FuncPEP v20: An Updated Database of Functional Short Peptides Translated from Non-Coding RNAs

Over the past decade, there have been reports of short novel functional peptides (less than 100 aa in length) translated from so-called non-coding RNAs (ncRNAs) that have been characterized using mass spectrometry (MS) and large-scale proteomics studies. Therefore, understanding the bivalent functions of some ncRNAs as transcripts that encode both functional RNAs and short peptides, which we named ncPEPs, will deepen our understanding of biology and disease. In 2020, we published the first database of functional peptides translated from non-coding RNAs-FuncPEP. Herein, we have performed an update including the newly published ncPEPs from the last 3 years along with the categorization of host ncRNAs. FuncPEP v2.0 contains 152 functional ncPEPs, out of which 40 are novel entries. A PubMed search from August 2020 to July 2023 incorporating specific keywords was performed and screened for publications reporting validated functional peptides derived from ncRNAs. We did not observe a significant increase in newly discovered functional ncPEPs, but a steady increase. The novel identified ncPEPs included in the database were characterized by a wide array of molecular and physiological parameters (i.e., types of host ncRNA, species distribution, chromosomal density, distribution of ncRNA length, identification methods, molecular weight, and functional distribution across humans and other species). We consider that, despite the fact that MS can now easily identify ncPEPs, there still are important limitations in proving their functionality

MicroRNA Profiles in Intestinal Epithelial Cells in a Mouse Model of Sepsis

Sepsis is a systemic inflammatory disorder that leads to the dysfunction of multiple organs. In the intestine, the deregulation of the epithelial barrier contributes to the development of sepsis by triggering continuous exposure to harmful factors. However, sepsis-induced epigenetic changes in gene-regulation networks within intestinal epithelial cells (IECs) remain unexplored. In this study, we analyzed the expression profile of microRNAs (miRNAs) in IECs isolated from a mouse model of sepsis generated via cecal slurry injection. Among 239 miRNAs, 14 miRNAs were upregulated, and 9 miRNAs were downregulated in the IECs by sepsis. Upregulated miRNAs in IECs from septic mice, particularly miR-149-5p, miR-466q, miR-495, and miR-511-3p, were seen to exhibit complex and global effects on gene regulation networks. Interestingly, miR-511-3p has emerged as a diagnostic marker in this sepsis model due to its increase in blood in addition to IECs. As expected, mRNAs in the IECs were remarkably altered by sepsis; specifically, 2248 mRNAs were decreased, while 612 mRNAs were increased. This quantitative bias may be possibly derived, at least partly, from the direct effects of the sepsis-increased miRNAs on the comprehensive expression of mRNAs. Thus, current in silico data indicate that there are dynamic regulatory responses of miRNAs to sepsis in IECs. In addition, the miRNAs that were increased with sepsis had enriched downstream pathways including Wnt signaling, which is associated with wound healing, and FGF/FGFR signaling, which has been linked to chronic inflammation and fibrosis. These modifications in miRNA networks in IECs may lead to both pro- and anti-inflammatory effects in sepsis. The four miRNAs discovered above were shown to putatively targe

Designing Supertough and Ultrastretchable Liquid Metal-Embedded Natural Rubber Composites for Soft-Matter Engineering

Functional elastomers with incredible toughness and stretchability are indispensable for applications in soft robotics and wearable electronics. Furthermore, coupled with excellent electrical and thermal properties, these materials are at the forefront of recent efforts toward widespread use in cutting-edge electronics and devices. Herein, we introduce a highly deformable eutectic-GaIn liquid metal alloy-embedded natural rubber (NR) architecture employing, for the first time, industrially viable solid-state mixing and vulcanization. Standard methods of rubber processing and vulcanization allow us to fragment and disperse liquid metals into submicron-sized droplets in cross-linked NR without compromising the elastic properties of the base matrix. In addition to substantial boosts in mechanical (strain at failure of up to ∼650%) and elastic (negligible hysteresis loss) performances, the tearing energy of the composite was enhanced up to 6 times, and a fourfold reduction in the crack growth rate was achieved over a control vulcanizate. Moreover, we demonstrate improved thermal conductivity and dielectric properties for the resulting composites. Therefore, this work provides a facile and scalable pathway to develop liquid metal-embedded soft elastomeric composites that could be instrumental toward potential applications in soft-matter engineering.Post-print / Final draf

Estradiol Mediates Colonic Epithelial Protection in Aged Mice After Stroke and Is Associated With Shifts in the Gut Microbiome

