VIPpred: a novel model for predicting variant impact on phosphorylation events driving carcinogenesis.

Disrupted protein phosphorylation due to genetic variation is a widespread phenomenon that triggers oncogenic transformation of healthy cells. However, few relevant phosphorylation disruption events have been verified due to limited biological experimental methods. Because of the lack of reliable benchmark datasets, current bioinformatics methods primarily use sequence-based traits to study variant impact on phosphorylation (VIP). Here, we increased the number of experimentally supported VIP events from less than 30 to 740 by manually curating and reanalyzing multi-omics data from 916 patients provided by the Clinical Proteomic Tumor Analysis Consortium. To predict VIP events in cancer cells, we developed VIPpred, a machine learning method characterized by multidimensional features that exhibits robust performance across different cancer types. Our method provided a pan-cancer landscape of VIP events, which are enriched in cancer-related pathways and cancer driver genes. We found that variant-induced increases in phosphorylation events tend to inhibit the protein degradation of oncogenes and promote tumor suppressor protein degradation. Our work provides new insights into phosphorylation-related cancer biology as well as novel avenues for precision therapy.

PhaSepDB in 2022: annotating phase separation-related proteins with droplet states, co-phase separation partners and other experimental information.

Phase separation (PS) proteins form droplets to regulate myriad membraneless organelles (MLOs) and cellular pathways such as transcription, signaling transduction and protein degeneration. PS droplets are usually liquid-like and can convert to hydrogel/solid-like under certain conditions. The PS behavior of proteins is regulated by co-PS partners and mutations, modifications, oligomerizations, repeat regions and alternative splicing of the proteins. With growing interest in PS condensates and associated proteins, we established PhaSepDB 1.0, which provided experimentally verified PS proteins and MLO-related proteins. The past few years witnessed a surge in PS-related research works; thus, we kept updating PhaSepDB. The current PhaSepDB contains 1419 PS entries, 770 low-throughput MLO-related entries and 7303 high-throughput MLO-related entries. We provided more detailed annotations of PS proteins, including PS verification experiments, regions used in experiments, phase diagrams of different experimental conditions, droplet states, co-PS partners and PS regulatory information. We believe that researchers can go further in studying PS proteins with the updated PhaSepDB (http://db.phasep.pro/).

Screening membraneless organelle participants with machine-learning models that integrate multimodal features.

Protein self-assembly is one of the formation mechanisms of biomolecular condensates. However, most phase-separating systems (PS) demand multiple partners in biological conditions. In this study, we divided PS proteins into two groups according to the mechanism by which they undergo PS: PS-Self proteins can self-assemble spontaneously to form droplets, while PS-Part proteins interact with partners to undergo PS. Analysis of the amino acid composition revealed differences in the sequence pattern between the two protein groups. Existing PS predictors, when evaluated on two test protein sets, preferentially predicted self-assembling proteins. Thus, a comprehensive predictor is required. Herein, we propose that properties other than sequence composition can provide crucial information in screening PS proteins. By incorporating phosphorylation frequencies and immunofluorescence image-based droplet-forming propensity with other PS-related features, we built two independent machine-learning models to separately predict the two protein categories. Results of independent testing suggested the superiority of integrating multimodal features. We performed experimental verification on the top-scored proteins DHX9, Ki-67, and NIFK. Their PS behavior in vitro revealed the effectiveness of our models in PS prediction. Further validation on the proteome of membraneless organelles confirmed the ability of our models to identify PS-Part proteins. We implemented a web server named PhaSePred (http://predict.phasep.pro/) that incorporates our two models together with representative PS predictors. PhaSePred displays proteome-level quantiles of different features, thus profiling PS propensity and providing crucial information for identification of candidate proteins.

Mesencephalic astrocyte-derived neurotrophic factor ameliorates inflammatory response in polycystic ovary syndrome via inhibiting TLR4-NF-κB-NLRP3 pathway.

Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder in women of reproductive age, which often leads to female infertility. Chronic inflammation is a significant factor in the development of PCOS. Our study aimed to explore the impact of mesencephalic astrocyte-derived neurotrophic factor (MANF), a scientifically validated anti-inflammatory factor, on 99 diagnosed PCOS patients. We also investigated its effects on PCOS mice induced with dehydroepiandrosterone (DHEA) and KGN cells induced with dihydrotestosterone (DHT). Our findings revealed a decrease in serum MANF levels in PCOS patients, which were negatively associated with serum tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) levels. The administration of recombinant human MANF (rhMANF) in PCOS mice demonstrated a decrease in pro-inflammatory cytokines and monocytes/macrophages in both peripheral blood and ovarian tissues. Furthermore, the inclusion of rhMANF notably ameliorated DHEA-induced ovarian dysfunction and fibrosis by negatively regulating the toll-like receptor 4 (TLR4)-nuclear factor kappa B (NF-κB)-NLR family, pyrin domain containing protein 3 (NLRP3) pathway. Additionally, in vitro experiments showed that the up-regulation of MANF offset DHT-induced inhibition of viability and apoptosis in KGN cells. Collectively, this study highlights the anti-inflammatory properties of MANF in PCOS and suggests its potential as a therapeutic approach for the management of PCOS.

Protective effects of curcumin on corneal endothelial cell PANoptosis and monocyte adhesion induced by tumor necrosis factor-alpha and interferon-gamma in rats.

Decrease of human corneal endothelial cell (CEC) density leads to corneal edema, progressive corneal opacity, and reduced visual acuity. A reduction in CEC density may be related to elevated levels of inflammatory cytokines, such as tumor necrosis factor (TNF)-α and interferon (INF)-γ. PANoptosis, characterized by the activation of apoptosis, necroptosis, and pyroptosis, could be a factor in the loss of CECs driven by TNF-α and INF-γ. Cytokines also stimulate monocytes adhesion to endothelium. It has been shown in previous research that curcumin plays protective roles against numerous corneal inflammatory diseases. However, it is not determined whether curcumin acts as an anti-PANoptotic agent or if it mitigates monocyte adhesion to CECs. Therefore, this research aimed to explor the potential therapeutic effects of curcumin and its underlying mechanisms in the loss of CECs. CEC injury models were established, and curcumin was injected subconjunctivally. Clinical evaluation of the corneas was conducted using a scoring system and anterior segment photography. Corneal observation was performed with hematoxylin and eosin staining and immunostaining of zona occludens-1(ZO-1). Apoptotic cells within the corneal endothelium were observed using TUNEL staining. The detection of primary proteins expression was accomplished through Western blot analysis. Interleukin (IL)-1ß and macrophage chemotactic protein 1 (MCP-1) levels were determined via ELISA, while the expression of cleaved caspase-3, gasdermin-D (GSDMD), phosphor-mixed lineage kinase domain-like protein (p-MLKL) and intercellular cell adhesion molecule-1 were confirmed by immunofluorescence. Myeloperoxidase (MPO) activity was measured in aqueous humors. Curcumin treatment attenuated the loss of CECs and corneal edema caused by TNF-α and IFN-γ. Besides, it decreased the count of TUNEL-positive cells, and inhibited the upregulation of cleaved caspase-3, cleaved caspase-6, cleaved caspase-7, and cleaved poly (ADP-ribose) polymerase. Moreover, both the expression and phosphorylation of MLKL and receptor-interacting protein 3 were decreased in curcumin-treated rats. Furthermore, curcumin also lowered the expression of cleaved caspase-1, diminished the levels of IL1ß and MCP-1, and inhibited the activity of MPO. Besides, the expression of intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1, as well as the number of CD11b-positive cells adhered to the CECs decreased for the administration of curcumin.

Collective effects of rising average temperatures and heat events on oviparous embryos.

Survival of the immobile embryo in response to rising temperature is important to determine a species' vulnerability to climate change. However, the collective effects of 2 key thermal characteristics associated with climate change (i.e., rising average temperature and acute heat events) on embryonic survival remain largely unexplored. We used empirical measurements and niche modeling to investigate how chronic and acute heat stress independently and collectively influence the embryonic survival of lizards across latitudes. We collected and bred lizards from 5 latitudes and incubated their eggs across a range of temperatures to quantify population-specific responses to chronic and acute heat stress. Using an embryonic development model parameterized with measured embryonic heat tolerances, we further identified a collective impact of embryonic chronic and acute heat tolerances on embryonic survival. We also incorporated embryonic chronic and acute heat tolerance in hybrid species distribution models to determine species' range shifts under climate change. Embryos' tolerance of chronic heat (T-chronic) remained consistent across latitudes, whereas their tolerance of acute heat (T-acute) was higher at high latitudes than at low latitudes. Tolerance of acute heat exerted a more pronounced influence than tolerance of chronic heat. In species distribution models, climate change led to the most significant habitat loss for each population and species in its low-latitude distribution. Consequently, habitat for populations across all latitudes will shift toward high latitudes. Our study also highlights the importance of considering embryonic survival under chronic and acute heat stresses to predict species' vulnerability to climate change.

