Advancing single-cell RNA-seq data analysis through the fusion of multi-layer perceptron and graph neural network.

The advancement of single-cell sequencing technology has smoothed the ability to do biological studies at the cellular level. Nevertheless, single-cell RNA sequencing (scRNA-seq) data presents several obstacles due to the considerable heterogeneity, sparsity and complexity. Although many machine-learning models have been devised to tackle these difficulties, there is still a need to enhance their efficiency and accuracy. Current deep learning methods often fail to fully exploit the intrinsic interconnections within cells, resulting in unsatisfactory results. Given these obstacles, we propose a unique approach for analyzing scRNA-seq data called scMPN. This methodology integrates multi-layer perceptron and graph neural network, including attention network, to execute gene imputation and cell clustering tasks. In order to evaluate the gene imputation performance of scMPN, several metrics like cosine similarity, median L1 distance and root mean square error are used. These metrics are utilized to compare the efficacy of scMPN with other existing approaches. This research utilizes criteria such as adjusted mutual information, normalized mutual information and integrity score to assess the efficacy of cell clustering across different approaches. The superiority of scMPN over current single-cell data processing techniques in cell clustering and gene imputation investigations is shown by the experimental findings obtained from four datasets with gold-standard cell labels. This observation demonstrates the efficacy of our suggested methodology in using deep learning methodologies to enhance the interpretation of scRNA-seq data.

Simultaneous Protonation and Metalation of a Porphyrin Covalent Organic Framework Enhance Photodynamic Therapy.

Covalent organic frameworks (COFs) have been explored for photodynamic therapy (PDT) of cancer, but their antitumor efficacy is limited by excited state quenching and low reactive oxygen species generation efficiency. Herein, we report a simultaneous protonation and metalation strategy to significantly enhance the PDT efficacy of a nanoscale two-dimensional imine-linked porphyrin-COF. The neutral and unmetalated porphyrin-COF (Ptp) and the protonated and metalated porphyrin-COF (Ptp-Fe) were synthesized via imine condensation between 5,10,15,20-tetrakis(4-aminophenyl)porphyrin and terephthalaldehyde in the absence and presence of ferric chloride, respectively. The presence of ferric chloride generated both doubly protonated and Fe3+-coordinated porphyrin units, which red-shifted and increased the Q-band absorption and disrupted exciton migration to prevent excited state quenching, respectively. Under light irradiation, rapid energy transfer from protonated porphyrins to Fe3+-coordinated porphyrins in Ptp-Fe enabled 1O2 and hydroxyl radical generation via type II and type I PDT processes. Ptp-Fe also catalyzed the conversion of hydrogen peroxide to hydroxy radical through a photoenhanced Fenton-like reaction under slightly acidic conditions and light illumination. As a result, Ptp-Fe-mediated PDT exhibited much higher cytotoxicity than Ptp-mediated PDT on CT26 and 4T1 cancer cells. Ptp-Fe-mediated PDT afforded potent antitumor efficacy in subcutaneous CT26 murine colon cancer and orthotopic 4T1 murine triple-negative breast tumors and prevented metastasis of 4T1 breast cancer to the lungs. This work underscores the role of fine-tuning the molecular structures of COFs in significantly enhancing their PDT efficacy.

EQ-5D-5L Population Norms for China Derived From a National Health Survey.

OBJECTIVES: To develop the EQ-5D-5L (5L) population norms for China and to assess the relationship between various factors and 5L data. METHODS: This study used data derived from the Psychology and Behavior Investigation of Chinese Residents, a national sample survey of 21 909 representative participants aged 12 years and above. Participants' health-related quality of life (HRQoL) was measured by the 5L. Their socioeconomic characteristics, behavioral factors, and health conditions were also obtained from the survey. Norm scores were generated and compared for different socioeconomic variables. Multiple linear and logistic regressions were used to assess the relationships of the 3 kinds of variables with the 5L utility, visual analog scale (VAS) scores and 5L health problems. RESULTS: The mean (SD) age of participants was 39.4 (18.9) years, and 50.0% of them were female. The mean (SD) utility and VAS scores were 0.940 (0.138) and 73.4 (21.6), respectively. Participants reported considerably more problems in anxiety/depression (26.2%) and pain/discomfort (22.2%) dimensions. The gender difference in HRQoL is attenuated. The participants older than 75 years suffered from a sharp decline in HRQoL; the participants in Shanghai and Tibet provinces reported lower utility and VAS scores and more health problems. Those who were younger, with better socioeconomic status and healthier lifestyles, and without diseases tended to report higher utility and VAS scores and fewer health problems. CONCLUSIONS: This study derived the 5L population norms for China based on a representative population sample.