The gut is a major source of bacteria and antigens that contribute to neuroinflammation after brain injury. Colonic epithelial cells (ECs) are responsible for secreting major cellular components of the innate defense system, including antimicrobial proteins (AMP) and mucins. These cells serve as a critical regulator of gut barrier function and maintain host-microbe homeostasis. In this study, we determined post-stroke host defense responses at the colonic epithelial surface in mice. We then tested if the enhancement of these epithelial protective mechanisms is beneficial in young and aged mice after stroke. AMPs were significantly increased in the colonic ECs of young males, but not in young females after experimental stroke. In contrast, mucin-related genes were enhanced in young females and contributed to mucus formation that maintains the distance between the host and gut bacteria. Bacterial community profiling was done using universal amplification of 16S rRNA gene sequences. The sex-specific colonic epithelial defense responses after stroke in young females were reversed with ovariectomy and led to a shift from a predominately mucin response to the enhanced AMP expression seen in males after stroke. Estradiol (E2) replacement prior to stroke in aged females increased mucin gene expression in the colonic ECs. Interestingly, we found that E2 treatment reduced stroke-associated neuronal hyperactivity in the insular cortex, a brain region that interacts with visceral organs such as the gut, in parallel to an increase in the composition of Lactobacillus and Bifidobacterium in the gut microbiota. This is the first study demonstrating sex differences in host defense mechanisms in the gut after brain injury

CD11bhigh B Cells Increase After Stroke and Regulate Microglia: CD11bhigh B Cells Increase After Stroke and Regulate MG

Recent studies have highlighted the deleterious contributions of B cells to post-stroke recovery and cognitive decline. Different B cell subsets have been proposed based on expression levels of transcription factors (e.g. T-bet) as well as specific surface proteins. CD11b (α-chain of integrin) is expressed by several immune cell types and is involved in regulation of cell motility, phagocytosis, and other essential functions of host immunity. Although B cells express CD11b, the CD11bhigh subset of B cells has not been well characterized, especially in immune dysregulation seen with aging and after stroke. Here, we investigate the role of CD11bhigh B cells in immune responses after stroke in young and aged mice. We evaluated the ability of CD11bhigh B cells to influence pro- and anti-inflammatory phenotypes of young and aged microglia (MG). We hypothesized that CD11bhigh B cells accumulate in the brain and contribute to neuroinflammation in aging and after stroke. We found that CD11bhigh B cells are a heterogeneous subpopulation of B cells, predominantly present in naïve aged mice. Their frequency increases in the brain after stroke in young and aged mice. Importantly, CD11bhigh B cells regulate MG phenotype and increase MG phagocytosis in both ex vivo and in vivo settings, likely by production of regulatory cytokines (e.g., TNF-α). As both APCs and adaptive immune cells with long-term memory function, B cells are uniquely positioned to regulate acute and chronic phases of the post-stroke immune response, and their influence is subset-specific

Feasibility of a randomized controlled trial to evaluate the impact of decision boxes on shared decision-making processes

BACKGROUND: Decision boxes (DBoxes) are two-page evidence summaries to prepare clinicians for shared decision making (SDM). We sought to assess the feasibility of a clustered Randomized Controlled Trial (RCT) to evaluate their impact. METHODS: A convenience sample of clinicians (nurses, physicians and residents) from six primary healthcare clinics who received eight DBoxes and rated their interest in the topic and satisfaction. After consultations, their patients rated their involvement in decision-making processes (SDM-Q-9 instrument). We measured clinic and clinician recruitment rates, questionnaire completion rates, patient eligibility rates, and estimated the RCT needed sample size. RESULTS: Among the 20 family medicine clinics invited to participate in this study, four agreed to participate, giving an overall recruitment rate of 20%. Of 148 clinicians invited to the study, 93 participated (63%). Clinicians rated an interest in the topics ranging 6.4-8.2 out of 10 (with 10 highest) and a satisfaction with DBoxes of 4 or 5 out of 5 (with 5 highest) for 81% DBoxes. For the future RCT, we estimated that a sample size of 320 patients would allow detecting a 9% mean difference in the SDM-Q-9 ratings between our two arms (0.02 ICC; 0.05 significance level; 80% power). CONCLUSIONS: Clinicians’ recruitment and questionnaire completion rates support the feasibility of the planned RCT. The level of interest of participants for the DBox topics, and their level of satisfaction with the Dboxes demonstrate the acceptability of the intervention. Processes to recruit clinics and patients should be optimized. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12911-015-0134-x) contains supplementary material, which is available to authorized users

Perspective: The Evolution of Hormones and Person Perception-A Quantitative Genetic Framework

Evolutionary biology provides a unifying theory for testing hypotheses about the relationship between hormones and person perception. Person perception usually receives attention from the perspective of sexual selection. However, because person perception is one trait in a suite regulated by hormones, univariate approaches are insufficient. In this Perspectives article, quantitative genetics is presented as an important but underutilized framework for testing evolutionary hypotheses within this literature. We note tacit assumptions within the current literature on psychiatric genetics, which imperil the interpretation of findings thus far. As regulators of a diverse manifold of traits, hormones mediate tradeoffs among an array of functions. Hormonal pleiotropy also provides the basis of correlational selection, a process whereby selection on one trait in a hormone-mediated suite generates selection on the others. This architecture provides the basis for conflicts between sexual and natural selection within hormone-mediated suites. Due to its role in person perception, psychiatric disorders, and reproductive physiology, the sex hormone estrogen is highlighted as an exemplar here. The implications of this framework for the evolution of person perception are discussed. Empirical quantification of selection on traits within hormone-mediated suites remains an important gap in this literature with great potential to illuminate the fundamental nature of psychiatric disorders

