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Throughout their life cycle, parasitic organisms experience a variety of environmental conditions. To ensure persistence and transmission, some protozoan parasites are capable of adjusting their replication or converting to distinct life cycle stages. Trypanosoma cruzi is a 'generalist' parasite that is competent to infect various insect (triatomine) vectors and mammalian hosts. Within the mammalian host, T. cruzi replicates intracellularly as amastigotes and can persist for the lifetime of the host. The persistence of the parasites in tissues can lead to the development of Chagas disease. Recent work has identified growth plasticity and metabolic flexibility as aspects of amastigote biology that are important determinants of persistence in varied growth conditions and under drug pressure. A better understanding of the link between amastigote and host/tissue metabolism will aid in the development of new drugs or therapies that can limit disease pathology.

Trypanosomatids are a diverse group of uniflagellate protozoa that include globally important pathogens such asTrypanosoma cruzi, the causative agent of Chagas disease. Trypanosomes lack the fatty acid synthase (FAS)-I system typically used forde novosynthesis of long chain fatty acids (LCFA) in other eukaryotes. Instead, these microbes have evolved a modular fatty acid elongase (ELO) system comprised of individual ELO enzymes that operate processively. The role of the ELO system in maintaining lipid homeostasis in trypanosomes has not been determined. Here we demonstrate that ELO2 and ELO3 are required for global lipidome maintenance in the insect stage ofT. cruziwhereas ELO1 is dispensable for this function. Instead, ELO1 activity is needed to sustain mitochondrial activity and normal growth. The cross-talk between microsomal ELO1 and the mitochondrion is a novel finding that merits examination of the trypanosomatid ELO pathway as critical for central metabolism.

Spreading antimalarial resistance threatens effective treatment of malaria, an infectious disease caused by Plasmodium parasites. We identified a compound, BCH070, that inhibits asexual growth of multiple antimalarial-resistant strains of Plasmodium falciparum (half maximal inhibitory concentration [IC50] = 1–2 µM), suggesting that BCH070 acts via a novel mechanism of action. BCH070 preferentially kills early ring-form trophozoites, and, importantly, equally inhibits ring-stage survival of wild-type and artemisinin-resistant parasites harboring the PfKelch13:C580Y mutation. Metabolomic analysis demonstrates that BCH070 likely targets multiple pathways in the parasite. BCH070 is a promising lead compound for development of new antimalarial combination therapy that retains activity against artemisinin-resistant parasites.

Introduction Dyspareunia frequently affects women after gynecological cancer treatment. The focus of previous studies has been on the biomedical factors contributing to dyspareunia in this population. To our knowledge, no study has yet examined the biopsychosocial factors associated with women's experiences of dyspareunia after gynecological cancer treatment. Moreover, cancer survivors appear to refrain from seeking care despite the consequences of dyspareunia. Objective The aim of this study is to examine gynecological cancer survivors’ experiences of dyspareunia and factors influencing their care-seeking behavior. Methods A nested qualitative study was performed with the participants of a clinical trial investigating a multimodal pelvic floor physical therapy intervention. This enabled a comprehensive understanding of women's experiences and care-seeking behavior, including factors that could influence whether they seek care as well as their decision to undertake treatment. Women were included in the trial if they had completed endometrial or cervical cancer treatment and if they had experienced a minimum vulvovaginal pain intensity of 5 out of 10 during most intercourse attempts for at least 3 months. Individual semi-structured telephone interviews were conducted. The questions pertaining to women's experiences and factors influencing their care-seeking behavior were constructed based on the Common-Sense Model of Self-Regulation (i.e., identity, timeline, causes, consequences, and control attributes). The interviewer adopted a biopsychosocial perspective of health to approach these topics during the interviews. Interviews were recorded and transcribed for analysis using the interpretative description framework. Results Of the 31 women included in the trial, 28 (90%) participated in the qualitative study. The participants had been diagnosed with different cancer stages and had received various treatments. For all participants, dyspareunia occurred after cancer treatment and persisted for a median time of 3 years (ranging from 3 months to 11 years). Loss of libido, lower vaginal lubrication, and reduced vaginal cavity were reported by women as contributing factors to dyspareunia. Participants explained how dyspareunia and these changes led them to engage in less, and even to interrupt, sexual activity. They also expressed that they were distressed, felt like less of a woman, and experienced low control and/or self-efficacy. Several women described that their condition had an impact on their relationship with their partner. Regarding factors influencing women's care-seeking behavior, participants emphasized that they were provided with insufficient information and support. Other barriers included balancing priorities, denial or reluctance, misbeliefs, resignation and acceptance, and negative emotions. Facilitators reported by women included acknowledgement of sexual dysfunction, desire for improvement, awareness of treatment possibilities, willingness to undertake treatment, and treatment acceptability. Conclusions Women's experiences of dyspareunia after gynecological cancer treatment highlight the complexity of this condition, which involves biopsychosocial factors. The related consequences described by women also stress the importance of appropriate management. As the current study provides insight to guide the provision of services, efforts should focus on promoting the facilitators and overcoming the barriers to seeking care for sexual dysfunction after gynecological cancer treatment. Disclosure No

