Biology subjects

Gonzalez, C.

Publications and source records attributed to Gonzalez, C..

At least 55 records · Page 3Linked to original sources

bioRxiv2021

Characterization of an Agarophyton chilense oleoresin containing PPARγ natural ligands with insulin-sensitizing effects in a C57BL/6J mouse model of diet-induced obesity and antioxidant activity in Caenorhabditis elegans.

The biomedical potential of the edible red seaweed Agarophyton chilense (former Gracilaria chilensis) has not been explored. Red seaweeds are enriched in polyunsaturated fatty acids and eicosanoids, which are known natural ligands of the PPAR{gamma} nuclear receptor. PPAR{gamma} is the molecular target of thiazolidinediones (TZDs), drugs used as insulin sensitizers to treat type 2 diabetes mellitus. TZDs medical use is limited due to undesired side effects, the fact that it has triggered the search for partial agonists without the TZDs side effects. We produced A.chilense oleoresin (Gracilex(R)) that induces the activation of PPAR{gamma} without inducing adipocyte differentiation, similar to PPAR{gamma} partial agonists. In a model of high-fat diet-induced obesity in male mice, we showed that treatment with Gracilex(R) improves insulin sensitivity, normalizing altered glucose and insulin parameters. Gracilex(R) was enriched in palmitic acid, arachidonic acid, oleic acid, and lipophilic antioxidants such as {beta}-carotene and tocopherols. Gracilex(R) possesses antioxidant activity in vitro (CUPRAC) and increased the antioxidant capacity in vivo in Caenorhabditis elegans. These findings support the idea that Gracilex(R) is an excellent source of healthy lipids targeting PPAR{gamma} with antioxidant activity and a high nutraceutical value.

physiology↗

bioRxiv2020

Enforced dimerization between XBP1s and ATF6f enhances the protective effects of the unfolded protein response (UPR) in models of neurodegeneration

Alteration to endoplasmic reticulum (ER) proteostasis is observed on a variety of neurodegenerative diseases associated with abnormal protein aggregation. Activation of the unfolded protein response (UPR) enables an adaptive reaction to recover ER proteostasis and cell function. The UPR is initiated by specialized stress sensors that engage gene expression programs through the concerted action of the transcription factors ATF4, ATF6f, and XBP1s. Although UPR signaling is generally studied as unique linear signaling branches, correlative evidence suggests that ATF6f and XBP1s may physically interact to regulate a subset of UPR-target genes. Here, we designed an ATF6f-XBP1s fusion protein termed UPRplus that behaves as a heterodimer in terms of its selective transcriptional activity. Cell-based studies demonstrated that UPRplus has stronger an effect in reducing the abnormal aggregation of mutant huntingtin and alpha-synuclein when compared to XBP1s or ATF6 alone. We developed a gene transfer approach to deliver UPRplus into the brain using adeno-associated viruses (AAVs) and demonstrated potent neuroprotection in vivo in preclinical models of Parkinsons and Huntingtons disease. These results support the concept where directing UPR-mediated gene expression toward specific adaptive programs may serve as a possible strategy to optimize the beneficial effects of the pathway in different disease conditions.

neuroscience↗

bioRxiv2020

PharmaNet: Pharmaceutical discovery with deep recurrent neural networks.

