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Abstract This data descriptor presents a curated dataset for pathogen detection and identification (Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans) directly from whole-blood samples. The dataset was created using differential cell lysis combined with rapid extraction, digestion, and mass spectrometry-based proteomics. Our method offers a rapid diagnostic alternative to traditional culture, enabling timely disease management, such as sepsis. Highlighting our dataset’s uniqueness, it features a three-tier structure: Spectral Libraries of Pathogens for identifying peptide peaks for putative biomarkers; Spiked pathogen in blood MS data for biomarker panel optimization through varied concentration samples; and Parallel Reaction Monitoring (PRM) data from sepsis patients for validating our biomarker panel, achieving 83.3% sensitivity within seven hours without microbial enrichment culture. This dataset serves as a comprehensive reference for bioinformatic tool development and biomarker panel proposals, advancing microbial detection, antimicrobial resistance, and epidemiological studies.

Abstract Depression is associated with dysregulated circadian rhythms, but the role of intrinsic clocks in mood-controlling brain regions remains poorly understood. We found increased circadian negative loop and decreased positive clock regulators expression in the medial prefrontal cortex (mPFC) of a mouse model of depression, and a subsequent clock countermodulation by the rapid antidepressant ketamine. Selective Bmal1KO in CaMK2a excitatory neurons revealed that the functional mPFC clock is an essential factor for the development of a depression-like phenotype and ketamine effects. Per2 silencing in mPFC produced antidepressant-like effects, while REV-ERB agonism enhanced the depression-like phenotype and suppressed ketamine action. Pharmacological potentiation of clock positive modulator ROR elicited antidepressant-like effects, upregulating plasticity protein Homer1a, synaptic AMPA receptors expression and plasticity-related slow wave activity specifically in the mPFC. Our data demonstrate a critical role for mPFC molecular clock in regulating depression-like behavior and the therapeutic potential of clock pharmacological manipulations influencing glutamatergic-dependent plasticity.

Abstract Angelman syndrome (AS) is a rare neurogenetic disorder caused by UBE3A deficiency and characterized by severe developmental delay, cognitive impairment, and motor dysfunction. In the present study, we performed RNA-seq on hippocampal samples from both wildtype (WT) and AS male mice, with or without contextual fear memory recall. There were 281 recall-associated differentially expressed genes (DEGs) in WT mice and 268 DEGs in AS mice, with 129 shared by the two genotypes. Gene ontology analysis showed that extracellular matrix and stimulation-induced response genes were prominently enriched in recall-associated DEGs in WT mice, while nuclear acid metabolism and tissue development genes were highly enriched in those from AS mice. Further analyses showed that the 129 shared DEGs belonged to nuclear acid metabolism and tissue development genes. Unique recall DEGs in WT mice were enriched in biological processes critical for synaptic plasticity and learning and memory, including the extracellular matrix network clustered around fibronectin 1 and collagens. In contrast, AS-specific DEGs were not enriched in any known pathways. These results suggest that memory recall in AS mice, while altering the transcriptome, fails to recruit memory-associated transcriptional programs, which could be responsible for the memory impairment in AS mice.

The steep and unstable terrain found on debris-covered glaciers, rock glaciers, talus slopes, moraines and other proglacial features often make terrestrial ground-penetrating radar (GPR) surveys unsafe or cost-prohibitive. To address these challenges, this research introduces a novel approach for studying buried ice using multi-low-frequency drone-based GPR. Monostatic antennas of 50, 100, and 200 MHz were flown along a transect spanning a debris-covered glacier and an ice–debris complex at Shár Shaw Tagà (Grizzly Creek) in southwest Yukon, Canada. The drone-based results were compared to manual GPR at two locations along the transect. The two manual segments were conducted using the same radar system in a bi-static mode and included common mid-point (CMP) surveys. Overall, the drone-based radar successfully identified buried ice and enabled estimation of ice body thickness. Notably, CMP results confirmed layer characteristics and enabled depths to be measured across the entire drone-based transect. Discrimination of detail across a range of depths was made possible by comparing the three low frequencies, highlighting the possibility of using this method for future investigations of debris thickness in addition to quantifying buried ice. This study confirms the effectiveness of drone-based GPR combined with manual CMP for surveying ice beneath previously inaccessible terrain.

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.

