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Summary: Dry and warm conditions have exacerbated the occurrence of large and severe wildfires over the past decade in Canada’s Northwest Territories (NT). Although temperatures are expected to increase during the 21st century, we lack understanding of how the climate-vegetation-fire nexus might respond. We used a dynamic global vegetation model to project annual burn rates, as well as tree species composition and biomass in the NT during the 21st century using the IPCC’s climate scenarios. Burn rates will decrease in most of the NT by the mid-21st century, concomitant with biomass loss of fire-prone evergreen needleleaf tree species, and biomass increase of broadleaf tree species. The southeastern NT is projected to experience enhanced fire activity by the late 21st century according to scenario RCP4.5, supported by a higher production of flammable evergreen needleleaf biomass. The results underlie the potential for major impacts of climate change on the NT’s terrestrial ecosystems.

Is grace still relevant for the contemporary performing arts? To answer this question, this article focuses on the historical opposition between grace and affectation. It highlights the theoretical trajectory of these concepts, which have been associated respectively with authenticity and innocence, and with pretense and theatricality. Their opposition is superimposed on another, that between man, perceived as neutral, pure and true, and woman, opaque, deceptive and volatile. The mention of the notion of grace in a seminal article by Michael Fried in the 1960s allows us to pinpoint the meanings with which grace and affectation were imbued in the mid-twentieth century in the art world. A debate seems to have emerged between, on the one hand, an essentialist conception of grace understood as presence by Fried, as well as some performance artists and postmodern dancers, and, on the other hand, the author Susan Sontag and her reflections on camp – which is a manifestation of theatricality, even affectation – and the irrelevance of the modern quest for presence. It would seem that while grace was related to the performative in performance art, it has undergone, like performativity itself, a transformation at the dawn of the twenty-first century, which has reconfigured its opposition to affectation. Trajal Harrell’s work contributes to this movement by staging an over-theatricality that exhausts the necessity of grace. This article concludes that, after the “performative turn,” grace still carries with it some traditional dynamics such as seduction and innocence, which are subverted with distancing strategies like exacerbation, parody and quotation; strategies associated to affectation, which becomes a source of pleasure for the spectator. The author coins the notion of grace of affectation, which finds echoes in several contemporary aesthetic discourses on theater and cinema.

Novel in vitro platforms based on human neurons are needed to improve early drug testing and address the stalling drug discovery in neurological disorders. Topologically controlled circuits of human induced pluripotent stem cell (iPSC)-derived neurons have the potential to become such a testing system. In this work, we build in vitro co-cultured circuits of human iPSC-derived neurons and rat primary glial cells using microfabricated polydimethylsiloxane (PDMS) structures on microelectrode arrays (MEAs). Our PDMS microstructures are designed in the shape of a stomach, which guides axons in one direction and thereby facilitates the unidirectional flow of information. Such circuits are created by seeding either dissociated cells or pre-aggregated spheroids at different neuron-to-glia ratios. Furthermore, an antifouling coating is developed to prevent axonal overgrowth in undesired locations of the microstructure. We assess the electrophysiological properties of different types of circuits over more than 50 days, including their stimulation-induced neural activity. Finally, we demonstrate the inhibitory effect of magnesium chloride on the electrical activity of our iPSC circuits as a proof-of-concept for screening of neuroactive compounds.

Introduction: Patient-Reported Outcomes (PRO) integrate a wide range of holistic dimensions that arenot captured within clinical outcomes. Particularly, from induction treatment to maintenance therapy, patient quality-of-life (QoL) of kidney transplant recipients have been sparsely investigated in international settings.Methods: In a prospective, multi-centric cohort study, including nine transplant centers in four countries, we explored the QoL during the year following transplantation using validated elicitation instruments (EQ-5D-3L index with VAS) in a population of kidney transplant patients receiving immunosuppressive therapies. Calcineurin inhibitors (tacrolimus and ciclosporin), IMPD inhibitor (mycophenolate mofetil), and mTOR inhibitors (everolimus and sirolimus) were the standard-of-care (SOC) medications, together with tapering glucocorticoid therapy. We used EQ-5D and VAS data as QoL measures alongside descriptive statistics at inclusion, per country and hospital center. We computed the proportions of patients with different immunosuppressive therapy patterns, and using bivariate and multivariate analyses, assessed the variations of EQ-5D and VAS between baseline (i.e., inclusion Month 0) and follow up visits (Month 12).Results: Among 542 kidney transplant patients included and followed from November 2018 to June 2021, 491 filled at least one QoL questionnaire at least at baseline (Month 0). The majority of patients in all countries received tacrolimus and mycophenolate mofetil, ranging from 90.0% in Switzerland and Spain to 95.8% in Germany. At M12, a significant proportion of patients switched immunosuppressive drugs, with proportion varying from 20% in Germany to 40% in Spain and Switzerland. At visit M12, patients who kept SOC therapy had higher EQ-5D (by 8 percentage points, p < 0.05) and VAS (by 4 percentage points, p < 0.1) scores than switchers. VAS scores were generally lower than EQ-5D (mean 0.68 [0.5–0.8] vs. 0.85 [0.8–1]).Discussion: Although overall a positive trend in QoL was observed, the formal analyses did not show any significant improvements in EQ-5D scores or VAS. Only when the effect of a therapy use was separated from the effect of switching, the VAS score was significantly worse for switchers during the follow up period, irrespective of the therapy type. If adjusted for patient characteristics and medical history (e.g., gender, BMI, eGRF, history of diabetes), VAS and EQ-5D delivered sound PRO measures for QoL assessments during the year following renal transplantation.

