Electrochemical Dimerization of o-Aminophenols and Hydrogen Borrowing-like Cascade to Synthesize N-Monoalkylated Aminophenoxazinones via Paired Electrolysis.

A novel electrocatalytic dimerization of o-aminphenols and a hydrogen borrowing-like cascade for synthesizing N-monoalkylated aminophenoxazinones have been developed. This electrocatalytic reaction uses a constant current mode in an undivided cell and is free of metal catalysis, open to the air, and eco-friendly. In particular, this protocol exhibits a wide substrate range and provides versatile N-monoalkylated aminophenoxazinones in medium to good yields. The results of our mechanistic research reveal that this protocol involves a cascade of electrochemical cyclocondensation of o-aminphenols and the hydrogen transfer process via paired electrolysis.

Implications of neuromuscular electrical stimulation on gait ability, balance and kinematic parameters after stroke: a systematic review and meta-analysis.

INTRODUCTIN: Improper gait patterns, impaired balance and foot drop consistently plague stroke survivors, preventing them from walking independently and safely. Neuromuscular electrical stimulation (NMES) technology can help patients reactivate their muscles and regain motor coordination. This study aims to systematically review and summarize the evidence for the potential benefits of NMES on the improvement of gait patterns after stroke. EVIDENCE ACQUISITION: PubMed, Cochrane Library, Embase, Science Direct and Web of Science were systematically searched until April 2024, to identify randomized controlled trials with the following criteria: stroke survivors as participants; NMES as intervention; conventional rehabilitation as a comparator; and gait assessment, through scales or quantitative parameters, as outcome measures. EVIDENCE SYNTHESIS: 29 publications involving 1711 patients met the inclusion criteria. Meta-analysis showed no significant differences in Ten-meter walk test, Fugl-Meyer assessment lower extremity, Modified Ashworth Assessment and asymmetry between the NMES group and the control group. Besides, NMES was associated with changes in outcome indicators such as quantitative gait analysis speed [SMD = 0.53, 95% CI (0.20, 0.85), P = 0.001], cadence [SMD = 0.76, 95% CI (0.32, 1.20), P = 0.0008], affected side step length [SMD = 0.73, 95% CI (0.16, 1.31), P = 0.01], angle of ankle dorsiflexion [WMD = 1.57, 95% CI (0.80, 2.33), P < 0.0001], Six-Minute Walk Test [WMD = 14.83, 95% CI (13.55, 16.11), P<0.00001]. According to the PEDro scale, 21 (72.4%) studies were of high quality and 8 were of moderate quality (27.6%). CONCLUSIONS: Taken together, the review synthesis indicated that NMES might play a potential role in stroke-induced walking dysfunction. And NMES may be superior for survivors in the chronic phase than the acute and subacute phases, and the efficacy of short sessions received by patients was greater than that of those who participated in a longer session. Additionally, further comparisons of the effects of NMES with different types or stimulation frequencies may provide unexpected benefits.

Dual-Mode Reconfigurable Split-Gate Logic Transistor through Van der Waals Integration.

As silicon-based transistors approach their physical size limitations, two-dimensional material-based reconfigurable functional electronic devices are considered the most promising novel device architectures beyond Moore strategies. While these devices have garnered significant attention, they often require complex device fabrication processes and extra electric fields. Additionally, the device performance is usually limited by the metal-semiconductor interface properties. In this Letter, we have constructed a reconfigurable logic device based on a WSe2 transistor with a nanofloating gate and split-gates through van der Waals integration. This device achieves a small Schottky barrier height due to the van der Waals contacts. By varying the split-gate biases, we can realize volatile reconfigurable homojunctions as well as AND, OR, NOR, and NAND logic operations with just a single device. Furthermore, with the charge trapping effect of nanofloating gate, we can also achieve nonvolatile reconfigurable homojunctions, as well as AND and OR logic operations. The volatile and nonvolatile logic operations are similar to the short-term plasticity and long-term plasticity, respectively, of synapses in the human brain. This work offers a potential approach for creating novel reconfigurable functional electronic devices with a simple fabrication process and low cost.

Protein-protein interactions in cGAS-STING pathway: a medicinal chemistry perspective.

