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Intracellular lysosomal trafficking and positioning are fundamental cellular processes critical for proper neuronal function. Among the diverse array of proteins involved in regulating lysosomal positioning, the Transient Receptor Potential Mucolipin 1 (TRPML1) and the Ragulator complex have emerged as central players. TRPML1, a lysosomal cation channel, has been implicated in lysosomal biogenesis, endosomal/lysosomal trafficking including in neuronal dendrites, and autophagy. LAMTOR1, a subunit of the Ragulator complex, also participates in the regulation of lysosomal trafficking. Here we report that LAMTOR1 regulates lysosomal positioning in dendrites of hippocampal neurons by interacting with TRPML1. LAMTOR1 knockdown (KD) increased lysosomal accumulation in proximal dendrites of cultured hippocampal neurons, an effect reversed by TRPML1 KD or inhibition. On the other hand, TRPML1 activation with ML-SA1 or prevention of TRPML1 interaction with LAMTOR1 using a TAT-decoy peptide induced dendritic lysosomal accumulation. LAMTOR1 KD-induced proximal dendritic lysosomal accumulation was blocked by the dynein inhibitor, ciliobrevin D, suggesting the involvement of a dynein-mediated transport. These results indicate that LAMTOR1-mediated inhibition of TRPML1 is critical for normal dendritic lysosomal distribution and that release of this inhibition or direct activation of TRPML1 results in abnormal dendritic lysosomal accumulation. The roles of LAMTOR1-TRPML1 interactions in lysosomal trafficking and positioning could have broad implications for understanding cognitive disorders associated with lysosomal pathology and calcium dysregulation.

ObjectiveDue to its favorable outcome regarding late morbidity and mortality, thoracic endovascular repair (TEVAR) is becoming more popular for uncomplicated type B aortic dissection (TBAD). This study aimed to compare preemptive endovascular treatment and optimal medical treatment (OMT) and OMT alone in patients presenting uncomplicated TBAD with predictors of aortic progression.DesignRetrospective multicenter studyMethodsWe analyzed patients with uncomplicated TBAD and risk factors of progression in two French academic centers. Aortic events [defined as aortic-related (re)intervention or aortic-related death after initial hospitalization], postoperative complications, non-aortic events, and radiologic aortic progression and remodeling were recorded and analyzed. Analysis was performed on an intention-to-treat basis.ResultsBetween 2011 and 2021, preemptive endovascular procedures at the acute and early subacute phase (

Osteoporosis after bariatric surgery is an increasing health concern as the rate of bariatric surgery has risen. In animal studies mimicking bariatric procedures, bone disease, together with decreased serum levels of Ca2+, Mg2+ and the gastric hormone Ghrelin were described. Ghrelin regulates metabolism by binding to and activating the growth hormone secretagogue receptor (GHSR) which is also expressed in the kidney. As calcium and magnesium are key components of bone, we tested the hypothesis that Ghrelin-deficiency contributes to osteoporosis via reduced upregulation of the renal calcium channel TRPV5 and the heteromeric magnesium channel TRPM6/7. We expressed GHSR with TRPV5 or TRPM6/7 channel in HEK293 cells and treated them with purified Ghrelin. Whole-cell current density was analyzed by patch-clamp recording. Nephron-specific gene expression was performed by tubular microdissection followed by qPCR in wild-type (WT) mice, and immunofluorescent imaging of GHSR-eGFP mice. Tubular magnesium homeostasis was analyzed in GHSR-null and WT mice at baseline and after caloric restriction. After Ghrelin exposure, whole-cell current density did not change for TRPV5 but increased for TRPM6/7 in a dose-dependent fashion. Applying the Ghrelin-mimetic (D-Trp7, Ala8,D-Phe10)-α-MSH (6–11) amide without and with the GHSR antagonist (D-Lys3)-GHRP6, we confirmed the stimulatory role of Ghrelin towards TRPM6/7. As GHSR initiates downstream signaling via protein kinase A (PKA), we found that the PKA inhibitor H89 abrogated TRPM6/7 stimulation by Ghrelin. Similarly, transfected Gαs, but not the Gαs mutant Q227L, nor Gαi2, Gαq, or Gα13 upregulated TRPM6/7 current density. In microdissected TALs and DCTs similar levels of GHSR mRNA were detected. In contrast, TRPM6 mRNA was expressed in the DCT and also detected in the TAL at 25% expression compared to DCT. Immunofluorescent studies using reporter GHSR-eGFP mice showed a strong eGFP signal in the TAL but surprisingly displayed no eGFP signal in the DCT. In 3-, 6-, and 9-month-old GHSR-null and WT mice, baseline serum magnesium was not significantly different, but 24-h urinary magnesium excretion was elevated in 9-month-old GHSR-null mice. In calorically restricted GHSR-null mice, we detected excess urinary magnesium excretion and reduced serum magnesium levels compared to WT mice. The kidneys from calorically restricted WT mice showed upregulated gene expression of magnesiotropic genes Hnf1b, Cldn-16, Cldn-19, Fxyd-2b, and Parvalbumin compared to GHSR-null mice. Our in vitro studies show that Ghrelin stimulates TRPM6/7 via GHSR and Gαs-PKA signaling. The murine studies are consistent with Ghrelin-GHSR signaling inducing reduced urinary magnesium excretion, particularly in calorically restricted mice when Ghrelin levels are elevated. This effect may be mediated by Ghrelin-upregulation of TRPM6 in the TAL and/or upregulation of other magnesiotropic genes. We postulate that rising Ghrelin levels with hunger contribute to increased renal Mg2+ reabsorption to compensate for lack of enteral Mg2+ uptake.

