Liquid-like condensates mediate competition between actin branching and bundling.

Cellular remodeling of actin networks underlies cell motility during key morphological events, from embryogenesis to metastasis. In these transformations, there is an inherent competition between actin branching and bundling, because steric clashes among branches create a mechanical barrier to bundling. Recently, liquid-like condensates consisting purely of proteins involved in either branching or bundling of the cytoskeleton have been found to catalyze their respective functions. Yet in the cell, proteins that drive branching and bundling are present simultaneously. In this complex environment, which factors determine whether a condensate drives filaments to branch or become bundled? To answer this question, we added the branched actin nucleator, Arp2/3, to condensates composed of VASP, an actin bundling protein. At low actin to VASP ratios, branching activity, mediated by Arp2/3, robustly inhibited VASP-mediated bundling of filaments, in agreement with agent-based simulations. In contrast, as the actin to VASP ratio increased, addition of Arp2/3 led to formation of aster-shaped structures, in which bundled filaments emerged from a branched actin core, analogous to filopodia emerging from a branched lamellipodial network. These results demonstrate that multi-component, liquid-like condensates can modulate the inherent competition between bundled and branched actin morphologies, leading to organized, higher-order structures, similar to those found in motile cells.

Steric pressure between glycosylated transmembrane proteins inhibits internalization by endocytosis.

Clathrin-mediated endocytosis is essential for the removal of transmembrane proteins from the plasma membrane in all eukaryotic cells. Many transmembrane proteins are glycosylated. These proteins collectively comprise the glycocalyx, a sugar-rich layer at the cell surface, which is responsible for intercellular adhesion and recognition. Previous work has suggested that glycosylation of transmembrane proteins reduces their removal from the plasma membrane by endocytosis. However, the mechanism responsible for this effect remains unknown. To study the impact of glycosylation on endocytosis, we replaced the ectodomain of the transferrin receptor, a well-studied transmembrane protein that undergoes clathrin-mediated endocytosis, with the ectodomain of MUC1, which is highly glycosylated. When we expressed this transmembrane fusion protein in mammalian epithelial cells, we found that its recruitment to endocytic structures was substantially reduced in comparison to a version of the protein that lacked the MUC1 ectodomain. This reduction could not be explained by a loss of mobility on the cell surface or changes in endocytic dynamics. Instead, we found that the bulky MUC1 ectodomain presented a steric barrier to endocytosis. Specifically, the peptide backbone of the ectodomain and its glycosylation each made steric contributions, which drove comparable reductions in endocytosis. These results suggest that glycosylation constitutes a biophysical signal for retention of transmembrane proteins at the plasma membrane. This mechanism could be modulated in multiple disease states that exploit the glycocalyx, from cancer to atherosclerosis.

Hepatitis C Treatment in People With HIV: Potential to Eliminate Disease and Disparity.

Access to direct acting antivirals (DAAs) may be associated with reductions in hepatitis C virus (HCV) viremia prevalence among people with human immunodeficiency virus (PWH). Among 3755 PWH, estimated HCV viremia prevalence decreased by 94.0% from 36% (95% confidence interval [CI], 27%-46%) in 2009 (pre-DAA era) to 2% (95% CI, 0%-4%) in 2021 (DAA era). Male sex, black race, and older age were associated with HCV viremia in 2009 but not in 2021. Injection drug use remained associated with HCV viremia in 2009 and 2021. Targeted interventions are needed to meet the HCV care needs of PWH who use drugs.

Lipid droplets as substrates for protein phase separation.

