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Centrally mediated

Joseph R Knoedler, Nirao M Shah
A long-standing goal in developmental neuroscience is to understand the mechanisms by which steroid sex hormones pattern the mammalian central nervous system along male or female pathways to enable subsequent displays of sexually dimorphic behaviors. In this article, we review recent advances in understanding the epigenetic and transcriptional mechanisms mediating sexual differentiation of the brain in mammals, flies, and worms. These studies suggest a model of sexual differentiation wherein master regulators of sex determination initiate a cascade of sexually dimorphic gene expression that controls development of neural pathways and behavioral displays in a strikingly modular manner...
October 10, 2018: Current Opinion in Neurobiology
Annette Künkele, Christopher Brown, Adam Beebe, Stephanie Mgebroff, Adam J Johnson, Agne Taraseviciute, Lisa S Rolczynski, Cindy A Chang, Olivia C Finney, Julie R Park, Michael C Jensen
Cytotoxic chemotherapy and radiation can render lymphocyte repertoires qualitatively and quantitatively defective. Thus, heavily treated patients are often poor candidates for the manufacture of autologous CAR-T cell products. In the USA and Europe, children with high-risk neuroblastoma undergo apheresis early in the course of their treatment to collect peripheral blood stem cells (PBSCs) for cryopreservation in preparation for high-dose chemotherapy followed by autologous stem cell rescue. Here, we investigate whether these cryopreserved chemotherapy and G-CSF-mobilized PBSCs can be utilized as starting material for CAR-T cell manufacturing...
October 10, 2018: Biology of Blood and Marrow Transplantation
Stefanie Kuerten, Leila J Jackson, Joel Kaye, Timothy L Vollmer
Growing evidence indicates that B cells play a key role in the pathogenesis of multiple sclerosis (MS). B cells occupy distinct central nervous system (CNS) compartments in MS, including the cerebrospinal fluid and white matter lesions. Also, it is now known that, in addition to entering the CNS, B cells can circulate into the periphery via a functional lymphatic system. Data suggest that the role of B cells in MS mainly involves their in situ activation in demyelinating lesions, leading to altered pro- and anti-inflammatory cytokine secretion, and a highly effective antigen-presenting cell function, resulting in activation of memory or naïve T cells...
October 12, 2018: CNS Drugs
Beimi Cui, Qiaona Pan, David Clarke, Marisol Ochoa Villarreal, Saima Umbreen, Bo Yuan, Weixing Shan, Jihong Jiang, Gary J Loake
Nitric oxide (NO) orchestrates a plethora of incongruent plant immune responses, including the reprograming of global gene expression. However, the cognate molecular mechanisms remain largely unknown. Here we show a zinc finger transcription factor (ZF-TF), SRG1, is a central target of NO bioactivity during plant immunity, where it functions as a positive regulator. NO accumulation promotes SRG1 expression and subsequently SRG1 occupies a repeated canonical sequence within target promoters. An EAR domain enables SRG1 to recruit the corepressor TOPLESS, suppressing target gene expression...
October 12, 2018: Nature Communications
Meng-Tong Li, Li-Hui Cao, Na Xiao, Min Tang, Bowen Deng, Tian Yang, Taishi Yoshii, Dong-Gen Luo
Circadian rhythms are orchestrated by a master clock that emerges from a network of circadian pacemaker neurons. The master clock is synchronized to external light/dark cycles through photoentrainment, but the circuit mechanisms underlying visual photoentrainment remain largely unknown. Here, we report that Drosophila has eye-mediated photoentrainment via a parallel pacemaker neuron organization. Patch-clamp recordings of central circadian pacemaker neurons reveal that light excites most of them independently of one another...
October 12, 2018: Nature Communications
Matteo Caleo, Matteo Spinelli, Francesca Colosimo, Ivica Matak, Ornella Rossetto, Zdravko Lackovic, Laura Restani
Botulinum neurotoxin type A (BoNT/A) is an effective treatment for several movement disorders, including spasticity and dystonia. BoNT/A acts by cleaving synaptosomal-associated protein of 25 kDa (SNAP-25) at the neuromuscular junction, thus blocking synaptic transmission and weakening overactive muscles. However, not all the therapeutic benefits of the neurotoxin are explained by peripheral neuroparalysis, suggesting an action of BoNT/A on central circuits. Currently, the specific targets of BoNT/A central activity remain unclear...
October 12, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Liisa Hantsoo, Sara Kornfield, Montserrat C Anguera, C Neill Epperson
During pregnancy, programming of the fetal central nervous system establishes vulnerabilities for emergence of neuropsychiatric phenotypes later in life. Psychosocial influences during pregnancy, such as stressful life events and chronic stress, correlate with offspring neuropsychiatric disorders and inflammation, respectively. Stress promotes inflammation, but the role of inflammation as a mediator between maternal psychosocial stress and offspring neuropsychiatric outcomes has not been extensively studied in humans...
