Evaluating hierarchical machine learning approaches to classify biological databases.

The rate of biological data generation has increased dramatically in recent years, which has driven the importance of databases as a resource to guide innovation and the generation of biological insights. Given the complexity and scale of these databases, automatic data classification is often required. Biological data sets are often hierarchical in nature, with varying degrees of complexity, imposing different challenges to train, test and validate accurate and generalizable classification models. While some approaches to classify hierarchical data have been proposed, no guidelines regarding their utility, applicability and limitations have been explored or implemented. These include 'Local' approaches considering the hierarchy, building models per level or node, and 'Global' hierarchical classification, using a flat classification approach. To fill this gap, here we have systematically contrasted the performance of 'Local per Level' and 'Local per Node' approaches with a 'Global' approach applied to two different hierarchical datasets: BioLip and CATH. The results show how different components of hierarchical data sets, such as variation coefficient and prediction by depth, can guide the choice of appropriate classification schemes. Finally, we provide guidelines to support this process when embarking on a hierarchical classification task, which will help optimize computational resources and predictive performance.

Local age-dependent neuromodulation in Rhodnius prolixus antennae.

Kissing bugs do not respond to host cues when recently molted and only exhibit robust host-seeking several days after ecdysis. Behavioral plasticity has peripheral correlates in antennal gene expression changes through the week after ecdysis. The mechanisms regulating these peripheral changes are still unknown, but neuropeptide, G-protein coupled receptor, nuclear receptor, and takeout genes likely modulate peripheral sensory physiology. We evaluated their expression in antennal transcriptomes along the first week postecdysis of Rhodnius prolixus 5th instar larvae. Besides, we performed clustering and co-expression analyses to reveal relationships between neuromodulatory (NM) and sensory genes. Significant changes in transcript abundance were detected for 50 NM genes. We identified 73 sensory-related and NM genes that were assigned to nine clusters. According to their expression patterns, clusters were classified into four groups: two including genes up or downregulated immediately after ecdysis; and two with genes with expression altered at day 2. Several NM genes together with sensory genes belong to the first group, suggesting functional interactions. Co-expression network analysis revealed a set of genes that seem to connect with sensory system maturation. Significant expression changes in NM components were described in the antennae of R. prolixus after ecdysis, suggesting that a local NM system acts on antennal physiology. These changes may modify the sensitivity of kissing bugs to host cues during this maturation interval.

Egg-laying by female Aedes aegypti shapes the bacterial communities of breeding sites.

BACKGROUND: Aedes aegypti, the main arboviral mosquito vector, is attracted to human dwellings and makes use of human-generated breeding sites. Past research has shown that bacterial communities associated with such sites undergo compositional shifts as larvae develop and that exposure to different bacteria during larval stages can have an impact on mosquito development and life-history traits. Based on these facts, we hypothesized that female Ae. aegypti shape the bacteria communities of breeding sites during oviposition as a form of niche construction to favor offspring fitness. RESULTS: To test this hypothesis, we first verified that gravid females can act as mechanical vectors of bacteria. We then elaborated an experimental scheme to test the impact of oviposition on breeding site microbiota. Five different groups of experimental breeding sites were set up with a sterile aqueous solution of larval food, and subsequently exposed to (1) the environment alone, (2) surface-sterilized eggs, (3) unsterilized eggs, (4) a non-egg laying female, or (5) oviposition by a gravid female. The microbiota of these differently treated sites was assessed by amplicon-oriented DNA sequencing once the larvae from the sites with eggs had completed development and formed pupae. Microbial ecology analyses revealed significant differences between the five treatments in terms of diversity. In particular, between-treatment shifts in abundance profiles were detected, showing that females induce a significant decrease in microbial alpha diversity through oviposition. In addition, indicator species analysis pinpointed bacterial taxa with significant predicting values and fidelity coefficients for the samples in which single females laid eggs. Furthermore, we provide evidence regarding how one of these indicator taxa, Elizabethkingia, exerts a positive effect on the development and fitness of mosquito larvae. CONCLUSIONS: Ovipositing females impact the composition of the microbial community associated with a breeding site, promoting certain bacterial taxa over those prevailing in the environment. Among these bacteria, we found known mosquito symbionts and showed that they can improve offspring fitness if present in the water where eggs are laid. We deem this oviposition-mediated bacterial community shaping as a form of niche construction initiated by the gravid female.

