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Abstract Objective The purpose of this study was to investigate the influence and predictive value of preoperative peripheral blood neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) index on the prognosis of colorectal anastomotic leakage (CAL) patients. Methods This study retrospectively analyzed the clinical data of 1016 patients who underwent radical resection for colorectal cancer at a single center between January 1, 2007 and December 31, 2023. In this study, NLR and PLR were analyzed before surgery. Kaplan–Meier survival analysis was performed according to the postoperative survival status of the patients. Nomogram and calibration curve were established by proportional hazards model (COX) to verify its predictive value. Results A total of 890 patients with colorectal cancer, 102 patients with CAL, and 788 patients with non- anastomotic leakage (AL) colorectal cancer were enrolled for a median follow-up of 96 months (quartile range 33–133). In this study, COX regression analysis showed that preoperative NLR and PLR could predict the prognosis of CAL patients, and the optimal cut-off points of NLR and PLR were 2.89 and 157.62, respectively. Kaplan–Meier survival curve results showed that 5-year overall survival (OS) and disease-free survival (DFS) in the low NLR and PLR group were significantly higher than those in the high NLR and PLR group. OS and DFS were divided into high, low NLR and PLR groups. Finally, based on COX model, a nomogram analysis was conducted to analyze the risk factors affecting OS and DFS, and the accuracy and practicality of the model were verified by calibration curve and decision curve. Conclusion Preoperative NLR and PLR can predict the long-term prognosis of colorectal cancer (CRC) and CAL patients, and patients with NLR ≥ 2.89 and PLR ≥ 157.62 have poor survival prognosis. Nomogram and calibration curve analysis will further improve the accuracy of OS and DFS prediction.

The approval of Epidiolex, an anti-epileptic drug containing cannabidiol (CBD) as its active component, has brought hope to patients with refractory epilepsy. However, the anti-seizure effect of full-spectrum hemp extract (HE), a CBD-enriched hemp oil, remains unclear. In this study, we investigated the anti-seizure effect of HE using drug-induced seizure models. Our findings revealed that HE significantly reduced seizure susceptibility comparable to CBD at the same doses. Moreover, we explored the pharmacokinetic properties of CBD in HE and observed improved characteristics such as faster oral absorption, enhanced brain distribution, and slower elimination. We further assessed the anti-seizure effects of the other five main non-addictive components in HE. Among these components, cannabichromene (CBC) and cannabinol (CBN) showed significant anti-seizure effects. To gain insights into the mechanisms of CBC and CBN, we investigated their allosteric modulation on the GABAA receptor. Our results revealed that CBC enhanced GABA-induced currents in both Xenopus laevis oocytes and mouse primary cortical neurons. Additionally, we identified V436 in the β2 subunit of the GABAA receptor as a critical binding site for CBC. These findings provide compelling evidence for the anti-seizure activities of HE and shed light on its underlying mechanisms. Our study provides insights into the broader therapeutic potential of hemp extracts and suggests their possible development as anti-seizure treatments.

Abstract Diabetes is a global chronic disease that seriously endangers human health and characterized by abnormally high blood glucose levels in the body. Diabetic wounds are common complications which associate with impaired healing process. Biomarkers monitoring of diabetic wounds is of great importance in the diabetes management. However, actual monitoring of biomarkers still largely relies on the complex process and additional sophisticated analytical instruments. In this work, we prepared hydrogels composed of different modules, which were designed to monitor different physiological indicators in diabetic wounds, including glucose levels, pH, and temperature. Glucose monitoring was achieved based on the combination of photonic crystal (PC) structure and glucose-responsive hydrogels. The obtained photonic crystal hydrogels (PCHs) allowed visual monitoring of glucose levels in physiological ranges by readout of intuitive structural color changes of PCHs during glucose-induced swelling and shrinkage. Interestingly, the glucose response of double network PCHs was completed in 15 min, which was twice as fast as single network PCHs, due to the higher volume fraction of glucose-responsive motifs. Moreover, pH sensing was achieved by incorporation of acid-base indicator dyes into hydrogels; and temperature monitoring was obtained by integration of thermochromic powders in hydrogels. These hydrogel modules effectively monitored the physiological levels and dynamic changes of three physiological biomarkers, both in vitro and in vivo during diabetic wound healing process. The multifunctional hydrogels with visual monitoring of biomarkers have great potential in wound-related monitoring and treatment. Graphical abstract

The gut microbiota plays a pivotal role in human metabolic health by influencing immune responses, digestion, and metabolic homeostasis. Recent research highlights the intricate interactions between gut microbiota and RNA, especially non-coding RNAs, in regulating metabolic processes. Dysbiosis of the gut microbiota has been linked to metabolic disorders such as type 2 diabetes, obesity, metabolic-associated fatty liver disease (MAFLD) and metabolic heart disease. Microbial metabolites, including short-chain fatty acids (SCFAs), modulate RNA expression, influencing lipid metabolism, glucose regulation, and inflammatory responses. Additionally, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) serve as critical regulators in these processes, with emerging evidence showing that gut-derived metabolites affect post-transcriptional gene regulation. This review synthesizes the current understanding of the gut microbiota-RNA axis and its role in metabolic diseases. By exploring the molecular mechanisms, particularly how gut microbiota-derived signals modulate RNA pathways, the review underscores the potential of targeting this axis for therapeutic interventions. Furthermore, it examines how dysbiosis leads to epigenetic changes such as m6A RNA methylation, contributing to disease pathogenesis. These insights offer a new perspective on the prevention and treatment of metabolic diseases, with potential applications in personalized medicine.

Abstract Animal experiments traditionally identify sensitizers in cosmetic materials. However, with growing concerns over animal ethics and bans on such experiments globally, alternative methods like machine learning are gaining prominence for their efficiency and cost‐effectiveness. In this study, to develop a robust sensitizer detector model, we first constructed benchmark data sets using data from previous studies and a public database, then 589 sensitizers and 831 nonsensitizers were collected. In addition, a graph‐based autoencoder and Mondrian conformal prediction (MCP) were combined to build a robust sensitizer detector, iSKIN. In the independent test set, the Matthews correlation coefficient (MCC) and the area under the receiver operating characteristic curve (ROCAUC) values of the iSKIN model without MCP were 0.472 and 0.804, respectively, which are higher than those of the three baseline models. When setting the significance level in MCP at 0.7, the MCC and ROCAUC values of iSKIN could achieve 0.753 and 0.927, respectively. Regrouping experiments proved that the MCP method is robust in the improvement of model performance. Through key structure analysis, seven key substructures in sensitizers were identified to guide cosmetic material design. Notably, long chains with halogen atoms and phenyl groups with two chlorine atoms at ortho‐positions were potential sensitizers. Finally, a user‐friendly web tool (http://www.iskin.work/) of the iSKIN model was deployed to be used by other researchers. In summary, the proposed iSKIN model has achieved state‐of‐the‐art performance so far, which can contribute to the safety evaluation of cosmetic raw materials and provide a reference for the chemical structure design of these materials.

