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Archi is a one-village language (1,000 speakers) belonging to the Lezgic branch of East Caucasian. It has a large and productive class of compound verbs combining a light verb and ‘coverbs’ of nominal, adjectival, verbal or unknown origin. It stands out among its closest relatives in the way it has created, under the influence of Lak, a large class of compounds using the verb bos ‘say’. We consider all coverbs used with bos and its allomorphs to be ideophones and propose a semantic classification of all ideophonic verbal compounds: sound and speech verbs, verbs of non-auditory sensations, ingestion, movement, and effortful activities. All primary data were extracted with partial paradigms and some examples from Chumakina et al.’s Archi online dictionary. Their phonotactic shapes, not substantially different from other parts of speech, are examined, as well as borrowings and specific ‘children’s speech’ ideophones.

Summary: Macrophages are major host cells for the protozoan Leishmania parasite. Depending on their activation state, they either contribute to the detection and elimination of Leishmania spp. or promote parasite resilience. Here, we report that the activation of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) in macrophages plays a pivotal role in the progression of Leishmania infantum infection by controlling inflammation and redox balance of macrophages. We also highlight the involvement of the NOX2/reactive oxygen species (ROS) axis in early Nrf2 activation and, subsequently, prostaglandin E2 (PGE2)/EP2r signaling in the sustenance of Nrf2 activation upon infection. Moreover, we establish a ferroptosis-like process within macrophages as a cell death program of L. infantum and the protective effect of Nrf2 in macrophages against L. infantum death. Altogether, these results identify Nrf2 as a critical factor for the susceptibility of L. infantum infection, highlighting Nrf2 as a promising pharmacological target for the development of therapeutic approaches for the treatment of visceral leishmaniasis.

Abstract Background In many countries, nitrous oxide is used in a gas mixture (EMONO) for short-term analgesia. Cases of addiction, with significant misuse, have been reported in hospitalized patients. Patients suffering from sickle cell disease (SCD) could represent a high-risk population for substance use disorder (SUD) due to their significant pain crisis and repeated use of EMONO. The objective of the PHEDRE study was to assess the prevalence of SUD for EMONO in French SCD patients. Results A total of 993 patients were included. Among 339 EMONO consumers, only 38 (11%) had a SUD, with very few criteria, corresponding mainly to a mild SUD due to a use higher than expected (in quantity or duration) and relational tensions with the care teams. Almost all patients (99.7%) were looking for an analgesic effect, but 68% of patients were also looking for other effects. The independent risks factors associated with at least one SUD criterion were: the feeling of effects different from the expected therapeutic effects of EMONO, at least one hospitalization for vaso occlusive crisis in the past 12 months and the presence of a SUD for at least one other analgesic drug. Conclusions The use of EMONO was not problematic for the majority of patients. Manifestations of SUD that led to tensions with healthcare teams should alert and lead to an evaluation, to distinguish a true addiction from a pseudoaddiction which may be linked to an insufficient analgesic treatment related to an underestimation of pain in SCD patients. Trial registration : Clinical Trials, NCT02580565. Registered 16 October 2015, https://clinicaltrials.gov/

Cynomolgus macaques may undergo surgical procedures for scientific and veterinary purposes. Recognition and assessment of pain using validated tools is a necessary first step for adequately managing pain in these primates. Grimace scales are one means of assessing the occurance of acute pain using action units such as facial expressions and posture. The aim of this study was to create and validate a Cynomolgus Macaque Grimace Scale (CMGS). Cynomolgus macaques (n = 43) were video recorded before and after a surgical procedure. Images were extracted from videos at timepoints at which breakthrough pain might be expected based on analgesic pharmacokinetics. Using the CMGS images were scored by 12 observers blinded to animal identification, times, and conditions. To validate the tool, detailed behavioral analyses emphasizing changes to baseline activity ethograms were compared to grimace scores. Four action units were identified related to potential pain including orbital tightening, brow lowering, cheek tightening, and hunched posture. The CMGS tool was found to have moderate inter- (ICCaverage action unit mean ± SD: 0.67 ± 0.28) and good intra- (ICCsingle mean ± SD: 0.79 ± 0.14) observer reliability. Grimace scores increased significantly (p

