A sequence-based model for identifying proteins undergoing liquid-liquid phase separation/forming fibril aggregates via machine learning.

Liquid-liquid phase separation (LLPS) and the solid aggregate (also referred to as amyloid aggregates) formation of proteins, have gained significant attention in recent years due to their associations with various physiological and pathological processes in living organisms. The systematic investigation of the differences and connections between proteins undergoing LLPS and those forming amyloid fibrils at the sequence level has not yet been explored. In this research, we aim to address this gap by comparing the two types of proteins across 36 features using collected data available currently. The statistical comparison results indicate that, 24 of the selected 36 features exhibit significant difference between the two protein groups. A LLPS-Fibrils binary classification model built on these 24 features using random forest reveals that the fraction of intrinsically disordered residues (FIDR ) is identified as the most crucial feature. While, in the further three-class LLPS-Fibrils-Background classification model built on the same screened features, the composition of cysteine and that of leucine show more significant contributions than others. Through feature ablation analysis, we finally constructed a model FLFB (Feature-based LLPS-Fibrils-Background protein predictor) using six refined features, with an average area under the receiver operating characteristics of 0.83. This work indicates using sequence features and a machine learning model, proteins undergoing LLPS or forming amyloid fibrils can be identified.

Evaluation of sequence-based predictors for phase-separating protein.

Liquid-liquid phase separation (LLPS) of proteins and nucleic acids underlies the formation of biomolecular condensates in cell. Dysregulation of protein LLPS is closely implicated in a range of intractable diseases. A variety of tools for predicting phase-separating proteins (PSPs) have been developed with the increasing experimental data accumulated and several related databases released. Comparing their performance directly can be challenging due to they were built on different algorithms and datasets. In this study, we evaluate eleven available PSPs predictors using negative testing datasets, including folded proteins, the human proteome, and non-PSPs under near physiological conditions, based on our recently updated LLPSDB v2.0 database. Our results show that the new generation predictors FuzDrop, DeePhase and PSPredictor perform better on folded proteins as a negative test set, while LLPhyScore outperforms other tools on the human proteome. However, none of the predictors could accurately identify experimentally verified non-PSPs. Furthermore, the correlation between predicted scores and experimentally measured saturation concentrations of protein A1-LCD and its mutants suggests that, these predictors could not consistently predict the protein LLPS propensity rationally. Further investigation with more diverse sequences for training, as well as considering features such as refined sequence pattern characterization that comprehensively reflects molecular physiochemical interactions, may improve the performance of PSPs prediction.

Shock Index Is a Validated Prediction Tool for the Short-Term Survival of Advanced Cancer Patients Presenting to the Emergency Department.

Advanced cancer patients who are not expected to survive past the short term can benefit from early initiation of palliative care in the emergency department (ED). This discussion, however, requires accurate prognostication of their short-term survival. We previously found in our retrospective study that shock index (SI) is an ideal risk stratification tool in predicting the 60-day mortality risk of advanced cancer patients presenting to the ED. This study is a follow-up prospective validation study conducted from January 2019 to April 2021. A total of 410 advanced cancer patients who presented to the ED of a medical centre and could be followed-up feasibly were recruited. Univariate and multivariable logistic regression analyses were performed with receiver operator calibrating (ROC) curve analysis. Non-survivors had significantly lower body temperatures, higher pulse rates, higher respiratory rates, lower blood pressures, and higher SI. Each 0.1 increment of SI increased the odds of 60-day mortality by 1.591. Area under ROC curve was 0.7819. At optimal cut-off of 0.94, SI had 66.10% accuracy. These results were similar to our previous study, thus validating the use of SI in predicting the 60-day mortality of advanced cancer patients presenting to the ED. Identified patients may be offered palliative care.

Methanol Intoxication After Suicidal Ingestion of Liquid Rodenticides: A Report of Two Cases.

Methanol is highly toxic to humans. Although methanol poisoning is not uncommon in developing countries, poisoning caused by ingestion of commercial products containing undeclared methanol has rarely been reported. Herein, we describe two patients who experienced methanol poisoning after ingestion of liquid rodenticides. A 39-year-old woman attempted suicide by ingesting liquid rodenticide which contained bromadiolone. She developed high anion gap metabolic acidosis and coagulopathy. Methanol poisoning was confirmed 20 hours later. She received oral ethanol therapy and hemodialysis. Vitamin K1 was also administered. She did not develop any hemorrhage or visual impairment and was discharged after 11 days. The rodenticide sample was tested and found to have a methanol concentration of 324 g/L. In another case, a 62-year-old man ingested the same brand of rodenticide. Laboratory data showed mild metabolic acidosis with an increased osmol gap, suggestive of methanol poisoning. He received hemodialysis and eventually recovered without sequelae. Liquid rodenticide may contain methanol as a solvent. Ingestion of a methanol-containing commercial product without a clear label can result in a considerable delay in diagnosis and management. Methanol poisoning should be considered for patients who present with unexplained metabolic acidosis following exposure to liquid rodenticides or other liquid commercial products.