The discovery and development of novel pharmaceuticals is an area of active research mainly due to the large investments required and long payback times. As of 2016, the development of a novel drug candidate required up to $ USD 2.6 billion in investment for only 10% rate of approval by the FDA. To help decreasing the costs associated with the process, a number of in silico approaches have been developed with relatively low success due to limited predicting performance. Here, we introduced a machine learning-based algorithm as an alternative for a more accurate search of new pharmacological candidates, which takes advantage of Recurrent Neural Networks (RNN) for active molecule prediction within large databases. Our approach, termed PharmaNet was implemented here to search for ligands against specific cell receptors within 102 targets of the DUD-E database, which contains 22886 active molecules. PharmaNet comprises three main phases. First, a SMILES representation of the molecule is converted into a raw molecular image. Second, a convolutional encoder processes the data to obtain a fingerprint molecular image that is finally analyzed by a Recurrent Neural Network (RNN). This approach enables precise predictions of the molecules target on the basis of the feature extraction, the sequence analysis and the relevant information filtered out throughout the process. Molecule Target prediction is a highly unbalanced detection problem and therefore, we propose that an adequate evaluation metric of performance is the area under the Normalized Average Precision (NAP) curve. PharmaNet largely surpasses the previous state-of-the-art method with 97.7% in the Receiver Operating Characteristic curve (ROC-AUC) and 65.5% in the NAP curve. We obtained a perfect performance for human farnesyl pyrophosphate synthase (FPPS), which is a potential target for antimicrobial and anticancer treatments. We decided to test PharmaNet for activity prediction against FPPS by searching in the CHEMBL data set. We obtained three (3) potential inhibitors that were further validated through both molecular docking and in silico toxicity prediction. Most importantly, one of this candidates, CHEMBL2007613, was predicted as a potential antiviral due to its involvement on the PCDH17 pathway, which has been reported to be related to viral infections.

bioinformatics↗

bioRxiv2020

Gut Microbiota-Targeted Diets Modulate Human Immune Status

Diet modulates the gut microbiome, and gut microbes, in turn, can impact the immune system. Here, we used two gut microbiota-targeted dietary interventions, plant-based fiber or fermented foods, to determine how each influences the human microbiome and immune system in healthy adults. Using a 17-week randomized, prospective study design combined with -omics measurements of microbiome and host, including extensive immune profiling, we found distinct effects of each diet. High-fiber consumers showed increased gut microbiome-encoded glycan-degrading CAZymes despite stable community diversity. Three distinct immunological trajectories in high fiber-consumers corresponded to baseline microbiota diversity. Alternatively, the high-fermented food diet steadily increased microbiota diversity and decreased inflammatory markers. The data highlight how coupling dietary interventions to deep and longitudinal immune and microbiome profiling can provide individualized and population-wide insight. Our results indicate that fermented foods may be valuable in countering the decreased microbiome diversity and increased inflammation pervasive in the industrialized society.

microbiology↗

bioRxiv2020

Opportunities and challenges for improving a Colombian public research program in plant breeding and plant genetic resources lead by Agrosavia

AO_SCPLOWGROSAVIAC_SCPLOW (Corporacion Colombiana de Investigacion Agropecuaria) is the Colombian state institution in charge of the agricultural research at the national level, including plant breeding. Since 2014, AO_SCPLOWGROSAVIAC_SCPLOW started to increase its research staff and has reset the leadership of public research to solve the needs of the agricultural sector population, focusing on small producers. However, the current team working on plant breeding and plant genetic resources are facing some challenges associated with generation gaps and the lack of a collaborative working plan for the next years. To identify the opportunities and actions in this research area, we surveyed all the 52 researchers working in AO_SCPLOWGROSAVIAC_SCPLOW in this area in 2017. We analyzed the opinions of researchers to detect the strengths and weaknesses of the program using a sentiment score. We also examined the networking to test both how consolidated the group is and if among top leaders are gender parity and also have a higher academic degree. Results showed that there is a mixed community of old and new researchers with clear gender bias in the proportion of male-female. Within the network, the interactions are weak, with several subgroups where the top-ten of both central leaders and the most influencer are frequently males with mostly an M.Sc. degree but with significant experience in the area. Researchers have an interest in 31 crops. From them, 26 are in the national germplasm bank, but this bank is not the primary source for their breeding programs. The top-five of plants with increasing interest are corn, cocoa tree, golden berries, oil palm, and sugarcane. Researchers also want to establish collaborations with 54 different institutions, where the Universidad Nacional de Colombia, which is the top public university in the country, is on the head. Researchers also perceived weaknesses in the marker-assisted selection, experimental design, and participatory plant breeding, but those criticisms have a positive sentiment score average of 1.55 (0.3 SE) across 31 texts analyzed. Based on all results, we identified five critical strategic principles to improve the plant-breeding research program. They include a gender diversity policy to hire new researchers strategically to reduce the gender gap and strength the generational shift. Better collaboration between the national germplasm bank and plant breeding research. A coordinate plan where the studies focus on food security crops that the government supports independently of market trends. And finally, adequate spaces for the projects design and training programs. Hence, we recommend the creation of a consultant group to implement these policies progressively in the next years.

