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In interacting dynamical systems, specific local interaction rules for system components give rise to diverse and complex global dynamics. Long dynamical cycles are a key feature of many natural interacting systems, especially in biology. Examples of dynamical cycles range from circadian rhythms regulating sleep to cell cycles regulating reproductive behavior. Despite the crucial role of cycles in nature, the properties of network structure that give rise to cycles still need to be better understood. Here, we use a Boolean interaction network model to study the relationships between network structure and cyclic dynamics. We identify particular structural motifs that support cycles, and other motifs that suppress them. More generally, we show that the presence of dynamical reflection symmetry in the interaction network enhances cyclic behavior. In simulating an artificial evolutionary process, we find that motifs that break reflection symmetry are discarded. We further show that dynamical reflection symmetries are over-represented in Boolean models of natural biological systems. Altogether, our results demonstrate a link between symmetry and functionality for interacting dynamical systems, and they provide evidence for symmetry's causal role in evolving dynamical functionality., (© 2024 The Author(s). Published by IOP Publishing Ltd on behalf of the Institute of Physics and Deutsche Physikalische Gesellschaft.)

This paper presents an exploratory study about the experiences of 25 inter-faith chaplains in five Canadian provinces. It utilizes a focus groups methodology. The goal of this qualitative research was to highlight the voices of the chaplains. Hence, the focus groups explored the unique and challenging experiences of chaplains' work in Canadian prisons. Data from all seven focus groups indicated that despite multiple challenges and obstacles, the correctional chaplains remain dedicated to their work and are committed to making a positive impact on their prisoners. Based on the data provided by the chaplains about the intrinsic rewards and various challenges they face in their day-to-day work, the paper makes several research and policy recommendations. The objective of such recommendations is to maximize the role that religion and/or spirituality could play in prisoners' positive adaptation, and eventual criminal desistance in a context of confinement characterized by loss of personal autonomy and self-identity., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Recent work has demonstrated that the relationship between structural and functional connectivity varies regionally across the human brain, with reduced coupling emerging along the sensory-association cortical hierarchy. The biological underpinnings driving this expression, however, remain largely unknown. Here, we postulate that intracortical myelination and excitation-inhibition (EI) balance mediate the heterogeneous expression of structure-function coupling (SFC) and its temporal variance across the cortical hierarchy. We employ atlas- and voxel-based connectivity approaches to analyze neuroimaging data acquired from two groups of healthy participants. Our findings are consistent across six complementary processing pipelines: 1) SFC and its temporal variance respectively decrease and increase across the unimodal-transmodal and granular-agranular gradients; 2) increased myelination and lower EI-ratio are associated with more rigid SFC and restricted moment-to-moment SFC fluctuations; 3) a gradual shift from EI-ratio to myelination as the principal predictor of SFC occurs when traversing from granular to agranular cortical regions. Collectively, our work delivers a framework to conceptualize structure-function relationships in the human brain, paving the way for an improved understanding of how demyelination and/or EI-imbalances induce reorganization in brain disorders., (© 2023. The Author(s).)

Introduction: HIV-1 eradication is hindered by the presence of inducible long-lived reservoirs of latently infected cells which rapidly disseminate viral particles upon treatment interruption. Eliminating these reservoirs by the so-called shock and kill strategy represents a crucial concept toward an HIV-1 cure. Several molecules called latency-reversing agents (LRAs) are under intensive investigations to reactivate virus gene expression. These studies are mainly conducted on CD4 + T cells where LRAs are well tolerated and did not induce global cellular activation. However, despite their broad spectrum, the putative impact of LRAs on other cellular reservoirs such as macrophages is still ill-defined., Methods: We investigated the impact of the protein kinase C (PKC) activator bryostatin-1, bromodomain inhibitor JQ1 and histone deacetylase inhibitor romidepsin used either alone or in combination on human primary monocyte-derived macrophages (MDMs)., Results: We demonstrate that bryostatin-1, JQ1, and romidepsin or their combinations are not toxic at nanomolar concentrations but induce metabolic and morphologic alterations of MDMs. Bryostatin-1 triggered the secretion of pro-inflammatory cytokines, while JQ-1 decreased it. Phagocytosis and endocytosis were modestly impaired upon bryostatin-1 treatment whereas efferocytosis was markedly downregulated by romidepsin. Despite its pro-inflammatory profile, bryostatin-1 did not induce classically activated macrophage markers. Finally, we reveal that conditioned medium from bryostatin-1-treated macrophages did not potentiate its reactivation feature., Conclusions: Our study reveals that LRAs can diversely impact basic physiologic features of human primary macrophages and could potentially decrease reactivation of nearby CD4 + T cells latently infected with HIV-1. Our observations further stress the need to include different cell populations when assessing HIV-1 cure strategies., (© 2022 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Cortical variations in cytoarchitecture form a sensory-fugal axis that shapes regional profiles of extrinsic connectivity and is thought to guide signal propagation and integration across the cortical hierarchy. While neuroimaging work has shown that this axis constrains local properties of the human connectome, it remains unclear whether it also shapes the asymmetric signaling that arises from higher-order topology. Here, we used network control theory to examine the amount of energy required to propagate dynamics across the sensory-fugal axis. Our results revealed an asymmetry in this energy, indicating that bottom-up transitions were easier to complete compared to top-down. Supporting analyses demonstrated that asymmetries were underpinned by a connectome topology that is wired to support efficient bottom-up signaling. Lastly, we found that asymmetries correlated with differences in communicability and intrinsic neuronal time scales and lessened throughout youth. Our results show that cortical variation in cytoarchitecture may guide the formation of macroscopic connectome topology.

The present study examined the relationships between quantitative and qualitative dimensions of excessive exercise (EE) with the physical self-perception's dimensions and perceptual perspectives of body image (i.e., allocentric/3rd person and egocentric/1st person perspectives). The e LoriCorps Immersive Body Rating Scale 1.1, the very short form version of the Physical Self-Inventory and the Exercise and Eating Disorder test were used. The study includes 36 people with anorexia and/or bulimia seeking an external and specialized transdisciplinary program for eating disorders. Results show a different correlational profile of physical self-perceptions depending on the dimension (qualitative or quantitative) used to define EE. Differences in the perspectives used to assess body dissatisfaction (allocentric or egocentric) were also found. Perceived physical appearance was the key predictor of the qualitative dimension of excessive exercise. Findings suggest that EE in patients with an eating disorder could be explained by the feeling of competence not only related to physical appearance but also to physical abilities., Competing Interests: SB is president of, and own shares in, Clinic and Development In Virtuo, a company that distributes virtual environments, and conflict of interest are managed under UQO’s conflict of interest policy. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ouellet, Monthuy-Blanc, Pauzé, Rousseau and Bouchard.)

Recently, neurocognitive studies have shown that food categorization is sensitive to both the properties of the food stimuli (e.g., calorie content) and the individual characteristics of subjects (e.g., BMI, eating disorders) asked to categorize these stimuli. Furthermore, groups of patients with eating disorders (ED) were described as relying more on moral criteria to form food categories than were control subjects. The present studies built on these seminal articles and aimed to determine whether certain food properties might trigger moral categories preferentially in subjects suffering from ED and in the general population. Using a Go/No-Go Association Task, Study 1 focused on the extent to which food categories are laden with moral attributes in ED patients compared to control subjects. Study 2 was a follow-up with a different design (an Implicit Association Test), another food variable (calorie content), and two non-clinical subgroups (orthorexic and healthy control subjects). Results revealed for the first time implicit associations between food variables cueing for energy density and moral attributes in the general population, the population suffering from anorexia nervosa, and subjects suffering from disordered eating such as orthorexia nervosa. These findings suggest that moralization of food is a pervasive phenomenon that can be measured with methods reputed to be less vulnerable to self-presentation or social desirability biases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lakritz, Tournayre, Ouellet, Iceta, Duriez, Masetti and Lafraire.)

