Delivery determinants of an type VI secretion system bifunctional peptidoglycan hydrolase.

is a Gram-negative opportunistic pathogen and is a common cause of nosocomial infections. The increasing development of antibiotic resistance in this organism is a global health concern. The clinical isolate AB307-0294 produces a type VI secretion system (T6SS) that delivers three antibacterial effector proteins that give this strain a competitive advantage against other bacteria in polymicrobial environments.

Unclear Trajectory and Uncertain Benefit: Creating a Lexicon for Clinical Uncertainty in Patients with Critical or Advanced Illness Using a Delphi Consensus Process.

Background: Clinical uncertainty is associated with increased resource utilization, worsened health-related quality of life for patients, and provider burnout, particularly during critical illness. Existing data are limited, because determining uncertainty from notes typically requires manual, qualitative review. We sought to develop a consensus list of descriptors of clinical uncertainty and then, using a thematic analysis approach, describe how respondents consider their use in intensive care unit (ICU) notes, such that future work can extract uncertainty data at scale.

Riverine connectivity modulates elemental fluxes through a 200- year period of intensive anthropic change in the Magdalena River floodplains, Colombia.

Tropical floodplain lakes are increasingly impacted by human activities, yet their pathways of spatial and temporal degradation, particularly under varying hydrological connectivity regimes and climate change, remain poorly understood. This study examines surface-sediment samples and Pb-dated sediment cores from six floodplain lakes, representing a gradient in hydrological connectivity in the lower Magdalena River Basin, Colombia. We analysed temporal and spatial variations in several sediment biogeochemical indicators: the concentration and flux of nutrients, heavy metals, and organic matter (OM), and redox conditions, flooding and erosion.

Identification of lipid senolytics targeting senescent cells through ferroptosis induction.

Cellular senescence is a key driver of the aging process and contributes to tissue dysfunction and age-related pathologies. Senolytics have emerged as a promising therapeutic intervention to extend healthspan and treat age-related diseases. Through a senescent cell-based phenotypic drug screen, we identified a class of conjugated polyunsaturated fatty acids, specifically α-eleostearic acid and its methyl ester derivative, as novel senolytics that effectively killed a broad range of senescent cells, reduced tissue senescence, and extended healthspan in mice.

Structure of a Rhs effector clade domain provides mechanistic insights into type VI secretion system toxin delivery.

The type VI secretion system (T6SS) is a molecular machine utilised by many Gram-negative bacteria to deliver antibacterial toxins into adjacent cells. Here we present the structure of Tse15, a T6SS Rhs effector from the nosocomial pathogen Acinetobacter baumannii. Tse15 forms a triple layered β-cocoon Rhs domain with an N-terminal α-helical clade domain and an unfolded C-terminal toxin domain inside the Rhs cage.

Living less safely through the pandemic in England for people with serious mental and physical health conditions: qualitative interviews with service users and carers of Black African, Caribbean, and South-Asian descent.

Background: COVID-19 Ethnic Inequalities in Mental health and Multimorbidities (COVEIMM) is a mixed methods study to explore whether COVID-19 exacerbated ethnic health inequalities in adults with serious mental and physical health conditions. We analysed data from electronic health records for England and conducted interviews in Birmingham and Solihull, Manchester, and South London. Sites were selected because they were pilot sites for the Patient and Carer Race Equality Framework being introduced by NHS England to tackle race inequalities in mental health.

Positive Intervertebral Discs Are Not Associated with Subsidence Following Anterior Cervical Discectomy and Fusion at 3 or 6 Months.

(), formerly known as (), is an anaerobic, low-virulent bacterium that has been associated with postoperative infections of the shoulder, knee, and cervical spine. Recent studies have highlighted an association between and the development of degenerative disc disease (DDD). The aim of this study is to ascertain whether increases the risk of subsidence following anterior cervical discectomy and fusion (ACDF).

"My Mom Is a Fighter": A Qualitative Analysis of the Use of Combat Metaphors in ICU Clinician Notes.

Background: A metaphor conceptualizes one, typically abstract, experience in terms of another, more concrete, experience with the goal of making it easier to understand. Although combat metaphors have been well described in some health contexts, they have not been well characterized in the setting of critical illness.

Research Question: How do clinicians use combat metaphors when describing critically ill patients and families in the electronic health record?

Study Design And Methods: We included notes written about patients aged 18 years or older admitted to ICUs within a large hospital system from 2012 through 2020.

Using lake sediments to assess the long-term impacts of anthropogenic activity in tropical river deltas.

Tropical river deltas, and the social-ecological systems they sustain, are changing rapidly due to anthropogenic activity and climatic change. Baseline data to inform sustainable management options for resilient deltas is urgently needed and palaeolimnology (reconstructing past conditions from lake or wetland deposits) can provide crucial long-term perspectives needed to identify drivers and rates of change. We review how palaeolimnology can be a valuable tool for resource managers using three current issues facing tropical delta regions: hydrology and sediment supply, salinisation and nutrient pollution.

Development of an early intervention in psychosis services fidelity questionnaire.

Purpose: We describe the development of an online fidelity questionnaire for early intervention in psychosis (EIP) services, to be used in population-level research, and that can be completed using self-reports from EIP staff.

