This review describes unique neuromodulatory influences on working memory prefrontal cortical (PFC) circuits that coordinate cognitive strength with arousal state. Working memory arises from ...recurrent excitation within layer III PFC pyramidal cell NMDA circuits, which are afflicted in aging and schizophrenia. Neuromodulators rapidly and flexibly alter the efficacy of these synaptic connections, while leaving the synaptic architecture unchanged, a process called dynamic network connectivity (DNC). Increases in calcium-cAMP signaling open ion channels in long, thin spines, gating network connections. Inhibition of calcium-cAMP signaling by stimulating α2A-adrenoceptors on spines strengthens synaptic efficacy and increases network firing, whereas optimal stimulation of dopamine D1 receptors sculpts network inputs to refine mental representation. Generalized increases in calcium-cAMP signaling during fatigue or stress disengage dlPFC recurrent circuits, reduce firing and impair top-down cognition. Impaired DNC regulation contributes to age-related cognitive decline, while genetic insults to DNC proteins are commonly linked to schizophrenia.
Arnsten et al. discuss dynamic network connectivity (DNC), a process by which neuromodulators alter the efficacy of synaptic connections in working memory PFC circuits. Impaired DNC regulation contributes to age-related cognitive decline, while genetic insults to DNC proteins are linked to schizophrenia.
Prenatal exposure of the developing brain to various environmental challenges increases susceptibility to late onset of neuropsychiatric dysfunction; still, the underlying mechanisms remain obscure. ...Here we show that exposure of embryos to a variety of environmental factors such as alcohol, methylmercury, and maternal seizure activates HSF1 in cerebral cortical cells. Furthermore, Hsf1 deficiency in the mouse cortex exposed in utero to subthreshold levels of these challenges causes structural abnormalities and increases seizure susceptibility after birth. In addition, we found that human neural progenitor cells differentiated from induced pluripotent stem cells derived from schizophrenia patients show higher variability in the levels of HSF1 activation induced by environmental challenges compared to controls. We propose that HSF1 plays a crucial role in the response of brain cells to prenatal environmental insults and may be a key component in the pathogenesis of late-onset neuropsychiatric disorders.
•HSF1 is activated in the cortex by various types of prenatal environmental stresses•Loss of HSF1 increases seizure susceptibility upon prenatal exposure to challenges•Hsp70 partially mediates the pluripotent roles of HSF1•Cell-to-cell variability of HSF1 activation is increased in schizophrenia iPSC-NPC
Hashimoto-Torii et al. show that HSF1 protects fetal brain development from various types of prenatal environmental challenges, and the cell-to-cell variability of HSF1 activation in response to environmental challenges is augmented in neural progenitor cells differentiated from schizophrenia iPS cells.
We recently developed adeno-associated virus (AAV) capsids to facilitate efficient and noninvasive gene transfer to the central and peripheral nervous systems. However, a detailed protocol for ...generating and systemically delivering novel AAV variants was not previously available. In this protocol, we describe how to produce and intravenously administer AAVs to adult mice to specifically label and/or genetically manipulate cells in the nervous system and organs, including the heart. The procedure comprises three separate stages: AAV production, intravenous delivery, and evaluation of transgene expression. The protocol spans 8 d, excluding the time required to assess gene expression, and can be readily adopted by researchers with basic molecular biology, cell culture, and animal work experience. We provide guidelines for experimental design and choice of the capsid, cargo, and viral dose appropriate for the experimental aims. The procedures outlined here are adaptable to diverse biomedical applications, from anatomical and functional mapping to gene expression, silencing, and editing.
Abstract
Motivation
DNA methylation datasets are growing ever larger both in sample size and genome coverage. Novel computational solutions are required to efficiently handle these data.
Results
We ...have developed meffil, an R package designed for efficient quality control, normalization and epigenome-wide association studies of large samples of Illumina Methylation BeadChip microarrays. A complete re-implementation of functional normalization minimizes computational memory without increasing running time. Incorporating fixed and random effects within functional normalization, and automated estimation of functional normalization parameters reduces technical variation in DNA methylation levels, thus reducing false positive rates and improving power. Support for normalization of datasets distributed across physically different locations without needing to share biologically-based individual-level data means that meffil can be used to reduce heterogeneity in meta-analyses of epigenome-wide association studies.
Availability and implementation
https://github.com/perishky/meffil/
Supplementary information
Supplementary data are available at Bioinformatics online.
Fucoxanthin and lipid metabolism: A minireview Muradian, Kh; Vaiserman, A; Min, K.-J ...
