Search

Abstract Background In April 2017, Suriname’s Ministry of Health alerted French Guiana’s Regional Health Agency (RHA) about an increase of imported malaria cases among people coming from an illegal gold mining site called Sophie, in French Guiana, a French overseas territory located in the Amazonian forest. Methods Due to safety issues and the remoteness of Sophie, the RHA requested the collaboration of the French Armed Forces for the epidemiological investigation. A medical unit, and six soldiers to ensure the security of the mission, were transported by helicopter. Results During the investigation, two malaria episodes were diagnosed among 46 persons. Twenty-six of them were from Sophie, where PCR-Plasmodium prevalence was estimated at 60% (15/26). This result was concordant with previous studies revealing high malaria endemicity in the gold miner population. The increase of imported cases in Suriname may have resulted from decreased access to under-the-counter anti-malarials and increased migration of gold miners to Suriname following a decline of the profitability of gold mining in a context of increased repression against illegal mining by the French army. Conclusion This investigation of a suspicious malaria epidemic confirms the importance of malaria among illegal gold miners. Their mobility along the Guiana Shield and their health-seeking behaviour are likely to spread malaria in populations for which significant efforts are undertaken to fight against this disease. Fighting malaria in this population remains more relevant than ever. A pilot study (Malakit project) is currently in progress to evaluate the efficacy of kits for self-diagnosis and self-treatment.

Following bi-parietal lesions patient AT showed a severe inability to relocate her attention within a visual field which perimetry proved to be near-normal. An experimental approach with tasks testing visuo-spatial attention demonstrated a shrinkage of A.T.’s attentional visual field. With her visual attention narrowed to a kind of functional tunnel vision, the patient exhibited simultanagnosia (Wolpert, 1924), a symptom previously described in 1909 by Balint under the label of Psychic paralysis of “Gaze”. In striking contrast AT showed an efficient and effortless perception of complex natural scenes, which, according to recent work in normal subjects, necessitate few if any attentional resources.

BACKGROUND: Efflux systems are involved in multidrug resistance in most Gram-negative non-fermentative bacteria. We have chosen Burkholderia thailandensis to dissect the development of multidrug resistance phenotypes under antibiotic pressure. METHODOLOGY/PRINCIPAL FINDINGS: We used doxycycline selection to obtain several resistant B. thailandensis variants. The minimal inhibitory concentrations of a large panel of structurally unrelated antibiotics were determined ± the efflux pump inhibitor phenylalanine-arginine ß-naphthylamide (PAßN). Membrane proteins were identified by proteomic method and the expressions of major efflux pumps in the doxycycline selected variants were compared to those of the parental strains by a quantitative RT-PCR analysis. Doxycycline selected variants showed a multidrug resistance in two major levels corresponding to the overproduction of two efflux pumps depending on its concentration: AmrAB-OprA and BpeEF-OprC. The study of two mutants, each lacking one of these pumps, indicated that a third pump, BpeAB-OprB, could substitute for the defective pump. Surprisingly, we observed antagonistic effects between PAßN and aminoglycosides or some ß-lactams. PAßN induced the overexpression of AmrAB-OprA and BpeAB-OprB pump genes, generating this unexpected effect. CONCLUSIONS/SIGNIFICANCE: These results may account for the weak activity of PAßN in some Gram-negative species. We clearly demonstrated two antagonistic effects of this molecule on bacterial cells: the blocking of antibiotic efflux and an increase in efflux pump gene expression. Thus, doxycycline is a very efficient RND efflux pump inducer and PAßN may promote the production of some efflux pumps. These results should be taken into account when considering antibiotic treatments and in future studies on efflux pump inhibitors.

IntroductionOral Squamous Cell Carcinomas (OSCC) are mostly related to tobacco consumption eventually associated to alcohol (Smoker/Drinker patients: SD), but 25-30% of the patients have no identified risk factors (Non-Smoker/Non-Drinker patients: NSND). We hypothesized that these patients have distinguishable immune profiles that could be useful for prognosis.Materials and MethodsCells present in immune tumor microenvironment (TME) and blood from 87 OSCC HPV-negative patients were analyzed using a multiparameter flow cytometry assay, in a prospective case-control study. Cytokine levels in tumor supernatants and blood were determined by a cytometric bead array (CBA) assay.ResultsNormal gingiva and blood from healthy donors (HD) were used as controls. A significant increase of granulocytes (p

BackgroundIndividuals affected by the post-covid condition (PCC) show an increased fatigue and the so-called post-exertion malaise (PEM) that led health professionals to advise against exercise although accumulating evidence indicates the contrary. The goal of this study is to determine the impact of a closely monitored 8-week mixed exercise program on physical capacity, symptoms, fatigue, systemic oxidative stress and plasma proteomic profiles of PCC cases.MethodsTwenty-five women and men with PCC were assigned sequentially to exercise (n = 15) and non-exercise (n = 10) groups. Individuals with no PCC served as a control group. The exercise program included cardiovascular and resistance exercises. Physical capacity, physical activity level and the presence of common PCC symptoms were measured before and after the intervention. Fatigue was measured the day following each exercise session. Plasma and PBMC samples were collected at the beginning and end of the training program. Glutathione and deoxyguanosine levels in PBMC and plasma proteomic profiles were evaluated.ResultsBicep Curl (+15% vs 4%; p = 0.040) and Sit-to-Stand test (STS-30 (+31% vs +11%; p = 0.043)) showed improvement in the exercise group when compared to the non-exercise group. An interaction effect was also observed for the level of physical activity (p =0.007) with a positive effect of the program on their daily functioning and without any adverse effects on general or post-effort fatigue. After exercise, glutathione levels in PBMCs increased in women but remained unchanged in men. Discernable changes were observed in the plasma proteomics profile with certain proteins involved in inflammatory response decreasing in the exercise group.ConclusionsSupervised exercise adapted to the level of fatigue and ability is safe and effective in PCC patients in improving their general physical capacity and wellbeing. Systemic molecular markers that accompany physical improvement can be monitored by analyzing plasma proteomics and markers of oxidative stress. Large-scale studies will help identify promising molecular markers to objectively monitor patient improvement.

