Predicting Outcome of Patients With Cerebral Hemorrhage Using a Computed Tomography-Based Interpretable Radiomics Model: A Multicenter Study.

OBJECTIVE: The aim of this study was to develop and validate an interpretable and highly generalizable multimodal radiomics model for predicting the prognosis of patients with cerebral hemorrhage. METHODS: This retrospective study involved 237 patients with cerebral hemorrhage from 3 medical centers, of which a training cohort of 186 patients (medical center 1) was selected and 51 patients from medical center 2 and medical center 3 were used as an external testing cohort. A total of 1762 radiomics features were extracted from nonenhanced computed tomography using Pyradiomics, and the relevant macroscopic imaging features and clinical factors were evaluated by 2 experienced radiologists. A radiomics model was established based on radiomics features using the random forest algorithm, and a radiomics-clinical model was further trained by combining radiomics features, clinical factors, and macroscopic imaging features. The performance of the models was evaluated using area under the curve (AUC), sensitivity, specificity, and calibration curves. Additionally, a novel SHAP (SHAPley Additive exPlanations) method was used to provide quantitative interpretability analysis for the optimal model. RESULTS: The radiomics-clinical model demonstrated superior predictive performance overall, with an AUC of 0.88 (95% confidence interval, 0.76-0.95; P < 0.01). Compared with the radiomics model (AUC, 0.85; 95% confidence interval, 0.72-0.94; P < 0.01), there was a 0.03 improvement in AUC. Furthermore, SHAP analysis revealed that the fusion features, rad score and clinical rad score, made significant contributions to the model's decision-making process. CONCLUSION: Both proposed prognostic models for cerebral hemorrhage demonstrated high predictive levels, and the addition of macroscopic imaging features effectively improved the prognostic ability of the radiomics-clinical model. The radiomics-clinical model provides a higher level of predictive performance and model decision-making basis for the risk prognosis of cerebral hemorrhage.

Chromatin remodeling complexes are involvesd in the regulation of ethanol production during static fermentation in budding yeast.

The budding yeast Saccharomyces cerevisiae remains a central position among biofuel-producing organisms. However, the gene expression regulatory networks behind the ethanol fermentation is still not fully understood. Using a static fermentation model, we have examined the ethanol yields on biomass of deletion mutants for all yeast nonessential genes encoding transcription factors and their related proteins in the yeast genome. A total of 20 (about 10%) transcription factors are identified to be regulators of ethanol production during fermentation. These transcription factors are mainly involved in cell cycling, chromatin remodeling, transcription, stress response, protein synthesis and lipid synthesis. Our data provides a basis for further understanding mechanisms regulating ethanol production in budding yeast.

The pH-sensing Rim101 pathway positively regulates the transcriptional expression of the calcium pump gene PMR1 to affect calcium sensitivity in budding yeast.

In Saccharomyces cerevisiae, the Rim101 pathway senses extracellular pH changes through a complex consisted of Rim8, Rim9 and Rim21 at the plasma membrane. Activation of this sensor complex induces a proteolytical complex composed of Rim13 and Rim20 and leads to the C-terminal processing and activation of the transcription factor Rim101. Deletion mutants for RIM8, RIM9, RIM13, RIM20, RIM21 and RIM101 causes yeast cells to be sensitive to calcium stress, but how they regulate calcium sensitivity remain unknown. Here we show that deletion mutations of these six Rim101 pathway components elevate the activation level of the calcium/calcineurin signaling and the transcriptional expression level of the vacuolar calcium pump gene PMC1, but lead to a reduction in transcriptional expression level of the ER/Golgi calcium pump gene PMR1 in yeast cells. Deletion of NRG1, encoding one of the repression targets of Rim101, rescues the transcriptional expression of PMR1 in all these mutants. Furthermore, ectopic expression of a constitutively active form of Rim101 or further deletion of NRG1 suppresses the calcium sensitivity of these six deletion mutants. Therefore, the pH-sensing Rim101 pathway positively regulates the transcriptional expression of PMR through its downstream target Nrg1 to affect the calcium sensitivity of yeast cells.

