Allosteric modulation by the fatty acid site in the glycosylated SARS-CoV-2 spike

The spike protein is essential to the SARS-CoV-2 virus life cycle, facilitating virus entry and mediating viral-host membrane fusion. The spike contains a fatty acid (FA) binding site between every two neighbouring receptor-binding domains. This site is coupled to key regions in the protein, but the impact of glycans on these allosteric effects has not been investigated. Using dynamical nonequilibrium molecular dynamics (D-NEMD) simulations, we explore the allosteric effects of the FA site in the fully glycosylated spike of the SARS-CoV-2 ancestral variant. Our results identify the allosteric networks connecting the FA site to functionally important regions in the protein, including the receptor-binding motif, an antigenic supersite in the N-terminal domain, the fusion peptide region, and another allosteric site known to bind heme and biliverdin. The networks identified here highlight the complexity of the allosteric modulation in this protein and reveal a striking and unexpected link between different allosteric sites. Comparison of the FA site connections from D-NEMD in the glycosylated and non-glycosylated spike revealed that glycans do not qualitatively change the internal allosteric pathways but can facilitate the transmission of the structural changes within and between subunits

On the extension of positive maps to Haagerup noncommutative L ^p-spaces

Let M be a von Neumann algebra, let φ be a normal faithful state on M and let Lp(M,φ) be the associated Haagerup noncommutative Lp-spaces, for 1≤p≤∞. Let D∈L1(M,φ) be the density of φ. Given a positive map T:M→M such that φ∘T≤C1φ for some C1≥0, we study the boundedness of the Lp-extension Tp,θ:D1−θpMDθp→Lp(M,φ) which maps D1−θpxDθp to D1−θpT(x)Dθp for all x∈M. Haagerup–Junge–Xu showed that Tp,12 is always bounded and left open the question whether Tp,θ is bounded for θ≠12. We show that for any 1≤p<2 and any θ∈[0,2−1(1−p−1−−−−√)]∪[2−1(1+p−1−−−−√),1], there exists a completely positive T such that Tp,θ is unbounded. We also show that if T is 2-positive, then Tp,θ is bounded provided that p≥2 or 1≤p<2 and θ∈[1−p/2,p/2]

Distinct pathway-based effects of blood pressure and body mass index on cardiovascular traits:comparison of novel Mendelian Randomization approaches

Background: Mendelian randomization (MR) leverages trait associated genetic variants as instrumental variables (IVs) to determine causal relationships in epidemiology. However, genetic IVs for complex traits are typically highly heterogeneous and, at a molecular level, exert effects on different biological processes. Exploration of the biological underpinnings of such heterogeneity can enhance our understanding of disease mechanisms and inform therapeutic strategies. Here, we introduce a new approach to instrument partitioning based on enrichment of Mendelian disease categories (Pathway-partitioned) and compare it to an existing method based on genetic colocalisation in contrasting tissues (Tissue-partitioned).Methods: We employed individual- and summary-level MR methodologies using SNPs grouped by pathway informed by proximity to Mendelian disease genes affecting the renal system or vasculature (for blood-pressure (BP)), or mental health and metabolic disorders (for body-mass index (BMI)). We compared the causal effects of Pathway-partitioned SNPs on cardiometabolic outcomes with those derived using Tissue-partitioned SNPs informed by colocalization with gene expression in kidney, artery (BP), or adipose and brain tissues (BMI). Additionally, we assessed the likelihood that estimates observed for partitioned exposures could emerge by chance using random SNP sampling.Results: Our Pathway-partitioned findings suggest the causal relationship between systolic BP and heart disease is predominantly driven by vessel- over renal-pathways. The stronger effect attributed to kidney- over artery-tissue in our Tissue-partitioned MR hints at a multifaceted interplay between pathways in the disease aetiology. We consistently identified a dominant role for vessel (Pathway) and artery (Tissue) driving the negative directional effect of diastolic BP on left ventricular stroke volume and positive directional effect of systolic BP on type-2 diabetes. We also found when dissecting the BMI pathway contribution to atrial fibrillation that metabolic-Pathway and brain-Tissue IVs predominantly drove the causal effects relative to mental-health and adipose in Pathway- and Tissue-partitioned MR analyses respectively. Conclusions: This study presents a novel approach to dissecting heterogeneity in MR by integrating clinical phenotypes associated with Mendelian disease. Our findings emphasize the importance of understanding pathway-/ tissue- specific contributions to complex exposures when interpreting causal relationships in MR. Importantly, we advocate caution and robust validation when interpreting pathway-partitioned effect size differences

Healthcare Professionals’ Emotions of Distance and Connection When Dealing With Patients’ Vaccine Hesitancy:Interaction Styles, Values, and Implications

