Mitogenomic Analysis and Phylogenetic Implications for the Deltocephaline Tribe Chiasmini (Hemiptera: Cicadellidae: Deltocephalinae).

The grassland leafhopper tribe Chiasmini (Cicadellidae: Deltocephalinae) presently comprises 324 described species worldwide, with the highest species diversity occurring in the Nearctic region but a greater diversity of genera occurring in the Old World. In China, this tribe comprises 39 described species in 11 genera, but the fauna remains understudied. The complete mitogenomes of three species of this tribe have been sequenced previously. In order to better understand the phylogenetic position of Chiasmini within the subfamily Deltocephalinae and to investigate relationships among Chiasmini genera and species, we sequenced and analyzed the complete mitogenomes of 13 species belonging to seven genera from China. Comparison of the newly sequenced mitogenomes reveals a closed circular double-stranded structure containing 37 genes with a total length of 14,805 to 16,269 bp and a variable number of non-coding A + T-rich regions. The gene size, gene order, gene arrangement, base composition, codon usage, and secondary structure of tRNAs of the newly sequenced mitogenomes of these 13 species are highly conserved in Chiasmini. The ATN codon is commonly used as the start codon in protein-coding genes (PCGs), except for ND5 in Doratura sp. and ATP6 in Nephotettix nigropictus, which use the rare GTG start codon. Most protein-coding genes have TAA or TAG as the stop codon, but some genes have an incomplete T stop codon. Except for the tRNA for serine (trnS1(AGN)), the secondary structure of the other 21 tRNAs is a typical cloverleaf structure. In addition to the primary type of G-U mismatch, five other types of tRNA mismatches were observed: A-A, A-C, A-G, U-C, and U-U. Chiasmini mitochondrial genomes exhibit gene overlaps with three relatively stable regions: the overlapping sequence between trnW and trnC is AAGTCTTA, the overlapping sequence between ATP8 and ATP6 is generally ATGATTA, and the overlapping sequence between ND4 and ND4L is generally TTATCAT. The largest non-coding region is the control region, which exhibits significant length and compositional variation among species. Some Chiasmini have tandem repeat structures within their control regions. Unlike some other deltocephaline leafhoppers, the sequenced Chiasmini lack mitochondrial gene rearrangements. Phylogenetic analyses of different combinations of protein-coding and ribosomal genes using maximum likelihood and Bayesian methods under different models, using either amino acid or nucleotide sequences, are generally consistent and also agree with results of prior analyses of nuclear and partial mitochondrial gene sequence data, indicating that complete mitochondrial genomes are phylogenetically informative at different levels of divergence within Chiasmini and among leafhoppers in general. Apart from Athysanini and Opsiini, most of the deltocephaline tribes are recovered as monophyletic. The results of ML and BI analyses show that Chiasmini is a monophyletic group with seven monophyletic genera arranged as follows: ((Zahniserius + (Gurawa + (Doratura + Aconurella))) + (Leofa + (Exitianus + Nephotettix))).

Study on the preparation of ascorbic acid reduced ultrafine copper powders in the presence of different protectants and the properties of copper powders based on methionine protection.

High-purity, monodisperse, and low-oxygen submicron copper powder particles with particle sizes in the range of 100-600 nm were synthesized under alkaline conditions using ascorbic acid (C6H8O6) as a reductant and copper chloride (CuCl2·2H2O) as a copper source. The redox potential of the Cu-Cl-H2O system was obtained by calculations and plotted on pH-E diagrams, and a one-step secondary reduction process (Cu(ii) → CuCl(i) → Cu2O(i) → Cu(0)) was proposed to slow down the reaction rate. The commonalities and differences in the nucleation and growth process of copper powders under methionine (Met), hexadecyl trimethyl ammonium bromide (CTAB), and sodium citrate dihydrate (SSC) as protectants and without the addition of protectants are compared, and the reaction mechanism is discussed. Among them, methionine (Met) showed excellent properties and the Cu2O(i) → Cu(0) process was further observed by in situ XRD. The synthesized copper powder particles have higher particle size controllability, dispersibility, antioxidant properties, and stability, and can be decomposed at lower temperatures (<280 °C). The resistivity can reach 21.4 µΩ cm when sintered at a temperature of 325 °C for 30 min. This green and simple synthesis process facilitates industrialization and storage, and the performance meets the requirements of electronic pastes.