RNA sequencing reveals an additional Crz1-binding motif in promoters of its target genes in the human fungal pathogen Candida albicans.

BACKGROUND: The calcium/calcineurin signaling pathway is mediated by the transcription factors NFAT (nuclear factor of activated T cells) in mammals and Crz1 (calcineurin-responsive zinc finger 1) in yeasts and other lower eukaryotes. A previous microarray analysis identified a putative Crz1-binding motif in promoters of its target genes in Candida albicans, but it has not been experimentally demonstrated. METHODS: An inactivation mutant for CaCRZ1 was generated through CRISPR/Cas9 approach. Transcript profiling was carried out by RNA sequencing of the wild type and the inactivation mutant for CaCRZ1 in response to 0.2 M CaCl2. Gene promoters were scanned by the online MEME (Multiple Em for Motif Elicitation) software. Gel electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) analysis were used for in vitro and in vivo CaCrz1-binding experiments, respectively. RESULTS: RNA sequencing reveals that expression of 219 genes is positively, and expression of 59 genes is negatively, controlled by CaCrz1 in response to calcium stress. These genes function in metabolism, cell cycling, protein fate, cellular transport, signal transduction, transcription, and cell wall biogenesis. Forty of these positively regulated 219 genes have previously been identified by DNA microarray analysis. Promoter analysis of these common 40 genes reveals a consensus motif [5'-GGAGGC(G/A)C(T/A)G-3'], which is different from the putative CaCrz1-binding motif [5'-G(C/T)GGT-3'] identified in the previous study, but similar to Saccharomyces cerevisiae ScCrz1-binding motif [5'-GNGGC(G/T)CA-3']. EMSA and ChIP assays indicate that CaCrz1 binds in vitro and in vivo to both motifs in the promoter of its target gene CaUTR2. Promoter mutagenesis demonstrates that these two CaCrz1-binding motifs play additive roles in the regulation of CaUTR2 expression. In addition, the CaCRZ1 gene is positively regulated by CaCrz1. CaCrz1 can bind in vitro and in vivo to its own promoter, suggesting an autoregulatory mechanism for CaCRZ1 expression. CONCLUSIONS: CaCrz1 differentially binds to promoters of its target genes to regulate their expression in response to calcium stress. CaCrz1 also regulates its own expression through the 5'-TGAGGGACTG-3' site in its promoter. Video abstract.

The protein kinase Cmk2 negatively regulates the calcium/calcineurin signalling pathway and expression of calcium pump genes PMR1 and PMC1 in budding yeast.

Through a genome-wide screen we have identified calcium-tolerant deletion mutants for five genes in the budding yeast Saccharomyces cerevisiae. In addition to CNB1 and RCN1 that are known to play a role in the calcium signalling pathway, the protein kinase gene CMK2, the sphingolipid homeostasis-related gene ORM2 and the gene SIF2 encoding the WD40 repeat-containing subunit of Set3C histone deacetylase complex are involved in the calcium sensitivity of yeast cells to extracellular calcium. Cmk2 and the transcription factor Crz1 have opposite functions in the response of yeast cells to calcium stress. Deletion of CMK2 elevates the level of calcium/calcineurin signalling and increases the expression level of PMR1 and PMC1, which is dependent on Crz1. Effects of Cmk2 on calcium sensitivity and calcium/calcineurin signalling are dependent on its kinase activity. Therefore, Cmk2 is a negative feedback controller of the calcium/calcineurin signalling pathway. Furthermore, the cmk2 crz1 double deletion mutant is more resistant than the crz1 deletion mutant, suggesting that Cmk2 has an additional Crz1-independent role in promoting calcium tolerance.

