Explore synergistic and competitive miRNA regulation mechanisms in the miRNA-mRNA regulatory network from the information decomposition perspective

Since multiple microRNAs can target 3' untranslated regions of the same mRNA transcript, it is likely that these endogenous microRNAs may form synergistic alliances, or compete for the same mRNA harbouring overlapping binding site matches. Synergistic and competitive microRNA regulation is an intriguing yet poorly elucidated mechanism. We here introduce a computational method based on the multivariate information measurement to quantify such implicit interaction effects between microRNAs. Our informatics method of integrating sequence and expression data is designed to establish the functional correlation between microRNAs. To demonstrate our method, we exploited TargetScan and The Cancer Genome Atlas data. As a result, we indeed observed that the microRNA pair with neighbouring binding site(s) on the mRNA is likely to trigger synergistic events, while the microRNA pair with overlapping binding site(s) on the mRNA is likely to cause competitive events, provided that the pair of microRNAs has a high functional similarity and the corresponding triplet presents a positive/negative 'synergy-redundancy' score.

Rec8 cohesin-mediated loop-axis chromatin architecture is required for meiotic recombination

During meiotic prophase, cohesin-dependent axial structures are formed in the synaptonemal complex (SC). However, the functional correlation between these structures and cohesion remains elusive. Here, we examined the formation of the cohesin-dependent axial structure in fission yeast, which forms atypical SCs composed of linear elements (LinEs) resembling the lateral elements of SC but lacking the central elements. The results demonstrated that Rec8 cohesin is crucial for the formation of the loop-axis structure within the atypical SC. Furthermore, the Rec8-mediated loop-axis structure is formed in the absence of LinEs and provides a structural platform for aligning homologous chromosomes. We also identified a rec8 mutant that lost the ability to assemble the loop-axis structure without losing cohesion. Remarkably, this mutant showed defects in the LinE assembly, resulting in a significant reduction in meiotic recombination. Collectively, our results demonstrate an essential role for the Rec8-dependent loop-axis structure in LinE assembly, facilitating meiotic recombination.

Blood-Brain Barrier Overview: Structural and Functional Correlation

The blood-brain barrier (BBB) is a semipermeable and extremely selective system in the central nervous system of most vertebrates, that separates blood from the brain’s extracellular fluid. It plays a vital role in regulating the transport of necessary materials for brain function, furthermore, protecting it from foreign substances in the blood that could damage it. In this review, we searched in Google Scholar, Pubmed, Web of Science, and Saudi Digital Library for the various cells and components that support the development and function of this barrier, as well as the different pathways to transport the various molecules between blood and the brain. We also discussed the aspects that lead to BBB dysfunction and its neuropathological consequences, with the identification of some of the most important biomarkers that might be used as a biomarker to predict the BBB disturbances. This comprehensive overview of BBB will pave the way for future studies to focus on developing more specific targeting systems in material delivery as a future approach that assists in combinatorial therapy or nanotherapy to destroy or modify this barrier in pathological conditions such as brain tumors and brain stem cell carcinomas.

Pulmonary Vascular Volume is Associated With DLCO and Fibrotic Score in Idiopathic Pulmonary Fibrosis: An Observational Study

Background: Idiopathic pulmonary fibrosis (IPF) is primarily a disease of old age. However, it is difficult to diagnose and has a complex disease course. High-resolution computed tomography (HRCT) and lung function test are crucial for its diagnosis and follow-up. However, the correlation of HRCT findings to lung function test results was not extensively investigated.Methods: This study retrospectively analysed the medical records and images of patients with IPF. Patients with evident emphysema and lung cancer were excluded. All included cases would be investigated through a multidiscipline discussion to confirm the diagnosis. The correlation of CT findings including fibrotic score, CT lung volume, pulmonary artery trunk (PA) diameter and pulmonary vascular volume (PVV) to the lung function test such as forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) was analysed.Results: A total of 32 patients were included. The fibrotic score and PVV were significantly correlated with DLCO (r = 0.59, p = 0.01; r = −0.43, p = 0.03, respectively) but not with FVC. The PVV was significantly correlated with fibrotic score (r = 0.59, p<0.01) and PA diameter (r = 0.47, p = 0.006).Conclusion: Our study shows the structural and functional correlation of IPF. The extent of lung fibrosis (fibrotic score) and PVV were associated with DLCO but not with FVC, especially for patients with IPF without significant FVC deficiency. The PA diameter, which reflects the pulmonary artery pressure, was associated with PVV.

