Clinical characteristics of autoimmune encephalitis with co-existence of multiple anti-neuronal antibodies.

BACKGROUND: An increasing number of cases of autoimmune encephalitis (AE) with co-existing multiple anti-neuronal antibodies have been reported in recent years. However, the clinical significance of the concurrent presence of multiple anti-neuronal antibodies in patients with AE remains unclear. METHODS: We retrospectively enrolled AE patients with multiple anti-neuronal antibodies treated at our center between August 2019 and February 2022. We also reviewed cases reported in multiple literature databases. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was followed on selection process. And then the clinical and laboratory data of these cases were collected for review and summary. RESULTS: A total of 83 AE cases with multiple antibodies (9 cases from our center and 74 cases from the literatures reviewed) were identified. In our center, nine patients presented with encephalitis symptoms, clinically characterized as disturbed consciousness, seizures, cognitive impairment, and psychiatric disorders. Of the 83 cases, 73 cases had co-existence of 2 types of antibodies, 8 cases had 3 types, and 2 cases had 4 types. Thirty-nine cases (39/83, 46.9%) were confirmed or suspected of also having a tumor, of which the most common was lung cancer (28/83, 33.7%). Partial or complete recovery was achieved in 57 cases (57/83, 68.6%), while 26 cases (26/83, 31.3%) died during treatment or follow-up. CONCLUSIONS: AE with co-existing multiple anti-neuronal antibodies is a specific subgroup, that is increasingly recognized in clinical practice. The co-existence of multiple anti-neuronal antibodies has a major impact on clinical features, disease progression, and prognosis.

c-Met is a chimeric antigen receptor T-cell target for treating recurrent nasopharyngeal carcinoma.

BACKGROUND AIMS: Radiation therapy is the standard treatment for patients with nasopharyngeal carcinoma (NPC), but relapse occurs in 10% to 20% of patients. The treatment of recurrent nasopharyngeal carcinoma (rNPC) remains challenging. Chimeric antigen receptors (CAR)-T-cell therapy has achieved good outcomes in the treatment of leukemia and seems to be a promising therapeutic strategy for solid tumors. c-Met has been found to be highly expressed in multiple cancer types, and the activation of c-Met leads to the proliferation and metastasis of cancer cells. However, the expression of c-Met in rNPC tissues and whether it can be used as a target for CAR-T therapy in rNPC remain to be investigated. METHODS: We detected the expression of c-Met in 24 primary human rNPC tissues and three NPC cell lines and constructed two different antibody-derived anti-c-Met CARs, namely, Ab928z and Ab1028z. To estimate the function of these two different c-Met-targeted CAR-T cells, CD69 expression, cytotoxicity and cytokine secretion of CAR-T cells were assessed after coculture with target cells. A cell line-derived xenograft mouse model also was used to evaluate these two anti-c-Met CAR-T cells. Furthermore, we determined whether combination with an anti-EGFR antibody could promote the antitumor effect of CAR-T cells in a patient-derived xenograft mouse model. RESULTS: High c-Met expression was detected in 23 of 24 primary human rNPC tissues by immunohistochemistry staining and in three NPC cell lines by flow cytometry. Ab928z-T cells and Ab1028z-T cells showed significantly upregulated expression of CD69 after coculture with targeted cells. However, Ab1028z-T cells showed superior cytokine secretion and antitumor activity. Furthermore, Ab1028z-T cells effectively suppressed tumor growth compared with control CAR-T cells, and the combination with nimotuzumab further enhanced the tumor-clearing ability of Ab1028z-T cells. CONCLUSIONS: We found that c-Met is highly expressed in rNPC tissues and confirmed its potential as a CAR-T target for rNPC. Our study provides a new idea for the clinical treatment of rNPC.

Modeling the Interaction and Uptake of Cd-As(V) Mixture to Wheat Roots Affected by Humic Acids, in Terms of root cell Membrane Surface Potential (ψ0).

The joint toxicological effects of Cd2+ and As(V) mixture on wheat root as affected by environmental factors, such as pH, coexisting cations, and humic acids etc., were investigated using hydroponic experiments. The interaction and toxicological mechanisms of co-existing Cd2+ and As(V) at the interface of solution and roots in presence of humic acid were further explored by incorporating root cell membrane surface potential ψ0 into a mechanistic model of combined biotic ligand model (BLM)-based Gouy-Chapman-Stern (GCS) model and NICA-DONNAN model. Besides, molecular dynamics (MD) simulations of lipid bilayer equilibrated with solution containing Cd2+ and H2AsO4- further revealed the molecular distribution of heavy metal(loid) ions under different membrane surface potentials. H2AsO4- and Cd2+ can be adsorbed on the surface of the membrane alone or as complexes, which consolidate the limitation of the macroscopic physical models.