The plasma membrane protein Rch1 and the Golgi/ER calcium pump Pmr1 have an additive effect on filamentation in Candida albicans.

Pmr1 is the Golgi/ER calcium pump, while Rch1 is a newly identified negative regulator of calcium influx in the plasma membrane of yeast cells. We show here that CaRch1 plays a dominant role over CaPmr1 in response of Candida albicans to SDS and tunicamycin stresses, while CaPmr1 has a major role in cell wall stress. Deletion of CaRCH1 increases the calcium/calcineurin signaling level in cells lacking CaPMR1. Calcineurin function is required for the role of CaRch1 in SDS stresses, while it is required for the function of CaPmr1 under all conditions examined. Disruption of CaRCH1 alone does not reduce the cell wall chitin, mannan or ß-glucan content, but lack of CaRCH1 slightly decreases the chitin content of cells lacking CaPMR1. Furthermore, CaRch1 and CaPmr1 have an additive effect on filamentation of C. albicans cells in vitro. Cells lacking both CaRCH1 and CaPMR1 and cells lacking CaPMR1 alone show a similar degree of virulence attenuation, being much more attenuated than cells lacking CaRCH1 alone. Therefore, CaRch1 genetically interacts with CaPmr1 in the regulation of in vitro filamentation in C. albicans.

Affect and stress detection based on feature fusion of LSTM and 1DCNN.

The impact of emotions on health, especially stress, is receiving increasing attention. It is important to provide a non-invasive affect detection system that can be continuously monitored for a long period of time. Multi-sensor fusion strategies can better improve the performance of affect detection models, but there are also problems such as insufficient feature extraction and poor spatiotemporal feature fusion. Therefore, this study proposes a feature-level fusion method based on long short-term memory and one-dimensional convolutional neural network to extract temporal and spatial features of electrocardiogram, electromyogram, electrical activity, temperature, accelerator and response data, respectively, and then fuse them in a summation fashion for affect and stress detection. In particular, we added the tanh activation function before feature fusion, which can improve the model's performance. We used the wearable affect and stress detection dataset to train the model, which includes three different emotion states (neutral, stress, and amusement) for three-class emotion classification with accuracy and F1-scores of 87.82% and 86.68%, respectively. Due to the importance of stress, we also studied binary classification for stress detection, where neutral and amusement were combined as non-stress, with accuracy and F1-scores of 94.9% and 94.98%, respectively. The performance of the proposed model outperforms other control models and can effectively improve the performance of affect and stress detection, and promote medical care, health care and elderly care.

Zinc and Central Nervous System Disorders.

Zinc (Zn2+) is the second most abundant necessary trace element in the human body, exerting a critical role in many physiological processes such as cellular proliferation, transcription, apoptosis, growth, immunity, and wound healing. It is an essential catalyst ion for many enzymes and transcription factors. The maintenance of Zn2+ homeostasis is essential for the central nervous system, in which Zn2+ is abundantly distributed and accumulates in presynaptic vesicles. Synaptic Zn2+ is necessary for neural transmission, playing a pivotal role in neurogenesis, cognition, memory, and learning. Emerging data suggest that disruption of Zn2+ homeostasis is associated with several central nervous system disorders including Alzheimer's disease, depression, Parkinson's disease, multiple sclerosis, schizophrenia, epilepsy, and traumatic brain injury. Here, we reviewed the correlation between Zn2+ and these central nervous system disorders. The potential mechanisms were also included. We hope that this review can provide new clues for the prevention and treatment of nervous system disorders.

[Incidence of comorbidities in hospitalized chronic obstructive pulmonary disease patients and correlated risk factors].