Microbiome function and neurodevelopment in Black infants: vitamin B12 emerges as a key factor.

The early life gut microbiome affects the developing brain, and therefore may serve as a target to support neurodevelopment of children living in stressful and under-resourced environments, such as Black youth living on the South Side of Chicago, for whom we observe racial disparities in health. Microbiome compositions/functions key to multiple neurodevelopmental facets have not been studied in Black children, a vulnerable population due to racial disparities in health; thus, a subsample of Black infants living in urban, low-income neighborhoods whose mothers participated in a prenatal nutrition study were recruited for testing associations between composition and function of the gut microbiome (16S rRNA gene sequencing, shotgun metagenomics, and targeted metabolomics of fecal samples) and neurodevelopment (developmental testing, maternal report of temperament, and observed stress regulation). Two microbiome community types, defined by high Lachnospiraceae or Enterobacteriaceae abundance, were discovered in this cohort from 16S rRNA gene sequencing analysis; the Enterobacteriaceae-dominant community type was significantly negatively associated with cognition and language scores, specifically in male children. Vitamin B12 biosynthesis emerged as a key microbiome function from shotgun metagenomics sequencing analysis, showing positive associations with all measured developmental skills (i.e., cognition, language, motor, surgency, effortful control, and observed stress regulation). Blautia spp. also were identified as substantial contributors of important microbiome functions, including vitamin B12 biosynthesis and related vitamin B12-dependent microbiome functions, anti-inflammatory microbial surface antigens, competitive mechanisms against pathobionts, and production of antioxidants. The results are promising with respect to the potential for exploring therapeutic candidates, such as vitamin B12 nutritional or Blautia spp. probiotic supplementation, to support the neurodevelopment of infants at risk for experiencing racial disparities in health.

Oral Metformin Inhibits Choroidal Neovascularization by Modulating the Gut-Retina Axis.

Purpose: Emerging data indicate that metformin may prevent the development of age-related macular degeneration (AMD). Whereas the underlying mechanisms of metformin's anti-aging properties remain undetermined, one proposed avenue is the gut microbiome. Using the laser-induced choroidal neovascularization (CNV) model, we investigate the effects of oral metformin on CNV, retinal pigment epithelium (RPE)/choroid transcriptome, and gut microbiota. Methods: Specific pathogen free (SPF) male mice were treated via daily oral gavage of metformin 300 mg/kg or vehicle. Male mice were selected to minimize sex-specific differences to laser induction and response to metformin. Laser-induced CNV size and macrophage/microglial infiltration were assessed by isolectin and Iba1 immunostaining. High-throughput RNA-seq of the RPE/choroid was performed using Illumina. Fecal pellets were analyzed for gut microbiota composition/pathways with 16S rRNA sequencing/shotgun metagenomics, as well as microbial-derived metabolites, including small-chain fatty acids and bile acids. Investigation was repeated in metformin-treated germ-free (GF) mice and antibiotic-treated/GF mice receiving fecal microbiota transplantation (FMT) from metformin-treated SPF mice. Results: Metformin treatment reduced CNV size (P < 0.01) and decreased Iba1+ macrophage/microglial infiltration (P < 0.005). One hundred forty-five differentially expressed genes were identified in the metformin-treated group (P < 0.05) with a downregulation in pro-angiogenic genes Tie1, Pgf, and Gata2. Furthermore, metformin altered the gut microbiome in favor of Bifidobacterium and Akkermansia, with a significant increase in fecal levels of butyrate, succinate, and cholic acid. Metformin did not suppress CNV in GF mice but colonization of microbiome-depleted mice with metformin-derived FMT suppressed CNV. Conclusions: These data suggest that oral metformin suppresses CNV, the hallmark lesion of advanced neovascular AMD, via gut microbiome modulation.

