Structural Dynamics of the Ubiquitin Specific Protease USP30 in Complex with a Cyanopyrrolidine-Containing Covalent Inhibitor.

Inhibition of the mitochondrial deubiquitinating (DUB) enzyme USP30 is neuroprotective and presents therapeutic opportunities for the treatment of idiopathic Parkinson's disease and mitophagy-related disorders. We integrated structural and quantitative proteomics with biochemical assays to decipher the mode of action of covalent USP30 inhibition by a small-molecule containing a cyanopyrrolidine reactive group, . The inhibitor demonstrated high potency and selectivity for endogenous USP30 in neuroblastoma cells.

Valproic Acid Causes Redox-Regulated Post-Translational Protein Modifications That Are Dependent upon P19 Cellular Differentiation States.

Valproic acid (VPA) is a common anti-epileptic drug and known neurodevelopmental toxicant. Although the exact mechanism of VPA toxicity remains unknown, recent findings show that VPA disrupts redox signaling in undifferentiated cells but has little effect on fully differentiated neurons. Redox imbalances often alter oxidative post-translational protein modifications and could affect embryogenesis if developmentally critical proteins are targeted.

Revised contraindications for the use of non-medical WB-electromyostimulation. Evidence-based German consensus recommendations.

Whole-body electromyostimulation has proven to be a highly effective alternative to conventional resistance-type exercise training. However, due to adverse effects in the past, very extensive contraindications have been put in place for the commercial, non-medical WB-EMS market. Considering recent positive innovations e.

Novel mechanisms of diversity generation in Acinetobacter baumannii resistance islands driven by Tn7-like elements.

Mobile genetic elements play an important role in the acquisition of antibiotic and biocide resistance, especially through the formation of resistance islands in bacterial chromosomes. We analyzed the contribution of Tn7-like transposons to island formation and diversification in the nosocomial pathogen Acinetobacter baumannii and identified four separate families that recognize different integration sites. One integration site is within the comM gene and coincides with the previously described Tn6022 elements suggested to account for the AbaR resistance island.

Structural Premise of Selective Deubiquitinase USP30 Inhibition by Small-Molecule Benzosulfonamides.

Dampening functional levels of the mitochondrial deubiquitylating enzyme Ubiquitin-specific protease 30 (USP30) has been suggested as an effective therapeutic strategy against neurodegenerative disorders such as Parkinson's Disease. USP30 inhibition may counteract the deleterious effects of impaired turnover of damaged mitochondria, which is inherent to both familial and sporadic forms of the disease. Small-molecule inhibitors targeting USP30 are currently in development, but little is known about their precise nature of binding to the protein.

Operationalising targeted next-generation sequencing for routine diagnosis of drug-resistant TB.

Background: Phenotypic drug susceptibility testing (pDST) for can take up to 8 weeks, while conventional molecular tests identify a limited set of resistance mutations. Targeted next-generation sequencing (tNGS) offers rapid results for predicting comprehensive drug resistance, and this study sought to explore its operational feasibility within a public health laboratory in Mumbai, India.

Methods: Pulmonary samples from consenting patients testing Xpert MTB-positive were tested for drug resistance by conventional methods and using tNGS.

Clinical utility of target-based next-generation sequencing for drug-resistant TB.

In high TB burden countries, access to drug susceptibility testing is a major bottleneck. Targeted next-generation sequencing (tNGS) is a promising technology for rapid resistance detection. This study assessed the role of tNGS for the diagnosis of drug-resistant TB (DR-TB).

The adverse effect of ambient temperature on respiratory deaths in a high population density area: the case of Malta.

Background: The effect of ambient temperature on respiratory mortality has been consistently observed throughout the world under different climate change scenarios. Countries experiencing greater inter-annual variability in winter temperatures (and may not be lowest winter temperatures) have greater excess winter mortality compared to countries with colder winters. This study investigates the association between temperature and respiratory deaths in Malta which has one of the highest population densities in the world with a climate that is very hot in summer and mild in winter.

The impact of COVID-19 on rural treatment-seeking families with children with overweight or obesity.

To examine the early impact of the COVID-19 pandemic on rural parental stress and family behaviors, parents who participated in a 2-4 grade pediatric obesity intervention completed a survey in May 2020. Parents (N=77) experienced 7.8±2.

The Impact of the COVID-19 Pandemic on Healthy Lifestyles in Rural Families.

The purpose of the current study is to understand how the early portion of COVID-19 pandemic impacted the health behaviors of rural families participating in a healthy lifestyles intervention. Caregivers of rural children participating in a healthy lifestyles intervention were invited to participate in a structured interview regarding how the COVID-19 pandemic affected their family and family health behaviors. Interviews were transcribed and the research team conducted a rigorous inductive thematic analysis.

Developing a model for health determinants research within local government: lessons from a large, urban local authority.

