Clinically Applicable Pan-Origin Cancer Detection for Lymph Nodes via AI-Based Pathology.

Lymph node metastasis is one of the most common ways of tumour metastasis. The presence or absence of lymph node involvement influences the cancer's stage, therapy, and prognosis. The integration of artificial intelligence systems in the histopathological diagnosis of lymph nodes after surgery is urgent. Here, we propose a pan-origin lymph node cancer metastasis detection system. The system is trained by over 700 whole slide images and is composed of two deep learning models to locate the lymph nodes and detect cancers. It achieved a area under the receiver operating characteristic (ROC) curve (AUC) of 0.958, with a 95.2% sensitivity and 72.2% specificity, on 1,402 whole-slide images (WSIs) from 49 organs at the National Cancer Center, China. Moreover, we demonstrated that the system could perform robustly with 1,051 WSIs from 52 organs from another medical center, with a AUC of 0.925. Our research represents a step forward in a pan-origin lymph node metastasis detection system, providing accurate pathological guidance by reducing the probability of missed diagnosis in routine clinical practice.

Can Positive Social Contact Encourage Residents' Community Citizenship Behavior? The Role of Personal Benefit, Sympathetic Understanding, and Place Identity.

Identified as an increasingly pivotal aspect, the benevolent extra-role characteristic of community citizenship behavior contributes to destination development efficiency and social cohesion. Based on the egoistic-altruistic motivation framework, this study investigated three motivations that propel residents to exercise community citizenship behaviors in a positive social contact context, namely self-focused, other-focused, and place-focused motivation. A conceptual model combined with positive contact, personal benefit, sympathetic understanding, place identity, and community citizenship behavior was developed and tested using partial least squares structural equation modeling (PLS-SEM) through data from 366 residents in Kaifeng, China. The findings showed that of the three motivations for community citizenship behaviors, place identity contributed the most, and personal benefits failed to predict community citizenship behaviors. Furthermore, sympathetic understanding with tourists was most fostered by residents from the perception of positive contact with tourists. These findings offer a novel theoretical framework for scholarly investigation and provide practical insights for tourism managers regarding strategies to influence residents' community citizenship behavior.

Essential and virulence-related protein interactions of pathogens revealed through deep learning.

Identification of bacterial protein-protein interactions and predicting the structures of the complexes could aid in the understanding of pathogenicity mechanisms and developing treatments for infectious diseases. Here, we developed a deep learning-based pipeline that leverages residue-residue coevolution and protein structure prediction to systematically identify and structurally characterize protein-protein interactions at the proteome-wide scale. Using this pipeline, we searched through 78 million pairs of proteins across 19 human bacterial pathogens and identified 1923 confidently predicted complexes involving essential genes and 256 involving virulence factors. Many of these complexes were not previously known; we experimentally tested 12 such predictions, and half of them were validated. The predicted interactions span core metabolic and virulence pathways ranging from post-transcriptional modification to acid neutralization to outer membrane machinery and should contribute to our understanding of the biology of these important pathogens and the design of drugs to combat them.

Streptomyces umbrella toxin particles block hyphal growth of competing species.

Streptomyces are a genus of ubiquitous soil bacteria from which the majority of clinically utilized antibiotics derive1. The production of these antibacterial molecules reflects the relentless competition Streptomyces engage in with other bacteria, including other Streptomyces species1,2. Here we show that in addition to small-molecule antibiotics, Streptomyces produce and secrete antibacterial protein complexes that feature a large, degenerate repeat-containing polymorphic toxin protein. A cryo-electron microscopy structure of these particles reveals an extended stalk topped by a ringed crown comprising the toxin repeats scaffolding five lectin-tipped spokes, which led us to name them umbrella particles. Streptomyces coelicolor encodes three umbrella particles with distinct toxin and lectin composition. Notably, supernatant containing these toxins specifically and potently inhibits the growth of select Streptomyces species from among a diverse collection of bacteria screened. For one target, Streptomyces griseus, inhibition relies on a single toxin and that intoxication manifests as rapid cessation of vegetative hyphal growth. Our data show that Streptomyces umbrella particles mediate competition among vegetative mycelia of related species, a function distinct from small-molecule antibiotics, which are produced at the onset of reproductive growth and act broadly3,4. Sequence analyses suggest that this role of umbrella particles extends beyond Streptomyces, as we identified umbrella loci in nearly 1,000 species across Actinobacteria.