MicroRNAs as a Therapeutic Target to Regulate Microglial Activation in Post­ Stroke Isolation in Aged Male Mice

Introduction: It is increasingly recognized that social Isolation (SI) leads to a wide array of behavioral and cognitive deficits. Isolation and loneliness are linked to all-cause mortality, as well as mortality from stroke and other vascular diseases. In addition, isolated or lonely individuals have significantly poorer cognitive and functional outcomes following stroke and have higher rates of stroke recurrence. These detrimental effects have also been recapitulated in animal models; animals isolated prior to, or at the time of stroke, have larger infarcts than pair-housed mice. However, the mechanisms mediating the effects of social factors on stroke recovery are unknown. An emerging subtype of microglia classified as “disease- associated microglia (DAM)” has been implicated in the progression of neurological diseases such as Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). MicroRNAs (miRNAs), a class of 18-25 nucleotide non-coding RNAs, have been shown to regulate the activation of microglia from a resting state to “disease-associated microglia (DAM)”. Preliminary work in the laboratory has shown post-stroke SI significantly alters miRNA profiles in the brain. Targeted miRNA-based therapies reduced pro-inflammatory cytokines and restores functional recovery in aged male mice placed in isolation immediately after stroke. Based on this preliminary data and previous reports, we hypothesize that differential expression of miRNAs may contribute to the deleterious effects of post- stroke SI through effects of accumulating presence of “disease-associated microglia”. The temporal profiles of miRNA changes were determined in mice placed in isolation three days after stroke. Methods: Aged (18-20 month) C57BL/6 male mice were used to examine the detrimental effects of post-stroke SI on miRNA profiles in the brain and to evaluate “disease- associated microglia (DAM)” phenotypes. Mice were randomly assigned to either continued pair housing (PH), or single housing (SI) three days after a 60-minute transient right middle cerebral artery occlusion (MCAO). At this time point (3d), the infarct is complete, and equivalent between groups, avoiding potential changes seen with differing infarct sizes. MiRNA profiling of the ipsilateral hemisphere was assessed at three time points (post-stroke SI D1, D4, and D27) using the QIAGEN NGS platform. Activation of “disease-associated microglia (DAM)” was determined by flow cytometry analysis at post-stroke SI D4. Results: Post-stroke SI results in a significant alteration of miRNA profiles within the brain across both acute and chronic time points. MiRNA-mRNA interactional analysis reveals miR-466i-3p, miR-10a-5p, and miR-10b-5p as pivotal nodes within the pool of miRNAs that interacted with the largest subset of miRNAs for post-stroke at SI D1, D4, and D27 respectively. Downstream pathway analysis utilizing two independent repositories showed four days of isolation results in microglial activation and 27 days of isolation leads to long-term depressive phenotypes (FDR adjusted p Summary and Conclusions: In summary, these results support our hypothesis that post-stroke SI results in the activation of microglia that may be regulated by particular classes of miRNAs. Studies manipulating these discovered targets are needed to determine if the detrimental effects of SI can be reversed to enhance post-stroke recovery

THE ROLE OF MICRORNAs ON SYSTEMIC AND CENTRAL NERVOUS SYSTEM- INFLAMMATION IN AGED MICE

MicroRNAs play a crucial role in multiple biological processes, including development, cell differentiation, proliferation, metabolism, and cell death. Aberrant regulation of microRNAs is seen in many diseases, such as sepsis, cardiovascular disease, neurological diseases such as stroke, and metabolic disorders. Because of their involvement in disease processes, microRNAs have been investigated as both potential biomarkers, and as therapeutic targets. Age-related inflammatory diseases including diabetes, obesity, and atherosclerosis are important risk factors for infection and sepsis. Intestinal barrier impairment occurs with aging and after brain injuries, including stroke. Both aging and stroke increase the risk of infection and sepsis and are a common cause of death in stroke patients. There has been a paucity of research examining the impact of microRNAs on stroke-induced sepsis, specifically regarding their involvement in regulating intestinal barrier integrity. In a mouse model of sepsis generated via cecal ligation and puncture, we found altered microRNA profiles in intestinal epithelial cells that functionally regulate and shape the IEC-specific transcriptome. We found increased expression of 14 microRNAs, and a decrease in the expression of 9 microRNAs in intestinal epithelial cell with sepsis. The expression of several microRNAs, such as miR-149-5p, miR-466q, miR-495, and miR-511-3p, was increased with disrupted intestinal barriers, and IECs of septic mice regulated Wnt signaling in pathway analysis. Some of these altered miRNAs were noted to be key drivers of oxidative stress, apoptosis, and ischemia which may explain the heightened risk of sepsis in stroke patients. Collectively, it is evident that systemic inflammation is a contributing factor for the development of infection and sepsis. In conclusion, social isolation exacerbates stroke outcomes, and alters microRNA expression profiles, suggesting a potential interplay between social factors, inflammation, microRNA regulation, and microglial activation in stroke pathology. Understanding these intricate connections could offer insights into novel therapeutic targets for effective stroke management. Future studies investigating microglial-specific miRNAs in the context of post-stroke social isolation and how they exacerbate pro-inflammatory cytokine activation and cognitive impairment are warranted