Children of color are more likely to have poor sleep health than White children, placing them at risk for behavioral problems in the classroom and lower academic performance. Few studies, however, have utilized standardized measures of both classroom behavior and achievement. This study examined whether children's sleep (parent and teacher report) in first grade concurrently related to independent observations of classroom behavior and longitudinally predicted achievement test scores in second grade in a sample of primarily Black (86%) children (n = 572; age = 6.8) living in historically disinvested neighborhoods. Higher teacher-reported child sleepiness was associated with lower adaptive behaviors and higher problem behaviors in the classroom, and predicted lower achievement. Parent-reported bedtime resistance and disordered breathing also predicted lower achievement.

Background: Chronic kidney disease often leads to kidney dysfunction due to renal fibrosis, regardless of the initial cause of kidney damage. Macrophages are crucial players in the progression of renal fibrosis as they stimulate inflammation, activate fibroblasts, and contribute to extracellular matrix deposition, influenced by their metabolic state. Nucleotide-binding domain and LRR-containing protein X (NLRX1) is an innate immune receptor independent of inflammasomes and is found in mitochondria, and it plays a role in immune responses and cell metabolism. The specific impact of NLRX1 on macrophages and its involvement in renal fibrosis is not fully understood. Methods: To explore the specific role of NLRX1 in macrophages, bone-marrow-derived macrophages (BMDMs) extracted from wild-type (WT) and NLRX1 knockout (KO) mice were stimulated with pro-inflammatory and pro-fibrotic factors to induce M1 and M2 polarization in vitro. The expression levels of macrophage polarization markers (Nos2, Mgl1, Arg1, and Mrc1), as well as the secretion of transforming growth factor β (TGFβ), were measured using RT-PCR and ELISA. Seahorse-based bioenergetics analysis was used to assess mitochondrial respiration in naïve and polarized BMDMs obtained from WT and NLRX1 KO mice. In vivo, WT and NLRX1 KO mice were subjected to unilateral ureter obstruction (UUO) surgery to induce renal fibrosis. Kidney injury, macrophage phenotypic profile, and fibrosis markers were assessed using RT-PCR. Histological staining (PASD and Sirius red) was used to quantify kidney injury and fibrosis. Results: Compared to the WT group, an increased gene expression of M2 markers—including Mgl1 and Mrc1—and enhanced TGFβ secretion were found in naïve BMDMs extracted from NLRX1 KO mice, indicating functional polarization towards the pro-fibrotic M2 subtype. NLRX1 KO naïve macrophages also showed a significantly enhanced oxygen consumption rate compared to WT cells and increased basal respiration and maximal respiration capacities that equal the level of M2-polarized macrophages. In vivo, we found that NLRX1 KO mice presented enhanced M2 polarization markers together with enhanced tubular injury and fibrosis demonstrated by augmented TGFβ levels, fibronectin, and collagen accumulation. Conclusions: Our findings highlight the unique role of NLRX1 in regulating the metabolism and function of macrophages, ultimately protecting against excessive renal injury and fibrosis in UUO.

Marine ecosystems are exposed to multiple stressors, mainly fisheries that, whenever mismanaged, may cause irreversible damages to whole food webs. Ecosystem models have been applied to forecast fisheries impact on fish stocks and marine food webs. These impacts have been studied through the use of multiple indicators that help to understand ecosystem responses to stressors. This study focused on a category of ecological indicators derived from the network theory to quantify energy flows inside the food web. These indicators were computed using two ecosystem models applied to the Eastern English Channel (i.e. Atlantis and OSMOSE). This work aimed at investigating how several ecological network indicators respond to different levels of fishing pressure and evaluating their robustness to model structure and fishing strategies. We applied a gradient of fishing mortality using two ecosystem models and carried out ecological network analysis to obtain network-derived indicators. The results revealed that the indicators response is highly driven by the food web structure, although the model assumptions buffered some results. The indicators computed from OSMOSE outputs were more sensitive to changes in fishing pressure than those from Atlantis. However, once the food web from Atlantis was simplified to mimic the structure of OSMOSE model, the indicators of the modified Atlantis became more sensitive to the intensity of fishing pressure. The indicators related to amount of energy flow and to the organization of the flows in the food web were sensitive to the increase of fishing mortality for all fishing strategies. These indicators suggested that increasing fishing mortality jeopardizes the amount of energy mobilized by the food webs and simplifies the ecological interactions, which has implications for the resilience of marine ecosystems. The study shed light on the trophic networks structure and functioning of the ecosystems whenever exposed to disturbances. Furthermore, these indicators might be adequate for whole ecosystem assessments of health and contribute to ecosystem management.