A new classification of mandible defects and condyle changed after mandible reconstruction with FFF.

Objectives: To explore a new classification of mandibular defects and changes in the preserved condyle after mandibular reconstruction with free fibular flap(FFF). Study design: We reviewed patients who underwent mandibular reconstruction with FFF from 2015 to 2021 and classified the mandibular defects into five categories: classⅠ(unilateral-mandibular excluding condyle), classⅡ(unilateral-mandibular including condyle), classⅢ(bilateral-mandibular excluding condyle), classⅣ(bilateral-mandibular including one condyle), and classⅤ(bilateral-mandibular including both condyles). Cone Beam Computed Tomography (CBCT) data were collected preoperatively(T0), at 7-10 postoperative days(T1), 6 postoperative months(T2), and 1 postoperative year(T3). We calculated the condylar surface area, volume, and displacement. Results: 62 cases were collected. The condylar surface areas and volumes in T2 and T3 values were lower than those of T0 and T1(P < 0.01) The condylar displacement was the lowest in ClassI and the largest in ClassⅣ(P < 0.01), while no significant differences in classesⅠ-Ⅲ(P < 0.05). Displacement during T1-T0 was greater than that during T2-T0 and T3-T0(P < 0.05). Conclusion: Mandibular reconstruction with FFF results in displacement and alteration of the condyle within a time interval, and this alteration stabilizes after 6 months. Mandibular defects that do not reach the midline, surgical alteration to preserve the condyle are not required. However, when the defects cross the midline, the condyle should be preserved as much as possible.

MiR-17-5p-engineered sEVs Encapsulated in GelMA Hydrogel Facilitated Diabetic Wound Healing by Targeting PTEN and p21.

Delayed wound healing is a major complication of diabetes, and is associated with impaired cellular functions. Current treatments are unsatisfactory. Based on the previous reports on microRNA expression in small extracellular vesicles (sEVs), miR-17-5p-engineered sEVs (sEVs17-OE) and encapsulated them in gelatin methacryloyl (GelMA) hydrogel for diabetic wounds treatment are fabricated. SEVs17-OE are successfully fabricated with a 16-fold increase in miR-17-5p expression. SEVs17-OE inhibited senescence and promoted the proliferation, migration, and tube formation of high glucose-induced human umbilical vein endothelial cells (HG-HUVECs). Additionally, sEVs17-OE also performs a promotive effect on high glucose-induced human dermal fibroblasts (HG-HDFs). Mechanism analysis showed the expressions of p21 and phosphatase and tensin homolog (PTEN), as the target genes of miR-17-5p, are downregulated significantly by sEVs17-OE. Accordingly, the downstream genes and pathways of p21 and PTEN, are activated. Next, sEVs17-OE are loaded in GelMA hydrogel to fabricate a novel bioactive wound dressing and to evaluate their effects on diabetic wound healing. Gel-sEVs17-OE effectively accelerated wound healing by promoting angiogenesis and collagen deposition. The cellular mechanism may be associated with local cell proliferation. Therefore, a novel bioactive wound dressing by loading sEVs17-OE in GelMA hydrogel, offering an option for chronic wound management is successfully fabricated.

Toward Autonomous Pulmonary Artery Catheterization: A Learning-based Robotic Navigation System.

