The value of a deep learning image reconstruction algorithm in whole-brain computed tomography perfusion in patients with acute ischemic stroke.

Background: Computed tomography perfusion (CTP) and computed tomography angiography (CTA) are valuable tools for diagnosing acute ischemic stroke (AIS). It is essential to obtain high-quality CTP and CTA images in short time. This study aimed to evaluate the image quality and diagnostic performance of brain CTP and CTA images generated from CTP reconstructed by a deep learning image reconstruction (DLIR) algorithm on patients with AIS. Methods: The study prospectively enrolled 54 patients with suspected AIS undergoing non-contrast CT and CTP within 24 hours. CTP datasets were reconstructed with three levels of adaptive statistical iterative reconstruction-Veo algorithm [ASIR-V 0% with filtered back projection (FBP), ASIR-V 40%, and ASIR-V 80%] and three levels of DLIR, including low (DLIR-L), medium (DLIR-M), and high (DLIR-H). CTA images were generated using the CTP datasets at the peak arterial phase. Objective parameters including signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and noise reduction rate. Subjective evaluation was assessed according to Abels scoring system. Perfusion parameters and detection accuracy for infarction core lesions were evaluated. The objective and subjective image quality of CTA images were also evaluated. Results: All reconstructions produced similar CT values (P>0.05). With the increase of ASIR-V and DLIR reconstruction strength, image noise decreased, while SNR and CNR increased for CTP images, especially in white matter. DLIR-H, DLIR-M, and ASIR-V80% yielded higher subjective scores than did ASIR-V40% and FBP. DLIR-H provided the highest noise reduction rate and detection accuracy. No significant difference was found in conventional parameters, the volume of infarct core, or ischemic penumbra among the 6 groups (P>0.05). The objective evaluation of reconstructed CTA images was comparable in DLIR-H, DLIR-M, and ASIR-V80% (P>0.05). The subjective scores of the DLIR-H and DLIR-M images were higher than those of the other groups, especially ASIR-V40% and FBP (P<0.05). Conclusions: Compared with FBP and ASIR-V40%, DLIR-H, DLIR-M, and ASIR-V80% improved the overall image quality of CTP and CTA images to varying degrees. Furthermore, DLIR-H and DLIR-M showed the best performance. DLIR-H is the best choice in diagnosing AIS with improved detection accuracy for cerebral infarction. Reconstructing CTA images using CTP datasets could reduce contrast agent and radiation dose.

The courage to venture: Revealing the effect of social trust on corporate venture capital.

In an uncertain and risky business environment, the decision for corporate venture capital (CVC) often requires courage and determination. This article empirically examines the relationship between social trust and corporate venture capital based on CVC data from Chinese companies spanning from 2006 to 2018. The findings reveal that social trust significantly positively influences a company's willingness and scale of involvement in venture capital. Further analysis highlights the variations in social trust effects under diverse governance environments, particularly in non-state-owned firms and firms with separate CEO and chairman roles. Meanwhile, in regions characterized by a more developed market environment and a robust legal framework, social trust demonstrates a more pronounced motivating effect. Moreover, social trust fosters innovation within CVC deals. Focused on emerging markets, this research delves into the significance of informal institutions in incentivizing corporate innovation and venture capital, offering a fresh perspective on the driving forces behind CVC.

Digital-scRRBS: A Cost-Effective, Highly Sensitive, and Automated Single-Cell Methylome Analysis Platform via Digital Microfluidics.

Single-cell DNA methylation sequencing is highly effective for identifying cell subpopulations and constructing epigenetic regulatory networks. Existing methylome analyses require extensive starting materials and are costly, complex, and susceptible to contamination, thereby impeding the development of single-cell methylome technology. In this work, we report digital microfluidics-based single-cell reduced representation bisulfite sequencing (digital-scRRBS), the first microfluidics-based single-cell methylome library construction platform, which is an automatic, effective, reproducible, and reagent-efficient technique to dissect the single-cell methylome. Using our digital microfluidic chip, we isolated single cells in 15 s and successfully constructed single-cell methylation sequencing libraries with a unique genome mapping rate of up to 53.6%, covering up to 2.26 million CpG sites. Digital-scRRBS demonstrates a high capacity for distinguishing cell identity and tracking DNA methylation during drug administration. Digital-scRRBS expands the applicability of single-cell methylation methods as a versatile tool for epigenetic analysis of rare cells and populations with high levels of heterogeneity.

