Maintaining moderate levels of hypochlorous acid promotes neural stem cell proliferation and differentiation in the recovery phase of stroke.

JOURNAL/nrgr/04.03/01300535-202503000-00029/figure1/v/2024-06-17T092413Z/r/image-tiff It has been shown clinically that continuous removal of ischemia/reperfusion-induced reactive oxygen species is not conducive to the recovery of late stroke. Indeed, previous studies have shown that excessive increases in hypochlorous acid after stroke can cause severe damage to brain tissue. Our previous studies have found that a small amount of hypochlorous acid still exists in the later stage of stroke, but its specific role and mechanism are currently unclear. To simulate stroke in vivo, a middle cerebral artery occlusion rat model was established, with an oxygen-glucose deprivation/reoxygenation model established in vitro to mimic stroke. We found that in the early stage (within 24 hours) of ischemic stroke, neutrophils produced a large amount of hypochlorous acid, while in the recovery phase (10 days after stroke), microglia were activated and produced a small amount of hypochlorous acid. Further, in acute stroke in rats, hypochlorous acid production was prevented using a hypochlorous acid scavenger, taurine, or myeloperoxidase inhibitor, 4-aminobenzoic acid hydrazide. Our results showed that high levels of hypochlorous acid (200 µM) induced neuronal apoptosis after oxygen/glucose deprivation/reoxygenation. However, in the recovery phase of the middle cerebral artery occlusion model, a moderate level of hypochlorous acid promoted the proliferation and differentiation of neural stem cells into neurons and astrocytes. This suggests that hypochlorous acid plays different roles at different phases of cerebral ischemia/reperfusion injury. Lower levels of hypochlorous acid (5 and 100 µM) promoted nuclear translocation of ß-catenin. By transfection of single-site mutation plasmids, we found that hypochlorous acid induced chlorination of the ß-catenin tyrosine 30 residue, which promoted nuclear translocation. Altogether, our study indicates that maintaining low levels of hypochlorous acid plays a key role in the recovery of neurological function.

Frequency ratio of the 229mTh nuclear isomeric transition and the 87Sr atomic clock.

Optical atomic clocks1,2 use electronic energy levels to precisely keep track of time. A clock based on nuclear energy levels promises a next-generation platform for precision metrology and fundamental physics studies. Thorium-229 nuclei exhibit a uniquely low-energy nuclear transition within reach of state-of-the-art vacuum ultraviolet (VUV) laser light sources and have, therefore, been proposed for construction of a nuclear clock3,4. However, quantum-state-resolved spectroscopy of the 229mTh isomer to determine the underlying nuclear structure and establish a direct frequency connection with existing atomic clocks has yet to be performed. Here, we use a VUV frequency comb to directly excite the narrow 229Th nuclear clock transition in a solid-state CaF2 host material and determine the absolute transition frequency. We stabilize the fundamental frequency comb to the JILA 87Sr clock2 and coherently upconvert the fundamental to its seventh harmonic in the VUV range by using a femtosecond enhancement cavity. This VUV comb establishes a frequency link between nuclear and electronic energy levels and allows us to directly measure the frequency ratio of the 229Th nuclear clock transition and the 87Sr atomic clock. We also precisely measure the nuclear quadrupole splittings and extract intrinsic properties of the isomer. These results mark the start of nuclear-based solid-state optical clocks and demonstrate the first comparison, to our knowledge, of nuclear and atomic clocks for fundamental physics studies. This work represents a confluence of precision metrology, ultrafast strong-field physics, nuclear physics and fundamental physics.

Derivatives of postbiotics (cell wall constituents) from Bacillus subtilis (LCBS1) relieve soybean meal-induced enteritis in bullfrog (Aquarana catesbeianus).