Providing imaging during interventional treatments of cardiovascular diseases is challenging. Magnetic Resonance Imaging (MRI) has gained popularity as it is radiation-free and returns high resolution of soft tissue. However, the clinician has limited access to the patient, e.g., to their femoral artery, within the MRI scanner to accurately guide and manipulate an MR-compatible catheter. At the same time, communication will need to be maintained with a clinician, located in a separate control room, to provide the most appropriate image to the screen inside the MRI room. Hence, there is scope to explore the feasibility of how autonomous catheterization robots could support the steering of catheters along trajectories inside complex vessel anatomies.In this paper, we present a Learning from Demonstration based Gaussian Mixture Model for a robot trajectory optimisation during pulmonary artery catheterization. The optimisation algorithm is integrated into a 2 Degree-of-Freedom MR-compatible interventional robot allowing for continuous and simultaneous translation and rotation. Our methodology achieves autonomous navigation of the catheter tip from the inferior vena cava, through the right atrium and the right ventricle into the pulmonary artery where an interventions is performed. Our results show that our MR-compatible robot can follow an advancement trajectory generated by our Learning from Demonstration algorithm. Looking at the overall duration of the intervention, it can be concluded that procedures performed by the robot (teleoperated or autonomously) required significantly less time compared to manual hand-held procedures.

Prognostic Significance of Advanced Age in Patients with T1a Renal Cell Carcinoma Treated by Microwave Ablation: A 16-Year Experience.

BACKGROUND: Previous studies have failed to investigate the specific effects of advanced age on survival outcomes by considering the Charlson Comorbidity Index (CCI) and age permutation in patients with T1a renal cell carcinoma (T1a RCC) treated by microwave ablation (MWA). Notably, RCC guidelines recommended radiofrequency ablation (RFA) and active surveillance (AS) are both treatment options for elderly T1a RCC, but whether MWA is superior to AS in light of higher heating efficiency and larger ablation zone compared with RFA is not clear. This study aimed to investigate the specific effects of advanced age on survival outcomes of T1a RCC patients stratified by CCI score and indicate better intervention for elderly T1a RCC between MWA and AS. METHODS: This was a retrospective study. We retrospectively reviewed 237 patients with T1a RCC who had undergone MWA over the last 16 years. Data were analyzed by Cox regression and Landmark analysis. Interaction tests and propensity score matching were used to account for potential biases. We compared the overall survival (OS) and cancer-specific survival (CSS) rates of patients ≥75 years in our study with corresponding figures from 4251 counterparts undergoing AS in published articles. RESULTS: Using patients ＜75 years with a CCI ≤2 as a reference, the hazard ratio (HR) and 95% confidence interval (CI) of OS for patients＜75 years with a CCI ≥3, patients ≥75 years with a CCI ≤2, and patients ≥75 years with CCI ≥3, were 2.954 (1.139-7.663), 3.48 (1.487-8.146), and 3.357 (1.162-9.698), respectively. The adverse effect of an age ≥75 years on OS was attenuated in patients with a CCI ≥3. The attenuation lasted for 62.5 months of follow-up (P = .017). Notably, advanced age exerted a protective effect on progression-free survival (PFS) in patients with a CCI ≥3, increasing the 8-year PFS from 67.8% to 100% (P = .049). Relative to 1-, 3-, 5-, and 8-year survival data for patients aged ≥75 undergoing AS, the OS rates for 5-year follow-up were always better in MWA. However, beyond 5 years, the OS rates dropped to levels that were similar to AS. CONCLUSIONS: Advanced age exerts adverse effects and significantly protective effects on OS and PFS, respectively, in T1a RCC patients with a CCI ≥ 3. According to our study, elderly patients with T1a RCC underwent radical MWA may yield a better medium-term OS relative to AS.

A deep learning model for predicting multidrug-resistant organism infection in critically ill patients.

