Sexually Dimorphic Serotonergic Dysfunction in a Mouse Model of Huntington's Disease and Depression

Depression is the most common psychiatric disorder in Huntington's disease (HD) patients. In the general population, women are more prone to develop depression and such susceptibility might be related to serotonergic dysregulation. There is yet to be a study of sexual dimorphism in the development and presentation of depression in HD patients. We investigated whether 8-week-old male and female R6/1 transgenic HD mice display depressive-like endophenotypes associated with serotonergic impairments. We also studied the behavioral effects of acute treatment with sertraline. We found that only female HD mice exhibited a decreased preference for saccharin as well as impaired emotionality-related behaviors when assessed on the novelty-suppressed feeding test (NSFT) and the forced-swimming test (FST). The exaggerated immobility time displayed by female HD in the FST was reduced by acute administration of sertraline. We also report an increased response to the 5-HT1A receptor agonist 8-OH-DPAT in inducing hypothermia and a decreased 5-HT2A receptor function in HD animals. While tissue levels of serotonin were reduced in both male and female HD mice, we found that serotonin concentration and hydroxylase-2 (TPH2) mRNA levels were higher in the hippocampus of males compared to female animals. Finally, the antidepressant-like effects of sertraline in the FST were blunted in male HD animals. This study reveals sex-specific depressive-related behaviors during an early stage of HD prior to any cognitive and motor deficits. Our data suggest a crucial role for disrupted serotonin signaling in mediating the sexually dimorphic depression-like phenotype in HD mice

Regulation of immunity during visceral Leishmania infection

Unicellular eukaryotes of the genus Leishmania are collectively responsible for a heterogeneous group of diseases known as leishmaniasis. The visceral form of leishmaniasis, caused by L. donovani or L. infantum, is a devastating condition, claiming 20,000 to 40,000 lives annually, with particular incidence in some of the poorest regions of the world. Immunity to Leishmania depends on the development of protective type I immune responses capable of activating infected phagocytes to kill intracellular amastigotes. However, despite the induction of protective responses, disease progresses due to a multitude of factors that impede an optimal response. These include the action of suppressive cytokines, exhaustion of specific T cells, loss of lymphoid tissue architecture and a defective humoral response. We will review how these responses are orchestrated during the course of infection, including both early and chronic stages, focusing on the spleen and the liver, which are the main target organs of visceral Leishmania in the host. A comprehensive understanding of the immune events that occur during visceral Leishmania infection is crucial for the implementation of immunotherapeutic approaches that complement the current anti-Leishmania chemotherapy and the development of effective vaccines to prevent disease.The research leading to these results has received funding from the European Community’s Seventh Framework Programme under grant agreement No.602773 (Project KINDRED). VR is supported by a post-doctoral fellowship granted by the KINDReD consortium. RS thanks the Foundation for Science and Technology (FCT) for an Investigator Grant (IF/00021/2014). This work was supported by grants to JE from ANR (LEISH-APO, France), Partenariat Hubert Curien (PHC) (program Volubilis, MA/11/262). JE acknowledges the support of the Canada Research Chair Program

Assessing the environmental impact of integrated inventory and warehouse management

There has been considerable research on the environmental impact of supply chains but most of this has concentrated on the transport elements. The environmental impact of warehousing has received relatively little attention except within the context of distribution networks. A high proportion of total warehouse emissions emanate from heating, cooling, air conditioning and lighting and these aspects are largely related to warehouse size. This in turn is greatly influenced by inventory management, affecting stockholding levels, and warehouse design, affecting the footprint required for holding a given amount of stock. Other emissions, such as those caused by material handling equipment, are closely related to warehouse throughput and equipment choice. There is a substantial gap in the literature regarding this interaction between inventory and warehouse management and its environmental impact. The purpose of this paper is to contribute to filling this gap. Therefore, an integrated simulation model has been built to examine this interaction and the results highlight the key effects of inventory management on warehouse-related greenhouse gas emissions. In particular, it is found that decisions on supply lead times, reorder quantities, and storage equipment all have an impact on costs and emissions and therefore this integrated approach will inform practical decision making. Additionally, it is intended that the paper provides a framework for further research in this important area

