Fight or flee, a vital choice for Clostridioides difficile.

Clostridioides difficile is a leading cause of healthcare-associated infections, causing billions of economic losses every year. Its symptoms range from mild diarrhea to life-threatening damage to the colon. Transmission and recurrence of C. difficile infection (CDI) are mediated by the metabolically dormant spores, while the virulence of C. difficile is mainly due to the two large clostridial toxins, TcdA and TcdB. Producing toxins or forming spores are two different strategies for C. difficile to cope with harsh environmental conditions. It is of great significance to understand the molecular mechanisms for C. difficile to skew to either of the cellular processes. Here, we summarize the current understanding of the regulation and connections between toxin production and sporulation in C. difficile and further discuss the potential solutions for yet-to-be-answered questions.

Assessment of the reversibility of resistance in the absence of antibiotics and its relationship with the resistance gene's fitness cost: a genetic study with mcr-1.

BACKGROUND: The intensive use of antibiotics has resulted in strong natural selection for the evolution of antimicrobial resistance (AMR), but whether, and under what circumstances, the removal of antibiotics would result in a rapid reduction in AMR has been insufficiently explored. We aimed to test the hypothesis that in the simple, yet common, case of AMR conferred by a single gene, removing antibiotics would quickly reduce the prevalence of resistance if the AMR gene imposes a high fitness cost and costless resistance is extremely rare among its proximal mutants. METHODS: In this genetic study, to test our hypothesis, we used the mcr-1 gene in Escherichia coli, which confers resistance to the last-resort antibiotic colistin, as a model. A high-throughput reverse genetics approach was used to evaluate mcr-1 variants for their fitness cost and resistance levels relative to a non-functional construct, by measuring relative growth rates in colistin-free media and at 2 µg/mL and 4 µg/mL colistin. We identified costless resistant mcr-1 mutants, and examined their properties within the context of the sequential organisation of mcr-1's functional domains as well as the evolutionary accessibility of these mutations. Finally, a simple population genetic model incorporating the measured fitness cost was constructed and tested against previously published real-world data of mcr-1 prevalence in colonised inpatients in China since the 2017 colistin ban in fodder additives. FINDINGS: We estimated the relative growth rates of 14 742 mcr-1 E coli variants (including the wild type), 3449 of which were single-nucleotide mutants. E coli showed 73·8% less growth per 24 h when carrying wild-type mcr-1 compared with the non-functional construct. 6252 (42·4%) of 14 741 mcr-1 mutants showed colistin resistance accompanied by significant fitness costs, when grown under 4 µg/mL colistin selection. 43 (0·3%) mcr-1 mutants exhibited costless resistance, most of which contained multiple mutations. Among the 3449 single mutants of mcr-1, 3433 (99·5%) had a fitness cost when grown in colistin-free media, with a mean relative growth of 0·305 (SD 0·193) compared with the non-functional variant. 3059 (88·7%) and 1833 (53·1%) of 3449 single mutants outgrew the non-functional mcr-1 in the presence of 2 µg/mL and 4 µg/mL colistin, respectively. Single mutations that gave rise to costless mutants were rare in all three domains of mcr-1 (transmembrane domain, flexible linker, and catalytic domain), but the linker domain was enriched with cost-reducing and resistance-enhancing mutations and depleted with cost-increasing mutations. The population genetics model based on the experimental data accurately predicts the rapid decline in mcr-1 prevalence in real-world data. INTERPRETATION: Many identified costless resistant variants that consist of multiple mutations are unlikely to evolve easily in nature. These findings for colistin and mcr-1 might be applicable to other cases in which AMR entails a substantial fitness cost that cannot be mitigated in proximal mutants. FUNDING: National Natural Science Foundation of China, and National Key Research and Development Program of China.

Hierarchical Piezoelectric Composites for Noninvasive Continuous Cardiovascular Monitoring.