BACKGROUND: This study aimed to apply the backpropagation neural network (BPNN) to develop a model for predicting multidrug-resistant organism (MDRO) infection in critically ill patients. METHODS: This study collected patient information admitted to the intensive care unit (ICU) of the Affiliated Hospital of Qingdao University from August 2021 to January 2022. All patients enrolled were divided randomly into a training set (80%) and a test set (20%). The least absolute shrinkage and selection operator and stepwise regression analysis were used to determine the independent risk factors for MDRO infection. A BPNN model was constructed based on these factors. Then, we externally validated this model in patients from May 2022 to July 2022 over the same center. The model performance was evaluated by the calibration curve, the area under the curve (AUC), sensitivity, specificity, and accuracy. RESULTS: In the primary cohort, 688 patients were enrolled, including 109 (15.84%) MDRO infection patients. Risk factors for MDRO infection, as determined by the primary cohort, included length of hospitalization, length of ICU stay, long-term bed rest, antibiotics use before ICU, acute physiology and chronic health evaluation II, invasive operation before ICU, quantity of antibiotics, chronic lung disease, and hypoproteinemia. There were 238 patients in the validation set, including 31 (13.03%) MDRO infection patients. This BPNN model yielded good calibration. The AUC of the training set, the test set and the validation set were 0.889 (95% CI 0.852-0.925), 0.919 (95% CI 0.856-0.983), and 0.811 (95% CI 0.731-0.891), respectively. CONCLUSIONS: This study confirmed nine independent risk factors for MDRO infection. The BPNN model performed well and was potentially used to predict MDRO infection in ICU patients.

ASPP1/2 positive patients with invasive breast cancers have good prognosis.

Although the expression of ASPP family members in multiple tumors has been studied, especially in various cell lines of breast cancer (BC), but the expressions pattern of ASPP family members in invasive BC tissues are not clear. We studied the expression and expression pattern of ASPPs family member in BCs, the relationship between ASPP family members and clinic-pathologic features of BCs was also analyzed. The results showed that the expression of ASPP1, ASPP2 and iASPP was observed on AE1/AE3+ tumor cells, and not on infiltrated lymphocytes and capillaries. The relationship between ASPP1 expression and pTNM stage has statistical difference (p＜0.01). The relationship between expression of ASPP2 and SBR grade has statistical difference (p＜0.05). The relationship between expression of iASPP and clinic-pathologic feature of patients has no statistical difference (p＞0.05). The patients with positive expression of ASPP1 and the patients with negative expression of ASPP1 have statistical difference in 3-year survival rate and 5-year survival rate (χ2 = 4.49, P = 0.03; χ2 = 3.79, P = 0.048). Overall, our work demonstrated that the expression of ASPP1/2 contributes to predict the prognosis of patients with BC.

Correction: Zhu et al. Gait Analysis with Wearables Is a Potential Progression Marker in Parkinson's Disease. Brain Sci. 2022, 12, 1213.

In the original publication [...].

P-MSC-derived extracellular vesicles facilitate diabetic wound healing via miR-145-5p/ CDKN1A-mediated functional improvements of high glucose-induced senescent fibroblasts.

Background: Persistent hyperglycaemia in diabetes causes functional abnormalities of human dermal fibroblasts (HDFs), partially leading to delayed skin wound healing. Extracellular vesicles (EVs) containing multiple pro-healing microRNAs (miRNAs) have been shown to exert therapeutic effects on diabetic wound healing. The present study aimed to observe the effects of EVs derived from placental mesenchymal stem cells (P-MSC-EVs) on diabetic wound healing and high glucose (HG)-induced senescent fibroblasts and to explore the underlying mechanisms. Methods: P-MSC-EVs were isolated by differential ultracentrifugation and locally injected into the full-thickness skin wounds of diabetic mice, to observe the beneficial effects on wound healing in vivo by measuring wound closure rates and histological analysis. Next, a series of assays were conducted to evaluate the effects of low (2.28 x 1010 particles/ml) and high (4.56 x 1010 particles/ml) concentrations of P-MSC-EVs on the senescence, proliferation, migration, and apoptosis of HG-induced senescent HDFs in vitro. Then, miRNA microarrays and real-time quantitative PCR (RT-qPCR) were carried out to detect the differentially expressed miRNAs in HDFs after EVs treatment. Specific RNA inhibitors, miRNA mimics, and small interfering RNA (siRNA) were used to evaluate the role of a candidate miRNA and its target genes in P-MSC-EV-induced improvements in the function of HG-induced senescent HDFs. Results: Local injection of P-MSC-EVs into diabetic wounds accelerated wound closure and reduced scar widths, with better-organized collagen deposition and decreased p16INK4a expression. In vitro, P-MSC-EVs enhanced the antisenescence, proliferation, migration, and antiapoptotic abilities of HG-induced senescent fibroblasts in a dose-dependent manner. MiR-145-5p was found to be highly enriched in P-MSC-EVs. MiR-145-5p inhibitors effectively attenuated the P-MSC-EV-induced functional improvements of senescent fibroblasts. MiR-145-5p mimics simulated the effects of P-MSC-EVs on functional improvements of fibroblasts by suppressing the expression of cyclin-dependent kinase inhibitor 1A and activating the extracellular signal regulated kinase (Erk)/protein kinase B (Akt) signaling pathway. Furthermore, local application of miR-145-5p agomir mimicked the effects of P-MSC-EVs on wound healing. Conclusions: These results suggest that P-MSC-EVs accelerate diabetic wound healing by improving the function of senescent fibroblasts through the transfer of miR-145-5p, which targets cyclin-dependent kinase inhibitor 1A to activate the Erk/Akt signaling pathway. P-MSC-EVs are promising therapeutic candidates for diabetic wound treatment.