IntroductionWithin adipose tissue (AT), different macrophage subsets have been described, which played pivotal and specific roles in upholding tissue homeostasis under both physiological and pathological conditions. Nonetheless, studying resident macrophages in-vitro poses challenges, as the isolation process and the culture for extended periods can alter their inherent properties.MethodsStroma-vascular cells isolated from murine subcutaneous AT were seeded on ultra-low adherent plates in the presence of macrophage colony-stimulating factor. After 4 days of culture, the cells spontaneously aggregate to form spheroids. A week later, macrophages begin to spread out of the spheroid and adhere to the culture plate.ResultsThis innovative three-dimensional (3D) culture method enables the generation of functional mature macrophages that present distinct genic and phenotypic characteristics compared to bone marrow–derived macrophages. They also show specific metabolic activity and polarization in response to stimulation, but similar phagocytic capacity. Additionally, based on single-cell analysis, AT-macrophages generated in 3D culture mirror the phenotypic and functional traits of in-vivo AT resident macrophages.DiscussionOur study describes a 3D in-vitro system for generating and culturing functional AT-resident macrophages, without the need for cell sorting. This system thus stands as a valuable resource for exploring the differentiation and function of AT-macrophages in vitro in diverse physiological and pathological contexts.

BackgroundChronic pain affects approximately 30% of the general population, severely degrades quality of life and professional life, and leads to additional health care costs. Moreover, the medical follow-up of patients with chronic pain remains complex and provides only fragmentary data on painful daily experiences. This situation makes the management of patients with chronic pain less than optimal and may partly explain the lack of effectiveness of current therapies. Real-life monitoring of subjective and objective markers of chronic pain using mobile health (mHealth) programs could better characterize patients, chronic pain, pain medications, and daily impact to help medical management. ObjectiveThis cohort study aimed to assess the ability of our mHealth tool (eDOL) to collect extensive real-life medical data from chronic pain patients after 1 year of use. The data collected in this way would provide new epidemiological and pathophysiological data on chronic pain. MethodsA French national cohort of patients with chronic pain treated at 18 pain clinics has been established and followed up using mHealth tools. This cohort makes it possible to collect the determinants and repercussions of chronic pain and their evolutions in a real-life context, taking into account all environmental events likely to influence chronic pain. The patients were asked to complete several questionnaires, body schemes, and weekly meters, and were able to interact with a chatbot and use educational modules on chronic pain. Physicians could monitor their patients’ progress in real time via an online platform. ResultsThe cohort study included 1427 patients and analyzed 1178 patients. The eDOL tool was able to collect various sociodemographic data; specific data for characterizing pain disorders, including body scheme; data on comorbidities related to chronic pain and its psychological and overall impact on patients’ quality of life; data on drug and nondrug therapeutics and their benefit-to-risk ratio; and medical or treatment history. Among the patients completing weekly meters, 49.4% (497/1007) continued to complete them after 3 months of follow-up, and the proportion stabilized at 39.3% (108/275) after 12 months of follow-up. Overall, despite a fairly high attrition rate over the follow-up period, the eDOL tool collected extensive data. This amount of data will increase over time and provide a significant volume of health data of interest for future research involving the epidemiology, care pathways, trajectories, medical management, sociodemographic characteristics, and other aspects of patients with chronic pain. ConclusionsThis work demonstrates that the mHealth tool eDOL is able to generate a considerable volume of data concerning the determinants and repercussions of chronic pain and their evolutions in a real-life context. The eDOL tool can incorporate numerous parameters to ensure the detailed characterization of patients with chronic pain for future research and pain management. Trial RegistrationClinicalTrials.gov NCT04880096; https://clinicaltrials.gov/ct2/show/NCT04880096

