Temperature-Sensitive Contact Modes Allosterically Gate TRPV3.

TRPV Ion channels are sophisticated molecular sensors designed to respond to distinct temperature thresholds. The recent surge in cryo-EM structures has provided numerous insights into the structural rearrangements accompanying their opening and closing; however, the molecular mechanisms by which TRPV channels establish precise and robust temperature sensing remain elusive. In this work we employ molecular simulations, multi-ensemble contact analysis, graph theory, and machine learning techniques to reveal the temperature-sensitive residue-residue interactions driving allostery in TRPV3. We find that groups of residues exhibiting similar temperature-dependent contact frequency profiles cluster at specific regions of the channel. The dominant mode clusters on the ankyrin repeat domain and displays a linear melting trend while others display non-linear trends. These modes describe the residue-level temperature response patterns that underlie the channel's functional dynamics. With network analysis, we find that the community structure of the channel changes with temperature. And that a network of high centrality contacts connects distant regions of the protomer to the gate, serving as a means for the temperature-sensitive contact modes to allosterically regulate channel gating. Using a random forest model, we show that the contact states of specific temperature-sensitive modes are indeed predictive of the channel gate's state. Supporting the physical validity of these modes and networks are several residues identified with our analyses that are reported in literature to be functionally critical. Our results offer high resolution insight into thermo-TRP channel function and demonstrate the utility of temperature-sensitive contact analysis.

Prediction of Chronic Obstructive Pulmonary Disease Exacerbation Events by Using Patient Self-reported Data in a Digital Health App: Statistical Evaluation and Machine Learning Approach.

BACKGROUND: Self-reporting digital apps provide a way of remotely monitoring and managing patients with chronic conditions in the community. Leveraging the data collected by these apps in prognostic models could provide increased personalization of care and reduce the burden of care for people who live with chronic conditions. This study evaluated the predictive ability of prognostic models for the prediction of acute exacerbation events in people with chronic obstructive pulmonary disease by using data self-reported to a digital health app. OBJECTIVE: The aim of this study was to evaluate if data self-reported to a digital health app can be used to predict acute exacerbation events in the near future. METHODS: This is a retrospective study evaluating the use of symptom and chronic obstructive pulmonary disease assessment test data self-reported to a digital health app (myCOPD) in predicting acute exacerbation events. We include data from 2374 patients who made 68,139 self-reports. We evaluated the degree to which the different variables self-reported to the app are predictive of exacerbation events and developed both heuristic and machine learning models to predict whether the patient will report an exacerbation event within 3 days of self-reporting to the app. The model's predictive ability was evaluated based on self-reports from an independent set of patients. RESULTS: Users self-reported symptoms, and standard chronic obstructive pulmonary disease assessment tests displayed correlation with future exacerbation events. Both a baseline model (area under the receiver operating characteristic curve [AUROC] 0.655, 95% CI 0.689-0.676) and a machine learning model (AUROC 0.727, 95% CI 0.720-0.735) showed moderate ability in predicting exacerbation events, occurring within 3 days of a given self-report. Although the baseline model obtained a fixed sensitivity and specificity of 0.551 (95% CI 0.508-0.596) and 0.759 (95% CI 0.752-0.767) respectively, the sensitivity and specificity of the machine learning model can be tuned by dichotomizing the continuous predictions it provides with different thresholds. CONCLUSIONS: Data self-reported to health care apps designed to remotely monitor patients with chronic obstructive pulmonary disease can be used to predict acute exacerbation events with moderate performance. This could increase personalization of care by allowing preemptive action to be taken to mitigate the risk of future exacerbation events.

Using explainable machine learning to characterise data drift and detect emergent health risks for emergency department admissions during COVID-19.

A key task of emergency departments is to promptly identify patients who require hospital admission. Early identification ensures patient safety and aids organisational planning. Supervised machine learning algorithms can use data describing historical episodes to make ahead-of-time predictions of clinical outcomes. Despite this, clinical settings are dynamic environments and the underlying data distributions characterising episodes can change with time (data drift), and so can the relationship between episode characteristics and associated clinical outcomes (concept drift). Practically this means deployed algorithms must be monitored to ensure their safety. We demonstrate how explainable machine learning can be used to monitor data drift, using the COVID-19 pandemic as a severe example. We present a machine learning classifier trained using (pre-COVID-19) data, to identify patients at high risk of admission during an emergency department attendance. We then evaluate our model's performance on attendances occurring pre-pandemic (AUROC of 0.856 with 95%CI [0.852, 0.859]) and during the COVID-19 pandemic (AUROC of 0.826 with 95%CI [0.814, 0.837]). We demonstrate two benefits of explainable machine learning (SHAP) for models deployed in healthcare settings: (1) By tracking the variation in a feature's SHAP value relative to its global importance, a complimentary measure of data drift is found which highlights the need to retrain a predictive model. (2) By observing the relative changes in feature importance emergent health risks can be identified.

Understanding the genetics of APOE and TOMM40 and role of mitochondrial structure and function in clinical pharmacology of Alzheimer's disease.

The methodology of Genome-Wide Association Screening (GWAS) has been applied for more than a decade. Translation to clinical utility has been limited, especially in Alzheimer's Disease (AD). It has become standard practice in the analyses of more than two dozen AD GWAS studies to exclude the apolipoprotein E (APOE) region because of its extraordinary statistical support, unique thus far in complex human diseases. New genes associated with AD are proposed frequently based on SNPs associated with odds ratio (OR) < 1.2. Most of these SNPs are not located within the associated gene exons or introns but are located variable distances away. Often pathologic hypotheses for these genes are presented, with little or no experimental support. By eliminating the analyses of the APOE-TOMM40 linkage disequilibrium region, the relationship and data of several genes that are co-located in that LD region have been largely ignored. Early negative interpretations limited the interest of understanding the genetic data derived from GWAS, particularly regarding the TOMM40 gene. This commentary describes the history and problem(s) in interpretation of the genetic interrogation of the "APOE" region and provides insight into a metabolic mitochondrial basis for the etiology of AD using both APOE and TOMM40 genetics.