Summary: The emergence of recombinant viruses is a threat to public health, as recombination may integrate variant-specific features that together result in escape from treatment or immunity. The selective advantages of recombinant SARS-CoV-2 isolates over their parental lineages remain unknown. We identified a Delta-Omicron (AY.45-BA.1) recombinant in an immunosuppressed transplant recipient treated with monoclonal antibody Sotrovimab. The single recombination breakpoint is located in the spike N-terminal domain adjacent to the Sotrovimab binding site. While Delta and BA.1 are sensitive to Sotrovimab neutralization, the Delta-Omicron recombinant is highly resistant. To our knowledge, this is the first described instance of recombination between circulating SARS-CoV-2 variants as a functional mechanism of resistance to treatment and immune escape.

Meteorological extreme events such as El Niño events are expected to affect tropical forest net primary production (NPP) and woody growth, but there has been no large-scale empirical validation of this expectation. We collected a large high-temporal resolution dataset (for 1-13 years depending upon location) of more than 172 000 stem growth measurements using dendrometer bands from across 14 regions spanning Amazonia, Africa and Borneo in order to test how much month-to-month variation in stand-level woody growth of adult tree stems (NPPstem) can be explained by seasonal variation and interannual meteorological anomalies. A key finding is that woody growth responds differently to meteorological variation between tropical forests with a dry season (where monthly rainfall is less than 100 mm), and aseasonal wet forests lacking a consistent dry season. In seasonal tropical forests, a high degree of variation in woody growth can be predicted from seasonal variation in temperature, vapour pressure deficit, in addition to anomalies of soil water deficit and shortwave radiation. The variation of aseasonal wet forest woody growth is best predicted by the anomalies of vapour pressure deficit, water deficit and shortwave radiation. In total, we predict the total live woody production of the global tropical forest biome to be 2.16 Pg C yr-1, with an interannual range 1.96-2.26 Pg C yr-1 between 1996-2016, and with the sharpest declines during the strong El Niño events of 1997/8 and 2015/6. There is high geographical variation in hotspots of El Niño-associated impacts, with weak impacts in Africa, and strongly negative impacts in parts of Southeast Asia and extensive regions across central and eastern Amazonia. Overall, there is high correlation (r = -0.75) between the annual anomaly of tropical forest woody growth and the annual mean of the El Niño 3.4 index, driven mainly by strong correlations with anomalies of soil water deficit, vapour pressure deficit and shortwave radiation.This article is part of the discussion meeting issue 'The impact of the 2015/2016 El Niño on the terrestrial tropical carbon cycle: patterns, mechanisms and implications'.

The gut microbiome contributes to inflammatory bowel disease (IBD), in which bacteria can be present within the epithelium. Epithelial barrier function is decreased in IBD, and dysfunctional epithelial mitochondria and endoplasmic reticulum (ER) stress have been individually associated with IBD. We therefore hypothesized that the combination of ER and mitochondrial stresses significantly disrupt epithelial barrier function. Here, we treated human colonic biopsies, epithelial colonoids, and epithelial cells with an uncoupler of oxidative phosphorylation, dinitrophenol (DNP), with or without the ER stressor tunicamycin and assessed epithelial barrier function by monitoring internalization and translocation of commensal bacteria. We also examined barrier function and colitis in mice exposed to dextran sodium sulfate (DSS) or DNP and co-treated with DAPK6, an inhibitor of death-associated protein kinase 1 (DAPK1). Contrary to our hypothesis, induction of ER stress (i.e. the unfolded protein response) protected against decreased barrier function caused by the disruption of mitochondrial function. ER stress did not prevent DNP-driven uptake of bacteria; rather, specific mobilization of the ATF6 arm of ER stress and recruitment of DAPK1 resulted in enhanced autophagic killing (xenophagy) of bacteria. Of note, epithelia with a Crohn's disease-susceptibility mutation in the autophagy gene ATG16L1 exhibited less xenophagy. Systemic delivery of the DAPK1 inhibitor DAPK6 increased bacterial translocation in DSS- or DNP-treated mice. We conclude that promoting ER stress-ATF6-DAPK1 signaling in transporting enterocytes counters the transcellular passage of bacteria evoked by dysfunctional mitochondria, thereby reducing the potential for metabolic stress to reactivate or perpetuate inflammation.