plant biology↗

bioRxiv2020

THE IMPACT OF THE HYDROXYMETHYLCYTOSINE EPIGENETIC SIGNATURE ON DNA STRUCTURE AND FUNCTION

We present a comprehensive, experimental and theoretical study of the impact of 5-hydroxymethylation of DNA cytosine. Using molecular dynamics, biophysical experiments and NMR spectroscopy, we found that Ten-Eleven translocation (TET) dioxygenases generate an epigenetic variant with structural and physical properties not too different to those of 5-methylcytosine. Experiments and simulations demonstrate that 5-methyl-cytosine (mC) and 5-hydroxymethyl-cytosine (hmC) generally lead to more rigid duplexes with poorer circularization efficiencies and lower ability to form nucleosomes. In particular, we can rule out the hypothesis that hydroxymethylation reverts to unmodified cytosine physical properties, as hmC is even more rigid than mC. Thus, we do not expect dramatic changes in the chromatin structure induced by differences in physical properties between d(mCpG) and d(hmCpG). On the contrary, our simulations suggest that methylated-DNA binding domains (MBD), associated with repression activities, are very sensitive to the substitution d(mCpG)[->] d(hmCpG), while MBD3 which has a dual activation/repression activity is not sensitive to the d(mCpG) [->] d(hmCpG) change. Overall, while changes in gene activity due to cytosine methylation are the result of the combination of stiffness-related chromatin reorganization and MBD binding, those associated to 5-hydroxylation of methylcytosine could be explained by a change in the balance of repression/activation pathways related to differential MBD binding.

biochemistry↗

bioRxiv2020

Exploring G and C-quadruplex structures as potential targets against the severe acute respiratory syndrome coronavirus 2

In this paper we report the analysis of the 2019-nCoV genome and related viruses using an upgraded version of the open-source algorithm G4-iM Grinder. This version improves the functionality of the software, including an easy way to determine the potential biological features affected by the candidates found. The quadruplex definitions of the algorithm were optimized for 2019-nCoV. Using a lax quadruplex definition ruleset, which accepts amongst other parameters two residue G- and C-tracks, hundreds of potential quadruplex candidates were discovered. These sequences were evaluated by their in vitro formation probability, their position in the viral RNA, their uniqueness and their conservation rates (calculated in over three thousand different COVID-19 clinical cases and sequenced at different times and locations during the ongoing pandemic). These results were compared sequentially to other Coronaviridae members, other Group IV (+)ssRNA viruses and the entire realm. Sequences found in common with other species were further analyzed and characterized. Sequences with high scores unique to the 2019-nCoV were studied to investigate the variations amongst similar species. Quadruplex formation of the best candidates was then confirmed experimentally. Using NMR and CD spectroscopy, we found several highly stable RNA quadruplexes that may be suitable theranostic targets against the 2019-nCoV. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=151 SRC="FIGDIR/small/257493v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@1ab4843org.highwire.dtl.DTLVardef@152ebeorg.highwire.dtl.DTLVardef@afd7aforg.highwire.dtl.DTLVardef@793707_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2020

Novel effector genes revealed by the genomic analysis of the phytopathogenic fungus Fusarium oxysporum f. sp. physali (Foph) that infects cape gooseberry plants