Organotypic hippocampal culture model reveals differential responses to highly similar Zika virus isolates.

INTRODUCTION: Zika virus (ZIKV) caused an outbreak in Brazil, in 2015, being associated to microcephaly. ZIKV has a strong neurotropism leading to death of infected cells in different brain regions, including the hippocampus, a major site for neurogenesis. The neuronal populations of the brain are affected differently by ZIKV from Asian and African ancestral lineages. However, it remains to be investigated whether subtle variations in the ZIKV genome can impact hippocampus infection dynamics and host response. OBJECTIVE: This study evaluated how two Brazilian ZIKV isolates, PE243 and SPH2015, that differ in two specific missense amino acid substitutions, one in the NS1 protein and the other in the NS4A protein, affect the hippocampal phenotype and transcriptome. METHODS: Organotypic hippocampal cultures (OHC) from infant Wistar rats were infected with PE243 or SPH2015 and analyzed in time series using immunofluorescence, confocal microscopy, RNA-Seq and RT-qPCR. RESULTS: Unique patterns of infection and changes in neuronal density in the OHC were observed for PE243 and SPH2015 between 8 and 48 h post infection (p.i.). Phenotypic analysis of microglia indicated that SPH2015 has a greater capacity for immune evasion. Transcriptome analysis of OHC at 16 h p.i. disclosed 32 and 113 differentially expressed genes (DEGs) in response to infection with PE243 and SPH2015, respectively. Functional enrichment analysis suggested that infection with SPH2015 activates mostly astrocytes rather than microglia. PE243 downregulated biological process of proliferation of brain cells and upregulated those associated with neuron death, while SPH2015 downregulated processes related to neuronal development. Both isolates downregulated cognitive and behavioral development processes. Ten genes were similarly regulated by both isolates. They are putative biomarkers of early hippocampus response to ZIKV infection. At 5, 7, and 10 days p.i., neuronal density of infected OHC remained below controls, and mature neurons of infected OHC showed an increase in the epigenetic mark H3K4me3, which is associated to a transcriptionally active state. This feature is more prominent in response to SPH2015. CONCLUSION: Subtle genetic diversity of the ZIKV affects the dynamics of viral dissemination in the hippocampus and host response in the early stages of infection, which may lead to different long-term effects in neuronal population.

Comparative metatranscriptome analysis of Brazilian milk and water kefir beverages.

The present study compared bacterial and fungal diversity of kefir beverages produced using milk (MK) or sugared water (WK) as propagation matrices and grains from the cities of Curitiba (CU) or Salvador (SA), Brazil, by sequencing the complete set of RNA transcripts produced in four products. In Brazil, milk and sugared water are used as matrices to propagate kefir grains. In all beverages, the bacterial community was composed of Lactobacillaceae and Acetobacteraceae. Saccharomycetaceae was the yeast family more abundant in WK, and Dipodascaceae and Pichiaceae in MK. Regarding KEGG mapping of functional orthologs, the four kefir samples shared 70% of KO entries of yeast genes but only 36% of bacterial genes. Concerning main metabolic processes, the relative abundance of transcripts associated with metabolism (energy metabolism) and environmental information processing (membrane transport) had the highest water/milk kefir ratio observed in Firmicutes. In contrast, transcripts associated with genetic information processing (protein translation, folding, sorting, and degradation) oppositely had the lowest water/milk ratios. Concluding, milk and water kefir have quite different communities of microorganisms. Still, the main mapped functional processes are similar, with only quantitative variation in membrane transport and energy acquisition in the water kefir and protein synthesis and turnover in the milk kefir.

Electronic Structure of Small Isolated and Supported Manganese Oxide Clusters.

In the present work, possible molecular models of the isolated manganese oxides and supported Mn3Ox/Al2O3 structures were built based on small clusters of passivated MnOx. The support was represented as a simplified model of the alumina tetramer cluster based on small fragments of AlOxHy. Combinations of MnOxHy and AlOxHy clusters were made to form both the isolated and supported manganese oxides clusters. The electronic structure of these systems was characterized by ab initio methods (DFT and CASPT2). It was observed that the vertical excitation energy of the isolated and supported Mn3OxHy clusters is significantly lower than that of the alumina cluster model, while both the isolated and supported Mn3OxHy wave function characters are qualitatively similar with respect to the ground state and electronic transition processes, suggesting that the alumina cluster behaves as an inert support, since there is little contribution of this component in the description of the low-lying electronic states. The present study also reports for the first time the spectroscopic parameters of several clusters containing the manganese transition metal atom.