Human viral encephalitis associated with suid herpesvirus 1.

BACKGROUND: Suid herpesvirus type 1 (SHV1) is a type of neurotropic virus able to infect various species. However, the clinical cases of human SHV1 encephalitis are still rarely reported, and the clinical characteristics, treatment, and prognosis of human SHV1 encephalitis are still unclear. METHODS: In this study, we reported 2 cases of human encephalitis associated with SHV1 infection and reviewed the other 18 cases from the literatures. A total of 20 cases with human SHV1 encephalitis were summarized and re-analyzed. RESULTS: Nineteen of 20 patients had a history of swine-related occupational exposure before illness onset. All patients initially presented with influenza-like symptoms and then developed seizures, disturbed consciousness, and endophthalmitis. All patients with clinical outcome of modified Rankin Scale of 5 or 6 suffered from rapid progressive respiratory failure. The results of cerebrospinal fluid (CSF) indicated aseptic or viral infection. MRI findings of SHV1 encephalitis were prone to distribute in temporal-frontal and insular cortex, which was similar to the pattern of herpes simplex virus encephalitis, while some cases with involvements of gray matter nuclei had a high rate of mortality. Metagenomic next-generation sequencing (mNGS) revealed that all patients had unique SHV1 sequences with variable reads in the CSF. CONCLUSIONS: The variant SHV1 can cause a new type of human viral encephalitis, characterized by acute, fulminating, and catastrophic central nervous system infection. Rapid progressive respiratory failure and extensive lesions of deep gray matter nuclei might be indicators to poor prognosis. No approved treatments for the encephalitis are available, but it is possible to diagnose encephalitis quickly by mNGS.

Diagnostic Value of Whole-Body DWI With Background Body Suppression Plus Calculation of Apparent Diffusion Coefficient at 3 T Versus 18F-FDG PET/CT for Detection of Bone Metastases.

OBJECTIVE. The purpose of this study is to evaluate the diagnostic performance of whole-body (WB) DWI with background body suppression (DWIBS) combined with calculation of the apparent diffusion coefficient (ADC) value at 3 T compared with the diagnostic performance of 18F-FDG PET/CT for detecting bone metastases in patients with malignant tumors. SUBJECTS AND METHODS. Thirty-nine consecutive patients with suspected bone metastases underwent both WB DWIBS and FDG PET/CT. Imaging findings were independently interpreted using qualitative and quantitative analyses. Pathologic findings or clinical or radiologic follow-up data were used as the diagnostic reference standard. The sensitivity, specificity, overall accuracy, positive predictive value, and negative predictive value of both modalities were calculated. The ADCs of benign lesions and metastases were compared. RESULTS. A total of 213 metastatic bone segments were confirmed among 39 patients. The sensitivity, specificity, overall accuracy, positive predictive value, and negative predictive value were 93.0%, 87.8%, 89.6%, 79.8%, and 96.0%, respectively, for WB DWIBS and 92.5%, 92.0%, 92.1%, 85.7% and 95.9%, respectively, for FDG PET/CT. The specificity of WB DWIBS in detecting bone metastases was significantly lower than that of FDG PET/CT (p < 0.05), whereas the sensitivity, overall accuracy, positive predictive value, and negative predictive value in detecting bone metastases were not significantly different between WB DWIBS and FDG PET/CT (p > 0.05). The ADCs for benign lesions were significantly higher than those for metastases (p < 0.001). In ROC curve analysis, the AUC value was 0.901. A cutoff ADC value of 920.5 × 10-6 mm2s-1 distinguished benign lesions from bone metastases with a sensitivity of 92.9% and a specificity of 73.4%. CONCLUSION. WB DWIBS coupled with ADC analysis at 3 T is effective for detecting bone metastases.

An astrocyte regenerative response from vimentin-containing cells in the spinal cord of amyotrophic lateral sclerosis's disease-like transgenic (G93A SOD1) mice.