Abstract Background Duchenne muscular dystrophy (DMD) is a progressive muscle degenerative disorder, culminating in a complete loss of ambulation, hypertrophic cardiomyopathy and a fatal cardiorespiratory failure. Necroptosis is the form of necrosis that is dependent upon the receptor‐interacting protein kinase (RIPK) 3; it is involved in several inflammatory and neurodegenerative conditions. We previously identified RIPK3 as a key player in the acute myonecrosis affecting the hindlimb muscles of the mdx dystrophic mouse model. Whether necroptosis also mediates respiratory and heart disorders in DMD is currently unknown. Methods Evidence of activation of the necroptotic axis was examined in dystrophic tissues from Golden retriever muscular dystrophy (GRMD) dogs and R‐DMDdel52 rats. A functional assessment of the involvement of necroptosis in dystrophic animals was performed on mdx mice that were genetically depleted for RIPK3. Dystrophic mice aged from 12 to 18 months were analysed by histology and molecular biology to compare the phenotype of muscles from mdxRipk3+/+and mdxRipk3−/− mice. Heart function was also examined by echocardiography in 40‐week‐old mice. Results RIPK3 expression in sartorius and biceps femoris muscles from GRMD dogs positively correlated to myonecrosis levels (r = 0.81; P = 0.0076). RIPK3 was also found elevated in the diaphragm (P ≤ 0.05). In the slow‐progressing heart phenotype of GRMD dogs, the phosphorylated form of RIPK1 at the Serine 161 site was dramatically increased in cardiomyocytes. A similar p‐RIPK1 upregulation characterized the cardiomyocytes of the severe DMDdel52 rat model, associated with a marked overexpression of Ripk1 (P = 0.007) and Ripk3 (P = 0.008), indicating primed activation of the necroptotic pathway in the dystrophic heart. MdxRipk3−/− mice displayed decreased compensatory hypertrophy of the heart (P = 0.014), and echocardiography showed a 19% increase in the relative wall thickness (P

Temporal correlations among demographic parameters can strongly influence population dynamics. Our empirical knowledge, however, is very limited regarding the direction and the magnitude of these correlations and how they vary among demographic parameters and species' life histories. Here, we use long-term demographic data from 15 bird and mammal species with contrasting pace of life to quantify correlation patterns among five key demographic parameters: juvenile and adult survival, reproductive probability, reproductive success and productivity. Correlations among demographic parameters were ubiquitous, more frequently positive than negative, but strongly differed across species. Correlations did not markedly change along the slow-fast continuum of life histories, suggesting that they were more strongly driven by ecological than evolutionary factors. As positive temporal demographic correlations decrease the mean of the long-run population growth rate, the common practice of ignoring temporal correlations in population models could lead to the underestimation of extinction risks in most species.

After a comprehensive review of the major learning management systems (LMS) in 2019--2020, Schoolcraft College began a transition from Anthology's Blackboard Original LMS to the updated Blackboard Ultra Course View. The learning management system impacts or informs the daily work-flows of several key stakeholders. As such, it was imperative to include members of these groups at all stages. While LMS transitions are unique to each institution, actively engaging support staff, faculty, students, and the vendor is key to a successful launch. Understanding the roles and responsibilities of each group creates a collaborative environment with a strong feedback loop that allows for a smoother change management process.