Child-Sum EATree-LSTMs: enhanced attentive Child-Sum Tree-LSTMs for biomedical event extraction.

BACKGROUND: Tree-structured neural networks have shown promise in extracting lexical representations of sentence syntactic structures, particularly in the detection of event triggers using recursive neural networks. METHODS: In this study, we introduce an attention mechanism into Child-Sum Tree-LSTMs for the detection of biomedical event triggers. We incorporate previous researches on assigning attention weights to adjacent nodes and integrate this mechanism into Child-Sum Tree-LSTMs to improve the detection of event trigger words. We also address a limitation of shallow syntactic dependencies in Child-Sum Tree-LSTMs by integrating deep syntactic dependencies to enhance the effect of the attention mechanism. RESULTS: Our proposed model, which integrates an enhanced attention mechanism into Tree-LSTM, shows the best performance for the MLEE and BioNLP'09 datasets. Moreover, our model outperforms almost all complex event categories for the BioNLP'09/11/13 test set. CONCLUSION: We evaluate the performance of our proposed model with the MLEE and BioNLP datasets and demonstrate the advantage of an enhanced attention mechanism in detecting biomedical event trigger words.

Well-TEMP-seq as a microwell-based strategy for massively parallel profiling of single-cell temporal RNA dynamics.

Single-cell RNA sequencing (scRNA-seq) reveals the transcriptional heterogeneity of cells, but the static snapshots fail to reveal the time-resolved dynamics of transcription. Herein, we develop Well-TEMP-seq, a high-throughput, cost-effective, accurate, and efficient method for massively parallel profiling the temporal dynamics of single-cell gene expression. Well-TEMP-seq combines metabolic RNA labeling with scRNA-seq method Well-paired-seq to distinguish newly transcribed RNAs marked by T-to-C substitutions from pre-existing RNAs in each of thousands of single cells. The Well-paired-seq chip ensures a high single cell/barcoded bead pairing rate (~80%) and the improved alkylation chemistry on beads greatly alleviates chemical conversion-induced cell loss (~67.5% recovery). We further apply Well-TEMP-seq to profile the transcriptional dynamics of colorectal cancer cells exposed to 5-AZA-CdR, a DNA-demethylating drug. Well-TEMP-seq unbiasedly captures the RNA dynamics and outperforms the splicing-based RNA velocity method. We anticipate that Well-TEMP-seq will be broadly applicable to unveil the dynamics of single-cell gene expression in diverse biological processes.

Deep transfer learning enables lesion tracing of circulating tumor cells.

Liquid biopsy offers great promise for noninvasive cancer diagnostics, while the lack of adequate target characterization and analysis hinders its wide application. Single-cell RNA sequencing (scRNA-seq) is a powerful technology for cell characterization. Integrating scRNA-seq into a CTC-focused liquid biopsy study can perhaps classify CTCs by their original lesions. However, the lack of CTC scRNA-seq data accumulation and prior knowledge hinders further development. Therefore, we design CTC-Tracer, a transfer learning-based algorithm, to correct the distributional shift between primary cancer cells and CTCs to transfer lesion labels from the primary cancer cell atlas to CTCs. The robustness and accuracy of CTC-Tracer are validated by 8 individual standard datasets. We apply CTC-Tracer on a complex dataset consisting of RNA-seq profiles of single CTCs, CTC clusters from a BRCA patient, and two xenografts, and demonstrate that CTC-Tracer has potential in knowledge transfer between different types of RNA-seq data of lesions and CTCs.

Dapagliflozin Attenuates Contrast-induced Acute Kidney Injury by Regulating the HIF-1α/HE4/NF-κB Pathway.