“Télétravail, Famille, Patrie” chronicles daily life under the lockdown that was imposed in March 2020, from the perspective of a single mother of three small children. Written in a sarcastic style, it focuses on the petty annoyances of the “new normal”, evoking daily chores through realistic dialogues and accurate descriptions of material life (the challenge of group outing, grocery shopping, not having an internet connection, home schooling, and so on).

Molecular cloning and controlled expression remain challenging when the target gene encodes a protein that is toxic to the host. We developed a set of multi-layer control systems to enable cloning of genes encoding proteins known to be highly toxic in Escherichia coli and other bacteria. The different multi-layer control systems combine a promoter–operator system on a transcriptional level with a riboswitch for translational control. Additionally, replicational control is ensured by using a strain that reduces the plasmid copy number. The use of weaker promoters (such as PBAD or PfdeA) in combination with the effective theophylline riboswitch is essential for cloning genes that encode notoriously toxic proteins that directly target translation and transcription. Controlled overexpression is possible, allowing the system to be used for evaluating in vivo effects of the toxin. Systems with a stronger promoter can be used for successful overexpression and purification of the desired protein but are limited to toxins that are more moderate and do not interfere with their own production.

Anti-COVID antibody therapeutics have been developed but not widely used due to their high cost and escape of neutralization from the emerging variants. Here, we describe the development of VHH-IgA1.1, a nanobody IgA fusion molecule as an inhalable, affordable and less invasive prophylactic and therapeutic treatment against SARS-CoV-2 Omicron variants. VHH-IgA1.1 recognizes a conserved epitope of SARS-CoV-2 spike protein Receptor Binding Domain (RBD) and potently neutralizes major global SARS-CoV-2 variants of concern (VOC) including the Omicron variant and its sub lineages BA.1.1, BA.2 and BA.2.12.1. VHH-IgA1.1 is also much more potent against Omicron variants as compared to an IgG Fc fusion construct, demonstrating the importance of IgA mediated mucosal protection for Omicron infection. Intranasal administration of VHH-IgA1.1 prior to or after challenge conferred significant protection from severe respiratory disease in K18-ACE2 transgenic mice infected with SARS-CoV-2 VOC. More importantly, for cost-effective production, VHH-IgA1.1 produced in Pichia pastoris had comparable potency to mammalian produced antibodies. Our study demonstrates that intranasal administration of affordably produced VHH-IgA fusion protein provides effective mucosal immunity against infection of SARS-CoV-2 including emerging variants.

Testicular tissue cryopreservation is the only option of fertility preservation in prepubertal boys. While it is considered experimental, since procedures to obtain mature spermatozoa from prepubertal testicular tissue are still under development, testicular tissue cryopreservation programs have emerged worldwide. Our aim was to study the feasibility and safety of a program of testicular tissue cryopreservation in prepubertal and adolescent boys facing gonadotoxic treatment in three University hospitals in Switzerland. Testicular tissue cryopreservation was accepted by 90% of families, with a total of 35 patients included. The average patient age was 8.5 years (range 7 months to 18.5 years). Malignancies were the most common diagnosis (31 patients, 88.6%) with 16 (45.7%) solid tumors and 15 (42.9%) hematological malignancies. Four (11.4%) patients had a benign condition. The main indication for testicular tissue cryopreservation was conditioning for hematologic stem cell transplantation (25 patients, 71.4%). Testicular tissue was cryopreserved according to the freezing protocol of Louvain Catholic University (Belgium), which includes either only immature testicular tissue freezing, or mature and immature testicular tissue freezing depending on the age of the patient and the presence or absence of haploid cells. The median number of spermatogonia per tubule cross-section was 2 (range 0–6) and spermatozoa were found in only one patient. Tumoral cells were found in one testicular biopsy of a leukemic patient. There were two minor adverse events and none of them required medical treatment or surgical revision. Five patients died during follow-up. Our data demonstrate the feasibility and safety of a program of testicular tissue cryopreservation coordinated by a multidisciplinary team of fertility preservation. Despite the experimental aspect of the procedure, the acceptation rate was high, which highlights the willingness of families and patients to participate in testicular tissue cryopreservation.

