A deep learning-driven discovery of berberine derivatives as novel antibacterial against multidrug-resistant Helicobacter pylori.

Helicobacter pylori (H. pylori) is currently recognized as the primary carcinogenic pathogen associated with gastric tumorigenesis, and its high prevalence and resistance make it difficult to tackle. A graph neural network-based deep learning model, employing different training sets of 13,638 molecules for pre-training and fine-tuning, was aided in predicting and exploring novel molecules against H. pylori. A positively predicted novel berberine derivative 8 with 3,13-disubstituted alkene exhibited a potency against all tested drug-susceptible and resistant H. pylori strains with minimum inhibitory concentrations (MICs) of 0.25-0.5 µg/mL. Pharmacokinetic studies demonstrated an ideal gastric retention of 8, with the stomach concentration significantly higher than its MIC at 24 h post dose. Oral administration of 8 and omeprazole (OPZ) showed a comparable gastric bacterial reduction (2.2-log reduction) to the triple-therapy, namely OPZ + amoxicillin (AMX) + clarithromycin (CLA) without obvious disturbance on the intestinal flora. A combination of OPZ, AMX, CLA, and 8 could further decrease the bacteria load (2.8-log reduction). More importantly, the mono-therapy of 8 exhibited comparable eradication to both triple-therapy (OPZ + AMX + CLA) and quadruple-therapy (OPZ + AMX + CLA + bismuth citrate) groups. SecA and BamD, playing a major role in outer membrane protein (OMP) transport and assembling, were identified and verified as the direct targets of 8 by employing the chemoproteomics technique. In summary, by targeting the relatively conserved OMPs transport and assembling system, 8 has the potential to be developed as a novel anti-H. pylori candidate, especially for the eradication of drug-resistant strains.

Harmonized cross-species cell atlases of trigeminal and dorsal root ganglia.

Sensory neurons in the dorsal root ganglion (DRG) and trigeminal ganglion (TG) are specialized to detect and transduce diverse environmental stimuli to the central nervous system. Single-cell RNA sequencing has provided insights into the diversity of sensory ganglia cell types in rodents, nonhuman primates, and humans, but it remains difficult to compare cell types across studies and species. We thus constructed harmonized atlases of the DRG and TG that describe and facilitate comparison of 18 neuronal and 11 non-neuronal cell types across six species and 31 datasets. We then performed single-cell/nucleus RNA sequencing of DRG from both human and the highly regenerative axolotl and found that the harmonized atlas also improves cell type annotation, particularly of sparse neuronal subtypes. We observed that the transcriptomes of sensory neuron subtypes are broadly similar across vertebrates, but the expression of functionally important neuropeptides and channels can vary notably. The resources presented here can guide future studies in comparative transcriptomics, simplify cell-type nomenclature differences across studies, and help prioritize targets for future analgesic development.

Parvalbumin gates chronic pain through the modulation of firing patterns in inhibitory neurons.

Spinal cord dorsal horn inhibition is critical to the processing of sensory inputs, and its impairment leads to mechanical allodynia. How this decreased inhibition occurs and whether its restoration alleviates allodynic pain are poorly understood. Here, we show that a critical step in the loss of inhibitory tone is the change in the firing pattern of inhibitory parvalbumin (PV)-expressing neurons (PVNs). Our results show that PV, a calcium-binding protein, controls the firing activity of PVNs by enabling them to sustain high-frequency tonic firing patterns. Upon nerve injury, PVNs transition to adaptive firing and decrease their PV expression. Interestingly, decreased PV is necessary and sufficient for the development of mechanical allodynia and the transition of PVNs to adaptive firing. This transition of the firing pattern is due to the recruitment of calcium-activated potassium (SK) channels, and blocking them during chronic pain restores normal tonic firing and alleviates chronic pain. Our findings indicate that PV is essential for controlling the firing pattern of PVNs and for preventing allodynia. Developing approaches to manipulate these mechanisms may lead to different strategies for chronic pain relief.

ElecFeX is a user-friendly toolbox for efficient feature extraction from single-cell electrophysiological recordings.

