Application of Deep Learning for Studying NMDA Receptors.

Artificial intelligence underwent remarkable advancement in the past decade, revolutionizing our way of thinking and unlocking unprecedented opportunities across various fields, including drug development. The emergence of large pretrained models, such as ChatGPT, has even begun to demonstrate human-level performance in certain tasks.However, the difficulties of deploying and utilizing AI and pretrained model for nonexpert limited its practical use. To overcome this challenge, here we presented three highly accessible online tools based on a large pretrained model for chemistry, the Uni-Mol, for drug development against CNS diseases, including those targeting NMDA receptor: the blood-brain barrier (BBB) permeability prediction, the quantitative structure-activity relationship (QSAR) analysis system, and a versatile interface of the AI-based molecule generation model named VD-gen. We believe that these resources will effectively bridge the gap between cutting-edge AI technology and NMDAR experts, facilitating rapid and rational drug development.

Usability of serum AIM2 as a predictive biomarker of stroke-associated pneumonia and poor prognosis after acute supratentorial intracerebral hemorrhage: A prospective longitudinal cohort study.

Background: Absent in melanoma 2 (AIM2) is implicated in inflammatory processes. We measured serum AIM2 with intent to unveil its predictive significance for stroke-associated pneumonia (SAP) and functional prognosis following acute intracerebral hemorrhage (ICH). Methods: In this prospective cohort study, serum AIM2 concentrations of 163 ICH patients were gauged upon admission and 57 of them also consented for measurements at days 1, 3, 5, 7, 10 and 14. Coupled with 57 individuals without health conditions, dynamic change of serum AIM2 levels were uncovered. National Institutes of Health Stroke Scale (NIHSS) scores and hematoma volume were identified as the dual indicators of severity. Poststroke six-month modified Rankin Scale (mRS) scores ranging from 3 to 6 indicated an unfavorable outcome. SAP was observed during the first seven days after ICH. Sequential univariate and multivariate analyses were performed to discern predictors of SAP and adverse prognosis. Results: The serum levels of AIM2 in patients exhibited a marked elevation upon admission, reaching peak levels on the third and fifth days, and remained notably elevated until day 14 compared to those of the control group. Serum AIM2 levels showed independent correlations with both NIHSS scores and the volume of hematoma. Additionally, AIM2 concentrations were independently associated with a poor prognosis and SAP at the six-month mark. Within the framework of restricted cubic spline analysis, serum AIM2 concentrations exhibited a linear correlation with the likelihood of developing SAP and experiencing a poor prognosis. In the context of receiver operating characteristic (ROC) curve analysis, serum AIM2 concentrations effectively differentiated risks of SAP and poor prognosis. By employing segmented analysis, serum AIM2 concentrations showed negligible interactions with several traditional variables, such as age, gender, smoking habits, alcohol consumption, and more. The integrated model incorporating serum AIM2, NIHSS scores, and the volume of hematoma was depicted by employing a nomogram and demonstrated strong predictive performance for poor prognosis or SAP across various evaluation metrics, including ROC curve analysis, calibration curve analysis, and decision curve analysis. Conclusion: Serum AIM2 levels show a marked increase shortly after intracerebral hemorrhage (ICH), which may accurately reflect stroke severity, and effectively predict SAP and poor neurological outcomes, and therefore serum AIM2 stands out as an encouraging predictive indicator for ICH.

A Prospective Study of the Diagnostic Performance of Photon-Counting CT Compared With MRI in the Characterization of Renal Masses.