Abstract While depression and chronic pain are frequently comorbid, underlying neuronal circuits and their psychopathological relevance remain poorly defined. Here we show in mice that hyperactivity of the neuronal pathway linking the basolateral amygdala to the anterior cingulate cortex is essential for chronic pain-induced depression. Moreover, activation of this pathway in naive male mice, in the absence of on-going pain, is sufficient to trigger depressive-like behaviors, as well as transcriptomic alterations that recapitulate core molecular features of depression in the human brain. These alterations notably impact gene modules related to myelination and the oligodendrocyte lineage. Among these, we show that Sema4a, which was significantly upregulated in both male mice and humans in the context of altered mood, is necessary for the emergence of emotional dysfunction. Overall, these results place the amygdalo-cingulate pathway at the core of pain and depression comorbidity, and unravel the role of Sema4a and impaired myelination in mood control.

Abstract Microneedling is a popular skin resurfacing and rejuvenation procedure. In order to develop better adjunct products for consumers, there is a scientific need to establish greater understanding of the mechanism in which microneedling stimulates regeneration within skin. The purpose of this study is to develop a physiologically relevant ex vivo tissue model which closely mimics the actual microneedling procedure to elucidate its mechanism of action. In this study, human ex vivo skin was subjected to microneedling treatment and cultured for 6 days. Histological analysis demonstrated that the ex vivo skin was able to heal from microneedling injury throughout the culture period. Microneedling treatment stimulated proliferation and barrier renewal of the skin. The procedure also increased the levels of inflammatory cytokines and angiogenic growth factors in a dynamic and time dependent fashion. The tissue demonstrated hallmark signs of epidermal regeneration through morphological and molecular changes after the treatment. This is one of the first works to date that utilizes microneedled ex vivo skin to demonstrate its regenerative behavior. Our model recapitulates the main features of the microneedling treatment and enables the evaluation of future cosmetic active ingredients used in conjunction with microneedling.

Abstract We propose a new quantum-safe digital signature algorithm called Multivariate Polynomial Public Key Digital Signature (MPPK/DS). The core of the algorithm is based on the modular arithmetic property that for a given element g, greater than equal to two, in a prime Galois field GF(p) and two multivariate polynomials P and Q, if P is equal to Q modulo p-1, then g to the power of P is equal to g to the power of Q modulo p. MPPK/DS is designed to withstand the key-only, chosen-message, and known-message attacks. Most importantly, making secret the element g disfavors quantum computers’ capability to solve the discrete logarithm problem. The security of the MPPK/DS algorithm stems from choosing a prime p associated with the field GF(p), such that p is a sum of a product of an odd prime number q multiplied with a power x of two and one. Given such a choice of a prime, choosing even coefficients of the publicly available polynomials makes it hard to find any private information modulo p-1. Moreover, it makes it exponentially hard to lift the solutions found modulo q to the ring of integers modulo p-1 by properly arranging x and q. However, finding private information modulo the components q and power x of two is an NP-hard problem since it involves solving multivariate equations over the chosen finite field. The time complexity of searching a private key from a public key or signatures is exponential over GF(p). The time complexity of perpetrating a spoofing attack is also exponential for a field GF(p). MPPK/DS can achieve all three NIST security levels with optimized choices of multivariate polynomials and the generalized safe prime p.

Abstract Epidermal growth factors (EGF) play a wide range of roles in embryogenesis, skin development, immune response homeostasis. They are involved in several pathologies as well, including several cancer types, psoriasis, chronic pain and chronic kidney disease. All members share the structural EGF domain, which is responsible for receptor interaction, thereby initiating transduction of signals. EGF growth factors have intense use in fundamental research and high potential for biotechnological applications. However, due to their structural organization with three disulfide bonds, recombinant production of these factors in prokaryotic systems is not straightforward. A significant fraction usually forms inclusion bodies. For the fraction remaining soluble, misfolding and incomplete disulfide bond formation may affect the amount of active factor in solution, which can compromise experimental conclusions and biotechnological applications. In this work, we describe a reliable procedure to produce seven human growth factors of the EGF family in Escherichia coli. Biophysical and stability analyses using limited proteolysis, light scattering, circular dichroism and nanoDSF show that the recombinant factors present folded and stable conformation. Cell proliferation and scratch healing assays confirmed that the recombinant factors are highly active at concentrations as low as 5 ng/ml.