Characterizing neurons by their electrophysiological phenotypes is essential for understanding the neural basis of behavioral and cognitive functions. Technological developments have enabled the collection of hundreds of neural recordings; this calls for new tools capable of performing feature extraction efficiently. To address the urgent need for a powerful and accessible tool, we developed ElecFeX, an open-source MATLAB-based toolbox that (1) has an intuitive graphical user interface, (2) provides customizable measurements for a wide range of electrophysiological features, (3) processes large-size datasets effortlessly via batch analysis, and (4) yields formatted output for further analysis. We implemented ElecFeX on a diverse set of neural recordings; demonstrated its functionality, versatility, and efficiency in capturing electrical features; and established its significance in distinguishing neuronal subgroups across brain regions and species. ElecFeX is thus presented as a user-friendly toolbox to benefit the neuroscience community by minimizing the time required for extracting features from their electrophysiological datasets.

Electrochemical Biosensor for Protein Concentration Monitoring Using Natural Wood Evaporation for Power Generation.

A high-sensitivity, low-cost, self-powered biomass electrochemical biosensor based on the "evaporating potential" theory is developed for protein detection. The feasibility of experimental evaluation methods was verified with a probe protein of bovine serum albumin. The sensor was then used to detect lung cancer marker CYFRA21-1, and the potential of our sensor for clinical diagnosis was demonstrated by serum analysis. This work innovatively exploits the osmotic power generation capability of natural wood to construct a promising electrochemical biosensor that was driven by kinetics during testing. The detection methods used for this sensor, chronoamperometry and AC impedance, showed potential for quantitative analysis and specific detection, respectively. Furthermore, the sensor could facilitate new insights into the development of high-sensitivity, low-cost, and easy-to-use electrochemical biosensors.

Strategies for Enhancing the Photocatalytic and Electrocatalytic Efficiency of Covalent Triazine Frameworks for CO2 Reduction.

Converting carbon dioxide (CO2) into fuel and high-value-added chemicals is considered a green and effective way to solve global energy and environmental problems. Covalent triazine frameworks (CTFs) are extensively utilized as an emerging catalyst for photo/electrocatalytic CO2 reduction reaction (CO2RR) recently recognized for their distinctive qualities, including excellent thermal and chemical stability, π-conjugated structure, rich nitrogen content, and a strong affinity for CO2, etc. Nevertheless, single-component CTFs have the problems of accelerated recombination of photoexcited electron-hole pairs and restricted conductivity, which limit their application for photo/electrocatalytic CO2RR. Therefore, emphasis will then summarize the strategies for enhancing the photocatalytic and electrocatalytic efficiency of CTFs for CO2RR in this paper, including atom doping, constructing a heterojunction structure, etc. This review first illustrates the synthesis strategies of CTFs and the advantages of CTFs in the field of photo/electrocatalytic CO2RR. Subsequently, the mechanism of CTF-based materials in photo/electrocatalytic CO2RR is described. Lastly, the challenges and future prospects of CTFs in photo/electrocatalytic CO2RR are addressed, which offers a fresh perspective for the future development of CTFs in photo/electrocatalytic CO2RR.

Dynamic and visual nomograms to online predict unfavorable outcome of mechanical thrombectomy for acute basilar artery occlusion.

BACKGROUND: The evidence of mechanical thrombectomy (MT) in basilar artery occlusion (BAO) was limited. This study aimed to develop dynamic and visual nomogram models to predict the unfavorable outcome of MT in BAO online. METHODS: BAO patients treated with MT were screened. Preoperative and postoperative nomogram models were developed based on clinical parameters and imaging features. An independent dataset was collected to perform external validation. Web-based calculators were constructed to provide convenient access. RESULTS: A total of 127 patients were included in the study, and 117 of them were eventually included in the analysis. The nomogram models showed robust discrimination, with an area under the receiver operating characteristic (ROC) of 0.841 (preoperative) and 0.916 (postoperative). The calibration curves showed good agreement. The preoperative predictors of an unfavorable outcome were previous stroke, the National Institutes of Health Stroke Scale (NIHSS) at admission, and the posterior circulation Alberta Stroke Program Early Computed Tomography Score (pc-ASPECTS). The postoperative predictors were previous stroke, NIHSS at 24 h, and pc-ASPECTS. CONCLUSION: Dynamic and visual nomograms were constructed and validated for the first time for BAO patients treated with MT, which provided precise predictions for the risk of an unfavorable outcome. The preoperative model may assist clinicians in selecting eligible patients, and the postoperative model may facilitate individualized poststroke management.

