Multifunctional Glycoconjugates for Recruiting Natural Antibodies against Cancer Cells

Invited for the cover of this issue is Olivier Renaudet and co-workers at the Université Grenoble Alpes and funded by the European Research Council (CoG “LEGO′” no. 647938). The image illustrates a synthetic chemist playing with supramolecular structures to kill cancer cells by using natural antibodies present in the blood stream. Read the full text of the article at 10.1002/chem.201903327

Optimization of Topical Therapy for Leishmania major Localized Cutaneous Leishmaniasis Using a Reliable C57BL/6 Model

When initiating the cutaneous disease named cutaneous leishmaniasis (CL), Leishmania parasites develop within the parasitophorous vacuoles of phagocytes residing in and/or recruited to the dermis, a process leading to more or less chronic dermis and epidermis-damaging inflammatory processes. Topical treatment of CL could be a mainstay in its management. Any improvements of topicals, such as new vehicles and shorter optimal contact regimes, could facilitate their use as an ambulatory treatment. Recently, WR279396, a third-generation aminoglycoside ointment, was designed with the aim to provide stability and optimal bioavailability for the molecules expected to target intracellular Leishmania. Two endpoints were expected to be reached: i) accelerated clearance of the maximal number of parasites, and ii) accelerated and stable repair processes without scars. A mouse model of CL was designed: it relies on the intradermal inoculation of luciferase-expressing Leishmania, allowing for in vivo bioluminescence imaging of the parasite load fluctuation, which can then be quantified simultaneously with the onset and resolution of clinical signs. These quantitative readout assays, deployed in real time, provide robust methods to rapidly assess efficacy of drugs/compounds i) to screen treatment modalities and ii) allow standardized comparison of different therapeutic agents

CandidaDB: a genome database for Candida albicans pathogenomics

CandidaDB is a database dedicated to the genome of the most prevalent systemic fungal pathogen of humans, Candida albicans. CandidaDB is based on an annotation of the Stanford Genome Technology Center C.albicans genome sequence data by the European Galar Fungail Consortium. CandidaDB Release 2.0 (June 2004) contains information pertaining to Assembly 19 of the genome of C.albicans strain SC5314. The current release contains 6244 annotated entries corresponding to 130 tRNA genes and 5917 protein-coding genes. For these, it provides tentative functional assignments along with numerous pre-run analyses that can assist the researcher in the evaluation of gene function for the purpose of specific or large-scale analysis. CandidaDB is based on GenoList, a generic relational data schema and a World Wide Web interface that has been adapted to the handling of eukaryotic genomes. The interface allows users to browse easily through genome data and retrieve information. CandidaDB also provides more elaborate tools, such as pattern searching, that are tightly connected to the overall browsing system. As the C.albicans genome is diploid and still incompletely assembled, CandidaDB provides tools to browse the genome by individual supercontigs and to examine information about allelic sequences obtained from complementary contigs. CandidaDB is accessible at http://genolist.pasteur.fr/CandidaDB

Social brain activation during mentalizing in a large autism cohort: The Longitudinal European Autism Project