Efectos colectivos del aumento de las temperaturas promedio y los eventos de calor en embriones ovíparos Resumen La supervivencia de los embriones inmóviles en respuesta al incremento de temperatura es importante para determinar la vulnerabilidad de las especies al cambio climático. Sin embargo, los efectos colectivos de dos características térmicas claves asociadas con el cambio climático (i. e., aumento de temperatura promedio y eventos de calor agudo) sobre la supervivencia embrionaria permanecen en gran parte inexplorados. Utilizamos mediciones empíricas y modelos de nicho para investigar cómo el estrés térmico crónico y agudo influye de forma independiente y colectiva en la supervivencia embrionaria de los lagartos en todas las latitudes. Recolectamos y criamos lagartos de cinco latitudes e incubamos sus huevos en un rango de temperaturas para cuantificar las respuestas específicas de la población al estrés por calor crónico y agudo. Posteriormente, mediante un modelo de desarrollo embrionario parametrizado con mediciones de tolerancia embrionaria al calor, identificamos un impacto colectivo de las tolerancias embrionarias al calor agudo y crónico en la supervivencia embrionaria. También incorporamos la tolerancia embrionaria crónica y aguda al calor en modelos de distribución de especies híbridas para determinar los cambios de distribución de las especies bajo el cambio climático. La tolerancia embrionaria al calor crónico (T­crónico) permaneció constante, mientras que la tolerancia al calor agudo (T­agudo) fue mayor en latitudes altas que en latitudes bajas. La tolerancia al calor agudo ejerció una influencia más pronunciada que la tolerancia al calor crónico. En los modelos de distribución de especies, el cambio climático provocó la pérdida de hábitat más significativa para cada población y especie en su distribución de latitudes bajas. En consecuencia, el hábitat para poblaciones en todas las latitudes se desplazará a latitudes altas. Nuestro estudio también resalta la importancia de considerar la supervivencia embrionaria bajo estrés térmico crónico y agudo para predecir la vulnerabilidad de las especies al cambio climático.

Aquaporin 4 Mediates the Effect of Iron Overload on Hydrocephalus After Intraventricular Hemorrhage.

BACKGROUND: Iron overload plays an important role in hydrocephalus development following intraventricular hemorrhage (IVH). Aquaporin 4 (AQP4) participates in the balance of cerebrospinal fluid secretion and absorption. The current study investigated the role of AQP4 in the formation of hydrocephalus caused by iron overload after IVH. METHODS: There were three parts to this study. First, Sprague-Dawley rats received an intraventricular injection of 100 µl autologous blood or saline control. Second, rats had IVH and were treated with deferoxamine (DFX), an iron chelator, or vehicle. Third, rats had IVH and were treated with 2-(nicotinamide)-1,3,4-thiadiazole (TGN-020), a specific AQP4 inhibitor, or vehicle. Rats underwent T2-weighted and T2* gradient-echo magnetic resonance imaging to assess lateral ventricular volume and intraventricular iron deposition at 7, 14, and 28 days after intraventricular injection and were then euthanized. Real-time quantitative polymerase chain reaction, western blot analysis, and immunofluorescence analyses were conducted on the rat brains to evaluate the expression of AQP4 at different time points. Hematoxylin and eosin-stained brain sections were obtained to assess the ventricular wall damage on day 28. RESULTS: Intraventricular injection of autologous blood caused a significant ventricular dilatation, iron deposition, and ventricular wall damage. There was increased AQP4 mRNA and protein expression in the periventricular tissue in IVH rats through day 7 to day 28. The DFX treatment group had a lower lateral ventricular volume and less intraventricular iron deposition and ventricular wall damage than the vehicle-treated group after IVH. The expression of AQP4 protein in periventricular tissue was also inhibited by DFX on days 14 and 28 after IVH. The use of TGN-020 attenuated hydrocephalus development after IVH and inhibited the expression of AQP4 protein in the periventricular tissue between day 14 and day 28 without a significant effect on intraventricular iron deposition or ventricular wall damage. CONCLUSIONS: AQP4 located in the periventricular area mediated the effect of iron overload on hydrocephalus after IVH.

Investigating phase separation properties of chromatin-associated proteins using gradient elution of 1,6-hexanediol.