Nutrition, metabolism, and cardiovascular diseases,
10/2015, Letnik:
25, Številka:
10
Journal Article
Recenzirano
Abstract Aims Accumulating data suggest that food supplementation with seaweeds which traditionally are an important part of food culture in South-East Asian countries might lead to essential health ...benefits. In this short review, we summarize findings from experimental studies on the effects of fucoxanthin (a carotenoid derived from brown seaweeds) on lipid metabolism, adiposity, and related conditions and discuss the possible underlying mechanisms. Data synthesis Supplementation of fucoxanthin or its derivatives consistently attenuated body and visceral fat weight gain, lipid accumulation in the liver, decreases insulin resistance, and improves the plasma lipid profile in rodents fed a high-fat diet. It should however be noted that in diabetic/obese KK-Ay mice with genetically compromised insulin signaling, fucoxanthin might increase the plasma levels of cholesterol and low-density lipoproteins. The anti-obesity effects of fucoxanthin are apparently mediated by the hormones leptin and adiponectin through their common target AMK-activated protein kinase, resulting in downregulation of lipogenic enzymes and upregulation of lipolytic enzymes. Fucoxanthin also suppresses adipocyte differentiation and induces the expression of uncoupling proteins in visceral adipose tissue. Conclusions The results of experimental studies suggest that consumption of fucoxanthin and its derivatives as nutritional supplements is a promising option for prevention and treatment of obesity and a wide variety of related pathologies, including metabolic syndrome, type 2 diabetes, and heart disease. Yet, clinical trials are warranted to assess a therapeutic value of fucoxanthin.
Summary Objective The objectives were to investigate the in vivo effects of treatment with rebamipide on pain severity and cartilage degeneration in an experimental model of rat osteoarthritis (OA) ...and to explore its mode of action. Materials and methods OA was induced in rats by intra-articular injection of monosodium iodoacetate (MIA). Oral administration of rebamipide was initiated on the day of MIA injection, 3 or 7 days after. Limb nociception was assessed by measuring the paw withdrawal latency and threshold. We analyzed the samples macroscopically and histomorphologically, and used immunohistochemistry to investigate the expression of matrix metalloproteinase-13 (MMP-13), interleukin-1β (IL-1β), hypoxia-inducible factor-2α (HIF-2α), inducible nitric oxide synthase (iNOS), and nitrotyrosine in knee joints. Real-time quantitative reverse transcription–polymerase chain reaction was used to quantify the mRNA for catabolic and anticatabolic factors in human OA chondrocytes. Results Rebamipide showed an antinociceptive property and attenuated cartilage degeneration. Rebamipide reduced the expression of MMP-13, IL-1β, HIF-2α, iNOS, and nitrotyrosine in OA cartilage in a dose-dependent manner. Nitrotyrosine expression in the subchondral bone region was decreased in the rebamipide-treated joints. mRNA expression of MMP-1, -3, and -13, and ADAMTS5 was attenuated in IL-1β-stimulated human OA chondrocytes. By contrast, rebamipide induced the mRNA expression of tissue inhibitor of metalloproteinase-1 and -3. Conclusion The results show the inhibitory effects of rebamipide on pain production and cartilage degeneration in experimentally induced OA. The suppression of oxidative damage and the restoration of extracellular matrix homeostasis of articular chondrocyte suggest that rebamipide is a potential therapeutic strategy for OA.
Epigenetic deregulation of gene expression has a role in the initiation and progression of prostate cancer (PCa). The histone methyltransferase MMSET/WHSC1 (Multiple Myeloma SET domain) is ...overexpressed in a number of metastatic tumors, but its mechanism of action has not been defined. In this work, we found that PCa cell lines expressed significantly higher levels of MMSET compared with immortalized, non-transformed prostate cells. Knockdown experiments showed that, in metastatic PCa cell lines, dimethylation of lysine 36 and trimethylation of lysine 27 on histone H3 (H3K36me2 and H3K27me3, respectively) depended on MMSET expression, whereas depletion of MMSET in benign prostatic cells did not affect chromatin modifications. Knockdown of MMSET in DU145 and PC-3 tumor cells decreased cell proliferation, colony formation in soft agar and strikingly diminished cell migration and invasion. Conversely, overexpression of MMSET in immortalized, non-transformed RWPE-1 cells promoted cell migration and invasion, accompanied by an epithelial-mesenchymal transition (EMT). Among a panel of EMT-promoting genes analyzed, TWIST1 expression was strongly activated in response to MMSET. Chromatin immunoprecipitation analysis demonstrated that MMSET binds to the TWIST1 locus and leads to an increase in H3K36me2, suggesting a direct role of MMSET in the regulation of this gene. Depletion of TWIST1 in MMSET-overexpressing RWPE-1 cells blocked cell invasion and EMT, indicating that TWIST1 was a critical target of MMSET, responsible for the acquisition of an invasive phenotype. Collectively, these data suggest that MMSET has a role in PCa pathogenesis and progression through epigenetic regulation of metastasis-related genes.
