Resistance Model Research Articles

Modeling and simulation of distribution and drug resistance of major pathogens in patients with respiratory system infections

BackgroundRespiratory tract infections (RTIs) are one of the leading causes of morbidity and mortality worldwide. The increase in antimicrobial resistance in respiratory pathogens poses a major challenge to the effective management of these infections.ObjectiveTo investigate the distribution of major pathogens of RTIs and their antimicrobial resistance patterns in a tertiary care hospital and to develop a mathematical model to explore the relationship between pathogen distribution and antimicrobial resistance.MethodsFive hundred patients with RTIs were included in the study and 475 bacterial strains were isolated from their respiratory specimens. Antimicrobial susceptibility testing and analysis of influencing factors were performed. A mathematical model was developed to simulate the relationship between pathogen distribution and drug resistance.ResultsThe most common pathogens were Streptococcus pneumoniae (30%), Haemophilus influenzae (20%), Pseudomonas aeruginosa (15%), Staphylococcus aureus (10%) and Klebsiella pneumoniae (10%). The distribution of pathogens varied according to age group and type of RTIs, with higher proportions of Pseudomonas aeruginosa and Staphylococcus aureus in hospital-acquired and ventilator-associated pneumonia. Isolated pathogens showed high and increasing rates of resistance to commonly used antibiotics. Model simulations suggest that a shift in the distribution of pathogens toward more resistant strains may lead to a significant increase in overall resistance rates, even if antibiotic use patterns remain unchanged.ConclusionThis study emphasizes the importance of regular monitoring of respiratory pathogen distribution and antimicrobial resistance patterns and the need for a comprehensive approach to managing RTIs, including implementation of antibiotic stewardship programs, infection control measures, and development of new therapies.

Polo-like Kinase 1 Inhibitors Demonstrate In Vitro and In Vivo Efficacy in Preclinical Models of Small Cell Lung Cancer

Objective: To investigate the preclinical efficacy and identify predictive biomarkers of polo-like kinase 1 (PLK1) inhibitors in small cell lung cancer (SCLC) models. Methods: We tested the cytotoxicity of selective PLK1 inhibitors (rigosertib, volasertib, and onvansertib) in a panel of SCLC cell lines. We confirmed the therapeutic efficacy of subcutaneous xenografts of representative cell lines and in four patient-derived xenograft models generated from patients with platinum-sensitive and platinum-resistant SCLC. We employed an integrated analysis of genomic and transcriptomic sequencing data to identify potential biomarkers of the activity and mechanisms of resistance in laboratory-derived resistance models. Results: Volasertib, rigosertib, and onvansertib showed strong in vitro cytotoxicity at nanomolar concentrations in human SCLC cell lines. Rigosertib, volasertib, and onvansertib showed equivalent efficacy to that of standard care agents (irinotecan and cisplatin) in vivo with significant growth inhibition superior to cisplatin in PDX models of platinum-sensitive and platinum-resistant SCLC. There was an association between YAP1 expression and disruptive or inactivation TP53 gene mutations, with greater efficacy of PLK1 inhibitors. Comparison of lab-derived onvansertib-resistant H526 cells to parental cells revealed differential gene expression with upregulation of NAP1L3, CYP7B1, AKAP7, and FOXG1 and downregulation of RPS4Y1, KDM5D, USP9Y, and EIF1AY highlighting the potential mechanisms of resistance in the clinical setting. Conclusions: We established the efficacy of PLK1 inhibitors in vitro and in vivo using PDX models of platinum-sensitive and resistant relapsed SCLC. An ongoing phase II trial is currently testing the efficacy of onvansertib in patients with SCLC (NCT05450965).