BACKGROUND: Chromatin-associated phase separation proteins establish various biomolecular condensates via liquid-liquid phase separation (LLPS), which regulates vital biological processes spatially and temporally. However, the widely used methods to characterize phase separation proteins are still based on low-throughput experiments, which consume time and could not be used to explore protein LLPS properties in bulk. RESULTS: By combining gradient 1,6-hexanediol (1,6-HD) elution and quantitative proteomics, we developed chromatin enriching hexanediol separation coupled with liquid chromatography-mass spectrometry (CHS-MS) to explore the LLPS properties of different chromatin-associated proteins (CAPs). First, we found that CAPs were enriched more effectively in the 1,6-HD treatment group than in the isotonic solution treatment group. Further analysis showed that the 1,6-HD treatment group could effectively enrich CAPs prone to LLPS. Finally, we compared the representative proteins eluted by different gradients of 1,6-HD and found that the representative proteins of the 2% 1,6-HD treatment group had the highest percentage of IDRs and LCDs, whereas the 10% 1,6-HD treatment group had the opposite trend. CONCLUSION: This study provides a convenient high-throughput experimental method called CHS-MS. This method can efficiently enrich proteins prone to LLPS and can be extended to explore LLPS properties of CAPs in different biological systems.

MloDisDB: a manually curated database of the relations between membraneless organelles and diseases.

Cells are compartmentalized by numerous membrane-bounded organelles and membraneless organelles (MLOs) to ensure temporal and spatial regulation of various biological processes. A number of MLOs, such as nucleoli, nuclear speckles and stress granules, exist as liquid droplets within the cells and arise from the condensation of proteins and RNAs via liquid-liquid phase separation (LLPS). By concentrating certain proteins and RNAs, MLOs accelerate biochemical reactions and protect cells during stress, and dysfunction of MLOs is associated with various pathological processes. With the development in this field, more and more relations between the MLOs and diseases have been described; however, these results have not been made available in a centralized resource. Herein, we build MloDisDB, a database which aims to gather the relations between MLOs and diseases from dispersed literature. In addition, the relations between LLPS and diseases were included as well. Currently, MloDisDB contains 771 curated entries from 607 publications; each entry in MloDisDB contains detailed information about the MLO, the disease and the functional factor in the relation. Furthermore, an efficient and user-friendly interface for users to search, browse and download all entries was provided. MloDisDB is the first comprehensive database of the relations between MLOs and diseases so far, and the database is freely accessible at http://mlodis.phasep.pro/.

A deep learning model with data integration of ultrasound contrast-enhanced micro-flow cines, B-mode images, and clinical parameters for diagnosing significant liver fibrosis in patients with chronic hepatitis B.

OBJECTIVE: To develop and investigate a deep learning model with data integration of ultrasound contrast-enhanced micro-flow (CEMF) cines, B-mode images, and patients' clinical parameters to improve the diagnosis of significant liver fibrosis (≥ F2) in patients with chronic hepatitis B (CHB). METHODS: Of 682 CHB patients who underwent ultrasound and histopathological examinations between October 2016 and May 2020, 218 subjects were included in this retrospective study. We devised a data integration-based deep learning (DIDL) model for assessing ≥ F2 in CHB patients. The model contained three convolutional neural network branches to automatically extract features from ultrasound CEMF cines, B-mode images, and clinical data. The extracted features were fused at the backend of the model for decision-making. The diagnostic performance was evaluated across fivefold cross-validation and compared against the other methods in terms of the area under the receiver operating characteristic curve (AUC), with histopathological results as the reference standard. RESULTS: The mean AUC achieved by the DIDL model was 0.901 [95% CI, 0.857-0.939], which was significantly higher than those of the comparative methods, including the models trained by using only CEMF cines (0.850 [0.794-0.893]), B-mode images (0.813 [0.754-0.862]), or clinical data (0.757 [0.694-0.812]), as well as the conventional TIC method (0.752 [0.689-0.808]), APRI (0.792 [0.734-0.845]), FIB-4 (0.776 [0.714-0.829]), and visual assessments of two radiologists (0.812 [0.754-0.862], and 0.800 [0.739-0.849]), all ps < 0.01, DeLong test. CONCLUSION: The DIDL model with data integration of ultrasound CEMF cines, B-mode images, and clinical parameters showed promising performance in diagnosing significant liver fibrosis for CHB patients. KEY POINTS: • The combined use of ultrasound contrast-enhanced micro-flow cines, B-mode images, and clinical data in a deep learning model has potential to improve the diagnosis of significant liver fibrosis. • The deep learning model with the fusion of features extracted from multimodality data outperformed the conventional methods including mono-modality data-based models, the time-intensity curve-based recognizer, fibrosis biomarkers, and visual assessments by experienced radiologists. • The interpretation of the feature attention maps in the deep learning model may help radiologists get better understanding of liver fibrosis-related features and hence potentially enhancing their diagnostic capacities.