Introduction Social determinants of health, such as living and working conditions, economical and environmental context and access to care, combine to impact the health of individuals and communities. In French Guiana (FG), the persons working in informal artisanal and small-scale gold mining in the rainforest are a particularly vulnerable population which lives in precarious conditions and far from the health system. Previous studies have demonstrated their high morbidity due to infectious diseases. This study aims to describe the social determinants of health in this specific population.Methods This international multicentre cross-sectional survey included people working on the informal FG gold mines at the crossing points located at both borders with Suriname and Brazil. After collecting written informed consent, a structured questionnaire was administered.Results From September to December 2022, 539 gold miners were included. These poorly educated migrants, mainly from Brazil (99.1%) did not have access to drinkable water (95.4%), lived in close contact with wild fauna by hunting, eating bushmeat or being bitten and were exposed to mercury by inhalation (58.8%) or ingestion (80.5%). They report frequent accidents (13.5%) and chronic treatment interruptions (26.6% of the 11.9% reporting chronic treatment). Half of them considered themselves in good health (56.4%).Conclusion This study shows a singular combination of adverse exposures of gold miners working in FG such as zoonoses, heavy metal poisoning, aggression of wild fauna. For ethical as well as public health reasons, actions towards health equity must be considered at different levels: individual, community, environmental, systemic and global level. As end users of minerals, we must assume our responsibilities for the well-being of the extractors by including health in political decisions to engage together in global health.Trial registration number NCT05540470.

Contrary to the common view of an ever more crowded planet, sparsely populated areas still account for a very sizable portion of the Earth. Their importance can be approached as an objective reality by figures and databases, but can also be shown by studying the mental representations that are associated with them and that seem quite universal, pointing out a number of salient features regardless of the geographical context. In order to prove this point, this paper proposes a synthesis about the place of sparsely populated areas across the world. Our first approach is to look at their reality using figures and databases, which allows to demonstrate that more than two third of the World is populated by less than one percent of the global population. We then show how sparsely populated areas are in the middle of many geographical debates, especially those around the concepts of periphery, margin or fringes. Using these elements, we explore five features which define these areas and the life of the people living in them.

Inflammatory bowel disease (IBD) flare-ups exhibit symptoms that are similar to other diseases and conditions, making diagnosis and treatment complicated. Currently, the gold standard for diagnosing and monitoring IBD is colonoscopy and biopsy, which are invasive and uncomfortable procedures, and the fecal calprotectin test, which is not sufficiently accurate. Therefore, it is necessary to develop an alternative method. In this study, our aim was to provide proof of concept for the application of Sequential Window Acquisition of All Theoretical Mass Spectra-Mass spectrometry (SWATH-MS) and machine learning to develop a non-invasive and accurate predictive model using the stool proteome to distinguish between active IBD patients and symptomatic non-IBD patients. Proteome profiles of 123 samples were obtained and data processing procedures were optimized to select an appropriate pipeline. The differentially abundant analysis identified 48 proteins. Utilizing correlation-based feature selection (Cfs), 7 proteins were selected for proceeding steps. To identify the most appropriate predictive machine learning model, five of the most popular methods, including support vector machines (SVMs), random forests, logistic regression, naive Bayes, and k-nearest neighbors (KNN), were assessed. The generated model was validated by implementing the algorithm on 45 prospective unseen datasets; the results showed a sensitivity of 96% and a specificity of 76%, indicating its performance. In conclusion, this study illustrates the effectiveness of utilizing the stool proteome obtained through SWATH-MS in accurately diagnosing active IBD via a machine learning model.

Sparsely populated areas are often characterized by incomplete territorial control by governments. This creates opportunities for informal and/or illegal activities, which can lead to the economic exploitation of the territories, paving the way for political domination or territorial conquest. Although these activities may not be officially recognized or accepted, they play a significant role in the symbolic, material, and economic construction of sparsely populated territories. This paper examines the case of informal gold mining in the interior of French Guiana, an overseas territory of France, through this perspective. Based on a detailed analysis of the interplay between formal territorial control by the government and informal exploration of natural resources by wildcat actors, it highlights the ways in which informal activities can shape the development and governance of these territories.

Abstract Radio-chemotherapy with 5-flu orouracil (5-FU) is the standard of care treatment for patients with colorectal cancer, but it is only effective for a third of them. Despite our understanding of the mechanism of action of 5-FU, drug resistance remains a significant limitation to the clinical use of 5-FU, as both intrinsic and acquired chemoresistance represents the major obstacles for the success of 5-FU-based chemotherapy. In order to identify the mechanism of acquired resistance, 5-FU chemoresistance was induced in CRC cell lines by passaging cells with increasing concentrations of 5-FU. To study global molecular changes, quantitative proteomics and transcriptomics analyses were performed on these cell lines, comparing the resistant cells as well as the effect of chemo and radiotherapy. Interestingly, a very high proportion of downregulated genes were annotated as transcription factors coding for Krüppel-associated box (KRAB) domain-containing zinc-finger proteins (KZFPs), the largest family of transcriptional repressors. Among nearly 350 KRAB-ZFPs, almost a quarter were downregulated after the induction of a 5-FU-resistance including a common one between the three CRC cell lines, ZNF649, whose role is still unknown. To confirm the observations of the proteomic and transcriptomic approaches, the abundance of 20 different KZFPs and control mRNAs was validated by RT-qPCR. In fact, several KZFPs were no longer detectable using qPCR in cell lines resistant to 5-FU, and the KZFPs that were downregulated only in one or two cell lines showed similar pattern of expression as measured by the omics approaches. This proteomic, transcriptomic and genomic analysis of intrinsic and acquired resistance highlights a possible new mechanism involved in the cellular adaptation to 5-FU and therefore identifies potential new therapeutic targets to overcome this resistance.