Abstract Networked-Control Systems (NCSs), a type of cyber-physical systems, consist of tightly integrated computing, communication and control technologies. While being very flexible environments, they are vulnerable to computing and networking attacks. Recent NCSs hacking incidents had major impact. They call for more research on cyber-physical security. Fears about the use of quantum computing to break current cryptosystems make matters worse. While the quantum threat motivated the creation of new disciplines to handle the issue, such as post-quantum cryptography, other fields have overlooked the existence of quantum-enabled adversaries. This is the case of cyber-physical defense research, a distinct but complementary discipline to cyber-physical protection. Cyber-physical defense refers to the capability to detect and react in response to cyber-physical attacks. Concretely, it involves the integration of mechanisms to identify adverse events and prepare response plans, during and after incidents occur. In this paper, we assume that the eventually available quantum computer will provide an advantage to adversaries against defenders, unless they also adopt this technology. We envision the necessity for a paradigm shift, where an increase of adversarial resources because of quantum supremacy does not translate into a higher likelihood of disruptions. Consistently with current system design practices in other areas, such as the use of artificial intelligence for the reinforcement of attack detection tools, we outline a vision for next generation cyber-physical defense layers leveraging ideas from quantum computing and machine learning. Through an example, we show that defenders of NCSs can learn and improve their strategies to anticipate and recover from attacks.

Children and adolescents with attentional-deficit/hyperactivity disorder (ADHD) present deficits in working memory (WM), but accounts for this phenomenon are still lacking. In this study, we used two variations of a complex-span task to test whether a specific WM mechanism, attentional refreshing, causes these deficits. Attentional refreshing is a maintenance strategy based on the sequential switch of attention between maintaining and processing information in WM. Its use is evidenced by a decrease in recall performance proportional to the distraction of attention away from the memoranda. In this study, we designed two experiments requiring children and adolescents with ADHD symptoms to maintain sequences of letters for subsequent recall, while performing a distracting task. In Experiment 1, the distracting task consisted of reading digits aloud. In Experiment 2, it consisted in making spatial judgements. The pace of the distracting tasks was varied to manipulate the level of attentional distraction. We observed that recall in ADHD participants was higher in the distracting conditions that give attention more opportunity to refresh letters. Moreover, ADHD participants had a similar recall performance to their age-matched typically developing peers. This study shows first evidence that individuals with ADHD can use attention to maintain verbal information in WM and calls for more research to understand their WM development.

Abstract Trypanosoma cruzi—the causative agent of Chagas disease—like other kinetoplastids, relies mostly on post-transcriptional mechanisms for regulation of gene expression. However, trypanosomatids undergo drastic changes in nuclear architecture and chromatin structure along their complex life cycle which, combined with a remarkable set of reversible histone post-translational modifications, indicate that chromatin is also a target for control of gene expression and differentiation signals in these organisms. Chromatin-modifying enzymes have a direct impact on gene expression programs and DNA metabolism. In this work, we have investigated the function of T. cruzi histone deacetylase 4 (TcHDAC4). We show that, although TcHDAC4 is not essential for viability, metacyclic trypomastigote TcHDAC4 null mutants show a thin cell body and a round and less condensed nucleus located very close to the kinetoplast. Sixty-four acetylation sites were quantitatively evaluated, which revealed H2AT85ac, H4K10ac and H4K78ac as potential target sites of TcHDAC4. Gene expression analyses identified three chromosomes with overrepresented regions of differentially expressed genes in the TcHDAC4 knockout mutant compared with the wild type, showing clusters of either up or downregulated genes. The adjacent chromosomal location of some of these genes indicates that TcHDAC4 participates in gene expression regulation during T. cruzi differentiation.

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.

Tree mortality has been shown to be the dominant control on carbon storage in Amazon forests, but little is known of how and why Amazon forest trees die. Here the authors analyse a large Amazon-wide dataset, finding that fast-growing species face greater mortality risk, but that slower-growing individuals within a species are more likely to die, regardless of size.

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.

Summary: In order to ascertain the significance of transmembrane tumor necrosis factor (tmTNF) reverse signaling in vivo, we generated a triple transgenic mouse model (3TG, TNFR1−/−, TNFR2−/−, and tmTNFKI/KI) in which all canonical tumor necrosis factor (TNF) signaling was abolished. In bone-marrow-derived macrophages harvested from these mice, various anti-TNF biologics induced the expression of genes characteristic of alternative macrophages and also inhibited the expression of pro-inflammatory cytokines mainly through the upregulation of arginase-1. Injections of TNF inhibitors during arthritis increased pro-resolutive markers in bone marrow precursors and joint cells leading to a decrease in arthritis score. These results demonstrate that the binding of anti-TNF biologics to tmTNF results in decreased arthritis severity. Collectively, our data provide evidence for the significance of tmTNF reverse signaling in the modulation of arthritis. They suggest a complementary interpretation of anti-TNF biologics effects in the treatment of inflammatory diseases and pave the way to studies focused on new arginase-1-dependent therapeutic targets.