BackgroundMixed results in the predictive ability of traditional biomarkers to determine cognitive functioning and changes in older adults have led to misdiagnosis and inappropriate treatment plans to address mild cognitive impairment and dementia among older adults. To address this critical gap, the primary goal of the current study is to investigate whether a digital neuro signature (DNS-br) biomarker predicted global cognitive functioning and change over time relative among cognitively impaired and cognitive healthy older adults. The secondary goal is to compare the effect size of the DNS-br biomarker on global cognitive functioning compared to traditional imaging and genomic biomarkers. The tertiary goal is to investigate which demographic and clinical factors predicted DNS-br in cognitively impaired and cognitively healthy older adults.MethodsWe conducted two experiments (Study A and Study B) to assess DNS for brain resilience (DNS-br) against the established FDG-PET brain imaging signature for brain resilience, based on a 10 min digital cognitive assessment tool. Study A was a semi-naturalistic observational study that included 29 participants, age 65+, with mild to moderate mild cognitive impairment and AD diagnosis. Study B was also a semi-naturalistic observational multicenter study which included 496 participants (213 mild cognitive impairment (MCI) and 283 cognitively healthy controls (HC), a total of 525 participants—cognitively healthy (n = 283) or diagnosed with MCI (n = 213) or AD (n = 29).ResultsDNS-br total score and majority of the 11 DNS-br neurocognitive subdomain scores were significantly associated with FDG-PET resilience signature, PIB ratio, cerebral gray matter and white matter volume after adjusting for multiple testing. DNS-br total score predicts cognitive impairment for the 80+ individuals in the Altoida large cohort study. We identified a significant interaction between the DNS-br total score and time, indicating that participants with higher DNS-br total score or FDG-PET in the resilience signature would show less cognitive decline over time.ConclusionOur findings highlight that a digital biomarker predicted cognitive functioning and change, which established biomarkers are unable to reliably do. Our findings also offer possible etiologies of MCI and AD, where education did not protect against cognitive decline.

From mid-March through early May 2020, France limited outdoor activities to one hour per day because of the Covid-19 epidemic. This inside lockdown could have a lasting impact on post-lockdown sedentary and physical activities and food choice. The aim of this study is to compare behaviors before and after the lockdown in a sample of French young adult students (sex ratio = 1:1, 22 ± 3 y old). Over a period of 4 days in both April and after mid-May 2020, 50 students used the WellBeNet smartphone application to record accelerometry data to evaluate their sedentary behavior and physical activity, and food consumption. Some behaviors remained stable for both periods: sedentary behavior, light-intensity activity, the number of meals per day, the number of portions of fruits, nuts, dairy products, vegetables, legumes and meat-fish-egg. Moderate-intensity activity duration was higher (+1.4%, p

ABSTRACT In October 2020, the National Cancer Institute (NCI) Serological Sciences Network (SeroNet) was established to study the immune response to COVID-19, and “to develop, validate, improve, and implement serological testing and associated technologies” (https://www.cancer.gov/research/key-initiatives/covid-19/coronavirus-research-initiatives/serological-sciences-network). SeroNet is comprised of 25 participating research institutions partnering with the Frederick National Laboratory for Cancer Research (FNLCR) and the SeroNet Coordinating Center. Since its inception, SeroNet has supported collaborative development and sharing of COVID-19 serological assay procedures and has set forth plans for assay harmonization. To facilitate collaboration and procedure sharing, a detailed survey was sent to collate comprehensive assay details and performance metrics on COVID-19 serological assays within SeroNet. In addition, FNLCR established a protocol to calibrate SeroNet serological assays to reference standards, such as the U.S. severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serology standard reference material and first WHO international standard (IS) for anti-SARS-CoV-2 immunoglobulin (20/136), to facilitate harmonization of assay reporting units and cross-comparison of study data. SeroNet institutions reported development of a total of 27 enzyme-linked immunosorbent assay (ELISA) methods, 13 multiplex assays, and 9 neutralization assays and use of 12 different commercial serological methods. FNLCR developed a standardized protocol for SeroNet institutions to calibrate these diverse serological assays to reference standards. In conclusion, SeroNet institutions have established a diverse array of COVID-19 serological assays to study the immune response to SARS-CoV-2 and vaccines. Calibration of SeroNet serological assays to harmonize results reporting will facilitate future pooled data analyses and study cross-comparisons. IMPORTANCE SeroNet institutions have developed or implemented 61 diverse COVID-19 serological assays and are collaboratively working to harmonize these assays using reference materials to establish standardized reporting units. This will facilitate clinical interpretation of serology results and cross-comparison of research data.

As a result of extreme weather conditions associated with anthropogenic climate change, fire regimes are expected to continue to change in the boreal forest over the 21st century and beyond. Consequently, changes in ecological attributes like stand composition, tree density and forest carbon stock can be expected. In the present study, we used an adjusted version of the CanFIRE model to project long-term (1971–2100) changes in burn rates, fire severity and fire-induced shifts in vegetation composition in response to anticipated scenarios of climate change, in the black spruce-feather moss subdomain of Western Quebec. The model provides decadal-scale estimates of the immediate physical effects of fire on forest communities by computing expected fire behavior and the resulting ecological effects. Changes in species composition of the forest is also computed based on mechanisms of succession in natural forest communities and fire-mediated vegetation transitions. Projections suggest an increase in potential burn rates across the study area under future weather conditions and also an overall reduction in percent tree mortality and total fuel consumption. This reduction is caused by negative feedback from vegetation composition that shifts to less-fire prone states. Although common forest communities will remain the same in the studied subdomain until 2100 (recurrence dynamics), significant losses of productive area (LPA) are projected, particularly in forest management units rich in forest communities dominated by black spruce or jack pine, as a result of regeneration failure due to very short intervals between successive fires. While remaining similar under moderate (RCP4.5) and high-end (RCP8.5) warming scenarios in all forest management units, LPA will vary from 25 to 36% of the percent cover by 2100 compared to 1970. These results provide insights to policy makers and land managers, and they attract attention to the pressing need to adjust management practices in the context of climate change.