Stability and Reactivity of the Phenalene and Olympicene Isomers.

The phenalene (triangulene) and olympicene molecules belong to the polycyclic aromatic hydrocarbon class, which have attracted substantial technological interest due to their unique electronic properties. Electronic structure calculations serve as a valuable tool in investigating the stability and reactivity of these molecular systems. In the present work, the multireference calculations, namely, the complete active space second-order perturbation theory and multireference averaged quadratic coupled cluster (MR-AQCC), were employed to study the reactivity and stability of phenalene and olympicene isomers, as well as their modified structures where the sp3-carbon at the borders were removed. The harmonic oscillator model of aromaticity (HOMA) and the nucleus-independent chemical shift as geometric and magnetic indexes calculated with density functional theory were utilized to assess the aromaticity of the studied molecules. These indexes were compared with properties such as the excitation energy and natural orbitals occupation. The reactivity analyzed using the HOMA index combined with MR-AQCC revealed the radical character of certain structures as well as the weakening of their aromaticity. Moreover, the results suggest that the removal of sp3-carbon atoms and the addition of hydrogen atoms did not alter the π network and the excitation energies of the phenalene molecules.

Lower motor unit discharge rates in gastrocnemius lateralis, but not in gastrocnemius medialis or soleus, in runners with Achilles tendinopathy: a pilot study.

OBJECTIVES: Deficits in muscle performance could be a consequence of a reduced ability of a motor neuron to increase the rate in which it discharges. This study aimed to investigate motor unit (MU) discharge properties of each triceps surae muscle (TS) and TS torque steadiness during submaximal intensities in runners with Achilles tendinopathy (AT). METHODS: We recruited runners with (n = 12) and without (n = 13) mid-portion AT. MU discharge rate was analysed for each of the TS muscles, using high-density surface electromyography during 10 and 20% isometric plantar flexor contractions. RESULTS: MU mean discharge rate was lower in the gastrocnemius lateralis (GL) in AT compared to controls. In AT, GL MU mean discharge rate did not increase as torque increased from 10% peak torque, 8.24 pps (95% CI 7.08 to 9.41) to 20%, 8.52 pps (7.41 to 9.63, p = 0.540); however, in controls, MU discharge rate increased as torque increased from 10%, 8.39 pps (7.25-9.53) to 20%, 10.07 pps (8.89-11.25, p < 0.001). There were no between-group difference in gastrocnemius medialis (GM) or soleus (SOL) MU discharge rates. We found no between-group differences in coefficient of variation of MU discharge rate in any of the TS muscles nor in TS torque steadiness. CONCLUSION: Our data demonstrate that runners with AT may have a lower neural drive to GL, failing to increase MU discharge rate to adjust for the increase in torque demand. Further research is needed to understand how interventions focussing on increasing neural drive to GL would affect muscle function in runners with AT.

Neuroprotection and gliosis attenuation by intravenous application of human mesenchymal stem cells (hMSC) following ventral root crush in mice.