Single-cell CRISPR-based transcriptome screens are potent genetic tools for concomitantly assessing the expression profiles of cells targeted by a set of guides RNA (gRNA), and inferring target gene functions from the observed perturbations. However, due to various limitations, this approach lacks sensitivity in detecting weak perturbations and is essentially reliable when studying master regulators such as transcription factors. To overcome the challenge of detecting subtle gRNA induced transcriptomic perturbations and classifying the most responsive cells, we developed a new supervised autoencoder neural network method. Our Sparse supervised autoencoder (SSAE) neural network provides selection of both relevant features (genes) and actual perturbed cells. We applied this method on an in-house single-cell CRISPR-interference-based (CRISPRi) transcriptome screening (CROP-Seq) focusing on a subset of long non-coding RNAs (lncRNAs) regulated by hypoxia, a condition that promote tumor aggressiveness and drug resistance, in the context of lung adenocarcinoma (LUAD). The CROP-seq library of validated gRNA against a subset of lncRNAs and, as positive controls, HIF1A and HIF2A, the 2 main transcription factors of the hypoxic response, was transduced in A549 LUAD cells cultured in normoxia or exposed to hypoxic conditions during 3, 6 or 24 h. We first validated the SSAE approach on HIF1A and HIF2 by confirming the specific effect of their knock-down during the temporal switch of the hypoxic response. Next, the SSAE method was able to detect stable short hypoxia-dependent transcriptomic signatures induced by the knock-down of some lncRNAs candidates, outperforming previously published machine learning approaches. This proof of concept demonstrates the relevance of the SSAE approach for deciphering weak perturbations in single-cell transcriptomic data readout as part of CRISPR-based screening.

Globally, groupers (Serranidae) are commercially important fish species. Hybridization within this family has been reported in captivity and natural environments, usually among congeneric species. However, intergeneric hybridization has been reported only occasionally. Given the commercial interest in these fish, artisanal or recreational fishermen easily notice “weird-looking” individuals. This is the case of an unidentified grouper noticed by a spearfisher in Lebanese Mediterranean waters. Visual comparisons raised the possibility that the observed specimen was a hybrid. Molecular analysis based on two mitochondrial and three nuclear markers was performed to investigate this potential hybrid’s affinity. The discordance of the phylogenetic gene trees of the mitochondrial and nuclear markers indicates that E. marginatus and M. rubra are potential parent species of a hybrid individual in our samples. The subsequent haploweb analysis based on the S7 nuclear marker reveals the affinity of the hybrid individual to both E. marginatus and M. rubra. In this specific hybridization case, the nuclear marker S7 emerges as a valuable diagnostic tool for species delineation and hybrid detection.