Background: Autism spectrum disorder (ASD) is a neurodevelopmental condition with key deficits in social functioning. It is widely assumed that the biological underpinnings of social impairment are neurofunctional alterations in the "social brain," a neural circuitry involved in inferring the mental state of a social partner. However, previous evidence comes from small-scale studies and findings have been mixed. We therefore carried out the to-date largest study on neural correlates of mentalizing in ASD. Methods: As part of the Longitudinal European Autism Project, we performed functional magnetic resonance imaging at six European sites in a large, well-powered, and deeply phenotyped sample of individuals with ASD (N = 205) and typically developing (TD) individuals (N = 189) aged 6 to 30 years. We presented an animated shapes task to assess and comprehensively characterize social brain activation during mentalizing. We tested for effects of age, diagnosis, and their association with symptom measures, including a continuous measure of autistic traits. Results: We observed robust effects of task. Within the ASD sample, autistic traits were moderately associated with functional activation in one of the key regions of the social brain, the dorsomedial prefrontal cortex. However, there were no significant effects of diagnosis on task performance and no effects of age and diagnosis on social brain responses. Besides a lack of mean group differences, our data provide no evidence for meaningful differences in the distribution of brain response measures. Extensive control analyses suggest that the lack of case-control differences was not due to a variety of potential confounders. Conclusions: Contrary to prior reports, this large-scale study does not support the assumption that altered social brain activation during mentalizing forms a common neural marker of ASD, at least with the paradigm we employed. Yet, autistic individuals show socio-behavioral deficits. Our work therefore highlights the need to interrogate social brain function with other brain measures, such as connectivity and network-based approaches, using other paradigms, or applying complementary analysis approaches to assess individual differences in this heterogeneous condition

CandidaDB: A genome database for Candida albicans pathogenomics

CandidaDB is a database dedicated to the genome of the most prevalent systemic fungal pathogen of humans, Candida albicans. CandidaDB is based on an annotation of the Stanford Genome Technology Center C.albicans genome sequence data by the European Galar Fungail Consortium. CandidaDB Release 2.0 (June 2004) contains information pertaining to Assembly 19 of the genome of C.albicans strain SC5314. The current release contains 6244 annotated entries corresponding to 130 tRNA genes and 5917 protein-coding genes. For these, it provides tentative functional assignments along with numerous pre-run analyses that can assist the researcher in the evaluation of gene function for the purpose of specific or large-scale analysis. CandidaDB is based on GenoList, a generic relational data schema and a World Wide Web interface that has been adapted to the handling of eukaryotic genomes. The interface allows users to browse easily through genome data and retrieve information. CandidaDB also provides more elaborate tools, such as pattern searching, that are tightly connected to the overall browsing system. As the C.albicans genome is diploid and still incompletely assembled, CandidaDB provides tools to browse the genome by individual supercontigs and to examine information about allelic sequences obtained from complementary contigs. CandidaDB is accessible at http://genolist.pasteur.fr/CandidaDB.Sequence data from C.albicans were obtained from the Stanford Genome Technology Center (http://www.sequence. stanford.edu/group/candida). Sequencing of C.albicans was accomplished with the support of the NIDR and the Burroughs Wellcome Fund. This work was supported by grants from the European Commission (QLK2-2000-00795; MCRTN-CT-2003-504148; ‘Galar Fungail Consortium’) to A.J.P.B., C.E., A.D., J.E., C.G., B.H., F.M.K., J.P.M. and R.S. and the Ministere de la Recherche et de la Technologie (PRFMMIP ‘Re´seau Infections Fongiques’) to C.E. and C.G. F.T. was supported by the Institut Pasteur Strategic Horizontal Program on Anopheles gambiae. N.M. was supported by a fellowship of the Junta de Castilla y Leon and by grants DGCYT (PM-98-0317 and BIO 2002-02124) to A.D. R.S. was supported in part by grants from the Spanish Ministerio de Ciencia y Tecnologia (BMC2003- 01023) and Agencia Valenciana de Ciencia i Tecnologia de la Generalitat Valenciana (Grupos 03/187)

Unravelling the rate of action of hits in the Leishmania donovani box using standard drugs amphotericin B and miltefosine