Multiomic analysis reveals cellular and epigenetic plasticity in intestinal pouches of ulcerative colitis patients.

Background & Aims: Total proctocolectomy with ileal pouch anal anastomosis (IPAA) is the standard of care for patients with severe treatment resistant ulcerative colitis (UC). Despite improvements in patient outcomes, about 50% of patients will develop inflammation of the pouch within 1-2 years following surgery. Establishment of UC pouches is associated with profound histological changes of the mucosa. A detailed characterization of these changes on a cellular and molecular level is crucial for an improved understanding of pouch physiology and diseases management. Methods: We generated cell-type-resolved transcriptional and epigenetic atlases of UC pouches using scRNA-seq and scATAC-seq data from paired biopsy samples from the ileal pouch and ileal segment above the pouch (pre-pouch) of UC-IPAA patients (n=6, female=2) without symptoms. We also collected data from paired biopsies of the terminal ileum (TI) and ascending colon (AC) from healthy controls (n=6, female=3). Results: We identified novel populations of colon-like absorptive and secretory epithelial cells, constituting a significant proportion of the epithelial cell fraction in the pouch but not in matched pre-pouch samples. Pouch-specific enterocytes expressed colon-specific genes, including CEACAM5, CA2. However, in contrast to normal colonic epithelium, these cells also expressed a range of inflammatory and secretory genes, similar to previously detected gene expression signatures in IBD patients. Comparison to longitudinal bulk RNA-seq data from UC pouches demonstrated that colon-like epithelial cells are present early after pouch functionalization and independently of subsequent pouchitis. Finally, single cell chromatin accessibility revealed activation colonic transcriptional regulators, including CDX1, NFIA, and EHF. Conclusion: UC pouches are characterized by partial colonic metaplasia of the epithelium. These data constitute a resource of transcriptomic and epigenetic signatures of cell populations in the pouch and provide an anchor for understanding the underlying molecular mechanisms of pouchitis.

MSCs overexpressing GDNF restores brain structure and neurological function in rats with intracerebral hemorrhage.

Mesenchymal stem cells (MSCs) have been applied in transplantation to treat intracerebral hemorrhage (ICH) but with limited efficacy. Accumulated evidence has shown that glial cell-derived neurotrophic factor (GDNF) plays a crucial part in neuronal protection and functional recovery of the brain after ICH; however, GDNF has difficulty crossing the blood-brain barrier, which limits its application. In this study, we investigated the influences of MSCs overexpressing GDNF (MSCs/GDNF) on the brain structure as well as gait of rats after ICH and explored the possible mechanisms. We found that cell transplantation could reverse the neurological dysfunction and brain damage caused by ICH to a certain extent, and MSCs/GDNF transplantation was superior to MSCs transplantation. Moreover, Transplantation of MSCs overexpressing GDNF effectively reduced the volume of bleeding foci and increased the level of glucose uptake in rats with ICH, which could be related to improving mitochondrial quality. Furthermore, GDNF produced by transplanted MSCs/GDNF further inhibited neuroinflammation, improved mitochondrial quality and function, promoted angiogenesis and the survival of neurons and oligodendrocytes, and enhanced synaptic plasticity in ICH rats when compared with simple MSC transplantation. Overall, our data indicate that GDNF overexpression heightens the curative effect of MSC implantation in treating rats following ICH.

The Host-specific Microbiota is Required for Diet-Specific Metabolic Homeostasis.