In 1984, Gary Lynch and Michel Baudry published in Science a novel biochemical hypothesis for learning and memory, in which they postulated that the calcium-dependent protease, calpain, played a critical role in regulating synaptic properties and the distribution of glutamate receptors, thereby participating in memory formation in hippocampus. Over the following 40 years, much work has been done to refine this hypothesis and to provide convincing arguments supporting what was viewed at the time as a simplistic view of synaptic biochemistry. We have now demonstrated that the two major calpain isoforms in the brain, calpain-1 and calpain-2, execute opposite functions in both synaptic plasticity/learning and memory and in neuroprotection/neurodegeneration. Thus, calpain-1 activation is required for triggering long-term potentiation (LTP) of synaptic transmission and learning of episodic memory, while calpain-2 activation limits the magnitude of LTP and the extent of learning. On the other hand, calpain-1 is neuroprotective while calpain-2 is neurodegenerative, and its prolonged activation following various types of brain insults leads to neurodegeneration. The signaling pathways responsible for these functions have been identified and involve local protein synthesis, cytoskeletal regulation, and regulation of glutamate receptors. Human families with mutations in calpain-1 have been reported to have impairment in motor and cognitive functions. Selective calpain-2 inhibitors have been synthesized and clinical studies to test their potential use to treat disorders associated with acute neuronal damage, such as traumatic brain injury, are being planned. This review will illustrate the long and difficult journey to validate a bold hypothesis.

The voltage-gated sodium channel Nav1.7 is encoded by SCN9A gene and plays a critical role in pain sensitivity. Several SCN9A gain-of-function (GOF) mutations have been found in patients with small fiber neuropathy (SFN) having chronic pain, including the R185H mutation. However, for most of these variants, their involvement in pain phenotype still needs to be experimentally elucidated. In order to delineate the impact of R185H mutation on pain sensitivity, we have established the Scn9aR185H mutant mouse model using the CRISPR/Cas9 technology. The Scn9aR185H mutant mice show no cellular alteration in the dorsal root ganglia (DRG) containing cell bodies of sensory neurons and no alteration of growth or global health state. Heterozygous and homozygous animals of both sexes were investigated for pain sensitivity. The mutant mice were more sensitive than the wild-type mice in the tail flick and hot plate tests, acetone, and von Frey tests for sensitivity to heat, cold, and touch, respectively, although with sexual dimorphic effects. The newly developed bioinformatic pipeline, Gdaphen is based on general linear model (GLM) and random forest (RF) classifiers as well as a multifactor analysis of mixed data and shows the qualitative and quantitative variables contributing the most to the pain phenotype. Using Gdaphen, tail flick, Hargreaves, hot plate, acetone, cold plate, and von Frey tests, sex and genotype were found to be contributing most to the pain phenotype. Importantly, the mutant animals displayed spontaneous pain as assessed in the conditioned place preference (CPP) assay. Altogether, our results indicate that Scn9aR185H mice show a pain phenotype, suggesting that the SCN9AR185H mutation identified in patients with SFN having chronic pain contributes to their symptoms. Therefore, we provide genetic evidence for the fact that this mutation in Nav1.7 channel plays an important role in nociception and in the pain experienced by patients with SFN who have this mutation. These findings should aid in exploring further pain treatments based on the Nav1.7 channel.

Major invasions of Indo-Pacific lionfish (Pterois volitans and P. miles) are underway in the Western Atlantic Ocean and the Mediterranean Sea. While the establishment of lionfish in the Western Atlantic is perhaps the most well-studied marine fish invasion to date, the rapidly expanding invasion in the Mediterranean is more recent and has received less attention. Here we review and synthesize successes and failures from two decades of lionfish management in the Western Atlantic to give policy recommendations for their management in the Mediterranean. Two failed approaches that were attempted multiple times in the Western Atlantic and that we advise against are (1) feeding lionfish to native fish to promote predation and (2) implementing bounty programs to incentivize lionfish harvest. Broadly, the most important management lessons that we recommend include (1) conducting routine removals by spearfishing with scuba, which can effectively suppress local abundances of lionfish; (2) encouraging the development of recreational and commercial lionfish fisheries, which can promote long-term, sustainable lionfish population control; and, (3) engaging local communities and resource users (e.g., with lionfish removal tournaments), which can concurrently achieve multiple objectives of promoting lionfish removals, market-development, research, and public education. Managers in the Western Atlantic often needed to adapt current conservation policies to enable lionfish removals in areas where spearfishing with scuba was otherwise prohibited for conservation purposes. The risk of abusing these policies was mitigated through the use of gear restrictions, diver trainings, and through participatory approaches that integrated scuba divers and stakeholder organizations in lionfish research and management. Our review of policies and practices in the Mediterranean Sea found that many of our recommended lionfish management approaches are not being done and indicate potential opportunities to implement these. We expect and fully recommend that work continues towards multinational cooperation to facilitate regional coordination of research, control, and management efforts with respect to the Mediterranean lionfish invasion. As with other major biological invasions, lionfish are unconstrained by political borders and their control will require rapid and strategic management approaches with broad cooperation among and between governments and stakeholders.