This study assesses the performance of UAV lidar system in measuring high-resolution snow depths in agro-forested landscapes in southern Québec, Canada. We used manmade, mobile ground control points in summer and winter surveys to assess the absolute vertical accuracy of the point cloud. Relative accuracy was determined by a repeat flight over one survey block. Estimated absolute and relative errors were within the expected accuracy of the lidar (~5 and ~7 cm, respectively). The validation of lidar-derived snow depths with ground-based measurements showed a good agreement, however with higher uncertainties observed in forested areas compared with open areas. A strip alignment procedure was used to attempt the correction of misalignment between overlapping flight strips. However, the significant improvement of inter-strip relative accuracy brought by this technique was at the cost of the absolute accuracy of the entire point cloud. This phenomenon was further confirmed by the degraded performance of the strip-aligned snow depths compared with ground-based measurements. This study shows that boresight calibrated point clouds without strip alignment are deemed to be adequate to provide centimeter-level accurate snow depth maps with UAV lidar. Moreover, this study provides some of the earliest snow depth mapping results in agro-forested landscapes based on UAV lidar.

The vertebral column or spine assembles around the notochord rod which contains a core made of large vacuolated cells. Each vacuolated cell possesses a single fluid-filled vacuole, and loss or fragmentation of these vacuoles in zebrafish leads to spine kinking. Here, we identified a mutation in the kinase gene dstyk that causes fragmentation of notochord vacuoles and a severe congenital scoliosis-like phenotype in zebrafish. Live imaging revealed that Dstyk regulates fusion of membranes with the vacuole. We find that localized disruption of notochord vacuoles causes vertebral malformation and curving of the spine axis at those sites. Accordingly, in dstyk mutants the spine curves increasingly over time as vertebral bone formation compresses the notochord asymmetrically, causing vertebral malformations and kinking of the axis. Together, our data show that notochord vacuoles function as a hydrostatic scaffold that guides symmetrical growth of vertebrae and spine formation.

Enteroendocrine cells (EECs) are specialized sensory cells in the intestinal epithelium that sense and transduce nutrient information. Consumption of dietary fat contributes to metabolic disorders, but EEC adaptations to high fat feeding were unknown. Here, we established a new experimental system to directly investigate EEC activity in vivo using a zebrafish reporter of EEC calcium signaling. Our results reveal that high fat feeding alters EEC morphology and converts them into a nutrient insensitive state that is coupled to endoplasmic reticulum (ER) stress. We called this novel adaptation 'EEC silencing'. Gnotobiotic studies revealed that germ-free zebrafish are resistant to high fat diet induced EEC silencing. High fat feeding altered gut microbiota composition including enrichment of Acinetobacter bacteria, and we identified an Acinetobacter strain sufficient to induce EEC silencing. These results establish a new mechanism by which dietary fat and gut microbiota modulate EEC nutrient sensing and signaling.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-020-20537-x

Abstract Following aquarium releases, invasive lionfishes have colonized large areas of the Caribbean and western Atlantic, resulting in an immense ecological damage. The early stages of that invasion are poorly known. Indeed, a lag of time between the introduction and detection often preclude genetic characterization of that crucial phase. With elevated awareness, the recent invasion of Pterois miles was quickly detected in the Mediterranean Sea. We hereby show that the very first individuals establishing populations in the Mediterranean Sea display haplotypes that nest within the large genetic diversity of Red Sea individuals, thus indicating an invasion via the Suez Canal. We also show that only two haplotypes are detected in the Mediterranean Sea, suggesting that few individuals may have been involved in the invasion. Thus, we conclude that the Mediterranean invasion is the result of a movement of individuals from the Red Sea, rather than from other means, and that low genetic diversity does not seem to have a negative effect on the success and spread of lionfish into the Mediterranean Sea.

Accumulating evidence indicates that the lysosomal Ragulator complex is essential for full activation of the mechanistic target of rapamycin complex 1 (mTORC1). Abnormal mTORC1 activation has been implicated in several developmental neurological disorders, including Angelman syndrome (AS), which is caused by maternal deficiency of the ubiquitin E3 ligase UBE3A. Here we report that Ube3a regulates mTORC1 signaling by targeting p18, a subunit of the Ragulator. Ube3a ubiquinates p18, resulting in its proteasomal degradation, and Ube3a deficiency in the hippocampus of AS mice induces increased lysosomal localization of p18 and other members of the Ragulator-Rag complex, and increased mTORC1 activity. p18 knockdown in hippocampal CA1 neurons of AS mice reduces elevated mTORC1 activity and improves dendritic spine maturation, long-term potentiation (LTP), as well as learning performance. Our results indicate that Ube3a-mediated regulation of p18 and subsequent mTORC1 signaling is critical for typical synaptic plasticity, dendritic spine development, and learning and memory.