The common assumption that population sleep duration has declined in the past few decades has not been supported by recent reviews, which have been limited to self-reported data. The aim of this review was to assess whether there has been a reduction in objectively recorded sleep duration over the last 50+ years. The literature was searched for studies published from 1960 to 2013, which assessed objective sleep duration (total sleep time (TST)) in healthy normal-sleeping adults. The search found 168 studies that met inclusion criteria, with 257 data points representing 6052 individuals ages 18-88 y. Data were assessed by comparing the regression lines of age vs. TST in studies conducted between 1960 and 1989 vs. 1990-2013. Weighted regression analyses assessed the association of year of study with age-adjusted TST across all data points. Regression analyses also assessed the association of year of study with TST separately for 10-y age categories (e.g., ages 18-27 y), and separately for polysomnographic and actigraphic data, and for studies involving a fixed sleep schedule and participants' customary sleep schedules. Analyses revealed no significant association of sleep duration with study year. The results are consistent with recent reviews of subjective data, which have challenged the notion of a modern epidemic of insufficient sleep.

Purpose: The purpose of this paper is understand how the different styles of sponsor management influence the prioritization of projects. Design/methodology/approach: The empiric analysis used in-depth interviews with 11 executives as method for data collection and qualitative content analysis using theory and data driven categories for analysis is performed. Findings: This research points to the emergence of opportunistic management style, and to evidences of lack of strategic alignment in the project prioritization process. Research limitations/implications: The lack of prioritization methods evidences to compare with project management style. Also, the number of project managers to interview as experts. Practical implications: The analysis shows that committees and post-project evaluation be established to mitigate failures in the prioritization process impacted from sponsor’s management styles influence. Originality/value: The paper provides a critical perspective about sponsor’s management styles and project prioritization context; it is important to highlight how different management styles of the sponsor result in different behaviors in the companies.

Non-technical summary We summarize what we assess as the past year's most important findings within climate change research: limits to adaptation, vulnerability hotspots, new threats coming from the climate–health nexus, climate (im)mobility and security, sustainable practices for land use and finance, losses and damages, inclusive societal climate decisions and ways to overcome structural barriers to accelerate mitigation and limit global warming to below 2°C. Technical summary We synthesize 10 topics within climate research where there have been significant advances or emerging scientific consensus since January 2021. The selection of these insights was based on input from an international open call with broad disciplinary scope. Findings concern: (1) new aspects of soft and hard limits to adaptation; (2) the emergence of regional vulnerability hotspots from climate impacts and human vulnerability; (3) new threats on the climate–health horizon – some involving plants and animals; (4) climate (im)mobility and the need for anticipatory action; (5) security and climate; (6) sustainable land management as a prerequisite to land-based solutions; (7) sustainable finance practices in the private sector and the need for political guidance; (8) the urgent planetary imperative for addressing losses and damages; (9) inclusive societal choices for climate-resilient development and (10) how to overcome barriers to accelerate mitigation and limit global warming to below 2°C. Social media summary Science has evidence on barriers to mitigation and how to overcome them to avoid limits to adaptation across multiple fields.

LIM kinase 1 (LIMK1) and LIM kinase 2 (LIMK2) are serine/threonine and tyrosine kinases and the only two members of the LIM kinase family. They play a crucial role in the regulation of cytoskeleton dynamics by controlling actin filaments and microtubule turnover, especially through the phosphorylation of cofilin, an actin depolymerising factor. Thus, they are involved in many biological processes, such as cell cycle, cell migration, and neuronal differentiation. Consequently, they are also part of numerous pathological mechanisms, especially in cancer, where their involvement has been reported for a few years and has led to the development of a wide range of inhibitors. LIMK1 and LIMK2 are known to be part of the Rho family GTPase signal transduction pathways, but many more partners have been discovered over the decades, and both LIMKs are suspected to be part of an extended and various range of regulation pathways. In this review, we propose to consider the different molecular mechanisms involving LIM kinases and their associated signalling pathways, and to offer a better understanding of their variety of actions within the physiology and physiopathology of the cell.

We investigate network nonlocality in the triangle scenario when all three parties have no input and binary outputs. Through an explicit example, we prove that this minimal scenario supports nonlocal correlations compatible with no-signaling and independence of the three sources, but not with realisations based on independent quantum or classical sources. This nonlocality is robust to noise. Moreover, we identify the equivalent to a Popescu-Rohrlich box in the minimal triangle scenario.