Background: The discovery of the CRISPR-Cas9 system and its applicability in mammalian embryos has revolutionized the way we generate genetically engineered animal models. To date, models harbouring conditional alleles (i.e. two loxP sites flanking an exon or a critical DNA sequence of interest) are amongst the most widely requested project type that are challenging to generate as they require simultaneous cleavage of the genome using two guides in order to properly integrate the repair template. An approach, using embryo sequential electroporation has been reported in the literature to successfully introduce loxP sites on the same allele. Here, we describe a modification of this sequential electroporation procedure that demonstrated the production of conditional allele mouse models for eight different genes via one of two possible strategies: either by consecutive sequential electroporation (strategy A) or non-consecutive sequential electroporation (strategy B). This latest strategy originated from using the by-product produced when using consecutive sequential electroporation (i.e. mice with a single targeted loxP site) to complete the project., Results: By using strategy A, we demonstrated successful generation of conditional allele models for three different genes (Icam1, Lox, and Sar1b), with targeting efficiencies varying between 5 and 13%. By using strategy B, we generated five conditional allele models (Loxl1, Pard6a, Pard6g, Clcf1, and Mapkapk5), with targeting efficiencies varying between 3 and 25%., Conclusion: Our modified electroporation-based approach, involving one of the two alternative strategies, allowed the production of conditional allele models for eight different genes via two different possible paths. This reproducible method will serve as another reliable approach in addition to other well-established methodologies in the literature for conditional allele mouse model generation., (© 2022. The Author(s).)

Recent studies have shed light on how the COVID-19 pandemic changed our lives, and most of them have documented its detrimental effect on eating habits. Until now, the effects of this global crisis on negative body image and its association with disordered eating behaviors remain largely understudied. This study aimed to investigate changes in frequency of disordered eating behaviors (i.e., restrictive eating, emotional eating, and overeating) and negative body image (i.e., shape and weight concern, and body dissatisfaction) among a community sample of women during the COVID-19 pandemic (October 2020-May 2021). Furthermore, we explored the possible relation between body image-related variables and changes in the frequency of disordered eating behaviors in the context of the pandemic. A total of 161 self-identified female participants enrolled in an online-based survey. Descriptive statistics showed that women did not report clinically significant levels of weight and body shape concerns, but participants reported being dissatisfied with their body. One sample Wilcoxon Signed Rank tests revealed a tendency toward an increasing of the frequency of all disordered eating behaviors during the COVID-19 pandemic. Multinomial logistic regressions showed that weight concerns predicted an overall increase in the frequency of restrictive eating behaviors, whereas higher body dissatisfaction was associated with a moderate self-perceived increase in the frequency of emotional eating. These results shed light on a risk pattern of phenomena in a non-clinical sample of women, as they represent the key risk factors for the development of eating disorders. Findings could have implications for designing and implementing prevention programs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Corno, Paquette, Monthuy-Blanc, Ouellet and Bouchard.)

While combination antiretroviral therapy maintains undetectable viremia in people living with HIV (PLWH), a lifelong treatment is necessary to prevent viremic rebound after therapy cessation. This rebound seemed mainly caused by long-lived HIV-1 latently infected cells reverting to a viral productive status. Reversing latency and elimination of these cells by the so-called shock-and-kill strategy is one of the main investigated leads to achieve an HIV-1 cure. Small molecules referred to as latency reversal agents (LRAs) proved to efficiently reactivate latent CD4 + T cells. However, the LRA impact on de novo infection or HIV-1 production in productively infected macrophages remains elusive. Nontoxic doses of bryostatin-1, JQ1, and romidepsin were investigated in human monocyte-derived macrophages (MDMs). Treatment with bryostatin-1 or romidepsin resulted in a downregulation of CD4 and CCR5 receptors, respectively, accompanied by a reduction of R5 tropic virus infection. HIV-1 replication was mainly regulated by receptor modulation for bryostatin-1, while romidepsin effects rely on upregulation of SAMHD1 activity. LRA stimulation of chronically infected cells did not enhance HIV-1 production or gene expression. Surprisingly, bryostatin-1 caused a major decrease in viral production. This effect was not viral strain specific but appears to occur only in myeloid cells. Bryostatin-1 treatment of infected MDMs led to decreased amounts of capsid and matrix mature proteins with little to no modulation of precursors. Our observations revealed that bryostatin-1-treated myeloid and CD4 + T cells respond differently upon HIV-1 infection. Therefore, additional studies are warranted to more fully assess the efficiency of HIV-1 eradicating strategies. IMPORTANCE HIV-1 persists in a cellular latent form despite therapy that quickly propagates infection upon treatment interruption. Reversing latency would contribute to eradicate these cells, closing the gap to a cure. Macrophages are an acknowledged HIV-1 reservoir during therapy and are suspected to harbor latency establishment in vivo . However, the impact of latency reversal agents (LRAs) on HIV-1 infection and viral production in human macrophages is poorly known but nonetheless crucial to probe the safety of this strategy. In this in vitro study, we discovered encouraging antireplicative features of distinct LRAs in human macrophages. We also described a new viral production inhibition mechanism by protein kinase C agonists that is specific to myeloid cells. This study provides new insights into HIV-1 propagation restriction potentials by LRAs in human macrophages and underline the importance of assessing latency reversal strategy on all HIV-1-targeted cells.

A growing number of studies have used virtual reality (VR) for the assessment and treatment of body image disturbances (BIDs). This study, conducted in a community sample of adolescents, documents the convergent and discriminant validity between (a) the traditional paper-based Figure Rating Scale (paper-based FRS), (b) the VR-based Body Rating Scale ( e LoriCorps-IBRS 1.1), and (c) the mobile app-based Body Rating Scale ( e LoriCorps-IBRS 1.1-Mobile). A total of 93 adolescents (14 to 18 years old) participated in the study. Body dissatisfaction and body distortion were assessed through the paper-based FRS, the e LoriCorps-IBRS 1.1 and the e LoriCorps-IBRS 1.1-Mobile. Eating disorder symptoms, body image avoidance, and social physique anxiety were also measured. Correlation analyses were performed. Overall, the results showed a good and statistically significant convergence between allocentric perspectives as measured by the paper-based FRS, the e LoriCorps-IBRS 1.1 and the e LoriCorps-IBRS 1.1-Mobile. As expected, the egocentric perspective measured in VR produced different results from the allocentric perspective, and from cognitive-attitudinal-affective dimensions of BIDs, with the exception of body distortion. These differences support the discriminant validity of the egocentric perspective of e LoriCorps-IBRS 1.1 and are consistent with emerging evidence, highlighting a difference between experiencing the body from an egocentric (i.e., the body as a subject) and allocentric (i.e., the body as an object) perspective. The egocentric perspective could reflect a perceptual-sensory-affective construction of BIDs, whereas allocentric measures seem to be more related to a cognitive-affective-attitudinal construction of BIDs. Moreover, the results support the validity of the e LoriCorps-IBRS 1.1-Mobile with promising perspectives of implementation among young populations.

