A Focused Review of Gamma Neuromodulation as a Therapeutic Target in Alzheimer's Spectrum Disorders.

The aging population of the world is increasing at an unprecedented rate which is expected to lead to a corresponding unparalleled increase in age related diseases. Of particular concern are the large number of older adults expected to develop Alzheimer's disease (AD), which will require extraordinary local, national and worldwide healthcare resources. In this context, innovative interventions are needed urgently to delay AD onset and thereby give our healthcare systems time to prepare and provide meaningful care to our aging populations. This focused review discusses the crucial role of frontal gamma oscillations as a therapeutic target to delay or ameliorate cognitive decline in AD. Frontal gamma oscillations, including from prefrontal cortical areas, serve as a biomarker for working memory and other cognitive functions, and their impairment is observed before clinical symptoms manifest. This review evaluates evidence from animal models and human subjects to highlight the correlation between gamma wave abnormalities and cognitive deterioration. Furthermore, the review summarizes 11 clinical studies using neuromodulation techniques designed to stimulate gamma oscillations in mild cognitive impairment (MCI) and AD patients, including transcranial electrical stimulation, transcranial magnetic stimulation, and rhythmic sensory stimulation. These interventions have shown promise in mitigating early-stage cognitive decline, as evidenced by improved performance on memory tests, increased gamma oscillatory responses, and some have even shown reduced brain atrophy. These early studies suggest that treatments that strengthen frontal gamma oscillatory responses through neuromodulation are a promising approach to delay cognitive decline, that may serve as an adjunct to other therapies or as a standalone treatment in some populations.

Novel EEG-Based Neurofeedback System Targeting Frontal Gamma Activity of Schizophrenia Patients to Improve Working Memory.

Patients with schizophrenia (SCZ) exhibit working memory (WM) deficits that are associated with deficient dorsal-lateral prefrontal cortical activity, including decreased frontal gamma power. We thus hypothesized that training SCZ patients to increase frontal gamma activity would improve their WM performance. We administered electroencephalographic (EEG) neurofeedback (NFB) to 31 participants with SCZ for 12 weeks (24 sessions), which provides real-time visual and auditory feedback related to frontal gamma activity. The EEG-NFB training significantly improved EEG markers of optimal working memory, e.g., frontal P3 amplitude and gamma power. Based on these promising results, we developed a novel, EEGLAB/MATLAB-based brain-computer interface (BCI) that delivers F3-F4 gamma coherence NFB with a dynamic threshold to SCZ patients randomized in a double-blind, placebo-controlled clinical trial. The BCI significantly increased F3-F4 gamma coherence after 12 weeks (24 sessions) of training, according to data from the first 12 subjects ( n=6 /group) who completed gamma- or placebo-NFB training.

Self-Supporting Electrocatalyst Film Based on Self-Assembly of Heterogeneous Bottlebrush and Polyoxometalate for Efficient Hydrogen Evolution Reaction.

Developing efficient electrocatalysts to promote the hydrogen evolution reaction (HER) is essential for a green and sustainable future energy supply. For practical applications, it is a challenge to achieve the self-assembly of electrocatalyst from microscopic to macroscopic scales. Herein, a facile strategy is proposed to fabricate a self-supporting electrocatalyst film (CNT-g-PSSCo/PW12 ) for HER by electrostatic interaction-induced self-assembly of cobalt polystyrene sulfonate-grafted carbon nanotube heterogeneous bottlebrush (CNT-g-PSSCo) and polyoxometalate (PW12 ). Co2+ ions of CNT-g-PSSCo can function as junctions for interconnecting neighboring bottlebrushes to form the 3D nanonetwork structure and enable electrostatic capture of negatively charged PW12 nanodots. Moreover, CNT backbones can provide highly conductive pathways to CNT-g-PSSCo/PW12 . Such a self-assembled CNT-g-PSSCo/PW12 displays a low overpotential of 31 mV at a current density of 10 mA cm-2 and a small Tafel slope of 25 mV dec-1 , showing high efficiency toward HER. Furthermore, CNT-g-PSSCo/PW12 with a stable self-supporting film morphology exhibits long-term electrocatalytic stability over 1000 CV cycles without noticeable overpotential change in acidic media. The findings may provide a new avenue for constructing self-assembled functional nanonetwork materials with well-orchestrated structural hierarchy for many applications in energy, environment, catalysis, medicine, and others.

