Impact of childhood maltreatment on aging: a comprehensive Mendelian randomization analysis of multiple age-related biomarkers.

BACKGROUND: Childhood maltreatment (CM) is linked to long-term adverse health outcomes, including accelerated biological aging and cognitive decline. This study investigates the relationship between CM and various aging biomarkers: telomere length, facial aging, intrinsic epigenetic age acceleration (IEAA), GrimAge, HannumAge, PhenoAge, frailty index, and cognitive performance. METHODS: We conducted a Mendelian randomization (MR) study using published GWAS summary statistics. Aging biomarkers included telomere length (qPCR), facial aging (subjective evaluation), and epigenetic age markers (HannumAge, IEAA, GrimAge, PhenoAge). The frailty index was calculated from clinical assessments, and cognitive performance was evaluated with standardized tests. Analyses included Inverse-Variance Weighted (IVW), MR Egger, and Weighted Median (WM) methods, adjusted for multiple comparisons. RESULTS: CM was significantly associated with shorter telomere length (IVW: ß = - 0.1, 95% CI - 0.18 to - 0.02, pFDR = 0.032) and increased HannumAge (IVW: ß = 1.33, 95% CI 0.36 to 2.3, pFDR = 0.028), GrimAge (IVW: ß = 1.19, 95% CI 0.19 to 2.2, pFDR = 0.040), and PhenoAge (IVW: ß = 1.4, 95% CI 0.12 to 2.68, pFDR = 0.053). A significant association was also found with the frailty index (IVW: ß = 0.31, 95% CI 0.13 to 0.49, pFDR = 0.006). No significant associations were found with facial aging, IEAA, or cognitive performance. CONCLUSIONS: CM is linked to accelerated biological aging, shown by shorter telomere length and increased epigenetic aging markers. CM was also associated with increased frailty, highlighting the need for early interventions to mitigate long-term effects. Further research should explore mechanisms and prevention strategies.

Application of improved harmonic Poisson segmented regression model in evaluating the effectiveness of Kala-Azar intervention in Yangquan City, China.

Background: The Centre for Disease Control and Prevention in Yangquan, China, has taken a series of preventive and control measures in response to the increasing trend of Kala-Azar. In response, we propose a new model to more scientifically evaluate the effectiveness of these interventions. Methods: We obtained the incidence data of Kala-Azar from 2017 to 2021 from the Centre for Disease Control and Prevention (CDC) in Yangquan. We constructed Poisson segmented regression model, harmonic Poisson segmental regression model, and improved harmonic Poisson segmented regression model, and used the three models to explain the intervention effect, respectively. Finally, we selected the optimal model by comparing the fitting effects of the three models. Results: The primary analysis showed an underlying upward trend of Kala-Azar before intervention [incidence rate ratio (IRR): 1.045, 95% confidence interval (CI): 1.027-1.063, p < 0.001]. In terms of long-term effects, the rise of Kala-Azar slowed down significantly after the intervention (IRR:0.960, 95%CI:0.927-0.995, p = 0.026), and the risk of Kala-Azar increased by 0.3% for each additional month after intervention (ß1 + ß3 = 0.003, IRR = 1.003). The results of the model fitting effect showed that the improved harmonic Poisson segmental regression model had the best fitting effect, and the values of MSE, MAE, and RMSE were the lowest, which were 0.017, 0.101, and 0.130, respectively. Conclusion: In the long term, the intervention measures taken by the Yangquan CDC can well curb the upward trend of Kala-Azar. The improved harmonic Poisson segmented regression model has higher fitting performance, which can provide a certain scientific reference for the evaluation of the intervention effect of seasonal infectious diseases.

An Ultra-Compact and Low-Cost LAMP-Based Virus Detection Device.