In complex mammals, the importance and host-specificity of microbial communities have been demonstrated through their positive effects on host immune fitness or performance. However, whether host metabolic physiology homeostasis depends on a specific bacterial community exclusive to the host remains unclear. Here, we show that the coevolved host-specific microbiota is required to maintain diet-specific flexible and sufficient metabolic homeostasis through a high colonization rate, modulating gut metabolites, and related targets. Using germ-free (GF) mice, we tested whether the fitness benefiting the host metabolic phenotype of microbiota was host-specific. We demonstrated that GF mice associated with exogenous microbiota (human microbiota (HM)), which exhibited different and reduced gut microbial species diversity, significantly elevated metabolic rate, and exhibited metabolic insufficiency, all characteristics of GF mice. Strikingly, the absence of the host-specific microbiome attenuated high-fat diet-specific metabolism features. Different diets caused different metabolic changes in only host-specific microbiota-associated mice, not the host-microbiota mismatched mice. While RNA sequencing revealed subtle changes in the expression of genes in the liver, GF mice and HM mice showed considerably altered expression of genes associated with metabolic physiology compared to GF mice associated with host-specific microbiota. The effect of diet outweighed microbiota in the liver transcriptome. These changes occurred in the setting of decreased luminal short-chain fatty acids (SCFAs) and the secondary bile acid (BAs) pool and downstream gut signaling targets in HM and GF mice, which affects whole-body metabolism. These data indicate that a foreign microbial community provides little metabolic benefit to the host when compared to a host-specific microbiome, due to the colonization selection pressure and microbiota-derived metabolites dysfunction. Overall, microbiome fitness effects on the host metabolic phenotype were host-specific. Understanding the impact of the host-specificity of the microbiome on metabolic homeostasis may provide important insights for building a better probiotic. Highlights: Microbiome fitness effects on the host metabolic phenotype were host-specific in mammals.Human microbiota-associated mice exhibited lower host metabolic fitness or performance, and similar functional costs in GF mice.Different diets cause different metabolic changes only in host-specific microbiota-associated mice, not the host-microbiota mismatched mice.The defective gut microbiota in host-specific microbiota, microbial metabolites and related targets likely drive the metabolic homeostasis.

Facile and eco-friendly fabrication of biocompatible hydrogel containing CuS@Ser NPs with mechanical flexibility and photothermal antibacterial activity to promote infected wound healing.

Bacterial infections can significantly impede wound healing and pose a serious threat to the patient's life. The excessive use of antibiotics to combat bacterial infections has led to the emergence of multi-drug-resistant bacteria. Therefore, there is a pressing need for alternative approaches, such as photothermal therapy (PTT), to address this issue. In this study, for the first time, CuS NPs with photothermal properties were synthesized using sericin as a biological template, named CuS@Ser NPs. This method is simple, green, and does not produce toxic and harmful by-products. These nanoparticles were incorporated into a mixture (XK) of xanthan gum and konjac glucomannan (KGM) to obtain XK/CuS NPs composite hydrogel, which could overcome the limitations of current wound dressings. The composite hydrogel exhibited excellent mechanical flexibility, photothermal response, and biocompatibility. It also demonstrated potent antibacterial properties against both Gram-positive and negative bacteria via antibacterial experiments and accelerated wound healing in animal models. Additionally, it is proved that the hydrogel promoted tissue regeneration by stimulating collagen deposition, angiogenesis, and reducing inflammation. In summary, the XK/CuS NPs composite hydrogel presents a promising alternative for the clinical management of infected wounds, offering a new approach to promote infected wound healing.

Identifying novel candidate compounds for therapeutic strategies in retinopathy of prematurity via computational drug-gene association analysis.

Purpose: Retinopathy of prematurity (ROP) is the leading cause of preventable childhood blindness worldwide. Although interventions such as anti-VEGF and laser have high success rates in treating severe ROP, current treatment and preventative strategies still have their limitations. Thus, we aim to identify drugs and chemicals for ROP with comprehensive safety profiles and tolerability using a computational bioinformatics approach. Methods: We generated a list of genes associated with ROP to date by querying PubMed Gene which draws from animal models, human studies, and genomic studies in the NCBI database. Gene enrichment analysis was performed on the ROP gene list with the ToppGene program which draws from multiple drug-gene interaction databases to predict compounds with significant associations to the ROP gene list. Compounds with significant toxicities or without known clinical indications were filtered out from the final drug list. Results: The NCBI query identified 47 ROP genes with pharmacologic annotations present in ToppGene. Enrichment analysis revealed multiple drugs and chemical compounds related to the ROP gene list. The top ten most significant compounds associated with ROP include ascorbic acid, simvastatin, acetylcysteine, niacin, castor oil, penicillamine, curcumin, losartan, capsaicin, and metformin. Antioxidants, NSAIDs, antihypertensives, and anti-diabetics are the most common top drug classes derived from this analysis, and many of these compounds have potential to be readily repurposed for ROP as new prevention and treatment strategies. Conclusion: This bioinformatics analysis creates an unbiased approach for drug discovery by identifying compounds associated to the known genes and pathways of ROP. While predictions from bioinformatic studies require preclinical/clinical studies to validate their results, this technique could certainly guide future investigations for pathologies like ROP.

