A nigroincertal projection mediates aversion and enhances coping responses to potential threat.

Recent studies have shown that the non-DA neurons in the ventral tegmental area (VTA) and substantia nigra (SN) not only modulate motivational behaviors but also regulate defensive behaviors. While zona incerta (ZI) is a threat-responsive substrate and receives innervations from the ventral midbrain, the function of the ventral midbrain-to-ZI connection remains poorly defined. Here, we demonstrate that the ZI receives heterogenous innervations from the ventral midbrain. By utilizing a retrograde AAV preferentially labeling non-DA neurons in the ventral midbrain, we found that ZI-projecting non-DA cells in the ventral midbrain are activated by restraint stress. We focused on the SN and found that SN-to-ZI GABAergic input is engaged by a predatory odor. Sustained pan-neuronal SN-to-ZI activation results in aversion and enhances defensive behaviors, likely through a disinhibition mechanism to recruit downstream brain regions that regulate defensive behaviors. Collectively, our results reveal a novel role of nigroincertal projection in mediating negative valence and regulating defensive behaviors.

Dominant dystrophic epidermolysis bullosa is associated with glycolytically active GATA3+ T helper 2 cells which may contribute to pruritus in lesional skin.

BACKGROUND: Dominant dystrophic epidermolysis bullosa (DDEB) is characterized by trauma-induced blisters and, in some individuals, intense pruritus. Precisely what causes itch in DDEB and optimal ways to reduce it have not been fully determined. OBJECTIVES: To characterize DDEB skin transcriptomes to identify therapeutic targets to reduce pruritus in patients. METHODS: Using bulk RNA sequencing, we evaluated affected and unaffected skin biopsy samples from six patients with DDEB (all with the very itchy pruriginosa subtype) and four healthy individuals. Single-cell transcriptomes of affected (n = 2) and unaffected (n = 1) DDEB skin and healthy skin (n = 2) were obtained. Dupilumab treatment was provided for three patients. RESULTS: The skin bulk transcriptome showed significant enrichment of T helper (Th)1/2 and Th17 pathways in affected DDEB skin compared with nonlesional DDEB skin and healthy skin. Single-cell transcriptomics showed an association of glycolytically active GATA3+ Th2 cells in affected DDEB skin. Treatment with dupilumab in three people with DDEB led to significantly reduced visual analogue scale (VAS) itch scores after 12 weeks (mean VAS 3.83) compared with pretreatment (mean VAS 7.83). Bulk RNAseq and quantitative polymerase chain reaction showed that healthy skin and dupilumab-treated epidermolysis bullosa (EB) pruriginosa skin have similar transcriptomic profiles and reduced Th1/Th2 and Th17 pathway enrichment. CONCLUSIONS: Single-cell RNAseq helps define an enhanced DDEB-associated Th2 profile and rationalizes drug repurposing of anti-Th2 drugs in treating DDEB pruritus.

Dominant dystrophic epidermolysis bullosa (DDEB) is a rare inherited skin disease that causes fragile skin that blisters easily, often triggered by minor injuries. These blisters are accompanied by intense itching, which can be distressing. The underlying cause of DDEB lies in genetic mutations in a gene called COL7A1. This gene encodes 'type VII collagen', a protein crucial for attaching the outer skin layer (epidermis) to the layer beneath (dermis). Although the genetic basis of DDEB is understood, the causes of itch are not known. As well as this, effective treatments for DDEB are lacking, which has driven scientists to explore innovative approaches like repurposing existing drugs. Drug repurposing involves using medications that have already been approved for other health conditions. One such drug is dupilumab, which is used for severe atopic dermatitis (eczema). Dupilumab targets immune cells called Th2 cells, which play a role in inflammation and allergies. While dupilumab has shown promise in relieving DDEB itching, the way it works in this condition is unclear. This study, carried out by a group of researchers in Taiwan, looked at gene expression in DDEB-affected and unaffected skin, and compared it to gene expression in healthy skin samples. We found heightened activity in Th2 immune cells and abnormal gene signals related to itching, similar to atopic dermatitis. These findings support using dupilumab and other anti-inflammatory drugs to alleviate itching in DDEB. Clinical trials will be crucial to evaluate the effectiveness of these drugs for managing DDEB symptoms. This research opens doors for enhanced treatment options and improving the quality of life of people living with DDEB.