OBJECTIVE: To explore the incidence of comorbidities in hospitalized chronic obstructive pulmonary disease (COPD) patients and influencing factors. METHODS: A retrospective review of medical records was performed for 495 hospitalized COPD patients in Peking University Third Hospital from January 2003 to December 2008. Their comorbidities were identified and ranked in prevalence. The risk factors of comorbidities were analyzed by multivariable Logistic regression. RESULTS: The most frequent comorbidities were: hypertension (60.0%), ischemic heart disease (16.0%), malignant tumor (10.9%), diabetes mellitus (10.5%), chronic heart failure (9.9%) and dyslipidemia (9.9%). The percentage of patients with ischemic heart disease in people with FEV(1)% Pred < 30%, 30% ≤ FEV(1)%Pred < 50%, 50% ≤ FEV(1)%Pred < 80% and FEV(1)%Pred ≥ 80% were 9.2%, 12.7%, 21.3% and 16.5% respectively (P = 0.052). The percentage of patients with dyslipidemia in people with FEV(1)%Pred < 30%, 30% ≤ FEV(1)%Pred < 50%, 50% ≤ FEV(1)%Pred < 80%, FEV(1)%Pred ≥ 80% were 5.3%, 5.7%, 10.9% and 20.3% respectively (P = 0.002). The percentage of patients with ischemic heart disease in people with body mass index (BMI) < 18.5, 18.5 - 23.9, 24.0 - 27.9, ≥ 28.0 kg/m(2) were 13.6%, 14.2%, 14.6% and 28.3% respectively (P = 0.051). The percentage of patients with dyslipidemia in people with BMI < 18.5, 18.5 - 23.9, 24.0 - 27.9, ≥ 28.0 kg/m(2) were 5.5%, 5.7%, 14.6% and 25.0% respectively (P = 0.000). The levels of C-reactive protein (CRP) were higher than the 75(th) percentile (OR = 2.371, P = 0.014), and complications with metabolic syndrome (OR = 2.694, P = 0.003) were independent risk factors of ischemic heart disease in COPD patients. CONCLUSIONS: The incidence of comorbidities varies in different COPD populations. Higher levels of CRP and complications with metabolic syndrome are independent risk factors of ischemic heart disease in COPD patients.

Pan-cancer analysis of cuproptosis regulation patterns and identification of mTOR-target responder in clear cell renal cell carcinoma.

BACKGROUND: The mechanism of cuproptosis, a novel copper-induced cell death by regulating tricarboxylic acid cycle (TCA)-related genes, has been reported to regulate oxidative phosphorylation system (OXPHOS) in cancers and can be regarded as potential therapeutic strategies in cancer; however, the characteristics of cuproptosis in pan-cancer have not been elucidated. METHODS: The multi-omics data of The Cancer Genome Atlas were used to evaluate the cuproptosis-associated characteristics across 32 tumor types. A cuproptosis enrichment score (CEScore) was established using a single sample gene enrichment analysis (ssGSEA) in pan-cancer. Spearman correlation analysis was used to identify pathway most associated with CEScore. Lasso-Cox regression was used to screen prognostic genes associated with OXPHOS and further construct a cuproptosis-related prognostic model in clear cell renal cell carcinoma (ccRCC). RESULTS: We revealed that most cuproptosis-related genes (CRGs) were differentially expressed between tumors and normal tissues, and somatic copy number alterations contributed to their aberrant expression. We established a CEScore index to indicate cuproptosis status which was associated with prognosis in most cancers. The CEScore was negatively correlated with OXPHOS and significantly featured prognosis in ccRCC. The ccRCC patients with high-risk scores show worse survival outcomes and bad clinical benefits of Everolimus (mTOR inhibitor). CONCLUSIONS: Our findings indicate the importance of abnormal CRGs expression in cancers. In addition, identified several prognostic CRGs as potential markers for prognostic distinction and drug response in the specific tumor. These results accelerate the understanding of copper-induced death in tumor progression and provide cuproptosis-associated novel therapeutic strategies.

Stretchable, conductive, breathable and moisture-sensitive e-skin based on CNTs/graphene/GelMA mat for wound monitoring.