Continuous monitoring of blood pressure (BP) and multiparametric analysis of cardiac functions are crucial for the early diagnosis and therapy of cardiovascular diseases. However, existing monitoring approaches often suffer from bulky and intrusive apparatus, cumbersome testing procedures, and challenging data processing, hampering their applications in continuous monitoring. Here, a heterogeneously hierarchical piezoelectric composite is introduced for wearable continuous BP and cardiac function monitoring, overcoming the rigidity of ceramic and the insensitivity of polymer. By optimizing the hierarchical structure and components of the composite, the developed piezoelectric sensor delivers impressive performances, ensuring continuous and accurate monitoring of BP at Grade A level. Furthermore, the hemodynamic parameters are extracted from the detected signals, such as local pulse wave velocity, cardiac output, and stroke volume, all of which are in alignment with clinical results. Finally, the all-day tracking of cardiac function parameters validates the reliability and stability of the developed sensor, highlighting its potential for personalized healthcare systems, particularly in early diagnosis and timely intervention of cardiovascular disease.

Effect of Sarcopenia on 10-Year Risk of Atherosclerotic Cardiovascular Disease in Patients with Type 2 Diabetes Mellitus.

Objective: To investigate the impact of sarcopenia on the 10-year risk of atherosclerotic cardiovascular disease (ASCVD) among individuals with type 2 diabetes mellitus (T2DM). Methods: This study included the clinical, laboratory, and body composition data of 1491 patients with T2DM who were admitted to the Department of Endocrinology and Metabolism at Tianjin Union Medical Center from July 2018 to July 2023. The China-PAR model was utilized to evaluate cardiovascular disease risk. Associations between ASCVD risk and various clinical parameters were analyzed, and the relationship between body composition parameters and ASCVD risk was assessed using logistic regression. Results: The analysis revealed that T2DM patients with sarcopenia had a higher 10-year ASCVD risk compared to those without sarcopenia, with reduced muscle mass independently predicting an increased risk of cardiovascular disease. This association was significant among female T2DM patients, while male T2DM patients with sarcopenia showed a marginally higher median ASCVD risk compared to their non-sarcopenic counterparts. ASCVD risk inversely correlated with body muscle parameters and positively correlated with fat content parameters. Specifically, height- and weight-adjusted fat mass (FM, FM%, FMI) were identified as risk factors for ASCVD. Conversely, muscle parameters adjusted for weight and fat (ASM%, SMM%, FFM%, ASM/FM, SMM/FM, FMM/FM) were protective against ASCVD risk. These findings highlight the critical role of sarcopenia in influencing cardiovascular disease risk among Chinese patients with T2DM, as predicted by the China-PAR model. Conclusion: This study highlights the importance of sarcopenia in T2DM patients, not only as an indicator of ASCVD risk, but possibly as an independent risk factor in this demographics.

Mass-Produced Skin-Inspired Piezoresistive Sensing Array with Interlocking Interface for Object Recognition.

E-skins, capable of responding to mechanical stimuli, hold significant potential in the field of robot haptics. However, it is a challenge to obtain e-skins with both high sensitivity and mechanical stability. Here, we present a bioinspired piezoresistive sensor with hierarchical structures based on polyaniline/polystyrene core-shell nanoparticles polymerized on air-laid paper. The combination of laser-etched reusable templates and sensitive materials that can be rapidly synthesized enables large-scale production. Benefiting from the substantially enlarged deformation of the hierarchical structure, the developed piezoresistive electronics exhibit a decent sensitivity of 21.67 kPa-1 and a subtle detection limit of 3.4 Pa. Moreover, an isolation layer is introduced to enhance the interface stability of the e-skin, with a fracture limit of 66.34 N/m. Furthermore, the e-skin can be seamlessly integrated onto gloves without any detachment issues. With the assistance of deep learning, it achieves a 98% accuracy rate in object recognition. We anticipate that this strategy will render e-skin with more robust interfaces and heightened sensing capabilities, offering a favorable pathway for large-scale production.

Upgrading CO2 to sustainable aromatics via perovskite-mediated tandem catalysis.