Mortality and associated influencing factors among oral cancer patients in western China: A retrospective cohort study from 2016 to 2021.

Few studies have examined oral cancer-related mortality in Guangxi. This study aimed to explore the incidence and characteristics of oral cancer and to identify the risk factors for oral cancer-related mortality. The study was conducted to provide a reference for clinical treatment and to improve the survival rate of patients with oral cancer. A total of 271 patients with oral cancer who were treated in the Stomatology Hospital of Guangxi Medical University from 2016 to 2017 were selected as the research subjects. The follow-up lasted until the middle of 2021. The survival rate and mean survival time of 271 patients were calculated by the Kaplan-Meier method. Cox proportional hazard models and stratified analysis were used to explore the related factors that affect the mortality of patients. Nomogram plots were used to visualize the relationships among multiple variables. Among 271 patients with oral cancer, the 2-year and 5-year overall survival rates were 83.8% and 68.5% respectively. The results of multivariate analysis showed that, age, pathological type, surgery and readmission were significant factors affecting survival. When the above factors were incorporated into nomogram plots and stratified analysis, the results showed that the risk of death after treatment in patients with oral cancer aged > 55 years was 1.693 times higher than that in patients aged ≤ 55 years (HR, hazard ratio [HR] = 1.795, 95% confidence intervals [CI] = 1.073, 3.004). The risk of death after surgical treatment was 0.606 times higher than that without surgical treatment (HR = 0.590, 95% CI = 0.367, 0.948). Patients who were readmitted had a 2.340-fold increased risk of death compared with patients who were not readmitted (HR = 2.340, 95% CI = 1.267,4.321). Older age, surgery, and readmission were risk factors for mortality among patients with oral cancer. The median survival time of 271 patients with oral cancer was 52.0 months. Patients under the age of 55 years old and those who choose surgical treatment tend to have a better prognosis and a longer survival. Oral cancer-related mortality is affected by age, treatment mode, readmission, and other factors. All of these factors are worthy of clinical attention for their prevention and control.

Genetic manipulation of Patescibacteria provides mechanistic insights into microbial dark matter and the epibiotic lifestyle.

Patescibacteria, also known as the candidate phyla radiation (CPR), are a diverse group of bacteria that constitute a disproportionately large fraction of microbial dark matter. Its few cultivated members, belonging mostly to Saccharibacteria, grow as epibionts on host Actinobacteria. Due to a lack of suitable tools, the genetic basis of this lifestyle and other unique features of Patescibacteira remain unexplored. Here, we show that Saccharibacteria exhibit natural competence, and we exploit this property for their genetic manipulation. Imaging of fluorescent protein-labeled Saccharibacteria provides high spatiotemporal resolution of phenomena accompanying epibiotic growth, and a transposon-insertion sequencing (Tn-seq) genome-wide screen reveals the contribution of enigmatic Saccharibacterial genes to growth on their hosts. Finally, we leverage metagenomic data to provide cutting-edge protein structure-based bioinformatic resources that support the strain Southlakia epibionticum and its corresponding host, Actinomyces israelii, as a model system for unlocking the molecular underpinnings of the epibiotic lifestyle.