Membrane-associated protein phase separation plays critical roles in cell biology, driving essential cellular phenomena from immune signaling to membrane traffic. Importantly, by reducing dimensionality from three to two dimensions, lipid bilayers can nucleate phase separation at far lower concentrations compared with those required for phase separation in solution. How might other intracellular lipid substrates, such as lipid droplets, contribute to nucleation of phase separation? Distinct from bilayer membranes, lipid droplets consist of a phospholipid monolayer surrounding a core of neutral lipids, and they are energy storage organelles that protect cells from lipotoxicity and oxidative stress. Here, we show that intrinsically disordered proteins can undergo phase separation on the surface of synthetic and cell-derived lipid droplets. Specifically, we find that the model disordered domains FUS LC and LAF-1 RGG separate into protein-rich and protein-depleted phases on the surfaces of lipid droplets. Owing to the hydrophobic nature of interactions between FUS LC proteins, increasing ionic strength drives an increase in its phase separation on droplet surfaces. The opposite is true for LAF-1 RGG, owing to the electrostatic nature of its interprotein interactions. In both cases, protein-rich phases on the surfaces of synthetic and cell-derived lipid droplets demonstrate molecular mobility indicative of a liquid-like state. Our results show that lipid droplets can nucleate protein condensates, suggesting that protein phase separation could be key in organizing biological processes involving lipid droplets.

Mpox in People With Human Immunodeficiency Virus: Predictors of Diagnosis, Outcomes, and Vaccine Effectiveness in a Multisite Cohort.

INTRODUCTION: Since its global reemergence in 2022, monkeypox (mpox) has demonstrated increased incidence and severity among people with human immunodeficiency virus (HIV [PWH]). Predictors of mpox diagnosis, vaccination, and outcomes among PWH are limited. METHODS: We included PWH with primary care visits after 1 January 2022 at 9 US sites participating in the Centers for AIDS Research Network of Integrated Clinic Systems Network. We identified mpox diagnosed between 1 June 2022 and 31 May 2023, through a combination of polymerase chain reaction result, diagnosis code, and/or tecovirimat receipt. We examined validated clinical diagnoses, laboratory results, vaccine data, and patient reported outcomes. We evaluated relative risks (RR) of mpox diagnosis, hospitalization, tecovirimat treatment, and vaccine receipt. FINDINGS: Among 19 777 PWH in care, 413 mpox cases (all male sex at birth) occurred (2.2 cases/100 person-years). Age <40 years, geographic region, Hispanic/Latine ethnicity, lack of antiretroviral therapy, detectable HIV viral load, and recent bacterial sexually transmitted infection predicted mpox diagnosis. PWH with CD4 200-349 cells/mm3 were most likely to be hospitalized (adjusted RR, 3.20; 95% confidence interval: 1.44-7.09) compared to CD4 ≥500, but half as likely as those with CD4 <200 to receive tecovirimat. Overall, smallpox/mpox vaccine effectiveness of ≥1 vaccine was 71% (adjusted RR, 0.29; 95% confidence interval: .14-.47) at preventing mpox, and 86% or better with CD4 ≥350 or HIV viral suppression. Non-Hispanic Black PWH were less likely to be vaccinated than other racial/ethnic identities. INTERPRETATION: PWH not on antiretroviral therapy or with unsuppressed HIV were more likely to be diagnosed with, and hospitalized for, mpox. Mpox/smallpox vaccine effectiveness was high, inclusive of those with low CD4 count and HIV viremia.

Gender-affirming hormonal therapy induces a gender-concordant fecal metagenome transition in transgender individuals.

BACKGROUND: Limited data exists regarding gender-specific microbial alterations during gender-affirming hormonal therapy (GAHT) in transgender individuals. This study aimed to investigate the nuanced impact of sex steroids on gut microbiota taxonomy and function, addressing this gap. We prospectively analyzed gut metagenome changes associated with 12 weeks of GAHT in trans women and trans men, examining both taxonomic and functional shifts. METHODS: Thirty-six transgender individuals (17 trans women, 19 trans men) provided pre- and post-GAHT stool samples. Shotgun metagenomic sequencing was used to assess the changes in gut microbiota structure and potential function following GAHT. RESULTS: While alpha and beta diversity remained unchanged during transition, specific species, including Parabacteroides goldsteinii and Escherichia coli, exhibited significant abundance shifts aligned with affirmed gender. Overall functional metagenome analysis showed a statistically significant effect of gender and transition (R2 = 4.1%, P = 0.0115), emphasizing transitions aligned with affirmed gender, particularly in fatty acid-related metabolism. CONCLUSIONS: This study provides compelling evidence of distinct taxonomic and functional profiles in the gut microbiota between trans men and women. GAHT induces androgenization in trans men and feminization in trans women, potentially impacting physiological and health-related outcomes. TRIAL REGISTRATION: Clinicaltrials.gov NCT02185274.