Background During the acute heart failure (AHF), acute kidney injury (AKI) is highly prevalent in critically ill patients. The occurrence of the latter condition increases the risk of mortality in patients with acute heart failure. The current research on the relationship between nutritional risk and the occurrence of acute kidney injury in patients with acute heart failure is very limited.Methods This retrospective cohort study utilized data from the Medical Information Mart for Intensive Care IV (MIMIC-IV, version 2.1) database. We included adult patients with AHF who were admitted to the intensive care unit in the study. Results: A total of 1310 critically ill patients with acute heart failure were included. The AUC of geriatric nutritional risk index (GNRI) (0.694) is slightly superior to that of controlling nutritional status (CONUT) (0.656) and prognostic nutritional index (PNI) (0.669). The Log-rank test revealed a higher risk of acute kidney injury in patients with high nutritional risk (p

Epilepsy is the fourth most common neuropsychiatric disorder. Although the approval of Epidiolex has ignited hope for patients, there is still a large gap in the field of anti-seizure research. The effect and underlying mechanism of full-spectrum hemp extract (HE) remains unclear. Here this study investigated the anti-seizure effect of HE on seizure models. The results showed that HE significantly reduced seizure susceptibility and prolonged seizure latency with better pharmacokinetic performance compared to CBD. This article then further explored the anti-seizure active components and their possible mechanism in HE. The results indicated that cannabichromene (CBC) and cannabinol (CBN) were involved in the anti-seizure process, especially CBC showed a strong allosteric enhancement effects on CBD binding site of the GABAA receptor, which implied that the GABAA receptor seemed to be the primary anti-epileptic target of HE. This article not only presents the great potential of HE as a candidate for new anti-epileptic drugs with less psychoactive, but also provides a valuable contribution to subsequent mechanism research and drug development on epilepsy.Abstract: Epilepsy is the fourth most coneuropsychiatric disorder. Although the approval of Epidiolex has ignited hope for patients, there is still a large gap in the field of anti-seizure research. The effect and underlying mechanism of full-spectrum hemp extract remains unclear. Here this study investigated the anti-seizure effect of HE on seizure models. The results showed that HE significantly reduced seizure susceptibility and prolonged seizure latency with better pharmacokinetic performance compared to CBD. This article then further explored the anti-seizure active components and their possible mechanism in HE. The results indicated that cannabichromene and cannabinol were involved in the anti-seizure process, especially CBC showed a strong allosteric enhancement effects on CBD binding site of the GABAA receptor, which implied that the GABAA receptor seemed to be the primary anti-epileptic target of HE. This article not only presents the great potential of HE as a candidate for new anti-epileptic drugs with less psychoactive, but also provides a valuable contribution to subsequent mechanism research and drug development on epilepsy.

Plant lead (Pb) tolerance and accumulation are key characteristics affecting phytoremediation efficiency. Bermudagrass is an excellent candidate for the remediation of Pb-polluted soil, and it needs to be mowed regularly. Here, we explored the effect of different mowing frequencies on the remediation of Pb-contaminated soil using bermudagrass. Mowing was found to decrease the biomass and photosynthetic efficiency of bermudagrass under Pb stress, thereby inhibiting its growth. Although mowing exacerbated membrane peroxidation, successive mowing treatments alleviated peroxidation damage by regulating enzymatic and nonenzymatic systems. A comprehensive evaluation of Pb tolerance revealed that all the mowing treatments reduced the Pb tolerance of bermudagrass, and a once-per-month mowing frequency had a less negative effect on Pb tolerance than did more frequent mowing. In terms of Pb enrichment, mowing significantly increased the Pb concentration, total Pb accumulation, translocation factor (TF), and bioenrichment factor (BCF) of bermudagrass. The total Pb accumulation was greatest under the once-a-month treatment, while the TF and BCF values were greatest under the three-times-a-month mowing treatment. Additionally, the decrease in soil pH and DOC were significantly correlated with the soil available Pb content and plant Pb accumulation parameters. The results showed that changes in the rhizosphere are crucial factors regulating Pb uptake in bermudagrass during mowing. Overall, once-a-month mowing minimally affects Pb tolerance and maximizes Pb accumulation, making it the optimal mowing frequency for soil Pb remediation by bermudagrass. This study provides a novel approach for the remediation of Pb-contaminated soil with bermudagrass based on mowing.

Climate change is one of the foremost challenges confronting the contemporary world. Carbon and water cycles and their interconnections of ecosystems are playing a pivotal role in assessing the impacts of climate change on ecosystems. The Qinling Mountains of China represent a focal area for research on global climate change and regional adaptation strategies. Based on historical and CMIP6 (Coupled Model Intercomparison Project Phase 6) future climatic data, the Biome-BGC model, which was sufficiently optimized with the Biome-BGC-PEST package, was used to simulate the historical and future trends of GPP (Gross primary productivity), ET (Evapotranspiration), and WUE (Ecosystem water use efficiency) in the Qinling Mountains, so as to elucidate the dynamics and spatiotemporal variations of carbon and water fluxes amidst climate change. The results showed that the GPP, ET, and WUE of the Qinling Mountains heterogeneously distributed in space, due to the dramatic disparities in carbon and water fluxes among different vegetation types in the Qinling Mountains. Among the various vegetation types, evergreen needle-leaved forest had the highest annual mean value of WUE. In the historical period of 1979-2018, deciduous broad-leaved forest had the highest annual mean value of GPP and ET, while evergreen needle-leaved forest would dominate in the future (2021-2100). For the annual GPP and ET flux variations, different vegetation cover types followed varying peak patterns in the Qinling Mountains. Deciduous broad-leaved forest, evergreen needle-leaved forest, and shrub meadow showed ’single-peak’ pattern annually, whereas the crop area displayed ’double-peak’ pattern due to the different growing seasons of crops. There also were temporal variations for the carbon and water fluxes within the same vegetation type. Future projections suggested a continuous increase in GPP and ET fluxes, underscoring the consistent role of the Qinling Mountains in water resource conservation and carbon sink amid evolving climatic conditions.

Abstract Voltage-gated sodium (NaV) channels mediate a plethora of electrical activities. NaV channels govern cellular excitability in response to depolarizing stimuli. Inactivation is an intrinsic property of NaV channels that regulates cellular excitability by controlling the channel availability. The fast inactivation, mediated by the Ile-Phe-Met (IFM) motif and the N-terminal helix (N-helix), has been well-characterized. However, the molecular mechanism underlying NaV channel slow inactivation remains elusive. Here, we demonstrate that the removal of the N-helix of NaVEh (NaVEhΔN) results in a slow-inactivated channel, and present cryo-EM structure of NaVEhΔN in a potential slow-inactivated state. The structure features a closed activation gate and a dilated selectivity filter (SF), indicating that the upper SF and the inner gate could serve as a gate for slow inactivation. In comparison to the NaVEh structure, NaVEhΔN undergoes marked conformational shifts on the intracellular side. Together, our results provide important mechanistic insights into NaV channel slow inactivation.