A review of local anesthetic-induced heart toxicity using human induced pluripotent stem cell-derived cardiomyocytes.

Local anesthetic (LA) cardiotoxicity is one of the main health problems in anesthesiology and pain management. This study reviewed the reported LA-induced cardiac toxicity types, risk factors, management, and mechanisms, with attention to the use of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in heart toxicity research. Important scientific databases were searched to find relevant articles. We briefly assessed the reported cardiotoxic effects of different types of LA drugs, including ester- and amide-linked LA agents. Furthermore, cardiotoxic effects and clinical manifestations, strategies for preventing and managing LA-induced cardiotoxic effects, pharmacokinetics, pharmacodynamics, and sodium channel dynamics regarding individual variability and genetic influences were discussed in this review. The applications and importance of hiPSC-CMs cellular model for evaluating the cardiotoxic effects of LA drugs were discussed in detail. This review also explored hiPSC-CMs' potential in risk assessment, drug screening, and developing targeted therapies. The main mechanisms underlying LA-induced cardiotoxicity included perturbation in sodium channels, ROS production, and disorders in the immune system response due to the presence of LA drugs. Furthermore, drug-specific characteristics including pharmacokinetics and pharmacodynamics are important determinants after LA drug injection. In addition, individual patient factors such as age, comorbidities, and genetic variability emphasize the need for a personalized approach to mitigate risks and enhance patient safety. The strategies outlined for the prevention and management of LA cardiotoxicity underscore the importance of careful dosing, continuous monitoring, and the immediate availability of resuscitation equipment. This comprehensive review can be used to guide future investigations into better understanding LA cardiac toxicities and improving patient safety.

Two point mutations N771S and K847N in the VHA-a of Phytophthora litchii confer resistance to fluopimomide.

The phytopathogenic oomycete Phytophthora litchii is the culprit behind the devastating disease known as "litchi downy blight", which causes large losses in litchi production. Although fluopimomide exhibits strong inhibitory efficacy against P. litchii, the exact mechanism of resistance is still unknown. The sensitivity of 137 P. litchii isolates to fluopimomide was assessed, and it was discovered that the median effective concentration (EC50) of the fungicide had a unimodal frequency distribution with a mean value of 0.763 ± 0.922 µg/mL. Comparing the resistant mutants to the equivalent parental isolates, the resistance mutants' survival fitness was much lower. While there was no cross-resistance between fluopimomide and other oomycete inhibitors, there is a notable positive cross-resistance between fluopimomide and fluopicolide. According to the thorough investigation, P. litchii had a moderate chance of developing fluopimomide resistance. The point mutations N771S and K847N in the VHA-a of P. litchii (PlVHA-a) were present in the fluopimomide-resistant mutants, and the two point mutations in PlVHA-a conferring fluopimomide resistance were verified by site-directed mutagenesis in the sensitive P. capsici isolate BYA5 and molecular docking.

A Stable Site-Isolated Mono(phosphine)-Rhodium Catalyst on a Metal-Organic Layer for Highly Efficient Hydrogenation Reactions.