Determinants of receipt of prostate cancer screening among men living with HIV enrolled in an urban HIV Clinic in the United States over the period of 2000-2020.

BACKGROUND: Prostate cancer is projected to account for the greatest proportion of cancer-related burden among men with HIV. However, incidence is reportedly lower than in men without HIV, potentially due to differences in screening. Factors influencing receipt of screening in men with HIV are unknown. We described receipt of prostate-specific antigen (PSA) testing and assessed factors for association with receipt of PSA test. METHODS: Demographics, measures of HIV and related care, and non-HIV care were assessed for association with receipt of first PSA test in men ≥40 years old each calendar year in 2000-2020 using univariable and multivariable Poisson regression. Models were additionally stratified by calendar period to identify changes in determinants of PSA test as prostate cancer screening guidelines changed. RESULTS: Men (n = 2,063) 72% Non-Hispanic Black, median age of 47 (IQR: 41, 53), contributed median of 4.7 years (IQR: 2.3, 10.0) of follow-up. Receipt of antiretroviral therapy (aIRR = 1.33; 95% CI: 1.14, 1.55), engagement in HIV care (aIRR = 2.09; 95% CI: 1.66, 2.62), history of testosterone-replacement therapy (aIRR = 1.34; 95% CI: 1.19, 1.50), urologist evaluation (aIRR = 1.66; 95% CI: 1.35, 2.05), and receipt of PSA test in preceding two years (no elevated PSA aIRR = 2.37; 95% CI: 2.16, 2.61; elevated PSA aIRR = 4.35; 95% CI: 3.24, 5.84) were associated with PSA testing in men aged 50 or older. Associations varied across calendar time. CONCLUSION: Findings suggest men with greater interaction with healthcare are more likely to receive PSA test. Measures of control of HIV did not appear to influence the decision to screen.

Cohort profile update: the Johns Hopkins HIV clinical cohort, 1989-2023.

The Johns Hopkins HIV Clinical Cohort, established in 1989, links comprehensive, longitudinal clinical data for adults with HIV receiving care in the Johns Hopkins John G. Bartlett Specialty Practice in Baltimore, Maryland, USA, to aid in understanding HIV care and treatment outcomes. Data include demographics, laboratory results, inpatient and outpatient visit information and clinical diagnoses, and prescribed and dispensed medications abstracted from medical records. A subset of patients separately consents to self-report patient-centric outcomes on standardized instruments approximately every 6 months, and another subset separately consents to contribute plasma and peripheral blood mononuclear cells to a linked specimen repository approximately annually. The cohort has cumulatively enrolled over 8000 people, with just under 2000 on average attending ≥ 1 HIV primary care visit in any given year. The cohort reflects the HIV epidemic in Baltimore: in 2021, median age was 57, 64% of participants were male, 77% were non-Hispanic Black, and 37% acquired HIV through injection drug use. This update to the cohort profile of the Johns Hopkins HIV Clinical Cohort illustrates both how the population of people with HIV in Baltimore, Maryland, USA has changed over three decades, and we have adapted data collection procedures over three decades to ensure this long-running cohort remains responsive to patient characteristics and research gaps in the provision of care to people with HIV and substance use.

Morphological control of bundled actin networks subject to fixed-mass depletion.