Simplified Analytic Particulate Filter Backpressure Models Revisited: Derivation of the Additive Flow Resistance Model

Simplified Analytic Particulate Filter Backpressure Models Revisited: Derivation of the Additive Flow Resistance Model

Longitudinal omics data and preclinical treatment suggest the proteasome inhibitor carfilzomib as therapy for ibrutinib-resistant CLL

Chronic lymphocytic leukemia is a malignant lymphoproliferative disorder for which primary or acquired drug resistance represents a major challenge. To investigate the underlying molecular mechanisms, we generate a mouse model of ibrutinib resistance, in which, after initial treatment response, relapse under therapy occurrs with an aggressive outgrowth of malignant cells, resembling observations in patients. A comparative analysis of exome, transcriptome and proteome of sorted leukemic murine cells during treatment and after relapse suggests alterations in the proteasome activity as a driver of ibrutinib resistance. Preclinical treatment with the irreversible proteasome inhibitor carfilzomib administered upon ibrutinib resistance prolongs survival of mice. Longitudinal proteomic analysis of ibrutinib-resistant patients identifies deregulation in protein post-translational modifications. Additionally, cells from ibrutinib-resistant patients effectively respond to several proteasome inhibitors in co-culture assays. Altogether, our results from orthogonal omics approaches identify proteasome inhibition as potentially attractive treatment for chronic lymphocytic leukemia patients resistant or refractory to ibrutinib.

An Updated Environmental Resistance Model for Predicting the Spread of Invasive Species

ABSTRACTAimPredictive models on invasive species spread can assist in identifying large‐scale invasion risk. Environmental resistance (ER) models, which predict spread based on ecological similarity to already‐invaded communities, offer one approach. However, gaps remain in understanding how different ER measurements perform across different taxa and how they can be integrated with future global change. Here, we aim to discern the primary drivers of invasion spread by comparing different ER models and then use the best models to forecast future invasion dynamics.LocationEastern US.Taxa1873 invasive plants and animals.MethodsWe developed different ER measurements, including biotic similarities among native plants in their species and phylogenetic assemblages, and functional traits, and abiotic similarities in climate, soil, and human disturbances. We obtained the best ER model for each invasive species to evaluate their potential invasion extents; and we further predicted their future range shifts under climate change.ResultsNative plant similarities provided the best proxy measure of ER for both invasive plants and animals. Invasion hotspots were identified in urban and coastal areas, and the predicted potential invasion ranges under current conditions extended from these hotspots to the neighboring areas. The invasion range for most invasives was predicted to increase under future climate change, with Arthropoda and Tracheophyta generally expanding the most among all taxa. The invasives that are predicted to expand their range in the future have already occupied larger areas than the invasives whose ranges are predicted to contract.Main ConclusionsThese results highlight the importance of maintaining diverse native communities in invasion control and raise the concern of increased invasion risk in the future. Our findings call for more efforts on invasion monitoring in areas near large cities, and increased capacity for early detection and rapid response to prevent the current invasives spreading more widely.

Vesicular mechanisms of drug resistance in apicomplexan parasites.

SUMMARYVesicular mechanisms of drug resistance are known to exist across prokaryotes and eukaryotes. Vesicles are sacs that form when a lipid bilayer 'bends' to engulf and isolate contents from the cytoplasm or extracellular environment. They have a wide range of functions, including vehicles of communication within and across cells, trafficking of protein intermediates to their rightful organellar destinations, and carriers of substrates destined for autophagy. This review will provide an in-depth understanding of vesicular mechanisms of apicomplexan parasites, Plasmodium and Toxoplasma (that respectively cause malaria and toxoplasmosis). It will integrate mechanistic and evolutionarily insights gained from these and other pathogenic eukaryotes to develop a new model for plasmodial resistance to artemisinins, a class of drugs that have been the backbone of modern campaigns to eliminate malaria worldwide. We also discuss extracellular vesicles that present major vesicular mechanisms of drug resistance in parasite protozoa (that apicomplexans are part of). Finally, we provide a broader context of clinical drug resistance mechanisms of Plasmodium, Toxoplasma, as well as Cryptosporidium and Babesia, that are prominent members of the phyla, causative agents of cryptosporidiosis and babesiosis and significant for human and animal health.

Ameliorative Effect of Combined Placenta-Derived Mesenchymal Stem Cells plus Platelet-rich Plasma on Polycystic Ovarian Model in Rats: A Biochemical and Histological Study.