Phosphine-ligated transition metal complexes play a pivotal role in modern catalysis, but our understanding of the impact of ligand counts on the catalysis performance of the metal center is limited. Here we report the synthesis of a low-coordinate mono(phosphine)-Rh catalyst on a metal-organic layer (MOL), P-MOL●Rh, and its applications in the hydrogenation of mono-, di-, and tri-substituted alkenes as well as aryl nitriles with turnover numbers (TONs) of up to 390000. Mechanistic investigations and density functional theory calculations revealed the lowering of reaction energy barriers by the low steric hindrance of site-isolated mono(phosphine)-Rh sites on the MOL to provide superior catalytic activity over homogeneous Rh catalysts. The MOL also prevents catalyst deactivation to enable recycle and reuse of P-MOL●Rh in catalytic hydrogenation reactions.

[Printing Process Quality Control of Bioprinting Medical Devices].

Objective: This study analyzes the risk points in the quality control of bioink and the main processes of bioprinting, clarifies and explores the quality control and supervision model for bioprinting medical devices, and provides theoretical and practical guidance to ensure the safety and effectiveness of bioprinting medical devices. Methods: The quality control risk points throughout the bioprinting process were comprehensively analyzed, with a particular focus on bioprinting materials and key processes. The regulatory model and methods for bioprinting medical devices were examined. This research concentrated on critical technologies such as extrusion, laser-assisted, and in situ bioprinting, assessing their potential for clinical applications and regulatory challenges. Results: Bioink from different sources should meet regulatory requirements. It is essential to ensure aseptic handling of raw materials and to validate sterilization under "worst-case" conditions. Conclusion: As bioprinting technology advances rapidly, corresponding research into materials, processes, and quality risk control should be conducted to ensure the concurrent development of the regulatory system. This will continuously contribute to the orderly progression of the entire industry and human health.

Self-adaptive Metal-Organic Framework Assembles Di-iron Active Sites to Mimic Monooxygenases.

Despite significant efforts, it remains a challenge to design artificial enzymes that can mimic both structures and functions of natural enzymes. Here, we report the post-synthetic construction of binuclear iron catalysts in MOF-253 to mimic natural di-iron monooxygenases. The adjacent bipyridyl (bpy) linkers in MOF-253 can freely rotate to form the [(bpy)FeIII(µ2-OH)]2 active site in a self-adaptive fashion. The composition and structure of the [(bpy)FeIII(µ2-OH)]2 active sites in MOF-253 were characterized by a combination of inductively coupled plasma-mass spectrometry, thermogravimetric analysis, X-ray absorption spectrometry, and Fourier-transform infrared spectroscopy. The MOF-based artificial monooxygenase effectively catalyzed oxidative transformations of organic compounds, including C-H oxidation and alkene epoxidation reactions, using O2 as the only oxidant, which indicates the successful recapitulation of the structure and functions of natural monooxygenases using readily accessible MOFs. The di-iron system exhibited at least 27 times higher catalytic activity than the corresponding mononuclear control. DFT calculations showed that the binuclear system had a 14.2 kcal/mol lower energy barrier than the mononuclear system in the rate-determining C-H activation process, suggesting the importance of cooperativity of the iron centers in the [(bpy)FeIII(µ2-OH)]2 active site in the rate-determining step. The stability and recyclability of the MOF-based artificial monooxygenase were also demonstrated.

Mechanoregulatory Cholesterol Oxidase-Functionalized Nanoscale Metal-Organic Framework Stimulates Pyroptosis and Reinvigorates T Cells.

Cancer cells alter mechanical tension in their cell membranes. New interventions to regulate cell membrane tension present a potential strategy for cancer therapy. Herein, the increase of cell membrane tension by cholesterol oxidase (COD) via cholesterol depletion in vitro and the design of a COD-functionalized nanoscale metal-organic framework, Hf-TBP/COD, for cholesterol depletion and mechanoregulation of tumors in vivo, are reported. COD is found to deplete cholesterol and disrupt the mechanical properties of lipid bilayers, leading to decreased cell proliferation, migration, and tolerance to oxidative stress. Hf-TBP/COD increases mechanical tension of plasma membranes and osmotic fragility of cancer cells, which induces influx of calcium ions, inhibits cell migration, increases rupturing propensity for effective caspase-1 mediated pyroptosis, and decreases tolerance to oxidative stress. In the tumor microenvironment, Hf-TBP/COD downregulates multiple immunosuppressive checkpoints to reinvigorate T cells and enhance T cell infiltration. Compared to Hf-TBP, Hf-TBP/COD improves anti-tumor immune response and tumor growth inhibition from 54.3% and 79.8% to 91.7% and 95% in a subcutaneous triple-negative breast cancer model and a colon cancer model, respectively.