The vascular wilt disease caused by the fungus Fusarium oxysporum f. sp. physali (Foph) is one of the most limiting factors for the production and export of cape gooseberry (Physalis peruviana) in Colombia. A previous study of the transcriptomic profile of a highly virulent strain of F. oxysporum in cape gooseberry plants, from a collection of 136 fungal isolates obtained from wilted cape gooseberry plants, revealed the presence of secreted in the xylem (SIX) effector genes, known to be involved in the pathogenicity of other F. oxysporum formae speciales (ff. spp.). This pathogenic strain was named Foph, due to its specificity for cape gooseberry hosts. Here, we sequenced the genome of Foph, using the Illumina MiSeq platform. We analyzed the assembled genome, focusing on the confirmation of the presence of homologues of SIX effectors and the identification of novel candidates of effector genes unique of Foph. By comparative and phylogenomic analyses based on single-copy orthologues, we identified that Foph is closely related to F. oxysporum ff. spp., associated with solanaceous hosts. We confirmed the presence of highly identical homologous genomic regions between Foph and Fol, that contain effector genes and identified seven new effector gene candidates, specific to Foph strains. We also conducted a molecular characterization of a panel of 29 F. oxysporum additional stains associated to cape gooseberry crops isolated from different regions of Colombia. These results suggest the polyphyletic origin of Foph and the putative independent acquisition of new candidate effectors in different clades of related strains. The novel effector candidates identified by sequencing and analyzing the genome of Foph, represent new sources involved in the interaction between Foph and cape gooseberry. These resources could be implemented to develop appropriate management strategies of the wilt disease caused by Foph in the cape gooseberry crop.

genomics↗

bioRxiv2020

Structures of the germline-specific Deadhead and Thioredoxin T proteins from Drosophila melanogaster reveal unique features among Thioredoxins

Thioredoxins (Trxs) are ubiquitous enzymes that regulate the redox state in cells. In Drosophila, there are two germline-specific Trxs, Deadhead (Dhd) and TrxT. Both proteins belong to the L(3)mbt malignant brain tumor signature and to the MMS survival network of genes that mediate the cellular response to DNA damage. Dhd is a maternal protein required for early embryogenesis that promotes protamine-histone exchange in fertilized eggs and midblastula transition. TrxT is testis-specific and associates with the lampbrush loops of the Y chromosome. Here we present the first structures of Dhd and TrxT that unveil new features of these Thioredoxins. Dhd is highly positively charged, unusual in canonical Trxs. This positively charged surface can facilitate its approximation to DNA and to protamine oligomers, to promote chromatin remodeling. On the other hand, TrxT contains a C-terminal extension, mostly unstructured and highly flexible, which wraps the conserved core through a closed conformation. This extension partially covers the catalytic site and modulates the redox activity of the protein. The information provided by these structures can guide future work aimed at understanding how redox inputs modulate the initial steps of embryo development in Drosophila and may help in the design of molecular inhibitors through a structure-based approach. HighlightsO_LIWe have determined the first structures of the germline-specific Trxs Dhd and TrxT. C_LIO_LIDhd has a highly positively charged surface that facilitates its approximation to DNA and protamine oligomers, to promote chromatin remodeling. C_LIO_LITrxT contains a C-terminal extension, highly unusual in canonical Trxs, mostly unstructured and highly flexible. C_LIO_LIThe TrxT C-terminal extension partially covers the catalytic site and modulates the redox activity of the protein. C_LIO_LIThe differences observed in Thioredoxins can help in fine-tuning specific molecules to be active against selected insect species. C_LI

molecular biology↗

bioRxiv2020

A mechanism for the extension and unfolding of parallel telomeric G-quadruplexes by human telomerase at single-molecule resolution

Telomeric G-quadruplexes (G4) were long believed to form a protective structure at telomeres, preventing their extension by the ribonucleoprotein telomerase. Contrary to this belief, we have previously demonstrated that parallel-stranded conformations of telomeric G4 can be extended by human and ciliate telomerase. However, a mechanistic understanding of the interaction of telomerase with structured DNA remained elusive. Here, we use single-molecule fluorescence resonance energy transfer (smFRET) microscopy and bulk-phase enzymology to propose a mechanism for the resolution and extension of parallel G4 by telomerase. Binding is initiated by the RNA template of telomerase interacting with the G-quadruplex; nucleotide addition then proceeds to the end of the RNA template. It is only through the large conformational change of translocation following synthesis that the G-quadruplex structure is completely unfolded to a linear product. Surprisingly, parallel G4 stabilization with either small molecule ligands or by chemical modification does not always inhibit G4 unfolding and extension by telomerase. These data reveal that telomerase is a parallel G-quadruplex resolvase.

biochemistry↗

bioRxiv2020

A NKp80-based identification strategy reveals that CD56neg NK cells are not completely dysfunctional in health and disease.