The unexpected fall of deforestation in the Brazilian Amazon in 2022 has shown that deforestation phenomena are complex and that for many observers it is difficult to find their way in statistics and geospatial databases that are produced using different methodologies and distinct definitions of what deforestation is and considering in diverging ways various types of environmental damages. In this context, this paper attempts to replace recent figures in a broader context spatially (considering the whole Amazon region beyond Brazil), temporally (looking at the phenomena since the 1980s) and thematically (presenting several sources of data). To do so, we first present the data that are available to the public about deforestation, distinguishing their (sometimes apparently contradictory) characteristics and underlining the Amazon’s inherent ecological and geographical complexity. In a second part, we describe the history of deforestation since 1985, first at the level of the whole basin (or pan-Amazonia) and then focusing on the Brazilian Amazon. Last, as to complete our panorama of the question of deforestation, we present quickly the causes of deforestation and the principal policies of the governments to face it, as well as the consequences of deforestation at the local, regional and global scales.

Artisanal small-scale gold mining, or garimpo in Portuguese, started in French Guiana in the 1990s. The French authorities have repressed it, but this has not led to the end of the activity. Based on extensive fieldwork, this paper aims to analyze the garimpo as an economic and social informal world built to be resilient to repression and to neutralize the high risks of clandestine exploitation. This system provides economic, social, and moral resources, all embodied in the garimpeiro identity, allowing a workforce made of thousands of individuals to act as a cohesive work organization. Resumen: Resiliencia de los mineros de oro ilegales brasileños en la Guayana Francesa: El garimpo como sistema económico y social La minería de oro artesanal a pequeña escala, o garimpo en portugués, comenzó en la Guayana Francesa en la década de 1990. Las autoridades francesas lo han reprimido, pero no ha supuesto el fin de la actividad. Basado en un extenso trabajo de campo, este artículo tiene como objetivo analizar al garimpo como un mundo económico y social informal construido para ser resistente a la represión y neutralizar los altos riesgos de la explotación clandestina. Este sistema proporciona recursos económicos, sociales y morales, todos encarnados en la identidad garimpeiro, permitiendo que una fuerza de trabajo compuesta por miles de indivi-duos actúe como una organización de trabajo cohesiva.

Helix-destabilizing DNA lesions induced by environmental mutagens such as UV light cause genomic instability by strongly blocking the progression of DNA replication forks (RFs). At blocked RF, single-stranded DNA (ssDNA) accumulates and is rapidly bound by Replication Protein A (RPA) complexes. Such stretches of RPA-ssDNA constitute platforms for recruitment/activation of critical factors that promote DNA synthesis restart. However, during periods of severe replicative stress, RPA availability may become limiting due to inordinate sequestration of this multifunctional complex on ssDNA, thereby negatively impacting multiple vital RPA-dependent processes. Here, we performed a genome-wide screen to identify factors that restrict the accumulation of RPA-ssDNA during UV-induced replicative stress. While this approach revealed some expected "hits" acting in pathways such as nucleotide excision repair, translesion DNA synthesis, and the intra-S phase checkpoint, it also identified SCAI, whose role in the replicative stress response was previously unappreciated. Upon UV exposure, SCAI knock-down caused elevated accumulation of RPA-ssDNA during S phase, accompanied by reduced cell survival and compromised RF progression. These effects were independent of the previously reported role of SCAI in 53BP1-dependent DNA double-strand break repair. We also found that SCAI is recruited to UV-damaged chromatin and that its depletion promotes nascent DNA degradation at stalled RF. Finally, we (i) provide evidence that EXO1 is the major nuclease underlying ssDNA formation and DNA replication defects in SCAI knockout cells and, consistent with this, (ii) demonstrate that SCAI inhibits EXO1 activity on a ssDNA gap in vitro. Taken together, our data establish SCAI as a novel regulator of the UV-induced replicative stress response in human cells.

The eukaryotic CDC45/MCM2-7/GINS (CMG) helicase unwinds the DNA double helix during DNA replication. The GINS subcomplex is required for helicase activity and is, therefore, essential for DNA replication and cell viability. Here, we report the identification of 7 individuals from 5 unrelated families presenting with a Meier-Gorlin syndrome–like (MGS-like) phenotype associated with hypomorphic variants of GINS3, a gene not previously associated with this syndrome. We found that MGS-associated GINS3 variants affecting aspartic acid 24 (D24) compromised cell proliferation and caused accumulation of cells in S phase. These variants shortened the protein half-life, altered key protein interactions at the replisome, and negatively influenced DNA replication fork progression. Yeast expressing MGS-associated variants of PSF3 (the yeast GINS3 ortholog) also displayed impaired growth, S phase progression defects, and decreased Psf3 protein stability. We further showed that mouse embryos homozygous for a D24 variant presented intrauterine growth retardation and did not survive to birth, and that fibroblasts derived from these embryos displayed accelerated cellular senescence. Taken together, our findings implicate GINS3 in the pathogenesis of MGS and support the notion that hypomorphic variants identified in this gene impaired cell and organismal growth by compromising DNA replication.

Ubiquitin pseudogenes are present in many organisms but whether they encode functional proteins has remained unclear. Here, the authors show that human UBB pseudogene 4 produces ubiquitin variants with amino acid compositions and cellular functions that are distinct from canonical ubiquitin.

During aging, changes in gene expression are associated with a decline in physical and cognitive abilities. Here, we investigate the connection between changes in mRNA and protein expression in the brain by comparing the transcriptome and proteome of the mouse cortex during aging. Our transcriptomic analysis revealed that aging mainly triggers gene activation in the cortex. We showed that an increase in mRNA expression correlates with protein expression, specifically in the anterior cingulate cortex, where we also observed an increase in cortical thickness during aging. Genes exhibiting an aging-dependent increase of mRNA and protein levels are involved in sensory perception and immune functions. Our proteomic analysis also identified changes in protein abundance in the aging cortex and highlighted a subset of proteins that were differentially enriched but exhibited stable mRNA levels during aging, implying the contribution of aging-related post- transcriptional and post-translational mechanisms. These specific genes were associated with general biological processes such as translation, ribosome assembly and protein degradation, and also important brain functions related to neuroplasticity. By decoupling mRNA and protein expression, we have thus characterized distinct subsets of genes that differentially adjust to cellular aging in the cerebral cortex.