Rupture and stretching of spinal roots are common incidents that take place in high-energy accidents. The proximal axotomy of motoneurons by crushing of ventral roots is directly related to the degeneration of half of the lesioned population within the first two weeks. Moreover, only a small percentage of surviving motoneurons can successfully achieve regeneration after such a proximal lesion, and new treatments are necessary to improve this scenario. In this sense, mesenchymal stem cells (MSC) are of great interest once they secrete a broad spectrum of bioactive molecules that are immunomodulatory and can restore the environment after a lesion. The present work aimed at studying the effects of human mesenchymal stem cells (hMSC) therapy after ventral root crush (VRC) in mice. We evaluated motoneuron survival, glial reaction, and synapse preservation at the ventral horn. For this purpose, C57BL/6 J were submitted to a crush procedure of L4 to L6 ventral roots and treated with a single intravenous injection of adipose-derived hMSC. Evaluation of the results was carried out at 7, 14, and 28 days after injury. Analysis of motoneuron survival and astrogliosis showed that hMSC treatment resulted in higher motoneuron preservation (motoneuron survival ipsi/contralateral ratio: VRC group = 53%, VRC + hMSC group = 66%; p < 0.01), combined with reduction of astrogliosis (ipsi/contralateral GFAP immunolabeling: VRC group = 470%, VRC + hMSC group = 250%; p < 0.001). The morphological classification and Sholl analysis of microglial activation revealed that hMSC treatment reduced type V and increased type II profiles, indicating an enhancement of surveying over activated microglial cells. The glial reactivity modulation directly influenced synaptic inputs in apposition to axotomized motoneurons. In the hMSC-treated group, synaptic maintenance was increased (ipsi/contralateral synaptophysin immunolabeling: VRC group = 53%, VRC + hMSC group = 64%; p < 0.05). Overall, the present data show that intravenous injection of hMSC has neuroprotective and anti-inflammatory effects, decreasing reactive astrogliosis, and microglial reaction. Also, such cell therapy results in motoneuron preservation, combined with significant maintenance of spinal cord circuits, in particular those related to the ventral horn.

Facilitation-inhibition control of motor neuronal persistent inward currents in young and older adults.

A well-coordinated facilitation-inhibition control of motor neuronal persistent inward currents (PICs) via diffuse neuromodulation and local inhibition is essential to ensure motor units discharge at required times and frequencies. Present best estimates indicate that PICs are reduced in older adults; however, it is not yet known whether PIC facilitation-inhibition control is also altered with ageing. We investigated the responses of PICs to (i) a remote handgrip contraction, which is believed to diffusely increase serotonergic input onto motor neurones, and (ii) tendon vibration of the antagonist muscle, which elicits reciprocal inhibition, in young and older adults. High-density surface electromyograms were collected from soleus and tibialis anterior of 18 young and 26 older adults during triangular-shaped plantar and dorsiflexion contractions to 20% (handgrip experiments) and 30% (vibration experiments) of maximum torque (rise-decline rate of 2%/s). A paired-motor-unit analysis was used to calculate ∆F, which is assumed to be proportional to PIC strength. ΔF increased in both soleus (0.55 peaks per second (pps), 16.0%) and tibialis anterior (0.42 pps, 11.4%) after the handgrip contraction independent of age. Although antagonist tendon vibration reduced ΔF in soleus (0.28 pps, 12.6%) independent of age, less reduction was observed in older (0.42 pps, 10.7%) than young adults (0.72 pps, 17.8%) in tibialis anterior. Our data indicate a preserved ability of older adults to amplify PICs following a remote handgrip contraction, during which increased serotonergic input onto the motor neurones is expected, in both lower leg muscles. However, PIC deactivation in response to reciprocal inhibition was impaired with ageing in tibialis anterior despite being preserved in soleus. KEY POINTS: Motor neuronal persistent inward currents (PICs) are facilitated via diffuse neuromodulation and deactivated by local inhibition to ensure motor units discharge at required times and frequencies, allowing normal motor behaviour. PIC amplitudes appear to be reduced with ageing; however, it is not known whether PIC facilitation-inhibition control is also altered. Remote handgrip contraction, which should diffusely increase serotonergic input onto motor neurones, facilitated PICs similarly in both soleus and tibialis anterior of young and older adults. Antagonist tendon vibration, which induces reciprocal inhibition, reduced PICs in soleus in both young and older adults but had less effect in tibialis anterior in older adults. Data from lower-threshold motor units during low-force contractions suggest that PIC facilitation is preserved with ageing in soleus and tibialis anterior. However, the effect of reciprocal inhibition on the contribution of PICs to motor neurone discharge seems reduced in tibialis anterior but preserved in soleus.

Runners with mid-portion Achilles tendinopathy have greater triceps surae intracortical inhibition than healthy controls.