Soybean meal (SM) serves as a primary alternative to fish meal in aquafeeds. However, a high-SM diet may result in intestinal injury. Our previous study demonstrated the probiotic effects of heat-inactivated Bacillus subtilis (LCBS1) on bullfrogs (Aquarana catesbeianus) fed a high-SM diet, probably attributed to the bioactive constituent of cell wall. Therefore, in this study, the main constituents of cell wall from LCBS1, including peptidoglycan (PGN), lipoteichoic acid (LTA), cell wall protein (CWP), and whole cell wall (WCW), were extracted and added to a high-SM (~55 %) diet to investigate their probiotic effects on bullfrogs and reveal the possible mechanisms. The results indicated that bullfrogs fed the LTA of LCBS1 showed the highest weight gain, feed efficiency, and protein efficiency ratio. Additionally, the LTA of LCBS1 could activate the humoral immunity and modulate intestinal microbiota. It might activate JAK2-STAT3 and MAPK-ERK pathways, as well as up-regulate tlr5 gene to promote intestinal cell proliferation, thereby alleviating jejunal injury. The WCW of LCBS1 effectively increased the growth performance of bullfrogs by improving the humoral immunity, enhancing intestinal barrier function, and alleviating intestinal inflammatory response. The PGN and CWP of LCBS1 could stimulate the humoral immunity and enhance intestinal barrier function, but had no significant effect on the growth performance of bullfrogs. In conclusion, the LTA might be the primary bioactive constituent of heat-inactivated LCBS1, with the beneficial effects of promoting intestinal cell proliferation and enhancing intestinal barrier function, therefore alleviating the intestinal injury induced by SM on bullfrogs. This study establishes a theoretical basis for the efficient utilization of plant proteins by the application of postbiotics additive in aquafeed, which further saves the feed costs and promotes development of economically sustainable aquaculture.

Prognostic significance of oligodendrocyte transcription factor 2 expression in glioma patients: A systematic review and meta-analysis.

BACKGROUND: Gliomas are the most common primary central nervous system neoplasm. Despite recent advances in the diagnosis and treatment of gliomas, patient prognosis remains dismal. Therefore, it is imperative to identify novel diagnostic biomarkers and therapeutic targets of glioma to effectively improve treatment outcomes. AIM: To investigate the association between oligodendrocyte transcription factor 2 (Olig2) expression and the outcomes of glioma patients. METHODS: The PubMed, Embase, Cochrane Library, and China National Knowledge Infrastructure databases were searched for studies (published up to October 2023) that investigated the relationship between Olig2 expression and prognosis of glioma patients. The quality of the studies was assessed using the Newcastle Ottawa Scale. Data analyses were performed using Stata Version 12.0 software. RESULTS: A total of 1205 glioma patients from six studies were included in the meta-analysis. High Olig2 expression was associated with better outcomes in glioma patients [hazard ratio (HR): 0.81; 95% (confidence interval) CI: 0.51-1.27; P = 0.000]. Furthermore, the results of subgroup meta-analysis showed that high expression of Olig2 was associated with poor overall survival in European patients (HR: 1.34; 95%CI: 0.79-2.27) and better prognosis in Asian patients (HR: 0.43; 95%CI: 0.22-0.84). The sensitivity analysis showed that no single study had a significant effect on pooled HR, and there was also no indication of publication bias according to the Egger's and Begger's P value test or funnel plot test. CONCLUSION: High Olig2 expression may have a positive impact on the prognosis of glioma patients, and should be investigated further as a prognostic biomarker and therapeutic target for glioma.

Silencing APLNR enhances the radiosensitivity of prostate cancer by modulating the PI3K/AKT/mTOR signaling pathway.

BACKGROUND: Aberrant expression of apelin receptor (APLNR) has been found to be involved in various cancers' development, however, its function in prostate cancer (PCa) remains unclear. The research aimed to investigate the role and potential mechanism of APLNR in PCa. METHODS: The mRNA expression of APLNR was detected via qRT-PCR assay. PCa cell proliferation and apoptosis were determined through plate cloning and flow cytometry. In addition, the expression of apoptosis-related proteins (Bax, Bcl-2, and cleaved caspase-3) was evaluated using western blot. DNA damage marker (γ-H2AX) was analyzed by immunofluorescence and western blot. GSEA analysis was performed for seeking enrichment pathways of APLNR in PCa, and the protein levels of PI3K, p-PI3K, AKT, p-AKT, mTOR, and p-mTOR were tested using western blot. RESULTS: APLNR expression was up-regulated in PCa tissues and cells. Silencing APLNR enhanced the sensitivity of PCa cells to radiotherapy, which was manifested by inhibiting cell proliferation, promoting cell apoptosis, and promoting DNA damage. Next, silencing APLNR inhibited the PI3K/AKT/mTOR pathway. Specifically, 740Y-P (the PI3K/AKT/mTOR pathway activator) reversed the effects of silencing APLNR on PCa cell proliferation, apoptosis and DNA damage. CONCLUSION: Silencing APLNR inhibited cell proliferation, promoted cell apoptosis, and enhanced the radiosensitivity of PCa cells, which was involved in the PI3K/AKT/mTOR signaling pathway. This study is conducive to the deeper understanding of PCa and further provides a new perspective for the treatment of PCa.