Polycystic ovary syndrome (PCOS) is a common cause of infertility in women, characterized by metabolic and hormonal irregularities. We investigated the effects of placenta-derived mesenchymal stem cells (PDMSCs) and platelet-rich plasma (PRP), as well as their combination on follicular development, hormonal profile, inflammatory parameters, and insulin resistance in a model of PCOS. In this study, 25 female Wistar rats were randomly allocated into five groups: Sham (given a dose of 1 mL of a 0.5% carboxymethylcellulose (CMC) solution), PCOS (administered 1mg/kg of letrozole (LTZ) dissolved in CMC for 21 days), PDMSC (treated with a single intraovarian dose of PDMSCs), PRP (treated with a single intraovarian dose of PRP), and a combined PDMSC and PRP-treated group. After two weeks, serum and ovarian samples were collected for biochemical and histological analyses. Our results demonstrated that the simultaneous administration of PDMSCs and PRP had a synergistic effect compared to monotherapy, leading to an increase in estradiol (E2) and follicle-stimulating hormone (FSH) serum levels, a decrease in luteinizing hormone (LH) and testosterone levels, as well as inflammatory factors. Moreover, the combined therapy was associated with significantly lower levels of the homeostatic model of insulin resistance (HOMA-IR), fasting insulin (FINS), and blood glucose (FBG) compared to monotherapy. The combined treatment also caused a significant reduction in cystic follicles and an elevated number of corpus luteum, primordial, primary, secondary, and antral follicles. In conclusion, the combination of PRP and PDMSCs may have an ameliorative effect on modifying metabolic abnormalities and accelerating ovarian regeneration in PCOS.

PCSK9 Expression in Vascular Smooth Muscle Cells: Role of Insulin Resistance and High Glucose

Beyond the regulation of cholesterol metabolism, a number of extrahepatic functions of proprotein convertase subtilisin/kexin type 9 (PCSK9) have been increasingly identified. The main purpose of this study was to verify whether PCSK9 expression in vascular smooth muscle cells (VSMC) is influenced by insulin resistance and high glucose (HG). In cultured rat aortic VSMC from lean insulin-sensitive Zucker rats (LZRs) and obese insulin-resistant Zucker rats (OZRs), a classical animal model of insulin resistance, we evaluated PCSK9 expression with or without the monoclonal antibodies against PCSK9 Alirocumab and Evolocumab or the synthetic PCSK9-binding peptide PEP 2-8. Effects and molecular mechanisms underlying altered PCSK9 expression were evaluated by proliferation and migration assay, reactive oxygen species (ROS) production, and involvement of PKC, NADPH-oxidase, MAPK/ERK-1/2 pathway activation. As a result, we found that, in comparison with LZR, VSMC from OZR showed basal PCSK9 overexpression mitigated by Alirocumab, Evolocumab, PEP 2-8, and the inhibitors of PKC, NADPH-oxidase, and MAPK. The finding of PCSK9 upregulation in VSMC from OZR paralleled with increased ROS production, proliferation, and migration. HG increased PCSK9 expression in VSMC from LZR, but not in OZR, via oxidative stress and with effects reduced by PCSK9 inhibitors. These findings suggest that a dysregulation of PCSK9 in VSMC could be involved in vascular damage in metabolic disorders, such as obesity and diabetes.

Mechanical properties of (Ba0.4Sr0.4Ca0.2Fe12O19)x/(Bi1.6, Pb0.4)-2223 composite impacted in seawater