Apolipoprotein E Polymorphism Impacts White Matter Injury Through Microglial Phagocytosis After Experimental Subarachnoid Hemorrhage.

Apolipoprotein E (apoE, protein; APOE, gene), divided into three alleles of E2, E3 and E4 in humans, is associated with the progression of white matter lesion load. However, mechanism evidence has not been reported regarding the APOE genotype in early white matter injury (WMI) under subarachnoid hemorrhage (SAH) conditions. In the present study, we investigated the effects of APOE gene polymorphisms, by constructing microglial APOE3 and APOE4-specific overexpression, on WMI and underlying mechanisms of microglia phagocytosis in a mice model of SAH. A total of 167 male C57BL/6J mice (weight 22-26 g) were used. SAH and bleeding environment were induced by endovascular perforation in vivo and oxyHb in vitro, respectively. Multi-technology approaches, including immunohistochemistry, high throughput sequencing, gene editing for adeno-associated viruses, and several molecular biotechnologies were used to validate the effects of APOE polymorphisms on microglial phagocytosis and WMI after SAH. Our results revealed that APOE4 significantly aggravated the WMI and decreased neurobehavioral function by impairing microglial phagocytosis after SAH. Indicators negatively associated with microglial phagocytosis increased like CD16, CD86 and the ratio of CD16/CD206, while the indicators positively associated with microglial phagocytosis decreased like Arg-1 and CD206. The increased ROS and aggravating mitochondrial damage demonstrated that the damaging effects of APOE4 in SAH may be associated with microglial oxidative stress-dependent mitochondrial damage. Inhibiting mitochondrial oxidative stress by Mitoquinone (mitoQ) can enhance the phagocytic function of microglia. In conclusion, anti-oxidative stress and phagocytosis protection may serve as promising treatments in the management of SAH.

Toll-like receptor 4-mediated microglial inflammation exacerbates early white matter injury following experimental subarachnoid hemorrhage.

Neuroinflammation has been reported to be associated with white matter injury (WMI) after subarachnoid hemorrhage (SAH). As the main resident immune cells of the brain, microglia can be activated into proinflammatory and anti-inflammatory phenotypes. Toll-like receptor 4 (TLR4), expressed on the surface of the microglia, plays a key role in microglial inflammation. However, the relationship between TLR4, microglial polarization, and WMI following SAH remains unclear. In this study, a total of 121 male adult C57BL/6 wild-type (WT) mice, 20 WT mice at postnatal day 1 (P1), and 41 male adult TLR4 gene knockout (TLR4-/-) mice were used to investigate the potential role of TLR4-induced microglial polarization in early WMI after SAH by radiological, histological, microstructural, transcriptional, and cytological evidence. The results indicated that microglial inflammation was associated with myelin loss and axon damage, shown as a decrease in myelin basic protein (MBP), as well as increase in degraded myelin basic protein (dMBP) and amyloid precursor protein (APP). Gene knockout of TLR4 revised microglial polarization toward the anti-inflammatory phenotype and protected the white matter at an early phase after SAH (24 h), as shown through reduction of toxic metabolites, preservation of myelin, reductions in APP accumulation, reductions in white matter T2 hyperintensity, and increases in FA values. Cocultures of microglia and oligodendrocytes, the cells responsible for myelin production and maintenance, were established to further elucidate the relationship between microglial polarization and WMI. In vitro, TLR4 inhibition decreased the expression of microglial MyD88 and phosphorylated NF-κB, thereby inhibiting M1 polarization and mitigating inflammation. Decrease in TLR4 in the microglia increased preservation of neighboring oligodendrocytes. In conclusion, microglial inflammation has dual effects on early WMI after experimental SAH. Future explorations on more clinically relevant methods for modulating neuroinflammation are warranted to combat stroke with both WMI and gray matter destruction.