Mitochondrial DNA (mtDNA) maintenance is essential to sustain a functionally healthy population of mitochondria within cells. Proper mtDNA replication and distribution within mitochondrial networks are essential to maintain mitochondrial homeostasis. However, the fundamental basis of mtDNA segregation and distribution within mitochondrial networks is still unclear. To address these questions, we developed an algorithm, Mitomate tracker to unravel the global distribution of nucleoids within mitochondria. Using this tool, we decipher the semi-regular spacing of nucleoids across mitochondrial networks. Furthermore, we show that mitochondrial fission actively regulates mtDNA distribution by controlling the distribution of nucleoids within mitochondrial networks. Specifically, we found that primary cells bearing disease-associated mutations in the fission proteins DRP1 and MYH14 show altered nucleoid distribution, and acute enrichment of enlarged nucleoids near the nucleus. Further analysis suggests that the altered nucleoid distribution observed in the fission mutants is the result of both changes in network structure and nucleoid density. Thus, our study provides novel insights into the role of mitochondria fission in nucleoid distribution and the understanding of diseases caused by fission defects., (© 2021. The Author(s).)

Thymidylate synthase (TS) is a key enzyme in nucleotide biosynthesis. A study performed by our group on human monocyte-derived macrophages (MDMs) infected with HIV-1 showed that many enzymes related to the folate cycle pathway, such as TS, are upregulated in productively infected cells. Here, we suggest that TS is essential for an effective HIV-1 infection in MDMs. Indeed, a TS specific small interfering RNA (siRNA) as well as the TS specific inhibitor Raltitrexed (RTX) caused a reduction in productively infected cells. Quantitative PCR analysis showed that this treatment decreased the efficacy of the early steps of the viral cycle. The RTX inhibitory effect was counteracted by dNTP addition. These results suggest that TS is essential for the early stages of HIV-1 infection by providing optimal dNTP concentrations in MDMs. TS and its related pathway may thus be considered as a potential therapeutic target for HIV-1 treatment., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Over the last decade, the vector-apodizing phase plate (vAPP) coronagraph has been developed from concept to on-sky application in many high-contrast imaging systems on 8 m class telescopes. The vAPP is a geometric-phase patterned coronagraph that is inherently broadband, and its manufacturing is enabled only by direct-write technology for liquid-crystal patterns. The vAPP generates two coronagraphic point spread functions (PSFs) that cancel starlight on opposite sides of the PSF and have opposite circular polarization states. The efficiency, that is, the amount of light in these PSFs, depends on the retardance offset from a half-wave of the liquid-crystal retarder. Using different liquid-crystal recipes to tune the retardance, different vAPPs operate with high efficiencies (${\gt}96\%$) in the visible and thermal infrared (0.55 µm to 5 µm). Since 2015, seven vAPPs have been installed in a total of six different instruments, including Magellan/MagAO, Magellan/MagAO-X, Subaru/SCExAO, and LBT/LMIRcam. Using two integral field spectrographs installed on the latter two instruments, these vAPPs can provide low-resolution spectra (${\rm{R}} \sim 30$) between 1 µm and 5 µm. We review the design process, development, commissioning, on-sky performance, and first scientific results of all commissioned vAPPs. We report on the lessons learned and conclude with perspectives for future developments and applications.

Biologic drugs account for a disproportionate share of the increase in pharmaceutical spending in the US and worldwide. Against this backdrop, many look to the expanding market for biosimilars-follow-on products to biologic drugs-as a vehicle for controlling pharmaceutical spending. This study explores the early years of entry of biosimilars and related follow-on products in the US. Using monthly sales data from the period 2005-19 for ten drug classes, we examine how quickly biosimilars/follow-on products gained market share and the subsequent trajectory of prevailing (national average invoice) prices. Our analysis suggests that although uptake has been slower than what is typically seen in generic drug markets, the most recent entrants have captured market share more rapidly than comparable earlier biosimilars/follow-on products. We also document that from biosimilar/follow-on products' time of entry, their lower prices help offset the overall trend in average annual reference-product price increases. Our findings can provide insight into future policy reforms aimed at increasing competition and use of biosimilars, leading to expanded patient access and significant cost savings.

Here, we report on a quasi-experimental study to explore the applicability and perceived benefits of the CRAFT program, which is based on mindfulness, yoga, positive psychology, and emotional intelligence, to improve higher education student musicians' health and well-being during the lockdown. A subset of student musicians at a Higher Conservatory of Music in Spain followed the CRAFT program during the academic year 2019/2020, 1 h per week as part of their curriculum. Students enrolled in CRAFT-based elective subjects formed the CRAFT program group ( n = 40), while other students represented the control group ( n = 53). The onset of the national lockdown elicited by the COVID-19 pandemic occurred halfway through the program, which was subsequently delivered in an online format. We administered an online survey to explore the effect that the exposure to the CRAFT program had in terms of how participants dealt with various health and well-being concerns arising from the COVID-19 lockdown. There was a significantly higher proportion of proactive participants in the CRAFT program group, 92%, than in the control group, 58%, in terms of implementing practices to improve their health and well-being during the lockdown. Additionally, significantly more participants acknowledged perceived benefits from their practices in the CRAFT program group, 78%, than in the control group, 52%. Among proactive participants, yoga/meditation was the most implemented in the CRAFT program group, followed by exercise, and other yoga/meditation practices, whereas in the control group, exercise and Alexander technique-based practices were the most applied. In the CRAFT program group, the highest rate of perceived benefits was from yoga/meditation CRAFT-based practices, 51%, followed by exercise, 32%, and other yoga/meditation practices, 27%, whereas in the control group, benefits were reported by 29% of exercising participants and 16% for those having practiced the Alexander technique. A similar pattern was observed when excluding participants with previous yoga/meditation experience. This study revealed how participants can independently apply learned skills from the CRAFT program in response to a naturally occurring life event of unprecedented global impact, suggesting that previous exposure to mindfulness and yoga is likely to have a beneficial effect on how young adults react towards exceptionally stressful conditions., Competing Interests: We acknowledge that one of the authors (MP) developed the CRAFT program. However, as stated in the author contributions, MP did not conceive this particular study and also was not responsible for both the data collection and analysis stages of this investigation, which was also a way to manage this particular potential conflict of interest. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bartos, Funes, Ouellet, Posadas and Krägeloh.)

The temporal focus hypothesis (TFH) proposes that whether the past or the future is conceptualized as being located in front depends on temporal focus: the balance of attention paid to the past (tradition) and the future (progress). How general is the TFH, and to what extent can cultures and subcultures be placed on a single line relating time spatialization and temporal focus in spite of stark differences in language, religion, history, and economic development? Data from 10 Western (sub)cultural groups (N = 1198,) were used to derive a linear model relating aggregated temporal focus and proportion of future-in-front responses. This model then successfully fitted 10 independently collected (sub)cultural groups in China and Vietnam (N = 899). Further analysis of the whole data set (N = 2,097) showed that the group-level relation arose at the individual level and allowed precise quantification of its influence. Finally, in an effort to apply the model to all relevant published data sets, we included recent data from Britain and South Africa: The former, but not the latter, fitted the model well. Temporal focus is a central factor that shapes how people around the world think of time in spatial terms.