In the present work, the effect of adding Ba0.4Sr0.4Ca0.2Fe12O19 hard nanoparticles and the immersion in seawater for different durations (0, 2, 6, 12, and 24 h) on the mechanical characteristics of the Bi, Pb-2223 superconductor phase were studied. A conventional solid-state reaction method was used to produce the (Ba0.4Sr0.4Ca0.2Fe12O19)x/(Bi1.6, Pb0.4)-2223 composites (0.00 ≤ x < 0.40 wt%). X-ray diffraction (XRD) confirmed the primary phase formation of the tetragonal (Bi1.6, Pb0.4)-2223. Scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDX) studies were also carried out to demonstrate the microstructural analyses of the samples during seawater immersion. Compared to the pure (Bi1.6, Pb0.4)-2223 phase, SEM and EDX verified the improvement of the adsorption of seawater elements upon adding the nanoparticles. This resulted in faster grain size reduction in the (Bi1.6, Pb0.4)-2223 phase than in the pure sample before immersion. Vickers microhardness () Measurements were performed for 30 s at room temperature, with applied stresses ranging from 0.49 to 9.80 N after immersion in the seawater for different durations (0, 2, 6, 12, and 24 h). For the sample with x = 0.04 wt%, values enhanced with percentages of 67.72% and 98.44%, before and after immersion in seawater for 24 h, respectively. This suggests that the mechanical properties of the (Bi1.6, Pb0.4)-2223 phase were enhanced by a small addition of these nanoparticles and the salts of seawater adsorbed on the sample’s surface. The modified proportional sample resistance (MPSR) model offered the most accurate theoretical analysis in the plateau limit region, before and after seawater immersions, with a less than 5% variance. Furthermore, the incorporation of Ba0.4Sr0.4Ca0.2Fe12O19 into the superconductor had a positive impact on several mechanical characteristics, including fracture toughness (K), yield strength (Y), and elastic modulus (E). All these mechanical parameter values followed the same trend, increasing with the increase in immersion time. However, they are at their height with the presence of 0.04 wt% of these nanoparticles. The toughness increased by 27.31% of the pure sample at this point. After that, when the immersion time rose from 0 to 24 h, this number increased by 42.59%.

Anchoring of Radially Expandable Microcapsule Robots in Blood Vessels Based on the Anchoring Method in Fan-Shaped Peristaltic Tubes

Radially expandable capsule robots are essential in alleviating thrombosis due to their unique anchoring and expansion capabilities within blood vessels. Despite their potential, research in this area remains limited, highlighting the need for further exploration. This study draws inspiration from the stable anchoring mechanisms observed in fan-shaped peristaltic tubes to establish a robust anchoring resistance model specifically for capsule robots in vascular environments. The research investigates the biomechanical characteristics of blood vessels under expansion conditions, deriving the longitudinal profile equation to better understand these interactions. Based on the established model, various optimization methods are proposed to enhance the anchoring performance of the capsule robots. To validate the model's accuracy, anchoring resistance is tested using a phantom vessel on an experimental platform. By integrating kinematic and mechanical analyses, an inchworm-type expansion force model is developed to evaluate anchoring performance quantitatively, allowing for an in-depth analysis of how design parameters influence anchoring resistance. This provides vital theoretical support for the design and optimization of capsule robots aimed at improving clinical outcomes in thrombotic conditions

Integrated computational assessment of concrete properties, durability, and environmental impacts

Due to the vast landscape of low carbon concretes that have been or can be developed, traditional empirical methods are impractical for comprehensive assessment of concrete performance. Here, we describe Panoramix 1.0, a Python-based tool that can predict physical and chemical properties of hydrated cements, and durability and environmental impacts of concretes. Applying it to CEM I concrete as a case study, we investigate the cement composition effects on the freeze–thaw resistance indicator (time to critical saturation degree, tCR). Results indicate that chemical composition of raw materials including Fe2O3 may influence freeze–thaw resistance, which is usually not considered in the current scheme of durability assessment. The results also show how the design space (i.e., feasible cement compositions) could be found for different types of concrete at specified minimum freeze–thaw resistance. We validate Panoramix by comparing its ranking of 28 concrete samples in terms of freeze–thaw performance (tCR) with experimental data for relative dynamic modulus of elasticity (RDME) reported in ten publications and measured using procedures from four different standards. By combining the composition-freeze–thaw resistance modelling with a life cycle assessment model, we show that the climate change impact (100-year global warming potential) per m3 CEM I concrete can be reduced from 313 to 286 kg CO2-eq. by decreasing the clinker-to-cement ratio while reducing tCR from 7 to 5.5 years.