In sub-Saharan Africa, smallholder farming systems continue to record very low yields despite the availability of appropriate crop management technologies. A 2-year field experiment was conducted in 2018 and 2019 at the Agricultural Research Station of Northern Benin to evaluate the growth response, grain yield attributes, and nutrient- and water- use efficiencies of different drought-tolerant (DT) maize varieties (TZEE-W-POP-STR QPM, TZE-Y-POP-STR, 2008Syn-EE-W DT-STR, and 2000Syn-EE-W of 80–90 days cycle), compared to DMR-ESR-W, a drought-susceptible (DS) variety of 90 days cycle, under different fertilizer options [no fertilizer control, microdosing option 1 (MD1, 25 kg N ha−1 + 4 kg P ha−1), option 2 (MD2, 25 kg N ha−1 + 8 kg P ha−1), option 3 (MD3, 35 kg N ha−1 + 8 kg P ha−1), and broadcast fertilizer at recommended rate (RR, 76 kg N ha−1 + 13 kg P ha−1). Generally, combining microdosing with DT varieties showed a very good performance by increasing the leaf area and biomass by 71 and 85%, respectively, at anthesis compared to the conventional practice. Microdosing increases grain and stover yields by 171 and 98%, respectively, compared to an unfertilized control with generally no difference between MD3 and RR treatments. Also, the DT varieties obtained the best yields (+19%), with the highest value observed with the TZE-Y variety. Significant interaction was found between varieties and fertilization for grain and stover yields. During the two cropping seasons, microdose fertilization increases the DT grain yield and gross return by 658 kg ha−1 and 203$USD, respectively, than their application on drought sensitive variety. The results of the current study demonstrated that there is a considerable potential for smallholder farmers of northern Benin to improve the maize productivity by means of DT varieties and of fertilizer microdosing. Using, especially, the MD3 option on the DT variety, TZE-Y, may be the best combination in optimizing the maize production in the sub-humid region of Benin, instead of the climate sensitive variety of the DMR-ESR under the microdosing or a common fertilization practice. However, further testing of the technologies through on-farm experiments are required before a precise advice can be given. Precisely, there is a need to evaluate these management options in farmer's fields, taking into account the climatic, soil, and management conditions to better assess and understand the variation in response and in economic benefits and risk.

Role distribution is a central issue for parents in the transition to parenthood, but little is known about the motivations in fathers to assume a specific role. Differences in work-family balance in each parent may be motivated by an individual choice mutually shared by both partners; however, in many couples, the parents may feel forced to adopt a traditional role distribution, either for financial reasons, or to comply with social expectations about what men and women should do when they are parents. This feeling of being socially constrained to adopt a role distribution that is not congruent with intrinsic motivations can generate dissatisfaction and may jeopardize the development of the interparental relationship. Coparenting refers to the emotional and instrumental support parents bring to each other in their parental tasks. It has been shown to be central in family functioning and a powerful predictor of children’s emotional and cognitive development. In this study, we aimed to assess the extent to which different motivations for role distribution in fathers are predictive of the quality of the coparental relationship. A convenience sample of 144 fathers from the French-speaking part of Switzerland completed online questionnaires about their motivations, coparental relationship, and sociodemographic characteristics. Results showed that the reasons for role distribution were mainly economical, practical, and in order to meet personal expectations. Multivariate general linear modeling showed that role distribution that is constrained to meet social expectations and age were predictive of a less cohesive coparental relationship, whereas a deliberate choice in role distribution was linked to a more cohesive coparental relationship.