Abstract The voltage-gated calcium channel CaV1.2 is essential for cardiac and vessel smooth muscle contractility and brain function. Accumulating evidence demonstrates that malfunctions of CaV1.2 are involved in brain and heart diseases. Pharmacological inhibition of CaV1.2 is therefore of therapeutic value. Here, we report cryo-EM structures of CaV1.2 in the absence or presence of the antirheumatic drug tetrandrine or antihypertensive drug benidipine. Tetrandrine acts as a pore blocker in a pocket composed of S6II, S6III, and S6IV helices and forms extensive hydrophobic interactions with CaV1.2. Our structure elucidates that benidipine is located in the DIII-DIV fenestration site. Its hydrophobic sidechain, phenylpiperidine, is positioned at the exterior of the pore domain and cradled within a hydrophobic pocket formed by S5DIII, S6DIII, and S6DIV helices, providing additional interactions to exert inhibitory effects on both L-type and T-type voltage gated calcium channels. These findings provide the structural foundation for the rational design and optimization of therapeutic inhibitors of voltage-gated calcium channels.

This paper focuses on the design of vehicle trajectories and their control systems. A method based on quintic polynomials is utilized to develop trajectories for intelligent vehicles, ensuring the smooth continuity of the trajectory and related state curves under varying conditions. The construction of lateral and longitudinal controllers is discussed, which includes a tracking error model derived from the two-degree-of-freedom dynamic model of a two-wheeled vehicle and the application of the Frenet coordinate system transformation. The vehicle tracking performance is regulated by these controllers. Experimental verification on a small intelligent vehicle platform operating on the Ackermann steering principle was conducted. The results confirm the tracking performance of the controllers under different conditions and validate the effectiveness and feasibility of the overall framework of the study.

Using the data from the first satellite of the Republic of China (ROCSAT-1) obtained during high-solar-activity periods (2000–2003), the distributions of plasma density enhancement (plasma blobs) with local time, season and longitude were investigated. Some new features of plasma blobs can be concluded: (a) The distribution of plasma blobs shows remarkable seasonal and interhemispheric asymmetries, with the higher occurrence in June solstice months and in the winter hemisphere. (b) The occurrence of plasma blobs displays longitude dependence, more in the −180~−90°E, −60~0°E and 90~180°E longitude regions. (c) The seasonal and interhemispheric asymmetries of plasma blobs also depend on the longitude. Meridional wind plays an important role in the formation and evolution of low-latitude plasma blobs. Inclination and declination may control the longitudinal distribution of plasma blobs.

Diabetic wounds are serious clinical complications which manifest wet condition due to the mass exudate, along with disturbed regulation of inflammation, severe oxidative stress and repetitive bacterial infection. Existing treatments for diabetic wounds remain unsatisfactory due to the lack of ideal dressings that encompass mechanical performance, adherence to moist tissue surfaces, quick repair, and diverse therapeutic benefits. Herein, we fabricated a wet adhesive, self-healing, glucose-responsive drug releasing hydrogel with efficient antimicrobial and pro-healing properties for diabetic wound treatment. PAE hydrogel was constructed with poly(acrylic acid-co-acrylamide) (AA-Am) integrated with a dynamic E-F crosslinker, which consisted of epigallocatechin gallate (EGCG) and 4-(2-acrylamidoethylcarbamoyl)-3-fluorophenylboronic acid (AFPBA). Due to the dynamic crosslinking nature of boronate esters, abundant catechol groups and hydrogen bonding, PAE hydrogel demonstrated excellent mechanical properties with about 1000 % elongation, robust adhesion to moist tissues, fast self-healing, and absorption of biofluids of 10 times of its own weight. Importantly, PAE hydrogel exhibited sustained and glucose-responsive release of EGCG. Together, the bioactive PAE hydrogel had effective antibacterial, antioxidative, and anti-inflammatory properties in vitro, and accelerated diabetic wound healing in rats via reducing tissue-inflammatory response, enhancing angiogenesis, and reprogramming of macrophages. Overall, this versatile hydrogel provides a straightforward solution for the treatment of diabetic wound, and shows potential for other wound-related application scenarios.

Abstract Intrinsic plasticity, a fundamental process enabling neurons to modify their intrinsic properties, plays a crucial role in shaping neuronal input‐output function and is implicated in various neurological and psychiatric disorders. Despite its importance, the underlying molecular mechanisms of intrinsic plasticity remain poorly understood. In this study, a new ubiquitin ligase adaptor, protein tyrosine phosphatase receptor type N (PTPRN), is identified as a regulator of intrinsic neuronal excitability in the context of temporal lobe epilepsy. PTPRN recruits the NEDD4 Like E3 Ubiquitin Protein Ligase (NEDD4L) to NaV1.2 sodium channels, facilitating NEDD4L‐mediated ubiquitination, and endocytosis of NaV1.2. Knockout of PTPRN in hippocampal granule cells leads to augmented NaV1.2‐mediated sodium currents and higher intrinsic excitability, resulting in increased seizure susceptibility in transgenic mice. Conversely, adeno‐associated virus‐mediated delivery of PTPRN in the dentate gyrus region decreases intrinsic excitability and reduces seizure susceptibility. Moreover, the present findings indicate that PTPRN exerts a selective modulation effect on voltage‐gated sodium channels. Collectively, PTPRN plays a significant role in regulating intrinsic excitability and seizure susceptibility, suggesting a potential strategy for precise modulation of NaV1.2 channels' function.

Abstract The nonselective calcium‐permeable Transient Receptor Potential Cation Channel Subfamily V Member4 (TRPV4) channel regulates various physiological activities. Dysfunction of TRPV4 is linked to many severe diseases, including edema, pain, gastrointestinal disorders, lung diseases, and inherited neurodegeneration. Emerging TRPV4 antagonists show potential clinical benefits. However, the molecular mechanisms of TRPV4 antagonism remain poorly understood. Here, cryo‐electron microscopy (cryo‐EM) structures of human TRPV4 are presented in‐complex with two potent antagonists, revealing the detailed binding pockets and regulatory mechanisms of TRPV4 gating. Both antagonists bind to the voltage‐sensing‐like domain (VSLD) and stabilize the channel in closed states. These two antagonists induce TRPV4 to undergo an apparent fourfold to twofold symmetry transition. Moreover, it is demonstrated that one of the antagonists binds to the VSLD extended pocket, which differs from the canonical VSLD pocket. Complemented with functional and molecular dynamics simulation results, this study provides crucial mechanistic insights into TRPV4 regulation by small‐molecule antagonists, which may facilitate future drug discovery targeting TRPV4.

Geoheritage represents typical geological phenomena formed through internal and external geological processes during the Earth's long evolution. It serves as a carrier of crucial information regarding the Earth's evolution, the origin of life, and changes in the geographic environment. Additionally, it is a valuable geological resource for human utilization. In order to provide essential information for the scientific protection and utilization of geoheritage resources, this paper summarizes and further categorizes the types, grades, and distribution characteristics of geoheritage in China based on extensive firsthand data obtained from recent investigations. The results can be summaried in four aspects: (1) As of the end of 2018, a total of 7,267 important geoheritage sites (including global, national, and provincial levels) have been discovered and surveyed in China. Among them, there are 3,154 geoheritage sites of basic geology, 3,935 geoheritage sites of geomorphic landscape, and 178 geoheritage sites of geological disaster. They can be further categorized into 13 classes and 46 sub-classes, such as stratigraphic sections, rock profiles, rock and soil landforms, and earthquake relics. (2) Through expert evaluations and comparative studies, there are 218 Grade I (global level) geoheritage sites, 1,919 Grade II (national level) geoheritage sites, 4,732 Grade III (provincial level) geoheritage sites, and 398 Grade IV (below provincial level) geoheritage sites in China. (3) Geoheritage in China are mainly distributed in five regions: Southwest China, East China, Central China, Northwest, and North China. The geoheritage sites of basic geology are mainly distributed in the Southwest China, Central China, East China, Northwest China, and North China, with the Southwest China having the highest number, accounting for approximately 27%. The geoheritage sites of geomorphic landscape are mainly distributed in the Southwest China, Northwest China, East China, Central China, and North China, with the Southwest China having the highest number, accounting for approximately 29%. The geoheritage sites of geological disaster are mainly distributed in the Southwest China, Northwest China, and Central China, with the Southwest China having the highest number, accounting for approximately 47%.