September 5, 2018: Biological Psychiatry
Jing Zheng, Yonggang Sha, Logan Roof, Oded Foreman, John Lazarchick, Jagadish Kummetha Venkta, Cleopatra Kozlowski, Cristina Gasparetto, Nelson Chao, Allen Ebens, Jianda Hu, Yubin Kang
Multiple myeloma remains an incurable disease, and continued efforts are required to develop novel agents and novel drug combinations with more effective anti-myeloma activity. Here, we show that the pan-PIM kinase inhibitors SGI1776 and CX6258 exhibit significant anti-myeloma activity and that combining a pan-PIM kinase inhibitor with the immunomodulatory agent lenalidomide in an in vivo myeloma xenograft mouse model resulted in synergistic myeloma cell killing without additional hematologic or hepatic toxicities...
October 9, 2018: Cancer Letters
Lin-Jie Shu, Jui-Yu Liao, Nai-Chun Lin, Chia-Lin Chung
Hormonal modulation plays a central role in triggering various resistant responses to biotic and abiotic stresses in plants. In cultivated strawberry (Fragaria x ananassa), the salicylic acid (SA)-dependent defense pathway has been associated with resistance to Colletotrichum spp. and the other pathogens. To better understand the SA-mediated defense mechanisms in strawberry, we analyzed two strawberry cultivars treated with SA for their resistance to anthracnose and gene expression profiles at 6, 12, 24, and 48 hr post-treatment...
2018: PloS One
Krishnan V Chakravarthy, Fang Xing, Kelly Bruno, Alexander R Kent, Adil Raza, Rene Hurlemann, Thomas M Kinfe
BACKGROUND: There is increasing literature evidence both clinically and experimentally on the existence of potent, adaptive interactions between the central and peripheral aspects of the neuroimmune system in the genesis and maintenance of chronic neuropathic extremity pain and nociceptive back pain. The neuroinflammatory pathways are modulated by the interaction of pro- and anti-inflammatory cytokines and chemokines, which are released by peripheral immune system-derived cell species (macrophages and leukocytes)...
October 12, 2018: Neuromodulation: Journal of the International Neuromodulation Society
Alon Amir, Jean-Francois Paré, Yoland Smith, Denis Paré
One of the main subcortical inputs to the basolateral nucleus of the amygdala (BL) originates from a group of dorsal thalamic nuclei located at or near the midline, mainly from the central medial (CMT) and paraventricular (PVT) nuclei. Although similarities between the responsiveness of BL, CMT, and PVT neurons to emotionally arousing stimuli suggest that these thalamic inputs exert a significant influence over BL activity, little is known about the synaptic relationships that mediate these effects. Thus, the present study used Phaseolus vulgaris-leucoagglutinin (PHAL) anterograde tracing and electron microscopy to shed light on the ultrastructural properties and synaptic targets of CMT and PVT axon terminals in the rat BL...
October 12, 2018: Journal of Comparative Neurology
Mohamad-Javad Vaseghi, Kamel Chibani, Wilena Telman, Michael Florian Liebthal, Melanie Gerken, Helena Schnitzer, Sara Mareike Mueller, Karl-Josef Dietz
Thiol-dependent redox regulation controls central processes in plant cells including photosynthesis. Thioredoxins reductively activate e.g. Calvin-Benson cycle enzymes. However the mechanism of oxidative inactivation is unknown despite its importance for efficient regulation. Here, the abundant 2-cysteine peroxiredoxin (2-CysPrx), but not its site-directed variants, mediates rapid inactivation of reductively activated fructose-1,6-bisphosphatase and NADPH-dependent malate dehydrogenase (MDH) in the presence of the proper thioredoxins...
October 12, 2018: ELife
Paula Dunayevich, Rodrigo Baltanás, José Antonio Clemente, Alicia Couto, Daiana Sapochnik, Gustavo Vasen, Alejandro Colman-Lerner
Cells make decisions based on a combination of external and internal signals. In yeast, the high osmolarity response (HOG) is a mitogen-activated protein kinase (MAPK) pathway that responds to a variety of stimuli, and it is central to the general stress response. Here we studied the effect of heat-stress (HS) on HOG. Using live-cell reporters and genetics, we show that HS promotes Hog1 phosphorylation and Hog1-dependent gene expression, exclusively via the Sln1 phosphorelay branch, and that the strength of the activation is larger in yeast adapted to high external osmolarity...