Timely and accurate detection of viruses is crucial for infection diagnosis and treatment. However, it remains a challenge to develop a portable device that meets the requirement of being portable, powerless, user-friendly, reusable, and low-cost. This work reports a compact ∅30 × 48 mm portable powerless isothermal amplification detection device (material cost ∼$1 USD) relying on LAMP (Loop-Mediated Isothermal Amplification). We have proposed chromatographic-strip-based microporous permeation technology which can precisely control the water flow rate to regulate the exothermic reaction. This powerless heating combined with phase-change materials can maintain a constant temperature between 50 and 70 °C for a duration of up to 49.8 min. Compared with the conventional methods, it avoids the use of an additional insulation layer for heat preservation, greatly reducing the size and cost. We have also deployed a color card and a corresponding algorithm to facilitate color recognition, data analysis, and storage using a mobile phone. The experimental results demonstrate that our device exhibits the same limit of detection (LOD) as the ProFlex PCR for SARS-CoV-2 pseudovirus samples, with that for both being 103 copies/µL, verifying its effectiveness and reliability. This work offers a timely, low-cost, and easy way for respiratory infectious disease detection, which could provide support in curbing virus transmission and protecting the health of humans and animals, especially in remote mountainous areas without access to electricity or trained professionals.

Sleep Deprivation Induces Gut Damage via Ferroptosis.

Sleep deprivation (SD) has been associated with a plethora of severe pathophysiological syndromes, including gut damage, which recently has been elucidated as an outcome of the accumulation of reactive oxygen species (ROS). However, the spatiotemporal analysis conducted in this study has intriguingly shown that specific events cause harmful damage to the gut, particularly to goblet cells, before the accumulation of lethal ROS. Transcriptomic and metabolomic analyses have identified significant enrichment of metabolites related to ferroptosis in mice suffering from SD. Further analysis revealed that melatonin could rescue the ferroptotic damage in mice by suppressing lipid peroxidation associated with ALOX15 signaling. ALOX15 knockout protected the mice from the serious damage caused by SD-associated ferroptosis. These findings suggest that melatonin and ferroptosis could be targets to prevent devastating gut damage in animals exposed to SD. To sum up, this study is the first report that proposes a noncanonical modulation in SD-induced gut damage via ferroptosis with a clearly elucidated mechanism and highlights the active role of melatonin as a potential target to maximally sustain the state during SD.

Study on plant protection unmanned aerial vehicle spraying technology based on the thrips population activity patterns during the cotton flowering period.

Over the years, thrips have transitioned from a minor nuisance to a major problem, significantly impacting the yield and quality of cotton. Unmanned aerial vehicles (UAVs) for plant protection have emerged as an effective alternative to traditional pesticide spraying equipment. UAVs offer advantages such as avoiding crop damage and enhancing pesticide deposition on the plants and have become the primary choice for pesticide application in cotton fields. In this study, a 2-year field experiment found that the thrips population in a cotton field in Xinjiang, China, exhibited gradual growth during the early flowering phase, peaking in late July. The thrips population gradually shifted from the lower canopy to the upper canopy as the cotton flowers opened layer by layer. From 09:00 to 11:00 (GMT+8) and 19:00 to 21:00 (GMT+8), thrips mainly flew outside the flowers, while from 17:00 to 19:00 (GMT+8), they mostly inhabited the inner whorls of flowers. The insecticides 10% cyantraniliprole oil dispersion and 10% spinetoram suspension concentrate, sprayed by UAV, had the best control effect on thrips, with 80.51% and 79.22% control effect after 7 days of spraying, respectively. The optimal spraying time for 10% cyantraniliprole oil dispersion was 19:00 (GMT+8), and the control effect on thrips reached 91.16% at 7 days of spraying. During the cotton flowering period, thrips inhabited flowers in the evening and flew outside during the day. The best control effect on thrips was achieved with UAV-sprayed 10% cyantraniliprole oil dispersion at 19:00 (GMT+8).

Triclosan Dioxygenase: A Novel Two-component Rieske Nonheme Iron Ring-hydroxylating Dioxygenase Initiates Triclosan Degradation.