The spatiotemporal associations between esophageal and gastric cancers provide evidence for its joint endoscopic screening in China: a population-based study.

BACKGROUND: The spatiotemporal epidemiological evidence supporting joint endoscopic screening for esophageal cancer (EC) and gastric cancer (GC) remains limited. This study aims to identify combined high-risk regions for EC and GC and determine optimal areas for joint and separate endoscopic screening. METHODS: We analyzed the association of incidence trends between EC and GC in cancer registry areas across China from 2006 to 2016 using spatiotemporal statistical methods. Based on these analyses, we divided different combined risk regions for EC and GC to implement joint endoscopic screening. RESULTS: From 2006 to 2016, national incidence trends for both EC and GC showed a decline, with an average annual percentage change of -3.15 (95% confidence interval [CI]: -5.33 to -0.92) for EC and -3.78 (95% CI: -4.98 to -2.56) for GC. A grey comprehensive correlation analysis revealed a strong temporal association between the incidence trends of EC and GC, with correlations of 79.00% (95% CI: 77.85 to 80.14) in males and 77.62% (95% CI: 76.50 to 78.73) in females. Geographic patterns of EC and GC varied, demonstrating both homogeneity and heterogeneity across different regions. The cancer registry areas were classified into seven distinct combined risk regions, with 33 areas identified as high-risk for both EC and GC, highlighting these regions as priorities for joint endoscopic screening. CONCLUSION: This study demonstrates a significant spatiotemporal association between EC and GC. The identified combined risk regions provide a valuable basis for optimizing joint endoscopic screening strategies for these cancers.

Strain-Mediated Defect Engineering toward Rapid Atomic Migration in Fe-Al Diffusion Couples.

In the pursuit of rapid atomic migration in lightweight Fe-Al diffusion couples, rationally designing short-circuit diffusion paths has become paramount. Herein, a strain-mediated defect engineering strategy was proposed for reducing the vacancy activation energy and enhancing diffusion behaviors along dislocations (DLs) and grain boundaries (GBs). Combining the modified Arrhenius-type relationship, an interfacial apparent activation energy of 139 kJ mol-1 was acquired utilizing defect engineering, which was decreased by about 49%. This was closely related to high-density vacancies, DLs, and GBs formed in strained Fe and Al materials, which provided more low activation energy paths for atomic migration. First-principles calculations indicated that the lattice diffusion barrier mediated by monovacancy was reduced with strain incorporation, attributed to the weakened atom-vacancy bond as a consequence of less electron transport. The synergistic effect of abnormal electron-charge distribution in the bulk and strong attraction force at the Al/Fe interface radically resulted in rapid atomic migration, collectively regulating the "breaking-forming bond" process.

Retrospective estimation of the time-varying effective reproduction number for a COVID-19 outbreak in Shenyang, China: An observational study.

The time-varying effective reproduction number Re(t) is essential for designing and adjusting public health responses. Retrospective analysis of Re(t) helps to evaluate health emergency capabilities. We conducted this study to estimate the Re(t) of the Corona Virus Disease 2019 (COVID-19) outbreak caused by SARS-CoV-2 Omicron in Shenyang, China. Data on the daily incidence of this Corona Virus Disease 2019 outbreak between March 5, 2022, and April 25, 2022, in Shenyang, China, were downloaded from the Nationwide Notifiable Infectious Diseases Reporting Information System. Infector-infectee pairs were identified through epidemiological investigation. Re(t) was estimated by R-studio Package "EpiEstim" based on Bayesian framework through parameter and nonparametric method, respectively. About 1134 infections were found in this outbreak, with 20 confirmed cases and 1124 asymptomatic infections. Fifty-four infector-infectee pairs were identified and formed a serial interval list, and 15 infector-infectee pairs were included in the generation time table. Re(t) calculated by parameter and nonparametric method all peaked on March 17, 2022, with a value of 2.58 and 2.54 and decreased to <1 after March 28, 2022. There was no statistical difference in the Re(t) distribution calculated using the 2 methods (t = 0.001, P > .05). The present study indicated that the decisive response of Shenyang, China, played a significant role in preventing the spread of the epidemic, and the retrospective analysis provided novel insights into the outbreak response to future public health emergencies.