Induction Mechanism of Ferroptosis, Necroptosis, and Pyroptosis: A Novel Therapeutic Target in Nervous System Diseases.

In recent years, three emerging cell deaths, ferroptosis, necroptosis and pyroptosis, have gradually attracted everyone's attention, and they also play an important role in the occurrence and development of various diseases. Ferroptosis is an idiographic iron-dependent form regulated cell death with the hallmark of accumulation of the intracellular reactive oxygen species (ROS). Necroptosis is a form of regulated necrotic cell death mediated by the receptor-interacting protein kinase 1(RIPK1) and receptor-interacting protein kinase 3RIPK3. Pyroptosis, also known as cell inflammatory necrosis, is a programmed cell necrosis mediated by Gasdermin D (GSDMD). It is manifested by the continuous swelling of the cells until the cell membrane ruptures, resulting in the release of the cell contents and the activation of a strong inflammatory response. Neurological disorders remain a clinical challenge and patients do not respond well to conventional treatments. Nerve cell death can aggravate the occurrence and development of neurological diseases. This article reviews the specific mechanisms of these three types of cell death and their relationship with neurological diseases and the evidence for the role of the three types of cell death in neurological diseases; understanding these pathways and their mechanisms is helpful for the treatment of neurological diseases.

Using Advanced Bioinformatics Tools to Identify Novel Therapeutic Candidates for Proliferative Vitreoretinopathy.

Purpose: Proliferative vitreoretinopathy (PVR) is the dreaded cause of failure following retinal detachment repair; however, no cures or preventative therapies exist to date. The purpose of this study was to use bioinformatics tools to identify drugs or compounds that interact with biomarkers and pathways involved in PVR pathogenesis that could be eligible for further testing for the prevention and treatment of PVR. Methods: We queried PubMed to compile a comprehensive list of genes described in PVR to date from human studies, animal models, and genomic studies found in the National Center for Biotechnology Information database. Gene enrichment analysis was performed using ToppGene on PVR-related genes against drug-gene interaction databases to construct a pharmacome and estimate the statistical significance of overrepresented compounds. Compounds with no clinical indications were filtered out from the resulting drug lists. Results: Our query identified 34 unique genes associated with PVR. Out of 77,146 candidate drugs or compounds in the drug databases, our analysis revealed multiple drugs and compounds that have significant interactions with genes involved in PVR, including antiproliferatives, corticosteroids, cardiovascular agents, antioxidants, statins, and micronutrients. Top compounds, including curcumin, statins, and cardiovascular agents such as carvedilol and enalapril, have well-established safety profiles and potentially could be readily repurposed for PVR. Other significant compounds such as prednisone and methotrexate have shown promising results in ongoing clinical trials for PVR. Conclusions: This bioinformatics approach of studying drug-gene interactions can identify drugs that may affect genes and pathways implicated in PVR. Predicted bioinformatics studies require further validation by preclinical or clinical studies; however, this unbiased approach could identify potential candidates among existing drugs and compounds that could be repurposed for PVR and guide future investigations. Translational Relevance: Novel repurposable drug therapies for PVR can be found using advanced bioinformatics models.

A Roadmap for the Human Gut Cell Atlas.