The reason for regeneration in the adult spinal cord during motor neuron degeneration in amyotrophic lateral sclerosis (ALS) remains largely unknown. To this end, we studied the alteration of vimentin (a neural precursor cells marker in CNS)-containing cells (VCCs) in spinal cord during different stages of ALS used C57BL/6J G93A SOD1 transgenic mice mimicking ALS. Results showed that VCCs were mostly distributed in the ependymal zone (EZ) surrounding the central canal of spinal cord in SOD1 wild type mice; a few of VCCs were sparsely distributed in other regions. However, the number of VCCs significantly increased in the spinal cord during the onset and progression stages of ALS. They were extensively distributed in the EZ, the anterior, the lateral and the posterior horn of grey matter, particularly in the posterior horn region at the progression stage. A majority of VCCs in the anterior, the lateral and the posterior horn of grey matter (outside of EZ) generated astrocytes, but no neurons, oligodendrocytes and microgliocytes. Our results suggested that there was a potential astrocyte regenerative response to motor neuron degeneration in motor neurons-degenerated regions in the adult spinal cord during the onset and progression stages of ALS-like disease. The regenerative responses in the adult spinal cord of ALS-like mice may be a potential pathway in attempting to repair the degenerated motor neurons and restore the dysfunctional neural circuitry.

The Possible Damaged Mechanism and the Preventive Effect of Monosialotetrahexosylganglioside in a Rat Model of Cerebral Ischemia-Reperfusion Injury.

BACKGROUND: The pathogenesis of cerebral ischemia-reperfusion injury (CIRI) is not completely clear and therapies are limited now. Therefore, our study aimed to investigate the possible pathogenesis and preventive approach of CIRI through analyzing changes of aspartate (Asp), glutamate (Glu), mitochondrial calcium (MCa), calmodulin (CaM), and malondialdehyde (MDA) contents and ultramicropathology in hippocampus and cerebral cortex of ischemic susceptible injured regions and the effect of monosialotetrahexosylganglioside (GM1) in the rat model of CIRI. METHODS: Contents of Asp, Glu, MCa, CaM, and MDA in hippocampus and cerebral cortex tissues were measured by a high-performance liquid chromatography, atomic absorption spectrophotometer, and ordinary spectrophotometer, respectively, changes of ultramicrostructure in neurons of the hippocampus CA1 region and frontal cerebral cortex were observed by a transmission electron microscope. RESULTS: Contents of Asp and Glu in hippocampus and cerebral cortex tissues of CIRI groups significantly decreased and contents of MCa, CaM, and MDA significantly increased than those in control groups, and the ultramicrostructure in neurons of the hippocampus CA1 region and frontal cerebral cortex revealed a significant damaged change, and GM1 significantly ameliorated changes of Asp, Glu, MCa, CaM, and MDA contents in hippocampus and ultrastructural changes in neurons of the hippocampus CA1 region and frontal cerebral cortex. CONCLUSIONS: Our findings further support that the abnormal release and/or reuptake of excitatory amino acid neurotransmitters, the disordered calcium homeostasis and the excessive production and/or reduced elimination of reactive oxygen species contribute to the pathogenesis of CIRI, and GM1 can partially prevent these pathogenesises to exert the protective effect on CIRI.

Effects of Twenty-four Move Shadow Boxing Combined with psychosomatic relaxation on Depression and Anxiety in Patients with Type-2 Diabetes.

BACKGROUND: The aim of the current study was to observe the effects of Twenty-four Move Shadow Boxing combined with psychosomatic relaxation on depression and anxiety in patients with Type-2 Diabetes. SUBJECTS AND METHODS: One hundred and twenty (120) patients with Type-2 Diabetes and depressive/anxious symptoms were divided into intervention group (60 cases) and control group (60 cases) according to the minimum distribution principle of unbalanced indicators. Twenty-four Move Shadow Boxing group used this intervention combined with psychosomatic relaxation. Control group underwent conventional treatment. All the patients in the two groups completed the Self-rating Depression Scale (SDS) and Self-Rating Anxiety Scale (SAS) before and after treatment. RESULTS: Among the 52 people included in the statistical analysis, the recovery rate was 13.3%. The differences between depression and anxiety scores in the intervention group before and after treatment were statistically significant (P<0.001), whereas these differences were non-significant in the control group (P=0.123). After the treatment, the glycated hemoglobin reduction in the intervention group was greater than that of the control group (t=2.438, P=0.016). CONCLUSION: The combination of Twenty-four Move Shadow Boxing and psychosomatic relaxation has a beneficial auxiliary therapeutic effect on depression and anxiety accompanying Type-2 Diabetes.