Protein-protein interactions (PPIs) play pivotal roles in biological processes and are closely linked with human diseases. Research on small molecule inhibitors targeting PPIs provides valuable insights and guidance for novel drug development. The cGAS-STING pathway plays a crucial role in regulating human innate immunity and is implicated in various pathological conditions. Therefore, modulators of the cGAS-STING pathway have garnered extensive attention. Given that this pathway involves multiple PPIs, modulating PPIs associated with the cGAS-STING pathway has emerged as a promising strategy for modulating this pathway. In this review, we summarize an overview of recent advancements in medicinal chemistry insights into cGAS-STING PPI-based modulators and propose alternative strategies for further drug discovery based on the cGAS-STING pathway.

[Box: see text].

MiLoPYP: self-supervised molecular pattern mining and particle localization in situ.

Cryo-electron tomography allows the routine visualization of cellular landscapes in three dimensions at nanometer-range resolutions. When combined with single-particle tomography, it is possible to obtain near-atomic resolution structures of frequently occurring macromolecules within their native environment. Two outstanding challenges associated with cryo-electron tomography/single-particle tomography are the automatic identification and localization of proteins, tasks that are hindered by the molecular crowding inside cells, imaging distortions characteristic of cryo-electron tomography tomograms and the sheer size of tomographic datasets. Current methods suffer from low accuracy, demand extensive and time-consuming manual labeling or are limited to the detection of specific types of proteins. Here, we present MiLoPYP, a two-step dataset-specific contrastive learning-based framework that enables fast molecular pattern mining followed by accurate protein localization. MiLoPYP's ability to effectively detect and localize a wide range of targets including globular and tubular complexes as well as large membrane proteins, will contribute to streamline and broaden the applicability of high-resolution workflows for in situ structure determination.

COMPARISON OF OXIRIS AND CONVENTIONAL CONTINUOUS RENAL REPLACEMENT THERAPY IN MANAGING SEVERE ABDOMINAL INFECTIONS: IMPACT ON SEPTIC SHOCK MORTALITY.

ABSTRACT: Objective: The objective of this study is to assess and compare the efficacy of oXiris with conventional continuous renal replacement therapy (CRRT) in managing severe abdominal infections. Methods: A retrospective analysis encompassing cases from 2017 to 2023 was conducted at the Department of Critical Care Medicine within the First Affiliated Hospital of Fujian Medical University. Parameters including heart rate (HR), mean arterial pressure (MAP), oxygenation index, lactate (Lac), platelet count, neutrophil ratio, procalcitonin, C-reactive protein (CRP), interleukin 6 (IL-6), norepinephrine dosage, Acute Physiology and Chronic Health Evaluation II (APACHE II), and Sequential Organ Failure Assessment (SOFA) were recorded prior to treatment initiation, at 24 h, and 72 h after treatment for both the oXiris and conventional CRRT groups. In addition, the duration of respiratory support, CRRT treatment, length of stay in the intensive care unit (ICU), total hospitalization period, and mortality rates at 14 and 28 days for both groups were recorded. Results: 1) Within the conventional CRRT group, notable enhancement was observed solely in Lac levels at 24 h after treatment compared with pretreatment levels. In addition, at 72 h after treatment, improvements were evident in HR, Lac, CRP, and IL-6 levels. 2) Conversely, the oXiris group exhibited improvements in HR, MAP, Lac, oxygenation index, neutrophil ratio, and IL-6 at 24 h after treatment when compared with baseline values. In addition, reductions were observed in APACHE II and SOFA scores. At 72 h after treatment, all parameters demonstrated enhancement except for platelet count. 3) Analysis of the changes in the indexes (Δ) between the two groups at 24 h after treatment revealed variances in HR, MAP, Lac, norepinephrine dosage, CRP levels, IL-6 levels, APACHE II scores, and SOFA scores. 4) The Δ indexes at 72 h after treatment indicated more significant improvements following oXiris treatment for both groups, except for procalcitonin. 5) The 14-day mortality rate (24.4%) exhibited a significant reduction in the oXiris group when compared with the conventional group (43.6%). However, no significant difference was observed in the 28-day mortality rate between the two groups. 6) Subsequent to multifactorial logistic regression analysis, the results indicated that oXiris treatment correlated with a noteworthy decrease in the 14-day and 28-day mortality rates associated with severe abdominal infections, by 71.3% and 67.6%, respectively. Conclusion: oXiris demonstrates clear advantages over conventional CRRT in the management of severe abdominal infections. Notably, it reduces the fatality rates, thereby establishing itself as a promising and potent therapeutic option.