BackgroundChronic lesion formation after cardiac tissue ablation is an important indicator for procedural outcome. Moreover, there is a lack of knowledge regarding the features that predict chronic lesion formation.ObjectiveThe aim of this study is to determine whether acute lesion visualization using late gadolinium enhanced magnetic resonance imaging (LGE-MRI) can reliably predict chronic lesion size.MethodsFocal lesions were created in left and right ventricles of canine models using either radiofrequency (RF) ablation or cryofocal ablation. Multiple ablation parameters were used. The first LGE-MRI was acquired within 1–5 h post-ablation and the second LGE-MRI was obtained 47–82 days later. Corview software was used to perform lesion segmentations and size calculations.Results:Fifty-Five lesions were created in different locations in the ventricles. Chronic volume size decreased by a mean of 62.5 % (95% CI 58.83–67.97, p < 0.0005). Similar regression of lesion volume was observed regardless of ablation location (p = 0.32), ablation technique (p = 0.94), duration (p = 0.37), power (p = 0.55) and whether lesions were connected or not (p = 0.35). There was no significant difference in lesion volume reduction assessed at 47–54 days and 72–82 days after ablation (p = 0.31). Chronic lesion volume was equal to 0.32 of the acute lesion volumes (R2 = 0.75).ConclusionChronic tissue injury related to catheter ablation can be reliably modeled as a linear function of the acute lesion volume as assessed by LGE-MRI, regardless of the ablation parameters.

The silver-cheeked toadfish (Lagocephalus sceleratus, from the pufferfish family Tetraodontidae) and the Pacific red lionfish (Pterois miles, family Scorpaenidae) have recently invaded the Mediterranean Sea. Lagocephalus sceleratus has spread throughout this entire sea with the highest concentrations in the eastern basin, while more recently, Pterois miles has spread from the Eastern to the Central Mediterranean Sea. Their effects on local biodiversity and fisheries are cause for management concern. Here, a comprehensive review of predators of these two species from their native Indo-Pacific and invaded Mediterranean and Western Atlantic ranges is presented. Predators of Tetraodontidae in general were reviewed for their native Indo-Pacific and Western Atlantic ranges, as no records were found specifically for L. sceleratus in its native range. Tetraodontidae predators in their native ranges included mantis shrimp (Stomatopoda), lizardfish (Synodus spp.), tiger shark (Galeocerdo cuvier), lemon shark (Negaprion brevirostris), sea snakes (Enhydrina spp.), catfish (Arius spp.), cobia (Rachycentron canadum), skipjack tuna (Katsuwonus pelamis), and common octopus (Octopus vulgaris). The only reported predator of adult L. sceleratus in the Mediterranean was loggerhead turtle (Caretta caretta), whereas juvenile L. sceleratus were preyed by common dolphinfish (Coryphaena hippurus) and garfish (Belone belone). Conspecific cannibalism of L. sceleratus juveniles was also confirmed in the Mediterranean. Pufferfish predators in the Western Atlantic included common octopus, frogfish (Antennaridae), and several marine birds. Predators of all lionfish species in their native Indo-Pacific range included humpback scorpionfish (Scorpaenopsis spp.), bobbit worms (Eunice aphroditois), moray eels (Muraenidae), and bluespotted cornetfish (Fistularia commersonii). Lionfish predators in the Mediterranean included dusky grouper (Epinephelus marginatus), white grouper (Epinephelus aeneus), common octopus, and L. sceleratus, whereas in the Western Atlantic included the spotted moray (Gymnothorax moringa), multiple grouper species (tiger Mycteroperca tigris, Nassau Epinephelus striatus, black Mycteroperca bonaci, red Epinephelus morio, and gag Mycteroperca microleps; Epinephelidae), northern red snapper (Lutjanus campechanus), greater amberjack (Seriola dumerilli), and nurse shark (Ginglymostoma cirratum). The sparse data found on natural predation for these species suggest that population control via predation may be limited. Their population control may require proactive, targeted human removals, as is currently practiced with lionfish in the Western Atlantic.

While calpains have been implicated in neurogenesis for a long time, there is still little information regarding the specific contributions of various isoforms in this process. We took advantage of the availability of mutant mice with complete deletion of calpain-1 to analyze its contribution to neurogenesis. We first used the incorporation of BrdU in newly-generated cells in the subgranular zone of the dentate gyrus to determine the role of calpain-1 deletion in neuronal proliferation. Our results showed that the lack of calpain-1 decreased the rate of cell proliferation in adult hippocampus. As previously shown, it also decreased the long-term survival of newly-generated neurons. We also used data from previously reported RNA and miRNA sequencing analyses to identify differentially expressed genes in brain of calpain-1 knock-out mice related to cell division, cell migration, cell proliferation and cell survival. A number of differentially expressed genes were identified, which could play a significant role in the changes in neurogenesis in calpain-1 knock out mice. The results provide new information regarding the role of calpain-1 in neurogenesis and have implications for better understanding the pathologies associated with calpain-1 mutations in humans.