October 11, 2018: Scientific Reports
Richard G J Hodel, L Lacey Knowles, Stuart F McDaniel, Adam C Payton, Jordan F Dunaway, Pamela S Soltis, Douglas E Soltis
A central goal of comparative phylogeography is to understand how species-specific traits interact with geomorphological history to govern the geographic distribution of genetic variation within species. One key biotic trait with an immense impact on the spatial patterns of intraspecific genetic differentiation is dispersal. Here we quantify how species-specific traits directly related to dispersal affect genetic variation in terrestrial organisms with adaptations for dispersal by sea, not land-the mangroves of the Caribbean...
October 11, 2018: Molecular Ecology
Haoqing Wang, Christopher O Barnes, Zhi Yang, Michel C Nussenzweig, Pamela J Bjorkman
HIV-1 Env, a trimer of gp120-gp41 heterodimers, mediates membrane fusion after binding host receptor CD4. Receptor binding displaces V1V2 loops from Env's apex, allowing coreceptor binding and opening Env to enable gp41-mediated fusion. We present 3.54 Å and 4.06 Å cryoelectron microscopy structures of partially open soluble native-like Env trimers (SOSIPs) bound to CD4. One structure, a complex with a coreceptor-mimicking antibody that binds both CD4 and gp120, stabilizes the displaced V1V2 and reveals its structure...
October 10, 2018: Cell Host & Microbe
Sankaran Sandhya, Aditi Maulik, Malyasree Giri, Mahavir Singh
BAF250a and BAF250b are subunits of the SWI/SNF chromatin-remodeling complex that recruit the complex to chromatin allowing transcriptional activation of several genes. Despite being the central subunits of the SWI/SNF complex, the structural and functional annotation of BAF250a/b remains poorly understood. BAF250a (nearly 2200 residues protein) harbors an N-terminal DNA binding ARID (~110 residues) and a C-terminal folded region (~250 residues) of unknown structure and function, recently annotated as BAF250_C...
2018: PloS One
Dharini Iyer, Quanyi Zhao, Robert Wirka, Ameay Naravane, Trieu Nguyen, Boxiang Liu, Manabu Nagao, Paul Cheng, Clint L Miller, Juyong Brian Kim, Milos Pjanic, Thomas Quertermous
Although numerous genetic loci have been associated with coronary artery disease (CAD) with genome wide association studies, efforts are needed to identify the causal genes in these loci and link them into fundamental signaling pathways. Recent studies have investigated the disease mechanism of CAD associated gene SMAD3, a central transcription factor (TF) in the TGFβ pathway, investigating its role in smooth muscle biology. In vitro studies in human coronary artery smooth muscle cells (HCASMC) revealed that SMAD3 modulates cellular phenotype, promoting expression of differentiation marker genes while inhibiting proliferation...
October 11, 2018: PLoS Genetics
Manisha N Chandwani, Patrick S Creisher, Lauren A O'Donnell
Viral infections of the central nervous system are accompanied by the expression of cytokines and chemokines that can be critical for the control of viral replication in the brain. The outcomes of cytokine/chemokine signaling in neural cells vary widely, with cell-specific effects on cellular activity, proliferation, and survival. Neural stem/progenitor cells (NSPCs) are often altered during viral infections, through direct infection by the virus or by the influence of immune cell activity or cytokine/chemokine signaling...
October 10, 2018: Viral Immunology
Ilamathi Raja, Vikram Kumar, Hariharan Sabapathy, Manoharan Kumariah, Kasthuri Rajendran, Jebasingh Tennyson
sRNAs are a class of gene regulators in bacteria, playing a central role in its response to environmental changes. Bioinformatic prediction facilitates the identification of sRNAs expressed at different conditions. We propose a novel method of prediction of sRNAs from the genome of Agrobacterium based on PWM matrix of conditional sigma factors. sRNAs predicted from the genome are integrated with the virulence specific transcriptome data to identify putative sRNAs that are over expressed during Agrobacterial virulence induction...
October 11, 2018: FEMS Microbiology Letters
Malte Borggrewe, Corien Grit, Wilfred F A Den Dunnen, Saskia M Burm, Jeffrey J Bajramovic, Randolph J Noelle, Bart J L Eggen, Jon D Laman
V-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA) is a negative checkpoint regulator (NCR) involved in inhibition of T cell-mediated immunity. Expression changes of other NCRs (PD-1, PD-L1/L2, CTLA-4) during inflammation of the central nervous system (CNS) were previously demonstrated, but VISTA expression in the CNS has not yet been explored. Here, we report that in the human and mouse CNS, VISTA is most abundantly expressed by microglia, and to lower levels by endothelial cells...
October 11, 2018: Glia
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