Harnessing transcription factor-driven ROS for synergistic multimodal lung cancer treatment.

Multimodal treatment of cancer is an unstoppable revolution in clinical application. However, designing a platform that integrates therapeutic modalities with different pharmacokinetic characteristics remains a great challenge. Herein, we designed a universal lipid nanoplatform equipping a ROS-cleavable docetaxel prodrug (DTX-L-DTX) and an NF-E2-related factor 2 (NRF2) inhibitor (clobetasol propionate, CP). This simply fabricated nanomedicine enables superior synergistic molecularly targeted/chemo/radio therapy for lung cancer cascade by a transcription factor-driven ROS self-sustainable motion. Chemotherapy is launched via ROS-triggered DTX release. Subsequently, CP inhibits the expression of NRF2 target genes, resulting in efficient targeted therapy, meanwhile inducing sustained ROS generation which in turn facilitates chemotherapy by overcoming ROS consumption during the DTX release process. Finally, the introduction of radiotherapy further amplifies ROS, offering continuous mutual feedback to amplify the ultimate treatment performance. This strategy is conceptually and operationally simple, providing solutions to challenges in clinical cancer treatment and beyond.

Flexible Terahertz Metasurface Absorbers Empowered by Bound States in the Continuum.

Terahertz absorbers are crucial to the cutting-edge techniques in the next-generation wireless communications, imaging, sensing, and radar stealth, as they fundamentally determine the performance of detectors and cloaking capabilities. It has long been a pressing task to find absorbers with customizable performance that can adapt to various environments with low cost and great flexibility. Here, perfect absorption empowered by bound states in the continuum (BICs) is demonstrated, allowing for the tailoring of absorption coefficient, bandwidth, and field of view. The one-port absorbers are interpreted using temporal coupled-mode theory highlighting the dominant role of BICs in the far-field radiation properties. Through a thorough investigation of BICs from the perspective of lattice symmetry, the radiation features of three BIC modes are unraveled using both multipolar and topological analysis. The versatile radiation capabilities of BICs provide ample freedom to meet specific requirements of absorbers, including tunable bandwidth, stable performance in a large field of view, and multiband absorption using a thin and flexible film without extreme geometric demands. These findings offer a systematic approach to developing optoelectronic devices and demonstrate the significant potential of BICs for optical and photonic applications, which will stimulate further studies on terahertz photonics and metasurfaces.

Machine learning-based gait adaptation dysfunction identification using CMill-based gait data.

Background: Combining machine learning (ML) with gait analysis is widely applicable for diagnosing abnormal gait patterns. Objective: To analyze gait adaptability characteristics in stroke patients, develop ML models to identify individuals with GAD, and select optimal diagnostic models and key classification features. Methods: This study was investigated with 30 stroke patients (mean age 42.69 years, 60% male) and 50 healthy adults (mean age 41.34 years, 58% male). Gait adaptability was assessed using a CMill treadmill on gait adaptation tasks: target stepping, slalom walking, obstacle avoidance, and speed adaptation. The preliminary analysis of variables in both groups was conducted using t-tests and Pearson correlation. Features were extracted from demographics, gait kinematics, and gait adaptability datasets. ML models based on Support Vector Machine, Decision Tree, Multi-layer Perceptron, K-Nearest Neighbors, and AdaCost algorithm were trained to classify individuals with and without GAD. Model performance was evaluated using accuracy (ACC), sensitivity (SEN), F1-score and the area under the receiver operating characteristic (ROC) curve (AUC). Results: The stroke group showed a significantly decreased gait speed (p = 0.000) and step length (SL) (p = 0.000), while the asymmetry of SL (p = 0.000) and ST (p = 0.000) was higher compared to the healthy group. The gait adaptation tasks significantly decreased in slalom walking (p = 0.000), obstacle avoidance (p = 0.000), and speed adaptation (p = 0.000). Gait speed (p = 0.000) and obstacle avoidance (p = 0.000) were significantly correlated with global F-A score in stroke patients. The AdaCost demonstrated better classification performance with an ACC of 0.85, SEN of 0.80, F1-score of 0.77, and ROC-AUC of 0.75. Obstacle avoidance and gait speed were identified as critical features in this model. Conclusion: Stroke patients walk slower with shorter SL and more asymmetry of SL and ST. Their gait adaptability was decreased, particularly in obstacle avoidance and speed adaptation. The faster gait speed and better obstacle avoidance were correlated with better functional mobility. The AdaCost identifies individuals with GAD and facilitates clinical decision-making. This advances the future development of user-friendly interfaces and computer-aided diagnosis systems.