Guidelines for assessment of gait and reference values for spatiotemporal gait parameters in older adults: The biomathics and canadian gait consortiums initiative

Abstract: Background: Gait disorders, a highly prevalent condition in older adults, are associated with several adverse health consequences. Gait analysis allows qualitative and quantitative assessments of gait that improves the understanding of mechanisms of gait disorders and the choice of interventions. This manuscript aims (1) to give consensus guidance for clinical and spatiotemporal gait analysis based on the recorded footfalls in older adults aged 65 years and over, and (2) to provide reference values for spatiotemporal gait parameters based on the recorded footfalls in healthy older adults free of cognitive impairment and multi-morbidities.Methods: International experts working in a network of two different consortiums (i.e., Biomathics and Canadian Gait Consortium) participated in this initiative. First, they identified items of standardized information following the usual procedure of formulation of consensus findings. Second, they merged databases including spatiotemporal gait assessments with GAITRite® system and clinical information from the “Gait, cOgnitiOn & Decline” (GOOD) initiative and the Generation 100 (Gen 100) study. Only healthy—free of cognitive impairment and multi-morbidities (i.e., ≤ 3 therapeutics taken daily)—participants aged 65 and older were selected. Age, sex, body mass index, mean values, and coefficients of variation (CoV) of gait parameters were used for the analyses. Results: Standardized systematic assessment of three categories of items, which were demographics and clinical information, and gait characteristics (clinical and spatiotemporal gait analysis based on the recorded footfalls), were selected for the proposed guidelines. Two complementary sets of items were distinguished: a minimal data set and a full data set. In addition, a total of 954 participants (mean age 72.8 ± 4.8 years, 45.8% women) were recruited to establish the reference values. Performance of spatiotemporal gait parameters based on the recorded footfalls declined with increasing age (mean values and CoV) and demonstrated sex differences (mean values). Conclusions: Based on an international multicenter collaboration, we propose consensus guidelines for gait assessment and spatiotemporal gait analysis based on the recorded footfalls, and reference values for healthy older adults

Les fibroblastes associés au cancer stimulent la résistance des cellules cancéreuses face aux traitements