ABSTRACT: Contrast-induced acute kidney injury (CI-AKI) causes clinically acquired nephropathy in patients who undergo coronary interventions. Hypoxic injury to proximal tubular epithelial cells is a pathological mechanism of CI-AKI. Previous studies have shown that hypoxia activates HIF-1α/HE4/NF-κB to enhance renal fibrosis, and the SGLT-2 inhibitor luseogliflozin inhibits hypoxia-inducible factor (HIF)-1α expression to reduce the progression of diabetic nephropathy. However, the therapeutic effects and mechanisms of SGLT-2 inhibitors on CI-AKI are unclear. We explored the role of the HIF-1α/HE4/NF-κB pathway in CI-AKI and how dapagliflozin effectively treats CI-AKI by inhibiting this pathway. In vitro, cells were divided into the control, hypoxia, hypoxia + dapagliflozin, and hypoxia + pSilencer-HIF-1α groups. Cellular hypoxia, apoptosis, and related protein expression were evaluated by immunofluorescence, western blotting, and flow cytometry, respectively. Dapagliflozin significantly decreased oxygen consumption, HIF-1α, human epididymis protein 4 (HE4), NF-κB expression, and apoptotic cells compared with the control (P < 0.01). In vivo, rats were divided into the control (C), diabetes (D), diabetes + contrast media, and diabetes + contrast media + dapagliflozin groups. Rats in the latter 2 groups were treated with dapagliflozin for 2 days. CI-AKI was induced by intravenously injecting indomethacin, N-nitro-l-arginine methyl ester, and iohexol. The effects of dapagliflozin on CI-AKI rats were elucidated by assessing renal function, H&E staining, and immunohistochemistry. Serum creatinine, urea nitrogen, TUNEL-positive tubular cells, HIF-1α, HE4, NF-κB expression, and histopathological scores were increased in diabetes + contrast media rats compared with C, D, and diabetes + dapagliflozin + contrast media rats (P < 0.01). Thus, dapagliflozin may ameliorate CI-AKI through suppression of HIF-1α/HE4/NF-κB signaling in vitro and in vivo.

LINEAGE: Label-free identification of endogenous informative single-cell mitochondrial RNA mutation for lineage analysis.

Single-cell RNA-sequencing (scRNA-seq) has become a powerful tool for biomedical research by providing a variety of valuable information with the advancement of computational tools. Lineage analysis based on scRNA-seq provides key insights into the fate of individual cells in various systems. However, such analysis is limited by several technical challenges. On top of the considerable computational expertise and resources, these analyses also require specific types of matching data such as exogenous barcode information or bulk assay for transposase-accessible chromatin with high throughput sequencing (ATAC-seq) data. To overcome these technical challenges, we developed a user-friendly computational algorithm called "LINEAGE" (label-free identification of endogenous informative single-cell mitochondrial RNA mutation for lineage analysis). Aiming to screen out endogenous markers of lineage located on mitochondrial reads from label-free scRNA-seq data to conduct lineage inference, LINEAGE integrates a marker selection strategy by feature subspace separation and de novo "low cross-entropy subspaces" identification. In this process, the mutation type and subspace-subspace "cross-entropy" of features were both taken into consideration. LINEAGE outperformed three other methods, which were designed for similar tasks as testified with two standard datasets in terms of biological accuracy and computational efficiency. Applied on a label-free scRNA-seq dataset of BRAF-mutated cancer cells, LINEAGE also revealed genes that contribute to BRAF inhibitor resistance. LINEAGE removes most of the technical hurdles of lineage analysis, which will remarkably accelerate the discovery of the important genes or cell-lineage clusters from scRNA-seq data.

Association of hemoglobin A1c with the incidence of hypertension: A large prospective study.

Background: Although hemoglobin A1c (HbA1c) is closely related to diabetes, its relationship with the incidence of hypertension is still unknown, so we aimed to evaluate the relationship between HbA1c and the incidence of hypertension in the general population. Method: In this large prospective cohort study with a median follow-up of 2 years, we included 4,074 participants from the China Health and Nutrition Survey (CHNS). Multivariate COX regression, subgroup analysis, receiver operator characteristic (ROC) curve and restricted cubic spline (RCS) were used to evaluate the relationship between HbA1c and incidental hypertension. Results: Compared with participants without incident hypertension, participants with incident hypertension had higher levels of HbA1c (P < 0.05). In univariate COX regression analysis, HbA1c was associated with the risk of hypertension (HR: 1.161, 95% CI: 1.105-1.221, P < 0.001). In multivariate COX regression analysis adjusted for confounding variables, HbA1c was still closely related to the risk of hypertension (HR: 1.102, 95% CI: 1.006-1.206, P = 0.037). And subgroup analysis showed that the relationship between HbA1c and hypertension remained significant in female, lower than high school and non-obese subgroups (P < 0.05). ROC curve also showed that HbA1c could predict the risk of hypertension (AUC = 0.583, 95% CI: 0.568-0.598, P < 0.001). Further RCS analysis showed that HbA1c was positively correlated with the risk of hypertension (P for nonlinearity = 0.642). Conclusion: HbA1c was linearly and positively associated with the incidence of hypertension.