Amplifying Radiotherapy by Evoking Mitochondrial Oxidative Stress Using a High-performance Aggregation-induced Emission Sonosensitizer.

INTRODUCTION: Developing effective methods to enhance tumor radiosensitivity is crucial for improving the therapeutic efficacy of radiotherapy (RT). Due to its deep tissue penetration, excellent safety profile, and precise controllability, sonosensitizer- based sonodynamic therapy (SDT) has recently garnered significant attention as a promising combined approach with RT. METHOD: However, the limited reactive oxygen species (ROS) generation ability in the aggregated state and the absence of specific organelle targeting in sonosensitizers hinder their potential to augment RT. This study introduces a fundamental principle guiding the design of high-performance sonosensitizers employed in the aggregated state. Building upon these principles, we develop a mitochondria-targeted sonosensitizer molecule (TCSVP) with aggregation-induced emission (AIE) characteristics by organic synthesis. Then, we demonstrate the abilities of TCSVP to target mitochondria and produce ROS under ultrasound in H460 cancer cells using confocal laser scanning microscopy (CLSM) and fluorescence microscopy. Subsequently, we examine the effectiveness of enhancing tumor radiosensitivity by utilizing TCSVP and ultrasound in both H460 cells and H460 and 4T1 tumor-bearing mice. RESULTS: The results indicate that evoking non-lethal mitochondrial oxidative stress in tumors by TCSVP under ultrasound stimulation can significantly improve tumor radiosensitivity (p <0.05). Additionally, the in vivo safety profile of TCSVP is thoroughly confirmed by histopathological analysis. CONCLUSION: This work proposes strategies for designing efficient sonosensitizers and underscores that evoking non-lethal mitochondrial oxidative stress is an effective method to enhance tumor radiosensitivity.

Recent advances in artificial neuromorphic applications based on perovskite composites.

High-performance perovskite materials with excellent physical, electronic, and optical properties play a significant role in artificial neuromorphic devices. However, the development of perovskites in microelectronics is inevitably hindered by their intrinsic non-ideal properties, such as high defect density, environmental sensitivity, and toxicity. By leveraging materials engineering, integrating various materials with perovskites to leverage their mutual strengths presents great potential to enhance ion migration, energy level alignment, photoresponsivity, and surface passivation, thereby advancing optoelectronic and neuromorphic device development. This review initially provides an overview of perovskite materials across different dimensions, highlighting their physical properties and detailing their applications and metrics in two- and three-terminal devices. Subsequently, we comprehensively summarize the application of perovskites in combination with other materials, including organics, nanomaterials, oxides, ferroelectrics, and crystalline porous materials (CPMs), to develop advanced devices such as memristors, transistors, photodetectors, sensors, light-emitting diodes (LEDs), and artificial neuromorphic systems. Lastly, we outline the challenges and future research directions in synthesizing perovskite composites for neuromorphic devices. Through the review and analysis, we aim to broaden the utilization of perovskites and their composites in neuromorphic research, offering new insights and approaches for grasping the intricate physical working mechanisms and functionalities of perovskites.

Near-Infrared Response Organic Synaptic Transistor for Dynamic Trace Extraction.

The development of neuromorphic hardware capable of detecting and recognizing moving targets through an in-sensor computing strategy is considered to be an important component of the construction of edge computing systems with distributed computation. In addition to responsiveness to visible light, the implementation of neuromorphic hardware should also demonstrate the ability to sense and process nonvisible light, which is essential for tracking target object trajectories in specialized environments. In this work, we fabricated an organic synaptic transistor with a near-infrared (NIR) response by incorporating doped LaF3: Yb/Ho upconversion quantum dots (UCQDs) into the channel of a Poly3-hexylthiophene (P3HT)-based organic field effect transistor (FET), serving as charge trapping and infrared sensing sites. The obtained synaptic transistor not only replicates common synaptic behaviors when exposed to NIR illumination but also demonstrates potential applications for the dynamic trajectory recognition of animals in the dark. Compared to other monitoring technologies, P3HT transistors doped with LaF3: Yb/Ho UCQDs exhibit distinct advantages, including a NIR response, high-efficiency computing, and sensitivity, which provide an experimental foundation and a design reference for the development of next-generation intelligent dynamic image recognition systems.