Perioperative toripalimab plus neoadjuvant chemotherapy might improve outcomes in resectable esophageal cancer: an interim analysis of a phase III randomized clinical trial.

BACKGROUND: In the era of immunotherapy, neoadjuvant immunochemotherapy (NAIC) for the treatment of locally advanced esophageal squamous cell carcinoma (ESCC) is used clinically but lacks of high-level clinical evidence. This study aimed to compare the safety and long-term efficacy of NAIC followed by minimally invasive esophagectomy (MIE) with those of neoadjuvant chemotherapy (NAC) followed by MIE. METHODS: A prospective, single-center, open-label, randomized phase III clinical trial was conducted at Henan Cancer Hospital, Zhengzhou, China. Patients were randomly assigned to receive either neoadjuvant toripalimab (240 mg) plus paclitaxel (175 mg/m2) + cisplatin (75 mg/m2) (toripalimab group) or paclitaxel + cisplatin alone (chemotherapy group) every 3 weeks for 2 cycles. After surgery, the toripalimab group received toripalimab (240 mg every 3 weeks for up to 6 months). The primary endpoint was event-free survival (EFS). The pathological complete response (pCR) and overall survival (OS) were key secondary endpoints. Adverse events (AEs) and quality of life were also assessed. RESULTS: Between May 15, 2020 and August 13, 2021, 252 ESCC patients ranging from T1N1-3M0 to T2-3N0-3M0 were enrolled for interim analysis, with 127 in the toripalimab group and 125 in the chemotherapy group. The 1-year EFS rate was 77.9% in the toripalimab group compared to 64.3% in the chemotherapy group (hazard ratio [HR] = 0.62; 95% confidence interval [CI] = 0.39 to 1.00; P = 0.05). The 1-year OS rates were 94.1% and 83.0% in the toripalimab and chemotherapy groups, respectively (HR = 0.48; 95% CI = 0.24 to 0.97; P = 0.037). The patients in the toripalimab group had a higher pCR rate (18.6% vs. 4.6%; P = 0.001). The rates of postoperative Clavien-Dindo grade IIIb or higher morbidity were 9.8% in the toripalimab group and 6.8% in the chemotherapy group, with no significant difference observed (P = 0.460). The rates of grade 3 or 4 treatment-related AEs did not differ between the two groups (12.5% versus 12.4%). CONCLUSIONS: The interim results of this ongoing trial showed that in resectable ESCC, the addition of perioperative toripalimab to NAC is safe, may improve OS and might change the standard treatment in the future.

Associations of Rest-Activity Rhythm Disturbances With Stroke Risk and Poststroke Adverse Outcomes.