The directional transformation of carbon dioxide (CO2) with renewable hydrogen into specific carbon-heavy products (C6+) of high value presents a sustainable route for net-zero chemical manufacture. However, it is still challenging to simultaneously achieve high activity and selectivity due to the unbalanced CO2 hydrogenation and C-C coupling rates on complementary active sites in a bifunctional catalyst, thus causing unexpected secondary reaction. Here we report LaFeO3 perovskite-mediated directional tandem conversion of CO2 towards heavy aromatics with high CO2 conversion (> 60%), exceptional aromatics selectivity among hydrocarbons (> 85%), and no obvious deactivation for 1000 hours. This is enabled by disentangling the CO2 hydrogenation domain from the C-C coupling domain in the tandem system for Iron-based catalyst. Unlike other active Fe oxides showing wide hydrocarbon product distribution due to carbide formation, LaFeO3 by design is endowed with superior resistance to carburization, therefore inhibiting uncontrolled C-C coupling on oxide and isolating aromatics formation in the zeolite. In-situ spectroscopic evidence and theoretical calculations reveal an oxygenate-rich surface chemistry of LaFeO3, that easily escape from the oxide surface for further precise C-C coupling inside zeolites, thus steering CO2-HCOOH/H2CO-Aromatics reaction pathway to enable a high yield of aromatics.

High-throughput mutagenesis and screening approach for the identification of drug-resistant mutations in the rifampicin resistance-determining region of mycobacteria.

Rifampicin is the most powerful first-line antibiotic for tuberculosis, which is caused by Mycobacterium tuberculosis. Although accumulating evidence from sequencing data of clinical M. tuberculosis isolates suggested that mutations in the rifampicin-resistance-determining region (RRDR) are strongly associated with rifampicin resistance, the comprehensive characterisation of RRDR polymorphisms that confer this resistance remains challenging. By incorporating I-SceI sites for I-SceI-based integrant removal and utilizing an L5 swap strategy, we efficiently replaced the integrated plasmid with alternative alleles, making mass allelic exchange feasible in mycobacteria. Using this method to establish a fitness-related gain-of function screen, we generated a mutant library that included all single-amino-acid mutations in the RRDR, and identified the important positions corresponding to some well-known rifampicin-resistance mutations (Q513, D516, S522, H525, R529, S531). We also detected a novel two-point mutation located in the RRDR confers a fitness advantage to M. smegmatis in the presence or absence of rifampicin. Our method provides a comprehensive insight into the growth phenotypes of RRDR mutants and should facilitate the development of anti-tuberculosis drugs.

Long Non-coding RNA X-Inactive Specific Transcript Promotes Esophageal Squamous Cell Carcinoma Progression via the MicroRNA 34a/Zinc Finger E-box-Binding Homeobox 1 Pathway.

BACKGROUND: The long non-coding RNA X-inactive specific transcript (XIST) plays a crucial role in transcriptional silencing of the X chromosome. Zinc finger E-box-binding homeobox 1 (ZEB1) is a transcription factor involved in epithelial-mesenchymal transition (EMT) regulation. AIMS: This study aimed to investigate the impact of XIST on esophageal squamous cell carcinoma (ESCC) progression and its underlying mechanism involving the miR-34a/ZEB1/E-cadherin/EMT pathway. METHODS: XIST and ZEB1 expression were analyzed using quantitative PCR and immunohistochemistry. XIST knockdown was achieved in KYSE150 ESCC cells using siRNA or shRNA lentivirus transfection. Proliferation, migration, and invasion abilities were assessed, and luciferase reporter assays were performed to confirm XIST-miR-34a-ZEB1 interactions. In vivo ESCC growth was evaluated using a xenograft mouse model. RESULTS: XIST and ZEB1 were upregulated in tumor tissues, correlating with metastasis and reduced survival. XIST knockdown inhibited proliferation, migration, and invasion of KYSE150 cells. It decreased ZEB1 expression, increased E-cadherin and miR-34a levels. Luciferase reporter assays confirmed miR-34a binding to XIST and ZEB1. XIST knockdown suppressed xenograft tumor growth. CONCLUSION: XIST promotes ESCC progression via the miR-34a/ZEB1/E-cadherin/EMT pathway. Targeting the XIST/miR-34a/ZEB1 axis holds therapeutic potential and serves as a prognostic biomarker in ESCC.

Improving the second-tier classification of methylmalonic acidemia patients using a machine learning ensemble method.