Gulf Women and Anti-European Imperialism: Forgotten Gender Discourses in Interwar Iran’s Shi’i Reformation Movement

Often treated as simply anti-modernism, a focus on three reformist figures with transnational intellectual ties—Shariat Sangelaji, Asadollah Kharaqani, and Muhammad Khalesizadeh—reveals how Iranian natives of the Gulf littoral contributed to reconstitute modern life by criticizing the global structures of power arising with European imperialism. Blurring the dichotomy of modern/traditional, Iran and the West, these intellectuals with trans-regional scholarly connections combined different aspects of modernity with a reading of Islamic practice to offer a global model of resistance for Muslims. A version of this Shi’i empowerment in the face of growing changes in the larger world and at home mobilized discussions about women in Iran as the source of the necessary social cohesion during the anti-imperialist struggle. A challenge to normative portrayals of Islam (and religion more generally) as an impediment to progress, studying these three Gulf scholars’ alternative modernity allows for identifying a campaign to free women from the consequences of their economic exploitation.

Prediction model for hot rolling force in electrical steel involving phase transformation using SSA-LSTM network and mathematical model

To enhance the rolling force prediction accuracy of non-oriented electrical steel involving phase transformation, a high-precision RFPM (rolling force prediction model) that combines the RFOM (rolling force optimisation model) with the SSA-LSTM (sparrow search algorithm and long short-term memory) network was established. The RFOM was developed by optimising the important influencing parameters, including the deformation resistance model in the phase separation region and stress state coefficient model, of rolling force. The SSA-LSTM network was proposed, which utilises the SSA to optimise the hyperparameters of the double-layer LSTM network, it enables learning the complex spatial data correlation of the rolling force and improves its prediction accuracy. The superiority of the proposed high-precision RFPM was verified, which adopts multiple evaluation indicators, by comparing the RFOM, the BP, the LSTM, and the SSA-LSTM models. The results manifest that the high-precision RFPM has better prediction performance, which has reached 94.40%, and it has better rolling force calculation accuracy, which the error ratio of δ≤5%, δ≤8%, and δ≤10% is 80.35%, 93.21%, and 97.14%, respectively. In addition, the proposed high-precision RFPM prediction time can meet the requirements of online real-time rolling force prediction. The rolling force accuracy of wide strips, especially non-oriented electrical steel involving phase transformation, can be significantly improved by optimising the factors affecting the rolling force of phase transformation electrical steel. The industrial data test shows that the high-precision RFPM based on the theoretical model and data-driven model can meet the requirements of on-site accuracy and online real-time control during the actual production in the large 1450 mm 4-high hot strip mills.

High Ano1 expression as key driver of resistance to radiation and cisplatin in HPV-negative head and neck squamous cell carcinoma

Human papilloma virus-negative head and neck squamous cell carcinoma (HNSCC) frequently harbors 11q13 amplifications. Among the oncogenes at this locus, CCND1 and ANO1 are linked to poor prognosis; however, their individual roles in treatment resistance remain unclear. The impact of Cyclin D1 and Ano1 overexpression on survival was analyzed using the TCGA HNSCC dataset and a Charité cohort treated with cisplatin (CDDP)-based radiochemotherapy. High Ano1 expression was primarily associated with poor overall survival in both datasets. The effects of CCND1 and ANO1 knockdown (KD) on radio- and drug sensitivity, along with changes in global protein expression, cell viability, growth, and DNA repair, were studied in an 11q13-amplified HNSCC cell line model of primary cisplatin resistance. Unique pathway alterations– VEGF in CCND1 KD and the Rho GTPase cycle in ANO1 KD– were observed, along with shared changes like DNA damage and cell cycle dysregulation. Silencing CCND1 or ANO1 increased CDDP sensitivity, while only ANO1 silencing increased radiosensitivity. Copanlisib and afatinib were identified as promising candidates for combination therapy of 11q13-amplified HNSCC tumors. We demonstrated a predominant role for Ano1 in treatment resistance in Cyclin D1highAno1high HNSCC tumors and identified novel potential treatment combinations for this high-risk patient group.

Expression of ABCB1, ABCC1, and LRP in Mesenchymal Stem Cells from Human Amniotic Fluid and Bone Marrow in Culture-Effects of In Vitro Osteogenic and Adipogenic Differentiation.