Coronary angiography was used to assess the effect of diabetes on off-pump coronary artery bypass graft patency.

This study aimed to examine the influence of diabetes on the left internal mammary artery (LIMA) and saphenous vein (SV) graft failure for 5-year follow-up. We enrolled 202 patients who underwent isolated off-pump coronary artery bypass grafting (CABG) surgery in 2014, angiographic follow-up occurred at 5 years after surgery. Angiographic outcomes in patients with or without diabetes were analyzed. Multivariate logistic regression analysis was used to identify independent predictors of graft dysfunction. A total of 66 (32.7%) patients had diabetes. Five-year rates of LIMA and SV graft failure were similar in patients with and without diabetes. In addition, in diabetics, the proportion of complete graft failure was significantly lower in the LIMA grafts (12/66, 18.2%) than in the SV grafts (57/133, 42.9%) (P = .001). In nondiabetic, the proportion of complete graft failure was also significantly lower in the LIMA grafts (28/136, 20.6%) than in the SV grafts (105/275, 38.2%) (P < .001). Multivariate logistic regression analysis showed that mean graft flow (MGF) was an independent predictor factor for LIMA (odds ratio = 1.186, 95% CI = 1.114-1.263, P < .001) and SV (odds ratio = 1.056, 95% CI = 1.035-1.077, P < .001) graft failure. Diabetes did not influence the patency of LIMA or SV grafts over a 5-year follow-up. LIMA grafts should be maximized in patients undergoing off-pump CABG surgery. Diabetes does not affect the patency of grafts CABG. Using angiography, our study proved that diabetes does not affect the patency of grafted vessels after CABG for 5 years.

Mendelian randomization based on immune cells in diabetic nephropathy.

Background: DKD, a leading cause of chronic kidney and end-stage renal disease, lacks robust immunological research. Recent GWAS utilizing SNPs and CNVs has shed light on immune mechanisms of kidney diseases. However, DKD's immunological basis remains elusive. Our goal is to unravel cause-effect relationships between immune cells and DKD using Mendelian randomization. Methodology: We analyzed FinnGen data (1032 DKD cases, 451,248 controls) with 731 immunocyte GWAS summaries (MP=32, MFI=389, AC=118, RC=192). We employed forward and reverse Mendelian randomization to explore causal links between immune cell traits and DKD. Sensitivity analysis ensured robustness, heterogeneity checks, and FDR correction minimized false positives. Results: Our study explored the causal link between diabetic nephropathy (DKD) and immunophenotypes using two-sample Mendelian Randomization (MR) with IVW. Nine immunophenotypes were significantly associated with DKD at p<0.05 after FDR correction. Elevated CD24, CD3 in Treg subsets, CD39+ CD4+, and CD33- HLA DR- AC correlated positively with DKD risk, while CD27 in B cells and SSC-A in CD4+ inversely correlated. Notably, while none showed significant protection, further research on immune cells' role in DKD may provide valuable insights. Conclusion: The results of this study show that the immune cells are closely related to DKD, which may be helpful in the future clinical study.

Screening and isolation of quorum sensing inhibitors of Pseudomonas aeruginosa from Phellodendron amurense extracts using bio-affinity chromatography.

Drug-resistant bacterial infections pose a significant challenge in the field of bacterial disease treatment. Finding new antibacterial pathways and targets to combat drug-resistant bacteria is crucial. The bacterial quorum sensing (QS) system regulates the expression of bacterial virulence factors. Inhibiting bacterial QS and reducing bacterial virulence can achieve antibacterial therapeutic effects, making QS inhibition an effective strategy to control bacterial pathogenicity. This article mainly focused on the PqsA protein in the QS system of Pseudomonas aeruginosa. An affinity chromatography medium was developed using the SpyTag/SpyCatcher heteropeptide bond system. Berberine, which can interact with the PqsA target, was screened from Phellodendron amurense by affinity chromatography. We characterized its structure, verified its inhibitory activity on P. aeruginosa, and preliminarily analyzed its mechanism using molecular docking technology. This method can also be widely applied to the immobilization of various protein targets and the effective screening of active substances.