Healthcare professionals (HCPs) play a primary role in the delivery of population-based vaccination programs. Their emotional well-being can influence the quality of their relationships with patients and generally the outcome of their consultations. This qualitative study sought to identify the types of emotions that HCPs feel during conversations with vaccine-hesitant patients and their styles of interaction. Semi-structured interviews were conducted between June and November 2022 with 41 HCPs (mainly general practitioners and nurses) responsible for vaccinating patients: 23 in England and 18 in France. Framework analysis showed that participants reported numerous emotions, some associated with connection to patients (such as self-confidence and satisfaction) and others with distance (including anger, frustration, unease, and exhaustion). We identified four clusters of emotions reported together when reflecting on interactions with vaccine-hesitant patients: “self-confidence and emotional empathy” (satisfaction, sadness regarding the patient’s situation); “anxiety and insecurity” (doubts about skills, concern for the patients); “exhaustion and weariness” (feeling of incompetence, nervousness); and “discredit and frustration” (feeling discredited, anger). Three styles of interaction were identified: most HCPs reassured and encouraged patients to get vaccinated (“patient-centered” style), some sought to convince them (“adamant” style), and some to inform them without discussion (“detached” style). In our study, HCPs describing a patient-centered interaction style emphasized emotions of connection more than of distance in their discourse, in contrast to those describing an adamant or detached style. Our results suggest that training programs offered to HCPs involved in vaccination discussions should consider the importance of emotions associated with vaccine discussions

What effects does carbohydrate counting to manage insulin-to-food dosage calculations have on behaviours and cognitions related to food and/or disordered eating?:A scoping review

Aims:Carbohydrate counting (CC) is often assumed to contribute to the high prevalence of disordered eating behaviour (DEB) seen in patients with type 1 diabetes. The aim of this project was to evaluate evidence, and measures used to explore associations between CC in type 1 diabetes and eating behaviour and/or DEB.Methods:Systematic literature searches for studies including carbohydrate counting or dose adjustment for normal eating (DAFNE), and specific eating behaviours and/or disordered eating using MEDLINE, Embase, PsycINFO, Web of Science and Scopus and the trial register Cochrane Central Register of Controlled Trials were conducted and tabulated for narrative synthesis.Results:Thirty-seven studies were included. 93% of studies that measured CC and eating behaviours reported an association between CC and eating behaviours (e.g. eating more or less of a particular food group); or cognitions about food (e.g. diet flexibility or restriction). 28% measured CC and DEB, of which 50% (n = 4) stated that people scoring highly for DEB are less likely to use CC. Measuring CC adherence in interventions was rare (22%). Responsibility for CC was not defined in paediatric studies, and only one study examined specific CC strategies.Conclusion:Evidence suggests that CC does influence changes in eating behaviour. Also limited empirical research suggests that patients who exhibit DEB are less likely to use CC. Measures for CC were limited and did not adequately measure adherence, transitions from parent-led to self-led management, the spectrum of CC strategies employed, or the reasons for the adaption/rejection of CC

Late Miocene weakening of the South Asian Monsoon:Insights from the Siwalik of Nepal

The South Asian Monsoon (SAM) is the strong summer monsoon within the Asian Monsoon System, driven by the thermal gradient between the warmer Asian landmass and the cooler Indian Ocean. High-resolution marine proxies indicate a decline in SAM strength after approximately 10 million years ago (Ma); however, terrestrial evidence has been limited. We present high-resolution and well-dated leaf assemblages from the Lower and Middle Siwalik of central Nepal, supported by paleoclimate modelling, which suggest a weakening of the SAM between 10.24 and 8.5 Ma. This decline is linked to a reduction in moisture supply, possibly due to a weakening of the Somali Jet. Our study highlights the potential of leaf physiognomy to reconstruct monsoon strength

Directed evolution of a beta‐lactamase samples a wide variety of conformational states

In directed evolution, enzyme activity is improved in successive generations of laboratory evolution, which can be described by a simple stepwise climb toward a peak in the fitness landscape. In a naive model of evolution, it can be assumed that each enzyme variant along this path is in a single, well‐defined state that differs slightly from the previous one. We analyzed the structural changes in mutants of the β‐lactamase BlaC from Mycobacterium tuberculosis obtained via directed evolution for increased ceftazidime hydrolysis activity. Crystal structures of three successive mutants only show an increase in the dynamics of a loop that lines the active site (Ω‐loop), enabling better access of the large substrate. However, NMR spectra of wild type and nine mutants of different branches of the directed evolution experiment show a much more diverse and complex picture of the conformational effects. Many mutants show micro‐millisecond dynamics for certain regions and most show peak doubling, indicative of two or more conformations being populated. Thus, the straightforward climb to increased ceftazidime activity in the fitness landscape masks a complex trajectory in the conformational landscape, emphasizing the complex and epistatic interplay that single mutations can have on the structure and dynamics of enzymes