Mesenchymal stem cells (MSCs) are multipotent cells with the potential to differentiate into various lineages. They have also the potential to protect themselves against harmful stimuli to maintain their functional integrity. Drug resistance-related transporters such as ABCB1 (P-glycoprotein; P-gp), ABCC1 (MRP1; multidrug resistance-related Protein 1), and LRP (lung resistance protein) may protect MSCs against toxic substances such as chemotherapeutic agents. This study evaluated ABCB1, ABCC1, and LRP before and after the differentiation of MSCs derived from human amniotic fluid (AF) and bone marrow (BM). P-gp expression in both AFMSCs and BMMSCs was analyzed by immunocytochemistry, and pump function was analyzed by cell viability assay with doxorubicin (DOX) and Rhodamine 123 (Rh 123) dye exclusion. ABCB1, ABCC1, and LRP gene expression was determined by RT-PCR both before and after osteogenic and adipogenic differentiation. The MES-SA/DX5 cell line was used as a model of resistance to DOX and the overexpression of P-gp. Both AFMSCs and BMMSCs displayed a high P-gp expression, although lower than MES-SA/DX5 control cells. It was shown that both, undifferentiated AFMSCs and BMMSCs, have high cell viability in response to DOX, similar to the MES-SA/DX5 lineage. ABCB1 was less expressed in BM than in AFMSCs in undifferentiated samples, while no differences were observed in the expression of ABCC1 and LRP. AFMSCs showed an increase in ABCB1 after osteogenic differentiation, whereas BMMSCs exhibited lower ABCB1 and ABCC1 expression after osteogenic and adipogenic differentiation. The findings suggest that ABCB1, ABCC1, and LRP gene expression in AFMSCs and BMMSCs is influenced by differentiation processes and further support the concept that these transporters modulate MSC differentiation in a cell source-dependent way.

A Microphysiological Model of Progressive Human Hepatic Insulin Resistance.

Hepatic insulin resistance is a fundamental phenomenon observed in both Type 2 diabetes (T2D) and metabolic (dysfunction) associated fatty liver disease (MAFLD). The relative contributions of nutrients, hyperinsulinemia, hormones, inflammation, and other cues are difficult to parse in vivo as they are convoluted by interplay between the local and systemic events. Here, we used a well-established human liver microphysiological system (MPS) to establish a physiologically-relevant insulin-responsive metabolic baseline and probe how primary human hepatocytes respond to controlled perturbations in insulin, glucose, and free fatty acids (FFAs). Replicate liver MPS were maintained in media with either 200 pM (normal) or 800 pM (T2D) insulin for up to 3 weeks. Conditions of standard glucose (5.5 mM), hyperglycemia (11 mM glucose), normal (20µM) and elevated FFA (100 µM), alone and in combination were used at each insulin concentration, either continuously or reversing back to standard media after 2 weeks of simulated T2D conditions. Hepatic glucose production, activation of signaling pathways, insulin clearance, transcriptome analysis, and intracellular lipid and bile acid accumulation were assessed. Hyperinsulinemia alone induces insulin resistance after one week of exposure, while hyperglycemia and increased FFAs significantly exacerbate this phenotype. Hyperinsulinemia, along with elevated glucose and FFAs, transcriptionally predisposes hepatocytes to insulin resistance through altered metabolic and immune signaling pathways. The phenotypes observed in hyperinsulinemia and nutrient overload are partially reversible upon return to normophysiologic conditions. Our enhanced in vitro model, replicating multiple aspects of the insulin-resistant condition, offers improved insights into disease mechanisms with relevance to human physiology. The many nutritional, hormonal, and systemic inflammatory factors that contribute to the loss of sensitivity to insulin in Type 2 Diabetes and other metabolic disorders are difficult to parse in human patients, and animal models fail to capture all the human dimensions of the relevant biology. We, therefore, developed a microphysiological systems model, involving a microfluidic platform that cultures a simulated human liver for weeks at a time, under controlled nutrient and hormone concentrations, to analyze how the effects of nutrition (glucose and free fatty acids) together with increased insulin cause pathological features seen in human liver in vivo . We found that continually high levels of insulin predispose the liver to some of these features, along with reversal when the nutritional and insulin levels were restored to healthy values.