Recombinant mannan-binding lectin magnetic beads increase pathogen detection in immunocompromised patients.

The microbiological diagnosis of infection for hematological malignancy patients receiving chemotherapy or allogeneic hematopoietic stem cell transplantation (allo-HSCT) patients relies primarily on standard microbial culture, especially blood culture, which has many shortcomings, such as having low positive rates, being time-consuming and having a limited pathogenic spectrum. In this prospective observational self-controlled test accuracy study, blood, cerebrospinal fluid (CSF), and bronchoalveolar lavage fluid (BALF) samples were collected from chemotherapy or allo-HSCT patients with clinical symptoms of infections who were hospitalized at Peking University First Hospital. Possible pathogens were detected by the method based on recombinant mannan-binding lectin (MBL) magnetic bead enrichment (M1 method) and simultaneously by a standard method. The analytical sensitivity of M1 method was close to that of standard culture method. Besides, the turn-around time of M1-method was significantly shorter than that of standard culture method. Moreover, the M1 method also added diagnostic value through the detection of some clinically relevant microbes missed by the standard method. M1 method could significantly increase the detection efficiency of pathogens (including bacteria and fungi) in immunocompromised patients. KEY POINTS: • The detection results of M1-method had a high coincidence rate with that of standard method • M1 method detected many pathogens which had not been found by standard clinic method.

Endothelial Mitochondria Transfer to Melanoma Induces M2-Type Macrophage Polarization and Promotes Tumor Growth by the Nrf2/HO-1-Mediated Pathway.

Gynecologic tract melanoma is a malignant tumor with poor prognosis. Because of the low survival rate and the lack of a standard treatment protocol related to this condition, the investigation of the mechanisms underlying melanoma progression is crucial to achieve advancements in the relevant gynecological surgery and treatment. Mitochondrial transfer between adjacent cells in the tumor microenvironment regulates tumor progression. This study investigated the effects of endothelial mitochondria on the growth of melanoma cells and the activation of specific signal transduction pathways following mitochondrial transplantation. Mitochondria were isolated from endothelial cells (ECs) and transplanted into B16F10 melanoma cells, resulting in the upregulation of proteins associated with tumor growth. Furthermore, enhanced antioxidation and mitochondrial homeostasis mediated by the Sirt1-PGC-1α-Nrf2-HO-1 pathway were observed, along with the inhibition of apoptotic protein caspase-3. Finally, the transplantation of endothelial mitochondria into B16F10 cells promoted tumor growth and increased M2-type macrophages through Nrf2/HO-1-mediated pathways in a xenograft animal model. In summary, the introduction of exogenous mitochondria from ECs into melanoma cells promoted tumor growth, indicating the role of mitochondrial transfer by stromal cells in modulating a tumor's phenotype. These results provide valuable insights into the role of mitochondrial transfer and provide potential targets for gynecological melanoma treatment.

Efficient Decoding of Compositional Structure in Holistic Representations.

We investigate the task of retrieving information from compositional distributed representations formed by hyperdimensional computing/vector symbolic architectures and present novel techniques that achieve new information rate bounds. First, we provide an overview of the decoding techniques that can be used to approach the retrieval task. The techniques are categorized into four groups. We then evaluate the considered techniques in several settings that involve, for example, inclusion of external noise and storage elements with reduced precision. In particular, we find that the decoding techniques from the sparse coding and compressed sensing literature (rarely used for hyperdimensional computing/vector symbolic architectures) are also well suited for decoding information from the compositional distributed representations. Combining these decoding techniques with interference cancellation ideas from communications improves previously reported bounds (Hersche et al., 2021) of the information rate of the distributed representations from 1.20 to 1.40 bits per dimension for smaller codebooks and from 0.60 to 1.26 bits per dimension for larger codebooks.

Validation of cardiac output estimation using the fourth-generation FloTrac/EV1000™ system in patients undergoing robotic-assisted off-pump coronary artery bypass surgery.