Background
Sentinel node navigation surgery reduces the extent of gastric and lymph node dissection, and may improve quality of life. The benefit and harm of laparoscopic sentinel node navigation ...surgery (LSNNS) for early gastric cancer is unknown. The SENORITA (SEntinel Node ORIented Tailored Approach) trial investigated the pathological and surgical outcomes of LSNNS compared with laparoscopic standard gastrectomy (LSG) with lymph node dissection.
Methods
The SENORITA trial was an investigator‐initiated, open‐label, parallel‐assigned, non‐inferiority, multicentre RCT conducted in Korea. The primary endpoint was 3‐year disease‐free survival. The secondary endpoints, morbidity and mortality within 30 days of surgery, are reported in the present study.
Results
A total of 580 patients were randomized to LSG (292) or LSNNS (288). Surgery was undertaken in 527 patients (LSG 269, LSNNS 258). LSNNS could be performed according to the protocol in 245 of 258 patients, and a sentinel node basin was detected in 237 (96·7 per cent) Stomach‐preserving surgery was carried out in 210 of 258 patients (81·4 per cent). Postoperative complications occurred in 51 patients in the LSG group (19·0 per cent) and 40 (15·5 per cent) in the LSNNS group (P = 0·294). Complications with a Clavien–Dindo grade of III or higher occurred in 16 (5·9 per cent) and 13 (5·0 per cent) patients in the LSG and LSNNS groups respectively (P = 0·647).
Conclusion
The rate and severity of complications following LSNNS for early gastric cancer are comparable to those after LSG with lymph node dissection. Registration number: NCT01804998 (
http://www.clinicaltrials.gov).
Antecedentes
La cirugía de navegación del ganglio centinela (sentinel node navigation surgery, SNNS) reduce la extensión de la resección gástrica y ganglionar, y puede mejorar la calidad de vida. Se desconoce el beneficio y el daño de la cirugía de navegación del ganglio centinela por vía laparoscópica (laparoscopic sentinel node navigation surgery, LSNNS) para el cáncer gástrico precoz. El ensayo clínico SENORITA investigó los resultados patológicos y quirúrgicos de LSNNS en comparación con la gastrectomía laparoscópica estándar (laparoscopic gastrectomy, LSG) con disección ganglionar (lymph node dissection, LND).
Métodos
El ensayo SENORITA fue un ensayo multicéntrico aleatorizado y controlado, iniciado por investigadores, abierto, con asignación a grupos paralelos y de no inferioridad llevado a cabo en Corea. El resultado primario fue la supervivencia libre de enfermedad a los 3 años. En el presente estudio, se describen los resultados secundarios correspondientes a morbilidad y mortalidad a los 30 días del postoperatorio.
Resultados
Un total de 580 pacientes fueron aleatorizados a LG (n = 292) o LSNNS (n = 288). La cirugía se realizó en 527 pacientes (LG 269, LSNNS 258). LSNNS pudo ser realizada de acuerdo con el protocolo en 245 de 258 pacientes y en 237 de 245 pacientes (96,7%) se detectó un ganglio centinela. La cirugía con preservación del estómago se realizó en 210 de 258 pacientes (81,4%). Las complicaciones postoperatorias se presentaron en 51 pacientes del grupo LSG (19,0%) y en 40 pacientes (15,5%) del grupo LSNNS (P = 0,294). Las complicaciones grado III o mayor de Clavien‐Dindo se detectaron en 16 (5,9%) y 13 pacientes (5,0%) de los grupos LSG y LSNNS, respectivamente (P = 0,647).
Conclusión
El porcentaje y la gravedad de las complicaciones tras LSNNS para cancer gástrico precoz son comparables a la LSG con LND.
The prospective, multicentre, randomized controlled phase III SENORITA trial evaluated the surgical and oncological outcomes of laparoscopic sentinel node navigation surgery (LSNNS) compared with laparoscopic standard gastrectomy (LSG) with lymph node dissection (LND) for early gastric cancer (EGC). LSNNS for EGC is a safe procedure in terms of postoperative morbidity and mortality compared with LSG and LND. ESD, endoscopic submucosal dissection; mITT, modified intention to treat; FAS, full analysis set; OGJ, oesophagogastric junction; LDG, laparoscopic distal gastrectomy; LTG, laparoscopic total gastrectomy; LPPG, laparoscopic pylorus‐preserving gastrectomy; LPG, laparoscopic proximal gastrectomy; ODG, open distal gastrectomy; OTG, open total gastrectomy; PP, per protocol; SBD, sentinel basin dissection; EFTR, endoscopic full‐thickness resection; LWR, laparoscopic wedge resection; LSR, laparoscopic segmental resection.
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