The first objective of this study was to test the convergent and discriminant validity between the " e LoriCorps Immersive Body Rating Scale" and the traditional paper-based figure rating scale (FRS). The second objective was to explore the contribution of the egocentric virtual reality (VR) perspective of e LoriCorps to understanding body image disturbances (BIDs). The sample consisted of 53 female and 13 male adults. Body size dissatisfaction, body size distortion, perceived body size, and ideal body size were assessed. Overall, outcomes showed good agreement between allocentric perspectives as measured via VR and the FRS. The egocentric VR perspective produced different results compared to both the allocentric VR perspective and the FRS. This difference revealed discriminant validity and suggested that e Loricorps' egocentric VR perspective might assess something different from the traditional conception of body dissatisfaction, which an allocentric VR perspective generally assesses. Finally, the egocentric VR perspective in assessing BIDs deserves to be studied more extensively to explore the possibility of finding two types of body image distortion: (a) an egocentric perceptual body distortion, referring to internal body sensation affected by intra-individual changes, and (b) an allocentric perceptual body distortion, referring to external body benchmarks constructed by inter-individual comparison occurring in a given cultural context.

Background: CRISPR-Cas9 gene-editing technology has facilitated the generation of knockout mice, providing an alternative to cumbersome and time-consuming traditional embryonic stem cell-based methods. An earlier study reported up to 16% efficiency in generating conditional knockout (cKO or floxed) alleles by microinjection of 2 single guide RNAs (sgRNA) and 2 single-stranded oligonucleotides as donors (referred herein as "two-donor floxing" method)., Results: We re-evaluate the two-donor method from a consortium of 20 laboratories across the world. The dataset constitutes 56 genetic loci, 17,887 zygotes, and 1718 live-born mice, of which only 15 (0.87%) mice contain cKO alleles. We subject the dataset to statistical analyses and a machine learning algorithm, which reveals that none of the factors analyzed was predictive for the success of this method. We test some of the newer methods that use one-donor DNA on 18 loci for which the two-donor approach failed to produce cKO alleles. We find that the one-donor methods are 10- to 20-fold more efficient than the two-donor approach., Conclusion: We propose that the two-donor method lacks efficiency because it relies on two simultaneous recombination events in cis, an outcome that is dwarfed by pervasive accompanying undesired editing events. The methods that use one-donor DNA are fairly efficient as they rely on only one recombination event, and the probability of correct insertion of the donor cassette without unanticipated mutational events is much higher. Therefore, one-donor methods offer higher efficiencies for the routine generation of cKO animal models.

Mitochondria are highly dynamic organelles that respond rapidly to a number of stressors to regulate energy transduction, cell death signaling, and reactive oxygen species generation. We hypothesized that mitochondrial remodeling, comprising both structural and functional alterations, following ionizing radiation (IR) may underlie some of the tenets of radiobiology. Mesenchymal stem cells (MSCs) are precursors of bone marrow stroma and are altered in acute myeloid leukemia and by radiation and chemotherapy. Here, we report on changes in mitochondrial remodeling in human MSCs following X-ray IR. Mitochondrial function was significantly increased in MSCs  4 h after IR as measured by mitochondrial oxygen consumption. Consistent with this elevated functional effect, electron transport chain supercomplexes were also increased in irradiated samples. In addition, mitochondria were significantly, albeit modestly, elongated, as measured by high-throughput automated confocal imaging coupled with automated mitochondrial morphometric analyses. We also demonstrate in fibroblasts that mitochondrial remodeling is required for the adaptation of cells to IR. To determine novel mechanisms involved in mitochondrial remodeling, we performed quantitative proteomics on isolated mitochondria from cells following IR. Label-free quantitative mitochondrial proteomics revealed notable changes in proteins in irradiated samples and identified prosaposin, and potentially its daughter protein saposin-B, as a potential candidate for regulating mitochondrial function following IR. Whereas research into the biologic effects of cellular irradiation has long focused on nuclear DNA effects, our experimental work, along with that of others, is finding that mitochondrial effects may have broader implications in the field of stress adaptation and cell death in cancer (including leukemia) and other disease states.-Patten, D. A., Ouellet, M., Allan, D. S., Germain, M., Baird, S. D., Harper, M.-E., Richardson, R. B. Mitochondrial adaptation in human mesenchymal stem cells following ionizing radiation.

Micro-Electro-Mechanical Systems (MEMS) Deformable Mirrors (DMs) enable precise wavefront control for optical systems. This technology can be used to meet the extreme wavefront control requirements for high contrast imaging of exoplanets with coronagraph instruments. MEMS DM technology is being demonstrated and developed in preparation for future exoplanet high contrast imaging space telescopes, including the Wide Field Infrared Survey Telescope (WFIRST) mission which supported the development of a 2040 actuator MEMS DM. In this paper, we discuss ground testing results and several projects which demonstrate the operation of MEMS DMs in the space environment. The missions include the Planet Imaging Concept Testbed Using a Recoverable Experiment (PICTURE) sounding rocket (launched 2011), the Planet Imaging Coronagraphic Technology Using a Reconfigurable Experimental Base (PICTURE-B) sounding rocket (launched 2015), the Planetary Imaging Concept Testbed Using a Recoverable Experiment - Coronagraph (PICTURE-C) high altitude balloon (expected launch 2019), the High Contrast Imaging Balloon System (HiCIBaS) high altitude balloon (launched 2018), and the Deformable Mirror Demonstration Mission (DeMi) CubeSat mission (expected launch late 2019). We summarize results from the previously flown missions and objectives for the missions that are next on the pad. PICTURE had technical difficulties with the sounding rocket telemetry system. PICTURE-B demonstrated functionality at >100 km altitude after the payload experienced 12-g RMS (Vehicle Level 2) test and sounding rocket launch loads. The PICTURE-C balloon aims to demonstrate 10 - 7 contrast using a vector vortex coronagraph, image plane wavefront sensor, and a 952 actuator MEMS DM. The HiClBaS flight experienced a DM cabling issue, but the 37-segment hexagonal piston-tip-tilt DM is operational post-flight. The DeMi mission aims to demonstrate wavefront control to a precision of less than 100 nm RMS in space with a 140 actuator MEMS DM.

The molecular basis for HIV-1 susceptibility in primary human monocyte-derived macrophages (MDMs) was previously evaluated by comparing the transcriptome of infected and bystander populations. Careful analysis of the data suggested that the ubiquitin ligase MDM2 acted as a positive regulator of HIV-1 replication in MDMs. In this study, MDM2 silencing through transcript-specific small interfering RNAs in MDMs induced a reduction in HIV-1 reverse transcription and integration along with an increase in the expression of p53-induced genes, including CDKN1A Experiments with Nutlin-3, a pharmacological inhibitor of MDM2 p53-binding activity, showed a similar effect on HIV-1 infection, suggesting that the observed restriction in HIV-1 production results from the release/activation of p53 and not the absence of MDM2 per se Knockdown and inhibition of MDM2 also both correlate with a decrease in the Thr592-phosphorylated inactive form of SAMHD1. The expression level of MDM2 and the p53 activation status are therefore important factors in the overall susceptibility of macrophages to HIV-1 infection, bringing a new understanding of signaling events controlling the process of virus replication in this cell type. IMPORTANCE Macrophages, with their long life span in vivo and their resistance to HIV-1-mediated cytopathic effect, might serve as viral reservoirs, contributing to virus persistence in an infected individual. Identification of host factors that increase the overall susceptibility of macrophages to HIV-1 might provide new therapeutic targets for the efficient control of viral replication in these cells and limit the formation of reservoirs in exposed individuals. In this study, we demonstrate the importance of p53 regulation by MDM2, which creates a cellular environment more favorable to the early steps of HIV-1 replication. Moreover, we show that p53 stabilization reduces virus infection in human macrophages, highlighting the important role of p53 in antiviral immunity., (Copyright © 2019 American Society for Microbiology.)