The pulmonary artery catheter (PAC)-despite its invasiveness-remains the gold standard for cardiac output (CO) monitoring. The FloTrac system, a less invasive hemodynamic monitor has been developed, which estimates CO using arterial pressure waveform analysis without external calibration. Recently, an upgraded version of FloTrac system with improved algorithm to follow changes in vascular resistance was introduced into the market. The aim of this study was to assess the reliability of the CO estimated from the fourth-generation FloTrac/EV1000 system (COFT) compared to that measured with PAC using the thermodilution method (COPAC) during robotic-assisted off-pump coronary artery bypass (OPCAB) surgery. COFT and COPAC were obtained simultaneously at 4 predefined time points during robotic-assisted OPCAB: 5 min after the induction of general anesthesia (T1), after starting one-lung ventilation (T2), after capnothorax (T3), and after mini-thoracotomy was performed (T4). The agreement of data was investigated by Bland-Altman analysis. Thirty-four patients were initially enrolled. After exclusion, 32 patients and a total of 128 paired CO measurements were obtained. The overall bias was 1.46 L/min, the 95% limits of agreements were - 3.40 to 6.33 L/min, and the percentage error was 72.98%. Regression analysis of the systemic vascular resistance index (SVRI) and the bias between COPAC and COFT showed that the bias was moderately correlated with the SVRI (r2 = 0.43; p < 0.0001). Despite a software upgrade, the reliability of the fourth-generation FloTrac/EV1000™ system during robotic-assisted OPCAB to estimate CO was not acceptable, especially in patients with low SVRI.

Digital oral health biomarkers for early detection of cognitive decline.

BACKGROUND: Oral health could influence cognitive function by stimulating brain activity and blood flow. The quantified oral status from oral inflammation, frailty and masticatory performance were rarely applied to the cognitive function screening. We aimed to adopt non-invasive digital biomarkers to quantify oral health and employ machine learning algorithms to detect cognitive decline in the community. METHODS: We conducted a prospective case-control study to recruit 196 participants between 50 and 80 years old from Puzi Hospital (Chiayi County, Taiwan) between December 01, 2021, and December 31, 2022, including 163 with normal cognitive function and 33 with cognitive decline. Demographics, daily interactions, electronically stored medical records, masticatory ability, plaque index, oral diadochokinesis (ODK), periodontal status, and digital oral health indicators were collected. Cognitive function was classified, and confirmed mild cognitive impairment diagnoses were used for sensitivity analysis. RESULTS: The cognitive decline group significantly differed in ODK rate (P = 0.003) and acidity from SILL-Ha (P = 0.04). Younger age, increased social interactions, fewer cariogenic bacteria, high leukocytes, and high buffering capacity led to lower risk of cognitive decline. Patients with slow ODK, high plaque index, variance of hue (VOH) from bicolor chewing gum, and acidity had increased risk of cognitive decline. The prediction model area under the curve was 0.86 and was 0.99 for the sensitivity analysis. CONCLUSIONS: A digital oral health biomarker approach is feasible for tracing cognitive function. When maintaining oral hygiene and oral health, cognitive status can be assessed simultaneously and early monitoring of cognitive status can prevent disease burden in the future.

Variation of body regional responses to Ustekinumab and Secukinumab in psoriasis patients: A real-world retrospective study and literature review.

Psoriasis in different body regions displays varying therapeutic responses to biologics, whereas currently relevant studies remain scarce. We retrospectively reviewed the treatment responses of patients with moderate-to-severe psoriasis, who completed the two-year reimbursed ustekinumab or secukinumab treatment in two medical centers in Southern Taiwan. Demographic profiles and body regional PASI scores (head/neck, trunk, upper and lower limbs) along the treatment course were recorded. The proportions of patients attaining PASI 75, 90, 100 and the extent of body regional PASI score improvements were compared in biologic naïve or experienced patients. A total of 57 and 67 patients receiving ustekinumab and secukinumab injections, respectively, were included. Overall, patients receiving secukinumab showed higher degrees of PASI score improvements along the two-year treatment course. The lower limbs had the highest, and the upper extremities and head/neck had the lowest post-treatment PASI scores regardless of prior biologic use in the groups of ustekinumab and secukinumab. The upper limbs showed the highest, while the lower limbs had the lowest complete remission rate (regional specific PASI 100) in response to ustekinumab (upper limbs 48.7%, lower limbs 25.6%) and secukinumab (upper limbs 77.1%, lower limbs 42.8%) in biologic naïve groups. Our study demonstrated that lower limbs were the most treatment-refractory area in response to ustekinumab and secukinumab injections, while the upper limbs and head/neck region had a better response.