The emerging contaminant triclosan (TCS) is widely distributed both in surface water and in wastewater and poses a threat to aquatic organisms and human health due to its resistance to degradation. The dioxygenase enzyme TcsAB has been speculated to perform the initial degradation of TCS, but its precise catalytic mechanism remains unclear. In this study, the function of TcsAB was elucidated using multiple biochemical and molecular biology methods. Escherichia coli BL21(DE3) heterologously expressing tcsAB from Sphingomonas sp. RD1 converted TCS to 2,4-dichlorophenol. TcsAB belongs to the group IA family of two-component Rieske nonheme iron ring-hydroxylating dioxygenases. The highest amino acid identity of TcsA and the large subunits of other dioxygenases in the same family was only 35.50%, indicating that TcsAB is a novel dioxygenase. Mutagenesis of residues near the substrate binding pocket decreased the TCS-degrading activity and narrowed the substrate spectrum, except for the TcsAF343A mutant. A meta-analysis of 1492 samples from wastewater treatment systems worldwide revealed that tcsA genes are widely distributed. This study is the first to report that the TCS-specific dioxygenase TcsAB is responsible for the initial degradation of TCS. Studying the microbial degradation mechanism of TCS is crucial for removing this pollutant from the environment.

Cat and dog feces as reservoirs of diverse novel antibiotic resistance genes.

Companion animals have the potential to greatly enhance the physical and mental health of humans, thus leading to an increased focus on the interactions between humans and pets. Currently, the inappropriate and excessive utilization of antimicrobial agents has become prevalent in veterinary clinical practice for pets. This antibiotic contamination phenomenon has a profound impact on the enrichment of antibiotic resistance bacteria (ARB) and antibiotic resistance genes (ARGs) in pets. However, the pet-associated resistome, especially the novel ARGs in pets, represents a relatively neglected area. In this study, we successfully constructed a total of 12 libraries using the functional metagenomics approach to assess the diversity of ARGs in pet cats and dogs from four pet hospitals. Through the integration of functional screening and high-throughput sequencing, a total of 122 antibiotic resistance determinants were identified, of which 15 were classified as putative novel ARGs originating from five classes. Functional assessment demonstrated that 6 novel ARGs including one ß-lactam, two macrolides, two aminoglycosides, and one rifamycin (RIF), namely blaPF, ermPF, msrPF, aac(6')PF, aph(3')PF, and arrPF, exhibited functionally activity in conferring bacterial phenotypic resistance by increasing the minimum inhibitory concentrations (MICs) with a 4- to 128-fold. Genetic context analysis demonstrated that, with the exception of aac(6')PF and arrPF, the remaining four novel ARGs were found adjacent to mobile genetic elements (MGEs) including IS elements or transposases, which provided a prerequisite for horizontal transfer of these novel ARGs, thereby offering an explanation for their detection in diverse samples collected from various sampling sites. The current study has unveiled the significant role of cat and dog feces as one source of reservoirs of diverse novel ARGs, while also highlighting the potential adverse consequences of their further spread to medically significant pathogens and human commensal organisms.

Process Manufacturing Intelligence Empowered by Industrial Metaverse: A Survey.

The intelligent goal of process manufacturing is to achieve high efficiency and greening of the entire production. Whereas the information system it used is functionally independent, resulting to knowledge gaps between each level. Decision-making still requires lots of knowledge workers making manually. The industrial metaverse is a necessary means to bridge the knowledge gaps by sharing and collaborative decision-making. Considering the safety and stability requirements of the process manufacturing, this article conducts a thorough survey on the process manufacturing intelligence empowered by industrial metaverse. First, it analyzes the current status and challenges of process manufacturing intelligence, and then summarizes the latest developments about key enabling technologies of industrial metaverse, such as interconnection technologies, artificial intelligence, cloud-edge computing, digital twin (DT), immersive interaction, and blockchain technology. On this basis, taking into account the characteristics of process manufacturing, a construction approach and architecture for the process industrial metaverse is proposed: a virtual-real fused industrial metaverse construction method that combines DTs with physical avatar, which can effectively ensure the safety of metaverse's application in industrial scenarios. Finally, we conducted preliminary exploration and research, to prove the feasibility of proposed method.

Harm from others' drinking among young adults in Taiwan: Predictors and deteriorating quality of life.