The re-emergence of commoning over the last decades is not incidental, but rather indicative of a large-scale transition to a more “generative” organization of society that is oriented toward the planet’s global carrying capacity. Digital commons governance frameworks are of particular importance for a new global paradigm of cooperation, one that can scale the organization of communities around common goals and resources to unprecedented levels of size, complexity and granularity. Distributed Ledger Technologies (DLTs) such as blockchain have lately given new impetus to the emergence of a new generation of authentic “sharing economy,” protected from capture by thorough distribution of power over infrastructure, that spans not only digital but also physical production of common value. The exploration of the frontiers of DLT-based commoning at the heart of this article considers three exemplary cases for this new generation of commons-oriented community frameworks: the Commons Stack, Holochain and the Commons Engine, and the Economic Space Agency. While these projects differ in their scope as well as in their relation to physical common-pool resources (CPRs), they all share the task of redefining markets so as to be more conducive to the production and sustainment of common value(s). After introducing each of them with regards to their specificities and commonalities, we analyze their capacity to foster commons-oriented economies and “money for the commons” that limit speculation, emphasize use-value over exchange-value, favor equity in human relations, and promote responsibility for the preservation of natural habitats. Our findings highlight the strengths of DLTs for a federated scaling of CPR governance frameworks that accommodates rather than obliterates cultural differences and creates webs of fractal belonging among nested communities.

During the last decades, depression has been diagnosed in increasing numbers, accompanied by rising prescription rates of antidepressants. Concomitantly, these pharmaceuticals are frequently detected in surface waters. Serotonin and noradrenalin reuptake inhibitors such as venlafaxine form the second largest group of antidepressants worldwide, and venlafaxine is the second most prescribed antidepressant in Germany. As drug targets are evolutionary highly conserved, venlafaxine can potentially change not only behavior and related physiological processes in humans but also in non-target species, especially aquatic organisms. In order to test this hypothesis for fish, we exposed brown trout larvae and juveniles to venlafaxine at concentrations ranging from 1 to 1,000 μg/L. Larvae were exposed for 5 months from the eyed ova stage until 8 weeks post yolk-sac consumption at 7 and 11 °C. Juveniles were exposed for 4 weeks at 7 °C. Mortality, weight, length, behavior during exposure and behavior in a stressful environment were recorded in both experiments. For larvae, additionally, hatching rate and heart rate were analyzed. In juvenile fish, tissue cortisol levels were determined. Our results clearly showed, that brown trout, irrespective of their life stage, change their behavior when being exposed to venlafaxine: During exposure, venlafaxine at 7 °C caused larvae to sojourn in the upper part of the aquaria for a longer time, with a lowest observed effect concentration of 100 μg/L. In a stressful environment with limited space, fish exposed to ≥10 μg/L venlafaxine were less active than controls. Furthermore, venlafaxine reduced the growth of larvae (length at ≥10 μg/L, weight at 1 mg/L) and their survival after 5 months (at 1 mg/L). Hatching rate and heart rate of larvae as well as tissue cortisol concentration of juveniles were not affected by venlafaxine treatment.

Calpains represent a family of calcium-dependent proteases participating in a multitude of functions under physiological or pathological conditions. Calpain-1 is one of the most studied members of the family, is ubiquitously distributed in organs and tissues, and has been shown to be involved in synaptic plasticity and neuroprotection in mammalian brain. Calpain-1 deletion results in a number of phenotypic alterations. While some of these alterations can be explained by the acute functions of calpain-1, the present study was directed at studying alterations in gene expression that could also account for these phenotypic modifications. RNA-seq analysis identified 354 differentially expressed genes (DEGs) in brain of calpain-1 knock-out mice, as compared to their wild-type strain. Most DEGs were classified in 10 KEGG pathways, with the highest representations in Protein Processing in Endoplasmic Reticulum, MAP kinase and Alzheimer’s disease pathways. Most DEGs were down-regulated and validation of a number of these genes indicated a corresponding decreased expression of their encoded proteins. The results indicate that calpain-1 is involved in the regulation of a significant number of genes affecting multiple brain functions. They also indicate that mutations in calpain-1 are likely to be involved in a number of brain disorders.