OBJECTIVES: The aim of this study was to assess the interreader reliability and per-RCC sensitivity of high-resolution photon-counting computed tomography (PCCT) in the detection and characterization of renal masses in comparison to MRI. MATERIALS AND METHODS: This prospective study included 24 adult patients (mean age, 52 ± 14 years; 14 females) who underwent PCCT (using an investigational whole-body CT scanner) and abdominal MRI within a 3-month time interval and underwent surgical resection (partial or radical nephrectomy) with histopathology (n = 70 lesions). Of the 24 patients, 17 had a germline mutation and the remainder were sporadic cases. Two radiologists (R1 and R2) assessed the PCCT and corresponding MRI studies with a 3-week washout period between reviews. Readers recorded the number of lesions in each patient and graded each targeted lesion's characteristic features, dimensions, and location. Data were analyzed using a 2-sample t test, Fisher exact test, and weighted kappa. RESULTS: In patients with von Hippel-Lindau mutation, R1 identified a similar number of lesions suspicious for neoplasm on both modalities (51 vs 50, P = 0.94), whereas R2 identified more suspicious lesions on PCCT scans as compared with MRI studies (80 vs 56, P = 0.12). R1 and R2 characterized more lesions as predominantly solid in MRIs (R1: 58/70 in MRI vs 52/70 in PCCT, P < 0.001; R2: 60/70 in MRI vs 55/70 in PCCT, P < 0.001). R1 and R2 performed similarly in detecting neoplastic lesions on PCCT and MRI studies (R1: 94% vs 90%, P = 0.5; R2: 73% vs 79%, P = 0.13). CONCLUSIONS: The interreader reliability and per-RCC sensitivity of PCCT scans acquired on an investigational whole-body PCCT were comparable to MRI scans in detecting and characterizing renal masses. CLINICAL RELEVANCE STATEMENT: PCCT scans have comparable performance to MRI studies while allowing for improved characterization of the internal composition of lesions due to material decomposition analysis. Future generations of this imaging modality may reveal additional advantages of PCCT over MRI.

NT-proBNP point-of-care testing for predicting mortality in end-stage renal disease: A survival analysis.

This study examines the predictive value of elevated N-terminal-pro brain natriuretic peptide (NT-pro BNP) levels for mortality among patients with end-stage renal disease (ESRD). Data from 768 ESRD patients, excluding those with cancer or lost follow-up, were analyzed using Kaplan-Meier curves and Cox proportional hazards models over three years. Results indicated that patients with very high NT-pro BNP levels had shorter average survival times and a significantly higher risk of mortality (hazard ratio 1.43). Advanced age, ICU admission, and comorbidities like cerebrovascular diseases and chronic obstructive pulmonary disease also contributed to increased mortality risks. Thus, elevated NT-pro BNP is an independent risk factor for mortality in ESRD patients.

Indoxyl sulphate-TNFα axis mediates uremic encephalopathy in rodent acute kidney injury.

Acute kidney injury (AKI) is often accompanied by uremic encephalopathy resulting from accumulation of uremic toxins in brain possibly due to impaired blood-brain barrier (BBB) function. Anionic uremic toxins are substrates or inhibitors of organic anionic transporters (OATs). In this study we investigated the CNS behaviors and expression/function of BBB OAT3 in AKI rats and mice, which received intraperitoneal injection of cisplatin 8 and 20 mg/kg, respectively. We showed that cisplatin treatment significantly inhibited the expressions of OAT3, synaptophysin and microtubule-associated protein 2 (MAP2), impaired locomotor and exploration activities, and increased accumulation of uremic toxins in the brain of AKI rats and mice. In vitro studies showed that uremic toxins neither alter OAT3 expression in human cerebral microvascular endothelial cells, nor synaptophysin and MAP2 expressions in human neuroblastoma (SH-SY5Y) cells. In contrast, tumour necrosis factor alpha (TNFα) and the conditioned medium (CM) from RAW264.7 cells treated with indoxyl sulfate (IS) significantly impaired OAT3 expression. TNFα and CM from IS-treated BV-2 cells also inhibited synaptophysin and MAP2 expressions in SH-SY5Y cells. The alterations caused by TNFα and CMs in vitro, and by AKI and TNFα in vivo were abolished by infliximab, a monoclonal antibody designed to intercept and neutralize TNFα, suggesting that AKI impaired the expressions of OAT3, synaptophysin and MAP2 in the brain via IS-induced TNFα release from macrophages or microglia (termed as IS-TNFα axis). Treatment of mice with TNFα (0.5 mg·kg-1·d-1, i.p. for 3 days) significantly increased p-p65 expression and reduced the expressions of Nrf2 and HO-1. Inhibiting NF-κB pathway, silencing p65, or activating Nrf2 and HO-1 obviously attenuated TNFα-induced downregulation of OAT3, synaptophysin and MAP2 expressions. Significantly increased p-p65 and decreased Nrf2 and HO-1 protein levels were also detected in brain of AKI mice and rats. We conclude that AKI inhibits the expressions of OAT3, synaptophysin and MAP2 due to IS-induced TNFα release from macrophages or microglia. TNFα impairs the expressions of OAT3, synaptophysin and MAP2 partly via activating NF-κB pathway and inhibiting Nrf2-HO-1 pathway.