Numerous conservation programs are now targeting the mitigation or reduction of anthropogenic pressures to restore biodiversity. The aspirational and ambitious objectives underlying these programs need to translate into timely management actions for maximum impact, a process whose first steps assume efficient monitoring and appropriate indicators. Capitalizing on a well-coordinated stranding network, we developed further a risk-based indicator informing indirectly on pressures resulting in at-sea-mortality events of small cetaceans. This indicator uses Extreme Value Theory to forecast the expected maximum number of cetacean strandings on the French seaboard adjacent to three sub-regions defined by the ’Marine Strategy Framework Directive’ of the European Union. A comparison of forecasts and observations allows (i) a risk assessment, and (ii) inference on the trajectory towards ’Good Environmental Status’ on a time-scale aligning with the 6-years cycle required by the Directive, thereby allowing stakeholders to make informed and timely decisions. We applied the use of the indicators on 3 species illustrating different case studies: the harbour porpoise (Phocoena phocoena) in the Channel, the common dolphin (Delphinus delphis) in the Bay of Biscay, and the striped dolphin (Stenella coeruleoalba) in the Western Mediterranean Sea. Our results showed notably how by-catch in fisheries remains a large threat on short-beaked common dolphins, with no sign of abating.

The management and conservation of biodiversity relies on information on both the abundance of species and the potential impact of threats. Globally, one of the largest threats towards marine biodiversity is bycatch in fisheries. Under the Marine Strategy Framework Directive (MSFD), EU Member States are required to assess the status of species, such as the harbour porpoise (Phocoena phocoena), in relation to their abundance and mortality due to bycatch every six years. The Vulnerable (HELCOM) Belt Sea population of harbour porpoise has been surveyed to determine its abundance six times using dedicated aerial or ship-based line-transect distance sampling surveys. Here, we estimated the first trend in population abundance over an 18 year period (2005-2022). Using the most recent abundance estimate, we computed a mortality limit applying the modified Potential Biological Removal (mPBR) method based on the regionally agreed conservation objective to restore or maintain 80% of carrying capacity over 100 years with an 80% probability. Over the past 18 years there has been a strong negative trend (-2.7% p.a.; 95% CI: -4.1%; + 1.3%) in abundance, with a 90.5% probability. The mortality limit was estimated to be 24 animals, which the current bycatch estimates (~900 porpoises/year from the commercial Danish and Swedish set net fishery fleets, with no data from Germany and other fishery types) exceed by far. The frequency and quality of data available on abundance for this population are higher than those available for the majority of marine species. Given the observed population decline and likely unsustainable levels of bycatch, the results presented here provide a strong basis to make informed, evidence-based management decisions for action for this population. Such action is needed urgently, before the dire situation of other porpoise species and populations around the globe is repeated.

Intense development of Offshore Wind Farms (OWFs) has occurred in the North Sea with several more farms planned for the near future. These OWFs pose a threat to marine megafauna stressing the need to mitigate the impact of human activities. To help mitigate impacts, the Before After Gradient (BAG) design was proposed. We explored the use of the BAG method on megafauna sightings recorded at different distances from OWFs in the southern North Sea. We predicted intra-annual variability in species distribution, then correlated species distribution with the presence of operational OWFs and investigated the potential impact the operation of prospective OWFs may have on species distribution. Four patterns of intra-annual variability were predicted: species most abundant in spring, in winter, in both spring and winter, or all year round. We recommend that future OWF constructions be planned in summer and early fall to minimise impact on cetaceans and that offshore areas off northern France and Belgium be avoided to minimise impact on seabirds. Our prospective analysis predicted a decreased density for most species with the operation of prospective OWFs. Prospective approaches, using e.g. a BAG design, are paramount to inform species conservation as they can forecast the likely responses of megafauna to anthropogenic disturbances.