The genus Anthroherpon Reitter, 1889 exhibits the most pronounced troglomorphic characters among Coleoptera, and represents one of the most spectacular radiations of subterranean beetles. However, radiation, diversification, and biogeography of this genus have never been studied in a phylogenetic context. This study provides a comprehensive evolutionary analysis of the Anthroherpon radiation, using a dated molecular phylogeny as a framework for understanding Anthroherpon diversification, reconstructing the ancestral range, and exploring troglomorphic diversity. Based on 16 species and 22 subspecies, i.e. the majority of Anthroherpon diversity, we reconstructed the phylogeny using Bayesian analysis of six loci, both mitochondrial and nuclear, comprising a total of 4143 nucleotides. In parallel, a morphometric analysis was carried out with 79 landmarks on the body that were subjected to geometric morphometrics. We optimized morphometric features to phylogeny, in order to recognize the way troglomorphy was expressed in different clades of the tree, and did character evolution analyses. Finally, we reconstructed the ancestral range of the genus using BioGeoBEARS. Besides further elucidating the suprageneric classification of the East-Mediterranean Leptodirini, our main findings also show that Anthroherpon dates back to the Early Miocene (ca. 22 MYA) and that the genus diversified entirely underground. Biogeographic reconstruction of the ancestral range shows the origin of the genus in the area comprising three high mountains in western Montenegro, which is in the accordance with the available data on the paleogeography of the Balkan Peninsula. Character evolution analysis indicates that troglomorphic morphometric traits in Anthroherpon mostly evolve neutrally but may diverge adaptively under syntopic competition.

UNLABELLED:Previous in vivo studies have suggested that nucleic acid polymers (NAPs) may reduce circulating levels of HBsAg in the blood by blocking its release from infected hepatocytes and that this effect may have clinical benefit. NAP treatment, was evaluated in two clinical studies in patients with HBeAg positive chronic HBV infection. The REP 101 study examined REP 2055 monotherapy in 8 patients and the REP 102 study examined REP 2139-Ca, in monotherapy in 12 patients, 9 of which transitioned to short term combined treatment with pegylated interferon alpha 2a or thymosin alpha 1. In both studies NAP monotherapy was accompanied by 2-7 log reductions of serum HBsAg, 3-9 log reductions in serum HBV DNA and the appearance of serum anti-HBsAg antibodies (10-1712 mIU / ml). Eight of the 9 patients transitioning to combined treatment with immunotherapy (pegylated interferon or thymosin alpha 1) in the REP 102 study experienced HBsAg loss and all 9 patients experienced substantial increases in serum anti-HBsAg antibody titers before withdrawal of therapy. For 52 weeks after removal of REP 2055 therapy, rebound of serum viremia (HBV DNA > 1000 copies / ml, HBsAg > 1IU / ml) was not observed in 3 / 8 patients. Suppression of serum virema was further maintained for 290 and 231 weeks in 2 of these patients. After withdrawal of all therapy in the 9 patients that transitioned to combination therapy in the REP 102 study, 8 patients achieved HBV DNA < 116 copies / ml after treatment withdrawal. Viral rebound occurred over a period of 12 to 123 weeks in 7 patients but was still absent in two patients at 135 and 137 weeks of follow-up. Administration tolerability issues observed with REP 2055 were rare with REP 2139-Ca but REP 2139-Ca therapy was accompanied by hair loss, dysphagia and dysgeusia which were considered related to heavy metal exposure endemic at the trial site. These preliminary studies suggest that NAP can elicit important antiviral responses during treatment which may improve the effect of immunotherapy. NAPs may be a potentially useful component of future combination therapies for the treatment of chronic hepatitis B. TRIAL REGISTRATION:ClinicalTrials.gov NCT02646163 and NCT02646189.

This paper introduces an explicit covert communication code for binary-input asynchronous discrete memoryless channels based on binary polar codes, in which legitimate parties exploit uncertainty created by both the channel noise and the time of transmission to avoid detection by an adversary. The proposed code jointly ensures reliable communication for a legitimate receiver and low probability of detection with respect to the adversary, both observing noisy versions of the codewords. Binary polar codes are used to shape the weight distribution of codewords and ensure that the average weight decays as the block length grows. The performance of the proposed code is severely limited by the speed of polarization, which in turn controls the decay of the average codeword weight with the block length. Although the proposed construction falls largely short of achieving the performance of random codes, it inherits the low-complexity properties of polar codes.