More than 40% of HIV infections occur via female reproductive tract (FRT) through heterosexual transmission. Epithelial cells that line the female genital mucosa are the first line of defense against HIV-1 and other sexually transmitted pathogens. These sentient cells recognize and respond to external stimuli by induction of a range of carefully balanced innate immune responses. Previously, we have shown that in response to HIV-1 gp120, the genital epithelial cells (GECs) from upper reproductive tract induce an inflammatory response that may facilitate HIV-1 translocation and infection. In this study, we report that the endometrial and endocervical GECs simultaneously induce biologically active interferon-β (IFNβ) antiviral responses following exposure to HIV-1 that act to protect the epithelial tight junction barrier. The innate antiviral response was directly induced by HIV-1 envelope glycoprotein gp120 and addition of gp120 neutralizing antibody inhibited IFNβ production. Interferon-β was induced by gp120 in upper GECs through Toll-like receptor 2 signaling and required presence of heparan sulfate on epithelial cell surface. The induction of IFNβ was dependent upon activation of transcription factor IRF3 (interferon regulatory factor 3). The IFNβ was biologically active, had a protective effect on epithelial tight junction barrier and was able to inhibit HIV-1 infection in TZM-bl indicator cells and HIV-1 replication in T cells. This is the first report that recognition of HIV-1 by upper GECs leads to induction of innate antiviral pathways. This could explain the overall low infectivity of HIV-1 in the FRT and could be exploited for HIV-1 prophylaxis.

A mental metaphor is a strategy that consists of completing the representation of a concept with structural components of a correlating concept. Three issues were addressed here to deepen our understanding of this mechanism: the use of mental metaphors between abstract concepts, the simultaneous activation of multiple mental metaphors and the importance of the focus of attention on the relevant dimensions of a mental metaphor. In two experiments, participants made temporal or valence judgments (with their left or right hand) on verbs with a negative or positive meaning and conjugated in the past or future form, allowing for the simultaneous activation of the "time is space", "valence is space," and "time is valence" mental metaphors. Left-past/right-future and left-negative/right-positive congruency effects were found, and these effects were greater in the temporal and valence judgment tasks, respectively, demonstrating the importance of attentional cuing. Simultaneously, a congruency effect between the abstract concepts of time and valence (past-negative/future-positive) was observed, revealing that a mental metaphor can occur between abstract concepts and that multiple metaphors can be processed simultaneously. These results are discussed in terms of different theories within the field of mental metaphors.

In this study, we investigated the effect of acetate, the most concentrated short-chain fatty acid (SCFA) in the gut and bloodstream, on the susceptibility of primary human CD4 + T cells to HIV-1 infection. We report that HIV-1 replication is increased in CD3/CD28-costimulated CD4 + T cells upon acetate treatment. This enhancing effect correlates with increased expression of the early activation marker CD69 and impaired class I/II histone deacetylase (HDAC) activity. In addition, acetate enhances acetylation of histones H3 and H4 and augments HIV-1 integration into the genome of CD4 + T cells. Thus, we propose that upon antigen presentation, acetate influences class I/II HDAC activity that transforms condensed chromatin into a more relaxed structure. This event leads to a higher level of viral integration and enhanced HIV-1 production. In line with previous studies showing reactivation of latent HIV-1 by SCFAs, we provide evidence that acetate can also increase the susceptibility of primary human CD4 + T cells to productive HIV-1 infection. IMPORTANCE Alterations in the fecal microbiota and intestinal epithelial damage involved in the gastrointestinal disorder associated with HIV-1 infection result in microbial translocation that leads to disease progression and virus-related comorbidities. Indeed, notably via production of short-chain fatty acids, bacteria migrating from the lumen to the intestinal mucosa could influence HIV-1 replication by epigenetic regulatory mechanisms, such as histone acetylation. We demonstrate that acetate enhances virus production in primary human CD4 + T cells. Moreover, we report that acetate impairs class I/II histone deacetylase activity and increases integration of HIV-1 DNA into the host genome. Therefore, it can be postulated that bacterial metabolites such as acetate modulate HIV-1-mediated disease progression., (Copyright © 2017 American Society for Microbiology.)

It has been proposed that macrophages could serve as long-lived compartments for HIV-1 infection under in vivo situations because these cells are resistant to the virus-mediated cytopathic effect, produce progeny virus over extended periods of time and are localized in tissues that are often less accessible by treatment. Comprehensive experimental studies are thus needed to characterize the HIV-1-induced modulation of host genes in these myeloid lineage cells. To shed light on this important issue, we performed comparative analyses of mRNA expression levels of host genes in uninfected bystander and HIV-1-infected human macrophages using an infectious reporter virus construct coupled with a large-scale RNA sequencing approach. We observed a rapid differential expression of several host factors in the productively infected macrophage population including genes regulating DNA replication factors and chromatin remodeling. A siRNA-mediated screening study to functionally identify host determinants involved in HIV-1 biology has provided new information on the virus molecular regulation in macrophages.

Mitochondria exist as a highly interconnected network that is exquisitely sensitive to variations in nutrient availability, as well as a large array of cellular stresses. Changes in length and connectivity of this network, as well as alterations in the mitochondrial inner membrane (cristae), regulate cell fate by controlling metabolism, proliferation, differentiation, and cell death. Given the key roles of mitochondrial dynamics, the process by which mitochondria constantly fuse and fragment, the measure of mitochondrial length and connectivity provides crucial information on the health and activity of various cell populations. However, despite the importance of accurately measuring mitochondrial networks, the tools required to rapidly and accurately provide this information are lacking. Here, we developed a novel probabilistic approach to automatically measure mitochondrial length distribution and connectivity from confocal images. This method accurately identified mitochondrial changes caused by starvation or the inhibition of mitochondrial function. In addition, we successfully used the algorithm to measure changes in mitochondrial inner membrane/matrix occurring in response to Complex III inhibitors. As cristae rearrangements play a critical role in metabolic regulation and cell survival, this provides a rapid method to screen for proteins or compounds affecting this process. The algorithm will thus provide a robust tool to dissect the molecular mechanisms underlying the key roles of mitochondria in the regulation of cell fate.