Depletion interactions are thought to significantly contribute to the organization of intracellular structures in the crowded cytosol. The strength of depletion interactions depends on physical parameters such as the depletant number density and the depletant size ratio. Cells are known to dynamically regulate these two parameters by varying the copy number of proteins of a wide distribution of sizes. However, mammalian cells are also known to keep the total protein mass density remarkably constant, to within 0.5% throughout the cell cycle. We thus ask how the strength of depletion interactions varies when the total depletant mass is held fixed, a.k.a. fixed-mass depletion. We answer this question via scaling arguments, as well as by studying depletion effects on networks of reconstituted semiflexible actin in silico and in vitro. We examine the maximum strength of the depletion interaction potential U∗ as a function of q, the size ratio between the depletant and the matter being depleted. We uncover a scaling relation U∗ ∼ qζ for two cases: fixed volume fraction φ and fixed mass density ρ. For fixed volume fraction, we report ζ < 0. For the fixed mass density case, we report ζ > 0, which suggests that the depletion interaction strength increases as the depletant size ratio is increased. To test this prediction, we prepared our filament networks at fixed mass concentrations with varying sizes of the depletant molecule poly(ethylene glycol) (PEG). We characterize the depletion interaction strength in our simulations via the mesh size. In experiments, we observe two distinct actin network morphologies, which we call weakly bundled and strongly bundled. We identify a mass concentration where different PEG depletant sizes lead to weakly bundled or strongly bundled morphologies. For these conditions, we find that the mesh size and intra-bundle spacing between filaments across the different morphologies do not show significant differences, while the dynamic light scattering relaxation time and storage modulus between the two states do show significant differences. Our results demonstrate the ability to tune actin network morphology and mechanics by controlling depletant size and give insights into depletion interaction mechanisms under the fixed-depletant-mass constraint relevant to living cells.

Membrane bending by protein phase separation.

Membrane bending is a ubiquitous cellular process that is required for membrane traffic, cell motility, organelle biogenesis, and cell division. Proteins that bind to membranes using specific structural features, such as wedge-like amphipathic helices and crescent-shaped scaffolds, are thought to be the primary drivers of membrane bending. However, many membrane-binding proteins have substantial regions of intrinsic disorder which lack a stable three-dimensional structure. Interestingly, many of these disordered domains have recently been found to form networks stabilized by weak, multivalent contacts, leading to assembly of protein liquid phases on membrane surfaces. Here we ask how membrane-associated protein liquids impact membrane curvature. We find that protein phase separation on the surfaces of synthetic and cell-derived membrane vesicles creates a substantial compressive stress in the plane of the membrane. This stress drives the membrane to bend inward, creating protein-lined membrane tubules. A simple mechanical model of this process accurately predicts the experimentally measured relationship between the rigidity of the membrane and the diameter of the membrane tubules. Discovery of this mechanism, which may be relevant to a broad range of cellular protrusions, illustrates that membrane remodeling is not exclusive to structured scaffolds but can also be driven by the rapidly emerging class of liquid-like protein networks that assemble at membranes.

Editorial Commentary: Addition of Dexmedetomidine to Local Analgesia for Knee Arthroscopy.

The search for the ideal pain management strategy after knee arthroscopy continues. For patients unable to receive regional anesthesia, peri-articular or intra-articular injections of local anesthetics with other medications offer a promising solution. Dexmedetomidine (a short-term sedative analgesic marketed under the names Dexdor and Precedex), when added to local anesthetics, may offer an increase in the length of time between surgery and the need for a rescue analgesic agent. Whether the addition of dexmedetomidine results in lower pain scores or decreased opioid consumption remains to be proven. Systemic effects of dexmedetomidine, such as sedation and hypotension, appear less likely to occur with intra-articular injections, suggesting a favorable safety profile. The effects of dexmedetomidine on chondrocytes, as well as the effects of combining medications in the intra-articular environment, are less well understood and should be a focus of further research. Similarly, there is still a need to identify the best patients, best procedures, best combination of medications, and best doses to optimize our approach to post-operative pain management via intra-articular injection.

