Structural and functional insights into the delivery of a bacterial Rhs pore-forming toxin to the membrane.

Bacterial competition is a significant driver of toxin polymorphism, which allows continual compensatory evolution between toxins and the resistance developed to overcome their activity. Bacterial Rearrangement hot spot (Rhs) proteins represent a widespread example of toxin polymorphism. Here, we present the 2.45 Å cryo-electron microscopy structure of Tse5, an Rhs protein central to Pseudomonas aeruginosa type VI secretion system-mediated bacterial competition. This structural insight, coupled with an extensive array of biophysical and genetic investigations, unravels the multifaceted functional mechanisms of Tse5. The data suggest that interfacial Tse5-membrane binding delivers its encapsulated pore-forming toxin fragment to the target bacterial membrane, where it assembles pores that cause cell depolarisation and, ultimately, bacterial death.

The Impact of COVID-19 on the Cardiovascular Health of Emerging Adults Aged 18-25: Findings From a Scoping Review.

There is limited knowledge regarding the cardiovascular impact of coronavirus disease 2019 (COVID-19) on emerging adults aged 18-25, a group that disproportionately contracts COVID-19. To guide future cardiovascular disease (CVD) research, policy, and practice, a scoping review was conducted to: (i) examine the impact of the COVID-19 pandemic on the cardiovascular health of emerging adults; and (ii) identify strategies to screen for and manage COVID-19-related cardiovascular complications in this age group. A comprehensive search strategy was applied to several academic databases and grey literature sources. An updated search yielded 6738 articles, 147 of which were extracted and synthesized. Reports identified COVID-19-associated cardiac abnormalities, vascular alterations, and multisystem inflammatory syndrome in emerging adults; based on data from student-athlete samples, prevalence estimates of myocarditis and cardiac abnormalities were 0.5%-3% and 0%-7%, respectively. Obesity, hypertension, CVD, congenital heart disease, and marginalization are potential risk factors for severe COVID-19, related cardiovascular complications, and mortality in this age group. As a screening modality for COVID-19-associated cardiac involvement, it is recommended that cardiac magnetic resonance imaging be indicated by a positive cardiac history and/or abnormal "triad" testing (cardiac troponin, electrocardiogram, and transthoracic echocardiogram) to improve diagnostic utility. To foster long-term cardiovascular health among emerging adults, cardiorespiratory fitness, health literacy and education, and telehealth accessibility should be priorities of health policy and clinical practice. Ultimately, surveillance data from the broader emerging adult population will be crucial to assess the long-term cardiovascular impact of both COVID-19 infection and vaccination, guide screening and management protocols, and inform CVD prevention efforts.

Il existe peu de données portant sur les répercussions de la maladie à coronavirus 2019 (COVID-19) sur le plan cardiovasculaire chez les jeunes adultes âgés de 18 à 25 ans, un groupe contractant la COVID-19 de façon disproportionnée. Afin d'orienter la recherche, les poli-tiques et les pratiques en matière de maladies cardiovasculaires (MCV), un examen exploratoire a été réalisé dans le but i) d'examiner les conséquences de la pandémie de la COVID-19 sur la santé cardiovasculaire des jeunes adultes, et ii) de proposer des stratégies de dépistage et de prise en charge des complications cardiovasculaires associées à la COVID-19 chez les personnes de cette tranche d'âge. Une recherche initiale exhaustive a été réalisée dans plusieurs bases de données universitaires et sources de littérature grise. Les résultats actualisés de cette recherche ont permis de recenser 6 738 articles, dont 147 ont été extraits et synthétisés. Les rapports faisaient état d'anomalies cardiaques, d'altérations vasculaires et de cas du syndrome inflammatoire multisystémique, tous associés à la COVID-19 chez les jeunes adultes. À la lumière des données sur les échantillons d'étudiants-athlètes, la prévalence des myocardites et des anomalies cardiaques se situait respectivement entre 0,5 et 3 %, et entre 0 et 7 % environ. Chez ce même groupe d'âge, l'obésité, l'hypertension, les MCV, les cardiopathies congénitales et la marginalisation constituent des facteurs de risque de COVID-19 sévère, de complications cardiovasculaires associées à la COVID-19 et de mortalité. Dans le cadre du dépistage des atteintes cardiaques associées à la COVID-19, il est recommandé, pour améliorer l'utilité diagnostique, d'indiquer l'imagerie par résonance magnétique cardiaque lors de l'existence d'antécédents cardiaques ou à la suite d'une « triade ¼ de dépistages anormaux (la troponine cardiaque, l'électrocardiogramme et l'échocardiographie transthoracique). Afin de favoriser une bonne santé cardiovasculaire à long terme chez les jeunes adultes, il est recommandé que la capacité cardiorespiratoire, la littératie dans le domaine de la santé, l'éducation et l'accès à la télésanté soient intégrés à titre de priorités dans les politiques de santé et la pratique clinique. En définitive, les données de surveillance portant sur cette large tranche d'âge seront essentielles pour évaluer les répercussions cardiovasculaires à long terme (autant celles d'infections à la COVID-19 que celles de la vaccination), pour orienter les protocoles de dépistage et de prise en charge, ainsi que pour éclairer les efforts de prévention des MCV.