Les patients atteints d'un cancer du rectum localement avancé reçoivent généralement une chimioradiothérapie à base de 5-FU et de radiation. Cependant, seulement 10 à 30 % d'entre eux obtiennent une réponse complète au traitement avec une excellente survie à long terme. En plus de la résistance inhérente des cellules cancéreuses au traitement, le microenvironnement de la tumeur semble jouer un rôle crucial dans a réponse tumorale. Les fibroblastes associés au cancer (CAFs), les cellules non cancéreuses prédominantes dans le cadre de la tumeur, sont organisés autour des cellules cancéruses et, avec la matrice extracellulaire (MEC) qu'ils produisent, forment une "capsule" autour de la tumeur. Nos études récentes indiquent que ces CAFs exercent des forces de compression sur les cellules cancéreuses, ce qui nous amène à émettre l'hypothèse que cette pression pourrait moduler la réponse des cellules cancéreuses au traitement.Pour étudier cela, nous avons développé un modèle de culture cellulaire en 3D mimant l'architecture tumorale, constitué de sphères tumorales englobées par dans du collagène I, peuplées de CAFs. De manière intéressante, nous avons découvert que la présence physique des CAFs augmentait la résistance des cellules tumorales au 5-FU, tandis que les molécules sécrétées par les CAFs avaient un impact limité. En utilisant des billes de polyacrylamide (billes PAA) comme substitut de forces de compression dans la même matrice de collagène 3D, nous avons constaté que les billes se réduisaient, suggérant une compression induite par les CAFs.En creusant davantage l'interaction entre les CAFs et les sphères tumorales, nous avons constaté que les CAFs se disposaient de manière similaire à ce qui est observé dans les échantillons de tumeurs réels, créant une structure de type capsule à la périphérie de la tumeur. En incorporant des billes PAA dans notre modèle et en inhibant la contractilité des CAFs, nous avons noté une réduction de la compression, laissant entendre un rôle actif des CAFs dans l'exercice de la pression. Nous avons étendu nos découvertes en traitant les sphères tumorales en présence de CAFs dont la capacité contractile de la myosine-IIA avait été réduite. De manière remarquable, la réduction de la capacité contractile des CAFs a restauré la sensibilité des cellules tumorales au 5-FU, mettant en évidence le rôle de la compression active induite par les CAFs dans la résistance au traitement.Pour tester si la pression est une cause directe de la résistance aux médicaments, nous avons comprimé des sphères cancéreuses en utilisant du dextran de poids moléculaire élevé en l'absence de CAFs. De manière intéressante, cette compression passive n'a pas modifié les niveaux de résistance des cellules tumorales. Ainsi, un puzzle est apparu : la compression statique via le dextran n'a pas conféré de résistance, tandis que la compression active par les CAFs est impliquée. Nous avons émis alors l'hypothèse que la différence réside dans la nature dynamique et cyclique de la compression induite par les CAFs. Pour confirmer cela, nous avons observé que les CAFs contractaient de manière dynamique le collagène-I, comme en témoigne leurs effets sur des piliers en PDMS. Nous avons conclu que la compression cyclique et oscillatoire exercée par les CAF pourrait être le facteur clé favorisant la résistance au traitement.Patients with locally advanced rectal cancer typically receive chemoradiotherapy involving 5-FU and radiation. However, only 10-30% achieve a complete response with excellent long-term survival. Aside from the cancer cells' inherent resistance to treatment, the tumor microenvironment seems to play a crucial role in treatment outcomes. Cancer-associated fibroblasts (CAFs), the predominant non-cancer cells in the tumor setting, align themselves along the edges of the tumor, and together with the extracellular matrix (ECM) they produce, they form a 'capsule' around the tumor. Our recent studies indicate that these CAFs exert compression forces on cancer cells, leading us to hypothesize that this pressure could modulate how cancer cells respond to therapy.To investigate this, we developed a 3D cell culture model mimicking tumor architecture, consisting of tumor spheres embedded in collagen I, populated with CAFs. Interestingly, we discovered that the physical presence of CAFs increased the tumor cells' resistance to 5-FU, while molecules secreted by CAFs had a minimal impact. Using polyacrylamide beads (PAA-beads) as a proxy for compressive forces in the same 3D collagen matrix, we found that the beads shrunk, suggesting CAF-induced compression.Further probing into the interaction between CAFs and tumor spheres revealed that CAFs align similarly to what is seen in actual tumor samples, creating a capsule-like structure around the tumor periphery. By incorporating PAA beads in our model and inhibiting CAF contractility, we noted reduced compression, hinting at an active role of CAFs in exerting pressure. We extended our findings by treating tumor spheres in the presence of Myosin-IIA-depleted CAFs. Remarkably, reducing CAF contractile ability restored the tumor cells' sensitivity to 5-FU, underscoring the role of active CAF-induced compression in therapy resistance. To test if pressure is a direct cause of drug resistance, we compressed cancer spheres using high molecular weight dextran in the absence of CAFs. Interestingly, this passive compression didn't alter the tumor cells' resistance levels. Thus, a puzzle emerged: static compression via dextran didn't confer resistance, whereas active compression by CAFs did. We hypothesized that the difference lies in the dynamic, cyclic nature of CAF-induced compression. Confirming this, we observed that CAFs contract collagen-I dynamically, as evidenced by their effect on PDMS pillars. We concluded that the cyclic, oscillatory compression exerted by CAFs may be the key factor in promoting treatment resistance

From finance to fascism: the real effect of Germany's 1931 banking crisis

Do financial crises radicalize voters? We study Germany's banking crisis of 1931, when two major banks collapsed and voting for radical parties soared. We collect new data on bank branches and firm-bank connections of 5,610 firms. Incomes plummeted in cities affected by the bank failures; connected firms curtailed payrolls. Nazi votes surged in locations exposed to Danatbank, led by a Jewish manager - but not in those suffering from the other bank's failure. Unobservables or pretrends do not explain the results. Danatbank's collapse boosted Nazi support, especially in cities with deep-seated anti-Semitism, suggesting a synergy between cultural and economic channels