Depth-resolved intersubject functional correlation of 7T BOLD signals reveals increased stimulus related information sharing across deep layers in premotor and parietal nodes for predictable actions

While the brain regions involved in action observation are relatively well documented in humans and primates, how these regions communicate to help understand and predict actions remains poorly understood. Traditional views emphasized a feed-forward architecture in which visual features are organized into increasingly complex representations that feed onto motor programs in parietal and then premotor cortices where the matching of observed actions upon the observer's own motor programs contributes to action understanding. Predictive coding models place less emphasis on feed-forward connections and propose that feed-back connections from premotor regions back to parietal and visual neurons represent predictions about upcoming actions that can supersede visual inputs when actions become predictable, with visual input then merely representing prediction errors. Here we leverage the notion that feed-back connections target deeper cortical layers than feed-forward connections to help adjudicate across these views. Specifically, we test whether observing sequences of hand actions in their natural order, which permits participants to predict upcoming actions, triggers more feed-back input to parietal regions than seeing the same actions in a scrambled sequence that hinders making predictions. Using submillimeter fMRI acquisition at 7T, we find that watching predictable sequences triggers more action-related activity (as measured using intersubject functional correlation) in deep layers of the parietal cortical area PFt than watching the exact same actions in scrambled and hence unpredictable sequence. In addition, functional connectivity analysis performed using intersubject functional connectivity confirms that this deep, action-related signals in PFt could originate from ventral premotor region BA44. This data showcases the utility of intersubject functional correlation in combination with 7T MRI to explore the architecture of social cognition under more naturalistic conditions, and provides evidence for models that emphasize the importance of feed-back connections in action prediction.

Effects of enhanced insect feeding on the faecal microbiota and transcriptome of a family of captive common marmosets (Callithrix jacchus)

Common marmosets have been widely used in biomedical research for years. Nutritional control is an important factor in managing their health, and insect intake would be beneficial for that purpose because common marmosets frequently feed on insects in natural habitats. Here, we examined the effect of enhanced insect feeding on the gut by analysing the faecal microbiota and transcripts of captive marmosets. A family consisting of six marmosets was divided into two groups. During the seven-day intervention period, one group (the insect feeding group, or Group IF) was fed one cricket and one giant mealworm per marmoset per day, while the other (the control group, or Group C) was not fed these insects. RNA was extracted from faecal samples to evaluate the ecology and transcripts of the microbiota, which were then compared among time points before (Pre), immediately after (Post), and two weeks after intervention (After) by total RNA sequencing. The gut microbiota of marmosets showed Firmicutes, Actinobacteria, Bacteroidetes, and Proteobacteria as dominant phyla. Linear discriminant analysis showed differential characteristics of microbiota with and without insect feeding treatment. Further analysis of differentially expressed genes revealed increases and decreases in Bacteroidetes and Firmicutes, respectively, corresponding to the availability of insects under both Post and After conditions. Significant changes specific to insect feeding were also detected within the transcriptome, some of which were synchronized with the fluctuations in the microbiota, suggesting a functional correlation or interaction between the two. The rapid changes in the microbiota and transcripts may be deeply connected to the original microbiota community shaped by marmoset feeding ecology in the wild. The results were informative for identifying the physiological impact of insect feeding to produce a better food regimen and for detecting transcripts that are currently unidentifiable.