Natural killer (NK) cells are usually identified by the absence of other lineage markers, due to the lack of a cell surface specific marker. CD56neg NK cells, classically identified as CD56negCD16+ are known to be expanded in some pathological conditions. However, studies on CD56neg NK cells had revealed different results regarding the phenotype and functionality of these cells. This could be due to, among others, the unstable expression of CD16, which hinders CD56neg NK cells identification. Hence, we aim to determine an alternative surface marker to CD16 to better identify CD56neg NK cells. Using multiparametric flow cytometry, we have found that NKp80 is a good alternative to CD16 not only in healthy donors but also in HIV-1 infected subjects and multiple myeloma patients. Furthermore, we found differences between the functionality of CD56negNKp80+ and CD56negCD16+ NK cells both in healthy donors and patients, suggesting that the effector functions of CD56neg NK cells are not as diminished as previously thought. We proposed NKp80 as a noteworthy marker to identify and accurately re-characterize human CD56neg NK cells.

immunology↗

bioRxiv2019

Long reads from Nanopore sequencing as a tool for animal microbiome studies

In the era of bioinformatics and metagenomics, the study of the ruminal microbiome has gained considerable relevance in the field of animal breeding, since the composition of the rumen microbiota significantly impacts production and the environment. Illumina sequencing is considered the gold standard for the analysis of microbiomes, but it is limited by obtaining only short DNA sequences to analyze. As an alternative, Oxford Nanopore Technologies (ONT) has developed a new sequencing technique based on nanopores that can be carried out in the MinION, a portable device with a low initial cost which long DNA readings can be obtained with. The aim of this study was to compare the performance of both types of sequencing applied to samples of ruminal content using a similar pipeline. The ONT sequencing provided similar results to the Illumina sequencing, although it was able to classify a greater number of readings at the species level, possibly due to the increase in the read size. The results also suggest that, due to the size of the reads, it would be possible to obtain the same amount of information in a smaller number of hours. However, detection of archaeal and eukaryotic species is still difficult to accomplish due to their low abundance in the rumen compared to bacteria, suggesting different pipelines and strategies are needed to obtain a whole representation of the less abundant species in the rumen microbiota.

microbiology↗

bioRxiv2019

Integrating untargeted metabolomics, genetically informed causal inference, and pathway enrichment to define the obesity metabolome

BackgroundObesity and its associated diseases are major health problems characterized by extensive metabolic disturbances. Understanding the causal connections between these phenotypes and variation in metabolite levels can uncover relevant biology and inform novel intervention strategies. Recent studies have combined metabolite profiling with genetic instrumental variable (IV) analyses to infer the direction of causality between metabolites and obesity, but often omitted a large portion of untargeted profiling data consisting of unknown, unidentified metabolite signals.\n\nMethodsWe expanded upon previous research by identifying body mass index (BMI)-associated metabolites in multiple untargeted metabolomics datasets, and then performing bidirectional IV analysis to classify these metabolites based on their inferred causal relationships with BMI. Meta-analysis and pathway analysis of both known and unknown metabolites across datasets were enabled by our recently developed bioinformatics suite, PAIRUP-MS.\n\nResultsWe identified 10 known metabolites that are more likely to be the causes (e.g. alpha-hydroxybutyrate) or effects (e.g. valine) of BMI, or may have more complex bidirectional cause-effect relationships with BMI (e.g. glycine). Importantly, we also identified about 5 times more unknown than known metabolites in each of these three categories. Pathway analysis incorporating both known and unknown metabolites prioritized 40 enriched (p < 0.05) metabolite sets for the cause versus effect groups, providing further support that these two metabolite groups are linked to obesity via distinct biological mechanisms.\n\nConclusionsThese findings demonstrate the potential utility of our approach to uncover causal connections with obesity from untargeted metabolomics datasets. Combining genetically informed causal inference with the ability to map unknown metabolites across datasets provides a path to jointly analyze many untargeted datasets with obesity or other phenotypes. This approach, applied to larger datasets with genotype and untargeted metabolite data, should generate sufficient power for robust discovery and replication of causal biological connections between metabolites and various human diseases.