Influence of dredging on sedimentary arsenic release for a tide-influenced waterfront body.

We evaluated the influence of sediment dredging on sedimentary As release for the Inner Lake, a typical tide-influenced waterfront body in the middle to lower reaches of the Yangtze River in Zhengjiang, China. By field investigation and laboratory experiment, the As content in the deposited sediment before dredging was analyzed and the relationship between dynamic disturbance and sedimentary As release intensity was established. Using a numerical model in which the factors of water current, suspended sediment, and As were coupled, the processes of As migration were simulated for typical years and tidal cycles before and after dredging. The results show that: (i) the amounts of sedimentary As release during the tidal cycles in the flood season and the dry season after dredging were reduced by 14.6 and 28.1%, respectively, compared with before dredging; (ii) after removal of the surface polluted sediment, the annual volumes of internal released As in the high-water year, common-water year, and low-water year were decreased to 11.89, 4.94, and 4.89 Mg, respectively; and (iii) the highest reduction rate could reach 27.5% in the common-water year, while the lowest was 10.92% in the high-water year because the massive water exchange with the Yangtze River in the high-water year resulted in an enhanced dynamic disturbance that played a more dominating role in the internal As release than the surface sediment removal. The results of this study may be useful for other researchers of water environment protection for waterfront bodies.

CycleTrans: Learning Neutral Yet Discriminative Features via Cycle Construction for Visible-Infrared Person Re-Identification.

Visible-infrared person re-identification (VI-ReID) is the task of matching the same individuals across the visible and infrared modalities. Its main challenge lies in the modality gap caused by the cameras operating on different spectra. Existing VI-ReID methods mainly focus on learning general features across modalities, often at the expense of feature discriminability. To address this issue, we present a novel cycle-construction-based network for neutral yet discriminative feature learning, termed CycleTrans. Specifically, CycleTrans uses a lightweight knowledge capturing module (KCM) to capture rich semantics from the modality-relevant feature maps according to pseudo anchors. Afterward, a discrepancy modeling module (DMM) is deployed to transform these features into neutral ones according to the modality-irrelevant prototypes. To ensure feature discriminability, another two KCMs are further deployed for feature cycle constructions. With cycle construction, our method can learn effective neutral features for visible and infrared images while preserving their salient semantics. Extensive experiments on SYSU-MM01 and RegDB datasets validate the merits of CycleTrans against a flurry of state-of-the-art (SOTA) methods, +1.88% on rank-1 in SYSU-MM01 and +1.1% on rank-1 in RegDB. Our code is available at https://github.com/DoubtedSteam/CycleTrans.

Field evaluation of a simple and rapid diagnostic test, RLDT to detect Shigella and enterotoxigenic E. coli in Indian children.

The diagnostic assays currently used to detect Shigella spp. (Shigella) and enterotoxigenic Escherichia coli (ETEC) are complex or elaborate which make them difficult to apply in resource poor settings where these diseases are endemic. The simple and rapid nucleic acid amplification-based assay "Rapid LAMP-based Diagnostic Test (RLDT)" was evaluated to detect Shigella spp (Shigella) and enterotoxigenic Escherichia coli (ETEC) and determine the epidemiology of these pathogens in Kolkata, India. Stool samples (n = 405) from children under five years old with diarrhea seeking care at the hospitals were tested, and 85(21%) and 68(17%) by RLDT, 91(23%) and 58(14%) by quantitative PCR (qPCR) and 35(9%) and 15(4%) by culture, were positive for Shigella and ETEC, respectively. The RLDT showed almost perfect agreement with qPCR, Kappa 0.96 and 0.89; sensitivity 93% and 98%; specificity 100% and 97% for Shigella and ETEC, respectively. While RLDT detected additional 12% Shigella and 13% ETEC than culture, all culture positives for Shigella and ETEC except one each were also positive by the RLDT, sensitivity 97% and 93% respectively. RLDT is a simple, sensitive, and rapid assay that could be implemented with minimum training in the endemic regions to strengthen the disease surveillance system and rapid outbreak detection.

Retention in care and antiretroviral therapy adherence among Medicaid beneficiaries with HIV, 2001-2015.