Divergent effects of climate change on the egg-laying opportunity of species in cold and warm regions.

Climate warming can substantially impact embryonic development and juvenile growth in oviparous species. Estimating the overall impacts of climate warming on oviparous reproduction is difficult because egg-laying events happen throughout the reproductive season. Successful egg laying requires the completion of embryonic development as well as hatching timing conducive to offspring survival and energy accumulation. We propose a new metric-egg-laying opportunity (EO)-to estimate the annual hours during which a clutch of freshly laid eggs yields surviving offspring that store sufficient energy for overwintering. We estimated the EO within the distribution of a model species, Sceloporus undulatus, under recent climate condition and a climate-warming scenario by combining microclimate data, developmental functions, and biophysical models. We predicted that EO will decline as the climate warms at 74.8% of 11,407 sites. Decreasing hatching success and offspring energy accounted for more lost EO hours (72.6% and 72.9%) than the occurrence of offspring heat stress (59.9%). Nesting deeper (at a depth of 12 cm) may be a more effective behavioral adjustment for retaining EO than using shadier (50% shade) nests because the former fully mitigated the decline of EO under the considered warming scenario at more sites (66.1%) than the latter (28.3%). We advocate for the use of EO in predicting the impacts of climate warming on oviparous animals because it encapsulates the integrative impacts of climate warming on all stages of reproductive life history.

Efectos divergentes del cambio climático sobre la oportunidad de desove de las especies en regiones cálidas y frías Resumen El calentamiento global puede tener un impacto considerable sobre el desarrollo embrionario y el crecimiento juvenil de las especies ovíparas. Es complicado estimar el impacto general que tiene el calentamiento global sobre la reproducción ovípara ya que los eventos de desove suceden durante la época reproductiva. El desove exitoso requiere que se complete el desarrollo embrionario y que el momento de eclosión sea favorable para la supervivencia de las crías y la acumulación de energía. Proponemos una nueva medida-oportunidad de desove (OD)-para estimar las horas anuales durante las cuales una puesta de huevos recién desovados produce crías que sobreviven y almacenan suficiente energía para invernar. Estimamos la OD dentro de un modelo de distribución de la especie Sceloporus undulatus bajo las recientes condiciones climáticas y bajo un escenario de calentamiento global mediante la combinación de datos microclimáticos, funciones del desarrollo y modelos biofísicos. Pronosticamos que la OD declinará conforme la temperatura aumente en 74.8% de los 11407 sitios. La disminución del éxito de eclosión y de la energía de las crías explicó más horas perdidas de OD (72.6% y 72.9%) que la presencia de estrés por calor en las crías (59.9%). Una anidación más profunda (a una profundidad de 12 cm) puede ser un ajuste conductual más efectivo para la retención de la OD que los nidos con mayor sombreado (50% de sombra) porque el primero mitigó por completo la declinación de la OD bajo el escenario de calentamiento en más sitios (66.1%) que el segundo ajuste (28.3%). Defendemos el uso de la OD en el pronóstico del impacto del calentamiento global sobre los animales ovíparos porque encapsula los impactos integrales que tiene el calentamiento global sobre todas las etapas de la vida reproductiva. 气候变化在寒冷和温暖地区对物种产卵机会造成不同影响.

Low temperature plasma suppresses proliferation, invasion, migration and survival of SK-BR-3 breast cancer cells.

BACKGROUND: Low temperature plasma (LTP) is a developing field in recent years to play important roles of sterilization, material modification and wound healing. Breast cancer is a common gynecological malignant tumor. Recent studies have shown that LTP is a promising selective anti-cancer treatment. The effect of LTP on breast cancer is still unclear. In this study, We treated breast cancer cell lines with low temperature plasma for different periods of time and analyzed the relevant differences. METHODS AND RESULTS: SK-BR-3 cell nutrient solution was firstly treated by ACP for 0, 10, 20, 40, 80 and 120 s, which was next used to cultivateSK-BR-3cells for overnight.we found that LTP was able to suppress cell vitality, proliferation, invasion and migration of SK-BR-3 cells. Also, SK-BR-3 apoptosis was induced by LTP in a time-dependent manner. CONCLUSION: These evidences suggest the negative effect of LTP on malignant development of SK-BR-3 cells, and LTP has the potential clinical application for breast cancer treatment.