Susceptibility to Treatment-Resistant Depression Within Families.

Importance: Antidepressant responses and the phenotype of treatment-resistant depression (TRD) are believed to have a genetic basis. Genetic susceptibility between the TRD phenotype and other psychiatric disorders has also been established in previous genetic studies, but population-based cohort studies have not yet provided evidence to support these outcomes. Objective: To estimate the TRD susceptibility and the susceptibility between TRD and other psychiatric disorders within families in a nationwide insurance cohort with extremely high coverage and comprehensive health care data. Design, Setting, and Participants: This cohort study assessed data from the Taiwan national health insurance database across entire population (N = 26 554 001) between January 2003 and December 2017. Data analysis was performed from August 2021 to April 2023. TRD was defined as having experienced at least 3 distinct antidepressant treatments in the current episode, each with adequate dose and duration, based on the prescribing records. Then, we identified the first-degree relatives of individuals with TRD (n = 34 467). A 1:4 comparison group (n = 137 868) of first-degree relatives of individuals without TRD was arranged for the comparison group, matched by birth year, sex, and kinship. Main Outcomes and Measures: Modified Poisson regression analyses were performed and adjusted relative risks (aRRs) and 95% CIs were calculated for the risk of TRD, the risk of other major psychiatric disorders, and different causes of mortality. Results: This study included 172 335 participants (88 330 male and 84 005 female; mean [SD] age at beginning of follow-up, 22.9 [18.1] years). First-degree relatives of individuals with TRD had lower incomes, more physical comorbidities, higher suicide mortality, and increased risk of developing TRD (aRR, 9.16; 95% CI, 7.21-11.63) and higher risk of other psychiatric disorders than matched control individuals, including schizophrenia (aRR, 2.36; 95% CI, 2.10-2.65), bipolar disorder (aRR, 3.74; 95% CI, 3.39-4.13), major depressive disorder (aRR, 3.65; 95% CI, 3.44-3.87), attention-deficit/hyperactivity disorders (aRR, 2.38; 95% CI, 2.20-2.58), autism spectrum disorder (aRR, 2.26; 95% CI, 1.86-2.74), anxiety disorder (aRR, 2.71; 95% CI, 2.59-2.84), and obsessive-compulsive disorder (aRR, 3.14; 95% CI, 2.70-3.66). Sensitivity and subgroup analyses validated the robustness of the findings. Conclusions and Relevance: To our knowledge, this study is the largest and perhaps first nationwide cohort study to demonstrate TRD phenotype transmission across families and coaggregation with other major psychiatric disorders. Patients with a family history of TRD had an increased risk of suicide mortality and tendency toward antidepressant resistance; therefore, more intensive treatments for depressive symptoms might be considered earlier, rather than antidepressant monotherapy.

Joint-tissue integrative analysis identifies high-risk genes for Parkinson's disease.