Evolutionary change has been demonstrated to occur rapidly in human-modified systems, yet understanding how multiple components of global change interact to affect adaptive evolution remains a critical knowledge gap. Climate change is predicted to impose directional selection on traits to reduce thermal stress, but the strength of directional selection may be mediated by changes in the thermal environment driven by land use. We examined how regional climatic conditions and land use interact to affect genetically based color polymorphism in the eastern red-backed salamander ( Plethodon cinereus ). P. cinereus is a woodland salamander with two primary discrete color morphs (striped, unstriped) that have been associated with macroclimatic conditions. Striped individuals are most common in colder regions, but morph frequencies can be variable within climate zones. We used path analysis to analyze morph frequencies among 238,591 individual salamanders across 1,170 sites in North America. Frequency of striped individuals was positively related to forest cover in populations occurring in warmer regions (>7°C annually), a relationship that was weak to nonexistent in populations located in colder regions (≤7°C annually). Our results suggest that directional selection imposed by climate warming at a regional scale may be amplified by forest loss and suppressed by forest persistence, with a mediating effect of land use that varies geographically. Our work highlights how the complex interaction of selection pressures imposed by different components of global change may lead to divergent evolutionary trajectories among populations.

Background: Many plants of boreal forest of Quebec have been used by Native Americans to treat a variety of microbial infections. However, the antiviral activities of these plants have been seldom evaluated on cellular models to validate their in vitro efficiencies. In this study, Cornus canadensis L. (Cornaceae), a plant used in Native American traditional medicine to treat possible antiviral infections, has been selected for further examination., Methods: The plant was extracted by decoction and infusion with water, water/ethanol 1:1 and ethanol to obtain extracts similar to those used by Native Americans. The effects of the extracts were tested on herpes simplex virus type-1 (HSV-1) using a plaque reduction assay. Moreover, bioassay-guided fractionation was achieved to isolate bioactive compounds., Results: Water/ethanol 1:1 infusion of C. canadensis leaves were the most active extracts to inhibit virus absorption with EC 50 of about 9 μg mL -1 , whereas for direct mode, both extraction methods using water or water/ethanol 1:1 as solvent were relatively similar with EC 50 ranging from 11 to 17 μg mL -1 . The fractionation led to the identification of active fractions containing hydrolysable tannins. Tellimagrandin I was found the most active compound with an EC 50 of 2.6 μM for the direct mode and 5.0 μM for the absorption mode., Conclusion: Altogether, the results presented in this work support the antiviral activity of Cornus canadensis used in Native American traditional medicine.

A shock-and-kill approach involving the simultaneous treatment of HIV-1-infected patients with latency-reversing agents (LRAs) and combination antiretroviral therapy was proposed as a means to eradicate viral reservoirs. Currently available LRAs cannot discriminate between HIV-1-infected and uninfected cells. Therefore, the risks and benefits of using broad-spectrum LRAs need to be carefully evaluated, particularly in the CNS, where inflammation and leukocyte transmigration must be tightly regulated. We used a real-time impedance-sensing system to dynamically record the impact of different classes of LRAs on the integrity of tight monolayers of the immortalized human cerebral microvascular endothelial cell line hCMEC/D3. Results show that prostratin and bryostatin-1 can significantly damage the integrity of an endothelial monolayer. Moreover, prostratin and bryostatin-1 induce secretion of some proinflammatory cytokines and an increase of ICAM-1 expression. Additional studies demonstrated that prostratin and bryostatin-1 also affect adhesion and transmigration of CD4 + and CD8 + T cells as well as monocytes in an in vitro human blood-brain barrier (BBB) model. Prostratin and bryostatin-1 could thus be considered as potent regulators of BBB permeability and inflammation that influence leukocyte transport across the BBB. Altogether, these findings contribute to a better understanding of the potential risks and benefits of using a shock-and-kill approach with LRAs on the normal physiological functions of the BBB., (Copyright © 2017 by The American Association of Immunologists, Inc.)

In this study, we investigated the effect of Toll-like receptor 2 (TLR2) ligation on the permissiveness of activated CD4 + T cells to HIV-1 infection by focusing our experiments on the relative susceptibility of cell subsets based on their expression of CCR6. Purified primary human CD4 + T cells were first subjected to a CD3/CD28 costimulation before treatment with the TLR2 agonist Pam3CSK4. Finally, cells were inoculated with R5-tropic HIV-1 particles that permit us to study the effect of TLR2 triggering on virus production at both population and single-cell levels. We report here that HIV-1 replication is augmented in CD3/CD28-costimulated CCR6 + CD4 + T cells upon engagement of the cell surface TLR2. Additional studies indicate that a higher virus entry and polymerization of the cortical actin are seen in this cell subset following TLR2 stimulation. A TLR2-mediated increase in the level of phosphorylated NF-κB p65 subunit was also detected in CD3/CD28-costimulated CCR6 + CD4 + T cells. We propose that, upon antigenic presentation, an engagement of TLR2 acts specifically on CCR6 + CD4 + T cells by promoting virus entry in an intracellular milieu more favorable for productive HIV-1 infection., Importance: Following primary infection, HIV-1 induces an immunological and structural disruption of the gut mucosa, leading to bacterial translocation and release of microbial components in the bloodstream. These pathogen-derived constituents include several agonists of Toll-like receptors that may affect gut-homing CD4 + T cells, such as those expressing the chemokine receptor CCR6, which are highly permissive to HIV-1 infection. We demonstrate that TLR2 ligation in CD3/CD28-costimulated CCR6 + CD4 + T cells leads to enhanced virus production. Our results highlight the potential impact of bacterial translocation on the overall permissiveness of CCR6 + CD4 + T cells to productive HIV-1 infection., (Copyright © 2017 American Society for Microbiology.)

Shorter regulatory review times for high-risk cardiovascular devices correlate with the likelihood of reports of adverse events., Competing Interests: Competing interests The authors declare no competing financial interests.

Clinical simulation has become established as a commonly used educational approach in respiratory therapy, though questions remain with regards to the evidence basis for its use in some contexts. In conjunction with the development of a new iteration of the National Competency Framework (NCF), the National Alliance of Respiratory Therapy Regulatory Bodies (NARTRB) reaffirmed its desire to continue to recognize the use of simulation as an educational tool. Given the expressed uncertainty as to best practices in the use of clinical simulation in entry-to-practice respiratory therapy education programs, the NARTRB requested the creation of an expert workgroup to develop a list of recommendations from which an implementation plan could be developed for the next iteration of the NCF. The resulting advisory workgroup recommendations are intended to inform the application of simulation in education programs relative to the attainment of entry-to-practice competencies as outlined in the current National Competency Profile. The recommendations presented focus on the use of clinical simulation for formative and summative assessment of respiratory therapy competencies. The recommendations indicate that the use of formative assessment in clinical simulations along with deliberate practice has been clearly shown to improve learning outcomes for which the simulations are designed. However, it is advised that the use of clinical simulation for the summative assessment of competency (e.g., to assess readiness for practice) be exercised cautiously in the context of respiratory therapy education. A number of requisite instructional design factors that should be considered before implementing summative simulation-based assessments are identified, including the validation of summative assessment tools.

HIV-1 infection is characterized by persistent viral replication, chronic immune activation, and CD4(+) T cell depletion. Moreover, several immune dysfunctions are observed in cells that are not targeted by the virus, such as B cells. Some B cell abnormalities include hypergammaglobulinemia, nonspecific B cell activation, class switching, increased cell turnover, breakage of tolerance, and a loss of the capacity to generate and maintain memory. Several cytokines and growth factors that are increased in the serum of HIV-1-infected individuals have been suggested to directly or indirectly trigger B cell activation, and one of these is BAFF. In this study, we investigate the ability of fully competent (R5-tropic) HIV-1 to induce BAFF production by monocyte-derived macrophages (MDMs). We demonstrate here that HIV-1 drives BAFF production in MDMs in a type-I IFN- and TLR-independent manner. Moreover, we determine that HIV-1 Nef accessory protein is dispensable in BAFF upregulation as a nef-deleted HIV-1 strain is still able to increase BAFF at levels similar to the wild type strain. Finally, we show that the macrophage phenotype status affects HIV-1 replication and BAFF induction, as both were abrogated in MDMs displaying a M1 phenotype. This study provides new useful information about the increased levels of BAFF observed during HIV-1 infection and highlights the importance of macrophages as a source of BAFF, a phenomenon that might contribute to B cell dysfunctions at inflammatory tissue sites in infected individuals., (Copyright © 2016 by The American Association of Immunologists, Inc.)