Abstract Background Choosing the appropriate antipsychotic drug (APD) treatment for patients with schizophrenia (SCZ) can be challenging, as the treatment response to APD is highly variable and difficult to predict due to the lack of effective biomarkers. Previous studies have indicated the association between treatment response and genetic and epigenetic factors, but no effective biomarkers have been identified. Hence, further research is imperative to enhance precision medicine in SCZ treatment. Methods Participants with SCZ were recruited from two randomized trials. The discovery cohort was recruited from the CAPOC trial (n = 2307) involved 6 weeks of treatment and equally randomized the participants to the Olanzapine, Risperidone, Quetiapine, Aripiprazole, Ziprasidone, and Haloperidol/Perphenazine (subsequently equally assigned to one or the other) groups. The external validation cohort was recruited from the CAPEC trial (n = 1379), which involved 8 weeks of treatment and equally randomized the participants to the Olanzapine, Risperidone, and Aripiprazole groups. Additionally, healthy controls (n = 275) from the local community were utilized as a genetic/epigenetic reference. The genetic and epigenetic (DNA methylation) risks of SCZ were assessed using the polygenic risk score (PRS) and polymethylation score, respectively. The study also examined the genetic-epigenetic interactions with treatment response through differential methylation analysis, methylation quantitative trait loci, colocalization, and promoter-anchored chromatin interaction. Machine learning was used to develop a prediction model for treatment response, which was evaluated for accuracy and clinical benefit using the area under curve (AUC) for classification, R 2 for regression, and decision curve analysis. Results Six risk genes for SCZ (LINC01795, DDHD2, SBNO1, KCNG2, SEMA7A, and RUFY1) involved in cortical morphology were identified as having a genetic-epigenetic interaction associated with treatment response. The developed and externally validated prediction model, which incorporated clinical information, PRS, genetic risk score (GRS), and proxy methylation level (proxyDNAm), demonstrated positive benefits for a wide range of patients receiving different APDs, regardless of sex [discovery cohort: AUC = 0.874 (95% CI 0.867–0.881), R 2 = 0.478; external validation cohort: AUC = 0.851 (95% CI 0.841–0.861), R 2 = 0.507]. Conclusions This study presents a promising precision medicine approach to evaluate treatment response, which has the potential to aid clinicians in making informed decisions about APD treatment for patients with SCZ. Trial registration Chinese Clinical Trial Registry ( https://www.chictr.org.cn/ ), 18. Aug 2009 retrospectively registered: CAPOC—ChiCTR-RNC-09000521 ( https://www.chictr.org.cn/showproj.aspx?proj=9014 ), CAPEC—ChiCTR-RNC-09000522 ( https://www.chictr.org.cn/showproj.aspx?proj=9013 ).

In this paper, we collect the annual data of 145 commercial banks in China from 2010 to 2019 and use a panel data fixed-effect model to study how fintech (financial technology) affects the influence of macroeconomic uncertainty on commercial banks' proactive risk-taking. We find that the development of fintech mitigates the dampening effect of macroeconomic uncertainty on commercial banks' proactive risk-taking. Specifically, fintech plays a mitigating role by motivating commercial banks to issue loans and hold transactional financial assets. With the increase of commercial banks’ proactive risk-taking, the mitigation effect of fintech monotonically diminishes. This mitigating effect is heterogeneous across different types of commercial banks, as it is relatively weak for banks with high capital adequacy ratios and large state-owned banks.

Objectives: To evaluate myocardial work in peritoneal dialysis patients by pressure-strain loop. To analyze the factors influencing myocardial work in peritoneal dialysis patients with preserved ejection fraction. Methods: We collected clinical data on possible effects on myocardial work in 105 maintenance peritoneal dialysis patients with preserved ejection fraction and applied ultrasonic pressure-strain loops to obtain the left ventricular global constructive work (GCW), Global work index (GWI), global work waste (GWW), and global work efficiency (GWE) of the patients. Then, the clinical data and myocardial work indices were statistically described and correlated. Results: Left ventricular hypertrophy was observed in 78 % of peritoneal dialysis patients with left ventricular ejection fraction preservation. There is a correlation between the left ventricular mass index and myocardial work indices (P

Quinidine has been used as an anticonvulsant to treat patients with KCNT1-related epilepsy by targeting gain-of-function KCNT1 pathogenic mutant variants. However, the detailed mechanism underlying quinidine’s blockade against KCNT1 (Slack) remains elusive. Here, we report a functional and physical coupling of the voltage-gated sodium channel NaV1.6 and Slack. NaV1.6 binds to and highly sensitizes Slack to quinidine blockade. Homozygous knockout of NaV1.6 reduces the sensitivity of native sodium-activated potassium currents to quinidine blockade. NaV1.6-mediated sensitization requires the involvement of NaV1.6’s N- and C-termini binding to Slack’s C-terminus and is enhanced by transient sodium influx through NaV1.6. Moreover, disrupting the Slack-NaV1.6 interaction by viral expression of Slack’s C-terminus can protect against SlackG269S-induced seizures in mice. These insights about a Slack-NaV1.6 complex challenge the traditional view of ‘Slack as an isolated target’ for anti-epileptic drug discovery efforts and can guide the development of innovative therapeutic strategies for KCNT1-related epilepsy.

NaV1.6 channel plays a critical role in neuronal excitability. Here, authors present human NaV1.6 structures in apo and 4,9-anhydro-tetrodotoxin bound forms, which reveal molecular mechanisms of NaV1.6 Na+ conductance and inhibition by the blocker.

The CaV2.3 channel is involved in synaptic plasticity and neurological disorders. Here, authors resolve the human CaV2.3 structure to explore functional heterogeneity of VSDs and elucidated the closed- and open-state inactivation mechanisms of the channel.

IntroductionCommunity satisfaction contributes to urban planning, community development, and policy formulation. Yet, we lack comprehensive knowledge about how different neighborhood features impact satisfaction, especially across diverse community types.MethodsRelied on a sample of 4,009 respondents in Beijing, this study examines the influence of neighborhood features on community satisfaction through neighborly interactions, focusing on the heterogeneity between urban and suburban communities, using structural equation models.ResultsThe results reveal that community service and community management exert significant influences on community satisfaction, primarily mediated by the role of neighborly interactions. Then, transportation convenience positively influences community satisfaction in urban areas, while no housing property has a negative effect in suburban communities.DiscussionThese results highlight varied neighborhood effects on community satisfaction, informing tailored urban planning and policies that address unique traits and requirements of different communities.

