The discovery of an anti-Candida xanthone with selective inhibition of Candida albicans GAPDH.

OBJECTIVES: This study aimed to discover novel antifungals targeting Candida albicans glyceraldehyde-3-phosphate dehydrogenase (CaGAPDH), have an insight into inhibitory mode, and provide evidence supporting CaGAPDH as a target for new antifungals. METHODS: Virtual screening was utilized to discover inhibitors of CaGAPDH. The inhibitory effect on cellular GAPDH was evaluated by determining the levels of ATP, NAD, NADH, etc., as well as examining GAPDH mRNA and protein expression. The role of GAPDH inhibition in C. albicans was supported by drug affinity responsive target stability and overexpression experiments. The mechanism of CaGAPDH inhibition was elucidated by Michaelis-Menten enzyme kinetics and site-specific mutagenesis based on docking. Chemical synthesis was used to produce an improved candidate. Different sources of GAPDH were used to evaluate inhibitory selectivity across species. In vitro and in vivo antifungal tests, along with anti-biofilm activity, were carried out to evaluate antifungal potential of GAPDH inhibitors. RESULTS: A natural xanthone was identified as the first competitive inhibitor of CaGAPDH. It demonstrated in vitro anti-C. albicans potential but also caused hemolysis. XP-W, a synthetic side-chain-optimized xanthone, demonstrated a better safety profile, exhibiting a 50-fold selectivity for CaGAPDH over human GAPDH. XP-W also exhibited potent anti-biofilm activity and displayed broad-spectrum anti-Candida activities in vitro and in vivo, including multi-azole-resistant C. albicans. CONCLUSIONS: These results demonstrate for the first time that CaGAPDH is a valuable target for antifungal drug discovery, and XP-W provides a promising lead.

M1/M4 receptors as potential therapeutic treatments for schizophrenia: A comprehensive study.

Muscarinic acetylcholine receptors (mAChRs) play a significant role in the pathophysiology of schizophrenia. Although activating mAChRs holds potential in addressing the full range of schizophrenia symptoms, clinical application of many non-selective mAChR agonists in cognitive deficits, positive and negative symptoms is hindered by peripheral side effects (gastrointestinal disturbances and cardiovascular effects) and dosage restrictions. Ligands binding to the allosteric sites of mAChRs, particularly the M1 and M4 subtypes, demonstrate activity in improving cognitive function and amelioration of positive and negative symptoms associated with schizophrenia, enhancing our understanding of schizophrenia. The article aims to critically examine current design concepts and clinical advancements in synthesizing and designing small molecules targeting M1/M4, providing theoretical insights and empirical support for future research in this field.

Determinants of successful disease control through voluntary quarantine dynamics on social networks.

In the wake of epidemics, quarantine measures are typically recommended by health authorities or governments to help control the spread of the disease. Compared with mandatory quarantine, voluntary quarantine offers individuals the liberty to decide whether to isolate themselves in case of infection exposure, driven by their personal assessment of the trade-off between economic loss and health risks as well as their own sense of social responsibility and concern for public health. To better understand self-motivated health behavior choices under these factors, here we incorporate voluntary quarantine into an endemic disease model -- the susceptible-infected-susceptible (SIS) model -- and perform comprehensive agent-based simulations to characterize the resulting behavior-disease interactions in structured populations. We quantify the conditions under which voluntary quarantine will be an effective intervention measure to mitigate disease burden. Furthermore, we demonstrate how individual decision-making factors, including the level of temptation to refrain from quarantine and the degree of social compassion, impact compliance levels of voluntary quarantines and the consequent collective disease mitigation efforts. We find that successful disease control requires either a sufficiently low level of temptation or a sufficiently high degree of social compassion, such that even complete containment of the epidemic is attainable. In addition to well-mixed populations, our simulation results are applicable to other more realistic social networks of contacts, including spatial lattices, small-world networks, and real social networks. Our work offers new insights into the fundamental social dilemma aspect of disease control through non-pharmaceutical interventions, such as voluntary quarantine and isolation, where the collective outcome of individual decision-making is crucial.

Vertical serpentine interconnect-enabled stretchable and curved electronics.