Strategies for improving the stability of perovskite for photocatalysis: A review of recent progress.

Photocatalysis is currently a hot research field, which provides promising processes to produce green energy sources and other useful products, thus eventually benefiting carbon emission reduction and leading to a low-carbon future. The development and application of stable and efficient photocatalytic materials is one of the main technical bottlenecks in the field of photocatalysis. Perovskite has excellent performance in the fields of photocatalytic hydrogen evolution reaction (HER), oxygen evolution reaction (OER), carbon dioxide reduction reaction (CO2RR), organic synthesis and pollutant degradation due to its unique structure, flexibility and resulting excellent photoelectric and catalytic properties. The stability problems caused by perovskite's susceptibility to environmental influences hinder its further application in the field of photocatalysis. Therefore, this paper innovatively summarizes and analyzes the existing methods and strategies to improve the stability of perovskite in the field of photocatalysis. Specifically, (i) component engineering, (ii) morphological control, (iii) hybridization and encapsulation are thought to improve the stability of perovskites while improving photocatalytic efficiency. Finally, the challenges and prospects of perovskite photocatalysts are discussed, which provides constructive thinking for the potential application of perovskite photocatalysts.

A review of polybrominated diphenyl ethers and novel brominated flame retardants in Chinese aquatic environment: Source, occurrence, distribution, and ecological risk assessment.

Due to the widespread commercial production and use of brominated flame retardants (BFRs) in China, their potential impact on human health development should not be underestimated. This review searched the literature on Polybrominated diphenyl ethers and Novel brominated flame retardant (PBDEs and NBFRs) (broad BFRs) in the aquatic environment (including surface water and sediment) in China over the last decade. It was found that PBDEs and NBFRs entered the aquatic environment through four main pathways, atmospheric deposition, surface runoff, sewage effluent and microplastic decomposition. The distribution of PBDEs and NBFRs in the aquatic environment was highly correlated with the local economic structure and population density. In addition, a preliminary risk assessment of existing PBDEs and PBDEs in sediments showed that areas with high-risk quotient values were always located in coastal areas with e-waste dismantling sites, which was mainly attributed to the historical legacy of electronic waste. This research provides help for the human health development and regional risk planning management posed by PBDEs and NBFRs.

Harmonized cross-species cell atlases of trigeminal and dorsal root ganglia.

Peripheral sensory neurons in the dorsal root ganglion (DRG) and trigeminal ganglion (TG) are specialized to detect and transduce diverse environmental stimuli including touch, temperature, and pain to the central nervous system. Recent advances in single-cell RNA-sequencing (scRNA-seq) have provided new insights into the diversity of sensory ganglia cell types in rodents, non-human primates, and humans, but it remains difficult to compare transcriptomically defined cell types across studies and species. Here, we built cross-species harmonized atlases of DRG and TG cell types that describe 18 neuronal and 11 non-neuronal cell types across 6 species and 19 studies. We then demonstrate the utility of this harmonized reference atlas by using it to annotate newly profiled DRG nuclei/cells from both human and the highly regenerative axolotl. We observe that the transcriptomic profiles of sensory neuron subtypes are broadly similar across vertebrates, but the expression of functionally important neuropeptides and channels can vary notably. The new resources and data presented here can guide future studies in comparative transcriptomics, simplify cell type nomenclature differences across studies, and help prioritize targets for future pain therapy development.

Epigenomic profiling of mouse nucleus accumbens at single-cell resolution.

The nucleus accumbens (NAc) is a key brain region involved in reward processing and is linked to multiple neuropsychiatric conditions such as substance use disorder, depression, and chronic pain. Recent studies have begun to investigate NAc gene expression at a single-cell resolution, however, our understanding of the cellular heterogeneity of the NAc epigenomic landscape remains limited. In this study, we utilize single-nucleus assay for transposase-accessible chromatin using sequencing (snATAC-seq) to map cell-type-specific differences in chromatin accessibility in the NAc. Our findings not only reveal the transcription factors and putative gene regulatory elements that may contribute to these cell-type-specific epigenomic differences but also provide a valuable resource for future studies investigating epigenomic changes that occur in neuropsychiatric disorders.