OBJECTIVES: This study aimed to investigate short-interval intracortical inhibition (SICI) and muscle function in the triceps surae of runners with mid-portion Achilles tendinopathy (AT). METHODS: Runners with (n = 11) and without (n = 13) AT were recruited. Plantar flexor isometric peak torque and rate of torque development (RTD) were measured using an isokinetic dynamometer. Triceps surae endurance was measured as single-leg heel raise (SLHR) to failure test. SICI was assessed using paired-pulse transcranial magnetic stimulation during a sustained contraction at 10% of plantar flexor isometric peak torque. RESULTS: Triceps surae SICI was 14.3% (95% CI: -2.1 to 26.4) higher in AT than in the control group (57.9%, 95% CI: 36.2 to 79.6; and 43.6% 95% CI: 16.2 to 71.1, p = 0.032) irrespective of the tested muscle. AT performed 16 (95% CI: 7.9 to 23.3, p < 0.001) fewer SLHR repetitions on the symptomatic side compared with controls, and 14 (95% CI: 5.8 to 22.0, p = 0.004), fewer SLHR repetitions on the non-symptomatic compared with controls. We found no between-groups differences in isometric peak torque (p = 0.971) or RTD (p = 0.815). PERSPECTIVE: Our data suggest greater intracortical inhibition for the triceps surae muscles for the AT group accompanied by reduced SLHR endurance, without deficits in isometric peak torque or RTD. The increased SICI observed in the AT group could be negatively influencing triceps surae endurance; thus, rehabilitation aiming to reduce intracortical inhibition should be considered to improve patient outcomes. Furthermore, SLHR is a useful clinical tool to assess plantar flexor function in AT patients.

Methotrexate promotes recovery of arthritis-induced alveolar bone loss and modifies the composition of the oral-gut microbiota.

OBJECTIVES: The impact of rheumatoid arthritis (RA) on the shaping of the oral and gut microbiome raises the question of whether and how RA treatment modifies microbial communities. We examined changes in the oral and gut microbiota in a mouse model of antigen-induced arthritis (AIA) treated or not with methotrexate (MTX). METHODS: Maxillae and stools were evaluated by the MiSeq platform of the V4 region of the 16S rRNA gene. Alveolar bone parameters were analysed by micro-computed tomography. Moreover, arthritis-induced changes in hyperalgesia and oedema were assessed, along with the impact on periodontal bone health. RESULTS: Microbial communities in MTX-treated AIA mice revealed distinct clusters compared to the control and AIA groups. Overall, MTX impacted the richness and variability of microorganisms in the oral-gut axis microbiome at the phylum level. Regarding the oral microbiome, while in the control group the most dominant phylum was Firmicutes, in the AIA group there was a shift towards the predominance of Campilobacteriota and Bacteroidetes associated with the disease. MTX treatment led to greater dominance of the health-associated phylum Proteobacteria. In the gut microbiome, AIA induction resulted in increased abundance of the Verrucomicrobiota phylum, and MTX treatment restored its levels compared to control. Importantly, the MTX-treated AIA animals had significantly less periodontal bone loss, as well as decreased hyperalgesia and joint oedema compared to the AIA animals. CONCLUSION: Data suggest the benefit of MTX treatment in protecting alveolar bone, in addition to providing new insights on the drug-microbiome interaction in the course of RA.

Soil Acidobacteria Strain AB23 Resistance to Oxidative Stress Through Production of Carotenoids.

Metagenomic studies revealed the prevalence of Acidobacteria in soils, but the physiological and ecological reasons for their success are not well understood. Many Acidobacteria exhibit carotenoid-related pigments, which may be involved in their tolerance of environmental stress. The aim of this work was to investigate the role of the orange pigments produced by Acidobacteria strain AB23 isolated from a savannah-like soil and to identify putative carotenoid genes in Acidobacteria genomes. Phylogenetic analysis revealed that strain AB23 belongs to the Occallatibacter genus from the class Acidobacteriia (subdivision 1). Strain AB23 produced carotenoids in the presence of light and vitamins; however, the growth rate and biomass decreased when cells were exposed to light. The presence of carotenoids resulted in tolerance to hydrogen peroxide. Comparative genomics revealed that all members of Acidobacteriia with available genomes possess the complete gene cluster for phytoene production. Some Acidobacteriia members have an additional gene cluster that may be involved in the production of colored carotenoids. Both colored and colorless carotenoids are involved in tolerance to oxidative stress. These results show that the presence of carotenoid genes is widespread among Acidobacteriia. Light and atmospheric oxygen stimulate carotenoid synthesis, but there are other natural sources of oxidative stress in soils. Tolerance to environmental oxidative stress provided by carotenoids may offer a competitive advantage for Acidobacteria in soils.