Stretchable and curved electronic devices are a promising technology trend due to their remarkable advantages. Many approaches have been developed to manufacture stretchable and curved electronics. Here, to allow such electronics to better serve practical applications, ranging from wearable devices to soft robotics, we propose a novel vertical serpentine conductor (VSC) with superior electrical stability to interconnect functional devices through a silicon-based microfabrication process. Conformal vacuum transfer printing (CVTP) technology was developed to transfer the networked platform onto complex curved surfaces to demonstrate feasibility. The mechanical and electrical performance were investigated numerically and experimentally. The VSC interconnected network provides a new approach for stretchable and curved electronics with high stretchability and reliability.

Cross-regulation in a three-component cell envelope stress signaling system of Brucella.

IMPORTANCE: As intracellular pathogens, Brucella must contend with a variety of host-derived stressors when infecting a host cell. The inner membrane, cell wall, and outer membrane, i.e. the cell envelope, of Brucella provide a critical barrier to host assault. A conserved regulatory mechanism known as two-component signaling (TCS) commonly controls transcription of genes that determine the structure and biochemical composition of the cell envelope during stress. We report the identification of previously uncharacterized TCS genes that determine Brucella ovis fitness in the presence of cell envelope disruptors and within infected mammalian host cells. Our study reveals a new molecular mechanism of TCS-dependent gene regulation, and thereby advances fundamental understanding of transcriptional regulatory processes in bacteria.

Cross regulation in a three-component cell envelope stress signaling system of Brucella.

A multi-layered structure known as the cell envelope separates the controlled interior of bacterial cells from a fluctuating physical and chemical environment. The transcription of genes that determine cell envelope structure and function is commonly regulated by two-component signaling systems (TCS), comprising a sensor histidine kinase and a cognate response regulator. To identify TCS genes that contribute to cell envelope function in the intracellular mammalian pathogen, Brucella ovis, we subjected a collection of non-essential TCS deletion mutants to compounds that disrupt cell membranes and the peptidoglycan cell wall. Our screen led to the discovery of three TCS proteins that coordinately function to confer resistance to cell envelope stressors and to support B. ovis replication in the intracellular niche. This tripartite regulatory system includes the known cell envelope regulator, CenR, and a previously uncharacterized TCS, EssR-EssS, which is widely conserved in Alphaproteobacteria. The CenR and EssR response regulators bind a shared set of sites on the B. ovis chromosomes to control transcription of an overlapping set of genes with cell envelope functions. CenR directly interacts with EssR and functions to stimulate phosphoryl transfer from the EssS kinase to EssR, while CenR and EssR control the cellular levels of each other via a post-transcriptional mechanism. Our data provide evidence for a new mode of TCS cross-regulation in which a non-cognate response regulator affects both the activity and protein levels of a cognate TCS protein pair.

Outlearning extortioners: unbending strategies can foster reciprocal fairness and cooperation.

Recent theory shows that extortioners taking advantage of the zero-determinant (ZD) strategy can unilaterally claim an unfair share of the payoffs in the Iterated Prisoner's Dilemma. It is thus suggested that against a fixed extortioner, any adapting coplayer should be subdued with full cooperation as their best response. In contrast, recent experiments demonstrate that human players often choose not to accede to extortion out of concern for fairness, actually causing extortioners to suffer more loss than themselves. In light of this, here we reveal fair-minded strategies that are unbending to extortion such that any payoff-maximizing extortioner ultimately will concede in their own interest by offering a fair split in head-to-head matches. We find and characterize multiple general classes of such unbending strategies, including generous ZD strategies and Win-Stay, Lose-Shift (WSLS) as particular examples. When against fixed unbending players, extortioners are forced with consequentially increasing losses whenever intending to demand a more unfair share. Our analysis also pivots to the importance of payoff structure in determining the superiority of ZD strategies and in particular their extortion ability. We show that an extortionate ZD player can be even outperformed by, for example, WSLS, if the total payoff of unilateral cooperation is smaller than that of mutual defection. Unbending strategies can be used to outlearn evolutionary extortioners and catalyze the evolution of Tit-for-Tat-like strategies out of ZD players. Our work has implications for promoting fairness and resisting extortion so as to uphold a just and cooperative society.

Thoracic empyema due to nontuberculous mycobacteria in an immunocompetent patient without pulmonary disease: a case report.

BACKGROUND: Pleural involvement by non-tuberculous mycobacteria (NTM), especially NTM empyema in the immunocompetent patient without pulmonary diseases is a rare disease. It is difficult to diagnose with only a few cases of immunodeficient patients in the literature. CASE PRESENTATION: We describe a 63-year-old male with empyema due to NTM and highlight the challenges of diagnosis. CONCLUSIONS: Non-tuberculous mycobacterial infection should be considered as a cause of pleuritis or empyema without pulmonary disease, however it is a real diagnostic dilemma.