Maternal low protein diet programs offspring to develop hypertension as adults. Transient exposure to angiotensin converting enzyme inhibitors or angiotensin II receptor blockers can result in improvement in hypertension. Male rats whose mothers received a low protein diet during the last half of pregnancy were given either vehicle, continuous enalapril (CE) in their drinking water or were given transient enalapril exposure (TE) after weaning at 21 days of age. The TE group had enalapril in their drinking water for 21 days starting from day 21 of life. All rats were studied at 6 months of age. Vehicle treated rats whose mothers were fed a low protein diet were hypertensive, had albuminuria, and demonstrated upregulation of the intrarenal renin-angiotensin system as evidenced by higher urinary angiotensinogen and urinary angiotensin II levels. In low protein rats both continuous and transient exposure to enalapril normalized blood pressure, urinary angiotensinogen and urinary angiotensin II levels at 6 months of age, but only continuous administration of enalapril decreased urinary albumin excretion. These data support the importance of the intrarenal renin-angiotensin system in mediating hypertension in programmed rats and transient exposure to enalapril can reprogram the hypertension and dysregulation of the intrarenal renin-angiotensin system.

Glutamatergic synapses are the most prevalent functional elements of information processing in the brain. Changes in pre-synaptic activity and in the function of various post-synaptic elements contribute to generate a large variety of synaptic responses. Previous studies have explored postsynaptic factors responsible for regulating synaptic strength variations, but have given far less importance to synaptic geometry, and more specifically to the subcellular distribution of ionotropic receptors. We analyzed the functional effects resulting from changing the subsynaptic localization of ionotropic receptors by using a hippocampal synaptic computational framework. The present study was performed using the EONS (Elementary Objects of the Nervous System) synaptic modeling platform, which was specifically developed to explore the roles of subsynaptic elements as well as their interactions, and that of synaptic geometry. More specifically, we determined the effects of changing the localization of ionotropic receptors relative to the presynaptic glutamate release site, on synaptic efficacy and its variations following single pulse and paired-pulse stimulation protocols. The results indicate that changes in synaptic geometry do have consequences on synaptic efficacy and its dynamics.

The large white butterfly, Pieris brassicae, shows a seasonal polyphenism of wing melanisation, spring individuals being darker than summer individuals. This phenotypic plasticity is supposed to be an adaptive response for thermoregulation in natural populations. However, the variation in individuals' response, the cause of this variation (genetic, non genetic but inheritable or environmental) and its relationship with fitness remain poorly known. We tested the relationships between thermal reaction norm of wing melanisation and adult lifespan as well as female fecundity. Butterflies were reared in cold (18°C), moderate (22°C), and hot (26°C) temperatures over three generations to investigate variation in adult pigmentation and the effects of maternal thermal environment on offspring reaction norms. We found a low heritability in wing melanisation (h(2) =0.18). Rearing families had contrasted thermal reaction norms. Adult lifespan of males and females from highly plastic families was shorter in individuals exposed to hot developmental temperature. Also, females from plastic families exhibited lower fecundity. We did not find any effect of maternal or grand-maternal developmental temperature on fitness. This study provides new evidence on the influence of phenotypic plasticity on life history-traits' evolution, a crucial issue in the context of global change.

Coloration of stinging insects is often based on contrasted patterns of light and black pigmentations as a warning signal to predators. However, in many social wasp species, geographic variation drastically modifies this signal through melanic polymorphism potentially driven by different selective pressures. To date, surprisingly little is known about the geographic variation of coloration of social wasps in relation to aposematism and melanism and to genetic and developmental constraints. The main objectives of this study are to improve the description of the colour variation within a social wasp species and to determine which factors are driving this variation. Therefore, we explored the evolutionary history of a polymorphic hornet, Vespa velutina Lepeletier, 1836, using mitochondrial and microsatellite markers, and we analysed its melanic variation using a colour space based on a description of body parts coloration. We found two main lineages within the species and confirmed the previous synonymy of V. auraria Smith, 1852, under V. velutina, differing only by the coloration. We also found that the melanic variation of most body parts was positively correlated, with some segments forming potential colour modules. Finally, we showed that the variation of coloration between populations was not related to their molecular, geographic or climatic differences. Our observations suggest that the coloration patterns of hornets and their geographic variations are determined by genes with an influence of developmental constraints. Our results also highlight that Vespa velutina populations have experienced several convergent evolutions of the coloration, more likely influenced by constraints on aposematism and Müllerian mimicry than by abiotic pressures on melanism.