Light-Activated Assembly of Connexon Nanopores in Synthetic Cells.

During developmental processes and wound healing, activation of living cells occurs with spatiotemporal precision and leads to rapid release of soluble molecular signals, allowing communication and coordination between neighbors. Nonliving systems capable of similar responsive release hold great promise for information transfer in materials and site-specific drug delivery. One nonliving system that offers a tunable platform for programming release is synthetic cells. Encased in a lipid bilayer structure, synthetic cells can be outfitted with molecular conduits that span the bilayer and lead to material exchange. While previous work expressing membrane pore proteins in synthetic cells demonstrated content exchange, user-defined control over release has remained elusive. In mammalian cells, connexon nanopore structures drive content release and have garnered significant interest since they can direct material exchange through intercellular contacts. Here, we focus on connexon nanopores and present activated release of material from synthetic cells in a light-sensitive fashion. To do this, we re-engineer connexon nanopores to assemble after post-translational processing by a protease. By encapsulating proteases in light-sensitive liposomes, we show that assembly of nanopores can be triggered by illumination, resulting in rapid release of molecules encapsulated within synthetic cells. Controlling connexon nanopore activity provides an opportunity for initiating communication with extracellular signals and for transferring molecular agents to the cytoplasm of living cells in a rapid, light-guided manner.

Associations between alcohol and cigarette use and type 1 and 2 myocardial infarction among people with HIV.

OBJECTIVES: People with HIV have a higher risk of myocardial infarction (MI) than the general population, with a greater proportion of type 2 MI (T2MI) due to oxygen demand-supply mismatch compared with type 1 (T1MI) resulting from atherothrombotic plaque disruption. People living with HIV report a greater prevalence of cigarette and alcohol use than do the general population. Alcohol use and smoking as risk factors for MI by type are not well studied among people living with HIV. We examined longitudinal associations between smoking and alcohol use patterns and MI by type among people living with HIV. DESIGN AND METHODS: Using longitudinal data from the Centers for AIDS Research Network of Integrated Clinical Systems cohort, we conducted time-updated Cox proportional hazards models to determine the impact of smoking and alcohol consumption on adjudicated T1MI and T2MI. RESULTS: Among 13 506 people living with HIV, with a median 4 years of follow-up, we observed 177 T1MI and 141 T2MI. Current smoking was associated with a 60% increase in risk of both T1MI and T2MI. In addition, every cigarette smoked per day was associated with a 4% increase in risk of T1MI, with a suggestive, but not significant, 2% increase for T2MI. Cigarette use had a greater impact on T1MI for men than for women and on T2MI for women than for men. Increasing alcohol use was associated with a lower risk of T1MI but not T2MI. Frequency of heavy episodic alcohol use was not associated with MI. CONCLUSIONS: Our findings reinforce the prioritization of smoking reduction, even without cessation, and cessation among people living with HIV for MI prevention and highlight the different impacts on MI type by gender.

Clinal variations in seedling traits and responses to water availability correspond to seed-source environmental gradients in a foundational dryland tree species.

BACKGROUND AND AIMS: In dryland ecosystems, conifer species are threatened by more frequent and severe droughts, which can push species beyond their physiological limits. Adequate seedling establishment will be critical for future resilience to global change. We used a common garden glasshouse experiment to determine how seedling functional trait expression and plasticity varied among seed sources in response to a gradient of water availability, focusing on a foundational dryland tree species of the western USA, Pinus monophylla. We hypothesized that the expression of growth-related seedling traits would show patterns consistent with local adaptation, given clinal variation among seed source environments. METHODS: We collected P. monophylla seeds from 23 sites distributed across rangewide gradients of aridity and seasonal moisture availability. A total of 3320 seedlings were propagated with four watering treatments representing progressively decreasing water availability. Above- and below-ground growth-related traits of first-year seedlings were measured. Trait values and trait plasticity, here representing the degree of variation among watering treatments, were modelled as a function of watering treatment and environmental conditions at the seed source locations (i.e. water availability, precipitation seasonality). KEY RESULTS: We found that, under all treatments, seedlings from more arid climates had larger above- and below-ground biomass compared to seedlings from sites experiencing lower growing-season water limitation, even after accounting for differences in seed size. Additionally, trait plasticity in response to watering treatments was greatest for seedlings from summer-wet sites that experience periodic monsoonal rain events. CONCLUSIONS: Our results show that P. monophylla seedlings respond to drought through plasticity in multiple traits, but variation in trait responses suggests that different populations are likely to respond uniquely to changes in local climate. Such trait diversity will probably influence the potential for future seedling recruitment in woodlands that are projected to experience extensive drought-related tree mortality.