Retinoid X receptor 1 is a specific lethal RNAi target disturbing chitin metabolism during hatching of Tetranychus cinnabarinus.

RNA interference (RNAi) can be developed as an alternative method of chemical pesticides for pest control. In this study, we noticed a specifically expressed gene (retinoid X receptor 1, TcRXR1) in the egg stage of T. cinnabarinus. RNAi was applied to investigate the function of TcRXR1. Results showed that with continuous feeding of dsTcRXR1, the larvae of T. cinnabarinus could still successfully develop to adult, which was in accordance with the low expression of TcRXR1 out of egg stage. High mortality of eggs was observed after eggs were treated with dsTcRXR1. To investigate the downstream genes of TcRXR1, the RNA samples after successful RNAi of TcRXR1 were analyzed by transcriptome analysis. According to function annotation of differentially expressed genes, 6 genes were selected for their potential function with the phenotype of dsTcRXR1, and among them, a chitinase gene (TcCHT-E) attained a high expression level in the late stage of egg, peaking just after the expression peak of TcRXR1. Mortality of eggs was observed under the effect of dsTcCHT-E as well as dsTcRXR1. In conclusion, TcRXR1 is a specific RNAi target for control of T. cinnabarinus, and its lethal mechanism might be disturbing chitin metabolism hatching of egg.

Paeoniflorin, ferulic acid, and atractylenolide III improved LPS-induced neuroinflammation of BV2 microglia cells by enhancing autophagy.

Microglia hyperactivation is an important cause of neuroinflammation in Alzheimer's disease (AD). Paeoniflorin (PF), ferulic acid (FA), and atractylenolide III (ATL) are potent in anti-inflammation and neuroprotection. Multiple components can act on different targets simultaneously to exert synergistic therapeutic effects and exploring the synergistic potential between compounds is an important area of research. We investigated the effects of PF, FA, and ATL, alone or in combination, on LPS-induced neuroinflammation and autophagy in BV2 microglia cells. We found that PF, FA, and ATL, alone or in combination, significantly reduced the production of inflammatory factors such as IL-6, IL-1ß, and TNF-α, especially in the PF + FA + ATL group, which performed the best. In addition, the combination of PF, FA, and ATL significantly increased the expression of autophagy-related proteins p-AMPK, p-ULK1, Beclin1, LC3, and TFEB and decreased the expression of p62. Moreover, the restoration of autophagic flux by the combination of PF, FA, and ATL was abrogated by the addition of the autophagy inhibitor Wortmannin. In conclusion, PF, FA, and ATL have a synergistic effect in reducing LPS-induced inflammatory factor release from BV2 microglia cells, and its protective effect may be through activation of the AMPK/ULK1/TFEB autophagic signaling pathway.

Novel Triazoles with Potent and Broad-Spectrum Antifungal Activity In Vitro and In Vivo.

Triazoles have demonstrated significant efficacy in the treatment of fungal infections. However, increasing drug resistance is a growing concern that negatively impacts their effectiveness. By designing a well-crafted side chain, triazoles can be endowed with advantages, like higher potency and the ability to overcome drug resistance. This highlights the diverse interactions between side chains and CYP51. To explore novel triazole antifungal agents, we synthesized three series of fluconazole-core compounds and focused on optimizing the chain based on molecule docking and in vitro results. The most potent S-F24 exhibited excellent broad-spectrum antifungal activity that was better or comparable to clinically used azoles. S-F24 maintained its potency even against multi-resistant Candida albicans. Additionally, S-F24 displayed a good safety profile with high selectivity, low hemolytic effects, and low tendency to induce resistance. Our findings collectively demonstrated that there was still a high potential for side-chain modification in the development of novel azoles.

Protective Effect of Ferulic Acid on Lipopolysaccharide-Induced BV2 Microglia Inflammation via AMPK/mTOR Signaling Pathway.