Abstract Duchenne muscular dystrophy (DMD) is a devastating X-linked muscular disease, caused by mutations in the DMD gene encoding Dystrophin and affecting 1:5000 boys worldwide. Lack of Dystrophin leads to progressive muscle wasting and degeneration resulting in cardiorespiratory failure. Despite the absence of a definitive cure, innovative therapeutic avenues are emerging. Myopathologic studies are important to further understand the biological mechanisms of the disease and to identify histopathologic benchmarks for clinical evaluations. We conducted a myopathologic analysis on twenty-four muscle biopsies from DMD patients, with particular emphasis on regeneration, fibro-adipogenic progenitors and muscle stem cells behavior. We describe an increase in content of fibro-adipogenic progenitors, central orchestrators of fibrotic progression and lipid deposition, concurrently with a decline in muscle regenerative capacity. This regenerative impairment strongly correlates with compromised activation and expansion of muscle stem cells. Furthermore, our study uncovers an early acquisition of a senescence phenotype by DMD-afflicted muscle stem cells. Here we describe the myopathologic trajectory intrinsic to DMD and establish muscle stem cell senescence as a pivotal readout for future therapeutic interventions.

Abstract Defecation by large whales is known to fertilise oceans with nutrients, stimulating phytoplankton and ecosystem productivity. However, our current understanding of these processes is limited to a few species, nutrients and ecosystems. Here, we investigate the role of cetacean communities in the worldwide biological cycling of two major nutrients and six trace nutrients. We show that cetaceans release more nutrients in mesotrophic to eutrophic temperate waters than in oligotrophic tropical waters, mirroring patterns of ecosystem productivity. The released nutrient cocktails also vary geographically, driven by the composition of cetacean communities. The roles of small cetaceans, deep diving cetaceans and baleen whales differ quantitatively and functionally, with contributions of small cetaceans and deep divers exceeding those of large whales in some areas. The functional diversity of cetacean communities expands beyond their role as top predators to include their role as active nutrient vectors, which might be equally important to local ecosystem dynamics.

Abstract Background The French Addictovigilance network has observed the existence of the intravenous use of oral morphine capsules among people suffering from opioid use disorders. According to persons who inject morphine, these capsules are easy to dissolve and then inject, giving them the image of an "injectable" opioid substitution treatment (OST). In France, validated OSTs are only available orally, so dissolving morphine capsules represents the only alternative for patients who are not sufficiently relieved by oral forms. This practice presents risks related to the potential persistence of particles of the oral galenic in the injectable solution, despite its filtration, but also risks—notably of overdose—related to the pharmacological effects of opioids and to variations of the quantities of morphine extracted during the dissolution of the capsules. We conducted an online survey among the people concerned to collect data on their needs and expectations regarding a possible injectable substitution. Method An anonymous online survey including all voluntary respondents residing in France and using oral morphine intravenously was conducted in partnership with the Psychoactif harm reduction organization, from 23/03/2020 to 01/04/2021. Results The analysis of the 157 exploitable questionnaires showed that 41% of the respondents obtained their drugs only from illegal markets. The others received, regularly or occasionally, medical prescriptions, reimbursed in 84% of cases. For 78% of the respondents, injection was the most frequent route of morphine administration, with 3.8 ± 2 injections per day. 56% of the respondents were receiving an OST, on prescription (79%), monthly (86%), in addition to morphine. Skenan® capsules were the most frequently used (81%) and 47.2% of the respondents had already experienced injection-related complications. 95% of the respondents were in favor of experimenting with an injectable morphine substitution. Those who never received medical prescriptions were the youngest (

(1) Background: Macrophagic myofasciitis (MMF) is an inflammatory histopathological lesion demonstrating long-term biopersistence of vaccine-derived aluminum adjuvants within muscular phagocytic cells. Affected patients suffer from widespread myalgia and severe fatigue consistent with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a poorly understood disorder suspected to result from chronic immune stimulation by infectious and inorganic particles. (2) Methods: In this study we determined the immuno-metabolic properties of MMF phagocytic cells compared to controls, at rest and upon exposure to aluminum oxyhydroxide adjuvant, with or without adsorbed antigens, using protein quantification and an oxygen consumption assay. (3) Results: MMF and control cells similarly internalized the adjuvant and vaccine but MMF cells specifically expressed Rubicon and Nox2, two molecules unique to the LC3-associated phagocytosis (LAP) machinery, a non-canonical autophagic pathway able to downregulate canonical autophagy. MMF cells exhibited an altered inflammatory secretome, producing more pain-inducing CXC chemokines and less TNF-α than controls, consistent with chronic myalgia and exhaustion of the immune system previously documented in ME/CFS. MMF cells exhibited mitochondrial metabolism dysfunction, with exacerbated reaction to adjuvanted vaccine, contrasting with limited spare respiratory capacity and marked proton leak weakening energy production. (4) Conclusions: MMF phagocytes seemingly use LAP to handle aluminum oxyhydroxide vaccine particles, secrete pain-inducing molecules, and exhibit exacerbated metabolic reaction to the vaccine with limited capacity to respond to ongoing energetic requests.