Unsupervised learning of brain state dynamics during emotion imagination using high-density EEG.

This study applies adaptive mixture independent component analysis (AMICA) to learn a set of ICA models, each optimized by fitting a distributional model for each identified component process while maximizing component process independence within some subsets of time points of a multi-channel EEG dataset. Here, we applied 20-model AMICA decomposition to long-duration (1-2 h), high-density (128-channel) EEG data recorded while participants used guided imagination to imagine situations stimulating the experience of 15 specified emotions. These decompositions tended to return models identifying spatiotemporal EEG patterns or states within single emotion imagination periods. Model probability transitions reflected time-courses of EEG dynamics during emotion imagination, which varied across emotions. Transitions between models accounting for imagined "grief" and "happiness" were more abrupt and better aligned with participant reports, while transitions for imagined "contentment" extended into adjoining "relaxation" periods. The spatial distributions of brain-localizable independent component processes (ICs) were more similar within participants (across emotions) than emotions (across participants). Across participants, brain regions with differences in IC spatial distributions (i.e., dipole density) between emotion imagination versus relaxation were identified in or near the left rostrolateral prefrontal, posterior cingulate cortex, right insula, bilateral sensorimotor, premotor, and associative visual cortex. No difference in dipole density was found between positive versus negative emotions. AMICA models of changes in high-density EEG dynamics may allow data-driven insights into brain dynamics during emotional experience, possibly enabling the improved performance of EEG-based emotion decoding and advancing our understanding of emotion.

Sex differences in microRNA expression in first and third trimester human placenta†.

Maternal and fetal pregnancy outcomes related to placental function vary based on fetal sex, which may be due to sexually dimorphic epigenetic regulation of RNA expression. We identified sexually dimorphic miRNA expression throughout gestation in human placentae. Next-generation sequencing identified miRNA expression profiles in first and third trimester uncomplicated pregnancies using tissue obtained at chorionic villous sampling (n = 113) and parturition (n = 47). Sequencing analysis identified 986 expressed mature miRNAs from female and male placentae at first and third trimester (baseMean>10). Of these, 11 sexually dimorphic (FDR < 0.05) miRNAs were identified in the first and 4 in the third trimester, all upregulated in females, including miR-361-5p, significant in both trimesters. Sex-specific analyses across gestation identified 677 differentially expressed (DE) miRNAs at FDR < 0.05 and baseMean>10, with 508 DE miRNAs in common between female-specific and male-specific analysis (269 upregulated in first trimester, 239 upregulated in third trimester). Of those, miR-4483 had the highest fold changes across gestation. There were 62.5% more female exclusive differences with fold change>2 across gestation than male exclusive (52 miRNAs vs 32 miRNAs), indicating miRNA expression across human gestation is sexually dimorphic. Pathway enrichment analysis identified significant pathways that were differentially regulated in first and third trimester as well as across gestation. This work provides the normative sex dimorphic miRNA atlas in first and third trimester, as well as the sex-independent and sex-specific placenta miRNA atlas across gestation, which may be used to identify biomarkers of placental function and direct functional studies investigating placental sex differences.

Peritoneum-Inspired Janus Porous Hydrogel with Anti-Deformation, Anti-Adhesion, and Pro-Healing Characteristics for Abdominal Wall Defect Treatment.