Interferon-responsive neutrophils and macrophages extricate SARS-CoV-2 Omicron critical patients from the nasty fate of sepsis.

The SARS-CoV-2 Omicron variant is characterized by its high transmissibility, which has caused a worldwide epidemiological event. Yet, it turns ominous once the disease progression degenerates into severe pneumonia and sepsis, presenting a horrendous lethality. To elucidate the alveolar immune or inflammatory landscapes of Omicron critical-ill patients, we performed single-cell RNA-sequencing (scRNA-seq) of bronchoalveolar lavage fluid (BALF) from the patients with critical pneumonia caused by Omicron infection, and analyzed the correlation between the clinical severity scores and different immune cell subpopulations. In the BALF of Omicron critical patients, the alveolar violent myeloid inflammatory environment was determined. ISG15+ neutrophils and CXCL10+ macrophages, both expressed the interferon-stimulated genes (ISGs), were negatively correlated with clinical pulmonary infection score, while septic CST7+ neutrophils and inflammatory VCAN+ macrophages were positively correlated with sequential organ failure assessment. The percentages of ISG15+ neutrophils were associated with more protective alveolar epithelial cells, and may reshape CD4+ T cells to the exhaustive phenotype, thus preventing immune injuries. The CXCL10+ macrophages may promote plasmablast/plasma cell survival and activation as well as the production of specific antibodies. As compared to the previous BALF scRNA-seq data from SARS-CoV-2 wild-type/Alpha critical patients, the subsets of neutrophils and macrophages with pro-inflammatory and immunoregulatory features presented obvious distinctions, suggesting an immune disparity in Omicron variants. Overall, this study provides a BALF single-cell atlas of Omicron critical patients, and suggests that alveolar interferon-responsive neutrophils and macrophages may extricate SARS-CoV-2 Omicron critical patients from the nasty fate of sepsis.

Rationally Improved Surface Charge Density of Triboelectric Nanogenerator with TiO2-MXene/Polystyrene Nanofiber Charge Trapping Layer for Biomechanical Sensing and Wound Healing Application.

Triboelectric nanogenerators (TENGs) have become reliable green energy harvesters by converting biomechanical motions into electricity. However, the inevitable charge leakage and poor electric field (EF) of conventional TENG result in inferior tribo-charge density on the active layer. In this paper, TiO2-MXene incorporated polystyrene (PS) nanofiber membrane (PTMx NFM) charge trapping interlayer is introduced into single electrode mode TENG (S-TENG) to prevent electron loss at the electrode interface. Surprisingly, this charge-trapping mechanism augments the surface charge density and electric output performance of TENGs. Polyvinylidene difluoride (PVDF) mixed polyurethane (PU) NFM is used as tribo-active layer, which improves the crystallinity and mechanical property of PVDF to prevent delamination during long cycle tests. Herein, the effect of this double-layer capacitive model is explained experimentally and theoretically. With optimization of the PTMx interlayer thickness, S-TENG exhibits a maximum open-circuit voltage of (280 V), short-circuit current of (20 µA) transfer charge of (120 nC), and power density of (25.2 µW cm-2). Then, this energy is utilized to charge electrical appliances. In addition, the influence of AC/DC EF simulation in wound healing management (vitro L929 cell migration, vivo tissue regeneration) is also investigated by changing the polarity of trans-epithelial potential (TEP) distribution in the wounded area.

Structures of trehalose-6-phosphate synthase, Tps1, from the fungal pathogen Cryptococcus neoformans: A target for antifungals.