Environmental and personal factors for osteoporosis or osteopenia from a large health check-up database: a retrospective cohort study in Taiwan.

BACKGROUND: Osteoporosis is an important public health issue in aging societies because of its associated morbidity, mortality, and decreased quality of life. The study aims to identify the association of low bone mineral density, including osteoporosis and osteopenia, with environmental and personal factors. METHODS: The data of participants aged ≥ 20 years with multiple visits were obtained from a health check-up database in Taiwan from 2008 to 2016. Multivariable logistic regressions were performed to identify the selected factors associated with low bone mineral density for multiple visit data. RESULTS: A total of 194,910 participants with 359,943 visits were included in this study. The prevalence of low bone mineral density (BMD) in the study population was 10.6% (n = 20.615). Older women, ever and current smokers (odds ratio (OR) = 1.04 [95% confidence interval (CI) = 1.01, 1.08]), or participants who were underweight (OR = 1.72 [1.64, 1.81]), consumed a vegetarian diet (OR = 1.32 [1.25, 1.39]), or had higher triglyceride levels (OR = 1.04 [1.01, 1.06]) were significantly associated with a higher risk of low BMD. Participants who had higher educational years (OR = 0.43 [0.41, 0.46]), higher physical activity (OR = 0.93 [0.89, 0.97]), appropriate sleep duration and better quality (OR = 0.98 [0.97, 0.99]), dairy intake (≥ 1 slice of yogurt or cheese/week, OR = 0.97 [0.95, 0.99]), higher uric acid (OR = 0.93 [0.91, 0.95]), higher walkability (OR = 0.997 [0.995,0.999]), and higher solar radiation exposure (OR = 0.997 [0.97,0.99]) were significantly associated with a lower risk of low BMD. CONCLUSION: Interventions in different directions, such as having better health behaviors, increasing sun exposure, and residing in a highly walkable environment, are beneficial for reducing the risk of low BMD.

Sonar Dome Geometry Design Using CFD to Reduce Ship Resistance at Cruise Speed.

The objective of this study is to design the hull-mounted sonar dome of a ship. The goal is to reduce the ship total resistance and improve the flow field around the sonar dome for the ship design speed. OpenFOAM 6 was applied to analyze the viscous flow around the ship bow and then optimize the sonar dome geometry. The length, width and depth of the original geometry were maintained. Only the local geometry was fine-tuned considering the back slope and front tip by using Rhinoceros 6. The verification and validation was performed for the original hull form against towing tank resistance data. The grid independence was checked for the optimal design in different design stages. To ensure less influence on the interior equipment installation and to be able to re-use the non-steel dome part, the best resistance reduction is almost 2%. With a larger allowance of shape deformation, the maximal reduction could reach slightly higher than 3%. The flow field is improved for smaller flow separation and vortex, and less fluid nose in sonar detection is expected. The main reason of the resistance reduction is the decrease of the pressure component. In conclusion, a sonar dome design procedure is proposed, and an optimal geometry is suggested.

Anti-Inflammatory Constituents of Antrodia camphorata on RAW 264.7 Cells Induced by Polyinosinic-Polycytidylic Acid.

Antrodia camphorata is an endemic mushroom in Taiwan. This study was designed to screen anti-inflammatory compounds from the methanolic extract of the mycelium of A. camphorata on nitric oxide (NO) production in RAW 264.7 cells induced by polyinosinic-polycytidylic acid (poly I:C), a synthetic analog of double-stranded RNA (dsRNA) known to be present in viral infection. A combination of bioactivity-guided isolation with an NMR-based identification led to the isolation of 4-acetylantroquinonol B (1), along with seven compounds. The structure of new compounds (4 and 5) was elucidated by spectroscopic experiments, including MS, IR, and NMR analysis. The anti-inflammatory activity of all isolated compounds was assessed at non-cytotoxic concentrations. 4-Acetylantroquinonol B (1) was the most potent compound against poly I:C-induced NO production in RAW 264.7 cells with an IC50 value of 0.57 ± 0.06 µM.

Effectiveness of 2 Pretreatment Methods in Antifogging of Goggles in a COVID-19 Isolation Ward: A Randomized Controlled Trial.