Implantable meshes used in tension-free repair operations facilitate treatment of internal soft-tissue defects. However, clinical meshes fail to achieve anti-deformation, anti-adhesion, and pro-healing properties simultaneously, leading to undesirable surgery outcomes. Herein, inspired by the peritoneum, a novel biocompatible Janus porous poly(vinyl alcohol) hydrogel (JPVA hydrogel) is developed to achieve efficient repair of internal soft-tissue defects by a facile yet efficient strategy based on top-down solvent exchange. The densely porous and smooth bottom-surface of JPVA hydrogel minimizes adhesion of fibroblasts and does not trigger any visceral adhesion, and its loose extracellular-matrix-like porous and rough top-surface can significantly improve fibroblast adhesion and tissue growth, leading to superior abdominal wall defect treatment to commercially available PP and PCO meshes. With unique anti-swelling property (maximum swelling ratio: 6.4%), JPVA hydrogel has long-lasting anti-deformation performance and maintains high mechanical strength after immersion in phosphate-buffered saline (PBS) for 14 days, enabling tolerance to the maximum abdominal pressure in an internal wet environment. By integrating visceral anti-adhesion and defect pro-healing with anti-deformation, the JPVA hydrogel patch shows great prospects for efficient internal soft-tissue defect repair.

Inhibition of Rev-erbα ameliorates muscular dystrophy.

Duchene muscular dystrophy leads to progressive muscle structural and functional decline due to chronic degenerative-regenerative cycles. Enhancing the regenerative capacity of dystrophic muscle provides potential therapeutic options. We previously demonstrated that the circadian clock repressor Rev-erbα inhibited myogenesis and Rev-erbα ablation enhanced muscle regeneration. Here we show that Rev-erbα deficiency in the dystrophin-deficient mdx mice promotes regenerative myogenic response to ameliorate muscle damage. Loss of Rev-erbα in mdx mice improved dystrophic pathology and muscle wasting. Rev-erbα-deficient dystrophic muscle exhibit augmented myogenic response, enhanced neo-myofiber formation and attenuated inflammatory response. In mdx myoblasts devoid of Rev-erbα, myogenic differentiation was augmented together with up-regulation of Wnt signaling and proliferative pathways, suggesting that loss of Rev-erbα inhibition of these processes contributed to the improvement in regenerative myogenesis. Collectively, our findings revealed that the loss of Rev-erbα function protects dystrophic muscle from injury by promoting myogenic repair, and inhibition of its activity may have therapeutic utilities for muscular dystrophy.

High-throughput miRNA sequencing of the human placenta: expression throughout gestation.

Aim: To understand miRNA changes across gestation in healthy human placentae. This is essential before miRNAs can be used as biomarkers or prognostic indicators during pregnancy. Materials & methods: Using next-generation sequencing, we characterize the normative human placenta miRNome in first (n = 113) and third trimester (n = 47). Results & conclusion: There are 801 miRNAs expressed in both first and third trimester, including 182 with similar expression across gestation (p ≥ 0.05, fold change ≤2) and 180 significantly different (false discovery rate <0.05, fold change >2). Of placenta-specific miRNA clusters, chromosome 14 miRNA cluster decreases across gestation and chromosome 19 miRNA cluster is overall highly expressed. Chromosome 13 clusters are upregulated in first trimester. This work provides a rich atlas of healthy pregnancies to direct functional studies investigating the epigenetic differences in first and third trimester placentae.

Lay abstract The human body produces miRNAs which affect the expression of genes and proteins. This study uses next-generation sequencing to identify the miRNA profile of first and third trimester human placentae using a large cohort (n = 113 first trimester; n = 47 third trimester). All pregnancies resulted in healthy babies. We identify miRNAs with significantly different expression between first and third trimester, as well as stably expressed miRNAs. This work provides a baseline for future studies which may use miRNAs to monitor maternal­fetal health throughout pregnancy.

Chronic circadian shift leads to adipose tissue inflammation and fibrosis.