Reliability and validity of the Chinese version of the trauma-specific frailty index (TSFI) for geriatric trauma patients.

BACKGROUND: Pre-traumatic frailty in geriatric trauma patients has caught attention from emergency medical workers and the assessment of it thus become one of the important aspects of risk management. Several tools are available to identify frailty, but limited tools have been validated for geriatric trauma patients in China to assess pre-traumatic frailty.The aim of this study is to translate the Trauma-Specific Frailty Index(TSFI) into Chinese, and to evaluate the reliability and validity of the translated version in geriatric trauma patients. METHODS: A cross-sectional study was conducted. The TSFI was translated with using the Brislin model, that included forward and backward translation. A total of 184 geriatric trauma patients were recruited by a convenience sampling between October and December 2020 in Hospital of Chengdu University of Traditional Chinese Medicine, Sichuan. Using reliability or internal consistency tests assessed with Cronbach's alpha coefficient, split-half reliability and test-retest reliability. Content validity and construct validity analysis were both performed. Sensitivity, specificity and maximum Youden index(YI) were used to determine the optimal cut-off value. The screening performance was examined by Kappa value. RESULTS: The total study population included 184 subjects, of which 8 participants were excluded, resulting in a study sample size of 176 elderly trauma patients (the completion rate was 95.7%). The Chinese version of Trauma-Specific Frailty Index(C-TSFI) have 15 items with 5 dimensions. Cronbach's alpha coefficient of the C-TSFI was 0.861, Cronbach's alpha coefficient of dimensions ranged from 0.837 to 0.875, the split-half reliability of the C-TSFI were 0.894 and 0.880 respectively, test-retest reliability ranged from 0.692 to 0.862. The correlation coefficient between items and the C-TSFI ranged from 0.439 to 0.761. The content validity index for items (I-CVI) of the C-TSFI scale was 0.86~1.00, and the scale of content validity index (S-CVI) was 0.93. The area under curve (AUC) of the C-TSFI was 0.932 (95%CI 0.904-0.96, P < 0.05), the maximum YI was 0.725, the sensitivity was 80.2%, the specificity was 92.3%, and the critical value was 0.31. Kappa value was 0.682 (P < 0.05). CONCLUSIONS: The Chinese version of TSFI could be used as a general assessment tool in geriatric trauma patients, and both its reliability and validity have been demonstrated.

Assessment of post-COVID-19 fatigue among female survivors 2 years after hospital discharge: a nested case-control study.

BACKGROUND: Fatigue is a common symptom of long COVID syndrome. Compared to male survivors, females have a higher incidence of post-COVID fatigue. Therefore, long-term follow-up is necessary to understand which groups of females are more vulnerable to post-COVID fatigue. METHODS: This is a nested case-control study of female COVID-19 survivors who were discharged from two designated hospitals in Wuhan, China in 2020, and received 2-year follow-up from March 1 to April 6, 2022. All patients completed the Checklist Individual Strength-subscale subjective fatigue (CIS-fatigue), a chronic obstructive pulmonary disease (COPD) assessment test (CAT), and the Hospital Anxiety and Depression Scale (HADS; including the HADS-Anxiety [HADS-A] and the HADS-Depression [HADS-D]). Individuals with CIS-fatigue scores of 27 or higher were classified as cases. The risk factors for fatigue was analysed with multivariable logistic regression analysis. RESULTS: A total of 899 female COVID-19 survivors were enrolled for analysis, including 47 cases and 852 controls. Compared with controls, cases had higher CAT, HADS-A and HADS-D scores, and showed a higher prevalence of symptoms, including anxiety (cases vs. controls, 44.7% vs. 4.0%, p < 0.001), chest tightness (21.2% vs. 2.3%, p < 0.001), dyspnoea (19.1% vs. 0.8%, p < 0.001) and so on. In multivariable logistic regression analysis, age (OR, 1.03; 95% CI, 1.01-1.06; p = 0.02) and cerebrovascular disease (OR, 11.32; 95% CI, 2.87-43.00; p < 0.001) were risk factors for fatigue. Fatigue had a statistically significant moderate correlation with depression (r = 0.44, p < 0.001), but not with CAT ≥ 10. CONCLUSION: Female COVID-19 patients who had cerebrovascular disease and older age have higher risk of fatigue. Patients with fatigue have higher CAT scores, and are more likely to have concurrent depression.