In neurodegenerative diseases, microglial activation and neuroinflammation are essential for the control and progression of neurodegenerative diseases. Mitigating microglium-induced inflammation is one strategy for hindering the progression of neurodegenerative diseases. Ferulic acid (FA) is an effective anti-inflammatory agent, but its potential role and regulation mechanism in neuroinflammatory reactions have not been fully studied. In this study, the neuroinflammation model was established by lipopolysaccharide (LPS), and the inhibitory effect of FA on neuroinflammation of BV2 microglia was studied. The results showed that FA significantly reduced the production and expression of reactive oxygen species (ROS), tumor necrosis factor-α (TNF-α), leukocyte-6 (IL-6) and interleukin-1ß (IL-1ß). We further studied the mechanism of FA's regulation of LPS-induced BV2 neuroinflammation and found that FA can significantly reduce the expression of mTOR in BV2 microglia induced by LPS, and significantly increase the expression of AMPK, indicating that FA may have an anti-inflammatory effect by activating the AMPK/mTOR signaling pathway to regulate the release of inflammatory mediators (such as NLRP3, caspase-1 p20 and IL-1ß). We further added an autophagy inhibitor (3-MA) and an AMPK inhibitor (compound C, CC) for reverse verification. The results showed that FA's inhibitory effects on TNF-α, IL-6 and IL-1ß and its regulatory effect on AMPK/mTOR were destroyed by 3-MA and CC, which further indicated that FA's inhibitory effect on neuroinflammation is related to its activation of the AMPK/mTOR autophagy signaling pathway. In a word, our experimental results show that FA can inhibit LPS-induced neuroinflammation of BV2 microglia by activating the AMPK/mTOR signaling pathway, and FA may be a potential drug for treating neuroinflammatory diseases.

Machine learning reveals sex differences in clinical features of acute exacerbation of chronic obstructive pulmonary disease: A multicenter cross-sectional study.

Introduction: Intrinsically, chronic obstructive pulmonary disease (COPD) is a highly heterogonous disease. Several sex differences in COPD, such as risk factors and prevalence, were identified. However, sex differences in clinical features of acute exacerbation chronic obstructive pulmonary disease (AECOPD) were not well explored. Machine learning showed a promising role in medical practice, including diagnosis prediction and classification. Then, sex differences in clinical manifestations of AECOPD were explored by machine learning approaches in this study. Methods: In this cross-sectional study, 278 male patients and 81 female patients hospitalized with AECOPD were included. Baseline characteristics, clinical symptoms, and laboratory parameters were analyzed. The K-prototype algorithm was used to explore the degree of sex differences. Binary logistic regression, random forest, and XGBoost models were performed to identify sex-associated clinical manifestations in AECOPD. Nomogram and its associated curves were established to visualize and validate binary logistic regression. Results: The predictive accuracy of sex was 83.930% using the k-prototype algorithm. Binary logistic regression revealed that eight variables were independently associated with sex in AECOPD, which was visualized by using a nomogram. The AUC of the ROC curve was 0.945. The DCA curve showed that the nomogram had more clinical benefits, with thresholds from 0.02 to 0.99. The top 15 sex-associated important variables were identified by random forest and XGBoost, respectively. Subsequently, seven clinical features, including smoking, biomass fuel exposure, GOLD stages, PaO2, serum potassium, serum calcium, and blood urea nitrogen (BUN), were concurrently identified by three models. However, CAD was not identified by machine learning models. Conclusions: Overall, our results support that the clinical features differ markedly by sex in AECOPD. Male patients presented worse lung function and oxygenation, less biomass fuel exposure, more smoking, renal dysfunction, and hyperkalemia than female patients with AECOPD. Furthermore, our results also suggest that machine learning is a promising and powerful tool in clinical decision-making.

Low-hysteresis, pressure-insensitive, and transparent capacitive strain sensor for human activity monitoring.

Wearable strain sensors have been widely used for human activity monitoring. Most reported strain sensors have mainly focused on material engineering, high stretchability and large gauge factors. Few works have focused on strain sensor's robustness and reliability, including low hysteresis, good long-term stability, good electrode material stability, and low coupling effects under multi-input signals, which are the factors that limit practical strain sensor applications. To develop a high-performance strain sensor, we propose a flexible capacitive sensor structure with three-dimensional (3D) interdigital electrodes fabricated by vertically aligned carbon nanotubes. Compared with a traditional resistive strain sensor and a capacitive strain sensor with vertical sandwich electrodes, a strain sensor with horizontal parallel interdigital electrodes can benefit from low cross talk in terms of the normal force and improve substrate transparency. Additionally, embedding 3D electrodes into the substrate improves ultrahigh robustness with a low-pressure coupling effect under normal force. Moreover, compared with other reported works, the electrode variation under strain is small (less than 1.6%), which means that the perturbation of inert properties on device performance is small. Finally, the fabricated strain sensor achieves an ultralow hysteresis (0.35%), excellent pressure-insensitive performance (less than 0.8%), fast response (60 ms), good long-term stability, and good transparency. As an application example, a flexible strain sensor was successfully demonstrated as a wearable device for the precise monitoring of different types of human activities, including bending of the finger, knee, elbow, wrist, and neck with large strain signals and small strain signals generated by a mouth-opening activity. This excellent performance indicates that the flexible strain sensor is a promising candidate for human motion detection, soft robotics, and medical care.