BACKGROUND: Many disease processes are influenced by circadian clocks and display ~24-hour rhythms. Whether disruptions to these rhythms increase stroke risk is unclear. We evaluated the association between 24-hour rest-activity rhythms, stroke risk, and major poststroke adverse outcomes. METHODS AND RESULTS: We examined ~100 000 participants from the UK Biobank (aged 44-79 years; ~57% women) assessed with actigraphy (6-7 days) and 5-year median follow-up. We derived (1) most active 10-hour activity counts across the 24-hour cycle and the timing of its midpoint timing; (2) the least active 5-hour count and its midpoint; (3) relative amplitude; (4) interdaily stability; and (5) intradaily variability, for stability and fragmentation of the rhythm. Cox proportional hazard models were constructed for time to (1) incident stroke (n=1652) and (2) poststroke adverse outcomes (dementia, depression, disability, or death). Suppressed relative amplitude (lowest quartile [quartile 1] versus the top quartile [quartile 4]) was associated with stroke risk (hazard ratio [HR], 1.61 [95% CI, 1.35-1.92]; P<0.001) after adjusting for demographics. Later most active 10-hour activity count midpoint timing (14:00-15:26; HR, 1.26 [95% CI, 1.07-1.49]; P=0.007) also had higher stroke risk than earlier (12:17-13:10) participants. A fragmented rhythm (intradaily variability) was also associated with higher stroke risk (quartile 4 versus quartile 1; HR, 1.26 [95% CI, 1.06-1.49]; P=0.008). Suppressed relative amplitude was associated with risk for poststroke adverse outcomes (quartile 1 versus quartile 4; HR, 2.02 [95% CI, 1.46-2.48]; P<0.001). All associations were independent of age, sex, race, obesity, sleep disorders, cardiovascular diseases or risks, and other comorbidity burdens. CONCLUSIONS: Suppressed 24-hour rest-activity rhythm may be a risk factor for stroke and an early indicator of major poststroke adverse outcomes.

Antitumor effects of a Sb-rich polyoxometalate on non-small-cell lung cancer by inducing ferroptosis and apoptosis.

Polyoxometalates (POMs) are a class of anionic metal-oxygen clusters with versatile biological activities. Over the past decade, an increasing number of POMs, especially Sb-rich POMs, have been proven to exert antitumor activity. However, the antitumor effects and mechanisms of POMs in the treatment of non-small cell lung cancer (NSCLC) remain largely unexplored. This study employed a Sb-rich {Sb21Tb7W56} POM (POM-1) for NSCLC therapy and investigated its mechanism of action. Our results demonstrated that POM-1 exhibited cytotoxicity against H1299 and A549 cells with IC50 values of 3.245 µM and 3.591 µM, respectively. The migration and invasion were also inhibited by 28.05% and 76.18% in H1299 cells, as well as 36.88% and 36.98% in A549 cells at a concentration of 5 µM. In a tumor xenograft mouse model, POM-1 suppressed tumor growth by 76.92% and 84.62% at doses of 25 and 50 mg kg-1, respectively. Transcriptomic analysis indicated the alteration of ferroptosis and apoptosis signaling pathways in POM-treated NSCLC cells. Subsequent experimentation confirmed the induction of ferroptosis, evidenced by 5.6-fold elevated lipid peroxide levels with treatment of 5 µM POM-1, alongside increased expression of ferroptosis-associated proteins. Additionally, the apoptosis induced by POM-1 was also validated by the 19.67% and 30.1% increase in apoptotic cells in H1299 and A549 cells treated with 5 µM POM-1, respectively, as well as the upregulated activation of caspase-3. In summary, this study reveals, for the first time, ferroptosis as the antitumor mechanism of Sb-rich POM, and that synergism with ferroptosis and apoptosis is a highly potent antitumor strategy for POM-based antitumor therapy.

Phylogenomic analysis uncovers an unexpected capacity for the biosynthesis of secondary metabolites in Pseudoalteromonas.

Pseudoalteromonas is a genus of marine bacteria and a promising source of natural products with antibacterial, antifungal, and antifouling bioactivities. To accelerate the exploration of new compounds from this genus, we applied the gene-first approach to study 632 public Pseudoalteromonas genomes. We identified 3968 biosynthetic gene clusters (BGCs) involved in the biosynthesis of secondary metabolites and classified them into 995 gene cluster families (GCFs). Surprisingly, only 9 GCFs (0.9 %) included an experimentally identified reference biosynthetic gene cluster from the Minimum Information about a Biosynthetic Gene cluster database (MIBiG), suggesting a striking novelty of secondary metabolites in Pseudoalteromonas. Bioinformatic analysis of the biosynthetic diversity encoded in the identified BGCs uncovered six dominant species of this genus, P. citrea, P. flavipulchra, P. luteoviolacea, P. maricaloris, P. piscicida, and P. rubra, that encoded more than 17 BGCs on average. Moreover, each species exhibited a species-specific distribution of BGC. However, a deep analysis revealed two BGCs conserved across five of the six dominant species. These BGCS encoded an unknown lanthipeptide and the siderophore myxochelin B implying an essential role of antibiotics for Pseudoalteromonas. We chemically profiled 11 strains from the 6 dominant species and identified four new antibiotics, korormicins L-O (1-4), from P. citrea WJX-3. Our results highlight the unexplored biosynthetic potential for bioactive compounds in Pseudoalteromonas and provide an important guideline for targeting exploration.