The loss of dopaminergic neurons in the substantia nigra and the abnormal accumulation of synuclein proteins and neurotransmitters in Lewy bodies constitute the primary symptoms of Parkinson's disease (PD). Besides environmental factors, scholars are in the early stages of comprehending the genetic factors involved in the pathogenic mechanism of PD. Although genome-wide association studies (GWAS) have unveiled numerous genetic variants associated with PD, precisely pinpointing the causal variants remains challenging due to strong linkage disequilibrium (LD) among them. Addressing this issue, expression quantitative trait locus (eQTL) cohorts were employed in a transcriptome-wide association study (TWAS) to infer the genetic correlation between gene expression and a particular trait. Utilizing the TWAS theory alongside the enhanced Joint-Tissue Imputation (JTI) technique and Mendelian Randomization (MR) framework (MR-JTI), we identified a total of 159 PD-associated genes by amalgamating LD score, GTEx eQTL data, and GWAS summary statistic data from a substantial cohort. Subsequently, Fisher's exact test was conducted on these PD-associated genes using 5,152 differentially expressed genes sourced from 12 PD-related datasets. Ultimately, 29 highly credible PD-associated genes, including CTX1B, SCNA, and ARSA, were uncovered. Furthermore, GO and KEGG enrichment analyses indicated that these genes primarily function in tissue synthesis, regulation of neuron projection development, vesicle organization and transportation, and lysosomal impact. The potential PD-associated genes identified in this study not only offer fresh insights into the disease's pathophysiology but also suggest potential biomarkers for early disease detection.

Vacancy Spectroscopy of Non-Abelian Kitaev Spin Liquids.

Spin vacancies in the non-Abelian Kitaev spin liquid are known to harbor Majorana zero modes, potentially enabling topological quantum computing at elevated temperatures. Here, we study the spectroscopic signatures of such Majorana zero modes in a scanning tunneling setup where a non-Abelian Kitaev spin liquid with a finite density of spin vacancies forms a tunneling barrier between a tip and a substrate. Our key result is a well-defined peak close to zero bias voltage in the derivative of the tunneling conductance whose voltage and intensity both increase with the density of vacancies. This "quasi-zero-voltage peak" is identified as the closest analog of the zero-voltage peak observed in topological superconductors that additionally reflects the fractionalized nature of spin-liquid-based Majorana zero modes. We further highlight a single-fermion Van Hove singularity at a higher voltage that reveals the energy scale of the emergent Majorana fermions in the Kitaev spin liquid. Our proposed signatures are within reach of current experiments on the candidate material α-RuCl_{3}.

Wolbachia infection-responsive immune genes suppress Plasmodium falciparum infection in Anopheles stephensi.

Wolbachia, a maternally transmitted symbiotic bacterium of insects, can suppress a variety of human pathogens in mosquitoes, including malaria-causing Plasmodium in the Anopheles vector. However, the mechanistic basis of Wolbachia-mediated Plasmodium suppression in mosquitoes is not well understood. In this study, we compared the midgut and carcass transcriptomes of stably infected Anopheles stephensi with Wolbachia wAlbB to uninfected mosquitoes in order to discover Wolbachia infection-responsive immune genes that may play a role in Wolbachia-mediated anti-Plasmodium activity. We show that wAlbB infection upregulates 10 putative immune genes and downregulates 14 in midguts, while it upregulates 31 putative immune genes and downregulates 15 in carcasses at 24 h after blood-fed feeding, the time at which the Plasmodium ookinetes are traversing the midgut tissue. Only a few of these regulated immune genes were also significantly differentially expressed between Wolbachia-infected and non-infected midguts and carcasses of sugar-fed mosquitoes. Silencing of the Wolbachia infection-responsive immune genes TEP 4, TEP 15, lysozyme C2, CLIPB2, CLIPB4, PGRP-LD and two novel genes (a peritrophin-44-like gene and a macro domain-encoding gene) resulted in a significantly greater permissiveness to P. falciparum infection. These results indicate that Wolbachia infection modulates mosquito immunity and other processes that are likely to decrease Anopheles permissiveness to Plasmodium infection.

Methylomonas defluvii sp. nov., a type I methane-oxidizing bacterium from a secondary sedimentation tank of a wastewater treatment plant.