Neuropathic pain is a challenging condition for which current therapies often remain unsatisfactory. Chronic administration of β2 adrenergic agonists, including formoterol currently used to treat asthma and chronic obstructive pulmonary disease, alleviates mechanical allodynia in the sciatic nerve cuff model of neuropathic pain. The limited clinical data currently available also suggest that formoterol would be a suitable candidate for drug repurposing. The antiallodynic action of β2 adrenergic agonists is known to require activation of the delta-opioid (DOP) receptor but better knowledge of the molecular mechanisms involved is necessary. Using a mouse line in which DOP receptors were selectively ablated in neurons expressing Nav1.8 sodium channels (DOP cKO), we showed that these DOP peripheral receptors were necessary for the antiallodynic action of the β2 adrenergic agonist formoterol in the cuff model. Using a knock-in mouse line expressing a fluorescent version of the DOP receptor fused with the enhanced green fluorescent protein (DOPeGFP), we established in a previous study, that mechanical allodynia is associated with a smaller percentage of DOPeGFP positive small peptidergic sensory neurons in dorsal root ganglia (DRG), with a reduced density of DOPeGFP positive free nerve endings in the skin and with increased DOPeGFP expression at the cell surface. Here, we showed that the density of DOPeGFP positive free nerve endings in the skin is partially restored and no increase in DOPeGFP translocation to the plasma membrane is observed in mice in which mechanical pain is alleviated upon chronic oral administration of formoterol. This study, therefore, extends our previous results by confirming that changes in the mechanical threshold are associated with changes in peripheral DOP profile. It also highlights the common impact on DOP receptors between serotonin noradrenaline reuptake inhibitors such as duloxetine and the β2 mimetic formoterol.

Distributed ledger technology (DLT) is increasingly proposed as a powerful tool to address the social and ecological challenges in the Global South. DLTs are opening up possible futures, one of which is a wave of infrastructure decentralization with common-centric and cosmo-local production. Shared logistics and supply chains for a circular economy, with collaborative and networked “flow” accounting allow the integration of contributive logics as well as the integration of social and ecological externalities, including practical knowledge on resource use limitations linked to planetary boundaries, as an integral part of ecosystems of productive collaboration. Indeed, DLTs remove the need for central intermediaries to validate transaction between parties, who instead place their trust in the encrypted, disintermediated system software. DLTs can be designed as a new unencloseable (non-commodifiable) medium of communication, which could lead to radically new forms of cooperation, organization, and governance. Yet these revolutionary possibilities will not be realized unless technologists consciously and strategically design systems redistributing sovereignty from elites to the people in financial, service, and national infrastructures. This paper concludes with a critical examination of the application of DLT in Puerto Rico and how DLTs could alter the production and exchange of “value” in service of a global popular sovereignty.

A functional definition of the habitat-concept based on ecological resources incorporates three interconnected parameters: composition, configuration, and availability of the resources. The intersection of those parameters represents the functional habitat of a given population or species. Resource composition refers to the co-occurrence of the resources required by each individual to complete its life cycle. Resource configuration refers both to the way individual resources are spatially distributed within the habitat and the way all the resources are organized in the habitat space. Resource availability refers to the accessibility and procureability of resources. Variation in these variables is predicted to influence the demography of the population. To test the suitability of this definition and its transferability across landscapes, we first conducted a very detailed study on habitat and resource use of five butterfly species within a large nature reserve. Second, we conducted a larger-scale study, focusing on metapopulations of two species. We monitored demography for each species and tested whether its variation can be explained by (1) the vegetation type, (2) the vegetation composition or (3) the availability and configuration of the species-specific ecological resources. To confirm that resource availability and configuration reflect habitat quality, we also assessed their impacts on individual morphology. Whatever the investigated spatial scale, our results quantitatively demonstrate the overall better performance of the resource-based habitat approach compared to other most commonly used approaches. Our analysis allowed us to assess the relative importance of each ecological resource in terms of both their availability and organization relative to the species' abundance, demography and individual fitness measures. Resource availability did not play the predominant role in defining habitat quality as it was in most cases overruled by resource organization. Finally, we confirmed the between-population transferability of the habitat definition and quality estimates while adopting a resource-based habitat approach. Our study clearly demonstrates the suitability of the resource-based definition of the habitat. Therefore, we argue that this approach should be favored for species of conservation concern. Although most conclusions so far have emerged from butterfly studies, the resource-based definition of the habitat should also be ecologically relevant to many other organisms.