Anemoside B4 attenuates RANKL-induced osteoclastogenesis by upregulating Nrf2 and dampens ovariectomy-induced bone loss.

Increased numbers and functional overactivity of osteoclasts are the pathological basis for bone loss diseases such as osteoporosis, which are characterized by cortical bone thinning, decreased trabecular bone quantity, and reduced bone mineral density. Effective inhibition of osteoclast formation and bone resorption are important means of treating such skeletal diseases. Anemoside B4 (AB4), the main active component of Pulsatilla chinensis, possesses a wide range of anti-inflammatory and immunoregulatory effects. However, its effect and mechanism in osteoclast differentiation remain unclear. In this study, we found through tartrate-resistant acidic phosphatase (TRAcP) staining and immunofluorescence staining that AB4 inhibited the differentiation, fusion, and bone-resorption functions of osteoclasts induced by receptor activator of nuclear factor κB ligand (RANKL) in vitro. Additionally, real time PCR (RT-qPCR) and western blot analysis showed AB4 downregulated the expression of osteoclast marker genes, including Nfatc1, Fos, and Ctsk, while upregulating Nrf2 expression. AB4 (5 mg/kg) alleviated bone loss in ovariectomized mice by inhibiting osteoclast formation. Furthermore, the knockout of Nrf2 weakened the inhibitory effects of AB4 on osteoclast formation and related gene expression. In summary, the results suggest AB4 can inhibit osteoclast differentiation and function by activating Nrf2 and indicate AB4 may be a candidate drug for osteoporosis.

Minor hallucinations in Parkinson's disease with probable rapid eye movement sleep behavior disorder.

Background: Rapid eye movement sleep behavior disorder (RBD) and minor hallucinations (MHs) are prevalent nonmotor symptoms in Parkinson's disease (PD). The purpose of this study was to explore the association of MHs in PD patients with probable RBD (pRBD). Methods: This cross-sectional study included 291 patients diagnosed with PD. Patients who scored 6 or higher on the Rapid Eye Movement Behavior Disorder (RBD) Screening Questionnaire were defined as pRBD. A comprehensive evaluation was performed for all patients, including the collection of demographic information, clinical assessment, and MH features. Results: Among the 291 PD patients, 69 (23.7%) had pRBD. MHs were observed in 35 (50.7%) patients with pRBD, significantly higher than 29.7% in patients without RBD (p = 0.015). The main type of MHs in pRBD was presence hallucinations with variable content. Patients with pRBD and MHs tended to be older, had a longer disease duration, and were more likely to take levodopa or dopamine-receptor agonists. Besides, the pRBD with MHs group had higher scores on the Nonmotor Symptoms Questionnaire (NMS-Quest) and Hamilton Anxiety Scale (HAMA). Binary logistic regression analysis revealed that longer disease duration and higher NMS-Quest scores were associated with MHs in PD patients with pRBD. Conclusion: A high prevalence of MHs was observed in PD patients with pRBD. The main type of MHs in pRBD was presence hallucinations. MHs in PD with RBD are mainly associated with disease duration and severity of nonmotor symptoms. These findings provide new insights into the interaction between MHs and RBD.

Regulation mechanisms underlying tail resorption in Bufo gargarizans metamorphosis.

Anurans have been excellent organisms for studying amphibian metamorphosis. Tail resorption is a remarkable event that occurs during amphibian metamorphosis. Although tail resorption has been previously studied in other anurans like Xenopus laevis and Rana chensinensis, there is no report on Bufo gargarizans. This paper thus explored the mechanism of tail resorption during metamorphosis in Bufo gargarizans tadpoles through some biological research methods. Histological results showed that the tail tissues of tadpoles gradually degraded as metamorphosis progressed. RNA sequencing analysis was performed to examine the expression level and functional enrichment of differentially expressed genes in the tail. In addition, we analyzed the mRNA expression levels of genes related to tail resorption by quantitative real-time polymerase chain reaction. We also speculated on three pathways that participate in the regulation of tail resorption based on the above results. The present study might provide a theoretical basis and novel insights for further research of complex molecular mechanisms of tail resorption in amphibians.