FoxL1+telocytes (TCFoxL1+) are novel gastrointestinal subepithelial cells that form a communication axis between the mesenchyme and epithelium. TCFoxL1+ are strategically positioned to be key contributors to the microenvironment through production and secretion of growth factors and extracellular matrix (ECM) proteins. In recent years, the alteration of the bone morphogenetic protein (BMP) signaling in TCFoxL1+ was demonstrated to trigger a toxic microenvironment with ECM remodeling that leads to the development of pre-neoplastic gastric lesions. However, a comprehensive analysis of variations in the ECM composition and its associated proteins in gastric neoplasia linked to TCFoxL1+ dysregulation has never been performed. This study provides a better understanding of how TCFoxL1+ defective BMP signaling participates in the gastric pre-neoplastic microenvironment. Using a proteomic approach, we determined the changes in the complete matrisome of BmpR1a△FoxL1+ and control mice, both in total antrum as well as in isolated mesenchyme-enriched antrum fractions. Comparative proteomic analysis revealed that the deconstruction of the gastric antrum led to a more comprehensive analysis of the ECM fraction of gastric tissues microenvironment. These results show that TCFoxL1+ are key members of the mesenchymal cell population and actively participate in the establishment of the matrisomic fraction of the microenvironment, thus influencing epithelial cell behavior.

Soundscapes are increasingly used as innovative entry doors in environmental studies. Facing huge libraries of sound files which cannot be processed manually, acoustic indices provide an overview to the information contained in them, as well as to allow for automatic processing. Studies dealing with such indices have, however, focused more on specific topics or indices than on the overall characteristics of the soundscapes they were analyzing. The aim of this paper is to propose a holistic approach to soundscapes. Our hypothesis is that sufficient number and variety of indices can help frame the characteristics of sound environments and that the use of clustering algorithms allows us to group them in families and study the distribution of those across space and time, revealing a geography that will not necessarily coincide with the obvious landscape/visual geography. To demonstrate this point, we have run indices analysis and classification on a soundscapes database recorded in the Sonoran Desert region (Southeastern Arizona, USA). The results show that sound indices reveal temporal variations and patterns of soundscapes and point out to sometimes surprising similarities between otherwise different environments. As sound indices capture a wealth of information which characterizes the environment at a given place and time, they could be used as proxies to continuous monitoring without having to store extreme amounts of data.

Abstract Objectives To assess the efficacy of several repurposed drugs to prevent hospitalisation or death in patients aged 65 or more with recent symptomatic SARS-CoV-2 infection (COVID-19) and no criteria for hospitalisation. Trial design Phase III, multi-arm (5) and multi-stage (MAMS), randomized, open-label controlled superiority trial. Participants will be randomly allocated 1:1:1:1:1 to the following strategies: Arm 1: Control arm Arms 2 to 5: Experimental treatment arms Planned interim analyses will be conducted at regular intervals. Their results will be reviewed by an Independent Data and Safety Monitoring Board. Experimental arms may be terminated for futility, efficacy or toxicity before the end of the trial. New experimental arms may be added if new evidence suggests that other treatments should be tested. A feasibility and acceptability substudy as well as an immunological substudy will be conducted alongside the trial. Participants Inclusion criteria are: 65-year-old or more; Positive test for SARS-CoV-2 on a nasopharyngeal swab; Symptoms onset within 3 days before diagnosis; No hospitalisation criteria; Signed informed consent; Health insurance. Exclusion criteria are: Inability to make an informed decision to participate (e.g.: dementia, guardianship); Rockwood Clinical Frailty Scale ≥7; Long QT syndrome; QTc interval > 500 ms; Heart rate 5.5 mmol/L or

Abstract Background Although malaria remains one of the major public health threats in inter-tropical areas, there is limited understanding of imported malaria in children by paediatricians and emergency practitioners in non-endemic countries, often resulting in misdiagnosis and inadequate treatment. Moreover, classical treatments (atovaquone-proguanil, quinine, mefloquine) are limited either by lengthy treatment courses or by side effects. Since 2010, the World Health Organization (WHO) has recommended the use of oral artemisinin-based combination therapy for the treatment of uncomplicated Plasmodium falciparum malaria worldwide. The benefits of artenimol–piperaquine in children have been validated in endemic countries but experience remains limited in cases of imported malaria. Methods This prospective observational study in routine paediatric care took place at the Emergency Department, Robert-Debré Hospital (Paris, France) from September 2012 to December 2014. Tolerance and efficacy of artenimol–piperaquine in children presenting with the following inclusion criteria were assessed: P. falciparum positive on thin or thick blood smear; and the absence of WHO-defined features of severity. Results Among 83 children included in this study, treatment with artenimol–piperaquine was successful in 82 children (98.8%). None of the adverse events were severe and all were considered mild with no significant clinical impact. This also applied to cardiological adverse events despite a significant increase of the mean post-treatment QTc interval. Conclusion Artenimol–piperaquine displays a satisfying efficacy and tolerance profile as a first-line treatment for children with imported uncomplicated falciparum malaria and only necessitates three once-daily oral intakes of the medication. Comparative studies versus artemether-lumefantrine or atovaquone-proguanil would be useful to confirm the results of this study.

Introduction Vasodilatory hypotension is common among intensive care unit (ICU) patients; vasopressors are considered standard of care. However, optimal mean arterial pressure (MAP) targets for vasopressor titration are unknown. The objective of the Optimal VAsopressor TitraTION in patients 65 years and older (OVATION-65) trial is to ascertain the effect of permissive hypotension (vasopressor titration to achieve MAP 60–65 mm Hg) versus usual care on biomarkers of organ injury in hypotensive patients aged ≥65 years.Methods and analysis OVATION-65 is an allocation-concealed randomised trial in 7 Canadian hospitals. Eligible patients are ≥65 years of age, in an ICU with vasodilatory hypotension, receiving vasopressors for ≤12 hours to maintain MAP ≥65 mm Hg during or after adequate fluid resuscitation, and expected to receive vasopressors for ≥6 additional hours. Patients are excluded for any of the following: active treatment for spinal cord or acute brain injury; vasopressors given solely for bleeding, ventricular failure or postcardiopulmonary bypass vasoplegia; withdrawal of life-sustaining treatments expected within 48 hours; death perceived as imminent; previous enrolment in OVATION-65; organ transplant within the last year; receiving extracorporeal life support or lack of physician equipoise. Patients are randomised to permissive hypotension versus usual care for up to 28 days. The primary outcome is high-sensitivity troponin T, a biomarker of cardiac injury, on day 3. Secondary outcomes include biomarkers of injury to other organs (brain, liver, intestine, skeletal muscle); lactate (a biomarker of global tissue dysoxia); resource utilisation; adverse events; mortality (90 days and 6 months) and cognitive function (6 months). Assessors of biomarkers, mortality and cognitive function are blinded to allocation.Ethics and dissemination This protocol has been approved at all sites. Consent is obtained from the eligible patient, the substitute decision-maker if the patient is incapable, or in a deferred fashion where permitted. End-of-grant dissemination plans include presentations, publications and social media platforms and discussion forums.Trial registration number NCT03431181.