Influence of tirofiban on stroke outcome after mechanical thrombectomy in acute vertebrobasilar artery occlusion.

BACKGROUND: Even undergoing mechanical thrombectomy (MT), patients with acute vertebrobasilar artery occlusion (AVBAO) still have a high rate of mortality. Tirofiban is a novel antiplatelet agent which is now widely empirically used in acute ischemic stroke (AIS). In this study, we aimed to evaluate the safety and efficacy of tirofiban as adjunctive therapy for MT in AVBAO. METHODS: From October 2016 to July 2021, consecutive AVBAO patients receiving MT were included in the prospective stroke registry. The short-term outcomes were (1) symptomatic intracerebral hemorrhage (sICH); (2) in-hospital death; (3) National Institute of Health Stroke Scale (NIHSS) at discharge. The Long-term outcomes were: (1) modified Rankin Scale (mRS) at 3 months; (2) death at 3 months. RESULTS: A total of 130 eligible patients were included in the study, 64 (49.2%) patients received tirofiban. In multivariate regression analysis, no significant differences were observed in all outcomes between the tirofiban and non-tirofiban group [sICH (adjusted OR 0.96; 95% CI, 0.12-7.82, p = 0.97), in-hospital death (adjusted OR 0.57; 95% CI, 0.17-1.89, p = 0.36), NIHSS at discharge (95% CI, -2.14-8.63, p = 0.24), mRS (adjusted OR 1.20; 95% CI, 0.40-3.62, p = 0.75), and death at 3 months (adjusted OR 0.83; 95% CI, 0.24-2.90, p = 0.77)]. CONCLUSIONS: In AVBAO, tirofiban adjunctive to MT was not associated with an increased risk of sICH. Short-term (in-hospital death, NIHSS at discharge) and long-term outcomes (mRS and death at 3 months) seem not to be influenced by tirofiban use.

Role of Intestinal Microbes in Chronic Liver Diseases.

With the recent availability and upgrading of many emerging intestinal microbes sequencing technologies, our research on intestinal microbes is changing rapidly. A variety of investigations have found that intestinal microbes are essential for immune system regulation and energy metabolism homeostasis, which impacts many critical organs. The liver is the first organ to be traversed by the intestinal portal vein, and there is a strong bidirectional link between the liver and intestine. Many intestinal factors, such as intestinal microbes, bacterial composition, and intestinal bacterial metabolites, are deeply involved in liver homeostasis. Intestinal microbial dysbiosis and increased intestinal permeability are associated with the pathogenesis of many chronic liver diseases, such as alcoholic fatty liver disease (AFLD), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), chronic hepatitis B (CHB), chronic hepatitis C (CHC), autoimmune liver disease (AIH) and the development of hepatocellular carcinoma (HCC). Intestinal permeability and dysbacteriosis often lead to Lipopolysaccharide (LPS) and metabolites entering in serum. Then, Toll-like receptors activation in the liver induces the exposure of the intestine and liver to many small molecules with pro-inflammatory properties. And all of these eventually result in various liver diseases. In this paper, we have discussed the current evidence on the role of various intestinal microbes in different chronic liver diseases. As well as potential new therapeutic approaches are proposed in this review, such as antibiotics, probiotics, and prebiotics, which may have an improvement in liver diseases.

High-frequency repetitive transcranial magnetic stimulation (rTMS) protects against ischemic stroke by inhibiting M1 microglia polarization through let-7b-5p/HMGA2/NF-κB signaling pathway.