An aerobic methanotroph was isolated from a secondary sedimentation tank of a wastewater treatment plant and designated strain OY6T. Cells of OY6T were Gram-stain-negative, pink-pigmented, motile rods and contained an intracytoplasmic membrane structure typical of type I methanotrophs. OY6T could grow at a pH range of 4.5-7.5 (optimum pH 6.5) and at temperatures ranging from 20 °C to 37 °C (optimum 30 °C). The major cellular fatty acids were C14 : 0, C16 : 1ω7c/C16 : 1ω6c and C16 : 1ω5c; the predominant respiratory quinone was MQ-8. The genome size was 5.41 Mbp with a DNA G+C content of 51.7 mol%. OY6T represents a member of the family Methylococcaceae of the class Gammaproteobacteria and displayed 95.74-99.64 % 16S rRNA gene sequence similarity to the type strains of species of the genus Methylomonas. Whole-genome comparisons based on average nucleotide identity (ANI) and digital DNA-DNA hybridisation (dDDH) confirmed that OY6T should be classified as representing a novel species. The most closely related type strain was Methylomonas fluvii EbBT, with 16S rRNA gene sequence similarity, ANI by blast (ANIb), ANI by MUMmer (ANIm) and dDDH values of 99.64, 90.46, 91.92 and 44.5 %, respectively. OY6T possessed genes encoding both the particulate methane monooxygenase enzyme and the soluble methane monooxygenase enzyme. It grew only on methane or methanol as carbon sources. On the basis of phenotypic, genetic and phylogenetic data, strain OY6T represents a novel species within the genus Methylomonas for which the name Methylomonas defluvii sp. nov. is proposed, with strain OY6T (=GDMCC 1.4114T=KCTC 8159T=LMG 33371T) as the type strain.

Deciphering the Roles of Extracellular Polymeric Substances (EPS) in Shaping Disinfection Kinetics through Permanent Removal via Genetic Disruption.

Extracellular polymeric substances (EPS) ubiquitously encapsulate microbes and play crucial roles in various environmental processes. However, understanding their complex interactions with dynamic bacterial behaviors, especially during the disinfection process, remains very limited. In this work, we investigated the impact of EPS on bacterial disinfection kinetics by developing a permanent EPS removal strategy. We genetically disrupted the synthesis of exopolysaccharides, the structural components of EPS, in Pseudomonas aeruginosa, a well-known EPS-producing opportunistic pathogen found in diverse environments, creating an EPS-deficient strain. This method ensured a lasting absence of EPS while maintaining bacterial integrity and viability, allowing for real-time in situ investigations of the roles of EPS in disinfection. Our findings indicate that removing EPS from bacteria substantially lowered their susceptibility threshold to disinfectants such as ozone, chloramine B, and free chlorine. This removal also substantially accelerated disinfection kinetics, shortened the resistance time, and increased disinfection efficiency, thereby enhancing the overall bactericidal effect. The absence of EPS was found to enhance bacterial motility and increase bacterial cell vulnerability to disinfectants, resulting in greater membrane damage and intensified reactive oxygen species (ROS) production upon exposure to disinfectants. These insights highlight the central role of EPS in bacterial defenses and offer promising implications for developing more effective disinfection strategies.

Injectable isoniazid-loaded bone cement based on hydrazone bonds achieving long-term release and decent mechanical properties.

A robust and easily manufactured high-strength and long-term release hydrazone-based isoniazid acrylic (HIA) bone cement is reported. The mechanical strength of HIA bone cement is similar to that of normal polymethyl methacrylate (PMMA) bone cement, far surpassing that of traditional isoniazid-containing antibiotic-loaded bone cement (INH bone cement). Isoniazid is connected to the bone cement through bioorthogonal hydrazone chemistry, and it possesses release properties superior to those of INH bone cement, allowing for the sustained release of isoniazid for up to 12 weeks. In vivo and in vitro studies also indicate that HIA cement exhibits better biocompatibility than INH bone cement. The results of this study not only signify progress in the realm of antimicrobial bone cement for addressing bone tuberculosis but also enhance our capacity to create and comprehend high-performing antimicrobial bone cement.

Investigating the in vitro antibacterial efficacy of composite bone cement incorporating natural product-based monomers and gentamicin.