INTRODUCTION: This study aimed to compare the effectiveness of the pretreatment of goggles with iodophor solution and antibacterial hand sanitizer to reduce the fogging of goggles. METHODS: A total of 90 health care workers were divided into a control group (n = 30), an iodophor solution group (n = 30), and an antibacterial hand sanitizer group (n = 30). This study evaluated the degree of fogging of goggles and the light transmission, comfort, eye irritation, and the impact of goggles on the medical work of staff. RESULTS: The antibacterial hand sanitizer group had the lowest amount of goggle fogging and the most transparent view. Participants in the control group reported the worst light transmission and comfort level, followed by the iodophor solution group. In contrast, the goggles in the antibacterial hand sanitizer group had the best light transmission and comfort level. The iodophor solution group participants reported more eye irritation. Participants in the control group reported that the goggles severely impacted their medical work, with a less severe impact reported by the iodophor solution group. The antibacterial hand sanitizer group did not report any impact on their medical work. DISCUSSION: When the goggles were internally coated with antibacterial hand sanitizer solution (diluted 1:1 with distilled water), the antifog effect was significant. Moreover, the goggles treated with antibacterial hand sanitizer had a clearer field of vision, were reported as non-irritating to the eyes, and significantly improved the efficiency of COVID-19 health care workers, including emergency nurses and providers.

P2P Lending Default Prediction Based on AI and Statistical Models.

Peer-to-peer lending (P2P lending) has proliferated in recent years thanks to Fintech and big data advancements. However, P2P lending platforms are not tightly governed by relevant laws yet, as their development speed has far exceeded that of regulations. Therefore, P2P lending operations are still subject to risks. This paper proposes prediction models to mitigate the risks of default and asymmetric information on P2P lending platforms. Specifically, we designed sophisticated procedures to pre-process mass data extracted from Lending Club in 2018 Q3-2019 Q2. After that, three statistical models, namely, Logistic Regression, Bayesian Classifier, and Linear Discriminant Analysis (LDA), and five AI models, namely, Decision Tree, Random Forest, LightGBM, Artificial Neural Network (ANN), and Convolutional Neural Network (CNN), were utilized for data analysis. The loan statuses of Lending Club's customers were rationally classified. To evaluate the models, we adopted the confusion matrix series of metrics, AUC-ROC curve, Kolmogorov-Smirnov chart (KS), and Student's t-test. Empirical studies show that LightGBM produces the best performance and is 2.91% more accurate than the other models, resulting in a revenue improvement of nearly USD 24 million for Lending Club. Student's t-test proves that the differences between models are statistically significant.

Association between local spatial accessibility of dental care services and dental care quality.

BACKGROUND: The aim of our study was to evaluate the allocation of dental resources and explore access to dental care in Taiwan. In addition, we tried to understand the spatiotemporal characteristics of dental care quality and analyze the relationship between dental care quality and areas with deficiencies in dental resources. METHODS: The study used a two-step floating catchment area to calculate the dental resources accessibility and explore the spatiotemporal distributions of dental care quality. The association between dental care quality and spatial accessibility was analyzed using a spatial error model. RESULTS: Most areas with deficient dental resources and lower dental care quality were remote townships, agricultural towns, or aging towns with spatial clustering. The quality of children's preventive dental care had increased over time. Most highly urbanized areas had higher dental care quality. The quality of some dental care types such as children's preventive care and full-mouth calculous removal was associated with higher accessibility. CONCLUSIONS: Understanding the spatiotemporal distribution of both dental care accessibility and quality can assist in allocation of dental care resources. Adequate dental resources may elevate dental care quality. Suggestions include policies to balance dental resources and routinely monitor improvement in areas with deficient dental care.

Plectin Missense Mutation p.Leu319Pro in the Pathogenesis of Autosomal Recessive Epidermolysis Bullosa Simplex.

is missing (Short communication).

Cytotoxic and Anti-inflammatory Terpenoids from the Whole Plant of Vaccinium emarginatum.