The circadian clock exerts temporal coordination of metabolic pathways. Clock disruption is intimately linked with the development of obesity and insulin resistance, and our previous studies found that the essential clock transcription activator, Brain and Muscle Arnt-like 1 (Bmal1), is a key regulator of adipogenesis. However, the metabolic consequences of chronic shiftwork on adipose tissues have not been clearly defined. Here, using an environmental lighting-induced clock disruption that mimics rotating shiftwork schedule, we show that chronic clock dysregulation for 6 months in mice resulted in striking adipocyte hypertrophy with adipose tissue inflammation and fibrosis. Both visceral and subcutaneous depots display enlarged adipocyte with prominent crown-like structures indicative of macrophage infiltration together with evidence of extracellular matrix remodeling. Global transcriptomic analyses of these fat depots revealed that shiftwork resulted in up-regulations of inflammatory, adipogenic and angiogenic pathways with disruption of normal time-of-the-day-dependent regulation. These changes in adipose tissues are associated with impaired insulin signaling in mice subjected to shiftwork, together with suppression of the mTOR signaling pathway. Taken together, our study identified the significant adipose depot dysfunctions induced by chronic shiftwork regimen that may underlie the link between circadian misalignment and insulin resistance.

The clock regulator Bmal1 protects against muscular dystrophy.

The muscle-intrinsic clock machinery is required for the maintenance of muscle growth, remodeling and function. Our previous studies demonstrated that the essential transcription activator of the molecular clock feed-back loop, Brain and Muscle Arnt-Like 1(Bmal1), plays a critical role in myogenic progenitor behavior to promote and regenerative myogenesis. Using genetic approaches targeting Bmal1 in the DMDmdx (mdx) dystrophic mouse model, here we report that the loss of Bmal1 function significantly accelerated dystrophic disease progression. In contrast to the mild dystrophic changes in mdx mice, the genetic loss-of-function of Bmal1 aggravated muscle damage in this dystrophic disease background, as indicated by persistently elevated creatine kinase levels, increased injury area and reduced muscle grip strength. Mechanistic studies revealed that markedly impaired myogenic progenitor proliferation and myogenic response underlie the defective new myofiber formation in the chronic dystrophic milieu. Taken together, our study identified the function of pro-myogenic clock gene Bmal1 in protecting against dystrophic damage, suggesting the potential for augmenting Bmal1 function to ameliorate dystrophic or degenerative muscle diseases.

Differential gene expression during placentation in pregnancies conceived with different fertility treatments compared with spontaneous pregnancies.

OBJECTIVE: To identify differences in the transcriptomic profiles during placentation from pregnancies conceived spontaneously vs. those with infertility using non-in vitro fertilization (IVF) fertility treatment (NIFT) or IVF. DESIGN: Cohort study. SETTING: Academic medical center. PATIENT(S): Women undergoing chorionic villus sampling at gestational age 11-13 weeks (n = 141), with pregnancies that were conceived spontaneously (n = 74), with NIFT (n = 33), or with IVF (n = 34), resulting in the delivery of viable offspring. INTERVENTION(S): Collection of chorionic villus samples from women who conceived spontaneously, with NIFT, or with IVF for gene expression analysis using RNA sequencing. MAIN OUTCOME MEASURE(S): Baseline maternal, paternal, and fetal demographics, maternal medical conditions, pregnancy complications, and outcomes. Differential gene expression of first-trimester placenta. RESULT(S): There were few differences in the transcriptome of first-trimester placenta from NIFT, IVF, and spontaneous pregnancies. There was one protein-coding differentially expressed gene (DEG) between the spontaneous and infertility groups, CACNA1I, one protein-coding DEG between the spontaneous and IVF groups, CACNA1I, and five protein-coding DEGs between the NIFT and IVF groups, SLC18A2, CCL21, FXYD2, PAEP, and DNER. CONCLUSION(S): This is the first and largest study looking at transcriptomic profiles of first-trimester placenta demonstrating similar transcriptomic profiles in pregnancies conceived using NIFT or IVF and spontaneous conceptions. Gene expression differences found to be highest in the NIFT group suggest that the underlying infertility, in addition to treatment-related factors, may contribute to the observed gene expression profiles.

In Vivo Real-Time Discrimination Among Glioma, Infiltration Zone, and Normal Brain Tissue via Autofluorescence Technology.