Convergent disk migration has long been suspected to be responsible for forming planetary systems with a chain of mean-motion resonances (MMRs). Dynamical evolution over time could disrupt the delicate resonant configuration. We present TOI-1136, a 700 ± 150 Myr old G star hosting at least six transiting planets between ∼2 and 5 R _⊕ . The orbital period ratios deviate from exact commensurability by only 10 ^−4 , smaller than the ∼10 ^−2 deviations seen in typical Kepler near-resonant systems. A transit-timing analysis measured the masses of the planets (3–8 M _⊕ ) and demonstrated that the planets in TOI-1136 are in true resonances with librating resonant angles. Based on a Rossiter–McLaughlin measurement of planet d, the star’s rotation appears to be aligned with the planetary orbital planes. The well-aligned planetary system and the lack of a detected binary companion together suggest that TOI-1136's resonant chain formed in an isolated, quiescent disk with no stellar flyby, disk warp, or significant axial asymmetry. With period ratios near 3:2, 2:1, 3:2, 7:5, and 3:2, TOI-1136 is the first known resonant chain involving a second-order MMR (7:5) between two first-order MMRs. The formation of the delicate 7:5 resonance places strong constraints on the system’s migration history. Short-scale (starting from ∼0.1 au) Type-I migration with an inner disk edge is most consistent with the formation of TOI-1136. A low disk surface density (Σ _1 au ≲ 10 ^3 g cm ^−2 ; lower than the minimum-mass solar nebula) and the resultant slower migration rate likely facilitated the formation of the 7:5 second-order MMR.

Energy policy faces a triple challenge: increasing resilience and guaranteeing the security of supply of both fossil and non-fossil energy, minimising the impact on consumer energy prices, and retaining consistency with Paris Agreement climate goals. High prices and producer rents, however, also present an opportunity: to open a conversation about applying the principle of extended producer responsibility (EPR) to fossil fuels. We demonstrate that this could deconflict energy security and climate policy at an affordable cost by stopping fossil fuels from causing further global warming. Implementing EPR through a combination of geological CO _2 storage and nature-based solutions can deliver net zero at comparable or lower costs than conventional scenarios driven with a global carbon price and subject to constraints on CO _2 storage deployment. It would also mean that the principal beneficiary of high fossil fuel prices, the fossil fuel industry itself, plays its part in addressing the climate challenge while reducing the risk of asset stranding.

Abstract Background The separate design concepts of dual-mobility cups and triple-taper femoral stems were developed to improve survivorship following total hip replacement (THR) by reducing instability/dislocation and enabling enhanced fixation. Successful outcomes at over two decades have been reported with earlier-generation devices based on these concepts. The current study aimed to provide the first long-term results with a unique pairing of later-generation dual-mobility cup and triple-taper cementless femoral stem after a decade of use in patients undergoing THR. Methods In this retrospective analysis, records were reviewed for all subjects implanted with this dual-mobility cup/cementless femoral stem combination at three centers between 2002 and 2005. Any subject who had not already had follow-up visit beyond 10 years, was not previously revised, and still living were invited for a single follow-up visit consisting of Merle d’Aubgine Scores, the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index, and standard radiographs. Results There were 244 THRs available for analysis. At a mean follow-up of 11.9 years, the Kaplan-Meier survivorship (endpoint: revision for any reason) was 99.1% (95% CI, 97.6–99.7) for the stem and 95.9% (95% CI, 93.1–97.6) for the cup. Merle d’Aubigne Scores were significantly improved from baseline and WOMAC scores were in the satisfactory range at the final follow-up. Radiographic analysis revealed no cases of stem subsidence, no cases of bone hypertrophy, 1 (0.4%) case of bone atrophy, and 3 (1.2%) cases of osteolysis around the stem. No subjects had radiolucent lines greater than 1 mm in any femoral Gruen zone. Evidence of cup migration was seen in 1 (0.4%) subject and 1 (0.4%) subject had evidence of osteolysis that was seen in Gruen zones I, II, IV, and V. Conclusions This combination of a later-generation dual-mobility cup and cementless triple-taper stem was associated with excellent survivorship and satisfactory functional outcomes at over 10 years follow-up. Trial registration ClinicalTrials.gov, NCT02648152. Date of registration: January 6, 2016. Retrospectively registered.