Icotinib, an EGFR tyrosine kinase inhibitor, as adjuvant therapy for patients with stage IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma: a multicenter, open-label, single-arm, phase II study (ICAPE).

The survival benefit of icotinib (an oral epidermal growth factor receptor [EGFR] tyrosine kinase inhibitor) in patients with advanced lung cancer has been confirmed in several studies. This study (ICAPE) evaluated the efficacy of icotinib as adjuvant therapy for patients with stage IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma. Patients with stage IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma were enrolled in the multicenter, open-label, single-arm, phase II study. Eligible patients received oral icotinib 125 mg thrice daily for 1.5 years after complete surgical resection. The primary endpoint was disease-free survival (DFS). Between March 2014 and January 2018, 79 patients were enrolled. The median follow-up time was 39.7 months with a median DFS and overall survival (OS) of 41.4 months (95% CI: 33.6-51.8) and 67.0 months (95% CI: 21.2-not reached [NR]), respectively. The 1-year, 3-year, and 5-year OS rates were 100%, 83.3%, and 61.7%, respectively. No significant difference was found in the median DFS between patients with Bcl-2 interacting mediator of cell death (BIM) mutant-type and wild-type (NR vs. 41.7 months; p = 0.75). No significant difference was found in the median DFS according to EGFR mutation types. Icotinib as adjuvant therapy demonstrated a favorable survival benefit in patients with stage IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma, indicating that icotinib might be a promising treatment option for this patient population. The optimal adjuvant duration of icotinib is still not clear and needs more incoming data to answer.

Melatonin inhibits atherosclerosis progression via galectin-3 downregulation to enhance autophagy and inhibit inflammation.

Autophagy deficiency in macrophages exacerbates inflammation in atherosclerosis (AS), and recently, galectin-3 (Gal-3) has been implicated as a critical promoter of inflammation in AS. Further, melatonin (Mel) exerts an autophagy-promoting effect in many chronic inflammatory diseases. In this study, we aimed to investigate whether Mel inhibits AS progression by downregulating Gal-3 to enhance autophagy and inhibit inflammation. Thus, we performed in vivo and in vitro experiments using high-fat diet (HFD)-fed ApoE-/-  mice and THP-1 macrophages, respectively. Smart-seq of AS plaque macrophages revealed that the differentially expressed genes (DEGs) downregulated by Mel were enriched in immune-related processes, and changes in inflammation status were confirmed based on lower levels of proinflammatory factors in Mel-treated HFD-fed ApoE-/-  mice and THP-1 macrophages. Further, via transcriptome-based multiscale network pharmacology platform (TMNP), the upstream target genes of the smart-seq DEGs were identified, and Gal-3 showed a high score. Gal-3 was downregulated both in vivo and in vitro by Mel treatment. Besides, the enrichment of the target genes predicted via the TMNP method indicated that autophagy considerably affected the DEGs. Mel treatment as well as Gal-3 knockdown downregulated most inflammatory response-related proteins could attribute to enhancing autophagy. Mechanistically, Mel treatment inhibited Gal-3 leading to lowering the activity of the nuclear transcription factor-kappa B (NF-κB) pathway, and promoting the nuclear localization of transcription factor EB (TFEB). However, increased secretion of Gal-3 activated the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway and impaired autophagy via binding to CD98. Thus, Mel promoted autophagy and restrained inflammation by downregulating Gal-3, implying that it holds promise as a treatment for AS.

Resistance mechanisms and remediation potential of hexavalent chromium in Pseudomonas sp. strain AN-B15.