In recent years, the neglected diseases drug discovery community has elected phenotypic screening as the key approach for the identification of novel hit compounds. However, when this approach is applied, important questions related to the mode of action for these compounds remain unanswered. One of such questions is related to the rate of action, a useful piece of information when facing the challenge of prioritising the most promising hit compounds. In the present work, compounds of the "Leishmania donovani box" were evaluated using a rate of action assay adapted from a replicative intracellular high content assay recently developed. The potency of each compound was determined every 24 hours up to 96 hours, and standard drugs amphotericin B and miltefosine were used as references to group these compounds according to their rate of action. Independently of this biological assessment, compounds were also clustered according to their minimal chemical scaffold. Comparison of the results showed a complete correlation between the chemical scaffold and the biological group for the vast majority of compounds, demonstrating how the assay was able to bring information on the rate of action for each chemical series, a property directly linked to the mode of action. Overall, the assay here described permitted us to evaluate the rate of action of the "Leishmania donovani box" using two of the currently available drugs as references and, also, to propose a number of fast-acting chemical scaffolds present in the box as starting points for future drug discovery projects to the wider scientific community. The results here presented validate the use of this assay for the determination of the rate of action early in the discovery process, to assist in the prioritisation of hit compounds

Preference for biological motion is reduced in ASD: implications for clinical trials and the search for biomarkers

Background: The neurocognitive mechanisms underlying autism spectrum disorder (ASD) remain unclear. Progress has been largely hampered by small sample sizes, variable age ranges and resulting inconsistent findings. There is a pressing need for large definitive studies to delineate the nature and extent of key case/control differences to direct research towards fruitful areas for future investigation. Here we focus on perception of biological motion, a promising index of social brain function which may be altered in ASD. In a large sample ranging from childhood to adulthood, we assess whether biological motion preference differs in ASD compared to neurotypical participants (NT), how differences are modulated by age and sex and whether they are associated with dimensional variation in concurrent or later symptomatology. Methods: Eye-tracking data were collected from 486 6-to-30-year-old autistic (N = 282) and non-autistic control (N = 204) participants whilst they viewed 28 trials pairing biological (BM) and control (non-biological, CTRL) motion. Preference for the biological motion stimulus was calculated as (1) proportion looking time difference (BM-CTRL) and (2) peak look duration difference (BM-CTRL). Results: The ASD group showed a present but weaker preference for biological motion than the NT group. The nature of the control stimulus modulated preference for biological motion in both groups. Biological motion preference did not vary with age, gender, or concurrent or prospective social communicative skill within the ASD group, although a lack of clear preference for either stimulus was associated with higher social-communicative symptoms at baseline. Limitations: The paired visual preference we used may underestimate preference for a stimulus in younger and lower IQ individuals. Our ASD group had a lower average IQ by approximately seven points. 18% of our sample was not analysed for various technical and behavioural reasons. Conclusions: Biological motion preference elicits small-to-medium-sized case–control effects, but individual differences do not strongly relate to core social autism associated symptomatology. We interpret this as an autistic difference (as opposed to a deficit) likely manifest in social brain regions. The extent to which this is an innate difference present from birth and central to the autistic phenotype, or the consequence of a life lived with ASD, is unclear

Saccade dysmetria indicates attenuated visual exploration in autism spectrum disorder

Background: Visual exploration in autism spectrum disorder (ASD) is characterized by attenuated social attention. The underlying oculomotor function during visual exploration is understudied, whereas oculomotor function during restricted viewing suggested saccade dysmetria in ASD by altered pontocerebellar motor modulation. Methods: Oculomotor function was recorded using remote eye tracking in 142 ASD participants and 142 matched neurotypical controls during free viewing of naturalistic videos with and without human content. The sample was heterogenous concerning age (6–30 years), cognitive ability (60–140 IQ), and male/female ratio (3:1). Oculomotor function was defined as saccade, fixation, and pupil-dilation features that were compared between groups in linear mixed models. Oculomotor function was investigated as ASD classifier and features were correlated with clinical measures. Results: We observed decreased saccade duration (∆M = −0.50, CI [−0.21, −0.78]) and amplitude (∆M = −0.42, CI [−0.12, −0.72]), which was independent of human video content. We observed null findings concerning fixation and pupil-dilation features (POWER =.81). Oculomotor function is a valid ASD classifier comparable to social attention concerning discriminative power. Within ASD, saccade features correlated with measures of restricted and repetitive behavior. Conclusions: We conclude saccade dysmetria as ASD oculomotor phenotype relevant to visual exploration. Decreased saccade amplitude and duration indicate spatially clustered fixations that attenuate visual exploration and emphasize endogenous over exogenous attention. We propose altered pontocerebellar motor modulation as underlying mechanism that contributes to atypical (oculo-)motor coordination and attention function in ASD