Deep skin wound needs a long wound healing process, in which external force on skin around wound can result in a sharp pain, wound re-damage and interstitial fluid flowing out, increasing the risk of deterioration and even amputation. While the conventional wound dressings cannot provide timely feedback of abnormal wound status and lose best time for wound treatment, real-time monitoring wound status is thus urgently needed for wound management. In this work, a breathable and stretchable electronic skin (i.e., e-skin) named CNTs/graphene/GelMA mat has been developed through electrospinning, ice-templating and in-situ loading method for evaluating wound status. The obtained porosity, swelling ratio and vapor transmission rate of the CNTs/graphene/GelMA mat are 55 %, 180 % and 3378.2 h-1 day-1, respectively. And owing to the good porous, nanofibrous architecture and excellent breathability of the mat, L929 cells grow and well spread on the CNTs/graphene/GelMA mat. In addition, the gauge factors of the prepared conductive CNTs/graphene/GelMA mat as a strain sensor are 15.4 and 72.9 in the strain ranges of 0-70 % and 70-85 %, respectively, matching the mechanical performance of human skin. The sensitivity coefficient of the mat for moisture sensing is 12.05, indicating its high efficiency for monitoring and warning interstitial fluid outflow from wound. Furthermore, the integration of CNTs/graphene/GelMA mat with a portable device is feasible to monitor strain and moisture on a rat model with abdominal wound. The healing process of the wounds treated with CNTs/graphene/GelMA mat is similar to that of GelMA mat, indicating that the dosage of CNTs and graphene in the CNTs/graphene/GelMA mat has negligible effect on the mat histocompatibility. The CNTs/graphene/GelMA mat demonstrates the application potential in wound management, home medical diagnosis and human-machine interactions.

[Causes of chronic obstructive pulmonary disease-related death and influencing factors of survival time].

OBJECTIVE: To study the causes of chronic obstructive pulmonary disease (COPD)-related death and influencing factors of survival time from first hospitalization due to acute exacerbation of chronic obstructive pulmonary disease (AECOPD). METHODS: All patients with a primary or secondary diagnosis of COPD (International Classification of Diseases (ICD)-10 Codes J40-J47) were continuously enrolled at our hospital from January 2006 to December 2008. A retrospective review was performed on the medical records of COPD patients who died during hospitalization. The causes of death were coded and analyzed according to the International Classification of Diseases (ICD)-10. The underlying causes of death were identified and ranked in order of prevalence. The medical records of first hospitalization due to AECOPD were reviewed. Retrospective analysis was performed for the clinical data. And Cox regression analysis was used to select the independent risk factors of influencing the survival time. RESULTS: Sixty-seven patients died during hospitalization. The median FEV(1) (forced expiratory volume in 1 second percentage) was 34%. The causes of death in the COPD inpatients were as follows: respiratory diseases (n = 39), cardio-cerebrovascular diseases (n = 16), malignant tumors (n = 10), diabetes mellitus (n = 1) and suicide (n = 1). Among them, 54 patients had a history of hospitalization due to AECOPD. Thirteen deceased patients were never hospitalized because of AECOPD. The mean interval between the first admission with AECOPD as the primary diagnosis and death was 38 months (range: 1 - 159). The independent risk factors of influencing the survival time were as follows: complications with coronary artery disease & severe pulmonary hypertension, age, body mass index (BMI) and serum level of C-reactive protein (CRP) (all P < 0.05). CONCLUSION: The major cause of death in moderate-severe COPD patients is respiratory disease. complicated with coronary artery disease & severe pulmonary hypertension, age, BMI and serum level of CRP are the independent risk factors of affecting the survival time from first hospitalization due to AECOPD.

A Colorimetric Dermal Tattoo Biosensor Fabricated by Microneedle Patch for Multiplexed Detection of Health-Related Biomarkers.