The retention of gel system in porous media results in the reduction of porosity and permeability. However, the length of the current experiment models (sandpack or core sample) are in the range of centimeter scale, which is too short to track the full movement path of gel particles. In this work, a series of gel flooding experiments were conducted on 2.5-m long slim sandpack models. Seven fluid collection/pressure monitoring points were equally distributed along the length of the slim sandpack to track the movement of gel particles during the flooding process. We quantified the adsorption capacity, adsorption velocity, and mechanical shear effect of polymer/cross-linking agent along the flowing direction. In addition, we also employed scanning electron microscope (SEM) equipment to observe the morphology of the gel and the pore structure along the flooding direction, which provides good evidences of the adsorption retention and mechanical shear effects. Results show that most of the polymers and cross-linking agent were adsorbed on the region near the inlet. We emphasized the advantages of using long sandpack/core to track the full movement path of the gel system. In addition, the morphology of the original gel system showed a network characteristic of hexagonal structure, which was dragged to an elongated structure or even totally broke when it was transported through the porous medium. This work provides the fundamental understandings of the dynamic adsorption behaviors of gel system, which could be useful for optimizing the components of gel system, selection of target oil reservoirs and their operational parameters during gel flooding in enhancing oil recovery.

ObjectivesThe aim of the present study was to describe the experience at a single institution in the management of hepatic epithelioid hemangioendothelioma (HEHE).MethodsWe included 51 patients with histologically confirmed HEHE. We performed log-rank (Cox–Mantel) survival analyses using Kaplan–Meier methods to test differences in survival between patients in different groups. Univariate Cox regression analyses and multivariate proportional hazards regression model were carried out to identify independent prognostic factors.ResultsDifferent imaging modalities were used to diagnose HEHE with various presentations. Liver resection (LR), liver transplantation (LT), systemic treatment (ST), and surveillance had been used in our study. A significant difference was noted between the LR group and the surveillance group with respect to mean survival (p = 0.006), as was in the LR group and the ST group (p = 0.036), and in surgical approach (LR and LT) and nonsurgical approach (ST and surveillance) (p = 0.008). The mean survival between the ST group and the surveillance group was not significantly different (p = 0.851). LR (p = 0.010) and surgical approach (p = 0.014) were favorable predictors of outcome, while macrovascular invasion (MaVI) (p = 0.037), lung metastasis (p = 0.040), and surveillance (p = 0.033) were poor prognostic factors in univariate analysis. Multivariate analysis showed that LR (p = 0.010) and surgical approach (p = 0.014) were independently associated with good OS, while surveillance (p = 0.033) was independently associated with poor OS. After adjusting for confounding factors, patients in the LR group have much better OS than those in the surveillance group (p = 0.013). However, there was no significant difference in OS between the LR group and ST group (p = 0.254), as was in the ST group and the surveillance group (p = 0.857).ConclusionsThe definitive diagnosis of HEHE was dependent on histopathology, and it was not possible to make a specific diagnosis without biopsy because the radiological findings were similar to those in some hepatic malignancies. ST was not recommended for patients who were not candidates for surgical approaches, and surgical approaches should be warranted regardless of disease stage. The retrospective nature and the small size of the data limited the generalizability of the study, designing a worldwide database that contains all data about patients with HEHE independent of their therapy, which was highly recommended.

Introduction: Cervical cancer remains a significant global health burden, and Doxorubicin is a crucial therapeutic agent against this disease. However, the precise molecular mechanisms responsible for its therapeutic effects are not fully understood.Methods: In this study, we employed a multi-omics approach that combined transcriptomic and metabolomic analyses with cellular and in vivo experiments. The goal was to comprehensively investigate the molecular landscape associated with Doxorubicin treatment in cervical cancer.Results: Our unbiased differential gene expression analysis revealed distinct alterations in gene expression patterns following Doxorubicin treatment. Notably, the ANKRD18B gene exhibited a prominent role in the response to Doxorubicin. Simultaneously, our metabolomic analysis demonstrated significant perturbations in metabolite profiles, with a particular focus on L-Ornithine. The correlation between ANKRD18B gene expression and L-Ornithine levels indicated a tightly controlled gene-metabolite network. These results were further confirmed through rigorous cellular and in vivo experiments, which showed reductions in subcutaneous tumor size and significant changes in ANKRD18B, L-Ornithine, and Doxorubicin concentration.Discussion: The findings of this study underscore the intricate interplay between transcriptomic and metabolomic changes in response to Doxorubicin treatment. These insights could have implications for the development of more effective therapeutic strategies for cervical cancer. The identification of ANKRD18B and L-Ornithine as key components in this process lays the groundwork for future research aiming to unravel the complex molecular networks that underlie Doxorubicin’s therapeutic mechanism. While this study provides a solid foundation, it also highlights the necessity for further investigation to fully grasp these interactions and their potential implications for cervical cancer treatment.

Summary: The sodium-activated Slo2.2 channel is abundantly expressed in the brain, playing a critical role in regulating neuronal excitability. The Na+-binding site and the underlying mechanisms of Na+-dependent activation remain unclear. Here, we present cryoelectron microscopy (cryo-EM) structures of human Slo2.2 in closed, open, and inhibitor-bound form at resolutions of 2.6–3.2 Å, revealing gating mechanisms of Slo2.2 regulation by cations and a potent inhibitor. The cytoplasmic gating ring domain of the closed Slo2.2 harbors multiple K+ and Zn2+ sites, which stabilize the channel in the closed conformation. The open Slo2.2 structure reveals at least two Na+-sensitive sites where Na+ binding induces expansion and rotation of the gating ring that opens the inner gate. Furthermore, a potent inhibitor wedges into a pocket formed by pore helix and S6 helix and blocks the pore. Together, our results provide a comprehensive structural framework for the investigation of Slo2.2 channel gating, Na+ sensation, and inhibition.

Excitatory amino acid transporter 2 (EAAT2) mediates glutamate uptake in the synapse. Here, authors report cryo-EM structures of the human EAAT2 in complexes with glutamate or selective inhibitor WAY-213613, revealing important insights into substrate recognition and selective inhibition.

In tissue engineering (TE), tissue-inducing scaffolds are a promising solution for organ and tissue repair owing to their ability to attract stem cells in vivo , thereby inducing endogenous tissue regeneration through topological cues. An ideal TE scaffold should possess biomimetic cross-scale structures, similar to that of natural extracellular matrices, at the nano- to macro-scale level. Although freeform fabrication of TE scaffolds can be achieved through 3D printing, this method is limited in simultaneously building multiscale structures. To address this challenge, low-temperature fields were adopted in the traditional fabrication processes, such as casting and 3D printing. Ice crystals grow during scaffold fabrication and act as a template to control the nano- and micro-structures. These microstructures can be optimized by adjusting various parameters, such as the direction and magnitude of the low-temperature field. By preserving the macro-features fabricated using traditional methods, additional micro-structures with smaller scales can be incorporated simultaneously, realizing cross-scale structures that provide a better mimic of natural organs and tissues. In this paper, we present a state-of-the-art review of three low-temperature-field-assisted fabrication methods—freeze casting, cryogenic 3D printing, and freeze spinning. Fundamental working principles, fabrication setups, processes, and examples of biomedical applications are introduced. The challenges and outlook for low-temperature-assisted fabrication are also discussed.