Disparities in HIV care by socioeconomic status, place of residence, and race/ethnicity prevent progress toward epidemic control. No study has comprehensively characterized the HIV care cascade among people with HIV enrolled in Medicaid - an insurance source for low-income individuals in the US. We analyzed data from 246,127 people with HIV enrolled in Medicaid 2001-2015, aged 18-64, living in 14 US states. We estimated monthly prevalence of four steps of the care cascade: retained in care/adherent to ART; retained/not adherent; not retained/adherent; not retained/not adherent. Beneficiaries were retained in care if they had an outpatient care encounter every six months. Adherence was based on medication possession ratio. We estimated prevalence using a non-parametric multi-state approach, accounting for death as a competing event and for Medicaid disenrollment using inverse probability of censoring weights. Across 2001-2015, the proportion of beneficiaries with HIV who were retained/ART adherent increased, overall and in all subgroups. By 2015, approximately half of beneficiaries were retained in care, and 42% of beneficiaries were ART adherent. We saw meaningful differences by race/ethnicity and region. Our work highlights an important disparity in the HIV care cascade by insurance status during this time period.

Receipt of Prostate-Specific Antigen Test in Medicaid Beneficiaries With and Without HIV in 2001-2015 in 14 States.

Studies have reported lower incidence of prostate cancer in men living with HIV compared with men without HIV for reasons that remain unclear. Lower prostate cancer screening in men living with HIV could explain these findings. We describe receipt of prostate-specific antigen (PSA) test each calendar year by HIV status in Medicaid beneficiaries enrolled in 14 U.S. states, 2001-2015. A total of 15,299,991 Medicaid beneficiaries aged 18-64 with ≥7 months of continuous enrollment were included in analyses. HIV diagnosis and PSA tests were identified using non-drug claims. Incidence rate ratios comparing receipt of PSA test by HIV status adjusted for age, race/ethnicity, state of residence, calendar year, comorbid conditions, benign prostatic conditions, and receipt of testosterone-replacement therapy were estimated using Poisson regression. Models were also stratified by state, and estimates were pooled using random-effects meta-analysis to account for heterogeneity by state. Models were additionally stratified by age and race/ethnicity. There were 42,503 PSA tests over 314,273 person-years and 1,669,835 PSA tests over 22,023,530 person-years observed in beneficiaries with and without HIV, respectively. The incidence of PSA test was slightly lower in men living with HIV than men without HIV (incidence rate ratio [IRR] = 0.98; 95% confidence interval [CI]: 0.97, 0.99) when adjusting for state. In the pooled estimate, the rate was higher among men living with HIV (IRR = 1.11; 95% CI: 0.97, 1.27). Pooled estimates indicated approximately equal or higher rates of PSA test in men living with HIV compared with men without HIV across models stratified by age and race/ethnicity groups. Findings do not support the hypothesis that differences in prostate cancer screening explain differences in incidence by HIV status.

Incidence of Colon Cancer Among Medicaid Beneficiaries With or Without Human Immunodeficiency Virus Under Comparable Colorectal Cancer Screening Patterns.

Background: People with human immunodeficiency virus (HIV; PWH) in the United States have a lower incidence of colon cancer than the general population. The lower incidence may be explained by differences in receipt of screening. Thus, we sought to estimate colon cancer incidence under scenarios in which Medicaid beneficiaries, with or without HIV, followed the same screening protocols. Methods: We used data from 1.5 million Medicaid beneficiaries who were enrolled in 14 US states in 2001-2015 and aged 50-64 years; 72 747 beneficiaries had HIV. We estimated risks of colon cancer and death by age, censoring beneficiaries when they deviated from 3 screening protocols, which were based on Medicaid's coverage policy for endoscopies during the time period, with endoscopy once every 2, 4, or 10 years. We used inverse probability weights to control for baseline and time-varying confounding and informative loss to follow-up. Analyses were performed overall, by sex, and by race/ethnicity. Results: PWH had a lower incidence of colon cancer than beneficiaries without HIV. Compared with beneficiaries without HIV, the risk difference at age 65 years was -1.6% lower (95% confidence interval, -2.3% to -.7%) among PWH with the 2-year protocol and -0.8% lower (-1.3% to -.3%) with the 10-year protocol. Results were consistent across subgroup and sensitivity analyses. Conclusions: Our findings suggest that the lower risk of colon cancer that has been observed among PWH aged 50-64 years compared with those without HIV is not due to differences in receipt of lower endoscopy. Keywords: colon cancer, colorectal cancer screening, endoscopy, Medicaid, human immunodeficiency virus.