Genetic determinism of cranial morphology in the mouse is still largely unknown, despite the localization of putative QTLs and the identification of genes associated with Mendelian skull malformations. To approach the dissection of this multigenic control, we have used a set of interspecific recombinant congenic strains (IRCS) produced between C57BL/6 and mice of the distant species Mus spretus (SEG/Pas). Each strain has inherited 1.3% of its genome from SEG/Pas under the form of few, small-sized, chromosomal segments.The shape of the nasal bone was studied using outline analysis combined with Fourier descriptors, and differential features were identified between IRCS BcG-66H and C57BL/6. An F2 cross between BcG-66H and C57BL/6 revealed that, out of the three SEG/Pas-derived chromosomal regions present in BcG-66H, two were involved. Segments on chromosomes 1 (∼32 Mb) and 18 (∼13 Mb) showed additive effect on nasal bone shape. The three chromosomal regions present in BcG-66H were isolated in congenic strains to study their individual effect. Epistatic interactions were assessed in bicongenic strains.Our results show that, besides a strong individual effect, the QTL on chromosome 1 interacts with genes on chromosomes 13 and 18. This study demonstrates that nasal bone shape is under complex genetic control but can be efficiently dissected in the mouse using appropriate genetic tools and shape descriptors.

Neocortical local field potentials have shown that gamma oscillations occur spontaneously during slow-wave sleep (SWS). At the macroscopic EEG level in the human brain, no evidences were reported so far. In this study, by using simultaneous scalp and intracranial EEG recordings in 20 epileptic subjects, we examined gamma oscillations in cerebral cortex during SWS. We report that gamma oscillations in low (30-50 Hz) and high (60-120 Hz) frequency bands recurrently emerged in all investigated regions and their amplitudes coincided with specific phases of the cortical slow wave. In most of the cases, multiple oscillatory bursts in different frequency bands from 30 to 120 Hz were correlated with positive peaks of scalp slow waves ("IN-phase" pattern), confirming previous animal findings. In addition, we report another gamma pattern that appears preferentially during the negative phase of the slow wave ("ANTI-phase" pattern). This new pattern presented dominant peaks in the high gamma range and was preferentially expressed in the temporal cortex. Finally, we found that the spatial coherence between cortical sites exhibiting gamma activities was local and fell off quickly when computed between distant sites. Overall, these results provide the first human evidences that gamma oscillations can be observed in macroscopic EEG recordings during sleep. They support the concept that these high-frequency activities might be associated with phasic increases of neural activity during slow oscillations. Such patterned activity in the sleeping brain could play a role in off-line processing of cortical networks.

Activation of several subtypes of glutamate receptors contributes to changes in postsynaptic calcium concentration at hippocampal synapses, resulting in various types of changes in synaptic strength. Thus, while activation of NMDA receptors has been shown to be critical for long-term potentiation (LTP) and long term depression (LTD) of synaptic transmission, activation of metabotropic glutamate receptors (mGluRs) has been linked to either LTP or LTD. While it is generally admitted that dynamic changes in postsynaptic calcium concentration represent the critical elements to determine the direction and amplitude of the changes in synaptic strength, it has been difficult to quantitatively estimate the relative contribution of the different types of glutamate receptors to these changes under different experimental conditions. Here we present a detailed model of a postsynaptic glutamatergic synapse that incorporates ionotropic and mGluR type I receptors, and we use this model to determine the role of the different receptors to the dynamics of postsynaptic calcium with different patterns of presynaptic activation. Our modeling framework includes glutamate vesicular release and diffusion in the cleft and a glutamate transporter that modulates extracellular glutamate concentration. Our results indicate that the contribution of mGluRs to changes in postsynaptic calcium concentration is minimal under basal stimulation conditions and becomes apparent only at high frequency of stimulation. Furthermore, the location of mGluRs in the postsynaptic membrane is also a critical factor, as activation of distant receptors contributes significantly less to calcium dynamics than more centrally located ones. These results confirm the important role of glutamate transporters and of the localization of mGluRs in postsynaptic sites in their signaling properties, and further strengthen the notion that mGluR activation significantly contributes to postsynaptic calcium dynamics only following high-frequency stimulation. They also provide a new tool to analyze the interactions between metabotropic and ionotropic glutamate receptors.