Understanding the role of financial capacity in the delivery of opioid use disorder treatment.

Opioid treatment programs must have adequate financial capacity to sustain operations and deliver a high standard of care for individuals suffering from opioid use disorder. However, there is limited consistency in the health services literature about the concept and relationship of organizational financial capacity and key outcome measures (wait time and retention). In this study, we explored five common measures of financial capacity that can be applied to opioid treatment programs: (a) reserve ratio, (b) equity ratio, (c) markup, (d) revenue growth, and (e) earned revenue. We used these measures to compare financial capacity among 135 opioid treatment programs across four data collection points: 2011 (66 programs), 2013 (77 programs), 2015 (75 programs), and 2017 (69 programs). We examined the relationship between financial capacity and wait time and retention. Findings from the literature review show inconsistencies in the definition and application of concepts associated with financial capacity across business and social service delivery fields. The analysis shows significant differences in components of financial capacity across years. We observed an increase in average earned revenue and markup in 2017 compared to prior years. The interaction between minorities and markup was significantly associated with higher likelihood of waiting (IRR = 1.077, p < .05). Earned revenue (IRR = 0.225, p < .05) was related to shorter wait time in treatment. The interaction between minorities and equity ratio is also significantly associated with retention (IRR = 0.796, p < .05). Our study offers a baseline view of the role of financial capacity in opioid treatment and suggests a framework to determine its effect on client-centered outcomes.

Editorial Commentary: Rate of Shoulder Instability, and Outcome After Arthroscopic Bankart Stabilization, Are Equal Among Men and Women When Similar Sports Are Compared.

Male athletes have been shown to have a higher incidence of shoulder instability and higher rates of recurrence after arthroscopic stabilization. However, when similar sports are compared, the incidence of instability effectively equalizes. When similar sports are compared, outcomes after arthroscopic Bankart repair may also equalize when compared by sex. Next, contact and collision athletes with shoulder instability have more severe intra-articular pathologies that affect their treatment and outcomes. As these sports become more available to women worldwide, we may see more women athletes with more complex shoulder instability-related pathology. Ultimately, the solution may be to ensure equal resources available to optimize surgical outcomes for athletes after surgery, regardless of sex. We must not leave female athletes on the bench.

Post-total joint arthroplasty opioid prescribing practices vary widely and are not associated with opioid refill: an observational cohort study.

INTRODUCTION: Optimized health system approaches to improving guideline-congruent care require evaluation of multilevel factors associated with prescribing practices and outcomes after total knee and hip arthroplasty. MATERIALS AND METHODS: Electronic health data from patients who underwent a total knee or hip arthroplasty between January 2016-January 2020 in the Military Health System Data were retrospectively analyzed. A generalized linear mixed-effects model (GLMM) examined the relationship between fixed covariates, random effects, and the primary outcome (30-day opioid prescription refill). RESULTS: In the sample (N = 9151, 65% knee, 35% hip), the median discharge morphine equivalent dose was 660 mg [450, 892] and varied across hospitals and several factors (e.g., joint, race and ethnicity, mental and chronic pain conditions, etc.). Probability of an opioid refill was higher in patients who underwent total knee arthroplasty, were white, had a chronic pain or mental health condition, had a lower age, and received a presurgical opioid prescription (all p < 0.01). Sex assigned in the medical record, hospital duration, discharge non-opioid prescription receipt, discharge morphine equivalent dose, and receipt of an opioid-only discharge prescription were not significantly associated with opioid refill. CONCLUSION: In the present study, several patient-, care-, and hospital-level factors were associated with an increased probability of an opioid prescription refill within 30 days after arthroplasty. Future work is needed to identify optimal approaches to reduce unwarranted and inequitable healthcare variation within a patient-centered framework.