Enhancing xylose utilization has been a major focus in Saccharomyces cerevisiae strain-engineering efforts. The incentive for these studies arises from the need to use all sugars in the typical carbon mixtures that comprise standard renewable plant-biomass-based carbon sources. While major advances have been made in developing utilization pathways, the efficient import of five carbon sugars into the cell remains an important bottleneck in this endeavor. Here we use an engineered S. cerevisiae BY4742 strain, containing an established heterologous xylose utilization pathway, and imposed a laboratory evolution regime with xylose as the sole carbon source. We obtained several evolved strains with improved growth phenotypes and evaluated the best candidate using genome resequencing. We observed remarkably few single nucleotide polymorphisms in the evolved strain, among which we confirmed a single amino acid change in the hexose transporter HXT7 coding sequence to be responsible for the evolved phenotype. The mutant HXT7(F79S) shows improved xylose uptake rates (Vmax = 186.4 ± 20.1 nmol•min(-1)•mg(-1)) that allows the S. cerevisiae strain to show significant growth with xylose as the sole carbon source, as well as partial co-utilization of glucose and xylose in a mixed sugar cultivation.

HIV-1 infection leads to numerous B cell abnormalities, including hypergammaglobulinemia, nonspecific B cell activation, nonspecific class switching, increased cell turnover, breakage of tolerance, increased immature/transitional B cells, B cell malignancies, as well as a loss of capacity to generate and maintain memory, all of which contribute to a global impairment of the immune humoral compartment. Several cytokines and soluble factors, which are increased in sera of HIV-1-infected individuals, have been suggested to directly or indirectly contribute to these B cell dysfunctions, and one of these is the B cell-activating factor (BAFF). We report in this study that HIV-1 (X4- and R5-tropic) upregulates BAFF expression and secretion by human monocytes. Moreover, we show that the virus-mediated production of BAFF by monocytes relies on a type I IFN response by a small percentage of plasmacytoid dendritic cells (pDCs) present in the monocyte cultures. HIV-1-induced type I IFN by pDCs triggers BAFF production in both classical and intermediate monocytes, but not in nonclassical monocytes, which nonetheless display a very strong basal BAFF production. We report also that basal BAFF secretion was higher in monocytes obtained from females compared with those from male donors. This study provides a novel mechanistic explanation for the increased BAFF levels observed during HIV-1 infection and highlights the importance of pDC/monocyte crosstalk to drive BAFF secretion., (Copyright © 2015 by The American Association of Immunologists, Inc.)

Visceral leishmaniasis is caused by the protozoan parasites Leishmania infantum and Leishmania donovani. This infection is characterized by an uncontrolled parasitization of internal organs which, when left untreated, leads to death. Disease progression is linked with the type of immune response generated and a strong correlation was found between disease progression and serum levels of the immunosuppressive cytokine IL-10. Other studies have suggested a role for B cells in the pathology of this parasitic infection and the recent identification of a B-cell population in humans with regulatory functions, which secretes large amounts of IL-10 following activation, have sparked our interest in the context of visceral leishmaniasis. We report here that incubation of human B cells with Leishmania infantum amastigotes resulted in upregulation of multiple cell surface activation markers and a dose-dependent secretion of IL-10. Conditioned media from B cells incubated with Leishmania infantum amastigotes were shown to strongly inhibit CD4(+) T-cell activation, proliferation and function (i.e. as monitored by TNF and IFNγ secretion). Blockade of IL-10 activity using a soluble IL-10 receptor restored only partially TNF and IFNγ production to control levels. The parasite-mediated IL-10 secretion was shown to rely on the activity of Syk, phosphatidylinositol-3 kinase and p38, as well as to require intracellular calcium mobilization. Cell sorting experiments allowed us to identify the IL-10-secreting B-cell subset (i.e. CD19(+)CD24(+)CD27(-)). In summary, exposure of human B cells to Leishmania infantum amastigotes triggers B cells with regulatory activities mediated in part by IL-10, which could favor parasite dissemination in the organism.

The effects of recent climate changes on earth ecosystems are likely among the most important ecological concerns in human history. Good bioindicators are essential to properly assess the magnitude of these changes. In the last decades, studies have suggested that the morph proportion of the eastern red-backed salamander (Plethodon cinereus), one of the most widely distributed and abundant vertebrate species in forests of eastern North America, could be used as a proxy for monitoring climate changes. Based on new discoveries in the northern areas of the species' range and on one of the largest compilation ever made for a vertebrate in North America (236 109 observations compiled from 1880 to 2013 in 1148 localities), we demonstrate however that climatic and geographic variables do not influence the colour morph proportions in P. cinereus populations. Consequently, we show that the use of colour morph proportions of this species do not perform as an indicator of climate change. Our findings indicate that bioindicator paradigms can be significantly challenged by new ecological research and more representative databases., (© 2014 Her Majesty the Queen in Right of Canada Global Change Biology © 2014 John Wiley & Sons Ltd.)

The affective prediction hypothesis assumes that visual expectation allows fast and accurate processing of emotional stimuli. The prediction corresponds to what an object is likely to be. It therefore facilitates its identification by setting aside what the object is unlikely to be. It has then been suggested that prediction might be inevitably associated with the inhibition of irrelevant possibilities concerning the object to identify. Several studies highlighted that the facilitation of emotional perception depends on low spatial frequency (LSF) extraction. However, most of them used paradigms in which only the object to identify was present in the scene. As a consequence, there have yet been no studies investigating the efficiency of prediction in the visual perception of stimuli among irrelevant information. In this study, we designed a novel priming emotional Stroop task in which participants had to identify emotional facial expressions (EFEs) presented along with a congruent or incongruent word. To further investigate the role of early extraction of LSF information in top-down prediction during emotion recognition, the target EFE was primed with the same EFE filtered in LSF or high spatial frequency (HSF). Results reveal a reduction of the Stroop interference in the LSF compared to the HSF priming condition, which supports that visual expectation, depending on early LSF information extraction, facilitates the inhibition of irrelevant information during emotion recognition.

Recent reports suggest that some galectins bind to enveloped viruses. They include influenza virus, human immunodeficiency virus-1 (HIV-1), human T-cell leukemia virus-1 (HTLV-1), and Nipah virus. It is also suggested that the interaction between viruses and galectins influences viral attachment to their susceptible cells, affecting the viral infectivity. Our work suggests that galectin-1 increases the infectivity of HIV-1 and HTVL-1. Indeed, galectin-1 promotes the initial adsorption of HIV-1 to CD4(+) cells through its binding to viral envelope gp120 and facilitates HIV-1 infection in a manner that is dependent on its recognition of β-galactoside residues. Thus, as galectin-1 can be considered as a pattern recognition receptor, HIV-1 exploits this host factor to promote its transmission or replication. In this chapter, we describe methods used to investigate this potential role of galectins in HIV-1 infection as a case in point for future studies on galectin-virus interactions.

