A chain mechanism for flagellum growth.

Bacteria swim by means of long flagella extending from the cell surface. These are assembled from thousands of protein subunits translocated across the cell membrane by an export machinery at the base of each flagellum. Unfolded subunits then transit through a narrow channel at the core of the growing flagellum to the tip, where they crystallize into the nascent structure. As the flagellum lengthens outside the cell, the rate of flagellum growth does not change. The mystery is how subunit transit is maintained at a constant rate without a discernible energy source in the channel of the external flagellum. We present evidence for a simple physical mechanism for flagellum growth that harnesses the entropic force of the unfolded subunits themselves. We show that a subunit docked at the export machinery can be captured by a free subunit through head-to-tail linkage of juxtaposed amino (N)- and carboxy (C)-terminal helices. We propose that sequential rounds of linkage would generate a multisubunit chain that pulls successive subunits into and through the channel to the flagellum tip, and by isolating filaments growing on bacterial cells we reveal the predicted chain of head-to-tail linked subunits in the transit channel of flagella. Thermodynamic analysis confirms that links in the subunit chain can withstand the pulling force generated by rounds of subunit crystallization at the flagellum tip, and polymer theory predicts that as the N terminus of each unfolded subunit crystallizes, the entropic force at the subunit C terminus would increase, rapidly overcoming the threshold required to pull the next subunit from the export machinery. This pulling force would adjust automatically over the increasing length of the growing flagellum, maintaining a constant rate of subunit delivery to the tip

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Review of \u3ci\u3eIn the Days of Our Grandmothers: A Reader in Aboriginal Women\u27s History in Canada\u3c/i\u3e Edited by Mary-Ellen KeIm and Lorna Townsend

This collection of articles published since the early 1990s makes a welcome contribution to the range of texts available for both Native Studies and Women\u27s Studies courses at the upper and graduate leveL In an excellent short introductory essay, Mary-Ellen KeIrn and Lorna Townsend provide a useful historiographic context for the collection and explain their desire to bring Aboriginal women out of the shadows by choosing essays that reflect contemporary scholarship and illustrate the diversity of Aboriginal women\u27s histories. They take contributor Jean Barman at her word in turning the past on its head and making Aboriginal women rather than men the focus of study, probing lived experience and moving beyond the universalizing and homogenizing tendencies that characterized an earlier generation of scholarship. Fourteen essays by some of the leading scholars in the field critically situate Aboriginal women in the fur trade, in Christian missions, in the economy, and in the law, demonstrating as well the use of alternative sources such as oral histories, stories, and visual images, and drawing on recent work on the gendered nature of colonialism. Several of these articles are familiar, having already been anthologized, but this is not necessarily a shortcoming since they gain new significance in the company of other work in the field. Where earlier studies may have looked for universal truths, the more recent scholarship exemplified by this collection has grappled with complexity and variation. Several authors stress the need to acknowledge individuality and change over time in combination with other factors such as location, age, status, and local conditions. As the editors admit, the selection is regionally imbalanced, with British Columbia and the Great Plains receiving the lion\u27s share of attention; and some attempt is made to cross national boundaries. On the other hand, articles by Jo-Anne Fiske and Joan Sangster give an overview of the role of the Canadian state and the law in the lives of Aboriginal women, pointing out how both have sexualized and subordinated them, though neither succeeded in preventing them from speaking out against their oppression and retaining considerable influence and power. Emma Larocque underscores a point fundamental to all the contributions: that while all Natives experience racism, Native women suffer from sexism as well

What’s traditional about “the traditional funeral”? Funeral rituals and the evolution of the funeral industry in Nova Scotia

The funeral services industry today promotes what it calls “the traditional funeral” as the preferred choice, a description that implies roots in the distant “folk” past. Archival research into the care of the dead in Nova Scotia reveals that the essential elements of the traditional funeral are indeed derived from pre-modern traditions, but have been adapted to modern consumer society by replacing community involvement with professional expertise. The funeral industry evolved slowly in Nova Scotia, particularly in rural areas where it took longer for services such as embalming to become available. Research shows that the transition from family control to professionalized funeral services was uneven, and in many cases did not happen until the 1950s – some decades later than was typical elsewhere. Consideration of the changing discourse of death suggests that the shift from community to traditional funerals had consequences for our experience of death.L’industrie des services funéraires promeut actuellement les funérailles dites « traditionnelles » comme l’option préférée des consommateurs. Par l’appel au concept de tradition, elle donne à ce type de funérailles des racines dans un passé folklorique lointain. Les recherches concernant les soins apportés au corps des défunts en Nouvelle-Écosse révèlent que si les éléments essentiels de ce genre de funérailles proviennent effectivement de traditions pré-modernes, ils ont été adaptés pour répondre aux exigences de la société de consommation moderne en substituant l’expertise professionnelle à la participation de la communauté. La transformation de l’industrie des services funéraires en Nouvelle-Écosse a été très lente, particulièrement dans les zones rurales où les services spécialisés, comme l’embaumement, se sont fait attendre plus longtemps qu’ailleurs. Les recherches démontrent ainsi que la transition entre des funérailles organisées par la famille et celles organisées par des services funéraires professionnels a varié d’une région à l’autre. Dans certains cas, le processus a été plus tardif qu’ailleurs, n’étant complété que dans les années 1950. L’étude de la transformation du discours au sujet de la mort suggère que la transition entre les funérailles familiales et professionnelles a eu d’importantes conséquences sur notre manière d’appréhender la mort

Rare missense variants in Tropomyosin-4 (TPM4) are associated with platelet dysfunction, cytoskeletal defects, and excessive bleeding.

BackgroundA significant challenge is faced for the genetic diagnosis of inherited platelet disorders in which candidate genetic variants can be found in more than 100 bleeding, thrombotic, and platelet disorder genes, especially within families in which there are both normal and low platelet counts. Genetic variants of unknown clinical significance (VUS) are found in a significant proportion of such patients in which functional studies are required to prove pathogenicity.ObjectiveTo identify the genetic cause in patients with a suspected platelet disorder and subsequently perform a detailed functional analysis of the candidate genetic variants found.MethodsGenetic and functional studies were undertaken in three patients in two unrelated families with a suspected platelet disorder and excessive bleeding. A targeted gene panel of previously known bleeding and platelet genes was used to identify plausible genetic variants. Deep platelet phenotyping was performed using platelet spreading analysis, transmission electron microscopy, immunofluorescence, and platelet function testing using lumiaggregometry and flow cytometry.ResultsWe report rare conserved missense variants (p.R182C and p.A183V) in TPM4 encoding tromomyosin-4 in 3 patients. Deep platelet phenotyping studies revealed similar platelet function defects across the 3 patients including reduced platelet secretion, and aggregation and spreading defects suggesting that TPM4 missense variants impact platelet function and show a disordered pattern of tropomyosin staining.ConclusionsGenetic and functional TPM4 defects are reported making TPM4 a diagnostic grade tier 1 gene and highlights the importance of including TPM4 in diagnostic genetic screening for patients with significant bleeding and undiagnosed platelet disorders, particularly for those with a normal platelet count