The understanding of bacterial resistance to hexavalent chromium [Cr(VI)] are crucial for the enhancement of Cr(VI)-polluted soil bioremediation. However, the mechanisms related to plant-associated bacteria remain largely unclear. In this study, we investigate the resistance mechanisms and remediation potential of Cr(VI) in a plant-associated strain, AN-B15. The results manifested that AN-B15 efficiently reduced Cr(VI) to soluble organo-Cr(III). Specifically, 84.3 % and 56.5 % of Cr(VI) was removed after 48 h in strain-inoculated solutions supplemented with 10 and 20 mg/L Cr(VI) concentrations, respectively. Transcriptome analyses revealed that multiple metabolic systems are responsible for Cr(VI) resistance at the transcriptional level. In response to Cr(VI) exposure, strain AN-B15 up-regulated the genes involved in central metabolism, providing the reducing power by which enzymes (ChrR and azoR) transformed Cr(VI) to Cr(III) in the cytoplasm. Genes involved in the alleviation of oxidative stress and DNA repair were significantly up-regulated to neutralize Cr(VI)-induced toxicity. Additionally, genes involved in organosulfur metabolism and certain ion transporters were up-regulated to counteract the starvation of sulfur, molybdate, iron, and manganese induced by Cr(VI) stress. Furthermore, a hydroponic culture experiment showed that toxicity and uptake of Cr(VI) by plants under Cr(VI) stress were reduced by strain AN-B15. Specifically, strain AN-B15 inoculation increased the fresh weights of the wheat root and shoot by 55.5 % and 18.8 %, respectively, under Cr(VI) stress (5 mg/L). The elucidation of bacterial resistance to Cr(VI) has an important implication for exploiting microorganism for the effective remediation of Cr(VI)-polluted soils.

A Multi-Layer Intrusion Detection System for SOME/IP-Based In-Vehicle Network.

The automotive Ethernet is gradually replacing the traditional controller area network (CAN) as the backbone network of the vehicle. As an essential protocol to solve service-based communication, Scalable service-Oriented MiddlewarE over IP (SOME/IP) is expected to be applied to an in-vehicle network (IVN). The increasing number of external attack interfaces and the protocol's vulnerability makes SOME/IP in-vehicle networks vulnerable to intrusion. This paper proposes a multi-layer intrusion detection system (IDS) architecture, including rule-based and artificial intelligence (AI)-based modules. The rule-based module is used to detect the SOME/IP header, SOME/IP-SD message, message interval, and communication process. The AI-based module acts on the payload. We propose a SOME/IP dataset establishment method to evaluate the performance of the proposed multi-layer IDS. Experiments are carried out on a Jetson Xavier NX, showing that the accuracy of AI-based detection reached 99.7761% and that of rule-based detection was 100%. The average detection time per packet is 0.3958 ms with graphics processing unit (GPU) acceleration and 0.6669 ms with only a central processing unit (CPU). After vehicle-level real-time analyses, the proposed IDS can be deployed for distributed or select critical advanced driving assistance system (ADAS) traffic for detection in a centralized layout.

Characterization of a Human Gastrointestinal Stromal Tumor Cell Line Established by SV40LT-Mediated Immortalization.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the digestive tract and originate from the interstitial cells of Cajal (ICC), which is the pacemaker for peristaltic movement in the gastrointestinal tract. Existing GIST cell lines are widely used as cell models for in vitro experimental studies because the mutation sites are known. However, the immortalization methods of these cell lines are unknown, and no Chinese patient-derived GIST cell lines have been documented. Here, we transfected simian virus 40 large T antigen (SV40LT) into primary GIST cells to establish an immortalized human GIST cell line (ImGIST) for the first time. The ImGIST cells had neuronal cell-like irregular radioactive growth and retained the fusion growth characteristics of GIST cells. They stably expressed signature proteins, maintained the biological and genomic characteristics of normal primary GIST cells, and responded well to imatinib, suggesting that ImGIST could be a potential in vitro model for research in GIST to explore the molecular pathogenesis, drug resistance mechanisms, and the development of new adjuvant therapeutic options.

Soil heavy metal source apportionment and environmental differentiation study in Dulan County, Qinghai Province, using geodetector analysis.