International audience

Context. Io’s spectacular activity is driven by tidal dissipation within its interior, which may undergo a large amount of melting. While tidal dissipation models of planetary interiors classically assume that anelastic dissipation is associated only with shear deformation, seismological observation of the Earth has revealed that bulk dissipation might be important in the case of partial melting. Aims. Although tidal dissipation in a partially molten layer within Io’s mantle has been widely studied in order to explain its abnormally high heat flux, bulk dissipation has never been included. The aim of this study is to investigate the role of melt presence on both shear and bulk dissipation, and the consequences for the heat budget and spatial pattern of Io’s tidal heating. Methods. The solid tides of Io are computed using a viscoelastic compressible framework. The constitutive equation including bulk dissipation is derived and a synthetic rheological law for the dependence of the viscous and elastic parameters on the melt fraction is used to account for the softening of a partially molten silicate layer. Results. Bulk dissipation is found to be negligible for melt fraction below a critical value called rheological critical melt fraction. This corresponds to a sharp transition from the solid behavior to the liquid behavior, which typically occurs for melt fractions ranging between 25 and 40%. Above rheological critical melt fraction, bulk dissipation is found to enhance tidal heating up to a factor of ten. The thinner the partially molten layer, the greater the effect. The addition of bulk dissipation also drastically modifies the spatial pattern of tidal dissipation for partially molten layers. Conclusions. Bulk dissipation can significantly affect the heat budget of Io, possibly contributing from 50 to 90% of the global tidal heat power. More generally, bulk dissipation may play a key role in the tidally induced activity of extrasolar lava worlds.

The mechanisms underlying resistance of the Chagas disease parasite, Trypanosoma cruzi, to current therapies are not well understood, including the role of metabolic heterogeneity. We found that limiting exogenous glutamine protects actively dividing amastigotes from ergosterol biosynthesis inhibitors (azoles), independent of parasite growth rate. The antiparasitic properties of azoles are derived from inhibition of lanosterol 14α-demethylase (CYP51) in the endogenous sterol synthesis pathway. We find that carbons from 13C-glutamine feed into amastigote sterols and into metabolic intermediates that accumulate upon CYP51 inhibition. Incorporation of 13C-glutamine into endogenously synthesized sterols is increased with BPTES treatment, an inhibitor of host glutamine metabolism that sensitizes amastigotes to azoles. Similarly, amastigotes are re-sensitized to azoles following addition of metabolites upstream of CYP51, raising the possibility that flux through the sterol synthesis pathway is a determinant of sensitivity to azoles and highlighting the potential role for metabolic heterogeneity in recalcitrant T. cruzi infection.