Chronic behavioral manipulation via orally delivered chemogenetic actuator in macaques

The chemogenetic technology referred to as designer receptors exclusively activated by designer drugs (DREADDs) offers reversible means to control neuronal activity for investigating its functional correlation with behavioral action. Deschloroclozapine (DCZ), a recently-developed highly potent and selective DREADDs actuator, displays a capacity to expand the utility of DREADDs for chronic manipulation without side-effects in nonhuman primates, which has not yet been validated. Here we investigated the pharmacokinetics and behavioral effects of orally administered DCZ in macaque monkeys. Pharmacokinetic analysis and positron emission tomography (PET) occupancy examination demonstrated that oral administration of DCZ yielded slower and prolonged kinetics, and that its bioavailability was 10-20% of that in the case of systemic injection. Oral DCZ (300-1000 μg/kg) induced significant working memory impairments for at least 4 h in monkeys with hM4Di expressed in the prefrontal cortex. Repeated daily oral doses of DCZ consistently caused similar impairments over two weeks without discernible desensitization. Our results indicate that orally delivered DCZ affords a less invasive strategy for chronic but reversible chemogenetic manipulation of neuronal activity in nonhuman primates, and this has potential for clinical application.

Characterization of early Alzheimer's-like pathological alterations in non-human primates with aging: a pilot study

Sporadic or late onset Alzheimer's disease (LOAD) is a multifactorial neurodegenerative disease with aging the most known risk factor. Non-human primates (NHPs) may serve as an excellent model to study LOAD because of their close similarity to humans in many aspects including neuroanatomy and neurodevelopment. Recent studies reveal AD-like pathology in old NHPs. In this pilot study, we took advantage of brain samples from 6 Cynomolgus macaques that were divided into two groups: middle aged (average age 14.81 years) and older (average age 19.33 years). We found multiple AD-like pathological alteration in the prefrontal cortex (but not in the hippocampus) of the older NHPs including tau hyperphosphorylation, increased activity of AMP-activated protein kinase (AMPK), decreased expression of protein phosphatase 2A (PP2A), impairments in mitochondrial morphology and postsynaptic densities (PSDs) formation. These findings may provide insights into the factors contributing to the development of LOAD, particularly during the early stage transitioning from middle to old age. Future endeavors are warranted to elucidate mechanisms underlying the regional (and perhaps cellular) vulnerability with aging and the functional correlation of such pathological changes in NHPs.

Crosstalks between NOD1 and Histone H2A Contribute to Host Defense against Streptococcus agalactiae Infection in Zebrafish

Correlation studies about NOD1 and histones have not been reported. In the present study, we report the functional correlation between NOD1 and the histone H2A variant in response to Streptococcus agalactiae infection. In zebrafish, NOD1 deficiency significantly promoted S. agalactiae proliferation and decreased larval survival. Transcriptome analysis revealed that the significantly enriched pathways in NOD1−/− adult zebrafish were mainly involved in immune and metabolism. Among 719 immunity-associated DEGs at 48 hpi, 74 DEGs regulated by NOD1 deficiency were histone variants. Weighted gene co-expression network analysis identified that H2A, H2B, and H3 had significant associations with NOD1 deficiency. Above all, S. agalactiae infection could induce the expression of intracellular histone H2A, as well as NOD1 colocalized with histone H2A, both in the cytoplasm and cell nucleus in the case of S. agalactiae infection. The overexpression of H2A variants such as zfH2A-6 protected against S. agalactiae infection and could improve cell survival in NOD1-deficient cells. Furthermore, NOD1 could interact with zfH2A-6 and cooperate with zfH2A-6 to inhibit the proliferation of S. agalactiae. NOD1 also showed a synergetic effect in inducing the expression of many antibacterial genes, especially antibacterial pattern recognition receptors PGRP2, PGRP5, and PGRP6. Collectively, these results firstly highlight the roles of NOD1 deficiency in the regulation of immune-related and metabolic pathways, and the correlation between zebrafish NOD1 and histone H2A variant in the defense against S. agalactiae infection.