The J-TEXT capability is enhanced compared to two years ago with several upgrades of its diagnostics and the increase of electron cyclotron resonance heating (ECRH) power to 1 MW. With the application of electron cyclotron wave (ECW), the ECW assisted plasma startup is achieved; the tearing mode is suppressed; the toroidal injection of 300 kW ECW drives around 24 kA current; fast electrons are generated with toroidal injected ECW and the runaway current conversion efficiency increases with ECRH power. The mode coupling between 2/1 and 3/1 modes are extensively studied. The coupled 2/1 and 3/1 modes usually lead to major disruption. Their coupling can be either suppressed or avoided by external resonant magnetic perturbation fields and hence avoids the major disruption. It is also found that the 2/1 threshold of external field is significantly reduced by a pre-excited 3/1 mode, which can be either a locked island or an external kink mode. The disruption control is studied by developing prediction methods capable of cross tokamak application and by new mitigation methods, such as the biased electrode or electromagnetic pellet injector. The high-density operation and related disruptions are studied from various aspects. Approaching the density limit, the collapse of the edge shear layer is observed and such collapse can be prevented by applying edge biasing, leading to an increased density limit. The density limit is also observed to increase, if the plasma is operated in the poloidal divertor configuration or the plasma purity is increased by increasing the pre-filled gas pressure or ECRH power during the start-up phase.

Voltage-gated sodium channels mediate electrical signaling. Here, authors report the cryo-EM structure of NaVEh from the marine plant Emiliania huxleyi, revealing an unexpected mechanism of N-type fast inactivation.

T-type calcium channels are implicated in many diseases. Here, multiple structures of CaV3.3 channel elucidate molecular mechanisms of T-type CaV channels activation at low voltage and interaction with different clinically used channel blockers.

Ionic surfactants are easily adsorbed by silt and clay particles, thus affecting the flocculation characteristics and settling behavior. The settling velocity, typical size, Zeta potential and surface tension of silt flocs were measured in the presence of two different kinds of ionic surfactants. The results indicated that the cetyltrimethylammonium bromide (CTAB, a typical cationic surfactant) can dramatically accelerate the settling of slit particles, while the linear alkylbenzene sulfonate (LAS, a typical anionic surfactant) slightly retarded silt sedimentation to some extent. In still water, the representative settling velocity dramatically increased from 0.36 cm s−1 to 0.43 cm s−1 with the increase of CTAB concentration, which increased by more than 20%. Oppositely, the sedimentation rate decreased from 0.36 cm s−1 to 0.33 cm s−1 with the increase of LAS concentration. In flowing water, as the flow rate increased from 0 to 20 cm s−1 and the ionic surfactant concentration increased from 0 to 10 mg L−1, the sedimentation rate decreased to 57% and 89% in the presence of CTAB and LAS respectively, which was due to an enhanced dispersion of silt particles and a breaking of flocs. The SEM image test shows that the floc particle size increased 1.5 times of the primary particle size under the high CTAB concentration. The flocculation induced by ionic surfactants greatly influences the sediment size as well as the law of settling velocity. The intrinsic influence mechanism was also discussed based on the variations of silt particle properties. This systematic study can be used for further development of flocculation models and particle size distribution of fine-grained soil.

Abstract Background Commitment of mouse dental papilla cells (mDPCs) to the odontoblast lineage is critical for dentin formation, and this biological process is regulated by a complex transcription factor network. The transcription factor Mycn is a proto-oncogene that plays an important role in tumorigenesis and normal embryonic development. An early study revealed that Mycn is exclusively expressed in dental mesenchymal cells at E15.5, which implies a potential role of Mycn in dentinogenesis. However, the role of Mycn in dentin formation remains elusive. Thus, it is of considerable interest to elucidate the role of Mycn in dentin formation. Methods Mycn fl/fl ; Osr2 IresCre (Mycn Osr2 ) and Mycn fl/fl ; K14 Cre (Mycn K14 ) transgenic mice were generated, and micro-CT scans were performed to quantitatively analyse the volumetric differences in the molars and incisors of the mutants and their littermates. Mycn was also knocked down in vitro, and alkaline phosphatase (ALP) and alizarin red staining (ARS) were conducted. Cleavage under targets and tagmentation (CUT&Tag) analysis and dual luciferase assays were performed to identify direct downstream targets of Mycn. Immunofluorescence and immunochemistry staining and western blotting (WB) were performed to analyse the expression levels of potential targets. Quantitative PCR, WB, ALP and ARS were performed to test the rescue efficiency. Results Mesenchymal ablation of Mycn (Mycn Osr2 ) led to defective dentin formation, while epithelial deletion (Mycn K14 ) had no obvious effects on tooth development. ALP and ARS staining revealed that the commitment capacity of mDPCs to the odontoblast lineage was compromised in Mycn Osr2 mice. CUT&Tag analysis identified Klf4 as a potential direct target of Mycn, and a dual luciferase reporter assay verified that Mycn could bind to the promotor region of Klf4 and directly activate its transcription. Reciprocally, forced expression of Klf4 partially recovered the odontoblastic differentiation capacity of mDPCs with Mycn knockdown. Conclusions Our results elucidated that mesenchymal Mycn modulates the odontoblastic commitment of dental papilla cells by directly regulating Klf4. Our study illustrated the role of Mycn in dentin development and furthers our general comprehension of the transcription factor networks involved in the dentinogenesis process. Thus, these results may provide new insight into dentin hypoplasia and bioengineered dentin regeneration.

Accurate model parameters of Static Var Generator (SVG) play an essential role in regulating bus voltage profiles of power grid with increased penetration of renewable energy under various contingencies. Aiming at addressing the known issues of low identification accuracy and long computation time faced by the traditional SVG parameter identification methods, this paper presents a multi-layer coarse-to-fine grid searching approach for calibrating SVG dynamic model parameters using particle swarm optimization. First, actual measurement data is collected through SVG-RTDS testbeds under various conditions, which is compared with transient stability simulation results to check for model accuracy. Then, nonlinear trajectory sensitivity analysis is performed using segmented curves to identify potential bad model parameters. Next, a multi-layer coarse-to-fine grid searching mechanism is used to narrow the parameter searching space, before particle swarm algorithm optimization is used for more precise identification of parameters. By comparing the identification results obtained by the traditional identification methods and the proposed approach via comprehensive case studies, it is found that the proposed coarse-to-fine parameter identification method achieved higher accuracy and faster computational speed.

IntroductionImproving sense of community belonging (SCB) would help people live longer, happier lives. Although the importance of neighborhood environment on SCB is stressed in the literature, few studies have paid attention to perceived environment, as well as consider mediation effects such as neighborhood social interactions and place satisfaction.MethodsRelied on a sample of 1051 respondents in Shanghai in 2018, this study investigates the associations between both objective and perceived neighborhood environment attributes and SCB in urban China, mediated by neighborly interactions and community satisfaction using structural equation modeling.ResultsThe results suggest that the influence of perceived neighborhood environment on SCB is more prominent than that of objective neighborhood environment. In detail, perceived pedestrian facilities and perceived leisure facilities are vital to SCB, while among objective neighborhood environmental elements, the influence of land use entropy, park density and street greenery are significant. Then, neighborhood environmental attributes can influence SCB by affecting neighborly interactions and community satisfaction. We also identify gender differences in the effects of neighborhood environment upon SCB.DiscussionGiven increasing awareness of the connection, neighborhood environment may prove to be valuable assets to improve individuals' psychosocial constructs such as SCB.