The mechanisms underlying resistance of the Chagas disease parasite,Trypanosoma cruzi,to current therapies are not well understood, including the potential role of metabolic heterogeneity in modulating susceptibility of intracellular amastigotes to trypanocidal compounds. We found that limiting exogenous glutamine protects actively dividing amastigotes from ergosterol biosynthesis inhibitors (azoles), independent of parasite growth rate. The antiparasitic properties of azoles are derived from inhibition of lanosterol 14α-demethylase (CYP51) in the endogenous sterol synthesis pathway. We find that carbons from13C-glutamine feed into amastigote sterols and into metabolic intermediates that accumulate upon CYP51 inhibition. Consistent with a model that decreased flux through the sterol biosynthetic pathway is protective for intracellular amastigotes exposed to azoles, we find that amastigotes become re-sensitized to azoles following addition of metabolites upstream of CYP51. Our results highlight the potential role of metabolic heterogeneity in recalcitrantT. cruziinfection, an avenue that is currently underexplored.

As a prospective study for a future exploration of Venus, we compute the tidal response of Venus' interior assuming various mantle compositions and temperature profiles representative of different scenarios of Venus' formation and evolution. The mantle density and seismic velocities are modeled from thermodynamical equilibria of mantle minerals and used to predict the moment of inertia, Love numbers and tide-induced phase lag characterizing the signature of the internal structure in the gravity field. The viscoelasticity of the mantle is parameterized using an Andrade rheology. From the models considered here, the moment of inertia lies in the range of 0.327 to 0.342, corresponding to a core radius of 2900 to 3450 km. Viscoelasticity of the mantle strongly increases the potential Love number relative to previously published elastic models. Due to the anelasticity effects, we show that the possibility of a completely solid metal core inside Venus cannot be ruled out based on the available estimate of k2 from the Magellan mission [Konopliv and Yoder, 1996]. A Love number k2 lower than 0.27 would indicate the presence of a fully solid iron core while, for larger values, solutions with an entirely or partially liquid core are possible. Precise determination of the Love numbers, k2 and h2, together with an estimate of the tidal phase lag, are required to determine the state and size of the core, as well as the composition and viscosity of the mantle.

The amount of detected planets with sizes comparable to that of the Earth is increasing drastically. Most of the Earth-size planet candidates orbit at close distances from their central star, and therefore are subjected to large tidal forces. Accurate determination of the tidal parameters of exoplanets taking into account their interior structure and rheology is essential to better constrain their rotational and orbital history, and hence their impact on climate stability and planetary habitability. In the present study, we compute the tidal response of rocky and ice-rich solid exoplanets for masses ranging between 0.1 and 10 Earth masses using a multilayer approach and an Andrade rheology. We show that the amplitude of tidal response, characterized by the gravitational Love number, k2, is mostly controlled by self-gravitation and increases as a function of planet mass. For rocky planets, k2 depends mostly on the relative size of the iron core, and hence on the bulk iron fraction. For ice-rich planets, the presence of outer ice layers reduces the amplitude of tidal response compared to ice-free rocky planets of similar masses. For both types of planet (rocky and ice-rich), we propose relatively simple scaling laws to predict the potential Love number value as a function of radius, planet mass and composition. For the dissipation rate, characterized by the Q−1 factor, we did not find any direct control by the planet mass. The dissipation rate is mostly sensitive to the forcing frequency and to the internal viscosity, which depends on the thermal evolution of the planet, which is in turn controlled by the planet mass and composition. The methodology described in the present study can be applied to any kind of solid planet and can be easily implemented into any thermal and orbital evolution code.