INTRODUCTION: This study aimed to investigate the prevalence of different forms of harm from others' drinking (HFOD), predictors and the relationship with multi-dimensional quality of life among young adults in an emerging alcohol market in Asia-Taiwan. METHODS: Data were extracted from a 2018 household survey with national representativeness on substance use experiences. The analytic sample comprised 4901 participants aged 18-34. Eight items were used to measure HFOD experiences. Five-dimensional quality of life was assessed by the EQ-5D-5L. Multivariable regressions with complex survey analyses were performed to estimate the prevalence and risk association. RESULTS: Almost 4.2% of young adults experienced any form of HFOD; psychological harm occurred more prevalently than physical harm (3.7% and 1.5%, respectively). Those aged 25-29 and 30-34 had a two- to three-fold risk of HFOD compared with those aged 18-24. Both non-drunk drinking and drunk drinking were associated with an increased risk of psychological HFOD (adjusted odds ratio 2.36 and 5.89, respectively), whereas the risk of physical HFOD was related only to drunk drinking (adjusted odds ratio 7.8). Psychological HFOD victimisation emerged as the strongest predictor for deteriorated quality of life (adjusted b -0.14; 95% confidence interval -0.24, -0.04), especially in the dimensions of pain/discomfort and anxiety/depression. Among HFOD victims, only 33% sought help. DISCUSSION AND CONCLUSIONS: The HFOD among young adults, commonly exhibited in psychological form, was linked with deteriorated quality of life; nonetheless, young HFOD victims are under-recognised. When devising interventions for alcohol harm, developmental perspectives should be integrated into policies implemented in healthcare and community settings.

Vericiguat attenuates doxorubicin-induced cardiotoxicity through the PRKG1/PINK1/STING axis.

Doxorubicin (DOX) is restricted due to its severe cardiotoxicity. There is still a lack of viable and effective drugs to prevent or treat DOX-induced cardiotoxicity(DIC). Vericiguat is widely used to treat heart failure with reduced ejection fraction. However, it is not clear whether vericiguat can improve DIC. In the present study, we constructed a DIC model using mice and neonatal rat cardiomyocytes and found that vericiguat ameliorated DOX-induced cardiac insufficiency in mice, restored DOX-induced mitochondrial dysfunction in neonatal rat cardiomyocytes, and inhibited the expression of inflammatory factors. Further studies showed that vericiguat improved mitochondrial dysfunction and reduced mtDNA leakage into the cytoplasm by up-regulating PRKG1, which activated PINK1 and then inhibited the STING/IRF3 pathway to alleviate DIC. These findings demonstrate for the first time that vericiguat has therapeutic potential for the treatment of DIC.

Resting for viability: Gordonia polyisoprenivorans ZM27, a robust generalist for petroleum bioremediation under hypersaline stress.

The intrinsic issue associated with the application of microbes for practical pollution remediation involves maintaining the expected activity of engaged strains or consortiums as effectively as that noted under laboratory conditions. Faced with various stress factors, degraders with dormancy ability are more likely to survive and exhibit degradation activity. In this study, a hydrocarbonoclastic and halotolerant strain, Gordonia polyisoprenivorans ZM27, was isolated via stimulation with resuscitation-promoting factor (Rpf). Long-term exposure to dual stresses of 10% NaCl and starvation induced ZM27 to enter a viable but nonculturable (VBNC)-like state, and ZM27 cells could be resuscitated upon Rpf stimulation. Notable changes in both morphological and physiological characteristics between VBNC-like ZM27 cells and resuscitated cells confirmed the response to Rpf and their robust resistance against harsh environments. Whole-genome sequencing and analysis indicated ZM27 could be a generalist degrader with dormancy ability. Subsequently, VBNC-like ZM27 was applied in a soil microcosm experiment to investigate the practical application potential under harsh conditions. VBNC-like ZM27 combined with Rpf stimulation exhibited the most effective biodegradation performance, and the initial n-hexadecane content (1000 mg kg-1) decreased by 63.29% after 14-day incubation. Based on 16S rRNA amplicon sequencing and analysis, Gordonia exhibited a positive response to Rpf stimulation. The relative abundance of genus Gordonia was negatively correlated with that of Alcanivorax, a genus of obligate hydrocarbon degrader with the greatest abundance during soil incubation. Based on the degradation profile and community analysis, generalist Gordonia may be more efficient in hydrocarbon degradation than specialist Alcanivorax under harsh conditions. The characteristics of ZM27, including its sustainable culturability under long-term stress, response to Rpf and robust performance in soil microcosms, are valuable for the remediation of petroleum pollution under stressful conditions. Our work validated the importance of dormancy and highlighted the underestimated role of low-activity degraders in petroleum remediation.