INTRODUCTION: Methylmalonic acidemia (MMA) is a disorder of autosomal recessive inheritance, with an estimated prevalence of 1:50,000. First-tier clinical diagnostic tests often return many false positives [five false positive (FP): one true positive (TP)]. In this work, our goal was to refine a classification model that can minimize the number of false positives, currently an unmet need in the upstream diagnostics of MMA. METHODS: We developed machine learning multivariable screening models for MMA with utility as a secondary-tier tool for false positives reduction. We utilized mass spectrometry-based features consisting of 11 amino acids and 31 carnitines derived from dried blood samples of neonatal patients, followed by additional ratio feature construction. Feature selection strategies (selection by filter, recursive feature elimination, and learned vector quantization) were used to determine the input set for evaluating the performance of 14 classification models to identify a candidate model set for an ensemble model development. RESULTS: Our work identified computational models that explore metabolic analytes to reduce the number of false positives without compromising sensitivity. The best results [area under the receiver operating characteristic curve (AUROC) of 97%, sensitivity of 92%, and specificity of 95%] were obtained utilizing an ensemble of the algorithms random forest, C5.0, sparse linear discriminant analysis, and autoencoder deep neural network stacked with the algorithm stochastic gradient boosting as the supervisor. The model achieved a good performance trade-off for a screening application with 6% false-positive rate (FPR) at 95% sensitivity, 35% FPR at 99% sensitivity, and 39% FPR at 100% sensitivity. CONCLUSIONS: The classification results and approach of this research can be utilized by clinicians globally, to improve the overall discovery of MMA in pediatric patients. The improved method, when adjusted to 100% precision, can be used to further inform the diagnostic process journey of MMA and help reduce the burden for patients and their families.

SENP3 mediates the activation of the Wnt/ß-catenin signaling pathway to accelerate the growth and metastasis of oesophagal squamous cell carcinoma in mice.

As a common malignant tumor, esophageal squamous cell carcinoma (ESCC) is occasionally seen in clinical practice. This type of disease has low incidence rate and mortality. The post-translational modification of small ubiquitin like modifiers (SUMO) can play a crucial role in regulating protein function, and can significantly impact the occurrence and development of diseases. SUMO-specific peptidase (SENP) affects cell activity by regulating the biological function of SUMO. SENP3 belongs to the SENP family, and available data indicate that many malignancies are associated with SENPs, it is currently unclear its role in ESCC. This study indicates that there is a high level of SENP3 expression in ESCC tumor cells. If the expression level of this gene is high, it can have a significant impact on ESCC cell lines and affect physiological activities such as invasion of KYSE170 cells. If the gene is knocked out, this situation will not occur. There is also research data indicating that this gene can effectively activate related signaling pathways, thereby promoting the physiological activities of malignant tumor cells. In a nude mouse xenograft tumor model, KYSE170 cells with SENP3 expression knockdown induced a smaller volume and weight of tumor tissue. Therefore, it can be clearly stated that SENP3 can enable Wnt/ ß- The catenin signaling pathway is stimulated, which in turn affects the physiological activities of ESCC cells, including the invasion process. The results of this article lay the foundation for clinical staff to carry out clinical management.

Ultrasmall single-layered NbSe2 nanotubes flattened within a chemical-driven self-pressurized carbon nanotube.

Pressure can alter interatomic distances and its electrostatic interactions, exerting a profound modifying effect on electron orbitals and bonding patterns. Conventional pressure engineering relies on compressions from external sources, which raises significant challenge in precisely applying pressure on individual molecules and also consume substantial mechanical energy. Here we report ultrasmall single-layered NbSe2 flat tubes (< 2.31 nm) created by self-pressurization during the deselenization of NbSe3 within carbon nanotubes (CNTs). As the internal force (4-17 GPa) is three orders of magnitude larger than the shear strength between CNTs, the flat tube is locked to prevent slippage. Electrical transport measurements indicate that the large pressure within CNTs induces enhanced intermolecular electron correlations. The strictly one-dimensional NbSe2 flat tubes harboring the Luttinger liquid (LL) state, showing a higher tunneling exponent [Formula: see text] than pure CNTs ([Formula: see text]). This work suggests a novel chemical approach to self-pressurization for generating new material configurations and modulating electron interactions.