Malaria parasites have a complex life cycle that includes specialized stages for transmission between their mosquito and human hosts. These stages are an understudied part of the lifecycle yet targeting them is an essential component of the effort to shrink the malaria map. The human parasite Plasmodium falciparum is responsible for the majority of deaths due to malaria. Our goal was to generate transgenic P. falciparum lines that could complete the lifecycle and produce fluorescent transmission stages for more in-depth and high-throughput studies. Using zinc-finger nuclease technology to engineer an integration site, we generated three transgenic P. falciparum lines in which tdtomato or gfp were stably integrated into the genome. Expression was driven by either stage-specific peg4 and csp promoters or the constitutive ef1a promoter. Phenotypic characterization of these lines demonstrates that they complete the life cycle with high infection rates and give rise to fluorescent mosquito stages. The transmission stages are sufficiently bright for intra-vital imaging, flow cytometry and scalable screening of chemical inhibitors and inhibitory antibodies.

Resume Introduction Colliger la terminologie concernant les troubles pelvi-perineaux de la femme a partir d’un consensus base sur la pratique clinique est devenu un besoin avere. Methodologie Cet article fait la synthese des travaux des membres et representants elus des Comites de standardisation et de terminologie de deux societes savantes internationales, a savoir l’International Urogynecological Association (IUGA) et l’International Continence Society (ICS). Ces comites etaient assistes par de nombreux relecteurs experts externes. Un vaste processus de relectures internes et externes, au nombre de neuf, a ete mis en place pour etudier en detail chaque definition, les decisions etant prises collectivement (consensus). Prealablement a sa diffusion pour commentaires sur les sites internet de l’ICS et de l’IUGA, le manuscrit a ete soumis a l’examen de cinq experts en kinesitherapie/physiotherapie, neurologie, urologie, urogynecologie et soins infirmiers. Resultats Une terminologie de la prise en charge conservatrice des troubles pelvi-perineaux de la femme a ete constituee, rassemblant plus de 200 definitions. Elle se fonde sur la pratique clinique, avec les symptomes, signes, evaluations, diagnostics et traitements definis les plus courants. Clarte et facilite d’utilisation ont ete les objectifs clefs pour la rendre intelligible aux praticiens et aux stagiaires en formation dans toutes les specialites impliquees dans les troubles pelvi-perineaux de la femme. Des revisions regulieres sont non seulement prevues mais seront necessaires pour garder ce document a jour et acceptable par le plus grand nombre. Conclusion A l’issue du consensus, un rapport a ete elabore sur la terminologie de la prise en charge conservatrice des troubles pelvi-perineaux de la femme afin d’apporter une aide significative pour la pratique clinique et encourager la recherche.

International audience; The Venusian geological features are poorly gravity-resolved, and the state of the core is not well constrained, preventing an understanding of Venus’ cooling history. The EnVision candidate mission to the ESA’s Cosmic Vision Programme consists of a low-altitude orbiter to investigate geological and atmospheric processes. The gravity experiment aboard this mission aims to determine Venus’ geophysical parameters to fully characterize its internal structure. By analyzing the radio-tracking data that will be acquired through daily operations over six Venusian days (four Earth’s years), we will derive a highly accurate gravity field (spatial resolution better than ~170 km), allowing detection of lateral variations of the lithosphere and crust properties beneath most of the geological features. The expected 0.3% error on the Love number k2, 0.1° error on the tidal phase lag and 1.4% error on the moment of inertia are fundamental to constrain the core size and state as well as the mantle viscosity.