Driving force for the hydration of the swelling clays: Case of montmorillonites saturated with alkaline-earth cations

International audienceImportant structural modifications occur in swelling clays upon water adsorption. The multi-scale evolution of the swelling clay structure is usually evidenced by various experimental techniques. However, the driving force behind such phenomena is still not thoroughly understood. It appears strongly dependent on the nature of the interlayer cation. In the case of montmorillonites saturated with alkaline cations, it was inferred that the compensating cation or the layer surface could control the hydration process and thus the opening of the interlayer space, depending on the nature of the interlayer cation. In the present study, emphasis is put on the impact of divalent alkaline-earth cations compensating the layer charge in montmorillonites. Since no experimental technique offers the possibility of directly determining the hydration contributions related to interlayer cations and layer surfaces, an approach based on the combination of electrostatic calculations and immersion data is developed here, as already validated in the case of montmorillonites saturated by alkaline cations. This methodology allows to estimate the hydration energy for divalent interlayer cations and therefore to shed a new light on the driving force for hydration process occurring in montmorillonites saturated with alkaline-earth cations. Firstly, the surface energy values obtained from the electrostatic calculations based on the Electronegativity Equalization Method vary from 450 mJ m−2 for Mg-montmorillonite to 1100 mJ m−2 for Ba-montmorillonite. Secondly, considering both the hydration energy for cations and layer surfaces, the driving force for the hydration of alkaline-earth saturated montmorillonites can be attributed to the interlayer cation in the case of Mg-, Ca-, Sr-montmorillonites and to the interlayer surface in the case of Ba-montmorillonites. These results explain the differences in behaviour upon water adsorption as a function of the nature of the interlayer cation, thereby allowing the macroscopic swelling trends to be better understood. The knowledge of hydration processes occurring in homoionic montmorillonites saturated with both the alkaline and the alkaline-earth cations may be of great importance to explain the behaviour of natural clay samples where mixtures of the two types of interlayer cation are present and also provides valuable information on the cation exchange occurring in the swelling clays

Multimodal MR-imaging reveals large-scale structural and functional connectivity changes in profound early blindness

In the setting of profound ocular blindness, numerous lines of evidence demonstrate the existence of dramatic anatomical and functional changes within the brain. However, previous studies based on a variety of distinct measures have often provided inconsistent findings. To help reconcile this issue, we used a multimodal magnetic resonance (MR)-based imaging approach to provide complementary structural and functional information regarding this neuroplastic reorganization. This included gray matter structural morphometry, high angular resolution diffusion imaging (HARDI) of white matter connectivity and integrity, and resting state functional connectivity MRI (rsfcMRI) analysis. When comparing the brains of early blind individuals to sighted controls, we found evidence of co-occurring decreases in cortical volume and cortical thickness within visual processing areas of the occipital and temporal cortices respectively. Increases in cortical volume in the early blind were evident within regions of parietal cortex. Investigating white matter connections using HARDI revealed patterns of increased and decreased connectivity when comparing both groups. In the blind, increased white matter connectivity (indexed by increased fiber number) was predominantly left-lateralized, including between frontal and temporal areas implicated with language processing. Decreases in structural connectivity were evident involving frontal and somatosensory regions as well as between occipital and cingulate cortices. Differences in white matter integrity (as indexed by quantitative anisotropy, or QA) were also in general agreement with observed pattern changes in the number of white matter fibers. Analysis of resting state sequences showed evidence of both increased and decreased functional connectivity in the blind compared to sighted controls. Specifically, increased connectivity was evident between temporal and inferior frontal areas. Decreases in functional connectivity were observed between occipital and frontal and somatosensory-motor areas and between temporal (mainly fusiform and parahippocampus) and parietal, frontal, and other temporal areas. Correlations in white matter connectivity and functional connectivity observed between early blind and sighted controls showed an overall high degree of association. However, comparing the relative changes in white matter and functional connectivity between early blind and sighted controls did not show a significant correlation. In summary,these findings provide complimentary evidence, as well as highlight potential contradictions,regarding the nature of regional and large scale neuroplastic reorganization resulting from early onset blindness