Psychotherapy process research: Identifying productive in-session processes to enhance treatment outcomes and therapist responsiveness.

This paper provides an overview of my research programme for the past 37 years. The focus of my work has been on identifying productive in-session processes to enhance treatment outcomes and therapist responsiveness. Two foci will be reviewed, first, my research on client and therapist interpersonal process and second, productive processing in psychotherapy in three different therapeutic approaches including EFT, CBT and CCT. Given that many competing theoretical perspectives are effective, I was curious about change processes that are common and unique to each. In my work, I employed a variety of research methodologies drawing on frameworks with alternative epistemological and ontological assumptions to capture specific in-session change processes in an attempt to reveal the richness and complexity of the phenomena being studied and illuminate the process of change.

Molecular mechanisms of steric pressure generation and membrane remodeling by disordered proteins.

Cellular membranes, which are densely crowded by proteins, take on an elaborate array of highly curved shapes. Steric pressure generated by protein crowding plays a significant role in shaping membrane surfaces. It is increasingly clear that many proteins involved in membrane remodeling contain substantial regions of intrinsic disorder. These domains have large hydrodynamic radii, suggesting that they may contribute significantly to steric congestion on membrane surfaces. However, it has been unclear to what extent they are capable of generating steric pressure, owing to their conformational flexibility. To address this gap, we use a recently developed sensor based on Förster resonance energy transfer to measure steric pressure generated at membrane surfaces by the intrinsically disordered domain of the endocytic protein, AP180. We find that disordered domains generate substantial steric pressure that arises from both entropic and electrostatic components. Interestingly, this steric pressure is largely invariant with the molecular weight of the disordered domain, provided that coverage of the membrane surface is held constant. Moreover, equivalent levels of steric pressure result in equivalent degrees of membrane remodeling, regardless of protein molecular weight. This result, which is consistent with classical polymer scaling relationships for semi-dilute solutions, helps to explain the molecular and physical origins of steric pressure generation by intrinsically disordered domains. From a physiological perspective, these findings suggest that a broad range of membrane-associated disordered domains are likely to play a significant and previously unknown role in controlling membrane shape.

Post-sequelae symptoms and comorbidities after COVID-19.

The frequency, severity, and forms of symptoms months after coronavirus 2019 (COVID-19) are poorly understood, especially in community settings. To better understand and characterize symptoms months after community-based COVID-19, a retrospective cohort analysis was conducted. Three hundred and twenty-eight consecutive persons with a positive test for SARS-CoV-2 in the Johns Hopkins Health System, Maryland, March-May 2020, were selected for the study. Symptom occurrence and severity were measured through questionnaires. Of 328 persons evaluated, a median of 242 days (109-478 days) from the initial positive SARS-CoV-2 test, 33.2% reported not being fully recovered and 4.9% reported symptoms that constrained daily activities. Compared to those who reported being fully recovered, those with post-acute sequelae were more likely to report a prior history of heart attack (p < 0.01). Among those reporting long-term symptoms, men and women were equally represented (men = 34.8%, women = 34.6%), but only women reported symptoms that constrained daily activities, and 56% of them were caregivers. The types of new or persistent symptoms varied, and for many, included a deviation from prior COVID-19 health, such as being less able to exercise, walk, concentrate, or breathe. A limitation is that self-report of symptoms might be biased and/or caused by factors other than COVID-19. Overall, even in a community setting, symptoms may persist months after COVID-19 reducing daily activities including caring for dependents.