LLPSDB v2.0: an updated database of proteins undergoing liquid-liquid phase separation in vitro.

SUMMARY: Emerging evidences have suggested that liquid-liquid phase separation (LLPS) of proteins plays a vital role both in a wide range of biological processes and in related diseases. Whether a protein undergoes phase separation not only is determined by the chemical and physical properties of biomolecule themselves, but also is regulated by environmental conditions such as temperature, ionic strength, pH, as well as volume excluded by other macromolecules. A web accessible database LLPSDB was developed recently by our group, in which all the proteins involved in LLPS in vitro as well as corresponding experimental conditions were curated comprehensively from published literatures. With the rapid increase of investigations in biomolecular LLPS and growing popularity of LLPSDB, we updated the database, and developed a new version LLPSDB v2.0. In comparison of the previously released version, more than double contents of data are curated, and a new class 'Ambiguous system' is added. In addition, the web interface is improved, such as that users can search the database by selecting option 'phase separation status' alone or combined with other options. We anticipate that this updated database will serve as a more comprehensive and helpful resource for users. AVAILABILITY AND IMPLEMENTATION: LLPSDB v2.0 is freely available at: http://bio-comp.org.cn/llpsdbv2. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Brain Computed Tomography in Stimulant Poisoning with Altered Consciousness.

BACKGROUND: Stimulant poisoning frequently causes altered mental status (AMS) and can result in severe cerebral vascular complications. The role of noncontrast brain computed tomography (CT) in acute stimulant-poisoned patients presenting with AMS remains unclear. OBJECTIVES: We examined the results and impacts of brain CT in acute stimulant-poisoned patients with AMS. METHODS: We performed a retrospective single-center study that included all adult patients who presented to the emergency department with stimulant poisoning and AMS (Glasgow coma scale [GCS] score <15) between January 1, 2010 and December 31, 2017. Patients who had concomitant head trauma or who presented with focal neurologic symptoms were excluded. The primary outcome was the rate of acute abnormalities on brain CT. The secondary outcomes were to identify factors that affected the decision to perform brain CT in stimulant-poisoned patients with AMS and whether obtaining the brain CT scan itself affected the patients' prognoses. RESULTS: The analysis included 66 patients, of whom 6 died from the poisoning. Noncontrast brain CT was performed in 31 patients and none had acute abnormalities. Patients who underwent brain CT were found to have worse GCS scores, higher body temperatures, higher intubation rates, higher admission rates, longer admission periods and intensive care unit stays, and a higher mortality rate. After adjusting for the propensity score, performing brain CT itself did not independently affect the patients' clinical outcomes. CONCLUSIONS: Nontrauma stimulant-poisoned patients presenting with AMS and without focal neurologic symptoms were unlikely to have acute abnormalities on brain CT. Patients who underwent brain CT scans had worse consciousness and greater disease severity.

Top-cited publications on point-of-care ultrasound: The evolution of research trends.

STUDY OBJECTIVES: Point-of-care ultrasound (POCUS) has been a rapidly growing and broadly used modality in recent decades. The purpose of this study was to determine how POCUS is incorporated into clinical medicine by analyzing trends of use in the published literature. METHODS: POCUS-related publications were retrieved from the Web of Science (WoS) database. The search results were ranked according to the number of times an article was cited during three time frames and average annual number of citations. Of the top 100 most cited publications in the four rankings, information regarding the publication journal, publication year, first author's nationality, field of POCUS application, and number of times the article was cited was recorded for trend analysis. RESULTS: A total of 7860 POCUS-related publications were retrieved, and publications related to POCUS increased from 8 in 1990 to 754 in 2016. The top 148 cited publications from the four ranking groups were included in this study. Trauma was the leading application field in which POCUS was studied prior to 2001. After 2004, thorax, cardiovascular, and procedure-guidance were the leading fields in POCUS research. >79% (118/148) of the top-cited publications were conducted by authors in the United States, Italy, and France. The majority of publications were published in critical care medicine and emergency medicine journals. CONCLUSIONS: In recent years, publications relating to POCUS have increased. POCUS-related research has mainly been performed in thorax, cardiovascular, and procedure-guidance ultrasonography fields, replacing trauma as the major field in which POCUS was previously studied.