Research in the field of bioengineered skin substitutes is motivated by the need to find new dressings for people affected by skin injuries (burns, diabetic ulcers), and to develop adequate skin models to test new formulations developed in vitro. Thanks to advances in tissue engineering, it is now possible to produce human skin substitutes without any exogenous material, using the self-assembly method developed by the Laboratoire d'Organogénèse Expérimentale. These human skin substitutes consist of a dermis and a stratified epidermis (stratum corneum and living epidermis). Raman microspectroscopy has been used to characterize and compare the molecular organization of skin substitutes with normal human skin. Our results confirm that the stratum corneum is a layer rich in lipids which are well ordered (trans conformers) in both substitutes and normal human skin. The amount of lipids decreases and more gauche conformers appear in the living epidermis in both cases. However, the results also show that there are fewer lipids in the substitutes and that the lipids are more organized in the normal human skin. Concerning the secondary structure of proteins and protein content, the data show that they are similar in the substitutes and in the normal human skin. In fact, the epidermis is rich in α-keratin, whereas the dermis contains mainly type I collagen., (Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Vascular relaxation to nitroglycerin (glyceryl trinitrate; GTN) requires its bioactivation by mechanisms that remain controversial. We report here that glyceraldehyde-3-phosphate dehydrogenase (GAPDH) catalyzes the release of nitrite from GTN. In assays containing dithiothreitol (DTT) and NAD(+), the GTN reductase activity of purified GAPDH produces nitrite and 1,2-GDN as the major products. A vmax of 2.6nmolmin(-)(1)mg(-)(1) was measured for nitrite production by GAPDH from rabbit muscle and a GTN KM of 1.2mM. Reductive denitration of GTN in the absence of DTT results in dose- and time-dependent inhibition of GAPDH dehydrogenase activity. Disulfiram, a thiol-modifying drug, inhibits both the dehydrogenase and GTN reductase activity of GAPDH, while DTT or tris(2-carboxyethyl)phosphine reverse the GTN-induced inhibition. Incubation of intact human erythrocytes or hemolysates with 2mM GTN for 60min results in 50% inhibition of GAPDH's dehydrogenase activity, indicating that GTN is taken up by these cells and that the dehydrogenase is a target of GTN. Thus, erythrocyte GAPDH may contribute to GTN bioactivation., (Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.)

Although women constitute half of all HIV-1-infected people worldwide (UNAIDS World AIDS Day Report, 2011), the earliest events in the female reproductive tract (FRT) during heterosexual HIV-1 transmission are poorly understood. Recently, we demonstrated that HIV-1 could directly impair the mucosal epithelial barrier in the FRT. This suggested that the HIV-1 envelope glycoprotein gp120 was being recognized by a membrane receptor on genital epithelial cells, leading to innate immune activation. In this study, we report that pattern-recognition receptors TLR2 and -4 bind to HIV-1 gp120 and trigger proinflammatory cytokine production via activation of NF-κB. The gp120-TLR interaction also required the presence of heparan sulfate (HS). Bead-binding assays showed that gp120 can bind to HS, TLR2, and TLR4, and studies in transfected HEK293 cells demonstrated that HS and TLR2 and -4 were necessary to mediate downstream signaling. Exposure to seminal plasma from HIV-1-infected and uninfected men with gp120 added to it induced a significant proinflammatory cytokine response from genital epithelial cells and disruption of tight junctions, indicating a role for gp120 in mucosal barrier disruption during HIV-1 heterosexual transmission. These studies provide, for the first time to our knowledge, a possible mechanism by which HIV-1 gp120 could directly initiate innate immune activation in the FRT during heterosexual transmission.

Keratins (Ks), the intermediate filament (IF) proteins of epithelia, are coordinately expressed as pairs in a cell-lineage and differentiation manner. Cortical thymic epithelial cells (cTECs) predominantly express the simple epithelium keratin 8/18 (K8/K18) pair, whereas medullary thymic epithelial cells (mTECs) express the stratified epithelium K5/K14 pair, with TECs exhibiting K5 and K8 at the cortico-medullary junction in mature thymus. In the work reported here, we used wild-type (WT) and K8-knockout (K8-null) mice to address the contribution of K8/K18 IFs in the maintenance of the thymic epithelial structure. K8-null thymus maintained the differential cell segregation at the cortex versus the medulla observed in WT thymus, and the distribution of immature thymocytes at the cortex. The K8/K18 loss did not affect thymocyte development. However, it massively perturbed the TEC morphology both at the cortex and the medulla, along with a prominent depletion of cTECs. Such tissue alterations coincided with an increase in apoptosis and a reduced expression of Albatross (Fas-binding factor-1), also known for its capacity to bind K8/18 IFs. In addition, the K8/K18 loss affected the distribution of K5/K14-positive mTECs, but not their differentiation status. Together, the results indicate that K8/K18 IFs constitute key promoters of the thymic epithelium integrity.

As erythrocyte-derived extracellular adenosine triphosphate (ATP) gains recognition as a key vasodilator, its accurate determination is critical. Erythrocytes' high hemoglobin content can act as an inner filter when measuring ATP concentrations by chemiluminescence. We evaluated two approaches to correct for this matrix effect: addition of cell-free hemoglobin to the ATP standards and standard addition of ATP to erythrocyte suspensions. In addition, we reduced sample hematocrit to minimize the absorbance. We conclude that extracellular ATP should be determined in erythrocyte suspensions at 0.06 to 0.004% hematocrit. This gives robust signals without matrix effects and requires only microliters of blood., (Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.)

Fatty acids are important precursors to biofuels. The Escherichia coli FadR is a transcription factor that regulates several processes in fatty acid biosynthesis, degradation, and membrane transport. By tuning the expression of FadR in an engineered E. coli host, we were able to increase fatty acid titer by 7.5-fold over our previously engineered fatty acid-producing strain, reaching 5.2±0.5g/L and 73% of the theoretical yield. The mechanism by which FadR enhanced fatty acid yield was studied by whole-genome transcriptional analysis (microarray) and targeted proteomics. Overexpression of FadR led to transcriptional changes for many genes, including genes involved in fatty acid pathways. The biggest transcriptional changes in fatty acid pathway genes included fabB, fabF, and accA. Overexpression of any of these genes alone did not result in a high yield comparable to fadR expression, indicating that FadR enhanced fatty acid production globally by tuning the expression levels of many genes to optimal levels., (Copyright © 2012. Published by Elsevier Inc.)

It has generally been assumed that high-level cognitive and emotional processes are based on amodal conceptual information. In contrast, however, "embodied simulation" theory states that the perception of an emotional signal can trigger a simulation of the related state in the motor, somatosensory, and affective systems. To study the effect of social context on the mimicry effect predicted by the "embodied simulation" theory, we recorded the electromyographic (EMG) activity of participants when looking at emotional facial expressions. We observed an increase in embodied responses when the participants were exposed to a context involving social valence before seeing the emotional facial expressions. An examination of the dynamic EMG activity induced by two socially relevant emotional expressions (namely joy and anger) revealed enhanced EMG responses of the facial muscles associated with the related social prime (either positive or negative). These results are discussed within the general framework of embodiment theory.