Loss of von Hippel-Lindau protein pVHL function promotes VHL diseases, including sporadic and inherited clear cell Renal Cell Carcinoma (ccRCC). Mechanisms controlling pVHL function and regulation, including folding and stability, remain elusive. Here, we have identified the conserved cochaperone prefoldin complex in a screen for pVHL interactors. The prefoldin complex delivers non-native proteins to the chaperonin T-complex-protein-1-ring (TRiC) or Cytosolic Chaperonin containing TCP-1 (CCT) to assist folding of newly synthesized polypeptides. The pVHL-prefoldin interaction was confirmed in human cells and prefoldin knock-down reduced pVHL expression levels. Furthermore, when pVHL was expressed in Schizosaccharomyces pombe, all prefoldin mutants promoted its aggregation. We mapped the interaction of prefoldin with pVHL at the exon2-exon3 junction encoded region. Low levels of the PFDN3 prefoldin subunit were associated with poor survival in ccRCC patients harboring VHL mutations. Our results link the prefoldin complex with pVHL folding and this may impact VHL diseases progression.

This article discusses, in an analytical and discursive way, a fieldwork experience on the landscapes of the natural spaces of northeastern Brazil. The methodology follows the field description of regional analysis and uses technical procedures for demographic and statistical studies to determine the route and perform analyzes. The main results point to the diversity of landscape conceptions as resource, product, image, mosaic and trajectory. The importance of fieldwork for performing complex and analytical landscape readings is highlighted.

The Tucson metropolitan area, located in the Sonoran Desert of southeastern Arizona (USA), is affected by both massive population growth and rapid climate change, resulting in important land use and land cover (LULC) changes. As its fragile arid ecosystem and scarce resources are increasingly under pressure, there is a crucial need to monitor such landscape transformations. For such ends, we propose a method to compute yearly 30 m resolution LULC maps of the region from 1986 to 2020, using a combination of Landsat imagery, derived transformation and indices, texture analysis and other ancillary data fed to a Random Forest classifier. The entire process was hosted in the Google Earth Engine with tremendous computing capacities that allowed us to process a large amount of data and to achieve high overall classification accuracy for each year, ranging from 86.7 to 96.3%. Conservative post-processing techniques were also used to mitigate the persistent confusions between the numerous isolated houses in the region and their desert surroundings and to smooth year-specific LULC changes in order to identify general trends. We then show that policies to lessen urban sprawl in the area had little effects and we provide an automated tool to continue monitoring such dynamics in the future.

Abstract Background Colorectal cancer is the third most common and the fourth most lethal cancer in the world. In the majority of cases, patients are diagnosed at an advanced stage or even metastatic, thus explaining the high mortality. The standard treatment for patients with locally advanced non-metastatic rectal cancer is neoadjuvant radio-chemotherapy (NRCT) with 5-fluorouracil (5-FU) followed by surgery, but the resistance rate to this treatment remains high with approximately 30% of non-responders. The lack of evidence available in clinical practice to predict NRCT resistance to 5-FU and to guide clinical practice therefore encourages the search for biomarkers of this resistance. Methods From twenty-three formalin-fixed paraffin-embedded (FFPE) biopsies performed before NRCT with 5-FU of locally advanced non-metastatic rectal cancer patients, we extracted and analysed the tumor proteome of these patients. From clinical data, we were able to classify the twenty-three patients in our cohort into three treatment response groups: non-responders (NR), partial responders (PR) and total responders (TR), and to compare the proteomes of these different groups. Results We have highlighted 384 differentially abundant proteins between NR and PR, 248 between NR and TR and 417 between PR and TR. Among these proteins, we have identified many differentially abundant proteins identified as having a role in cancer (IFIT1, FASTKD2, PIP4K2B, ARID1B, SLC25A33: overexpressed in TR; CALD1, CPA3, B3GALT5, CD177, RIPK1: overexpressed in NR). We have also identified that DPYD, the main degradation enzyme of 5-FU, was overexpressed in NR, as well as several ribosomal and mitochondrial proteins also overexpressed in NR. Data are available via ProteomeXchange with identifier PXD008440. Conclusions From these retrospective study, we implemented a protein extraction protocol from FFPE biopsy to highlight protein differences between different response groups to RCTN with 5-FU in patients with locally advanced non-metastatic rectal cancer. These results will pave the way for a larger cohort for better sensitivity and specificity of the signature to guide decisions in the choice of treatment.

Abstract NudCD1, also known as CML66 or OVA66, is a protein initially identified as overexpressed in patients with chronic myelogenous leukemia. The mRNA of NudCD1 is expressed in heart and testis of normal tissues, and is overexpressed in several cancers. Previous studies have shown that the expression level of the protein correlates with tumoral phenotype, possibly interacting upstream of the Insulin Growth Factor - 1 Receptor (IGF-1R). The gene encoding the NudCD1 protein consists of 12 exons that can be alternative spliced, leading to the expression of three different isoforms. These isoforms possess a common region of 492 amino acids in their C-terminus region and have an isoform specific N-terminus. To determine the distinct function of each isoforms, we have localised the isoforms within the cells using immunofluorescence microscopy and used a quantitative proteomics approach (SILAC) to identify specific protein interaction partners for each isoforms. Localization studies showed a different subcellular distribution for the different isoforms, with the first isoform being nuclear, while the other two isoforms have distinct cytoplasmic and nuclear location. We found that the different NudCD1 isoforms have unique interacting partners, with the first isoform binding to a putative RNA helicase named DHX15 involved in mRNA splicing.