Impairment of bile acid metabolism and altered composition by lead and copper in Bufo gargarizans tadpoles.

Lead (Pb) and copper (Cu) are two common heavy metal contaminants in environments, and liver is recognized as one of the main target organs for toxicity of Pb and Cu in animal organisms. Bile acids play a critical role in regulating hepatic metabolic homeostasis by activating farnesoid X receptor (Fxr). However, there were few studies on the interactions between bile acids and liver pathology caused by heavy metals. In this work, the histopathological changes, targeted metabolome and transcriptome responses in the liver of Bufo gargarizans tadpoles to Pb and/or Cu were examined. We found that exposure to Pb and/or Cu altered the hepatic bile acid profile, resulting in increased hydrophobicity and toxicity of the bile acid pool. And the expression of genes involved in bile acid metabolism and their downstream signaling pathways in the liver were significantly altered by Pb and/or Cu exposure. The alteration of bile acid profiles and the expression of genes related to bile acid metabolism might induce oxidative stress and inflammation, ultimately inducing hepatocyte injury observed in the histological sections. To our knowledge, this is the first study to provide histological, biochemical, and molecular evidence for establishing the link between Pb and Cu exposure, disturbances in hepatic bile acid metabolism, and liver injury.

Discovery of a glutathione utilization pathway in Francisella that shows functional divergence between environmental and pathogenic species.

Glutathione (GSH) is an abundant metabolite within eukaryotic cells that can act as a signal, a nutrient source, or serve in a redox capacity for intracellular bacterial pathogens. For Francisella, GSH is thought to be a critical in vivo source of cysteine; however, the cellular pathways permitting GSH utilization by Francisella differ between strains and have remained poorly understood. Using genetic screening, we discovered a unique pathway for GSH utilization in Francisella. Whereas prior work suggested GSH catabolism initiates in the periplasm, the pathway we define consists of a major facilitator superfamily (MFS) member that transports intact GSH and a previously unrecognized bacterial cytoplasmic enzyme that catalyzes the first step of GSH degradation. Interestingly, we find that the transporter gene for this pathway is pseudogenized in pathogenic Francisella, explaining phenotypic discrepancies in GSH utilization among Francisella spp. and revealing a critical role for GSH in the environmental niche of these bacteria.

Sleep structure and related clinical characteristics in drug-naïve Parkinson's disease with subjectively different sleep quality.

Background: Sleep disturbance is a common non-motor symptom of Parkinson's disease (PD). Most polysomnography (PSG) studies are conducted when patients are in their "on medication" state. Our study aimed to investigate changes in the sleep structure in drug-naive PD patients with poor subjective sleep quality based on polysomnography (PSG) and to explore potential correlations between sleep structure and clinical features of the disease. Methods: A total of 44 drug-naive PD patients were included. All patients completed a standardized questionnaire to obtain demographic and clinical characteristics and underwent whole-night PSG recording. Patients with PSQI scores >5.5 were considered poor sleepers, and patients with PSQI scores <5.5 were considered to be good sleepers. Results: There were 24 (54.5%) PD patients in the good sleeper group and 20 (24.5%) PD patients in the poor sleeper group. We observed that poor sleepers had severe non-motor symptoms (NMS) and worse life quality. The PSG displayed that they had a longer wake-up time after sleep onset (WASO) and lower sleep efficiency (SE). Correlation analysis revealed that the micro-arousal index was positively associated with UPDRS-III, and the N1 sleep percentage was negatively associated with the NMS score in good sleepers. For poor sleepers, rapid eye movement (REM) sleep percentage was negatively related to the Hoehn-Yahr (H-Y) stage, WASO increased with UPDRS-III, periodic limb movement index (PLMI) increased with the NMS score, and N2 sleep percentage was negatively related to the score of life quality. Conclusion: Night awakening is the main manifestation of decreased sleep quality in drug-naive PD patients. Poor sleepers have severe non-motor symptoms and poor life quality. Additionally, the increase in nocturnal arousal events may predict the progression of motor dysfunction.