The number of studies investigating the human gastrointestinal tract using various single-cell profiling methods has increased substantially in the past few years. Although this increase provides a unique opportunity for the generation of the first comprehensive Human Gut Cell Atlas (HGCA), there remains a range of major challenges ahead. Above all, the ultimate success will largely depend on a structured and coordinated approach that aligns global efforts undertaken by a large number of research groups. In this Roadmap, we discuss a comprehensive forward-thinking direction for the generation of the HGCA on behalf of the Gut Biological Network of the Human Cell Atlas. Based on the consensus opinion of experts from across the globe, we outline the main requirements for the first complete HGCA by summarizing existing data sets and highlighting anatomical regions and/or tissues with limited coverage. We provide recommendations for future studies and discuss key methodologies and the importance of integrating the healthy gut atlas with related diseases and gut organoids. Importantly, we critically overview the computational tools available and provide recommendations to overcome key challenges.

TRPM4 Drives Cerebral Edema by Switching to Alternative Splicing Isoform After Experimental Traumatic Brain Injury.

Traumatic brain injury (TBI) affects persons of all ages and is recognized as a major cause of death and disability worldwide; it also brings heavy life burden to patients and their families. The treatment of those with secondary injury after TBI is still scarce, however. Alternative splicing (AS) is a crucial post-transcriptional regulatory mechanism associated with various physiological processes, while the contribution of AS in treatment after TBI is poorly illuminated. In this study, we performed and analyzed the transcriptome and proteome datasets of brain tissue at multiple time points in a controlled cortical impact (CCI) mouse model. We found that AS, as an independent change against the transcriptional level, is a novel mechanism linked to cerebral edema after TBI. Bioinformatics analysis further indicated that the transformation of splicing isoforms after TBI was related to cerebral edema. Accordingly, we found that the fourth exon of transient receptor potential channel melastatin 4 (Trpm4) abrogated skipping at 72 h after TBI, resulting in a frameshift of the encoded amino acid and an increase in the proportion of spliced isoforms. Using magnetic resonance imaging (MRI), we have shown the numbers of 3nEx isoforms of Trpm4 may be positively correlated with volume of cerebral edema. Thus alternative splicing of Trpm4 becomes a noteworthy mechanism of potential influence on edema. In summary, alternative splicing of Trpm4 may drive cerebral edema after TBI. Trpm4 is a potential therapeutic targeting cerebral edema in patients with TBI.

Effect of Early External Ventricular Drainage on Perihemorrhagic Edema and Functional Outcome in Patients with Intraventricular Hemorrhage.

OBJECTIVE: External ventricular drainage (EVD) is the most common neurosurgical procedure that allows drainage of cerebrospinal fluid and intraventricular blood. A specific time threshold for insertion of an EVD catheter in patients with spontaneous intracerebral hemorrhage and intraventricular hemorrhage has not been established. This study aimed to evaluate the association of early EVD with functional outcome in patients with intracerebral hemorrhage and intraventricular hemorrhage. METHODS: Propensity score matching was used to account for baseline imbalances. Modified Rankin Scale score at 3 and 6 months, mortality rates at 3 and 6 months, postoperative complications, time course of edema evolution, and peak perihemorrhagic edema (PHE) were compared in patients who received early EVD versus routine EVD. RESULTS: The rate of favorable outcome at 3 months was higher in the early EVD group compared with the routine EVD group. There were no differences between groups in modified Rankin Scale score at 6 months or mortality rates at 3 and 6 months. Absolute peak PHE and relative PHE volumes were significantly less in the early EVD group compared with the routine EVD group. The incidence of postoperative infections was lower in the early EVD group compared with the routine EVD group. CONCLUSIONS: Early EVD was associated with improved functional outcome at 3 months, reduced PHE, and lower rate of infection in intracerebral hemorrhage and intraventricular hemorrhage. However, survival at 3 and 6 months and functional outcome at 6 months were not improved.

Plasma metabolites with mechanistic and clinical links to the neurovascular disease cavernous angioma.