Deep Learning-Enabled Vasculometry Depicts Phased Lesion Patterns in High Myopia Progression.

PURPOSE: To investigate the potential phases in myopic retinal vascular alterations for further elucidating the mechanisms underlying the progression of high myopia (HM). METHODS: For this retrospective study, participants diagnosed with high myopia at Beijing Tongren Hospital were recruited. Based on bionic mechanisms of human vision, an intelligent image processing model was developed and utilized to extract and quantify the morphological characteristics of retinal vasculatures in different regions measured by papilla-diameter (PD), including vascular caliber, arteriole-to-venule ratio (AVR), tortuosity, the angle of the vascular arch (AVA), the distance of the vascular arch (DVA), density, fractal dimension, and venular length. In addition, the optic disc and the area of peripapillary atrophy (PPA) were also quantified. The characteristics of the overall population, as well as patients aged less than 25 years old, were compared by different genders. Univariate and multiple linear regression analyses were conducted to investigate the correlation of retinal vasculature parameters with PPA width, and detailed trends of the vascular indicators were analyzed to explore the potential existence of staged morphological changes. FINDINGS: The study included 14,066 fundus photographs of 5775 patients (aged 41.2 ± 18.6 years), of whom 7379 (61.2 %) were female. The study included 12,067 fundus photographs of 5320 patients (aged 41.2 ± 18.6 years). Significant variations in the morphological parameters of retinal vessels were observed between males and females. After adjusting for age and sex, multiple linear regression analysis showed that an increased PPA width ratio was associated with lower AVA (1PD), DVA (1PD), vascular caliber (0.5-1.0 PD), tortuosity (0.5-1.0 PD), density and fractal dimension (all P < 0.001, Spearman's ρ < 0). Overall, the changes in retinal vascular morphology showed two phases: tortuosity (0.5-1.0PD) and AVA (1PD) decreased rapidly in the first stage but significantly more slowly in the second stage, while vascular density and fractal dimension showed a completely opposite trend with an initial slow decline followed by a rapid decrease. CONCLUSIONS: This study identified two distinct phases of retinal vascular morphological changes during the progression of HM. Traction lesions were predominant in the initial stage, while atrophic lesions were predominant in the later stage. These findings provide further insight into the development mechanism of HM from the perspective of retinal vasculature.

Effect of Sheet Properties of Cellulosic Polyglycidyl Methacrylate-Grafted Fibers in a Cationic Polyacrylamide/SiO2/Anionic Polyacrylamide Retention Aid System.

As increasing fiber hydrophobicity can significantly improve the paper dewatering process, we found that replacing SBKP and HBKP with 0.5% superhydrophobic CPGMA can significantly improve the dewatering of paper sheets. Therefore, it can be concluded that if CPGMA has little effect on paper properties, it will have potential industrial value in the papermaking industry. Consequently, it is necessary to further study the effect of the CPGMAs@CPAM/SiO2/APAM system on paper properties. To evaluate the application potential of the system in the papermaking industry, we investigated the effects of CPGMAs, which replaced the fibers in the stocks, on the paper properties in the CPAM/SiO2/APAM system. The findings demonstrate that as the CPGMA replacement increased, the paper's tensile strength, bursting strength, tear resistance, and folding endurance all declined. The trend can be segmented into two phases: a rapid decrease for substitution amounts below 0.5% and a gradual decline for substitution amounts exceeding 0.5%. When replaced with a small amount of CPGMAs, there was a negligible effect on these properties. Second, the paper air permeability increased with the CPGMA substitution amount in the stock. Furthermore, the trend of paper air permeability can be divided into two stages-a rapid stage with a substitution amount of <0.5% and a slow stage with a substitution amount of >0.5%. A small amount of CPGMAs could distinctly improve the paper's air permeability. Third, CPGMAs, which replaced fibers in the stock, minutely affected the paper formation. A small amount of CPGMAs substantially boosted the efficacy of the process of paper manufacture and certain characteristics of the paper, and it had a negligible impact on the strength of paper. The CPGMAs@CPAM/SiO2/APAM technology has the potential to improve the retention and filtration performance of CPAM/SiO2/APAM.