NADPH-Cytochrome P450 Reductase Ccr1 Is a Target of Tamoxifen and Participates in Its Antifungal Activity via Regulating Cell Wall Integrity in Fission Yeast.

Invasive fungal diseases are a leading cause of mortality among immunocompromised populations. Treatment is notoriously difficult due to the limited number of antifungal drugs as well as the emergence of drug resistance. Tamoxifen (TAM), a selective estrogen receptor modulator frequently used for the treatment of breast cancer, has been found to have antifungal activities and may be a useful addition to the agents used to treat fungal infectious diseases. However, the molecular mechanisms underlying its antifungal actions remain obscure. Here, we screened for mutations that confer sensitivity to azole antifungal drugs by using the fission yeast Schizosaccharomyces pombe as a model and isolated a mutant with a mutation in cls1 (ccr1), an allele of the gene encoding the NADPH-cytochrome P450 reductase Ccr1. We found that strains with a deletion of the ccr1+ gene exhibited hypersensitivities to various drugs, including antifungal drugs (azoles, terbinafine, micafungin), the immunosuppressor FK506, and the anticancer drugs TAM and 5-fluorouracil (5-FU). Unexpectedly, the overexpression of Ccr1 caused yeast cell resistance to TAM but not the other drugs tested here. Additionally, strains with a deletion of Ccr1 displayed pleiotropic phenotypes, including defects in cell wall integrity and vacuole fusion, enhanced calcineurin activity, as well as increased intracellular Ca2+ levels. Overexpression of the constitutively active calcineurin suppressed the drug-sensitive phenotypes of the Δccr1 cells. Notably, TAM treatment of wild-type cells resulted in pleiotropic phenotypes, similar to those of cells lacking Ccr1. Furthermore, TAM inhibited Ccr1 NADPH-cytochrome P450 reductase activities in a dose-dependent manner. Moreover, TAM treatment also inhibited the NADPH-cytochrome P450 reductase activities of Candida albicans and resulted in defective cell wall integrity. Collectively, our findings suggest that Ccr1 is a novel target of TAM and is involved in the antifungal activity of TAM by regulating cell wall integrity in fission yeast.

Influence of Japanese diet consumption during pregnancy and lactation on lipid metabolism in offspring.

OBJECTIVE: Previous studies have demonstrated that obesity is rare among those who consume the Japanese diet because of its lower caloric content compared with the American diet. Meanwhile, it has been reported that maternal caloric restriction, which induces antiobesity effects, during pregnancy and lactation increases the likelihood of a low birthweight infant, which increases the risks for obesity and diabetes later in life. The aim of this study was to examine the influence of maternal consumption of the Japanese diet during pregnancy and lactation on the risk for obesity and diabetes in the offspring later in life. METHODS: Pregnant mice were divided into three groups and fed either a control diet, Western diet, or Japanese diet, and their offspring were raised until 7 wk old. RESULTS: Examinations of 18-d-old and 7-wk-old offspring showed no effect of consistently eating a Japanese diet during pregnancy and lactation on the health conditions of 18-d-old offspring, but 7-wk-old offspring showed a decrease in visceral fat and liver triacylglycerol levels. In addition, 7-wk-old offspring from mothers who consumed the Japanese diet during pregnancy and lactation showed a decrease in the homeostatic model assessment of insulin resistance and a reduced risk for developing diabetes. This tendency was also confirmed in 18-d-old offspring. Evaluation of the mechanism revealed that fatty acid synthesis in the liver of the offspring was suppressed by the mother's consumption of the Japanese diet. CONCLUSION: From these results, maternal consumption of the Japanese diet during pregnancy and lactation did not adversely affect the offspring, and continual intake of this diet reduced the risk for developing obesity and diabetes in the offspring later in life.

Effect of the Japanese diet during pregnancy and lactation or post-weaning on the risk of metabolic syndrome in offspring.