Anoikis-related genes combined with single cell sequencing: Insights into model specification of lung adenocarcinoma and applicability for prognosis and therapy.

Background: Anoikis has therapeutic potential against different malignancies including lung adenocarcinoma. This study used anoikis and bioinformatics to construct a prognostic model for lung adenocarcinoma and explore new therapeutic strategies. Methods: Several bioinformatic algorithms (co-expression analysis, univariate Cox analysis, multivariate Cox analysis, and cross-validation) were used to screen anoikis-related genes (ARGs) to construct a risk model. Lung adenocarcinoma patients were divided into training and testing groups at a ratio of 1:1. The prognostic model was validated by risk score comparison between high- and low-risk groups using receiver operating characteristic curve (ROC), nomograms, independent prognostic analysis and principal component analysis. In addition, two anoikis-related genes patterns were classified utilizing consensus clustering method and were compared with each other in survival time, immune microenvironment, and regulation in pathway. Single cell sequencing was applied to analyze anoikis-related genes constructed the model. Results: This study demonstrated the feasibility of the model based on seven anoikis-related genes, as well as identifying axitinib, nibtinib and sorafenib as potential therapeutic strategies for LUAD. Risk score based on this model had could be used as an independent prognostic factor for lung adenocarcinoma (HR > 1; p < 0.001) and had the highest accuracy to predict survival compared with the clinical characteristics. Single cell sequencing analysis discovered Keratin 14 (KRT14, one of the seven anoikis-related genes) was mainly expressed in malignant cells in various cancers. Conclusion: We identified seven anoikis-related genes and constructed an accurate risk model based on bioinformatics analysis that can be used for prognostic prediction and for the design of therapeutic strategies in clinical practice.

Diagnosis and Prognosis of Non-small Cell Lung Cancer based on Machine Learning Algorithms.

BACKGROUND: Non-small cell lung cancer (NSCLC) has been the subject of intense scholarly debate. We aimed to identify the potential biomarkers via bioinformatics analysis. METHODS: Three datasets were downloaded from gene expression omnibus database (GEO). R software was applied to screen differentially expressed genes (DEGs)and analyze immune cell infiltrates. Gene set enrichment analysis (GSEA) showed significant function and pathway in two groups. The diagnostic markers were further investigated by multiple machine learning algorithms (least absolute shrinkage and selection operator (LASSO) and support vector machine-recursive feature elimination (SVM-RFE)). Various online analytic platforms were utilized to explore the expression and prognostic value of differential genes. Furthermore, western blotting was performed to test the effects of genes on cell proliferation in vitro. RESULTS: We identified 181 DEGs shared by two datasets and selected nine diagnostic markers. Those genes were also significantly overexpressed in the third dataset. Topoisomerase II alpha (TOP2A) is overexpressed in lung cancer and associated with a poor prognosis, which was confirmed using immunohistochemistry (IHC) and Western blotting. Additionally, TOP2A showed a negative correlation with immune cells, such as CD8+ T cells, eosinophils and natural killer (NK) cell. CONCLUSION: Collectively, for the first time, we applied multiple machine learning algorithms, online databases and experiments in vitro to show that TOP2A is a potential biomarker for lung adenocarcinoma and could facilitate the development of new treatment strategies.

5-methyladenosine regulators play a crucial role in development of chronic hypersensitivity pneumonitis and idiopathic pulmonary fibrosis.

5-methyladenosine (m5C) modification regulates gene expression and biological functions in oncologic areas. However, the effect of m5C modification in chronic hypersensitivity pneumonitis (CHP) and idiopathic pulmonary fibrosis (IPF) remains unknown. Expression data for 12 significant m5C regulators were obtained from the interstitial lung disease dataset. Five candidate m5C regulators, namely tet methylcytosine dioxygenase 2, NOP2/Sun RNA methyltransferase 5, Y-box binding protein 1, tRNA aspartic acid methyltransferase 1, and NOP2/Sun RNA methyltransferase 3 were screened using random forest and nomogram models to predict risks of pulmonary fibrosis. Next, we applied the consensus clustering method to stratify the samples with different m5C patterns into two groups (cluster A and B). Finally, we calculated immune cell infiltration scores via single-sample gene set enrichment analysis, then compared immune cell infiltration, related functions as well as the expression of programmed cell death 1 (PD-1, PDCD1) and programmed death protein ligand-1 (PD-L1, CD274) between the two clusters. Principal component analysis of m5C-related scores across the 288 samples revealed that cluster A had higher immune-related expression than B. Notably, T helper cell (Th) 2 type cytokines and Th1 signatures were more abundant in clusters A and B, respectively. Our results suggest that m5C is associated with and plays a crucial role in development of pulmonary fibrosis. These m5C patterns could be potential biomarkers for identification of CHP and IPF, and guide future development of immunotherapy or other new drugs strategies for pulmonary fibrosis.