Abstract Since the generation of a mouse strain conditionally expressing the active intracellular domain of Notch1 (N1ICD), many laboratories have exploited this model (RosaN1-ICD) to assess the impact of constitutive Notch1 signalling activation in normal and pathological processes. It should be underscored that Cre-recombination leads to the expression of a C-terminally truncated form of N1ICD (N1ICDdC) in the RosaN1-ICD mutant mice. Given that no studies were undertaken to delineate whether deletion of this region leaves intact N1ICD function, stable cell lines with single targeted integration of inducible N1ICD and N1ICDdC were generated. We found that C-terminal deletion of N1ICD stabilized the protein but did not promote the activity of Notch responsive promoters. Furthermore, despite higher expression levels, N1ICDdC failed to phenocopy N1ICD in the promotion of anchorage-independent growth. Our results thus suggest that the C-terminal region of N1ICD plays a role in shaping the Notch response. Therefore, it should be taken into consideration that N1ICD is truncated when interpreting phenotypes of RosaN1-ICD mutant mice.

The economic modernization of the Amazon fostered by the Brazilian military government during the 1960s and 1970s was largely realized without taking into consideration the presence of local households which lived from the extraction of forest products (mainly non-timber). When they began to be expulsed, a political resistance, often guided by the Catholic Church, appeared as well as the creation of unions based on traditional identities, especially that of rubber tappers. During the 1980s, these unions made a strategic alliance with the ecologist movement which started to consider traditional populations, whose lifestyle depended on the forest, as allies for the protection of the Amazon rainforest. The movement gained a decisive momentum at the end of the decade by putting forward new proposals of land tenure for traditional populations, grounded on collective land rights. This strategy has been very efficient during the 1990s and 2000s, during which about 1,300,000 km2 of rainforest were set apart and reserved for the use of “traditional communities” under a variety of legal status. But it has also led to mix under the same “collective” etiquette and principles a number of different ways of using and managing land and natural resources. This assumption however should be nuanced by a careful analysis of the resource management systems existing in each case, for they are in general complex and mix varying proportions of individual and collective decisions. The aim of this paper is to explore this question using the example of the Chico Mendes agroextractive settlement (PAE-CM), inhabited by about 100 rubber tapper families and symbolic of the political struggle of traditional populations in the Amazon for being the home of the rubber tapper leader Chico Mendes assassinated in 1988. Applying Ostrom “design principles”, we try to catch what are the local institutional arrangements and to see if they suggest collective or individual management, and what the boundaries between both categories are. As a conclusion, we find that the PAE-CM’s system is much less collective than expected, and also very much controlled by external authorities, in a logic pretty much away from the idea of a CPR system. This finding is useful to understand the shortcomings in the actual management of the PAE but also to foresee difficulties which will probably arise in the management of many of the areas which have gained collective land rights or collective management statutes in the Amazon.

Introduction The number of older people diagnosed with amnestic mild cognitive impairment (aMCI), the prodromal state of Alzheimer's disease (AD), is increasing worldwide. However, some patients with aMCI never convert to the AD type of dementia, with some remaining stable and others reverting to normal. This overdiagnosis bias has been largely overlooked and gone unexplained. There is ample evidence in the laboratory that negative ageing stereotypes (eg, the culturally shared belief that ageing inescapably causes severe cognitive decline) contribute to the deteriorating cognitive performances of healthy older adults, leading them to perform below their true abilities. The study described here is intended to test for the first time whether such stereotypes also impair patients’ cognitive performances during neuropsychological examinations in memory clinics, resulting in overdiagnosis of aMCI.Methods and analysis The ongoing study is a 4-year randomised clinical trial comparing patients’ physiological stress and cognitive performances during neuropsychological testing in memory clinics. A total of 260 patients attending their first cognitive evaluation will be randomised to either a standard condition of test administration, assumed here to implicitly activate negative ageing stereotypes or a reduced-threat instruction condition designed to alleviate the anxiety arising from these stereotypes. Both groups will be tested with the same test battery and stress biomarkers. For 30 patients diagnosed with aMCI in each group (n=60), biomarkers of neurodegeneration and amyloidopathy will be used to distinguish between aMCI with normal versus abnormal AD biomarkers. A 9-month follow-up will be performed on all patients to identify those whose cognitive performances remain stable, deteriorate or improve.Ethics and dissemination This protocol has been approved by the French National Agency for Medicines and Health Products Safety and the Sud-Est I French Ethics Committee (2017-A00946-47). Results will be published in peer-reviewed journals.Trial registration number NCT03138018.

The 2018 election in Brazil has allowed a ultra-conservative political force to power, leading to new challenges to Indigenous land rights in the country. Despite the warranties offered by the 1988 Constitution, the government of Jair Bolsonaro is determined to halt any new demarcation of Indigenous lands, and to shrink as much as possible the existing ones. In such an adverse political landscape for Brazil’s Indigenous peoples and their supporters, this paper is an attempt to sum up what the stakes are. We start by remembering where Brazil’s Indigenous lands are and what are the juridical grounds which sustain them. We then analyze the ideological background of the actual government regarding Indigenous peoples and the measures it has taken since January 2019. Last, we propose three more or less optimistic scenarios for the near future in which we try to identify the fracture lines

Membrane trafficking controls vesicular transport of cargo between cellular compartments. Vesicular trafficking is essential for cellular homeostasis and dysfunctional trafficking is linked to several pathologies such as neurodegenerative diseases. Following endocytosis, early endosomes act as sorting stations of internalized materials, routing cargo toward various fates. One important class of membrane trafficking regulators are RAB GTPases. RAB21 has been associated with multiple functions and regulates integrin internalization, endosomal sorting of specific clathrin-independent cargo and autophagy. Although RAB21 is mostly associated with early endosomes, it has been shown to mediate a specific sorting event at the Golgi. From mass spectrometry data, we identified a GTP-favored interaction between RAB21 and TMED10 and 9, essential regulators of COPI and COPII vesicles. Using RAB21 knockout cells, we describe the role of RAB21 in modulating TMED10 Golgi localization. Taken together, our study suggests a new potential function of RAB21 in modulating TMED10 trafficking, with relevance to neurodegenerative disorders.