Omega-3 fatty acids in contrast to omega-6 protect against pneumococcal pneumonia.

PURPOSE: The aim of this study was to assess if long-term supplementation of omega-3 fatty acids or a diet rich in omega-6 fatty acids ameliorates disease severity in a murine model of pneumococcal pneumonia. We hypothesize that long-term dietary supplementation of omega-3 fatty acids will reduce inflammation, disease severity and improve survival compared to omega-6 fatty acids. METHODS: Mice receiving diets supplemented with Omega-3 or Omega-6 for two months were intranasally infected with Streptococcus pneumoniae. We analyzed survival, bacterial burden, histopathology and inflammatory biomarkers. RESULTS: Our results showed that Omega-3 supplementation had increased survival (p = 0.005), less bacteremia (p = 0.0001) and lower bacterial burden in the lungs (p = 0.0002) when compared to the Omega-6 supplementation. Overall, Omega-3 reduced lung pathology, in particular peribronchial inflammation and cell death. Analyses of lung homogenates showed the Omega-3 cohort had decreased levels of the inflammatory cytokine interleukin-6 and an increase in anti-inflammatory cytokine interleukin-10. CONCLUSIONS: Supplementation of mouse diets with Omega-3 fatty acids improved survival, bacterial invasion in the blood and lungs as well as decreased overall lung tissue inflammation and cell death when compared to the Omega-6 supplemented diets. Translation of these findings in humans may improve outcomes of patients at risk for pneumonia.

Identification of Magic Numbers in Homonuclear Clusters: The ε3 Stability Ranking Function.

With the rise of cluster-assembled materials, an index that is able to rank and identify stable clusters or molecules is of great interest in materials sciences and engineering. In the present work, we applied a stability ranking function (ε3) in nanoclusters formed by simple metals (Na, Mg), main group elements (Al), or transition metals (Ti, Cu). The ε3 function parameters are molecular properties derived from the wave function. These parameters can be divided into kinetic and thermodynamic descriptors, in which the kinetic descriptors are the ionization potential and electronic excitation energy, while the atomization free Gibbs energy is the thermodynamic one. This simple ε3 function was able to identify the possible magic numbers of the studied clusters across the periodic table in a good agreement with previous experimental and theoretical works.

MicrobiomeDB: a systems biology platform for integrating, mining and analyzing microbiome experiments.

MicrobiomeDB (http://microbiomeDB.org) is a data discovery and analysis platform that empowers researchers to fully leverage experimental variables to interrogate microbiome datasets. MicrobiomeDB was developed in collaboration with the Eukaryotic Pathogens Bioinformatics Resource Center (http://EuPathDB.org) and leverages the infrastructure and user interface of EuPathDB, which allows users to construct in silico experiments using an intuitive graphical 'strategy' approach. The current release of the database integrates microbial census data with sample details for nearly 14 000 samples originating from human, animal and environmental sources, including over 9000 samples from healthy human subjects in the Human Microbiome Project (http://portal.ihmpdcc.org/). Query results can be statistically analyzed and graphically visualized via interactive web applications launched directly in the browser, providing insight into microbial community diversity and allowing users to identify taxa associated with any experimental covariate.

Staphylococcus epidermidis role in the skin microenvironment.

Wound healing is a complex dynamic physiological process in response to cutaneous destructive stimuli that aims to restore the cutaneous' barrier role. Deciphering the underlying mechanistic details that contribute to wound healing will create novel therapeutic strategies for skin repair. Recently, by using state-of-the-art technologies, it was revealed that the cutaneous microbiota interact with skin immune cells. Strikingly, commensal Staphylococcus epidermidis-induced CD8+ T cells induce re-epithelization of the skin after injury, accelerating wound closure. From a drug development perspective, the microbiota may provide new therapeutic candidate molecules to accelerate skin healing. Here, we summarize and evaluate recent advances in the understanding of the microbiota in the skin microenvironment.

Serum leptin levels correlate negatively with the capacity of vitamin D to modulate the in vitro cytokines production by CD4+ T cells in asthmatic patients.