Methods: A review of key literature sources on the components of EIP services was used to identify those components eligible for inclusion in the questionnaire. A modified Delphi approach, using experts in EIP services, was used to select the most important components to include in the questionnaire.

Preliminary evaluation of a questionnaire for assessing fidelity of early intervention for psychosis services.

Purpose: Fast, easy, and cost-effective methods are needed for fidelity assessment, quality improvement initiatives, and population-based studies in Early Intervention for Psychosis (EIP) services. Having an online questionnaire assessing the fidelity of EIP services, completed by staff self-reports, and having evidence of reliability and validity, could fill that gap. We assess the reliability and validity of the Early Intervention for Psychosis Services Fidelity Questionnaire (EIPS-FQ), developed in Part I of this set of papers.

Unravelling long-term impact of water abstraction and climate change on endorheic lakes: A case study of Shortandy Lake in Central Asia.

Endorheic lakes, lacking river outflows, are highly sensitive to environmental changes and human interventions. Central Asia (CA) has over 6000 lakes that have experienced substantial water level variability in the past century, yet causes of recent changes in many lakes remain unexplored. Modelling hydrological processes for CA lakes poses challenges in separating climatic change impacts from human management impacts due to limited data and long-term variability in hydrological regimes.

Chemoproteomics validates selective targeting of M1 alanyl aminopeptidase as an antimalarial strategy.

New antimalarial drug candidates that act via novel mechanisms are urgently needed to combat malaria drug resistance. Here, we describe the multi-omic chemical validation of M1 alanyl metalloaminopeptidase as an attractive drug target using the selective inhibitor, MIPS2673. MIPS2673 demonstrated potent inhibition of recombinant (A-M1) and (A-M1) M1 metalloaminopeptidases, with selectivity over other and human aminopeptidases, and displayed excellent in vitro antimalarial activity with no significant host cytotoxicity.

Chemoproteomics validates selective targeting of Plasmodium M1 alanyl aminopeptidase as an antimalarial strategy.

New antimalarial drug candidates that act via novel mechanisms are urgently needed to combat malaria drug resistance. Here, we describe the multi-omic chemical validation of M1 alanyl metalloaminopeptidase as an attractive drug target using the selective inhibitor, MIPS2673. MIPS2673 demonstrated potent inhibition of recombinant ( A-M1) and ( A-M1) M1 metalloaminopeptidases, with selectivity over other and human aminopeptidases, and displayed excellent antimalarial activity with no significant host cytotoxicity.

On-target, dual aminopeptidase inhibition provides cross-species antimalarial activity.

To combat the global burden of malaria, development of new drugs to replace or complement current therapies is urgently required. Here, we show that the compound is a selective, nanomolar inhibitor of both and aminopeptidases M1 and M17, leading to inhibition of end-stage hemoglobin digestion in asexual parasites. can kill sexual-stage , is active against murine malaria, and does not show any shift in activity against a panel of parasites resistant to other antimalarials.

Transient social-ecological dynamics reveal signals of decoupling in a highly disturbed Anthropocene landscape.

Understanding the transient dynamics of interlinked social-ecological systems (SES) is imperative for assessing sustainability in the Anthropocene. However, how to identify critical transitions in real-world SES remains a formidable challenge. In this study, we present an evolutionary framework to characterize these dynamics over an extended historical timeline.

Tumor Biomechanics Alters Metastatic Dissemination of Triple Negative Breast Cancer via Rewiring Fatty Acid Metabolism.

In recent decades, the role of tumor biomechanics on cancer cell behavior at the primary site has been increasingly appreciated. However, the effect of primary tumor biomechanics on the latter stages of the metastatic cascade, such as metastatic seeding of secondary sites and outgrowth remains underappreciated. This work sought to address this in the context of triple negative breast cancer (TNBC), a cancer type known to aggressively disseminate at all stages of disease progression.

BTB domain mutations perturbing KCTD15 oligomerisation cause a distinctive frontonasal dysplasia syndrome.

Introduction: encodes an oligomeric BTB domain protein reported to inhibit neural crest formation through repression of Wnt/beta-catenin signalling, as well as transactivation by TFAP2. Heterozygous missense variants in the closely related paralogue KCTD1 cause scalp-ear-nipple syndrome.

Methods: Exome sequencing was performed on a two-generation family affected by a distinctive phenotype comprising a lipomatous frontonasal malformation, anosmia, cutis aplasia of the scalp and/or sparse hair, and congenital heart disease.

Drebrin is Required for Myosin-facilitated Actin Cytoskeletal Remodeling during Pulmonary Alveolar Development.

Alveolar septation increases gas-exchange surface area and requires coordinated cytoskeletal rearrangement in lung fibroblasts (LFs) to balance the demands of contraction and cell migration. We hypothesized that DBN (drebrin), a modulator of the actin cytoskeleton in neuronal dendrites, regulates the remodeling of the LF cytoskeleton. Using mice bearing a transgelin-Cre-targeted deletion of Dbn in pulmonary fibroblasts and pericytes, we examined alterations in alveolar septal outgrowth, LF spreading and migration, and actomyosin function.