OBJECTIVE: The objective of this study is to investigate the impact of four natural product extracts, namely, aloe-emodin, quercetin, curcumin, and tannic acid, on the in vitro bacteriostatic properties and biocompatibility of gentamicin-loaded bone cement and to establish an experimental groundwork supporting the clinical utility of antibiotic-loaded bone cements (ALBC). METHODS: Based on the components, the bone cement samples were categorized as follows: the gentamicin combined with aloe-emodin group, the gentamicin combined with quercetin group, the gentamicin combined with curcumin group, the gentamicin combined with tannic acid group, the gentamicin group, the aloe-emodin group, the quercetin group, the curcumin group, and the tannic acid group. Using the disk diffusion test, we investigated the antibacterial properties of the bone cement material against Staphylococcus aureus (n = 4). We tested cell toxicity and proliferation using the cell counting kit-8 (CCK-8) and examined the biocompatibility of bone cement materials. RESULTS: The combination of gentamicin with the four natural product extracts resulted in significantly larger diameters of inhibition zones compared to gentamicin alone, and the difference was statistically significant (P < 0.05). Except for the groups containing tannic acid, cells in all other groups showed good proliferation across varying time intervals without displaying significant cytotoxicity (P < 0.05). CONCLUSION: In this study, aloe-emodin, quercetin, curcumin, and tannic acid were capable of enhancing the in vitro antibacterial performance of gentamicin-loaded bone cement against S. aureus. While the groups containing tannic acid displayed moderate cytotoxicity in in vitro cell culture, all other groups showed no discernible cytotoxic effects.

Characterization of humoral and cellular immunologic responses to an mRNA-based human cytomegalovirus vaccine from a phase 1 trial of healthy adults.

mRNA-1647 is an investigational mRNA-based vaccine against cytomegalovirus (CMV) that contains sequences encoding the CMV proteins glycoprotein B and pentamer. Humoral and cellular immune responses were evaluated in blood samples collected from healthy CMV-seropositive and CMV-seronegative adults who participated in a phase 1 trial of a three-dose series of mRNA-1647 (NCT03382405). Neutralizing antibody (nAb) titers against fibroblast and epithelial cell infection in sera from CMV-seronegative mRNA-1647 recipients were higher than those in sera from control CMV-seropositive samples and remained elevated up to 12 months after dose 3. nAb responses elicited by mRNA-1647 were comparable across 14 human CMV (HCMV) strains. Frequencies of antigen-specific memory B cells increased in CMV-seropositive and CMV-seronegative participants after each mRNA-1647 dose and remained elevated for up to 6 months after dose 3. mRNA-1647 elicited robust increases in frequencies and polyfunctionality of CD4+ T helper type 1 and effector CD8+ T cells in samples from CMV-seronegative and CMV-seropositive participants after stimulation with HCMV-specific peptides. The administration of three doses of mRNA-1647 to healthy adults elicited high nAb titers with wide-breadth, long-lasting memory B cells, and strong polyfunctional T-cell responses. These findings support further clinical development of the mRNA-1647 vaccine against CMV.IMPORTANCECytomegalovirus (CMV), a common virus that can infect people of all ages, may lead to serious health problems in unborn babies and those with a weakened immune system. Currently, there is no approved vaccine available to prevent CMV infection; however, the investigational messenger RNA (mRNA)-based CMV vaccine, mRNA-1647, is undergoing evaluation in clinical trials. The current analysis examined samples from a phase 1 trial of mRNA-1647 in healthy adults to better understand how the immune system reacts to vaccination. Three doses of mRNA-1647 produced a long-lasting immune response, thus supporting further investigation of the vaccine in the prevention of CMV infection.CLINICAL TRIALSRegistered at ClinicalTrials.gov (NCT03382405).

High myopia at high altitudes.