Systematic prediction of degrons and E3 ubiquitin ligase binding via deep learning.

BACKGROUND: Degrons are short linear motifs, bound by E3 ubiquitin ligase to target protein substrates to be degraded by the ubiquitin-proteasome system. Mutations leading to deregulation of degron functionality disrupt control of protein abundance due to mistargeting of proteins destined for degradation and often result in pathologies. Targeting degrons by small molecules also emerges as an exciting drug design strategy to upregulate the expression of specific proteins. Despite their essential function and disease targetability, reliable identification of degrons remains a conundrum. Here, we developed a deep learning-based model named Degpred that predicts general degrons directly from protein sequences. RESULTS: We showed that the BERT-based model performed well in predicting degrons singly from protein sequences. Then, we used the deep learning model Degpred to predict degrons proteome-widely. Degpred successfully captured typical degron-related sequence properties and predicted degrons beyond those from motif-based methods which use a handful of E3 motifs to match possible degrons. Furthermore, we calculated E3 motifs using predicted degrons on the substrates in our collected E3-substrate interaction dataset and constructed a regulatory network of protein degradation by assigning predicted degrons to specific E3s with calculated motifs. Critically, we experimentally verified that a predicted SPOP binding degron on CBX6 prompts CBX6 degradation and mediates the interaction with SPOP. We also showed that the protein degradation regulatory system is important in tumorigenesis by surveying degron-related mutations in TCGA. CONCLUSIONS: Degpred provides an efficient tool to proteome-wide prediction of degrons and binding E3s singly from protein sequences. Degpred successfully captures typical degron-related sequence properties and predicts degrons beyond those from previously used motif-based methods, thus greatly expanding the degron landscape, which should advance the understanding of protein degradation, and allow exploration of uncharacterized alterations of proteins in diseases. To make it easier for readers to access collected and predicted datasets, we integrated these data into the website http://degron.phasep.pro/ .

Preparation of Biochar with Developed Mesoporous Structure from Poplar Leaf Activated by KHCO3 and Its Efficient Adsorption of Oxytetracycline Hydrochloride.

The effective removal of oxytetracycline hydrochloride (OTC) from the water environment is of great importance. Adsorption as a simple, stable, and cost-effective technology is regarded as an important method for removing OTC. Herein, a low-cost biochar with a developed mesoporous structure was synthesized via pyrolysis of poplar leaf with potassium bicarbonate (KHCO3) as the activator. KHCO3 can endow biochar with abundant mesopores, but excessive KHCO3 cannot continuously promote the formation of mesoporous structures. In comparison with all of the prepared biochars, PKC-4 (biochar with a poplar leaf to KHCO3 mass ratio of 5:4) shows the highest adsorption performance for OTC as it has the largest surface area and richest mesoporous structure. The pseudo-second-order kinetic model and the Freundlich equilibrium model are more consistent with the experimental data, which implies that the adsorption process is multi-mechanism and multi-layered. In addition, the maximum adsorption capacities of biochar are slightly affected by pH changes, different metal ions, and different water matrices. Moreover, the biochar can be regenerated by pyrolysis, and its adsorption capacity only decreases by approximately 6% after four cycles. The adsorption of biochar for OTC is mainly controlled by pore filling, though electrostatic interactions, hydrogen bonding, and π-π interaction are also involved. This study realizes biomass waste recycling and highlights the potential of poplar leaf-based biochar for the adsorption of antibiotics.

Photoluminescence of monolayer MoS2 modulated by water/O2/laser irradiation.