Identification of a broadly conserved family of enzymes that hydrolyze (p)ppApp.

Bacteria produce a variety of nucleotide second messengers to adapt to their surroundings. Although chemically similar, the nucleotides guanosine penta- and tetraphosphate [(p)ppGpp] and adenosine penta- and tetraphosphate [(p)ppApp] have distinct functions in bacteria. (p)ppGpp mediates survival under nutrient-limiting conditions and its intracellular levels are regulated by synthetases and hydrolases belonging to the RelA-SpoT homolog (RSH) family of enzymes. By contrast, (p)ppApp is not known to be involved in nutrient stress responses and is synthesized by RSH-resembling toxins that inhibit the growth of bacterial cells. However, it remains unclear whether there exists a family of hydrolases that specifically act on (p)ppApp to reverse its toxic effects. Here, we present the structure and biochemical characterization of adenosine 3'-pyrophosphohydrolase 1 (Aph1), the founding member of a monofunctional (p)ppApp hydrolase family of enzymes. Our work reveals that Aph1 adopts a histidine-aspartate (HD)-domain fold characteristic of phosphohydrolase metalloenzymes and its activity mitigates the growth inhibitory effects of (p)ppApp-synthesizing toxins. Using an informatic approach, we identify over 2,000 putative (p)ppApp hydrolases that are widely distributed across bacterial phyla and found in diverse genomic contexts, and we demonstrate that 12 representative members hydrolyze ppApp. In addition, our in silico analyses reveal a unique molecular signature that is specific to (p)ppApp hydrolases, and we show that mutation of two residues within this signature broadens the specificity of Aph1 to promiscuously hydrolyze (p)ppGpp in vitro. Overall, our findings indicate that like (p)ppGpp hydrolases, (p)ppApp hydrolases are widespread in bacteria and may play important and underappreciated role(s) in bacterial physiology.

Lack of evidence that Pseudomonas aeruginosa AmpDh3-PA0808 constitute a type VI secretion system effector-immunity pair.

Type VI secretion systems (T6SSs) are cell envelope-spanning protein complexes that Gram-negative bacteria use to inject a diverse arsenal of antibacterial toxins into competitor cells. Recently, Wang et al. reported that the H2-T6SS of Pseudomonas aeruginosa delivers the peptidoglycan recycling amidase, AmpDh3, into the periplasm of recipient cells where it is proposed to act as a peptidoglycan degrading toxin. They further reported that PA0808, the open reading frame downstream of AmpDh3, encodes an immunity protein that localizes to the periplasm where it binds to and inactivates intercellularly delivered AmpDh3, thus protecting against its toxic activity. Given that AmpDh3 has an established role in cell wall homeostasis and that no precedent exists for cytosolic enzymes moonlighting as T6SS effectors, we attempted to replicate these findings. We found that cells lacking PA0808 are not susceptible to bacterial killing by AmpDh3 and that PA0808 and AmpDh3 do not physically interact in vitro or in vivo. Additionally, we found no evidence that AmpDh3 is exported from cells, including by strains with a constitutively active H2-T6SS. Finally, subcellular fractionation experiments and a 1.97 Å crystal structure reveal that PA0808 does not contain a canonical signal peptide or localize to the correct cellular compartment to confer protection against a cell wall targeting toxin. Taken together, these results cast doubt on the assertion that AmpDh3-PA0808 constitutes an H2-T6SS effector-immunity pair.

Interventions to Support Mental Health among Those with Health Conditions That Present Risk for Severe Infection from Coronavirus Disease 2019 (COVID-19): A Scoping Review of English and Chinese-Language Literature.

This study aimed to address knowledge gaps related to the prevention and management of mental health responses among those with a condition that presents risk of severe COVID-19 infection. A scoping review that mapped English and Chinese-language studies (2019-2020) located in MEDLINE (Ovid), Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycInfo, Sociological Abstracts, Embase, China National Knowledge Infrastructure (CNKI), Wanfang Data, and Airiti Library was undertaken. Search terms related to COVID-19, mental health, and physical health were used and articles that included all three of these factors were extracted (n = 77). With the exception of one hospital-based pilot study, there were no intervention studies targeting mental health in those at risk of severe COVID-19 infection. Promising practices such as integrated care models that appropriately screen for mental health issues, address health determinants, and include use of digital resources were highlighted. Patient navigator programs, group online medical visits, peer support, and social prescribing may also support those with complex needs. Future policies need to address digital health access inequities and the implementation of multi-integrated health and social care. Furthermore, research is needed to comprehensively assess multi-integrated interventions that are resilient to public health crises.