Abstract Objective The purpose of this side product of another unpublished research project, was to address the effects of a training program on skeletal muscle adaptations of people with myotonic dystrophy type 1 (DM1), under a multifaceted perspective. The objective of this study was to look at training induced muscular adaptations by evaluating changes in muscle strength, myofiber cross-sectional area (CSA), proportion of myofiber types and with indirect markers of muscle growth [proportion of centrally nucleated fibers (CNF) and density of neutrophils and macrophages]. Two men with DM1 underwent a 12-week strength/endurance training program (18 sessions). Two muscle biopsies were obtained pre- and post-training program. Results Muscular adaptations occurred only in Patient 1, who attended 72% of the training sessions compared to 39% for Patient 2. These adaptations included increase in the CSA of type I and II myofibers and changes in their proportion. No changes were observed in the percentage of CNF, infiltration of neutrophils and macrophages and muscle strength. These results illustrate the capacity of skeletal muscle cells to undergo adaptations linked to muscle growth in DM1 patients. Also, these adaptations seem to be dependent on the attendance. Trial registration Clinicaltrials.gov NCT04001920 retrospectively registered on June 26th, 2019

Abstract Streptococcus suis serotype 2 is an important porcine pathogen and zoonotic agent causing sudden death, septic shock and meningitis, with exacerbated inflammation being a hallmark of the infection. A rapid, effective and balanced innate immune response against S. suis is critical to control bacterial growth without causing excessive inflammation. Even though interleukin (IL)-1 is one of the most potent and earliest pro-inflammatory mediators produced, its role in the S. suis pathogenesis has not been studied. We demonstrated that a classical virulent European sequence type (ST) 1 strain and the highly virulent ST7 strain induce important levels of IL-1 in systemic organs. Moreover, bone marrow-derived dendritic cells and macrophages contribute to its production, with the ST7 strain inducing higher levels. To better understand the underlying mechanisms involved, different cellular pathways were studied. Independently of the strain, IL-1β production required MyD88 and involved recognition via TLR2 and possibly TLR7 and TLR9. This suggests that the recognized bacterial components are similar and conserved between strains. However, very high levels of the pore-forming toxin suilysin, produced only by the ST7 strain, are required for efficient maturation of pro-IL-1β via activation of different inflammasomes resulting from pore formation and ion efflux. Using IL-1R−/− mice, we demonstrated that IL-1 signaling plays a beneficial role during S. suis systemic infection by modulating the inflammation required to control and clear bacterial burden, thus promoting host survival. Beyond a certain threshold, however, S. suis-induced inflammation cannot be counterbalanced by this signaling, making it difficult to discriminate its role.

ABSTRACT BACKGROUND: Irritable bowel syndrome (IBS) is a clinical disorder associated with high socioeconomic burden. Despite its importance, management of IBS remains difficult and several interventions have been hypothesized as beneficial for this condition. This study identified and summarized all Cochrane systematic reviews (SRs) about the effects of interventions for managing IBS patients. DESIGN AND SETTING: Review of systematic reviews, carried out in the Discipline of Evidence-Based Medicine, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP). METHODS: Review of Cochrane SRs addressing interventions for IBS. RESULTS: We included six SRs assessing acupuncture, bulking agents, antispasmodics, antidepressants, herbal medicines, homeopathy, hypnotherapy and psychological therapy for IBS. The certainty of evidence ranged from unknown to moderate, mainly due to imprecision in the estimates and high risk of bias from the primary studies included. There was moderate certainty of evidence that acupuncture had no important benefit regarding improvement of symptoms and quality of life, compared with sham acupuncture. There was also very low certainty of evidence that homeopathic asafoetida, used alone or in association with nux, was better than placebo regarding self-reported overall improvement. CONCLUSION: There was moderate certainty of evidence that acupuncture had no important benefit regarding improvement of symptoms and quality of life. Further well-designed and well-conducted randomized clinical trials are needed in order to reduce the uncertainties regarding the most commonly used interventions for patients with IBS.

Code-switching is a complex bilingual behavior that can be affected by a variety of factors related to characteristics of the speaker, the interlocutor, and the broader sociolinguistic context. A better understanding of these factors is important for interpreting children’s use of code-switching in different elicitation contexts across research studies and in applied settings, such as language sample analysis for clinical assessment. In the current study, we used a conversation sample protocol with a code-switching adult interlocutor to examine the use of English, Spanish, intra-sentential and inter-sentential code-switching, and alignment with the interlocutor by Spanish/English bilingual children with a wide range of language abilities. In a single-language comparison condition, the same examiner engaged the child in conversation using only English or only Spanish. Key findings include that children exhibited limited use of code-switching in the English condition and similar frequency of code-switching in the Spanish, compared to the code-switching, conditions. Children exhibited a tendency to align with the examiner in their use of English vs. Spanish and their use of intra-sentential code-switching during the code-switching context, although they generally code-switched less than the examiner. There was also considerable variability across children. Predictors of this variability included children’s age and language proficiency. However, language proficiency was not associated with the frequency of children’s intra-sentential code-switching in a code-switching context. Parent-report measures of code-switching experience exhibited limited associations with the children’s observed code-switching behavior; inter-sentential switches into English showed the most direct associations. Based on the findings from this exploratory study, we highlight the importance of including a code-switching context when analyzing language samples from bilingual children, considering both the target child and the interlocutor’s behavior, and continuing to refine indirect report measures of code-switching experience.