Screening for Vulnerability in Older Cancer Patients: The ONCODAGE Prospective Multicenter Cohort Study:

Background: Geriatric Assessment is an appropriate method for identifying older cancer patients at risk of life-threatening events during therapy. Yet, it is underused in practice, mainly because it is time- and resource-consuming. This study aims to identify the best screening tool to identify older cancer patients requiring geriatric assessment by comparing the performance of two short assessment tools the G8 and the Vulnerable Elders Survey (VES-13). Patients and Methods: The diagnostic accuracy of the G8 and the (VES-13) were evaluated in a prospective cohort study of 1674 cancer patients accrued before treatment in 23 health care facilities. 1435 were eligible and evaluable. Outcome measures were multidimensional geriatric assessment (MGA), sensitivity (primary), specificity, negative and positive predictive values and likelihood ratios of the G8 and VES-13, and predictive factors of 1-year survival rate. Results: Patient median age was 78.2 years (70-98) with a majority of females (69.8%), various types of cancer including 53.9% breast, and 75.8% Performance Status 0-1. Impaired MGA, G8, and VES-13 were 80.2%, 68.4%, and 60.2%, respectively. Mean time to complete G8 or VES-13 was about five minutes. Reproducibility of the two questionnaires was good. G8 appeared more sensitive (76.5% versus 68.7%, P5 0.0046) whereas VES-13 was more specific (74.3% versus 64.4%, P<0.0001). Abnormal G8 score (HR = 2.72), advanced stage (HR = 3.30), male sex (HR = 2.69) and poor Performance Status (HR = 3.28) were independent prognostic factors of 1-year survival. Conclusion: With good sensitivity and independent prognostic value on 1-year survival, the G8 questionnaire is currently one of the best screening tools available to identify older cancer patients requiring geriatric assessment, and we believe it should be implemented broadly in daily practice. Continuous research efforts should be pursued to refine the selection process of older cancer patients before potentially life-threatening therapy

Identification of Leishmania Proteins Preferentially Released in Infected Cells Using Change Mediated Antigen Technology (CMAT)

Although Leishmania parasites have been shown to modulate their host cell's responses to multiple stimuli, there is limited evidence that parasite molecules are released into infected cells. In this study, we present an implementation of the change mediated antigen technology (CMAT) to identify parasite molecules that are preferentially expressed in infected cells. Sera from mice immunized with cell lysates prepared from L. donovani or L. pifanoi-infected macrophages were adsorbed with lysates of axenically grown amastigotes of L. donovani or L. pifanoi, respectively, as well as uninfected macrophages. The sera were then used to screen inducible parasite expression libraries constructed with genomic DNA. Eleven clones from the L. pifanoi and the L. donovani screen were selected to evaluate the characteristics of the molecules identified by this approach. The CMAT screen identified genes whose homologs encode molecules with unknown function as well as genes that had previously been shown to be preferentially expressed in the amastigote form of the parasite. In addition a variant of Tryparedoxin peroxidase that is preferentially expressed within infected cells was identified. Antisera that were then raised to recombinant products of the clones were used to validate that the endogenous molecules are preferentially expressed in infected cells. Evaluation of the distribution of the endogenous molecules in infected cells showed that some of these molecules are secreted into parasitophorous vacuoles (PVs) and that they then traffic out of PVs in vesicles with distinct morphologies. This study is a proof of concept study that the CMAT approach can be applied to identify putative Leishmania parasite effectors molecules that are preferentially expressed in infected cells. In addition we provide evidence that Leishmania molecules traffic out of the PV into the host cell cytosol and nucleus