Land tenure in the Western US, in particular in the most recent states, reflects the processes of appropriation which took place after the annexing of Northern Mexico by the US in 1848. It is characterized by a high proportion of public (federal and state) lands, as well as by a spatial configuration where influences of the homesteading and of land grants to railroad companies are still highly visible. Another aspect of land tenure in those states is its complexity, the number of public agencies involved and the multiple scales of intervention implied in its management. The state of Arizona is a good example of such dynamics. The paper therefore describes the private appropriation of lands in this state and the current extent of private lands. We then review the categories of public lands and their history. Finally, we pinpoint a number of difficulties that derive from the contemporary configuration of land tenure in Arizona, especially when local policies are to be developed.

Since the 1988 Constitution, Indigenous peoples in Brazil have been granted extensive land rights. In the Amazon, those rights have been largely implemented and large Indigenous territories have been recognized. Those account today for more than 22% of the Amazon region, or more than 1,1 million km². The Indigenous peoples of the Amazon are therefore facing a new situation. They must find the balance between the preservation of their lands, new social needs and external pressures. In this article, we try to analyze what are the factors underlying the sustainability of those Indigenous territories. To that end, we first expose the current situation of the Indigenous territories of the Brazilian Amazon regarding land tenure, as well as social and demographic aspects. We then analyze the public policies and external pressures as crucial factors for their vulnerability. Last, we explore the economic alternatives available to Indigenous peoples in the current context.

Generations of explorers have been fascinated by The Tumuc Humac mounts, or montanhas Tumucumaque in Portuguese. The real geographical nature of such “mounts”, however, is rather dubious since if they correspond to real-life experiences for some, other consider that they do not even exist. They seem to correspond more to a myth, carrying several levels of interpretation at the same time. Given this context, what does “crossing the Tumuc Humac” mean? Using historical documents as well as field experience of this region, we explore in this article the different historical and geographical aspects conveyed by this question. We first expose the historical context in which the Tumuc Humac appear in the scientific literature. Then we describe how they were turned in a controlled-access area, and the difficulty for such control to be efficient. Last, we reflect on the topographical configuration of this region and its implication in terms of expeditions. For it is possible to cross the Tumuc Humac, finding the right way being the real difficulty.

This text presents reflections on my participation in the "jungle platoon leader" training course organized by the French Foreign Legion in its training center in French Guiana, the Training Centre in Equatorial Forest (CEFE). Besides describing the running of the course in the manner of a field book, I compare the teachings received on this occasion with others from other contexts, including with my experience among Native Americans. In taking stock of the contributions of this adventure for the practice of geography in the Amazonian forest, I finally answer a question that Molière would not have disowned: "What the Hell would he be doing in this galley?".

O artigo explora as consequências da instalação de projetos de desenvolvimento sustentável em três comunidades tradicionais da Amazônia, buscando não somente fazer um balanço dos impactos objetivos, mas também as relações que se estabelecem entre essas comunidades e as entidades que promovem os projetos. Evidenciamos a existência da um mal-entendido criativo entre essas duas partes em torno do papel dos projetos e da posição da outra parte.

Colorectal cancer is the third most common and the fourth most lethal cancer worldwide. In most of cases, patients are diagnosed at an advanced or even metastatic stage, thus explaining the high mortality. The lack of proper clinical tests and the complicated procedures currently used for detecting this cancer, as well as for predicting the response to treatment and the outcome of a patient’s resistance in guiding clinical practice, are key elements driving the search for biomarkers. In the present overview, the different biomarkers (diagnostic, prognostic, treatment resistance) discovered through proteomics studies in various colorectal cancer study models (blood, stool, biopsies), including the different proteomic techniques used for the discovery of these biomarkers, are reviewed, as well as the various tests used in clinical practice and those currently in clinical phase. These studies define the limits and perspectives related to proteomic biomarker research for personalised medicine in colorectal cancer.

A ação do INCRA na Amazônia revela um paradoxo: por mais que a ocupação humana daquela região fosse uma estratégia dos governos militares, é na fase democrática recente que a reforma agrária brasileira intensifica a instalação de agricultores em assentamentos. A institucionalização de políticas de proteção do meio ambiente se revela contraditória com as práticas de proteção social que têm, na Amazônia, um foco de destaque num modelo de reforma agrária que provoca inevitáveis consequências ambientais.The action of INCRA in the Amazon region shows a paradox: on the one hand the human occupation of that region was a strategy of the military regime, but on the other hand it is after the democratization that the agrarian reform policy intensifies the settlement of peasants in the Brazilian Amazon. The institutionalization of policies aiming at protecting the environment is contradictory with the social protection, as in the Amazon it is very much based on a model of agrarian reform that provokes deforestation.

In the past 10 years, deforestation in the Amazon has been annually decreasing, the figures in 2014 representing less than 20 % of what they were in 2004. Does this mean Brazil now controls the phenomenon? Answering this question is a complex task because deforestation unfolds through several dimensions: economic (what are the rationales behind deforestation), social (access to land, land conflicts), environmental (impacts on climate, local or global effects, biodiversity) and geopolitical (the role of Brazil in international negotiations on climate and GES emissions). The enormous size of the Amazon rainforest adds to this complexity, as the issues at stake are not necessarily the same throughout the region. Despite this complexity, we will provide a synthesis of the principal issues underlying deforestation. We will first recall how, when and where this phenomenon appeared and expanded in the Brazilian Amazon, and what the consequences are on multiple scales. We will then analyse the causes and the social stakeholders involved. Lastly, we will present the actions led by the Brazilian Federal government since 2004 to curb the phenomenon. The conclusion will lead us to think about the limits of current policies and the challenges which remain to be addressed.Keywords: Amazonia, deforestation, greenhouse gases, climate change

In the last 10 years, the deforested land in the Amazon has been annually decreasing, the deforestation for 2014 representing less than 20 % of the 2004 figures. Does this mean that Brazil now controls the phenomenon? Answering this question is a complex task since the deforestation unfolds through several dimensions: economic (what are the rationales of the deforestation), social (access to land, land conflicts), environmental (impact on the climate, local or global effects, biodiversity) or geopolitical (Brazil’s role on the international negotiations on climate and GES emissions). The enormous size of the Amazon adds to this complexity, as the various factors do not necessarily combine everywhere in the same way. Despite this complexity, we propose here a synthesis of the principal issues underlying the deforestation. We first recall how, when and where this phenomenon appeared and grew in the Brazilian Amazon, and what the consequences at multiple scales are. We then analyze the causes and the social actors involved. Lastly, we present the actions led by the Brazilian Federal government since 2004 to curb the phenomenon. The conclusion leads us to think about the limits of current policies and the challenges which remain to be addressed.