Non-fibril amyloid aggregation at the air/water interface: self-adaptive pathway resulting in a 2D Janus nanofilm.

The amyloid states of proteins are implicated in several neurodegenerative diseases and bioadhesion processes. However, the classical amyloid fibrillization mechanism fails to adequately explain the formation of polymorphic aggregates and their adhesion to various surfaces. Herein, we report a non-fibril amyloid aggregation pathway, with disulfide-bond-reduced lysozyme (R-Lyz) as a model protein under quasi-physiological conditions. Very different from classical fibrillization, this pathway begins with the air-water interface (AWI) accelerated oligomerization of unfolded full-length protein, resulting in unique plate-like oligomers with self-adaptive ability, which can adjust their conformations to match various interfaces such as the asymmetric AWI and amyloid-protein film surface. The pathway enables a stepwise packing of the plate-like oligomers into a 2D Janus nanofilm, exhibiting a divergent distribution of hydrophilic/hydrophobic residues on opposite sides of the nanofilm. The resulting Janus nanofilm possesses a top-level Young's modulus (8.3 ± 0.6 GPa) among amyloid-based materials and exhibits adhesive strength two times higher (145 ± 81 kPa) than that of barnacle cement. Furthermore, we found that such an interface-directed pathway exists in several amyloidogenic proteins with a similar self-adaptive 2D-aggregation process, including bovine serum albumin, insulin, fibrinogen, hemoglobin, lactoferrin, and ovalbumin. Thus, our findings on the non-fibril self-adaptive mechanism for amyloid aggregation may shed light on polymorphic amyloid assembly and their adhesions through an alternative pathway.

Paracetamol-induced Liver Injury in An Experimental Rat Model: Noninvasive Assessment using DKI and the Effect of Gadoxetate on DKI Parameters.

PURPOSE: To explore the potential of diffusion kurtosis imaging (DKI) for assessing the degree of liver injury in a paracetamol-induced rat model and to simultaneously investigate the effect of intravenous gadoxetate on DKI parameters. METHODS: Paracetamol was used to induce hepatoxicity in 39 rats. The rats were pathologically classified into 3 groups: normal (n=11), mild necrosis (n=18), and moderate necrosis (n=10). DKI was performed before and, 15 min, 25 min, and 45 min after gadoxetate administration. Repeated-measures ANOVA with Tukey's multiple comparison test was used to investigate the effect of gadoxetate on mean diffusivity (MD) and mean diffusion kurtosis (MK) and to assess the differences in MD and MK among the three groups. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic accuracy of the MD values when discriminating between the necrotic groups. RESULTS: Gadoxetate had no significant effect on either the MD or the MK, and the effect size was small. The MD in the moderate necrosis group was significantly lower than that in the other two groups (F = 13.502, p < 0.001; η2 = 0.428 [95% CI: 0.082-0.637]), while the MK did not significantly differ among the three groups (F = 2.702, p = 0.081; η2 = 0.131 [95% CI: 0.001-0.4003]). The AUCs of MD for discriminating the moderate necrosis or normal group from the other groups were 0.921 (95% CI: 0.832-1.000) and 0.831 (95% CI: 0.701-0.961), respectively. CONCLUSION: It would be better to measure the MD and MK before gadoxetate injection. MD showed potential for assessing the degree of liver necrosis in a paracetamol-induced liver injury rat model.