A nitrous oxide/oxygen fixed mixture to reduce pain induced by the hypodermic injection: study protocol for a randomized, controlled trial.

BACKGROUND: Patients with hematological malignancies received multiple hypodermic injections of recombinant human granulocyte colony-stimulating factor. Procedural pain is one of the most common iatrogenic causes of pain in patients with hematological malignancies. It is also identified as the most commonly occurring problem in clinical care in the Department of Hematology and Oncology at Shenzhen University General Hospital. However, providing immediate relief from pain induced by hypodermic injection of recombinant human granulocyte colony-stimulating factor remains a major challenge. This trial aims to evaluate the safety and analgesic efficacy of a fixed nitrous oxide/oxygen mixture for patients with hematological malignancies and experiencing procedural pain caused by hypodermic injection of recombinant human granulocyte colony-stimulating factor in the department. METHODS: The nitrous oxide/oxygen study is a single-center, randomized, double-blind, placebo-controlled trial involving patients with hematological malignancies who require hypodermic injections of recombinant human granulocyte colony-stimulating factor for treatment. This trial was conducted in the Hematology and Oncology Department of Shenzhen University General Hospital. A total of 54 eligible patients were randomly allocated to either the fixed nitrous oxide/oxygen mixture group (n = 36) or the oxygen group (n = 18). Neither the investigators nor the patients known about the randomization list and the nature of the gas mixture in each cylinder. Outcomes were monitored at the baseline (T0), immediately after hypodermic injection of recombinant human granulocyte colony-stimulating factor (T1), and 5 min after hypodermic injection of recombinant human granulocyte colony-stimulating factor (T2) for each group. The primary outcome measure was the score in the numerical rating scale corresponding to the highest level of pain experienced during hypodermic injection of recombinant human granulocyte colony-stimulating factor. Secondary outcomes included the fear of pain, anxiety score, four physiological parameters, adverse effects, total time of gas administration, satisfaction from both patients and nurses, and the acceptance of the patients. DISCUSSION: This study focused on the safety and analgesic efficacy during hypodermic injection of recombinant human granulocyte colony-stimulating factor procedure. Data on the feasibility and safety of nitrous oxide/oxygen therapy was provided if proven beneficial to patients with hematological malignancies during hypodermic injection of recombinant human granulocyte colony-stimulating factor and widely administered to patients with procedural pain in the department. TRIAL REGISTRATION: Chinese Clinical Trial Register, ChiCTR2200061507. Registered on June 27, 2022. http://www.chictr.org.cn/edit.aspx?pid=170573&htm=4.

Synthesis of 12-Connected Three-Dimensional Covalent Organic Framework with lnj Topology.

The structural exploration of three-dimensional covalent organic frameworks (3D COFs) is of great significance to the development of COF materials. Different from structurally diverse MOFs, which have a variety of connectivity (3-24), now the valency of 3D COFs is limited to only 4, 6, and 8. Therefore, the exploration of organic building blocks with higher connectivity is a necessary path to broaden the scope of 3D COF structures. Herein, for the first time, we have designed and synthesized a 12-connected triptycene-based precursor (triptycene-12-CHO) with 12 symmetrical distributions of aldehyde groups, which is also the highest valency reported until now. Based on this unique 12-connected structure, we have successfully prepared a novel 3D COF with lnj topology (termed 3D-lnj-COF). The as-synthesized 3D COF exhibits honeycomb main pores and permanent porosity with a Brunauer-Emmett-Teller surface area of 1159.6 m2 g-1. This work not only provides a strategy for synthesizing precursors with a high connectivity but also provides inspiration for enriching the variety of 3D COFs.

Tandemly duplicated MYB genes are functionally diverged in the regulation of anthocyanin biosynthesis in soybean.