With the discovery of TRAPPIST-1 and its seven planets residing within 0.06 au, it is becoming increasingly necessary to carry out correct treatments of tidal interactions. The eccentricity, rotation, and obliquity of the planets of TRAPPIST-1 do indeed result from the tidal evolution over the lifetime of the system. Tidal interactions can also lead to tidal heating in the interior of the planets (as for Io), which may then be responsible for volcanism or surface deformation. In the majority of studies aimed at estimating the rotation of close-in planets or their tidal heating, the planets are considered as homogeneous bodies and their rheology is often taken to be a Maxwell rheology. Here, we investigate the impact of taking into account a multi-layer structure and an Andrade rheology in the way planets dissipate tidal energy as a function of the excitation frequency. We use an internal structure model, which provides the radial profile of structural and rheological quantities (such as density, shear modulus, and viscosity) to compute the tidal response of multi-layered bodies. We then compare the outcome to the dissipation of a homogeneous planet (which only take a uniform value for shear modulus and viscosity). We find that for purely rocky bodies, it is possible to approximate the response of a multi-layer planet by that of a homogeneous planet. However, using average profiles of shear modulus and viscosity to compute the homogeneous planet response leads to an overestimation of the averaged dissipation. We provide fitted values of shear modulus and viscosity that are capable of reproducing the response of various types of rocky planets. However, we find that if the planet has an icy layer, its tidal response can no longer be approximated by a homogeneous body because of the very different properties of the icy layers (in particular, their viscosity), which leads to a second dissipation peak at higher frequencies. We also compute the tidal heating profiles for the outer TRAPPIST-1 planets (e to h).

There has been an increasing need for the terminology for the conservative management of female pelvic floor dysfunction to be collated in a clinically-based consensus report.This report combines the input of members and elected nominees of the Standardization and Terminology Committees of two International Organizations, the International Urogynecological Association (IUGA) and the International Continence Society (ICS), assisted at intervals by many external referees. An extensive process of nine rounds of internal and external review was developed to exhaustively examine each definition, with decision-making by collective opinion (consensus). Before opening up for comments on the webpages of ICS and IUGA, five experts from physiotherapy, neurology, urology, urogynecology and nursing were invited to comment on the paper.A terminology report for the conservative management of female pelvic floor dysfunction, encompassing over 200 separate definitions, has been developed. It is clinically-based with the most common symptoms, signs, assessments, diagnoses and treatments defined. Clarity and user-friendliness have been key aims to make it interpretable by practitioners and trainees in all the different specialty groups involved in female pelvic floor dysfunction. Ongoing review is not only anticipated but will be required to keep the document updated and as widely acceptable as possible.A consensus-based terminology report for the conservative management of female pelvic floor dysfunction has been produced aimed at being a significant aid to clinical practice and a stimulus for research.

Intracellular infection and multi-organ colonization by the protozoan parasite, Trypanosoma cruzi, underlie the complex etiology of human Chagas disease. While T. cruzi can establish cytosolic residence in a broad range of mammalian cell types, the molecular mechanisms governing this process remain poorly understood. Despite the anticipated capacity for fatty acid synthesis in this parasite, recent observations suggest that intracellular T. cruzi amastigotes may rely on host fatty acid metabolism to support infection. To investigate this prediction, it was necessary to establish baseline lipidome information for the mammalian-infective stages of T. cruzi and their mammalian host cells. An unbiased, quantitative mass spectrometric analysis of lipid fractions was performed with the identification of 1079 lipids within 30 classes. From these profiles we deduced that T. cruzi amastigotes maintain an overall lipid identity that is distinguishable from mammalian host cells. A deeper analysis of the fatty acid moiety distributions within each lipid subclass facilitated the high confidence assignment of host- and parasite-like lipid signatures. This analysis unexpectedly revealed a strong host lipid signature in the parasite lipidome, most notably within its glycerolipid fraction. The near complete overlap of fatty acid moiety distributions observed for host and parasite triacylglycerols suggested that T. cruzi amastigotes acquired a significant portion of their lipidome from host triacylglycerol pools. Metabolic tracer studies confirmed long-chain fatty acid scavenging by intracellular T. cruzi amastigotes, a capacity that was significantly diminished in host cells deficient for de novo triacylglycerol synthesis via the diacylglycerol acyltransferases (DGAT1/2). Reduced T. cruzi amastigote proliferation in DGAT1/2-deficient fibroblasts further underscored the importance of parasite coupling to host triacylglycerol pools during the intracellular infection cycle. Thus, our comprehensive lipidomic dataset provides a substantially enhanced view of T. cruzi infection biology highlighting the interplay between host and parasite lipid metabolism with potential bearing on future therapeutic intervention strategies., Author summary The development of human Chagas disease is associated with persistent intracellular infection with the protozoan parasite, Trypanosoma cruzi, which displays tropism for tissues with characteristically high fatty acid flux, such as heart and adipose tissues. Previous studies have highlighted fatty acid metabolism as likely critical to support the growth and survival of this intracellular pathogen, however biochemical data supporting this prediction is currently lacking. Employing an untargeted lipid mass spectrometry approach, we defined the lipidome of intracellular T. cruzi parasites and their mammalian host cells. Comparative analyses revealed that the fatty acid signatures in the triacylglycerol (TG) pools were highly conserved between parasite and host, suggesting a major route of fatty acid acquisition by this pathogen via host TG. Metabolic tracer studies demonstrated intracellular parasite incorporation of exogenous palmitate into both neutral and phospholipid subclasses that was diminished in host cells deficient for TG synthesis. Moreover, parasites grown in these cells displayed reduced proliferation, demonstrating the importance of parasite coupling to host TG pools during the intracellular infection cycle.