Immune Cell-Based Microrobots for Remote Magnetic Actuation, Antitumor Activity, and Medical Imaging.

Translating medical microrobots into clinics requires tracking, localization, and performing assigned medical tasks at target locations, which can only happen when appropriate design, actuation mechanisms, and medical imaging systems are integrated into a single microrobot. Despite this, these parameters are not fully considered when designing macrophage-based microrobots. This study presents living macrophage-based microrobots that combine macrophages with magnetic Janus particles coated with FePt nanofilm for magnetic steering and medical imaging and bacterial lipopolysaccharides for stimulating macrophages in a tumor-killing state. The macrophage-based microrobots combine wireless magnetic actuation, tracking with medical imaging techniques, and antitumor abilities. These microrobots are imaged under magnetic resonance imaging and optoacoustic imaging in soft-tissue-mimicking phantoms and ex vivo conditions. Magnetic actuation and real-time imaging of microrobots are demonstrated under static and physiologically relevant flow conditions using optoacoustic imaging. Further, macrophage-based microrobots are magnetically steered toward urinary bladder tumor spheroids and imaged with a handheld optoacoustic device, where the microrobots significantly reduce the viability of tumor spheroids. The proposed approach demonstrates the proof-of-concept feasibility of integrating macrophage-based microrobots into clinic imaging modalities for cancer targeting and intervention, and can also be implemented for various other medical applications.

Innovative Delivery System Combining CRISPR-Cas12f for Combatting Antimicrobial Resistance in Gram-Negative Bacteria.

Antimicrobial resistance poses a significant global challenge, demanding innovative approaches, such as the CRISPR-Cas-mediated resistance plasmid or gene-curing system, to effectively combat this urgent crisis. To enable successful curing of antimicrobial genes or plasmids through CRISPR-Cas technology, the development of an efficient broad-host-range delivery system is paramount. In this study, we have successfully designed and constructed a novel functional gene delivery plasmid, pQ-mini, utilizing the backbone of a broad-host-range Inc.Q plasmid. Moreover, we have integrated the CRISPR-Cas12f system into the pQ-mini plasmid to enable gene-curing in broad-host of bacteria. Our findings demonstrate that pQ-mini facilitates the highly efficient transfer of genetic elements to diverse bacteria, particularly in various species in the order of Enterobacterales, exhibiting a broader host range and superior conjugation efficiency compared to the commonly used pMB1-like plasmid. Notably, pQ-mini effectively delivers the CRISPR-Cas12f system to antimicrobial-resistant strains, resulting in remarkable curing efficiencies for plasmid-borne mcr-1 or blaKPC genes that are comparable to those achieved by the previously reported pCasCure system. In conclusion, our study successfully establishes and optimizes pQ-mini as a broad-host-range functional gene delivery vector. Furthermore, in combination with the CRISPR-Cas system, pQ-mini demonstrates its potential for broad-host delivery, highlighting its promising role as a novel antimicrobial tool against the growing threat of antimicrobial resistance.

Amphiphilic Polymer Electrolyte Blocking Lattice Oxygen Evolution from High-Voltage Nickel-rich Cathodes for Ultra-Thermal Stabile Batteries.

Ni-rich cathodes have been intensively adopted in Li-ion batteries to pursuit high energy density, which still suffering irreversible degradation at high voltage. Some unstable lattice O2- species in Ni-rich cathodes would be oxidized to singlet oxygen 1O2 and released at high volt, which lead to irreversible phase transfer from the layered rhombohedral (R) phase to a spinel-like (S) phase. To overcome the issue, the amphiphilic copolymers (UMA-Fx) electrolyte were prepared by linking hydrophobic C-F side chains with hydrophilic subunits, which could self-assemble on Ni-rich cathode surface and convert to stable cathode-electrolyte interphase layer. Thereafter, the oxygen releasing of polymer coated cathode was obviously depressed and substituted by the Co oxidation (Co3+→Co4+) at high volt (>4.2 V), which could suppressed irreversible phase transfer and improve cycling stability. Moreover, the amphiphilic polymer electrolyte was also stable with Li anode and had high ion conductivity. Therefore, the NCM811//UMA-F6//Li pouch cell exhibited outstanding energy density (362.97 Wh/kg) and durability (cycled 200 times at 4.7 V), which could be stalely cycled even at 120°C without short circuits or explosions.