Abstract A reversed migration capillary electrophoresis (RMCE) has been developed to determine linear alkylbenzene sulfonates (LAS). The sample stacking and separation conditions have been systematically investigated and optimized under reversed separation voltage at a low pH value. The separation effect of LAS homologs has been greatly improved based on the relative motion of electrophoresis and electroosmotic flow. RMCE demonstrates a good linear range of 0.1 mg/l to 10.0 mg/l, and the detection limit of LAS homologs reaches 0.001–0.004 mg/l. The relative standard deviations (n=6) of peak area and migration time were 2.25–4.40% and 0.67–0.75%, respectively. RMCE has also been applied for LAS detection in practical wastewater. The results show RMCE exhibits easy pretreatment, fast detection, high sensitivity, good peak shapes and resolution, and less solvent consumption, compared with the established high-performance liquid chromatography method.

The unique structure and physical properties of perovskite-type catalysts make them highly promising for catalyzing efficient coal combustion. Mesoporous perovskite LaNixFe1−xO3 (x = 0.2, 0.4, 0.6, 0.8) coal combustion catalysts were synthesized using the sol–gel method. The effects of the doping amount of B-site doped nickel on both the crystal structure and catalytic performance were investigated. X-ray diffraction, scanning electron microscopy, and nitrogen adsorption–desorption tests were used to characterize the catalyst samples. Thermogravimetric analysis (TG) and activation energy (Ea) calculations were used to assess the catalyst’s activity for the catalytic combustion of anthracite coal (JF coal, originating from Shanxi, China). Results revealed that nickel doping created lattice distortion and Ni-Fe alloy interactions. The difference in nickel doping significantly affects the morphology and catalytic activity of perovskite. The addition of LaNi0.6Fe0.4O3 (NI6) with a mass fraction of 5% resulted in the highest average burning rate value (va = 4.52%/min) of JF coal among all synthesized catalysts. The Ea of JF coal catalytic combustion, calculated using the Coats–Redfern method and the Doyle method, showed a good agreement with the TG curves. The LaNixFe1-xO3 series catalysts were found to significantly decrease the Ea of JF coal combustion, with a maximum reduction of 42% compared to the case without any catalyst added. Among the synthesized catalysts, NI6 exhibited a favorable catalytic combustion performance and is thus a promising candidate for the clean and efficient utilization of coal resources.

Abstract Background Ananas comosus var. bracteatus is a colorful plant used as a cut flower or landscape ornamental. The unique foliage color of this plant includes both green and red leaves and, as a trait of interest, deserves investigation. In order to explore the pigments behind the red section of the chimeric leaves, the green and red parts of chimeric leaves of Ananas comosus var. bracteatus were sampled and analyzed at phenotypic, cellular and molecular levels in this study. Results The CIELAB results indicated that the a* values and L* values samples had significant differences between two parts. Freehand sections showed that anthocyanin presented limited accumulation in the green leaf tissues but obviously accumulation in the epidermal cells of red tissues. Transcriptomic and metabolomic analyses were performed by RNA-seq and LC-ESI-MS/MS. Among the 508 identified metabolites, 10 kinds of anthocyanins were detected, with 6 significantly different between the two samples. The cyanidin-3,5-O-diglucoside content that accounts for nearly 95.6% in red samples was significantly higher than green samples. RNA-Seq analyses showed that 11 out of 40 anthocyanin-related genes were differentially expressed between the green and red samples. Transcriptome and metabolome correlations were determined by nine quadrant analyses, and 9 anthocyanin-related genes, including MYB5 and MYB82, were correlated with 7 anthocyanin-related metabolites in the third quadrant in which genes and metabolites showing consistent change. Particularly, the PCCs between these two MYB genes and cyanidin-3,5-O-diglucoside were above 0.95. Conclusion Phenotypic colors are closely related to the tissue structures of different leaf parts of Ananas comosus var. bracteatus, and two MYB transcription factors might contribute to differences of anthocyanin accumulation in two parts of Ananas comosus var. bracteatus chimeric leaves. This study lay a foundation for further researches on functions of MYBs in Ananas comosus var. bracteatus and provides new insights to anthocyanin accumulation in different parts of chimeric leaves.

Abstract In mammals, many organs lack robust regenerative abilities. Lost cells in impaired tissue could potentially be compensated by converting nearby cells in situ through in vivo reprogramming. Small molecule-induced cell reprogramming offers a temporally flexible and non-integrative strategy for altering cell fate, which is, in principle, favorable for in vivo reprogramming in organs with notoriously poor regenerative abilities, such as the brain. Here, we demonstrate that in the adult mouse brain, small molecules can reprogram astrocytes into neurons. The in situ chemically induced neurons resemble endogenous neurons in terms of neuron-specific marker expression, electrophysiological properties, and synaptic connectivity. Our study demonstrates the feasibility of in vivo chemical reprogramming in the adult mouse brain and provides a potential approach for developing neuronal replacement therapies.

Jingliang Zhang et al. examine how dysfunctional PKA signaling impacts neuronal activity and seizure susceptibility in a mouse model of temporal lobe epilepsy. Their data suggest that autophosphorylation of the RIIβ subunit regulates neuronal excitability, and may act as a future therapeutic target.

Myrothamnus flabellifolia is the only woody resurrection plant discovered so far and could recover from extreme desiccation condition. However, few genes related to its strong drought tolerance have been characterized, and the underlying molecular mechanisms remains mysterious. Members of WRKY transcription factor family are effective in regulating abiotic stress responses or tolerance in various plants. An early dehydration-induced gene encoding a WRKY transcription factor namely MfWRKY41 was isolated from M. flabellifolia, which is homologous to AtWRKY41 of Arabidopsis. It contains a typical WRKY domain and zinc finger motif, and is located in the nucleus. Comparing to wild type, the four transgenic lines overexpressing MfWRKY41 showed better growth performance under drought and salt treatments, and exhibited higher chlorophyll content, lower water loss rate and stomatal aperture and better osmotic adjustment capacity. These results indicated that MfWRKY41 of M. flabellifolia positively regulates drought as well as salinity responses. Interestingly, the root system architecture, including lateral root number and primary root length, of the transgenic lines was enhanced by MfWRKY41 under both normal and stressful conditions, and the antioxidation ability was also significantly improved. Therefore, MfWRKY41 may have potential application values in genetic improvement of plant tolerance to drought and salinity stresses. The molecular mechanism involving in the regulatory roles of MfWRKY41 is worthy being explored in the future.