Effects of Mao tea from Nankun Mountain on nonalcoholic fatty liver disease in mice.

Non-alcoholic fatty liver disease (NAFLD) poses a significant health threat due to its potential progression to liver fibrosis, cirrhosis, and even liver cancer. Without proper management, NAFLD can lead to severe complications and significantly impact overall health and longevity. This study explores the potential anti-steatosis effects of Nankun Mountain Mao tea (MT) on hepatic lipid accumulation using both in vitro and in vivo models. In vitro experiments reveal that MT reduces lipid accumulation in hepatocytes and counteracts hepatic steatosis induced by palmitic acid and oleic acid. In vivo investigations on high-fat diet (HFD)-fed and high-fat, fructose, and cholesterol (HFFC)-fed mice demonstrate that MT administration alleviates hepatic steatosis by reducing lipid accumulation, enhancing liver function, and mitigating inflammation. Transcriptomic analyses unveil the molecular mechanisms underlying the impact of MT on lipid metabolism and inflammation. It turns out that MT inhibits de novo lipid synthesis and NF-κB pathway against NAFLD. Furthermore, target prediction analysis identifies potential bioactive components group (BCG) within MT that may contribute to its anti-steatosis properties. Validation studies on primary hepatocytes confirm the effectiveness of these bioactive components in diminishing lipid accumulation and inflammation, suggesting their role in the therapeutic efficacy of MT against NAFLD.

A genome-scale deep learning model to predict gene expression changes of genetic perturbations from multiplex biological networks.

Systematic characterization of biological effects to genetic perturbation is essential to the application of molecular biology and biomedicine. However, the experimental exhaustion of genetic perturbations on the genome-wide scale is challenging. Here, we show TranscriptionNet, a deep learning model that integrates multiple biological networks to systematically predict transcriptional profiles to three types of genetic perturbations based on transcriptional profiles induced by genetic perturbations in the L1000 project: RNA interference, clustered regularly interspaced short palindromic repeat, and overexpression. TranscriptionNet performs better than existing approaches in predicting inducible gene expression changes for all three types of genetic perturbations. TranscriptionNet can predict transcriptional profiles for all genes in existing biological networks and increases perturbational gene expression changes for each type of genetic perturbation from a few thousand to 26 945 genes. TranscriptionNet demonstrates strong generalization ability when comparing predicted and true gene expression changes on different external tasks. Overall, TranscriptionNet can systemically predict transcriptional consequences induced by perturbing genes on a genome-wide scale and thus holds promise to systemically detect gene function and enhance drug development and target discovery.

Zero-power infrared switch with two-phase microfluidic flow and a 2D material thermal isolation layer.

Wireless sensor nodes (WSNs) play an important role in many fields, including environmental monitoring. However, unattended WSNs face challenges in consuming power continuously even in the absence of useful information, which makes energy supply the bottleneck of WSNs. Here, we realized zero-power infrared switches, which consist of a metasurface and two-phase microfluidic flow. The metasurface can recognize the infrared signal from the target and convert it into heat, which triggers the two-phase microfluidic flow switch. As the target is not present, the switch is turned off. The graphene/MoS2/graphene 2D material heterostructure (thickness <2 nm) demonstrates an exceptionally high thermal resistance of 4.2 K/W due to strong phonon scattering and reduces the heat flow from the metasurface to the supporting substrate, significantly increasing the device sensitivity (the displacement of the two-phase microfluidic flow increases from ~1500 to ~3000 µm). The infrared switch with a pair of symmetric two-phase microfluidic flows can avoid spurious triggering resulting from environmental temperature changes. We realized WSNs with near-zero standby power consumption by integrating the infrared switch, sensors, and wireless communication module. When the target infrared signal appears, the WSNs are woken and show superb visual/auditory sensing performance. This work provides a novel approach for greatly lengthening the lifespan of unattended WSNs.