Background: Optic nerve sheath diameter (ONSD) increases significantly at high altitudes, and is associated with the presence and severity of acute mountain sickness (AMS). Exposure to hypobaria, hypoxia, and coldness when hiking also impacts intraocular pressure (IOP). To date, little is known about ocular physiological responses in trekkers with myopia at high altitudes. This study aimed to determine changes in the ONSD and IOP between participants with and without high myopia (HM) during hiking and to test whether these changes could predict symptoms of AMS. Methods: Nine participants with HM and 18 without HM participated in a 3-day trek of Xue Mountain. The ONSD, IOP, and questionnaires were examined before and during the trek of Xue Mountain. Results: The ONSD values increased significantly in both HM (p = 0.005) and non-HM trekkers (p = 0.018) at an altitude of 1,700 m. In the HM group, IOP levels were greater than those in the non-HM group (p = 0.034) on the first day of trekking (altitude: 3,150 m). No statistically significant difference was observed between the two groups for the values of ONSD. Fractional changes in ONSD at an altitude of 1,700 m were related to the development of AMS (r pb = 0.448, p = 0.019) and the presence of headache symptoms (r pb = 0.542, p = 0.004). The area under the ROC curve for the diagnostic performance of ONSD fractional changes at an altitude of 1,700 m was 0.859 for predicting the development of AMS and 0.803 for predicting the presence of headache symptoms. Conclusion: Analysis of changes in ONSD at moderate altitude could predict AMS symptoms before an ascent to high altitude. Myopia may impact physiological accommodation at high altitudes, and HM trekkers potentially demonstrate suboptimal regulation of aqueous humor in such environments.

Deep-Learning Density Functional Perturbation Theory.

Calculating perturbation response properties of materials from first principles provides a vital link between theory and experiment, but is bottlenecked by the high computational cost. Here, a general framework is proposed to perform density functional perturbation theory (DFPT) calculations by neural networks, greatly improving the computational efficiency. Automatic differentiation is applied on neural networks, facilitating accurate computation of derivatives. High efficiency and good accuracy of the approach are demonstrated by studying electron-phonon coupling and related physical quantities. This work brings deep-learning density functional theory and DFPT into a unified framework, creating opportunities for developing ab initio artificial intelligence.

A novel class of inhibitors that disrupts the stability of integrin heterodimers identified by CRISPR-tiling-instructed genetic screens.

The plasma membrane is enriched for receptors and signaling proteins that are accessible from the extracellular space for pharmacological intervention. Here we conducted a series of CRISPR screens using human cell surface proteome and integrin family libraries in multiple cancer models. Our results identified ITGAV (integrin αV) and its heterodimer partner ITGB5 (integrin ß5) as the essential integrin α/ß pair for cancer cell expansion. High-density CRISPR gene tiling further pinpointed the integral pocket within the ß-propeller domain of ITGAV for integrin αVß5 dimerization. Combined with in silico compound docking, we developed a CRISPR-Tiling-Instructed Computer-Aided (CRISPR-TICA) pipeline for drug discovery and identified Cpd_AV2 as a lead inhibitor targeting the ß-propeller central pocket of ITGAV. Cpd_AV2 treatment led to rapid uncoupling of integrin αVß5 and cellular apoptosis, providing a unique class of therapeutic action that eliminates the integrin signaling via heterodimer dissociation. We also foresee the CRISPR-TICA approach to be an accessible method for future drug discovery studies.

Impact of the pulmonary ventilation function on the prognosis of suspected asthma patients: A retrospective observational study.

OBJECTIVE: Asthma is a common chronic respiratory diseases, and the relationship between pulmonary ventilation function and the prognosis of patients with suspected asthma is not well understood. This study aims to explore the impact of pulmonary ventilation functions on the prognosis of patients with suspected asthma. METHODS: This retrospective observational study included patients with suspected asthma who were diagnosed and treated at the Guangdong Provincial Hospital of Traditional Chinese Medicine between August 2015 and January 2020. The primary outcome of interest was improvement in asthma symptoms, as measured by bronchial provocation test (BPT) results within 1 year after diagnosis. The impact of pulmonary ventilation functions on prognosis was explored by multivariable logistic regression analysis. RESULTS: Seventy-two patients were included in the study. Patients with normal (OR = 0.123, P = 0.004) or generally normal (OR = 0.075, P = 0.039) pulmonary ventilation function were more likely to achieve improvement in asthma symptoms compared with patients with mild obstruction. There were no significant differences between the improvement and non-improvement groups in baseline characteristics. CONCLUSION: These results suggest that suspected asthma patients with normal or generally normal pulmonary ventilation function are more likely to achieve improvement in asthma symptoms within one year compared to patients with mild obstruction.

Prognostic Significance of Aortic Valve Calcification in Relation to Coronary Artery Calcification for Cardiovascular Diseases.

