Searching for Structure: Characterizing the Protein Conformational Landscape with Clustering-Based Algorithms.

The identification and characterization of the main conformations from a protein population are a challenging and inherently high-dimensional problem. Here, we evaluate the performance of the Secondary sTructural Ensembles with machine LeArning (StELa) double-clustering method, which clusters protein structures based on the relationship between the φ and ψ dihedral angles in a protein backbone and the secondary structure of the protein, thus focusing on the local properties of protein structures. The classification of states as vectors composed of the clusters' indices arising naturally from the Ramachandran plot is followed by the hierarchical clustering of the vectors to allow for the identification of the main features of the corresponding free energy landscape (FEL). We compare the performance of StELa with the established root-mean-squared-deviation (RMSD)-based clustering algorithm, which focuses on global properties of protein structures and with Combinatorial Averaged Transient Structure (CATS), the combinatorial averaged transient structure clustering method based on distributions of the φ and ψ dihedral angle coordinates. Using ensembles of conformations from molecular dynamics simulations of intrinsically disordered proteins (IDPs) of various lengths (tau protein fragments) or short fragments from a globular protein, we show that StELa is the clustering method that identifies many of the minima and relevant energy states around the minima from the corresponding FELs. In contrast, the RMSD-based algorithm yields a large number of clusters that usually cover most of the FEL, thus being unable to distinguish between states, while CATS does not sample well the FELs for long IDPs and fragments from globular proteins.

A preliminary investigation of epigenome-wide DNA methylation and temperament during infancy.

This study provides preliminary evidence for an epigenetic architecture of infant temperament. At 12 months of age, blood was collected and assayed for DNA methylation and maternally reported infant temperament was assessed using the Infant Behavior Questionnaire in 67 mother-infant dyads. Epigenome-wide analyses showed that the higher order temperament dimensions Surgency and Negative Affect were associated with DNA methylation. The epigenetic signatures of Surgency and Negative Affect were situated at genes involved in synaptic signaling and plasticity. Although replication is required, these results are consistent with a biologically based model of temperament, create new avenues for hypothesis-driven research into epigenetic pathways that underlie individual differences in temperament, and demonstrate that infant temperament has a widespread epigenetic signature in the methylome.

The quaternary question: Determining allostery in spastin through dynamics classification learning and bioinformatics.

The nanomachine from the ATPases associated with various cellular activities superfamily, called spastin, severs microtubules during cellular processes. To characterize the functionally important allostery in spastin, we employed methods from evolutionary information, to graph-based networks, to machine learning applied to atomistic molecular dynamics simulations of spastin in its monomeric and the functional hexameric forms, in the presence or absence of ligands. Feature selection, using machine learning approaches, for transitions between spastin states recognizes all the regions that have been proposed as allosteric or functional in the literature. The analysis of the composition of the Markov State Model macrostates in the spastin monomer, and the analysis of the direction of change in the top machine learning features for the transitions, indicate that the monomer favors the binding of ATP, which primes the regions involved in the formation of the inter-protomer interfaces for binding to other protomer(s). Allosteric path analysis of graph networks, built based on the cross-correlations between residues in simulations, shows that perturbations to a hub specific for the pre-hydrolysis hexamer propagate throughout the structure by passing through two obligatory regions: the ATP binding pocket, and pore loop 3, which connects the substrate binding site to the ATP binding site. Our findings support a model where the changes in the terminal protomers due to the binding of ligands play an active role in the force generation in spastin. The secondary structures in spastin, which are found to be highly degenerative within the network paths, are also critical for feature transitions of the classification models, which can guide the design of allosteric effectors to enhance or block allosteric signaling.

Cost-effectiveness and Acceptance in Children and Parents of the Hall Technique: Systematic Review of Clinical Trials.

AIMS: The purpose of this systematic review was to evaluate the cost-effectiveness and acceptance of children and their parents of the Hall technique (HT) for dental rehabilitation in pediatric dentistry. BACKGROUND: The approach of the HT is that of minimally invasive treatment of the dental element and is used exclusively on primary molars. Various studies in the literature point to HT as a restorative option well accepted by children and parents and quite predictable, with low retreatment rates and good cost-effectiveness for the management of primary molars with carious lesions. However, no systematic review in the literature has approached randomized clinical trials on these topics to produce a high level of evidence and help establish clinical HT protocols. REVIEW RESULTS: Eight articles were selected for the systematic review. The HT was more cost-effective than procedures using other restorative materials. Regarding acceptance, in terms of esthetics, high percentages of satisfaction were reported for parents and children, with a divergence between studies in the comparison of esthetic preference with atraumatic restorative treatment. However, when considering crown cementation pain, comfort, anxiety, preference, and satisfaction, the HT was generally better evaluated when compared to other restorative materials. CONCLUSION: The HT is an excellent restorative option when considering cost-effectiveness and acceptance and is recommended for use in daily clinical practice. CLINICAL SIGNIFICANCE: Results indicate that HT is superior to other restorative materials regarding its acceptance by children and parents in terms of pain, comfort, anxiety, and crown preference and satisfaction. There were also high percentages of satisfaction with esthetics. Hall technique may initially appear expensive for dentists, but its effectiveness over time and the lesser need for consultations and reinventions ensure better cost-benefit than other restorative materials. How to cite this article: Valentim FB, Moreira KMS, Carneiro VC, et al. Cost-effectiveness and Acceptance in Children and Parents of the Hall Technique: Systematic Review of Clinical Trials. J Contemp Dent Pract 2023;24(12):1016-1025.