Elucidating material sources and investigating the impact of various environmental factors on material source accumulation are important for the environmental restoration of the Qinghai-Tibet Plateau. This study was conducted within the Borhan Buda Mountain Range of Dulan County, Qinghai Province, China, where 6274 surface soil samples were collected. The geoaccumulation index was employed to assess the levels of heavy metals, including As, Cr, Cu, Hg, Ni, Pb, Sb, Sn, and Zn, in the soil. A comprehensive approach combining principal component analysis (PCA) and geodetector analysis was employed to assess the spatial variation in soil heavy metal origins and the factors that influence them. The findings indicate that the mean concentrations of Pb exceed the background values for the soil in Qinghai Province, with Hg exhibiting low pollution, whereas the other elements showed no contamination. PCA indicated that the soil elements in the Borhan Buda Mountain Range were influenced by four sources, all attributed to the geological background. Geodetector analysis of the factor contributions suggested that geological factors had the strongest explanatory power for the four material sources. Furthermore, the risk detection results demonstrated significant variations in the material source contributions among most subregions when considering three environmental factors in pairs. Interaction detection revealed that the combined influence of two environmental factors on material source contributions was greater than that of the individual factors. Additionally, ecological detection demonstrated significant differences in material source contributions one, two, and three between land cover types and geological backgrounds, whereas no significant differences were observed in material source four between land cover types and geological backgrounds. This study offers valuable insights into the sources of soil elements in Dulan County and the influence of environmental factors on these sources, thereby contributing an essential knowledge base for the protection and management of soil heavy metals in the region.

Generation and Stabilization of a Dinickel Catalyst in a Metal-Organic Framework for Selective Hydrogenation Reactions.

Although many monometallic active sites have been installed in metal-organic frameworks (MOFs) for catalytic reactions, there are no effective strategies to generate bimetallic catalysts in MOFs. Here we report the synthesis of a robust, efficient, and reusable MOF catalyst, MOF-NiH, by adaptively generating and stabilizing dinickel active sites using the bipyridine groups in MOF-253 with the formula of Al(OH)(2,2'-bipyridine-5,5'-dicarboxylate) for Z-selective semihydrogenation of alkynes and selective hydrogenation of C=C bonds in α,ß-unsaturated aldehydes and ketones. Spectroscopic studies established the dinickel complex (bpy⋅- )NiII (µ2 -H)2 NiII (bpy⋅- ) as the active catalyst. MOF-NiH efficiently catalyzed selective hydrogenation reactions with turnover numbers of up to 192 and could be used in five cycles of hydrogenation reactions without catalyst leaching or significant decrease of catalytic activities. The present work uncovers a synthetic strategy toward solution-inaccessible Earth-abundant bimetallic MOF catalysts for sustainable catalysis.

Heterogeneity of Age-Related Neural Hyperactivity along the CA3 Transverse Axis.

Age-related memory deficits are correlated with neural hyperactivity in the CA3 region of the hippocampus. Abnormal CA3 hyperactivity in aged rats has been proposed to contribute to an imbalance between pattern separation and pattern completion, resulting in overly rigid representations. Recent evidence of functional heterogeneity along the CA3 transverse axis suggests that proximal CA3 supports pattern separation while distal CA3 supports pattern completion. It is not known whether age-related CA3 hyperactivity is uniformly represented along the CA3 transverse axis. We examined the firing rates of CA3 neurons from young and aged, male, Long-Evans rats along the CA3 transverse axis. Consistent with prior studies, young CA3 cells showed an increasing gradient in mean firing rate from proximal to distal CA3. However, aged CA3 cells showed an opposite, decreasing trend, in that CA3 cells in aged rats were hyperactive in proximal CA3, but possibly hypoactive in distal CA3, compared with young (Y) rats. We suggest that, in combination with altered inputs from the entorhinal cortex and dentate gyrus (DG), the proximal CA3 region of aged rats may switch from its normal function that reflects the pattern separation output of the DG and instead performs a computation that reflects an abnormal bias toward pattern completion. In parallel, distal CA3 of aged rats may create weaker attractor basins that promote abnormal, bistable representations under certain conditions.SIGNIFICANCE STATEMENT Prior work suggested that age-related CA3 hyperactivity enhances pattern completion, resulting in rigid representations. Implicit in prior studies is the notion that hyperactivity is present throughout a functionally homogeneous CA3 network. However, more recent work has demonstrated functional heterogeneity along the CA3 transverse axis, in that proximal CA3 is involved in pattern separation and distal CA3 is involved in pattern completion. Here, we show that age-related hyperactivity is present only in proximal CA3, with potential hypoactivity in distal CA3. This result provides new insight in the role of CA3 in age-related memory impairments, suggesting that the rigid representations in aging result primarily from dysfunction of computational circuits involving the dentate gyrus (DG) and proximal CA3.