Two new Δ12 ursene-type triterpenoid coumaroyl esters (1: and 2: ), one new Δ7,15 isopimarane-type diterpenoid glycoside (20: ), and two new irido-δ-lactone-type iridoids (21: and 22: ), together with 17 known pentacyclic triterpenoids (3:  - 19: ), were isolated during the phytochemical investigation of a methanol extract of the whole plant of Vaccinium emarginatum. Their structures were determined by detailed analysis of standard spectroscopic data (MS, IR, 1D, and 2D NMR) and comparison with data of known analogs. The isolates were evaluated for their cytotoxicity against the PC-3 and Du145 prostate cancer cell lines (as assessed by an MTT cell proliferation assay), as well as for their anti-inflammatory activity via the inhibition of nitric oxide production in lipopolysaccharide-induced murine macrophage RAW 264.7 cells. Among the isolates, the triterpenoid coumaroyl and feruloyl esters (1, 3: , and 4: ) exhibited strong cytotoxicity against PC-3 prostate cancer cells, with 85.6 - 90.2% inhibition at 10.0 µg/mL. The pomolic acid coumaroyl and feruloyl esters (1: and 3: ) also showed moderate anti-inflammatory activity against nitric oxide production in lipopolysaccharide-induced RAW 264.7 cells, with 59.2 (± 1.0) and 47.1% (± 0.2) inhibition at 12.5 µg/mL, respectively.

Correction to: 4-Phenylbutyric acid protects against vasculitic peripheral neuropathy induced by ischaemia-reperfusion through attenuating endoplasmic reticulum stress.

Unfortunately, Fig. 5 was incorrectly published in the original publication. The complete corrected Fig. 5 is given below.

Association between periodontitis and all-cause and cancer mortality: retrospective elderly community cohort study.

BACKGROUND: Periodontal infection induces inflammation, which may increase the risk of tumor-promoting effects. The aim of this study was to assess the association between periodontitis and all-cause mortality, and all-cancer and specific cancers' mortality in a health examination cohort of the elderly in the communities. METHODS: A dataset of health examinations for the elderly with cause of death from 2005 to 2012 was obtained from the Department of Health, Taipei City Government. We enrolled 82,548 study participants with 262,035 visits. A Cox proportional hazards model and Cox frailty model were used for calculating the hazard ratios under different periodontal status by using SAS and Rstudio. RESULTS: Being male, elderly, having a low education level, and smoking were risk factors for mortality in this retrospective elderly community cohort study. Participants with periodontitis followed across time had significantly higher hazard ratios (HRs) for all-cause mortality and all-cancer mortality (HR = 1.092, 95% confidence interval (CI):1.038 to 1.149, HR = 1.114, 95% CI:1.032 to 1.203, respectively) in the Cox frailty models after adjusting for age, marital status, education level, sex, and smoking status. After adjusting for age and sex, the hazard ratio was 1.185 (95% CI: 1.027 to 1.368) for lung cancer mortality, and 1.340 (95% CI: 1.019 to 1.762) for prostate cancer mortality in the periodontitis group with each visit. CONCLUSIONS: The findings indicated that being male, having a low education level, and daily smoking were risk factors for mortality, and showed mixed evidence that periodontal disease is associated with all-cause, all-cancer and specific-cancer mortality including lung and prostate cancer. We suggest the importance of regular health screening in order to achieve early disease detection and lower mortality risk.

Serum soluble lymphocyte activation gene-3 as a diagnostic biomarker in Parkinson's disease: A pilot multicenter study.

OBJECTIVE: Lymphocyte activation gene-3 (LAG-3) could mediate pathological α-synuclein transmission in neurodegeneration and may be involved in the pathogenesis of Parkinson's disease (PD). The aim of the present study was to explore soluble LAG-3 (sLAG-3) as a potential diagnostic biomarker for PD. METHODS: Serum sLAG-3 concentrations were measured by a quantitative ELISA for patients with PD, essential tremor (ET) and age- and sex-matched controls. The relationships between sLAG-3 and clinical phenotype were assessed via correlation analysis and logistic regression. RESULTS: Serum sLAG-3 levels in patients with PD were significantly higher than those in ET patients and age- and sex-matched controls. The area under the curve of serum sLAG-3 in differentiating PD from age- and sex-matched controls was 0.82. Serum sLAG-3 was associated with non-motor symptoms and excessive daytime sleep. CONCLUSION: sLAG-3 is a candidate novel biomarker for PD. © 2018 International Parkinson and Movement Disorder Society.