Noncoding RNA regulates the expression of Krm1 and Dkk2 to synergistically affect aortic valve lesions.

Calcific aortic valve disease (CAVD) is becoming an increasingly important global medical problem, but effective pharmacological treatments are lacking. Noncoding RNAs play a pivotal role in the progression of cardiovascular diseases, but their relationship with CAVD remains unclear. Sequencing data revealed differential expression of many noncoding RNAs in normal and calcified aortic valves, with significant differences in circHIPK3 and miR-182-5p expression. Overexpression of circHIPK3 ameliorated aortic valve lesions in a CAVD mouse model. In vitro experiments demonstrated that circHIPK3 inhibits the osteogenic response of aortic valve interstitial cells. Mechanistically, DEAD-box helicase 5 (DDX5) recruits methyltransferase 3 (METTL3) to promote the N6-methyladenosine (m6A) modification of circHIPK3. Furthermore, m6A-modified circHIPK3 increases the stability of Kremen1 (Krm1) mRNA, and Krm1 is a negative regulator of the Wnt/ß-catenin pathway. Additionally, miR-182-5p suppresses the expression of Dickkopf2 (Dkk2), the ligand of Krm1, and attenuates the Krm1-mediated inhibition of Wnt signaling. Activation of the Wnt signaling pathway significantly contributes to the promotion of aortic valve calcification. Our study describes the role of the Krm1-Dkk2 axis in inhibiting Wnt signaling in aortic valves and suggests that noncoding RNAs are upstream regulators of this process.

Mechanisms of gastrointestinal toxicity in neuromyelitis optica spectrum disorder patients treated with mycophenolate mofetil: insights from a mouse model and human study.

Mycophenolate mofetil (MMF) is commonly utilized for the treatment of neuromyelitis optica spectrum disorders (NMOSD). However, a subset of patients experience significant gastrointestinal (GI) adverse effects following MMF administration. The present study aims to elucidate the underlying mechanisms of MMF-induced GI toxicity in NMOSD. Utilizing a vancomycin-treated mouse model, we compiled a comprehensive data set to investigate the microbiome and metabolome in the GI tract to elucidate the mechanisms of MMF GI toxicity. Furthermore, we enrolled 17 female NMOSD patients receiving MMF, who were stratified into non-diarrhea NMOSD and diarrhea NMOSD (DNM) groups, in addition to 12 healthy controls. The gut microbiota of stool samples was analyzed using 16S rRNA gene sequencing. Vancomycin administration prevented weight loss and tissue injury caused by MMF, affecting colon metabolomes and microbiomes. Bacterial ß-glucuronidase from Bacteroidetes and Firmicutes was linked to intestinal tissue damage. The DNM group showed higher alpha diversity and increased levels of Firmicutes and Proteobacteria. The ß-glucuronidase produced by Firmicutes may be important in causing gastrointestinal side effects from MMF in NMOSD treatment, providing useful information for future research on MMF. IMPORTANCE: Neuromyelitis optica spectrum disorder (NMOSD) patients frequently endure severe consequences like paralysis and blindness. Mycophenolate mofetil (MMF) effectively addresses these issues, but its usage is hindered by gastrointestinal (GI) complications. Through uncovering the intricate interplay among MMF, gut microbiota, and metabolic pathways, this study identifies specific gut bacteria responsible for metabolizing MMF into a potentially harmful form, thus contributing to GI side effects. These findings not only deepen our comprehension of MMF toxicity but also propose potential strategies, such as inhibiting these bacteria, to mitigate these adverse effects. This insight holds broader implications for minimizing complications in NMOSD patients undergoing MMF therapy.