We examined the effects on offspring of ingestion of the 1975 Japanese diet during pregnancy and lactation and after weaning in mice. Pregnant dams were divided into groups that were fed the Japanese diet or a control diet and raised until offspring were weaned. The offspring after weaning were further divided into groups that were raised on the Japanese diet or the control diet. Ingestion of the Japanese diet after weaning suppressed accumulation of visceral fat in offspring, and reduced the amount of lipids in serum and liver. This effect was weakened if the Japanese diet was only ingested during pregnancy and lactation. Therefore, it was suggested that ingestion of the Japanese diet of mothers during pregnancy and lactation weakens the lipid accumulation inhibitory effect of the Japanese diet in children.

Autofluorescence imaging endoscopy can distinguish non-erosive reflux disease from functional heartburn: A pilot study.

AIM: To investigate whether autofluorescence imaging (AFI) endoscopy can distinguish non-erosive reflux disease (NERD) from functional heartburn (FH). METHODS: In this prospective observational trial, 127 patients presenting with typical reflux symptoms for > 6 mo were screened. All the participants underwent endoscopy, during which white light imaging (WLI) was followed by AFI. Finally 84 patients with normal esophageal appearance on WLI were enrolled. It was defined as being suggestive of NERD if one or more longitudinal purple lines longer than one centimeter were visualized in the distal part of the esophagus during AFI endoscopy. Ambulatory 24-h multichannel intraluminal impedance and pH monitoring was also performed. After standard proton-pump inhibitor (PPI) tests, subjects were divided into an NERD group and an FH group and the diagnostic performance of AFI endoscopy to differentiate NERD from FH was evaluated. RESULTS: Of 84 endoscopy-negative patients, 36 (42.9%) had a normal pH/impedance test. Of these, 26 patients with favorable responses to PPI tests were classified as having NERD. Finally 10 patients were diagnosed with FH and the others with NERD. Altogether, 68 (81.0%) of the 84 patients were positive on AFI endoscopy. In the NERD group, there were 67 (90.5%) patients with abnormal esophageal findings on AFI endoscopy while only 1 (10%) patient was positive on AFI endoscopy in the FH group. The sensitivity and specificity of AFI in differentiating NERD from FH were 90.5% (95%CI: 81.5%-96.1%) and 90.0% (95%CI: 55.5%-99.7%), respectively. Meanwhile, the accuracy, positive predictive value and negative predictive value of AFI in differentiating between NERD and FH were 90.5% (95%CI: 84.2%-96.8%), 98.5% (95%CI: 92.1%-99.9%) and 56.3% (95%CI: 30.0%-80.2%), respectively. CONCLUSION: Autofluorescence imaging may serve as a complementary method in evaluating patients with NERD and FH.

Gastrointestinal problems in modern wars: clinical features and possible mechanisms.

Gastrointestinal problems are common during wars, and they have exerted significant adverse effects on the health of service members involved in warfare. The spectrum of digestive diseases has varied during wars of different eras. At the end of the 20th century, new frontiers of military medical research emerged due to the occurrence of high-tech wars such as the Gulf War and the Kosovo War, in which ground combat was no longer the primary method of field operations. The risk to the military personnel who face trauma has been greatly reduced, but disease and non-battle injuries (DNBIs) such as neuropsychological disorders and digestive diseases seemed to be increased. Data revealed that gastrointestinal symptoms such as constipation, diarrhea, dyspepsia, and noncardiac chest pain are common among military personnel during modern wars. In addition, a large number of deployed soldiers and veterans who participated in recent wars presented with chronic gastrointestinal complaints, which fulfilled with the Rome III criteria for functional gastrointestinal disorders (FGIDs). It was also noted that many veterans who returned from the Gulf War suffered not only from chronic digestive symptoms but also from neuropsychological dysfunction; however, they also showed symptoms of other systems. Presently, this broad range of unexplained symptoms is known as "Gulf War syndrome". The mechanism that underlies Gulf War syndrome remains unclear, but many factors have been associated with this syndrome such as war trauma, stress, infections, immune dysfunction, radiological factors, anthrax vaccination and so on. Some have questioned if the diagnosis of FGIDs can be reached given the complexity of the military situation. As a result, further studies are needed to elucidate the pathogenesis of gastrointestinal disease among military personnel.