Brazil’s indigenous population is very minoritary, accounting for less than 0,43% of the overall population. Despite its small number, it is a highly diverse population (305 different ethnic groups) and it holds a unique place in the country’s cultural matrix. The constitution of 1988 was an important step for Brazil’s indigenous peoples since it has granted them extensive land rights. Since then, over 1,3 millions square kilometers, or over 13,5% of the overall country area, have been recognized as “indigenous lands”. However, the concrete Indians’ place in the Brazilian society remains highly controversial.Based upon the 2010 census figures and upon fresh geographical databases about Indian lands, our article tries to offer a synthetic view of the indigenous question in Brazil. We first analyze the figures about indigenous population and its repartition upon the Brazilian territory. In a second part, we present the different mechanisms beneficiating to indigenous peoples, among which the most important is the allotment of “indigenous lands”. But those are not evenly spread: the Amazon region, which holds only 43% of Brazil’s Indians, concentrates 99% of the country’s overall area of indigenous lands. We then show that the indigenous people in Brazil are still stuck in nationwide polemics about their small number as opposed to their supposed huge territories.

A fully mature mRNA is usually associated to a reference open reading frame encoding a single protein. Yet, mature mRNAs contain unconventional alternative open reading frames (AltORFs) located in untranslated regions (UTRs) or overlapping the reference ORFs (RefORFs) in non-canonical +2 and +3 reading frames. Although recent ribosome profiling and footprinting approaches have suggested the significant use of unconventional translation initiation sites in mammals, direct evidence of large-scale alternative protein expression at the proteome level is still lacking. To determine the contribution of alternative proteins to the human proteome, we generated a database of predicted human AltORFs revealing a new proteome mainly composed of small proteins with a median length of 57 amino acids, compared to 344 amino acids for the reference proteome. We experimentally detected a total of 1,259 alternative proteins by mass spectrometry analyses of human cell lines, tissues and fluids. In plasma and serum, alternative proteins represent up to 55% of the proteome and may be a potential unsuspected new source for biomarkers. We observed constitutive co-expression of RefORFs and AltORFs from endogenous genes and from transfected cDNAs, including tumor suppressor p53, and provide evidence that out-of-frame clones representing AltORFs are mistakenly rejected as false positive in cDNAs screening assays. Functional importance of alternative proteins is strongly supported by significant evolutionary conservation in vertebrates, invertebrates, and yeast. Our results imply that coding of multiple proteins in a single gene by the use of AltORFs may be a common feature in eukaryotes, and confirm that translation of unconventional ORFs generates an as yet unexplored proteome.

Created in a multidisciplinary research program, the IDURAMAZ system of indicators focuses on the territorial impacts of different projects of sustainable development implemented in Amazonian rural areas during the last twenty years. Originally constructed to be subdivided in 4 synthetic indexes, 14 indicators and 44 sub-indicators related to socioeconomic, environmental, institutional and generational questions, we wanted to reduce the number of its components and its architecture in order to obtain a dashboard of more relevant indicators. During the realization of the key indicators selection, we focused on two main goals. First, making our methodology more intelligible to the targeted public by conserving the most explicit indicators and limiting the use of composed ones (those that are constructed with different variables). Second, facilitating the research on the determinants of sustainability, which means the most important criteria for the success or the failure of the projects realized in its name. This paper exposes the principles that have piloted the selection of the key indicators, the results obtained as to the key factors of sustainability and some reflections about the themes to be added. Behind the reflections on the DURAMAZ project and its indicators system, this paper has a more general range on the way to select a core set of indicators to approach the question of sustainability.

A análise do processo de sustentabilidade representa um grande desafio científico enquanto a Amazônia constitui um verdadeiro laboratório onde estão sendo testadas inúmeras concepções desse conceito. Haveria pontos ou mecanismos comuns entre estas? Esse é o ponto que pesquisou o programa DURAMAZ, que teve como objetivo de desvendar fatores chaves, ou “determinantes” do desenvolvimento sustentável (DS) na Amazônia brasileira através da identificação dos impactos geográficos, demográficos e socioeconômicos de 13 projetos de DS. Apresentamos os pontos-chaves da metodologia, assim como algumas visões de síntese sobre a aplicação do conceito de desenvolvimento sustentável. Entender as dinâmicas internas de cada uma dessas experiências foi a meta principal, assim como entender as razões de um bom desempenho. O resultado final do programa de pesquisa reside na construção de um sistema de indicadores a partir de bancos de dados sistematizados (socioeconômico, demográfico/biográfico e geográfico) e na análise de seus resultados.

A análise do processo de sustentabilidade representa um grande desafio científico enquanto a Amazônia constitui um verdadeiro laboratório onde estão sendo testadas inúmeras concepções desse conceito. Haveria pontos ou mecanismos comuns entre estas? Esse é o ponto que pesquisou o programa DURAMAZ, que teve como objetivo de desvendar fatores chaves, ou “determinantes” do desenvolvimento sustentável (DS) na Amazônia brasileira através da identificação dos impactos geográficos, demográficos e socioeconômicos de 13 projetos de DS. Apresentamos os pontos-chaves da metodologia, assim como algumas visões de síntese sobre a aplicação do conceito de desenvolvimento sustentável. Entender as dinâmicas internas de cada uma dessas experiências foi a meta principal, assim como entender as razões de um bom desempenho. O resultado final do programa de pesquisa reside na construção de um sistema de indicadores a partir de bancos de dados sistematizados (socioeconômico, demográfico/biográfico e geográfico) e na análise de seus resultados.