Macrophages contribute to the pathogenesis of rheumatoid arthritis (RA). They can display different states of activation or “polarization,” notably the so-called inflammatory “M1” and the various alternative “M2” polarizations, characterized by distinct functions. Data regarding the effects of RA anti-cytokine biological disease-modifying anti-rheumatic drugs (bDMARDs) on macrophage polarization are scarce. We aimed to assess in vitro modulation of macrophage polarization by bDMARDs targeting pro-inflammatory cytokines in RA. We generated monocyte derived macrophages using blood samples from 20 RA patients with active RA and 30 healthy controls. We evaluated in vitro the impact on M1 inflammatory macrophages of: etanercept (ETA), adalimumab (ADA), certolizumab (CZP), tocilizumab (TCZ), and rituximab (RTX). We assessed the impact on macrophage polarization using flow cytometry and RTqPCR to study the expression of surface markers and perform functional studies of cytokine production, phagocytosis, and negative feedback control of inflammation. Among evaluated bDMARDs, anti-TNF agents modulated the polarization of inflammatory macrophages by decreasing inflammatory surface markers (CD40, CD80) and favoring alternative markers (CD16, CD163, MerTK). Anti-TNF agents also induced alternative functions in macrophages activated in inflammatory condition with (i) the inhibition of inflammatory cytokines (TNF, IL-6, IL-12), (ii) an increase in phagocytosis. These findings were mechanistically related to an increase in early IL-10 production, responsible for higher negative feedback control of inflammation involving SOCS3 and Gas6. This IL-10 effect was STAT3-dependent. Anti-TNF agents not only inhibit in vitro inflammatory functions of macrophages, but also favor resolution of inflammation through polarization toward alternative features specifically involving the IL-10/STAT3 axis.

Attention-deficit hyperactivity disorder (ADHD) is characterized by deficits in executive functions and decision making during childhood and adolescence. Contradictory results exist whether altered event-related potentials (ERPs) in adults are associated with the tendency of ADHD patients toward risky behavior. Clinically diagnosed ADHD patients (n = 18) and healthy controls (n = 18), aged between 18 and 29 (median 22 Yo), were screened with the Conners' Adult ADHD Rating Scales and assessed by the Mini-International Neuropsychiatric Interview, adult ADHD Self-Report Scale, and by the 60-item HEXACO Personality Inventory. The characteristic personality traits of ADHD patients were the high level of impulsiveness associated with lower values of agreeableness. All participants performed a probability gambling task (PGT) with two frequencies of the feedback information of the outcome. For each trial, ERPs were triggered by the self-paced trial onset and by the gamble selection. After trial onset, N2-P3a ERP component associated with the attentional load peaked earlier in the ADHD group than in controls. An N500 component related to the feedback frequency condition after trial onset and an N400-like component after gamble selection suggest a large affective stake of the decision making and an emphasized post-decisional evaluation of the choice made by the ADHD participants. By combining ERPs, related to the emotions associated with the feedback frequency condition, and behavioral analyses during completion of PGT, this study provides new findings on the neural dynamics that differentiate controls and young ADHD adults. In the patients' group, we raise the hypothesis that the activity of frontocentral and centroparietal neural circuits drive the decision-making processes dictated by an impaired cognitive workload followed by the build-up of large emotional feelings generated by the conflict toward the outcome of the gambling choice. Our results can be used for new investigations aimed at studying the fine spatiotemporal distribution of cortical activity, and the neural circuits that underly the generation of that activity, associated with the behavioral deficits characteristic of ADHD.

In massive catastrophic events, occupational health practitioners are more and more frequently involved in the management of such situations. We aim to describe the multiple aspects of the role that occupational health practitioners might play, by focusing on the recent example of the Paris terrorist attack of November 2015.During and after the Paris attack, occupational practitioners in collaboration with emergency and security professionals were involved in psychological care, assembling information, follow-up, return-to-work, and improving in-company safety plans.Based on this experience and other industrial disasters, we distinguish three phases: the critical phase, the post-critical phase, and the anticipation phase. In the critical phase, the occupational practitioner cares for patients before the emergency professionals take charge, initiates the psychological management, and may also play an organizational role for company health aspects. In the post-critical phase, he or she would be involved in monitoring those affected by the events, and participate in preventing, to the extent possible, post-traumatic stress disorder, helping victims in the return-to-work process, and improving procedures and organizing drills. In addition to their usual work of primary prevention, occupational practitioners should endeavor to improve preparedness in the anticipation phase, by taking part in contingency planning, training in first aid, and defining immediately applicable protocols.In conclusion, recent events have highlighted the essential role of occupational health services in anticipation of a crisis, management during the crisis, and follow-up.