Aotus nancymaae, the owl monkey, provides a useful laboratory model for research to develop drugs and vaccines against human falciparum malaria; however, many Plasmodium falciparum parasites are unable to invade A. nancymaae erythrocytes, rendering the parasites noninfective to the monkeys. In previous work, we identified a key polymorphism that determined the inheritance of erythrocyte invasion in a genetic cross of two P. falciparum clones that were virulent (GB4) or noninfective (7G8) to A. nancymaae. This polymorphism, an isoleucine-to-lysine polymorphism at position 204 (I204K) of the GB4 erythrocyte binding protein PfRH5, was nevertheless not found in several other P. falciparum lines that could also invade A. nancymaae erythrocytes. Alternative PfRH5 polymorphisms occur at different positions in these virulent parasites, and additional polymorphisms are found in P. falciparum parasites that cannot infect A. nancymaae. By allelic replacement methods, we have introduced the polymorphisms of these A. nancymaae-virulent or noninfective parasites at codons 204, 347, 358, 362, 410, and 429 of the endogenous PfRH5 gene in the noninfective 7G8 line. 7G8 transformants expressing the polymorphisms of the A. nancymaae-virulent parasites show neuraminidase-sensitive (sialic acid-dependent) invasion into the monkey erythrocytes, whereas 7G8 transformants expressing the PfRH5 alleles of noninfective parasites show little or no invasion of these erythrocytes. Parasites harboring PfRH5 polymorphisms 204K or 204R are also able to invade rat erythrocytes and are differentially sensitive to the removal of surface sialic acids by neuraminidase. These studies offer insights into the PfRH5 receptor-binding domain and interactions that support the invasion of various primate and rodent erythrocytes by P. falciparum.

Summary Sleep consolidates experience-dependent brain plasticity, but the precise cellular mechanisms mediating this process are unknown [1]. De novo cortical protein synthesis is one possible mechanism. In support of this hypothesis, sleep is associated with increased brain protein synthesis [2, 3] and transcription of messenger RNAs (mRNAs) involved in protein synthesis regulation [4, 5]. Protein synthesis in turn is critical for memory consolidation and persistent forms of plasticity in vitro and in vivo [6, 7]. However, it is unknown whether cortical protein synthesis in sleep serves similar functions. We investigated the role of protein synthesis in the sleep-dependent consolidation of a classic form of cortical plasticity in vivo (ocular dominance plasticity, ODP; [8, 9]) in the cat visual cortex. We show that intracortical inhibition of mammalian target of rapamycin (mTOR)-dependent protein synthesis during sleep abolishes consolidation but has no effect on plasticity induced during wakefulness. Sleep also promotes phosphorylation of protein synthesis regulators (i.e., 4E-BP1 and eEF2) and the translation (but not transcription) of key plasticity related mRNAs ( ARC and BDNF ). These findings show that sleep promotes cortical mRNA translation. Interruption of this process has functional consequences, because it abolishes the consolidation of experience in the cortex.