Detection of biomarkers associated with body conditions provides in-depth healthcare information and benefits to disease management, where the key challenge is to develop a minimally invasive platform with the ability to directly detect multiple biomarkers in body fluid. Dermal tattoo biosensor holds the potential to simultaneously detect multiple health-related biomarkers in skin interstitial fluid because of the features of minimal invasion, easy operation, and equipment-free result reading. Herein, a colorimetric dermal tattoo biosensor fabricated by a four-area segmented microneedle patch is developed for multiplexed detection of health-related biomarkers. The biosensor exhibits color changes in response to the change of biomarker concentration (i.e., pH, glucose, uric acid, and temperature), which can be directly read by naked eyes or captured by a camera for semi-quantitative measurement. It is demonstrated that the colorimetric dermal tattoo biosensor can simultaneously detect multiple biomarkers in vitro, ex vivo, and in vivo, and monitor the changes of the biomarker concentration for at least 4 days, showing its great potential for long-term health monitoring.

Smart Glove Integrated with Tunable MWNTs/PDMS Fibers Made of a One-Step Extrusion Method for Finger Dexterity, Gesture, and Temperature Recognition.

Flexible wearable devices have proven to be emerging tools for motion monitoring, personal healthcare, and rehabilitation training. The development of a multifunctional, flexible sensor and the integration of sensors and a smart chip for signal reading and transmission play a critical role in building a smart wearable device. In this work, a smart glove based on multiwalled carbon nanotubes/poly(dimethylsiloxane) (MWNTs/PDMS) fibers is developed for gesture and temperature recognition. First, the well-tunable, stretchable, and thermal-sensitive MWNTs/PDMS fibers are fabricated via a facile and cost-effective one-step extrusion method. The obtained fibers exhibit an outstanding linear relationship between resistance change and strain in the range of 0-120% and excellent cyclic stability and durability after 20 000 cycles of 50% tension. They also present a linear relationship of resistance change and temperature of 0.55% °C-1 with a correlation coefficient of 0.998 in the range of 0-100 °C. The fibers, as parts of wearable sensors, are then integrated into a smart glove along with a custom-made data acquisition chip to recognize finger dexterity, gestures, and temperature signals and output them through a screen display, an audio system, and Bluetooth transmission. The highly integrated, low-cost, and multifunctional glove holds great potential for various applications, such as sign language recognition, rehabilitation training, and telemedicine in the Internet-of-Things era.

Disruption of ergosterol and tryptophan biosynthesis, as well as cell wall integrity pathway and the intracellular pH homeostasis, lead to mono-(2-ethylhexyl)-phthalate toxicity in budding yeast.

Endocrine disrupting chemicals (EDCs) are substances in the environment, food, and consumer products that interfere with hormone homeostasis, metabolism or reproduction in humans and animals. One such EDC, the plasticizer di-(2-ethylhexyl)-phthalate (DEHP), exerts its function through its principal bioactive metabolite, mono-(2-ethylhexyl)-phthalate (MEHP). To fully understand the effects of MEHP on cellular processes and metabolism as well as to assess the impact of genetic alteration on the susceptibility to MEHP-induced toxicity, we screened MEHP-sensitive mutations on a genome-scale in the eukaryotic model organism Saccharomyces cerevisiae. We identified a total of 96 chemical-genetic interactions between MEHP and gene mutations in this study. In response to MEHP treatment, most of these gene mutants accumulated higher intracellular MEHP content, which correlated with their MEHP sensitivity. Twenty-seven of these genes are involved in the metabolism, twenty-two of them play roles in protein sorting, and ten of them regulate ion homeostasis. Functional categorization of these genes indicated that the biosynthetic pathways of both ergosterol and tryptophan, as well as cell wall integrity and the intracellular pH homeostasis, were involved in the protective response of yeast cells to the MEHP toxicity. Our study demonstrated that a collection of yeast gene deletion mutants is useful for a functional toxicogenomic analysis of EDCs, which could provide important clues to the effects of EDCs on higher eukaryotic organisms.