Human activities in the oceans are increasing and can result in additional mortality on many marine Protected, Endangered or Threatened Species (PETS). It is necessary to implement ambitious measures that aim to restore biodiversity at all nodes of marine food webs and to manage removals resulting from anthropogenic activities. We developed a stochastic surplus production model (SPM) linking abundance and removal processes under the assumption that variations in removals reflect variations in abundance. We then consider several ‘harvest’ control rules, included two candidate ones derived from this SPM (which we called ‘Anthropogenic Removals Threshold’, or ART), to manage removals of PETS. The two candidate rules hinge on the estimation of a stationary removal rate. We compared these candidate rules to other existing control rules (e.g. potential biological removal or a fixed percentage rule) in three scenarios: (i) a base scenario whereby unbiased but noisy data are available, (ii) scenario whereby abundance estimates are overestimated and (iii) scenario whereby abundance estimates are underestimated. The different rules were tested on a simulated set of data with life-history parameters close to a small-sized cetacean species of conservation interest in the North-East Atlantic, the harbour porpoise (Phocoena phocoena), and in a management strategy evaluation framework. The effectiveness of the rules were assessed by looking at performance metrics, such as time to reach the conservation objectives, the removal limits obtained with the rules or temporal autocorrelation in removal limits. Most control rules were robust against biases in data and allowed to reach conservation objectives with removal limits of similar magnitude when averaged over time. However, one of the candidate rule (ART) displayed greater alignment with policy requirements for PETS such as minimizing removals over time.

Background: Epinephrine delivery via an intranasal spray (neffy) is being evaluated as an additional option to treat severe allergic reaction and may provide clinical benefit by reducing the time to dosing in community settings by avoiding needles. Given that hypotension is a hallmark symptom of severe allergic reactions, a preclinical study was conducted to evaluate the impact of this factor on epinephrine absorption via neffy. Objective: The objective of this study was to evaluate the absorption of epinephrine via neffy in a dog model of anaphylaxis with severe hypotension. Methods: Epinephrine absorption via neffy was evaluated in anesthetized beagle dogs under both normal conditions and hypotension associated with anaphylaxis. A total of 14 dogs (10 males and 4 females) were dosed with neffy, 1.0 mg, under normal conditions, followed by neffy, 1.0 mg, under conditions of anaphylaxis. Results: The mean maximum concentration of epinephrine was higher during anaphylaxis than under normal conditions (2,670 ± 2,150 pg/mL and 1,330 ± 739 pg/mL [P < .05]). Relative to normal conditions, anaphylaxis resulted in higher overall epinephrine exposure (area under the curve from 0 to 45 minutes = 54,400 ± 18,100 min × pg/mL and 34,300 ± 21,500 minutes × pg/mL [P < .05]), which is likely due to the increase in vascular permeability commonly observed during severe allergic reactions. Conclusion: Taken together with real-world evidence from nasal naloxone treatment for opioid overdose demonstrating that the reduced blood flow or hypotension associated with overdose does not appear to suppress naloxone’s efficacy, the current findings demonstrate that epinephrine is well absorbed following neffy delivery during the hypotension associated with severe anaphylaxis reactions.