BACKGROUND: Surgery is the first-line therapy for glioblastoma. There is evidence that extent of resection is significantly associated with patient survival. Unfortunately, optimal surgical resection is usually limited because of the difficulty in discriminating tumor-infiltrated region and normal brain tissue. This study aimed to develop a tool to distinguish between infiltration zone and normal tissue in real time during glioma surgery. METHODS: In an in vivo study, C6 glioma cells were implanted into the left cerebral hemispheres of 6 rats to mimic tumorigenesis. A newly designed optical fiber-embedded needle probe was used to measure the autofluorescence of both cerebral hemispheres at various depths 5 days after the implantation. These rats were then sacrificed, and both cerebral hemispheres were removed for histopathologic analysis. RESULTS: Comparative analyses of corresponding areas by histopathology and autofluorescence revealed highly significant (P < 0.001) differences among the normal tissue, infiltration zone, tumors, and the contralateral cerebral hemispheres. The area of the receiver operating characteristic curve was 0.978, and the sensitivity and specificity of tumor delineation were 93.9% and 94.4%, respectively. CONCLUSIONS: The newly designed in vivo fiber-optic probe can distinguish tumor-infiltration zones from normal brain tissue in this in vivo study. Therefore, it may help neurosurgeons to increase extent of resection without damaging normal brain tissue and thus potentially improve the patients' survival and quality of life.

Regulation of Nur77 expression by ß-catenin and its mitogenic effect in colon cancer cells.

The orphan nuclear receptor Nur77 is an immediate-early response gene whose expression is rapidly induced by various extracellular stimuli. The aims of this study were to study the role of Nur77 expression in the growth and survival of colon cancer cells and the mechanism by which Nur77 expression was regulated. We showed that levels of Nur77 were elevated in a majority of human colon tumors (9/12) compared to their nontumorous tissues and that Nur77 expression could be strongly induced by different colonic carcinogens including deoxycholic acid (DCA). DCA-induced Nur77 expression resulted in up-regulation of antiapoptotic BRE and angiogenic VEGF, and it enhanced the growth, colony formation, and migration of colon cancer cells. In studying the mechanism by which Nur77 was regulated in colon cancer cells, we found that ß-catenin was involved in induction of Nur77 expression through its activation of the transcriptional activity of AP-1 (c-Fos/c-Jun) that bound to and transactivated the Nur77 promoter. Together, our results demonstrate that Nur77 acts to promote the growth and survival of colon cancer cells and serves as an important mediator of the Wnt/ß-catenin and AP-1 signaling pathways.

Oncogenic potential of retinoic acid receptor-gamma in hepatocellular carcinoma.

Retinoic acid receptors (RAR; alpha, beta, and gamma), members of the nuclear receptor superfamily, mediate the pleiotropic effects of the vitamin A metabolite retinoic acid (RA) and derivatives (retinoids) in normal and cancer cells. Abnormal expression and function of RARs are often involved in the growth and development of cancer. However, the underlying molecular mechanisms remain largely elusive. Here, we report that levels of RARgamma were significantly elevated in tumor tissues from a majority of human hepatocellular carcinoma (HCC) and in HCC cell lines. Overexpression of RARgamma promoted colony formation by HCC cells in vitro and the growth of HCC xenografts in animals. In HepG2 cells, transfection of RARgamma enhanced, whereas downregulation of RARgamma expression by siRNA approach impaired, the effect of RA on inducing the expression of alpha-fetoprotein, a protein marker of hepatocarcinogenesis. In studying the possible mechanism by which overexpression of RARgamma contributed to liver cancer cell growth and transformation, we observed that RARgamma resided mainly in the cytoplasm of HCC cells, interacting with the p85alpha regulatory subunit of phosphatidylinositol 3-kinase (PI3K). The interaction between RARgamma and p85alpha resulted in activation of Akt and NF-kappaB, critical regulators of the growth and survival of cancer cells. Together, our results show that overexpression of RARgamma plays a role in the growth of HCC cells through nongenomic activation of the PI3K/Akt and NF-kappaB signaling pathways.