BACKGROUND: Microglia assume opposite phenotypes in response to ischemic brain injury, exerting neurotoxic and neuroprotective effects under different ischemic stages. Modulating M1/M2 polarization is a potential therapy for treating ischemic stroke. Repetitive transcranial magnetic stimulation (rTMS) held the capacity to regulate neuroinflammation and astrocytic polarization, but little is known about rTMS effects on microglia. Therefore, the present study aimed to examine the rTMS influence on microglia polarization and the underlying possible molecular mechanisms in ischemic stroke models. METHODS: Previously reported 10 Hz rTMS protocol that regulated astrocytic polarization was used to stimulate transient middle cerebral artery occlusion (MCAO) rats and oxygen and glucose deprivation/reoxygenation (OGD/R) injured BV2 cells. Specific expression levels of M1 marker iNOS and M2 marker CD206 were measured by western blotting and immunofluorescence. MicroRNA expression changes detected by high-throughput second-generation sequencing were validated by RT-PCR and fluorescence in situ hybridization (FISH) analysis. Dual-luciferase report assay and miRNA knock-down were applied to verify the possible mechanisms regulated by rTMS. Microglia culture medium (MCM) from different groups were collected to measure the TNF-α and IL-10 concentrations, and detect the influence on neuronal survival. Finally, TTC staining and modified Neurological Severity Score (mNSS) were used to determine the effects of MCM on ischemic stroke volume and neurological functions. RESULTS: The 10 Hz rTMS inhibited ischemia/reperfusion induced M1 microglia and significantly increased let-7b-5p level in microglia. HMGA2 was predicted and proved to be the target protein of let-7b-5p. HMGA2 and its downstream NF-κB signaling pathway were inhibited by rTMS. Microglia culture medium (MCM) collected from rTMS treated microglia contained lower TNF-α concentration but higher IL-10 concentration than no rTMS treated MCM, reducing ischemic volumes and neurological deficits of MCAO mice. However, knockdown of let-7b-5p by antagomir reversed rTMS effects on microglia phenotype and associated HMGA/NF-κB activation and neurological recovery. CONCLUSION: High-frequency rTMS could alleviate ischemic stroke injury through inhibiting M1 microglia polarization via regulating let-7b-5p/HMGA2/NF-κB signaling pathway in MCAO models.

A Dynamic Nomogram to Identify Patients at High Risk of Poor Outcome in Stroke Patients with Chronic Kidney Disease.

Background and Purpose: Predicting poor outcome for stroke patients with chronic kidney disease (CKD) in clinical practice is difficult. There are no tools available to use for predicting poor outcome in these patients. We aimed to construct and validate a dynamic nomogram to identify CKD-stroke patients at high risk of a 3-month poor outcome. Patients and Methods: We used data for 502 CKD patients who had an acute ischemic stroke, from Nanjing First Hospital, between September 2014 and September 2020, to train the nomogram. An additional 108 patients enrolled from October 2020 to May 2021 were used for temporal external validation. The performance of the nomogram was evaluated by the area under the receiver operating characteristics curve (AUC) and a calibration plot. The clinical utility of the nomogram was measured by decision curve analysis (DCA) and the clinical impact curve (CIC). Results: The median age of the cohort was 79 (70-84) years. Age, urea, premorbid modified Rankin Scale (mRS), National Institutes of Health Stroke Scale (NIHSS) on admission, hemiplegia, mechanical thrombectomy, early neurological deterioration, and respiratory infection were used as predictors of 3-month poor outcome to develop the nomogram. In the training set, the AUC of the dynamic nomogram was 0.873 and the calibration plot showed good predictive ability, and both DCA and CIC indicated the excellent clinical usefulness and applicability of the nomogram. In the external validation set, the AUC was 0.875 and the calibration plot also showed good agreement. Conclusion: This is the first dynamic nomogram constructed for CKD-stroke patients to precisely and expediently identify patients with a high risk of 3-month poor outcome. The outstanding performance and great clinical predictive utility demonstrated the ability of the dynamic nomogram to help clinicians to deploy preventive interventions.

Isolation and characterization of the anthocyanins derived from red radishes (Raphanus sativus L.) and the protective ability of ß-lactoglobulin against heat-induced oxidation.