Origami Paper-Based Stretchable Humidity Sensor for Textile-Attachable Wearable Electronics.

Flexible and stretchable humidity sensors for wearable purposes have become increasingly important in health care and physiological signal monitoring. However, to the authors' knowledge, there is no report on flexible and stretchable paper-based humidity sensors that are low-cost, easily fabricated, and environmentally friendly. In this work, for the first time, we propose a stretchable, textile-compatible paper-based origami humidity sensor (POHS). The POHS can achieve good stretchability by integrating origami folding structures with a paper substrate, in which an airlaid paper acts as both a sensing material and a sensor substrate. This sensor has high sensitivity, good response, and recovery properties with excellent stability during deformation. This sensor has proved to be capable of dynamically monitoring the breathing rate after 300 folding and unfolding cycles. The flexible and stretchable nature of our POHS ensures that it is compatible for textile attachment and its utility for wearable applications, including respiration rate monitoring and diaper wetting detection. The facile fabrication process and convenient disposal method of the POHS proposed in this study provide feasible solutions for the development of low-cost wearable humidity sensors.

Highly coordinated nationwide massive travel restrictions are central to effective mitigation and control of COVID-19 outbreaks in China.

COVID-19, the disease caused by the novel coronavirus 2019, has caused grave woes across the globe since it was first reported in the epicentre of Wuhan, Hubei, China, in December 2019. The spread of COVID-19 in China has been successfully curtailed by massive travel restrictions that rendered more than 900 million people housebound for more than two months since the lockdown of Wuhan, and elsewhere, on 23 January 2020. Here, we assess the impact of China's massive lockdowns and travel restrictions reflected by the changes in mobility patterns across and within provinces, before and during the lockdown period. We calibrate movement flow between provinces with an epidemiological compartment model to quantify the effectiveness of lockdowns and reductions in disease transmission. Our analysis demonstrates that the onset and phase of local community transmission in other provinces depends on the cumulative population outflow received from the epicentre Hubei. Moreover, we show that synchronous lockdowns and consequent reduced mobility lag a certain time to elicit an actual impact on suppressing the spread. Such highly coordinated nationwide lockdowns, applied via a top-down approach along with high levels of compliance from the bottom up, are central to mitigating and controlling early-stage outbreaks and averting a massive health crisis.

Highly coordinated nationwide massive travel restrictions are central to effective mitigation and control of COVID-19 outbreaks in China.

The COVID-19, the disease caused by the novel coronavirus 2019 (SARS-CoV-2), has caused graving woes across the globe since first reported in the epicenter Wuhan, Hubei, China, December 2019. The spread of COVID-19 in China has been successfully curtailed by massive travel restrictions that put more than 900 million people housebound for more than two months since the lockdown of Wuhan on 23 January 2020 when other provinces in China followed suit. Here, we assess the impact of China's massive lockdowns and travel restrictions reflected by the changes in mobility patterns before and during the lockdown period. We quantify the synchrony of mobility patterns across provinces and within provinces. Using these mobility data, we calibrate movement flow between provinces in combination with an epidemiological compartment model to quantify the effectiveness of lockdowns and reductions in disease transmission. Our analysis demonstrates that the onset and phase of local community transmission in other provinces depends on the cumulative population outflow received from the epicenter Hubei. As such, infections can propagate further into other interconnected places both near and far, thereby necessitating synchronous lockdowns. Moreover, our data-driven modeling analysis shows that lockdowns and consequently reduced mobility lag a certain time to elicit an actual impact on slowing down the spreading and ultimately putting the epidemic under check. In spite of the vastly heterogeneous demographics and epidemiological characteristics across China, mobility data shows that massive travel restrictions have been applied consistently via a top-down approach along with high levels of compliance from the bottom up.