Invasive fungal diseases are a major threat to human health, resulting in more than 1.5 million annual deaths worldwide. The arsenal of antifungal therapeutics remains limited and is in dire need of drugs that target additional biosynthetic pathways that are absent from humans. One such pathway involves the biosynthesis of trehalose. Trehalose is a disaccharide that is required for pathogenic fungi to survive in their human hosts. In the first step of trehalose biosynthesis, trehalose-6-phosphate synthase (Tps1) converts UDP-glucose and glucose-6-phosphate to trehalose-6-phosphate. Here, we report the structures of full-length Cryptococcus neoformans Tps1 (CnTps1) in unliganded form and in complex with uridine diphosphate and glucose-6-phosphate. Comparison of these two structures reveals significant movement toward the catalytic pocket by the N terminus upon ligand binding and identifies residues required for substrate binding, as well as residues that stabilize the tetramer. Intriguingly, an intrinsically disordered domain (IDD), which is conserved among Cryptococcal species and closely related basidiomycetes, extends from each subunit of the tetramer into the "solvent" but is not visible in density maps. We determined that the IDD is not required for C. neoformans Tps1-dependent thermotolerance and osmotic stress survival. Studies with UDP-galactose highlight the exquisite substrate specificity of CnTps1. In toto, these studies expand our knowledge of trehalose biosynthesis in Cryptococcus and highlight the potential of developing antifungal therapeutics that disrupt the synthesis of this disaccharide or the formation of a functional tetramer and the use of cryo-EM in the structural characterization of CnTps1-ligand/drug complexes.

Accurate size-based protein localization from cryo-ET tomograms.

Cryo-electron tomography (cryo-ET) combined with sub-tomogram averaging (STA) allows the determination of protein structures imaged within the native context of the cell at near-atomic resolution. Particle picking is an essential step in the cryo-ET/STA image analysis pipeline that consists in locating the position of proteins within crowded cellular tomograms so that they can be aligned and averaged in 3D to improve resolution. While extensive work in 2D particle picking has been done in the context of single-particle cryo-EM, comparatively fewer strategies have been proposed to pick particles from 3D tomograms, in part due to the challenges associated with working with noisy 3D volumes affected by the missing wedge. While strategies based on 3D template-matching and deep learning are commonly used, these methods are computationally expensive and require either an external template or manual labelling which can bias the results and limit their applicability. Here, we propose a size-based method to pick particles from tomograms that is fast, accurate, and does not require external templates or user provided labels. We compare the performance of our approach against a commonly used algorithm based on deep learning, crYOLO, and show that our method: i) has higher detection accuracy, ii) does not require user input for labeling or time-consuming training, and iii) runs efficiently on non-specialized CPU hardware. We demonstrate the effectiveness of our approach by automatically detecting particles from tomograms representing different types of samples and using these particles to determine the high-resolution structures of ribosomes imaged in vitro and in situ.

Development of a marital self-disclosure programme for alleviating the fear of cancer recurrence in patients with gastric cancer and undergoing chemotherapy: a modified Delphi method.

Aim: This study aimed to develop a marital self-disclosure programme to alleviate the fear of cancer recurrence in patients with gastric cancer who are undergoing chemotherapy. Design: Delphi method. Methods: Data from available literature and stakeholder interviews were utilised to formulate the initial draft of a marital self-disclosure programme aimed to alleviate the fear of cancer recurring in patients with gastric cancer and undergoing chemotherapy. A panel of experts subsequently conducted a two-round modified Delphi method to finalise the programme. Results: A total of 13 experts participated in the first round of consultation, while 11 experts were involved in the second round, as two experts withdrew due to unavailability. The response rates of both rounds of expert consultation were 100 and 84.62%, respectively, and the expert authority coefficients (Cr) of the programme were 0.83 and 0.84, respectively. The coordination coefficients of the expert opinions were 0.124 (χ2 = 61.214, p = 0.010) and 0.167 (χ2 = 69.668, p = 0.001) for each Delphi round. The average score of the second round was (4.545 ± 0.688) to (5.000 ± 0), with a full score ratio of 0.55-1.00. The coefficient of variation (CV) ranged from 0 to 0.031. Outcomes from both rounds of consultations were considered acceptable and credible. The finalised marital self-disclosure programme for alleviating the fear of cancer recurrence in patients with gastric cancer undergoing chemotherapy consists of two parts; disclosure guidance for patients and their spouse with nine items, and the structure and themes of marital self-disclosure with 31 items. Patient or public contribution: After two rounds of expert consultations, the marital self-disclosure programme for patients with gastric cancer undergoing chemotherapy is suggested to be scientifically valid and reliable. This programme is anticipated to potentially support patients and their spouses effectively by providing a reliable intervention plan focused on alleviating the fear of cancer recurrence.