The East African Community (EAC) mobile laboratory networks in Kenya, Burundi, Tanzania, Rwanda, Uganda, and South Sudan-from project implementation to outbreak response against Dengue, Ebola, COVID-19, and epidemic-prone diseases.

BACKGROUND: East Africa is home to 170 million people and prone to frequent outbreaks of viral haemorrhagic fevers and various bacterial diseases. A major challenge is that epidemics mostly happen in remote areas, where infrastructure for Biosecurity Level (BSL) 3/4 laboratory capacity is not available. As samples have to be transported from the outbreak area to the National Public Health Laboratories (NPHL) in the capitals or even flown to international reference centres, diagnosis is significantly delayed and epidemics emerge. MAIN TEXT: The East African Community (EAC), an intergovernmental body of Burundi, Rwanda, Tanzania, Kenya, Uganda, and South Sudan, received 10 million € funding from the German Development Bank (KfW) to establish BSL3/4 capacity in the region. Between 2017 and 2020, the EAC in collaboration with the Bernhard-Nocht-Institute for Tropical Medicine (Germany) and the Partner Countries' Ministries of Health and their respective NPHLs, established a regional network of nine mobile BSL3/4 laboratories. These rapidly deployable laboratories allowed the region to reduce sample turn-around-time (from days to an average of 8h) at the centre of the outbreak and rapidly respond to epidemics. In the present article, the approach for implementing such a regional project is outlined and five major aspects (including recommendations) are described: (i) the overall project coordination activities through the EAC Secretariat and the Partner States, (ii) procurement of equipment, (iii) the established laboratory setup and diagnostic panels, (iv) regional training activities and capacity building of various stakeholders and (v) completed and ongoing field missions. The latter includes an EAC/WHO field simulation exercise that was conducted on the border between Tanzania and Kenya in June 2019, the support in molecular diagnosis during the Tanzanian Dengue outbreak in 2019, the participation in the Ugandan National Ebola response activities in Kisoro district along the Uganda/DRC border in Oct/Nov 2019 and the deployments of the laboratories to assist in SARS-CoV-2 diagnostics throughout the region since early 2020. CONCLUSIONS: The established EAC mobile laboratory network allows accurate and timely diagnosis of BSL3/4 pathogens in all East African countries, important for individual patient management and to effectively contain the spread of epidemic-prone diseases.

Dance as Lifeline: Transforming Means for Engagement and Connection in Times of Social Isolation.

Over the past 20 years, dance has emerged as a safe, effective, and evidence-based community intervention that helps thousands of people living with Parkinson's disease around the globe maintain well-being and improve quality of life. From its initial emergence to the present, COVID-19 has posed fundamental challenges to people living with Parkinson's, forcing them to balance the need and desire to stay active and socially connected with the requirement to adhere to strict shelter-at-home orders. As cities and towns worldwide began shutting down in early 2020, people living with Parkinson's found themselves unable to access live dance activities that had provided consistent, reliable physical support; joyful cognitive stimulation; emotional connection; and social engagement. Government sanctioned closures and stay-at-home orders increased the potential for apathy, isolation, anxiety, and stress-factors that are already heightened in people with Parkinson's. COVID-19 also exacerbated disparities based on race, language, socioeconomic background, and age, inequities already present in the Parkinson's community and in Parkinson's-focused dance programming. In this article, the authors provide a description and analysis of ways one dance for Parkinson's program addressed multiples challenges through three key initiatives: online group classes in English and Spanish, telephone-based resources for people without internet access, and robust online training opportunities for teaching artists. The authors outline ways in which the pandemic has increased the inclusive nature of dance for Parkinson's programming and suggest that changes implemented during the pandemic will permanently alter program delivery for the better when it is safe to restore group classes in community settings.

Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism.