Field evaluation of a simple and rapid diagnostic test, RLDT to detect Shigella and enterotoxigenic E. coli in Indian children.

The diagnostic assays currently used to detect Shigella spp. (Shigella) and enterotoxigenic Escherichia coli (ETEC) are complex or elaborate which make them difficult to apply in resource poor settings where these diseases are endemic. The simple and rapid nucleic acid amplification-based assay "Rapid LAMP-based Diagnostic Test (RLDT)" was evaluated to detect Shigella spp (Shigella) and enterotoxigenic Escherichia coli (ETEC) and determine the epidemiology of these pathogens in Kolkata, India. Stool samples (n = 405) from children under five years old with diarrhea seeking care at the hospitals were tested, and 85(21%) and 68(17%) by RLDT, 91(23%) and 58(14%) by quantitative PCR (qPCR) and 35(9%) and 15(4%) by culture, were positive for Shigella and ETEC, respectively. The RLDT showed almost perfect agreement with qPCR, Kappa 0.96 and 0.89; sensitivity 93% and 98%; specificity 100% and 97% for Shigella and ETEC, respectively. While RLDT detected 12% more Shigella and 13% more ETEC than culture, all culture positives for Shigella and ETEC except one each were also positive by the RLDT, sensitivity 97% and 93% respectively. RLDT is a simple, sensitive, and rapid assay that could be implemented with minimum training in the endemic regions to strengthen the disease surveillance system and rapid outbreak detection.

A Real-Time Global Inference Network for One-Stage Referring Expression Comprehension.

Referring expression comprehension (REC) is an emerging research topic in computer vision, which refers to the detection of a target region in an image given a test description. Most existing REC methods follow a multistage pipeline, which is computationally expensive and greatly limits the applications of REC. In this article, we propose a one-stage model toward real-time REC, termed real-time global inference network (RealGIN). RealGIN addresses the issues of expression diversity and complexity of REC with two innovative designs: adaptive feature selection (AFS) and Global Attentive ReAsoNing (GARAN). Expression diversity concerns varying expression content, which includes information such as colors, attributes, locations, and fine-grained categories. To address this issue, AFS adaptively fuses features of different semantic levels to tackle the changes in expression content. In contrast, expression complexity concerns the complex relational conditions in expressions that are used to identify the referent. To this end, GARAN uses the textual feature as a pivot to collect expression-aware visual information from all regions and then diffuses this information back to each region, which provides sufficient context for modeling the relational conditions in expressions. On five benchmark datasets, i.e., RefCOCO, RefCOCO+, RefCOCOg, ReferIT, and Flickr30k, the proposed RealGIN outperforms most existing methods and achieves very competitive performances against the most advanced one, i.e., MAttNet. More importantly, under the same hardware, RealGIN can boost the processing speed by 10-20 times over the existing methods.

Structural and mechanistic insights into the MCM8/9 helicase complex.

MCM8 and MCM9 form a functional helicase complex (MCM8/9) that plays an essential role in DNA homologous recombination repair for DNA double-strand break. However, the structural characterization of MCM8/9 for DNA binding/unwinding remains unclear. Here, we report structures of the MCM8/9 complex using cryo-electron microscopy single particle analysis. The structures reveal that MCM8/9 is arranged into a heterohexamer through a threefold symmetry axis, creating a central channel that accommodates DNA. Multiple characteristic hairpins from the N-terminal oligosaccharide/oligonucleotide (OB) domains of MCM8/9 protrude into the central channel and serve to unwind the duplex DNA. When activated by HROB, the structure of MCM8/9's N-tier ring converts its symmetry from C3 to C1 with a conformational change that expands the MCM8/9's trimer interface. Moreover, our structural dynamic analyses revealed that the flexible C-tier ring exhibited rotary motions relative to the N-tier ring, which is required for the unwinding ability of MCM8/9. In summary, our structural and biochemistry study provides a basis for understanding the DNA unwinding mechanism of MCM8/9 helicase in homologous recombination.