Nuplazid suppresses esophageal squamous cell carcinoma growth in vitro and in vivo by targeting PAK4.

BACKGROUND: Due to the high recurrence and low 5-year survival rates of esophageal squamous cell carcinoma (ESCC) after treatment, the discovery of novel drugs for recurrence chemoprevention is of particular importance. METHODS: We screened the FDA-approved drug library and found that Nuplazid, an atypical antipsychotic that acts as an effective 5-HT 2 A receptor inverse agonist, could potentially exert anticancer effects in vitro and in vivo on ESCC. RESULTS: Pull-down results indicated that Nuplazid binds with p21-activated kinase 4 (PAK4), and a kinase assay showed that Nuplazid strongly suppressed PAK4 kinase activity. Moreover, Nuplazid exhibited inhibitory effects on ESCC in vivo. CONCLUSIONS: Our findings indicate that Nuplazid can suppress ESCC progression through targeting PAK4.

Characterization and genomic analysis of a Demerecviridae phage SP76 with lytic multiple-serotypes of Salmonella.

With the increase in antimicrobial resistance of Salmonella, phages have been paid more attention to as an alternative to antibiotics. In this study, a phage designated as SP76 was isolated from sewage. It can lyse several serotypes of Salmonella, including S. typhimurium (21/33), S. enteritidis (7/7), S. dublin (4/4), S. pullorum (2/2) and S. choleraesuis (1/2). SP76 showed a latent time of about 10 min, and maintained good lytic activity at a pH range of 3-10 and temperatures between 4 and 37 °C. Moreover, its optimal multiplicity of infection (MOI) was 0.0001. Based on the results of genomic sequence and analysis, SP76 was found to have a genome of 111,639 bp that encoded 166 predicted ORFs and belong to the Demerecviridae family, order Caudovirales. No virulence or lysogen formation gene clusters were identified in the SP76 genome. A pan-genome analysis based on 100 phages within the subfamily Markadamsvirinae indicated that SP76 had 23 core genes and 1199 accessory genes. We grouped the subfamily Markadamsvirinae and found that the main difference was in group III. In vitro bacteriostasis, experiments showed that the phage SP76 reduced planktonic bacteria by 1.52 log10 CFU/mL, and biofilms (24 h old) by 0.372 log10 CFU/mL, respectively. Thus, we isolated a safe and efficient phage that might be a good antibacterial agent.

Learning and Predicting from Dynamic Models for COVID-19 Patient Monitoring.

COVID-19 has challenged health systems to learn how to learn. This paper describes the context, methods and challenges for learning to improve COVID-19 care at one academic health center. Challenges to learning include: (1) choosing a right clinical target; (2) designing methods for accurate predictions by borrowing strength from prior patients' experiences; (3) communicating the methodology to clinicians so they understand and trust it; (4) communicating the predictions to the patient at the moment of clinical decision; and (5) continuously evaluating and revising the methods so they adapt to changing patients and clinical demands. To illustrate these challenges, this paper contrasts two statistical modeling approaches - prospective longitudinal models in common use and retrospective analogues complementary in the COVID-19 context - for predicting future biomarker trajectories and major clinical events. The methods are applied to and validated on a cohort of 1,678 patients who were hospitalized with COVID-19 during the early months of the pandemic. We emphasize graphical tools to promote physician learning and inform clinical decision making.