The metacommunity framework is crucial to the study of functional relations along environmental gradients. Changes in resource grain associated with increasing habitat fragmentation should generate uncoupled responses of interacting species with contrasted dispersal abilities.Here we tested whether the intensity of parasitism was modified by increasing habitat fragmentation in the well know predator-prey system linking the parasitoid Cotesia glomerata (Hymenoptera: Braconidae) to its main host Pieris brassicae (Lepidoptera: Pieridae). We collected information on herbivorous abundance and parasitism rate along an urbanization gradient from the periphery to the centre of Paris. We showed that butterfly densities were not influenced by habitat fragmentation, whereas parasitism rate sharply decreased along this gradient.Our results provide novel insights into the mechanisms underlying the persistence of species in highly fragmented areas. They suggest that differential dispersal abilities could alter functional relationships between prey and predator, notably by a lack of natural predators.

Individual dispersal decisions may be affected by the internal state of the individual and the external information of its current environment. Here we estimated the influence of dispersal on survival and investigated if individual phenotype (sex and wing length) and environmental condition (conspecific density and sex-ratio) affected dispersal decisions in the banded damselfly, Calopteryx splendens. As suspected from the literature, we showed that the proportion of dispersing individuals was higher in females than in males. We also found negative-density dependent dispersal in both sexes and influence of sex-ratio on dispersal. Individuals moved less when sex-ratio was male biased. These results are consistent with a lek mating system where males aggregate in a place and hold mating territories. Contrary to our expectations, neither dispersal nor survival was affected by wing length. Nevertheless, mean adult survival was about 8% lower in dispersing individuals than in residents. This might reflect a mortality cost due to dispersal.

Perturbation of lipid metabolism, especially of cholesterol homeostasis, can be catastrophic to mammalian brain, as it has the highest level of cholesterol in the body. This notion is best illustrated by the severe progressive neurodegeneration in Niemann-Pick Type C (NPC) disease, one of the lysosomal storage diseases, caused by mutations in the NPC1 or NPC2 gene. In this study, we found that growth cone collapse induced by genetic or pharmacological disruption of cholesterol egress from late endosomes/lysosomes was directly related to a decrease in axonal and growth cone levels of the phosphorylated form of the tumor suppressor factor p53. Cholesterol perturbation-induced growth cone collapse and decrease in phosphorylated p53 were reduced by inhibition of p38 mitogen-activated protein kinase (MAPK) and murine double minute (Mdm2) E3 ligase. Growth cone collapse induced by genetic (npc1-/-) or pharmacological modification of cholesterol metabolism was Rho kinase (ROCK)-dependent and associated with increased RhoA protein synthesis; both processes were significantly reduced by P38 MAPK or Mdm2 inhibition. Finally, in vivo ROCK inhibition significantly increased phosphorylated p53 levels and neurofilaments in axons, and axonal bundle size in npc1-/- mice. These results indicate that NPC-related and cholesterol perturbation-induced axonal pathology is associated with an abnormal signaling pathway consisting in p38 MAPK activation leading to Mdm2-mediated p53 degradation, followed by ROCK activation. These results also suggest new targets for pharmacological treatment of NPC disease and other diseases associated with disruption of cholesterol metabolism.

Mounting evidence shows that contrasting selection pressures generate variability in dispersal patterns among individuals or populations of the same species, with potential impacts on both species dynamics and evolution. However, this variability is hardly considered in empirical works, where a single dispersal function is considered to adequately reflect the species-specific dispersal ability, suggesting thereby that within-species variation is negligible as regard to inter-specific differences in dispersal abilities. We propose here an original method to make the comparison of intra- and inter-specific variability in dispersal, by decomposing the diversity of that trait along a phylogeny of closely related species. We used as test group European butterflies that are classic study organisms in spatial ecology. We apply the analysis separately to eight metrics that reflect the dispersal propensity, the dispersal ability or the dispersal efficiency of populations and species. At the inter-specific level, only the dispersal ability showed the signature of a phylogenetic signal while neither the dispersal propensity nor the dispersal efficiency did. At the within-species level, the partitioning of dispersal diversity showed that dispersal was variable or highly variable among populations: intra-specific variability represented from 11% to 133% of inter-specific variability in dispersal metrics. This finding shows that dispersal variation is far from negligible in the wild. Understanding the processes behind this high within-species variation should allow us to properly account for dispersal in demographic models. Accordingly, to encompass the within species variability in life histories the use of more than one value per trait per species should be encouraged in the construction of databases aiming at being sources for modelling purposes.