SUMMARY In the absence of seismological measurements, observations of the topography and gravity fields of solid planets are the primary constraints on their internal structure. To compute the synthetic geoid and topography induced by the dynamics of planetary interiors, we introduce a 3-D numerical tool describing mantle convection beneath an elastic lithosphere. Although the energy conservation is treated in the whole spherical domain, the deformation aspect is solved using a hybrid technique (finite volume method for the viscous flow, spectral method for elastic deformation). The mechanical coupling is achieved via the imposition of the traction at the surface of the viscous flow as a basal boundary condition for the elastic deformation. We present both response functions and full thermal convection cases computed with our new method for planetary bodies of varying dimensions: the filtering effect of the lithosphere on the dynamic topography and geoid is specific for each planetary body, justifying the importance of such a tool. Furthermore, since our approach specifically focuses on the mechanical coupling at the base of the lithosphere, it will permit future, more elaborate, rheological treatments. It also enables to discriminate between the radial and tangential components of the viscous traction. The latter is found to have a significant influence on the elastic deformation. The effect on geoid is prominent. More specifically, while a thin elastic lithosphere is usually considered to play little role on the dynamic topography and geoid of Venus, a ∼35 per cent reduction is obtained for geoid height in the numerical example we propose. On a planet with thicker elastic lithosphere such as Mars, the consequence of this filtering effect is to rule out the possibility of a dynamical support for the Tharsis Rise, even for the lowest admissible values of elastic thickness in this region.

Several lines of evidence suggest that suicide may have, in part, a genetic predisposition. In this study, we identified a family with high rates of suicidal behavior and assessed brain gene expression levels in the proband. A neuronally-expressed solute carrier for glutamine (Sodium-coupled neutral amino acid transporter 1 (SNAT1), also known as solute carrier family 38, member 1 (SLC38A1)) was identified as severely decreased across all brain regions. Follow-up analysis by semi-quantitative polymerase chain reaction (qPCR) and Western blot confirmed the reduction of SNAT1. We categorized the SNAT1 gene in human brain, cloned the gene promoter and assessed in silico the expression pattern of SNAT1 in >25 tissues from human. Complete DNA sequencing of the SNAT1 gene was performed in the family and 276 controls. The family was homozygous for rare alleles which suggests a possible association between low expression of SNAT1 and suicidal behavior.

T-type voltage-dependent calcium channels may play an important role in synaptic plasticity, but lack of specific antagonists has hampered investigation into this possible function. We investigated the role of the T-type channel in a canonical model of in-vivo cortical plasticity triggered by monocular deprivation. We identified a compound (TTA-I1) with subnanomolar potency in standard voltage clamp assays and high selectivity for the T-type channel. When infused intracortically, TTA-I1 reduced cortical plasticity triggered by monocular deprivation while preserving normal visual response properties. These results show that the T-type calcium channel plays a central role in cortical plasticity.

SummarySleep is thought to consolidate changes in synaptic strength, but the underlying mechanisms are unknown. We investigated the cellular events involved in this process during ocular dominance plasticity (ODP)—a canonical form of in vivo cortical plasticity triggered by monocular deprivation (MD) and consolidated by sleep via undetermined, activity-dependent mechanisms. We find that sleep consolidates ODP primarily by strengthening cortical responses to nondeprived eye stimulation. Consolidation is inhibited by reversible, intracortical antagonism of NMDA receptors (NMDARs) or cAMP-dependent protein kinase (PKA) during post-MD sleep. Consolidation is also associated with sleep-dependent increases in the activity of remodeling neurons and in the phosphorylation of proteins required for potentiation of glutamatergic synapses. These findings demonstrate that synaptic strengthening via NMDAR and PKA activity is a key step in sleep-dependent consolidation of ODP.