Socio-economic, cultural and environmental conditions strongly affect health across the life course. Local government plays a key role in influencing these wider determinants of health and levels of inequality within their communities. However, they lack the research infrastructure and culture that would enable them to develop an evidence-based approach to tackling the complex drivers of those conditions.

Relative Effectiveness of Four Different Guards In Preventing Beaver Cutting of Urban Trees.

Beavers are expanding into cities as they recolonize their historic range. While they increase the ecological functioning of urban green areas, human-beaver conflicts occur. Public support to deal with conflicts has shifted from population to forage control.

Palliative Care Practice During the COVID-19 Pandemic: A Descriptive Qualitative Study of Palliative Care Clinicians.

Context: COVID-19 created unprecedented demand for palliative care at a time when in-person communication was highly restricted, straining efforts to care for patients and families.

Objectives: To qualitatively explore the challenges presented by the COVID-19 pandemic from the perspective of palliative care clinicians. Specifically we sought to: 1) Describe the strategies adopted by palliative care clinicians to cope with new challenges including patient and clinician isolation, prognostication of an emergent disease, and rapidly rising numbers of severely ill patients; 2) Identify additions or adjustments to in-person and system-related palliative care training, methods, and tools made during pandemics.

Development of a Risk Behavior Diagnosis Scale for E-cigarette Use.

Adolescent use of electronic cigarettes has risen dramatically, prompting concerns about the health effects. There is need for brief measures to assess adolescents' perceived threat and efficacy related to e-cigarette use and cessation. A 12-item Likert-type scale was modeled after the Risk Behavior Diagnosis Scale and designed to assess threat (ie, severity and susceptibility of threat) and efficacy (ie, self-efficacy and response efficacy) as they relate to e-cigarette use.

When the patients stayed home: the impact of the COVID-19 pandemic on acute cardiac admissions and cardiac mortality in Malta.

Aim: This study aimed to investigate the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on all types of acute cardiac admissions (ACAs) and cardiac mortality in Malta.

Methods: Number, characteristics and delay to presentation of ACAs to our institution during the study period (28 February-30 April 2020) were compared with the corresponding 2019 period. Non-parametric correlation analyses between daily SARS-CoV-2 cases in Malta, Italy and the UK and daily ACAs were performed.

The utility of arterial blood gas parameters and chest radiography in predicting appropriate intubations in burn patients with suspected inhalation injury-A retrospective cohort study.

Background: This study evaluates the utility of arterial blood gas (ABG) parameters and chest radiography in predicting intubation need in patients with burn injuries with suspected inhalation injury.

Methods: Patients with suspected inhalation injury admitted to a single centre, Burn Intensive Care Unit, between April 4th 2016 and July 5th 2019, were included. Admission ABG parameters and chest radiograph opacification were compared with whether the patient received an appropriate intubation: defined as intubation for a duration of over 48 h.

Cervical cancer and screening: knowledge, awareness and attitudes of women in Malta.

Objectives: This study comes at an opportune time due to recent introduction of the National Cervical Cancer Screening programme in Malta. It aims to assess the knowledge of 25-64 year-old females on cervical cancer and attitudes towards screening.

Study Design: A cross-sectional, telephone-based, quantitative survey conducted in 2017.

Real-time monitoring shows substantial excess all-cause mortality during second wave of COVID-19 in Europe, October to December 2020.

The European monitoring of excess mortality for public health action (EuroMOMO) network monitors weekly excess all-cause mortality in 27 European countries or subnational areas. During the first wave of the coronavirus disease (COVID-19) pandemic in Europe in spring 2020, several countries experienced extraordinarily high levels of excess mortality. Europe is currently seeing another upsurge in COVID-19 cases, and EuroMOMO is again witnessing a substantial excess all-cause mortality attributable to COVID-19.

The effect of global warming on mortality.

There is a significant relationship between ambient temperature and mortality. In healthy individuals with no underlying co-morbid conditions, there is an efficient heat regulation system which enables the body to effectively handle thermal stress. However, in vulnerable groups, especially in elderly over the age of 65 years, infants and individuals with co-morbid cardiovascular and/or respiratory conditions, there is a deficiency in thermoregulation.

Rethink Vape: Development and evaluation of a risk communication campaign to prevent youth E-cigarette use.

Introduction: E-cigarettes are now the most common form of tobacco use among adolescents, and use is associated with increased risk of initiation of cigarette smoking. This project used a community-engaged research process to develop and pilot a risk communication campaign to prevent youth vaping.

Method: The research team worked with a 36-member Teen Advisory Council and a 19-member Expert Panel.

USP30 sets a trigger threshold for PINK1-PARKIN amplification of mitochondrial ubiquitylation.

The mitochondrial deubiquitylase USP30 negatively regulates the selective autophagy of damaged mitochondria. We present the characterisation of an N-cyano pyrrolidine compound, FT3967385, with high selectivity for USP30. We demonstrate that ubiquitylation of TOM20, a component of the outer mitochondrial membrane import machinery, represents a robust biomarker for both USP30 loss and inhibition.