Risk Assessment of Non-Point Source Pollution Based on the Minimum Cumulative Resistance Model: A Case Study of Shenyang, China

Urban non-point source (NPS) pollution is an important risk factor that leads to the deterioration of urban water quality, affects human health, and destroys the ecological balance of the water environment. Reasonable risk prevention and control of urban NPS pollution are conducive to reducing the cost of pollution management. Therefore, based on the theory of “source–sink” in landscape ecology, combined with the minimum cumulative resistance (MCR) model, this study considered the influence of geographic-environment factors in Shenyang’s built-up area on pollutants in the process of entering the water body under the action of surface runoff, and evaluated its risk. The results indicated that the highest pollution loads are generated by road surfaces. High-density residential zones and industrial zones are the main sources of urban NPS pollution. Impervious surface ratios and patch density were the dominant environmental factors affecting pollutant transport, with contributions of 56% and 40%, respectively. The minimum cumulative resistance to urban NPS pollution transport is significantly and positively correlated with the distance from water bodies and roads. Higher risk areas are mainly concentrated in the center of built-up areas and roads near the Hun River. Green spaces, business zones, public service zones, development zones, and educational zones demonstrate the highest average risk index values, exceeding 29. In contrast, preservation zones showed the lowest risk index (7.3). Compared with the traditional risk index method, the method proposed in this study could accurately estimate the risk of urban NPS pollution and provide a new reference for risk assessments of urban NPS pollution.

S6K1 is a Targetable Vulnerability in Tumors Exhibiting Plasticity and Therapy Resistance.

Background: Most tumors initially respond to treatment, yet refractory clones subsequently develop owing to resistance mechanisms associated with cancer cell plasticity and heterogeneity. Methods: We used a chemical biology approach to identify protein targets in cancer cells exhibiting diverse driver mutations and representing models of tumor lineage plasticity and therapy resistance. An unbiased screen of a drug library was performed against cancer cells followed by synthesis of chemical analogs of the most effective drug. The cancer subtype target range of the leading drug was determined by PRISM analysis of over 900 cancer cell lines at the Broad Institute, MA. RNA-sequencing and enrichment analysis of differentially expressed genes, as well as computational molecular modeling and pull-down with biotinylated small molecules were used to identify and validate RPS6KB1 (p70S6K or S6K1) as an essential target. Genetic restoration was used to test the functional role of S6K1 in cell culture and xenograft models. Results: We identified a novel derivative of the antihistamine drug ebastine, designated Super-ebastine (Super-EBS), that inhibited the viability of cancer cells representing diverse KRAS and EGFR driver mutations and models of plasticity and treatment resistance. Interestingly, PRISM analysis indicated that over 95% of the diverse cancer cell lines tested were sensitive to Super-EBS and the predicted target was the serine/threonine kinase S6K1. S6K1 is upregulated in various cancers relative to counterpart normal/benign tissues and phosphorylated-S6K1 predicts poor prognosis for cancer patients. We noted that inhibition of S6K1 phosphorylation was necessary for tumor cell growth inhibition, and restoration of phospho-S6K1 rendered tumor cells resistant to Super-EBS. Inhibition of S6K1 phosphorylation by Super-EBS induced caspase-2 dependent apoptosis via inhibition of the Cdc42/Rac-1/p-PAK1 pathway that led to actin depolymerization and caspase-2 activation. The essential role of S6K1 in the action of Super-EBS was recapitulated in xenografts, and knockout of S6K1 abrogated tumor growth in mice. Conclusion: S6K1 is a therapeutic vulnerability in tumors exhibiting intrinsic and/or acquired resistance to treatment.

Transfer-Matrix Modeling of the Access Region Resistance in Graphene based Dirac-Source FETs

Transfer-Matrix Modeling of the Access Region Resistance in Graphene based Dirac-Source FETs

Frost resistance and life prediction model of ultrafine GGBS equal strength concrete under negative temperature curing

Frost resistance and life prediction model of ultrafine GGBS equal strength concrete under negative temperature curing