This study employed the "two-step dialysis" method and AB-8 or D101 macroporous resin chromatography to isolate the anthocyanins in red radishes (ARR). The red radish juice was dialyzed twice at 3000 and 500 Da, respectively. UHPLC-QqQ-MS/MS revealed 24 types of ARRs, of which pelargonidin (Pg)-3-diglucoside-5-(malonyl)glucoside (P3D5MG), Pg-3-diglucoside-5-glucoside (P3D5G), Pg-3-(feruloyl)diglucoside-5-(malonyl)glucoside (P3FD5MG), Pg, and malvidin (Mv) represented the main compounds. The total anthocyanin content in the ARR prepared via the "two-step dialysis" method was 29.69% and 18.44% higher than that obtained using AB-8 and D101 macroporous resins, respectively. The ARRs inhibited heat-induced ß-lactoglobulin (ß-Lg) oxidation. The amino acid residue microenvironment and secondary ß-Lg structure were modified via ARR binding. The energy involved in P3D5MG and ß-Lg binding was -392 kJ/mol, which was significantly lower than that during the binding process of P3D5M, P3FD5MG, Pg, and Mv to ß-Lg (-338 to -168 kJ/mol). These results indicated that "two-step dialysis" was a promising method for deriving natural pigment with strong antioxidant activity from red radishes. PRACTICAL APPLICATION: As a natural food colorant, anthocyanins have attracted increasing attention in the food industry in recent years. This study used "two-step dialysis" to effectively separate ARRs. Moreover, the anthocyanins in ARR can bind to ß-Lg to protect against heating-induced oxidation. Therefore, ARRs may not only act as a food pigment but also as antioxidants.

Human and mouse trigeminal ganglia cell atlas implicates multiple cell types in migraine.

Sensitization of trigeminal ganglion neurons contributes to primary headache disorders such as migraine, but the specific neuronal and non-neuronal trigeminal subtypes that are involved remain unclear. We thus developed a cell atlas in which human and mouse trigeminal ganglia are transcriptionally and epigenomically profiled at single-cell resolution. These data describe evolutionarily conserved and human-specific gene expression patterns within each trigeminal ganglion cell type, as well as the transcription factors and gene regulatory elements that contribute to cell-type-specific gene expression. We then leveraged these data to identify trigeminal ganglion cell types that are implicated both by human genetic variation associated with migraine and two mouse models of headache. This trigeminal ganglion cell atlas improves our understanding of the cell types, genes, and epigenomic features involved in headache pathophysiology and establishes a rich resource of cell-type-specific molecular features to guide the development of more selective treatments for headache and facial pain.

Internet Use and Quality of Life: The Multiple Mediating Effects of Risk Perception and Internet Addiction.

The impact of internet use on quality of life (QoL) has become an increasing focus of academic research. This paper aims to explore the internal influencing mechanisms of internet use (i.e., leisure-oriented internet use (LIU); work-oriented internet use (WIU)) on QoL, with a focus on the multiple mediating effects of risk perception and internet addiction. We constructed a theoretical framework from a psychological perspective and tested the hypotheses using hierarchical regression analysis with a sample of 1535 participants. The results showed that: (1) LIU had a positive effect on QoL, while WIU did not have a significant impact on QoL; (2) both risk perception and internet addiction had a negative influence on QoL; (3) risk perception positively impacted internet addiction; (4) risk perception and internet addiction had multiple mediating effects on the relationship between internet use and QoL.

Green light exposure aggravates high-fat diet feeding-induced hepatic steatosis and pancreatic dysfunction in male mice.

The increased incidence of metabolic syndrome (MetS) has been demonstrated to be closely associated with external environments, such as unhealthy ambient light exposure. Of note, spectral distribution of the light functions as a critical determinant of light's pathophysiological effects. However, the effects of the lighting spectrum on metabolic homeostasis and the specific target organs remain elusive. To address this concern, we in this study high-fat diet (HFD)-fed obese mice with different spectra of the light, and divided them into white light (WL)-treated group, green light (GL)-treated group and blue light (BL)-treated group. We found that compared with BL- or WL-treated obese mice, animals exposed to GL showed worsened metabolic status, including increased body weight gain, impaired glucose tolerance/insulin sensitivity, increased levels of serum lipids, and decreased levels of serum insulin. At the organ level, GL exposure particularly exacerbated hepatic lipid accumulation and enlarged the islet volume. Taking advantages of metabolomics and transcriptomics analyses, we screened out taurocholic acid (TCA) and adenosine (AD) as two promising metabolites mediating the deleterious effects of GL on the liver and islets, respectively. In detail, GL aggravates HFD-induced lipid synthesis and gluconeogenesis in the liver via the reduction of TCA, while triggering inflammation and cellular dysfunction in islets via the induction of AD. Collectively, our findings confirmed that GL and the HFD have a synergistic effect in the induction of metabolic disorders. DATA AVAILABILITY: All data supported the paper are present in the paper and/or the Supplementary Materials. The original datasets are also available from the corresponding author upon request.