Design, synthesis, and biological evaluation of imidazolylacetophenone oxime derivatives as novel brain-penetrant agents for Alzheimer's disease treatment.

Alzheimer's disease (AD, also known as dementia) has become a serious global health problem along with population aging, and neuroinflammation is the underlying cause of cognitive impairment in the brain. Nowadays, the development of multitarget anti-AD drugs is considered to be one effective approach. Imidazolylacetophenone oxime ethers or esters (IOEs) were multifunctional agents with neuroinflammation inhibition, metal chelation, antioxidant and neuroprotection properties against Alzheimer's disease. In this study, IOEs derivatives 1-8 were obtained by structural modifications of the oxime and imidazole groups, and the SARs showed that (Z)-oxime ether (derivative 2) had stronger anti-neuroinflammatory and neuroprotective ability than (E)-congener. Then, IOEs derivatives 9-30 were synthesized based on target-directed ligands and activity-based groups hybridization strategy. In vitro anti-AD activity screening revealed that some derivatives exhibited potentially multifunctional effects, among which derivative 28 exhibited the strongest inhibitory activity on NO production with EC50 value of 0.49 µM, and had neuroprotective effects on 6-OHDA-induced cell damage and RSL3-induced ferroptosis. The anti-neuroinflammatory mechanism showed that 28 could inhibit the release of pro-inflammatory factors PGE2 and TNF-α, down-regulate the expression of iNOS and COX-2 proteins, and promote the polarization of BV-2 cells from pro-inflammatory M1 phenotype to anti-inflammatory M2 phenotype. In addition, 28 can dose-dependently inhibit acetylcholinesterase (AChE) and Aß42 aggregation. Moreover, the selected nuclide [18F]-labeled 28 was synthesized to explore its biodistribution by micro-PET/CT, of which 28 can penetrate the blood-brain barrier (BBB). These results shed light on the potential of 28 as a new multifunctional candidate for AD treatment.

Integration of Hydrogels and 3D Bioprinting Technologies for Chronic Wound Healing Management.

The integration of hydrogel-based bioinks with 3D bioprinting technologies presents an innovative approach to chronic wound management, which is particularly challenging to treat because of its multifactorial nature and high risk of complications. Using precise deposition techniques, 3D bioprinting significantly alters traditional wound care paradigms by enabling the fabrication of patient-specific wound dressings that imitate natural tissue properties. Hydrogels are notably beneficial for these applications because of their abundant water content and mechanical properties, which promote cell viability and pathophysiological processes of wound healing, such as re-epithelialization and angiogenesis. This article reviews key 3D printing technologies and their significance in enhancing the structural and functional outcomes of wound-care solutions. Challenges in bioink viscosity, cell viability, and printability are addressed, along with discussions on the cross-linking and mechanical stability of the constructs. The potential of 3D bioprinting to revolutionize chronic wound management rests on its capacity to generate remedies that expedite healing and minimize infection risks. Nevertheless, further studies and clinical trials are necessary to advance these therapies from laboratory to clinical use.

[Water and heat transfer characteristics in summer maize farmland and its response to environmental factors in the old course of Yellow River]. / é»„æ²³æ• é“åŒºå¤çŽ‰ç±³å†œç”°æ°´çƒ­ä¼ è¾“ç‰¹å¾åŠå¯¹çŽ¯å¢ƒå› å­çš„å“åº”.