Gene duplications have long been recognized as a driving force in the evolution of genes, giving rise to novel functions. The soybean (Glycine max) genome is characterized by a large number of duplicated genes. However, the extent and mechanisms of functional divergence among these duplicated genes in soybean remain poorly understood. In this study, we revealed that 4 MYB genes (GmMYBA5, GmMYBA2, GmMYBA1, and Glyma.09g235000)-presumably generated by tandem duplication specifically in the Phaseoleae lineage-exhibited a stronger purifying selection in soybean compared to common bean (Phaseolus vulgaris). To gain insights into the diverse functions of these tandemly duplicated MYB genes in anthocyanin biosynthesis, we examined the expression, transcriptional activity, induced metabolites, and evolutionary history of these 4 MYB genes. Our data revealed that Glyma.09g235000 is a pseudogene, while the remaining 3 MYB genes exhibit strong transcriptional activation activity, promoting anthocyanin biosynthesis in different soybean tissues. GmMYBA5, GmMYBA2, and GmMYBA1 induced anthocyanin accumulation by upregulating the expression of anthocyanin pathway-related genes. Notably, GmMYBA5 showed a lower capacity for gene induction compared to GmMYBA2 and GmMYBA1. Metabolomics analysis further demonstrated that GmMYBA5 induced distinct anthocyanin accumulation in Nicotiana benthamiana leaves and soybean hairy roots compared to GmMYBA2 and GmMYBA1, suggesting their functional divergence leading to the accumulation of different metabolites accumulation following gene duplication. Together, our data provide evidence of functional divergence within the MYB gene cluster following tandem duplication, which sheds light on the potential evolutionary directions of gene duplications during legume evolution.

Association of radiotherapy for stage I-III breast cancer survivors and second primary malignant cancers: a population-based study.

PURPOSE: With life span extending, breast cancer survivors may face the possibility of developing second primary cancers (SPCs). The objective of this research is to investigate the risk factors, risk attribute to radiotherapy and the survivalship for SPCs. METHODS: A total of 445 523 breast cancer patients were enrolled from Surveillance, Epidemiology, and End Results database in 2000-2018. The risk factors for SPCs development were confirmed by competing risk model, and then were integrated to the nomogram establishment. The cumulative incidence of SPCs including SBC (second breast cancer), SGC (second gynecological cancer), and SLC (second lung cancer) were estimated. The radiotherapy-associated risk for SPCs were evaluated by Poisson regression in radiotherapy and no-radiotherapy. Propensity score matching was used to reduce possible bias for survival comparison. RESULTS: There were 57.63% patients in radiotherapy. The risk factors for developing SPCs were age, year, race, tumor size, stage, radiotherapy, grade, surgery, and histology. The cumulative incidence of SPCs was 7.75% in no-radiotherapy and 10.33% in radiotherapy. SLC, SBC, and SGC also appeared the similar results. The increased risk of developing SPCs were associated with radiotherapy in majority subgroups. The dynamic radiotherapy-associated risk for SPCs by age slightly increased risk was observed. Regardless radiotherapy or no-radiotherapy, the 10-year overall survival for SBC (radiotherapy: 59.41%; no-radiotherapy: 55.53%) and SGC (radiotherapy: 48.61%; no-radiotherapy: 35.53%) were worse than that among matched patients with only primary cancers. CONCLUSIONS: Breast cancer survivors remained a high radiotherapy-associated risk for developing SPCs. The prognosis in radiotherapy was better than in no-radiotherapy for some specific SPCs. Largely attention should be paid to these patients.

Arginine-Enhanced Antimicrobial Activity of Nanozymes against Gram-Negative Bacteria.

The continuous reduction of clinically available antibiotics has made it imperative to exploit more effective antimicrobial therapies, especially for difficult-to-treat Gram-negative pathogens. Herein, it is shown that the combination of an antimicrobial nanozyme with the clinically compatible basic amino acid L-arginine affords a potent treatment for infections with Gram-negative pathogens. In particular, the antimicrobial activity of the antimicrobial nanozyme is dramatically increased by ≈1000-fold after L-arginine stimulation. Specifically, the combination therapy enhances bacterial outer and inner membrane permeability and promotes intracellular reactive oxygen species (ROS) generation. Moreover, the metabolomic and transcriptomic results reveal that combination treatment leads to the increased ROS-mediated damage by inhibiting the tricarboxylic acid cycle and oxidative phosphorylation, thereby inducing an imbalance of the antioxidant and oxidant systems. Importantly, L-arginine dramatically significantly accelerates the healing of infected wounds in mouse models of multidrug-resistant peritonitis-sepsis and skin wound infection. Overall, this work demonstrates a novel synergistic antibacterial strategy by combining the antimicrobial nanozymes with L-arginine, which substantively facilitates the nanozyme-mediated killing of pathogens by promoting ROS production.