The low photoluminescence (PL) quantum yields of transition metal dichalcogenide monolayers have been a limiting factor for their optoelectronic applications. Various and even inconsistent mechanisms have been proposed to modulate their PL efficiencies. Herein, we use PL/Raman microspectroscopy and the corresponding in situ mapping, atomic force microscopy, and field-effect transistor (FET) characterization to investigate the changes in the structural and optical properties of monolayer MoS2. Relatively low power density (<4.08 × 105 W cm-2) of laser irradiation in ambient air can cause a slight PL suppression effect on monolayer MoS2, whereas relatively high power density (∼1.02 × 106 W cm-2) of laser irradiation brings significant PL enhancement. Experiments under different atmospheres reveal that the laser-irradiation-induced enhancement only occurs in the atmosphere containing O2 and is more remarkable in pure O2. In addition, physically adsorbed water can also induce PL enhancement of monolayer MoS2. FET devices suggest that the adsorbed water produces a p-doping effect on MoS2, and the laser irradiation in ambient air generates an n-doping effect, and both types of doping can enhance the PL intensity. The island-shaped defects caused by laser irradiation can be stabilized by oxygen atoms and act as trapping centers for excited trions or electrons, thus reducing the non-radiative recombination ratio and enhancing the PL intensity. The physically adsorbed water works in a similar way. A low power density of laser irradiation can sweep away the originally adsorbed H2O on the surface, thus reducing the PL.

Spatial distribution of cumulative impact on terrestrial ecosystem of the Fildes Peninsula, Antarctica.

Antarctica, an area that is devoted to global peace and research, is being challenged by climate change, human activities, and pollution. There have been a number of studies concerning the state of the Antarctic ecological environment. However, a comprehensive and quantitative assessment of the impact of threats on the Antarctica ecological environment is still lacking. In this study, a cumulative impact assessment performed on the basis of expert judgement was used to estimate species-specific differences on the impact of seven threats: climate change, organic and nonorganic pollutants, station construction, power generation, oil spilling, and tourism. The terrestrial area of the Fildes Peninsula was divided into 103 cells using a raster grid of 0.25 km2, and cumulative impact assessment was applied to each cell. The analysis results indicated that cumulative impact scores (IC) ranged from 0 to 39.4, and the cumulative scores were divided into six categories ranging from very low impact (IC ≤ 7.08) to very high impact (IC > 20.54). More than half of the terrestrial area (57.3%) experienced "Very Low Impact" or "Low impact" scores. For single factors, climate change was identified as a rapidly growing and significant threat facing the terrestrial ecosystems of Antarctica. In addition, tourism had the greatest impact among all human activities. The analytical process and resulting map indicate that it is necessary to develop international policies on the restriction of tourist activity space and strength the organic pollutant controls for terrestrial ecosystem protection in the Fildes Peninsula, Antarctica.

Self-Sterilizing Polymeric Membrane Sensors Based on 6-Chloroindole Release for Prevention of Marine Biofouling.

A self-sterilizing strategy based on antimicrobial organic agent release is proposed for polymeric membrane sensors to prevent marine biofouling. A solid-contact polymeric membrane calcium ion-selective electrode (Ca2+-ISE) is selected as a model sensor. 6-Cholorindole (6-Cl indole) is utilized as the biocidal agent due to its potential antimicrobial activity and environmental friendliness. The plasticized polymeric membrane doped with 6-Cl indole shows a markedly improved antimicrobial activity against the bacterial cells collected from seawater and effectively prevents the formation of a biofilm on the sensor surface, while displaying response properties (i.e., linear range, selectivity, and response time) similar to those of the undoped membrane. Importantly, the present sensor can preserve an improved antimicrobial activity when kept in the artificial seawater for 45 days, indicating highly stable antibacterial properties of the membrane electrode. Additionally, the 6-Cl indole-doped Ca2+-ISE exhibits no significant loss of analytical performance after exposure to a rather concentrated bacterial suspension (∼109 colony-forming units per mL (CFU mL-1)) for 7 days. The proposed antimicrobial agent release methodology can be extended to develop polymeric membrane-based marine sensors with stable biofouling resistances against bacterial colonization.

Highly Selective Binding and Inhibition of Pyr-His-Pro-NH2 (TRH) Function using a Polypyridinyl Macrocyclic Receptor with an Amphiphilic Cavity.

Macrocycle, cyclo[4] [(1,3-(4,6)-dimethylbezene)[4](2,6-(3,5)-dimethylpyridine (B4P4), shows highly selective binding affinity with protirelin (Pyr-His-Pro-NH2 ; TRH) among the tested 26 drug or drug adductive substrates. The stable complexation in a 1:1 manner was fully characterized in solution, gas phase, and solid state study. Furthermore, B4P4 acts as an efficient TRH inhibitor even at [macrocycle]:[drug] <1:300, both in membrane transport and cellar incubation. The current work provides an unprecedented strategy for macrocycles to be efficiently used in drug target therapy.