Accurate assessment of material and energy exchange between land and atmosphere is essential for water resources management and sustainable development of agriculture. To understand the characteristics of energy distribution and the dynamic change process of water and heat fluxes within the maize farmland ecosystem in the old course of Yellow River and their response to meteorological factors, we utilized the eddy covariance measurements and the full-element automatic weather station to continuously observe energy fluxes and conventional meteorological elements of summer maize farmland in the old course of Yellow River during 2019-2020. We analyzed the variation of energy fluxes and the effects of environmental factors, such as temperature, precipitation, and wind speed. Additionally, we calculated the energy closure rate and the proportion of energy distribution during the growth stage. The results showed that the peaks of net radiation, sensible heat flux, and latent heat flux occurred between 11:00 and 14:00, and the peak of soil heat flux occurred between 14:00 and 15:00. In terms of energy distribution, energy consumption of summer maize farmland during the whole growth period was dominated by latent heat flux and sensible heat flux. Energy was mainly consumed by sensible heat flux at sowing-emergence stage, accounting for 37.1% of net radiation, respectively. Energy in the rest of growth stages was dominated by latent heat flux. The energy closure rate during the whole growth period was better, with a coefficient of determination of 0.83, and the closure rate was higher in day and lower at night. Precipitation affected latent heat flux and sensible heat flux, and latent heat flux was more sensitive to precipitation. The increase of latent heat flux after rainfall was lower in late growth stage than in early growth stage. During the whole growth period of summer maize, solar radiation was the most significant meteorological factor affecting both sensible heat flux and latent heat flux, followed by vapor pressure deficit. The contribution of temperature and vapor pressure deficit to latent heat flux was significantly higher than sensible heat flux, while the relative contribution of wind speed, relative humidity, and solar radiation to latent heat flux was lower than sensible heat flux. Leaf area index and fractional vegetation cover had a significant positive correlation with latent heat flux and a significant negative correlation with sensible heat flux. Our results could deepen the understanding of water and heat transfer law of summer maize farmland in the old course of Yellow River, providing a theoretical basis for efficient water use of crops.

Five-Axis Curved-Surface Multi-Material Printing on Conformal Surface to Construct Aqueous Zinc-Ion Battery Modules.

Compact batteries and electronic devices offer a plethora of advantages, including space optimization, portability, integration capability, responsiveness, and reliability. These attributes are crucial technical enablers for the design and implementation of various electronic devices and systems within scientific exploration. Thus, the group harnesses additive manufacturing technology, specifically utilizing five-axis curved-surface multi-material printing equipment, to fabricate aqueous zinc-ion batteries with tungsten-doped manganese dioxide cathode for enhanced adaptability and customization. The five-axis linkage motion system facilitates shorter ion transportation paths for compact batteries and ensures precise and efficient molding of non-developable curved surfaces. Afterward, the compact cell is integrated with a printed nano-silver serpentine resistor temperature sensor, and an integrated functional circuit is created using intense-pulse sintering. Incorporating an emitting Light Emitting Diode (LED) allows temperature measurement through variations in LED brightness. The energy storage module with a high degree of conformity on the carrier surface has the advantages of small size and improved space utilization. The capability to produce Zinc-ion batteries (ZIBs) on curved surfaces presents new avenues for innovation in energy storage technologies, paving the way for the realization of flexible and conformal power sources.

Discovery of a potential bladder cancer inhibitor CHNQD-01281 by regulating EGFR and promoting infiltration of cytotoxic T cells.

As one of the common malignancies that threaten human life, bladder cancer occurs frequently with a high mortality rate in the world, due to its invasion, recurrence and drug resistance. Natural products from marine microorganisms are becoming the hotspots in discovery of new candidate drug entities, especially in the area of cancer. Brefeldin A (BFA) is a natural Arf-GEFs inhibitor, but due to the low aqueous solubility, strong toxicity, and poor bioavailability, it is urgent to conduct structural optimization research. Herein, a new BFA pyridine acrylate derivative CHNQD-01281 with improved solubility was prepared and found to exert moderate to strong antiproliferative activity on a variety of human cancer cell lines. It was noteworthy that CHNQD-01281 was most sensitive to two bladder cancer cell lines T24 and J82 (IC50 = 0.079 and 0.081 µmol/L) with high selectivity index (SI = 14.68 and 14.32), suggesting a superior safety to BFA. In vivo studies revealed that CHNQD-01281 remarkably suppressed tumor growth in a T24 nude mice xenograft model (TGI = 52.63%) and prolonged the survival time (ILS = 68.16%) in an MB49 allogeneic mouse model via inducing infiltration of cytotoxic T cells. Further mechanism exploration indicated that CHNQD-01281 regulated both EGFR/PI3K/AKT and EGFR/ERK pathways and mediated the chemotactic effect of chemokines on immune effector cells. Overall, CHNQD-01281 may serve as a potential therapeutic agent for bladder cancer through multiple mechanisms. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-024-00246-w.