concentration of petroleum hydrocarbons to plant roots. The results showed that KB1 strains and alfalfa plants could effectively enhance the degradation of petroleum hydrocarbons, which provided new ideas for improving bioremediation strategies.

Shell Modulation of Hollow Metal Sulfide Nanocomposite for Stable Potassium Storage at Room and High Temperature.

The large size of K-ion makes the pursuit of stable high-capacity anodes for K-ion batteries (KIBs) a formidable challenge, particularly for high temperature KIBs as the electrode instability becomes more aggravated with temperature climbing. Herein, we demonstrate that a hollow ZnS@C nanocomposite (h-ZnS@C) with a precise shell modulation can resist electrode disintegration to enable stable high-capacity potassium storage at room and high temperature. Based on a model electrode, we identify an interesting structure-function correlation of the h-ZnS@C: with an increase in the shell thickness, the cyclability increases while the rate and capacity decrease, shedding light on the design of high-performance h-ZnS@C anodes via engineering the shell thickness. Typically, the h-ZnS@C anode with a shell thickness of 60 nm can deliver an impressive comprehensive performance at room temperature; the h-ZnS@C with shell thickness increasing to 75 nm can achieve an extraordinary stability (88.6 % capacity retention over 450 cycles) with a high capacity (450 mAh g-1) and a superb rate even at an extreme temperature of 60 °C, which is much superior than those reported anodes. This contribution envisions new perspectives on rational design of functional metal sulfides composite toward high-performance KIBs with insights into the significant structure-function correlation.

Highly Efficient Thiolate-Based Ionic Liquid Catalysts for Reduction of CO2: Selective N-Functionalization of Amines to Form N-Formamides and N-Methylamines.

Developing efficient catalysts to convert CO2 into value-added chemicals is valuable for reducing carbon emissions. Herein, a kind of novel thiolate-based ionic liquid with sulfur as the active site was designed and synthesized, which served as highly efficient catalyst for the reductive N-functionalization of CO2 by amines and hydrosilane. By adjusting the CO2 pressure, various N-formamides and N-methylamines were selectively obtained in high yields. Remarkably, at the catalyst loading of 0.1 mol %, the N-formylation reaction of N-methylaniline exhibited an impressive turnover frequency (TOF) up to 600 h-1, which could be attributed to the roles of the ionic liquids in activating hydrosilane and amine. In addition, control experiments and NMR monitoring experiments provided evidence that the reduction of CO2 by hydrosilane yielded formoxysilane intermediates that subsequently reacted with amines to form N-formylated products. Alternatively, the formoxysilane intermediates could further react with hydrosilane and amine to produce 4-electron-reduced aminal products. These aminal products served as crucial intermediates in the N-methylation reactions.