Bamboo (Bambusoideae) belongs to the grass family (Poaceae) and has been utilized as one of the most important nontimber forest resources in the world. Moso bamboo (Phyllostachys edulis) is a large woody bamboo with high ecological and economic values. Global climate change brings potential challenges to the normal growth of moso bamboo, and hence its production. Despite the release of moso bamboo genome sequence, the knowledge on genome-wide responses to abiotic stress is still limited. In this study, we generated a transcriptome data set with respect to dehydration and cold responses of moso bamboo using RNA-seq technology. The differentially expressed genes (DEGs) under treatments of dehydration and cold stresses were identified. By combining comprehensive gene ontology (GO) analysis, time-series analysis, and co-expression analysis, candidate genes involved in dehydration and cold responses were identified, which encode abscisic acid (ABA)/water deficit stress (WDS)-induced protein, late embryogenesis abundant (LEA) protein, 9-cis-epoxycarotenoid dioxygenase (NCED), anti-oxidation enzymes, transcription factors, etc. Additionally, we used PeLEA14, a dehydration-induced gene encoding an “atypical” LEA protein, as an example to validate the function of the identified stress-related gene in tolerance to abiotic stresses, such as drought and salt. In this study, we provided a valuable genomic resource for future excavation of key genes involved in abiotic stress responses and genetic improvement of moso bamboo to meet the requirement for environmental resilience and sustainable production.

Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive carbohydrate metabolism disorder. The main symptoms of FBS are hepatomegaly, nephropathy, postprandial hyperglycemia, fasting hypoglycemia, and growth retardation. Hypokalemia is a rare clinical feature in patients with FBS. In this study, we present a neonate suffering from FBS. She presented with hypokalemia, dysglycaemia, glycosuria, hepatomegaly, abnormality of liver function, and brain MRI. Trio whole-exome sequencing (WES) and Sanger sequencing were performed to identify the causal gene variants. A compound heterozygous mutation (NM_000340.2; p. Trp420*) of SLC2A2 was identified. Here, we report a patient with FBS in a consanguineous family with diabetes, severe hypokalemia, and other typical FBS symptoms. Patients with common clinical features may be difficult to diagnose just by phenotypes in the early stage of life, but WES could be an important tool. We also discuss the use of insulin in patients with FBS and highlight the importance of a continuous glucose monitoring system (CGMS), not only in diagnosis but also to avoid hypoglycemic events.

Autism spectrum disorder (ASD) affects ~2% of the population in the US, and monogenic forms of ASD often result in the most severe manifestation of the disorder. Recently, SCN2A has emerged as a leading gene associated with ASD, of which abnormal sleep pattern is a common comorbidity. SCN2A encodes the voltage-gated sodium channel NaV1.2. Predominantly expressed in the brain, NaV1.2 mediates the action potential firing of neurons. Clinical studies found that a large portion of children with SCN2A deficiency have sleep disorders, which severely impact the quality of life of affected individuals and their caregivers. The underlying mechanism of sleep disturbances related to NaV1.2 deficiency, however, is not known. Using a gene-trap Scn2a-deficient mouse model (Scn2atrap), we found that Scn2a deficiency results in increased wakefulness and reduced non-rapid-eye-movement (NREM) sleep. Brain region-specific Scn2a deficiency in the suprachiasmatic nucleus (SCN) containing region, which is involved in circadian rhythms, partially recapitulates the sleep disturbance phenotypes. At the cellular level, we found that Scn2a deficiency disrupted the firing pattern of spontaneously firing neurons in the SCN region. At the molecular level, RNA-sequencing analysis revealed differentially expressed genes in the circadian entrainment pathway including core clock genes Per1 and Per2. Performing a transcriptome-based compound discovery, we identified dexanabinol (HU-211), a putative glutamate receptor modulator, that can partially reverse the sleep disturbance in mice. Overall, our study reveals possible molecular and cellular mechanisms underlying Scn2a deficiency-related sleep disturbances, which may inform the development of potential pharmacogenetic interventions for the affected individuals.

Abstract Background The basic helix-loop-helix (bHLH) proteins, a large transcription factors family, are involved in plant growth and development, and defensive response to various environmental stresses. The resurrection plant Myrothamnus flabellifolia is known for its extremely strong drought tolerance, but few bHLHs taking part in abiotic stress response have been unveiled in M. flabellifolia. Results In the present research, we cloned and characterized a dehydration-inducible gene, MfbHLH38, from M. flabellifolia. The MfbHLH38 protein is localized in the nucleus, where it may act as a transcription factor. Heterologous expression of MfbHLH38 in Arabidopsis improved the tolerance to drought and salinity stresses, as determined by the studies on physiological indexes, such as contents of chlorophyll, malondialdehyde (MDA), proline (Pro), soluble protein, and soluble sugar, water loss rate of detached leaves, reactive oxygen species (ROS) accumulation, as well as antioxidant enzyme activities. Besides, MfbHLH38 overexpression increased the sensitivity of stomatal closure to mannitol and abscisic acid (ABA), improved ABA level under drought stress, and elevated the expression of genes associated with ABA biosynthesis and ABA responding, sucha as NCED3, P5CS, and RD29A. Conclusions Our results presented evidence that MfbHLH38 enhanced tolerance to drought and salinity stresses in Arabidopsis through increasing water retention ability, regulating osmotic balance, decreasing stress-induced oxidation damage, and possibly participated in ABA-dependent stress-responding pathway.

Systematic administration of anti-inflammatory cytokine interleukin 4 (IL-4) has been shown to improve recovery after cerebral ischemic stroke. However, whether IL-4 affects neuronal excitability and how IL-4 improves ischemic injury remain largely unknown. Here we report the neuroprotective role of endogenous IL-4 in focal cerebral ischemia–reperfusion (I/R) injury. In multi-electrode array (MEA) recordings, IL-4 reduces spontaneous firings and network activities of mouse primary cortical neurons. IL-4 mRNA and protein expressions are upregulated after I/R injury. Genetic deletion of Il-4 gene aggravates I/R injury in vivo and exacerbates oxygen-glucose deprivation (OGD) injury in cortical neurons. Conversely, supplemental IL-4 protects Il-4−/− cortical neurons against OGD injury. Mechanistically, cortical pyramidal and stellate neurons common for ischemic penumbra after I/R injury exhibit intrinsic hyperexcitability and enhanced excitatory synaptic transmissions in Il-4−/− mice. Furthermore, upregulation of Nav1.1 channel, and downregulations of KCa3.1 channel and α6 subunit of GABAA receptors are detected in the cortical tissues and primary cortical neurons from Il-4−/− mice. Taken together, our findings demonstrate that IL-4 deficiency results in neural hyperexcitability and aggravates I/R injury, thus activation of IL-4 signaling may protect the brain against the development of permanent damage and help recover from ischemic injury after stroke.

Abstract Background Lysine succinylation, an important protein posttranslational modification (PTM), is widespread and conservative. The regulatory functions of succinylation in leaf color has been reported. The chimeric leaves of Ananas comosus var. bracteatus are composed of normal green parts and albino white parts. However, the extent and function of lysine succinylation in chimeric leaves of Ananas comosus var. bracteatus has yet to be investigated. Results Compared to the green (Gr) parts, the global succinylation level was increased in the white (Wh) parts of chimeric leaves according to the Western blot and immunohistochemistry analysis. Furthermore, we quantitated the change in the succinylation profiles between the Wh and Gr parts of chimeric leaves using label-free LFQ intensity. In total, 855 succinylated sites in 335 proteins were identified, and 593 succinylated sites in 237 proteins were quantified. Compared to the Gr parts, 232 (61.1%) sites in 128 proteins were quantified as upregulated targets, and 148 (38.9%) sites in 70 proteins were quantified as downregulated targets in the Wh parts of chimeric leaves using a 1.5-fold threshold (P