AIMS: Both coronary artery calcification (CAC) and aortic valve calcification (AVC) are strongly associated with cardiovascular diseases (CVD), but data about the prognostic significance of multiple cardiovascular calcifications are limited. We aim to investigate the interaction relationship of AVC and CAC for major events. METHODS: We included 6,695 participants from the Multi-Ethnic Study of Atherosclerosis at baseline, and divided them into four groups: 1) no AVC or CAC; 2) only AVC; 3) only CAC; 4) with CAC and CAC. Cox regression model and Kaplan-Meier method were used to analyze CVD outcomes. We evaluated the interaction between AVC and CAC, and their added predictive value based on the pooled cohort equations (PCEs). The subgroup analyses were also explored. RESULTS: Among 6,695 participants (mean age 62.2 ± 10.2 years, 47.2% male), after follow-up, 943 cases (14.1%) of CVD and 1274 cases (19.0%) of all-cause death occurred. For participants with both AVC and CAC, the risk of CVD significantly increased {HR =3.43 (2.69-4.37), P <0.001}, even higher than the sum of the ones with only AVC and only CAC. This trend remained the same for all-cause death and among subgroup analysis. The addictive interaction was statistically significant (P <0.001). When added AVC and CAC, the predictive value of PCEs increased. CONCLUSIONS: Our results indicated a synergistical interaction between valve calcification and coronary calcification to cardiovascular diseases. Management for both AVC and CAC may bring health co-benefits in preventing poor outcomes.

We investigated the interaction relationship between AVC and CAC in 6,695 participants with measurements for cardiovascular calcifications at baseline in MESA study, and the prognostic significance of AVC in relation to CAC. Our study found that CAC and AVC worked independently and synergistically to predict the risk of cardiovascular diseases and all-cause death. Our results have shown that patients suffering from both CAC and AVC are more likely to develop a poor prognosis, therefore it's necessary to implement earlier and more positive intervention for CVD prevention in this certain subpopulation.

Comparison of deep learning-assisted blinking analysis system and Lipiview interferometer in dry eye patients: a cross-sectional study.

BACKGROUND: Abnormal blinking pattern is associated with ocular surface diseases. However, blink is difficult to analyze due to the rapid movement of eyelids. Deep learning machine (DLM) has been proposed as an optional tool for blinking analysis, but its clinical practicability still needs to be proven. Therefore, the study aims to compare the DLM-assisted Keratograph 5M (K5M) as a novel method with the currently available Lipiview in the clinic and assess whether blinking parameters can be applied in the diagnosis of dry eye disease (DED). METHODS: Thirty-five DED participants and 35 normal subjects were recruited in this cross-sectional study. DED questionnaire and ocular surface signs were evaluated. Blinking parameters including number of blinks, number of incomplete blinking (IB), and IB rate were collected from the blinking videos recorded by the K5M and Lipiview. Blinking parameters were individually collected from the DLM analyzed K5M videos and Lipiview generated results. The agreement and consistency of blinking parameters were compared between the two devices. The association of blinking parameters to DED symptoms and signs were evaluated via heatmap. RESULTS: In total, 140 eyes of 70 participants were included in this study. Lipiview presented a higher number of IB and IB rate than those from DLM-assisted K5M (P ≤ 0.006). DLM-assisted K5M captured significant differences in number of blinks, number of IB and IB rate between DED and normal subjects (P ≤ 0.035). In all three parameters, DLM-assisted K5M also showed a better consistency in repeated measurements than Lipiview with higher intraclass correlation coefficients (number of blinks: 0.841 versus 0.665; number of IB: 0.750 versus 0.564; IB rate: 0.633 versus 0.589). More correlations between blinking parameters and DED symptoms and signs were found by DLM-assisted K5M. Moreover, the receiver operating characteristic analysis showed the number of IB from K5M exhibiting the highest area under curve of 0.773. CONCLUSIONS: DLM-assisted K5M is a useful tool to analyze blinking videos and detect abnormal blinking patterns, especially in distinguishing DED patients from normal subjects. Large sample investigations are therefore warranted to assess its clinical utility before implementation.