BACKGROUND: Cavernous angiomas (CAs) affect 0.5% of the population, predisposing to serious neurologic sequelae from brain bleeding. A leaky gut epithelium associated with a permissive gut microbiome, was identified in patients who develop CAs, favoring lipid polysaccharide producing bacterial species. Micro-ribonucleic acids along with plasma levels of proteins reflecting angiogenesis and inflammation were also previously correlated with CA and CA with symptomatic hemorrhage. METHODS: The plasma metabolome of CA patients and CA patients with symptomatic hemorrhage was assessed using liquid-chromatography mass spectrometry. Differential metabolites were identified using partial least squares-discriminant analysis (p < 0.05, FDR corrected). Interactions between these metabolites and the previously established CA transcriptome, microbiome, and differential proteins were queried for mechanistic relevance. Differential metabolites in CA patients with symptomatic hemorrhage were then validated in an independent, propensity matched cohort. A machine learning-implemented, Bayesian approach was used to integrate proteins, micro-RNAs and metabolites to develop a diagnostic model for CA patients with symptomatic hemorrhage. RESULTS: Here we identify plasma metabolites, including cholic acid and hypoxanthine distinguishing CA patients, while arachidonic and linoleic acids distinguish those with symptomatic hemorrhage. Plasma metabolites are linked to the permissive microbiome genes, and to previously implicated disease mechanisms. The metabolites distinguishing CA with symptomatic hemorrhage are validated in an independent propensity-matched cohort, and their integration, along with levels of circulating miRNAs, enhance the performance of plasma protein biomarkers (up to 85% sensitivity and 80% specificity). CONCLUSIONS: Plasma metabolites reflect CAs and their hemorrhagic activity. A model of their multiomic integration is applicable to other pathologies.

Cavernous angiomas (CAs) are clusters of abnormal blood vessels found in the brain or spinal cord. A blood test that could identify people with CAs that have recently bled would help determine who need surgery or closer medical monitoring. We looked at the blood of people with CAs to compare the levels of metabolites, a type of small molecule produced within the body, in those who had recently bled and those who had not. We found that some metabolites may contribute to CA and have an impact on CA symptoms. Monitoring the levels of these metabolites can determine whether there had been a recent bleed. In the future, drugs or other therapies could be developed that would block or change the levels of these molecules and possibly be used to treat CA disease.

Imbalanced gut microbiota predicts and drives the progression of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis in a fast-food diet mouse model.

Nonalcoholic fatty liver disease (NAFLD) is multifactorial in nature, affecting over a billion people worldwide. The gut microbiome has emerged as an associative factor in NAFLD, yet mechanistic contributions are unclear. Here, we show fast food (FF) diets containing high fat, added cholesterol, and fructose/glucose drinking water differentially impact short- vs. long-term NAFLD severity and progression in conventionally-raised, but not germ-free mice. Correlation and machine learning analyses independently demonstrate FF diets induce early and specific gut microbiota changes that are predictive of NAFLD indicators, with corresponding microbial community instability relative to control-fed mice. Shotgun metagenomics showed FF diets containing high cholesterol elevate fecal pro-inflammatory effectors over time, relating to a reshaping of host hepatic metabolic and inflammatory transcriptomes. FF diet-induced gut dysbiosis precedes onset and is highly predictive of NAFLD outcomes, providing potential insights into microbially-based pathogenesis and therapeutics.

A single cell-based computational platform to identify chemical compounds targeting desired sets of transcription factors for cellular conversion.

Cellular conversion can be induced by perturbing a handful of key transcription factors (TFs). Replacement of direct manipulation of key TFs with chemical compounds offers a less laborious and safer strategy to drive cellular conversion for regenerative medicine. Nevertheless, identifying optimal chemical compounds currently requires large-scale screening of chemical libraries, which is resource intensive. Existing computational methods aim at predicting cell conversion TFs, but there are no methods for identifying chemical compounds targeting these TFs. Here, we develop a single cell-based platform (SiPer) to systematically prioritize chemical compounds targeting desired TFs to guide cellular conversions. SiPer integrates a large compendium of chemical perturbations on non-cancer cells with a network model and predicted known and novel chemical compounds in diverse cell conversion examples. Importantly, we applied SiPer to develop a highly efficient protocol for human hepatic maturation. Overall, SiPer provides a valuable resource to efficiently identify chemical compounds for cell conversion.