A new variant of the colistin resistance gene MCR-1 with co-resistance to ß-lactam antibiotics reveals a potential novel antimicrobial peptide.

The emerging and global spread of a novel plasmid-mediated colistin resistance gene, mcr-1, threatens human health. Expression of the MCR-1 protein affects bacterial fitness and this cost correlates with lipid A perturbation. However, the exact molecular mechanism remains unclear. Here, we identified the MCR-1 M6 variant carrying two-point mutations that conferred co-resistance to ß-lactam antibiotics. Compared to wild-type (WT) MCR-1, this variant caused severe disturbance in lipid A, resulting in up-regulation of L, D-transpeptidases (LDTs) pathway, which explains co-resistance to ß-lactams. Moreover, we show that a lipid A loading pocket is localized at the linker domain of MCR-1 where these 2 mutations are located. This pocket governs colistin resistance and bacterial membrane permeability, and the mutated pocket in M6 enhances the binding affinity towards lipid A. Based on this new information, we also designed synthetic peptides derived from M6 that exhibit broad-spectrum antimicrobial activity, exposing a potential vulnerability that could be exploited for future antimicrobial drug design.

Oral pathogens exacerbate Parkinson's disease by promoting Th1 cell infiltration in mice.

BACKGROUND: Parkinson's disease (PD) is a common chronic neurological disorder with a high risk of disability and no cure. Periodontitis is an infectious bacterial disease occurring in periodontal supporting tissues. Studies have shown that periodontitis is closely related to PD. However, direct evidence of the effect of periodontitis on PD is lacking. Here, we demonstrated that ligature-induced periodontitis with application of subgingival plaque (LIP-SP) exacerbated motor dysfunction, microglial activation, and dopaminergic neuron loss in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice. RESULTS: The 16S rRNA gene sequencing revealed that LIP-SP induced oral and gut dysbiosis. Particularly, Veillonella parvula (V. parvula) and Streptococcus mutans (S. mutans) from oral ligatures were increased in the fecal samples of MPTP + LIP-SP treated mice. We further demonstrated that V. parvula and S. mutans played crucial roles in LIP-SP mediated exacerbation of motor dysfunction and neurodegeneration in PD mice. V. parvula and S. mutans caused microglial activation in the brain, as well as T helper 1 (Th1) cells infiltration in the brain, cervical lymph nodes, ileum and colon in PD mice. Moreover, we observed a protective effect of IFNγ neutralization on dopaminergic neurons in V. parvula- and S. mutans-treated PD mice. CONCLUSIONS: Our study demonstrates that oral pathogens V. parvula and S. mutans necessitate the existence of periodontitis to exacerbate motor dysfunction and neurodegeneration in MPTP-induced PD mice. The underlying mechanisms include alterations of oral and gut microbiota, along with immune activation in both brain and peripheral regions. Video Abstract.

Voltage-Mode Ferroelectric Synapse for Neuromorphic Computing.

Ferroelectric materials with a modulable polarization extent hold promise for exploring voltage-driven neuromorphic hardware, in which direct current flow can be minimized. Utilizing a single active layer of an insulating ferroelectric polymer, we developed a voltage-mode ferroelectric synapse that can continuously and reversibly update its states. The device states are straightforwardly manifested in the form of variable output voltage, enabling large-scale direct cascading of multiple ferroelectric synapses to build a deep physical neural network. Such a neural network based on potential superposition rather than current flow is analogous to the biological counterpart driven by action potentials in the brain. A high accuracy of over 97% for the simulation of handwritten digit recognition is achieved using the voltage-mode neural network. The controlled ferroelectric polarization, revealed by piezoresponse force microscopy, turns out to be responsible for the synaptic weight updates in the ferroelectric synapses. The present work demonstrates an alternative strategy for the design and construction of emerging artificial neural networks.