bioinformatics↗

bioRxiv2019

Lymphocyte subpopulations and mast cells intestinal changes as indicators of inflammatory bowel disease in dogs

Inflammatory bowel disease (IBD) is a disease with recurring gastrointestinal symptoms. Lymphocytes and mast cells are proposed as important components in the immunopathology of IBD in dogs. Mast cells depend on degranulation, a process that compromises mucosal permeability and normal intestinal barrier function, which alters the normal inflammatory process by allowing recruitment of lymphocytes in dogs with IBD. In this study, T and B lymphocyte populations and mast cells were examined in situ in 39 intestinal samples of dogs affected by IBD, by immunohistochemistry. Both T lymphocytes and mast cells numbers were significantly higher in the lamina propria of the intestinal wall of dogs with IBD compared with control dogs. Out of the total number of mast cells detected by CD117 expression significantly less cells appear to be granulated according to granule staining with Toluidine Blue, suggesting that an important degranulation process takes place in IBD. Single and double immune staining for tryptase and chymase showed that mast cells can express only one or both enzymes. Tryptase positive cells were significantly higher in number that chymase positive and tryptase/chymase positive cells. T lymphocytes were concentrated mostly at the upper portion of the intestinal villi lamina propria while mast cells were distributed mainly among crypts. These results suggest that populations of T lymphocytes and mast cells play a role in the immunopathology and development of IBD in dogs, also these changes could be helpful as complementary indicators of canine IBD.

immunology↗

bioRxiv2019

Ubiquitination of the yeast receptor Atg32 modulates mitophagy

Mitophagy, the process that degrades mitochondria selectively through autophagy, is involved in the quality control of these organelles. In yeast, the presence of the Atg32 protein on the outer mitochondrial membrane allows for the recognition and targeting of superfluous or damaged mitochondria for degradation. Some posttranslational modifications, such as phosphorylation, are crucial for the execution of the mitophagy process. In our study, we showed that in the stationary phase of growth, and to a lesser extent during starvation, the Atg32 protein level decreases. The fact that a decline in Atg32 level can be prevented by inhibition of the proteolytic activity of proteasome may indicate that Atg32 is also ubiquitylated. In fact, mass spectrometry analysis of purified Atg32 protein showed ubiquitination of lysine residue in position 282. These different patterns of posttranslational modifications of Atg32 could allow cells to control the mitophagy process carefully.

cell biology↗

bioRxiv2019

Co-occurrence or dependence? Using spatial analyses to explore the interaction between palms and triatomines.