BACKGROUND: The use of levothyroxine to treat subclinical hypothyroidism is controversial. We aimed to determine whether levothyroxine provided clinical benefits in older persons with this condition. METHODS: We conducted a double-blind, randomized, placebo-controlled, parallel-group trial involving 737 adults who were at least 65 years of age and who had persisting subclinical hypothyroidism (thyrotropin level, 4.60 to 19.99 mIU per liter; free thyroxine level within the reference range). A total of 368 patients were assigned to receive levothyroxine (at a starting dose of 50 µg daily, or 25 µg if the body weight was <50 kg or the patient had coronary heart disease), with dose adjustment according to the thyrotropin level; 369 patients were assigned to receive placebo with mock dose adjustment. The two primary outcomes were the change in the Hypothyroid Symptoms score and Tiredness score on a thyroid-related quality-of-life questionnaire at 1 year (range of each scale is 0 to 100, with higher scores indicating more symptoms or tiredness, respectively; minimum clinically important difference, 9 points). RESULTS: The mean age of the patients was 74.4 years, and 396 patients (53.7%) were women. The mean (±SD) thyrotropin level was 6.40±2.01 mIU per liter at baseline; at 1 year, this level had decreased to 5.48 mIU per liter in the placebo group, as compared with 3.63 mIU per liter in the levothyroxine group (P<0.001), at a median dose of 50 µg. We found no differences in the mean change at 1 year in the Hypothyroid Symptoms score (0.2±15.3 in the placebo group and 0.2±14.4 in the levothyroxine group; between-group difference, 0.0; 95% confidence interval [CI], -2.0 to 2.1) or the Tiredness score (3.2±17.7 and 3.8±18.4, respectively; between-group difference, 0.4; 95% CI, -2.1 to 2.9). No beneficial effects of levothyroxine were seen on secondary-outcome measures. There was no significant excess of serious adverse events prespecified as being of special interest. CONCLUSIONS: Levothyroxine provided no apparent benefits in older persons with subclinical hypothyroidism. (Funded by European Union FP7 and others; TRUST ClinicalTrials.gov number, NCT01660126 .).

The impact of maternal stress on infant alpha-amylase is buffered by high infant regulation and low infant negative reactivity.

This study examined the main and interactive effects of maternal perceived stress and infant temperament-surgency, negative affectivity, and orienting/regulation-on infant salivary alpha-amylase (sAA) responses to stress. Saliva samples were collected prior to and following two naturalistic stressors: maternal separation conducted at 9 months and blood draw/immunizations conducted at 12 months. sAA area under the curve (AUC) was computed to determine response of the sympathetic nervous system to each stressor. Results revealed significant interactions of maternal stress and infant negative affectivity and orienting/regulation with sAA AUC. Relations between maternal stress and infant sAA AUC were stronger among infants with higher levels of negative affectivity and lower levels of orienting/regulation. These results highlight the need to examine both infant characteristics and environmental factors when investigating the development of stress response systems.

Indicators for early assessment of palliative care in lung cancer patients: a population study using linked health data.

BACKGROUND: Analysing linked, routinely collected data may be useful to identify characteristics of patients with suspected lung cancer who could benefit from early assessment for palliative care. The aim of this study was to compare characteristics of newly diagnosed lung cancer patients dying within 30 days of diagnosis (short term survivors) with those surviving more than 30 days. To identify indicators for early palliative care assessment we distinguished between characteristics available at diagnosis (age, gender, smoking status, marital status, comorbid disease, admission type, tumour stage and histology) from those available post diagnosis. A second aim was to examine the association between receiving any tumour-directed treatment, place of death and survival time. METHODS: A retrospective observational population based study comparing lung cancer patients who died within 30 days of diagnosis (short term survivors) with those who survived longer using Chi-squared tests and logistic regression. Incident lung cancer (ICD-03:C34) patients diagnosed 2005-2012 inclusive who died before 01-01-2014 (n = 14,228) were identified from the National Cancer Registry of Ireland linked to death certificate data and acute hospital episode data. RESULTS: One in five newly diagnosed lung cancer patients died within 30 days of diagnosis. After adjusting for stage and histology, death within 30 days was higher in patients who were aged 80 years or older (adjusted OR 2.46; 95%CI 2.05-3.96; p < 0.001), patients with emergency admissions at diagnosis (adjusted OR 2.96; 95%CI 2.61-3.37; p < 0.001) and patients with any comorbidities at diagnosis (adjusted OR 1.32 95%CI 1.15-1.52; p < 0.001). Overall, 75% of those who died within 30 days died in hospital compared to 43% of longer term survivors. CONCLUSIONS: We have shown a high proportion of lung cancer patients who die within 30 days of diagnosis are older, have comorbidities and are admitted through the emergency department. These characteristics, available at diagnosis, may be useful prognostic factors to guide decisions on early assessment for palliative care for lung cancer patients. Patients who die shortly after diagnosis are more likely to die in hospital so reporting place of death by survival time may be useful to evaluate interventions to reduce deaths in acute hospitals.