Both obesity and low vitamin D levels have been associated with allergic asthma (AA) severity. In the present study, severity of AA was associated with obesity but to the in vitro IgE production. In those patients, higher levels of IL-5, IL-6 and IL-17 were quantified in CD4+ T-cell cultures as compared with patients with mild and moderate AA. In addition, the lowest IL-10 levels were detected in the cell cultures from patients with a worse prognosis. Interestingly, the occurrence of AA elevates the plasma levels of leptin, and this adipokine was positively correlated with the release of IL-5, IL-6 and IL-17, but inversely correlated with IL-10 production, by CD4+ T-cells from patients. In AA-derived CD4+ T-cell cultures, 1,25(OH)2D3 was less efficient at inhibiting IL-5, IL-6 and IL-17 production, and up regulating IL-10 release, as those from healthy subjects. Interestingly, the in vitro immunomodulatory effects of vitamin D were inversely correlated with serum leptin levels. In summary, our findings suggested that obesity, probably due to the overproduction of leptin, negatively impacts AA as it favors imbalance between Th2/Th17 and regulatory phenotypes. The deleterious effects of leptin may also be due to its ability to counter-regulate the immunosuppressive effects of vitamin D.

Oral delivery of pancreatitis-associated protein by Lactococcus lactis displays protective effects in dinitro-benzenesulfonic-acid-induced colitis model and is able to modulate the composition of the microbiota.

Antimicrobial peptides secreted by intestinal immune and epithelial cells are important effectors of innate immunity. They play an essential role in the maintenance of intestinal homeostasis by limiting microbial epithelium interactions and preventing unnecessary microbe-driven inflammation. Pancreatitis-associated protein (PAP) belongs to Regenerating islet-derived III proteins family and is a C-type (Ca+2 dependent) lectin. PAP protein plays a protective effect presenting anti-inflammatory properties able to reduce the severity of colitis, preserving gut barrier and epithelial inflammation. Here, we sought to determine whether PAP delivered at intestinal lumen by recombinant Lactococcus lactis strain (LL-PAP) before and after chemically induced colitis is able to reduce the severity in two models of colitis. After construction and characterization of our recombinant strains, we tested their effects in dinitro-benzenesulfonic-acid (DNBS) and Dextran sulfate sodium (DSS) colitis model. After the DNBS challenge, mice treated with LL-PAP presented less severe colitis compared with PBS and LL-empty-treated mice groups. After the DSS challenge, no protective effects of LL-PAP could be detected. We determined that after 5 days administration, LL-PAP increase butyrate producer's bacteria, especially Eubacterium plexicaudatum. Based on our findings, we hypothesize that a treatment with LL-PAP shifts the microbiota preventing the severity of colon inflammation in DNBS colitis model. These protective roles of LL-PAP in DNBS colitis model might be through intestinal microbiota modulation.

Genomic signatures and co-occurrence patterns of the ultra-small Saccharimonadia (phylum CPR/Patescibacteria) suggest a symbiotic lifestyle.

The size of bacterial genomes is often associated with organismal metabolic capabilities determining ecological breadth and lifestyle. The recently proposed Candidate Phyla Radiation (CPR)/Patescibacteria encompasses mostly unculturable bacterial taxa with relatively small genome sizes with potential for co-metabolism interdependencies. As yet, little is known about the ecology and evolution of CPR, particularly with respect to how they might interact with other taxa. Here, we reconstructed two novel genomes (namely, Candidatus Saccharibacter sossegus and Candidatus Chaer renensis) of taxa belonging to the class Saccharimonadia within the CPR/Patescibacteria using metagenomes obtained from acid mine drainage (AMD). By testing the hypothesis of genome streamlining or symbiotic lifestyle, our results revealed clear signatures of gene losses in these genomes, such as those associated with de novo biosynthesis of essential amino acids, nucleotides, fatty acids and cofactors. In addition, co-occurrence analysis provided evidence supporting potential symbioses of these organisms with Hydrotalea sp. in the AMD system. Together, our findings provide a better understanding of the ecology and evolution of CPR/Patescibacteria and highlight the importance of genome reconstruction for studying metabolic interdependencies between unculturable Saccharimonadia representatives.