BackgroundTriatomine kissing bugs are responsible for the vectorial transmission of the parasite Trypanosoma cruzi, etiological agent of Chagas disease, a zoonosis affecting 10 million people and with 25 million at risk of infection. Triatomines are associated with particular habitats that offer shelter and food. Several triatomine species of the Rhodnius genus have close association with palm crowns, where bugs can obtain blood from the associated fauna. The Rhodnius - palm interaction has been reported in several places of Central and South America. However, the association in the distributions of Rhodnius species and palms has not been quantitatively determined.\n\nMethodology/Principal FindingsBroad distributions of eight Rhodnius species and 16 palm species with Rhodnius-infestation reports were estimated using Ecological Niche Models. Rhodnius species distributions in their total range were compared to their distributions in areas with palms. Rhodnius species presence was found to be higher in areas with palms. However, that tendency notoriously depended on palm species. Rhodnius species presence increased several times in areas with particular palm species. Moreover, a possible relationship was found between Rhodnius and palm species richness, indicating the Amazon region as the convergent region where several Rhodnius and palm species intersected. Finally, palm distribution was evaluated as predictor of Rhodnius species distributions, but their inclusion in the distributions models did not improve their performance.\n\nConclusions/SignificanceThe distributions of some Rhodnius and palm species showed a high spatial association, which can be based on species interaction or niche similarity. Based on distribution convergence, the Amazon region appear to be the origin of the Rhodnius-palm association. The direct relationship between palms and Rhodnius species richness could be based on the habitat heterogeneity offered by different palm species. Despite spatial association, palm presence would not be a relevant predictor of Rhodnius species distributions in comparison to other environmental variables. Inclusion of other input data as hosts distribution could help to increase model predictability.\n\nAuthor summaryThe infestation of palms with Rhodnius genus kissing bugs (Chagas disease vectors) is important from the public health perspective, since insects living in palms can infest nearby houses. The migration of these bugs to households could threaten vector control programs since reinfestation of treated dwellings can occur. Association between Rhodnius and palms species distributions has been previously suggested but never quantitatively determined. The strong association between one palm species and one Rhodnius species can be used as a factor to predict the presence of Rhodnius bugs in definite areas. In this study, we estimated by models the distributions of eight Rhodnius species and 18 Rhodnius-infested palm species. Rhodnius distributions models showed a biased presence toward areas with certain palm species. That specific association was very strong in some cases; however, the presence of associated palm species was used in Rhodnius distributions models, but that did not improve the predictability of the models. Palm presence appear to be not essential for the Rhodnius current distribution because they could inhabit other habitats; but that association could be relevant to the Rhodnius evolutionary and biogeographic history.

ecology↗

bioRxiv2018

Nanobody-antigen catch-bond reveals NK cell mechanosensitivity

Antibodies are key tools in biomedical research and medicine. Their binding properties are classically measured in solution and characterized by an affinity. However, in physiological conditions, antibodies can bridge an immune effector cell and an antigen presenting cell, implying that mechanical forces apply to the bonds. For example, in antibody-dependent cell cytotoxicity, a major mode of action of therapeutic monoclonal antibodies, the Fab domains bind the antigens on the target cell, while the Fc domain binds to the activating receptor CD16 (also known as FcgRIII) of an immune effector cell, in a quasi bi-dimensional environment (2D). Therefore, there is a strong need to investigating antigen/antibody binding under force (2D), to better understand and predict antibody activity in vivo. We used two anti-CD16 nanobodies targeting two different epitopes and laminar flow chamber assay to measure the association and dissociation of single bonds formed between microsphere-bound CD16 antigens and surface-bound anti-CD16 nanobodies (or single domain antibodies), simulating 2D encounters. The two nanobodies exhibit similar 2D association kinetics, characterized by a strong dependence on the molecular encounter duration. However, their 2D dissociation kinetics strongly differ as a function of applied force: one exhibits a slip bond behaviour where off-rate increases with force; the other exhibits a catch bond behaviour with off-rate decreasing with force. This is the first time, to our knowledge, that catch bond behaviour was reported for antigen-antibody bond. We further exploit this property to show how Natural Killer cells spread differentially on surfaces coated with these molecules, revealing NK cells mechanosensitivity. Our results may also have strong implications for the design of efficient bispecific antibodies for therapeutic applications.

biophysics↗

bioRxiv2018

Quantitative Assessment of Protein Activity in Orphan Tissues and Single Cells Using the metaVIPER Algorithm

We and others have shown that transition and maintenance of biological states is controlled by master regulator protein, which can be inferred by interrogating tissue-specific regulatory models (interactomes) with transcriptional signatures, using the VIPER algorithm. Yet, some tissues may lack molecular profiles necessary for interactome inference (orphan tissues), or, as for single cells isolated from heterogeneous samples, their tissue context may be undetermined. To address this problem, we introduce metaVIPER, a novel algorithm designed to assess protein activity in tissue-independent by integrative analysis of multiple, non-tissue-matched interactomes. This assumes that transcriptional targets of each protein will be recapitulated by one or more available interactome. We confirmed the algorithms value in assessing protein dysregulation induced by somatic mutations, as well as in assessing protein activity in orphan tissues and, most critically, in single cells, thus allowing transformation of noisy and potentially biased RNA-Seq signatures into reproducible protein-activity signatures.

systems biology↗