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https://www.readbyqxmd.com/read/28812623/a-thousand-empirical-adaptive-landscapes-and-their-navigability
#1
José Aguilar-Rodríguez, Joshua L Payne, Andreas Wagner
The adaptive landscape is an iconic metaphor that pervades evolutionary biology. It was mostly applied in theoretical models until recent years, when empirical data began to allow partial landscape reconstructions. Here, we exhaustively analyse 1,137 complete landscapes from 129 eukaryotic species, each describing the binding affinity of a transcription factor to all possible short DNA sequences. We find that the navigability of these landscapes through single mutations is intermediate to that of additive and shuffled null models, suggesting that binding affinity-and thereby gene expression-is readily fine-tuned via mutations in transcription factor binding sites...
January 23, 2017: Nature ecology & evolution
https://www.readbyqxmd.com/read/28812418/neurotoxicity-of-cgmp-in-the-vertebrate-retina-from-the-initial-research-on-rd-mutant-mice-to-zebrafish-genetic-approaches
#2
Maria Iribarne, Ichiro Masai
Zebrafish are an excellent animal model for research on vertebrate development and human diseases. Sophisticated genetic tools including large-scale mutagenesis methodology make zebrafish useful for studying neuronal degenerative diseases. Here, we review zebrafish models of inherited ophthalmic diseases, focusing on cGMP metabolism in photoreceptors. cGMP is the second messenger of phototransduction, and abnormal cGMP levels are associated with photoreceptor death. cGMP concentration represents a balance between cGMP phosphodiesterase 6 (PDE6) and guanylate cyclase (GC) activities in photoreceptors...
August 16, 2017: Journal of Neurogenetics
https://www.readbyqxmd.com/read/28811534/distinct-projection-patterns-of-different-classes-of-layer-2-principal-neurons-in-the-olfactory-cortex
#3
Camille Mazo, Julien Grimaud, Yasuyuki Shima, Venkatesh N Murthy, C Geoffrey Lau
The broadly-distributed, non-topographic projections to and from the olfactory cortex may suggest a flat, non-hierarchical organization in odor information processing. Layer 2 principal neurons in the anterior piriform cortex (APC) can be divided into 2 subtypes: semilunar (SL) and superficial pyramidal (SP) cells. Although it is known that SL and SP cells receive differential inputs from the olfactory bulb (OB), little is known about their projections to other olfactory regions. Here, we examined axonal projections of SL and SP cells using a combination of mouse genetics and retrograde labeling...
August 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28811514/differential-epitope-recognition-in-the-immunodominant-staphylococcal-antigen-a-of-staphylococcus-aureus-by-mouse-versus-human-igg-antibodies
#4
Dennis G A M Koedijk, Francisco Romero Pastrana, Hedzer Hoekstra, Sanne van den Berg, Jaap Willem Back, Carolien Kerstholt, Rianne C Prins, Irma A J M Bakker-Woudenberg, Jan Maarten van Dijl, Girbe Buist
The immunodominant staphylococcal antigen A (IsaA) is a potential target for active or passive immunization against the important human pathogen Staphylococcus aureus. Consistent with this view, monoclonal antibodies against IsaA were previously shown to be protective against S. aureus infections in mouse models. Further, patients with the genetic blistering disease epidermolysis bullosa (EB) displayed high IsaA-specific IgG levels that could potentially be protective. Yet, mice actively immunized with IsaA were not protected against S...
August 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28811332/de-novo-lipid-synthesis-facilitates-gemcitabine-resistance-through-endoplasmic-reticulum-stress-in-pancreatic-cancer
#5
Saber Tadros, Surendra K Shukla, Ryan J King, Venugopal Gunda, Enza Vernucci, Jaime Abrego, Nina CHaika, Fang Yu, Audrey J Lazenby, Lyudmyla Berim, Jean L Grem, Aaron Sasson, Pankaj K Singh
Pancreatic adenocarcinoma is moderately responsive to gemcitabine-based chemotherapy, the most widely used single agent therapy for pancreatic cancer. While the prognosis in pancreatic cancer remains grim in part due to poor response to therapy, previous attempts at identifying and targeting the resistance mechanisms have not been very successful. By leveraging TCGA dataset, we identified lipid metabolism as the metabolic pathway that most significantly correlated with poor gemcitabine response in pancreatic cancer patients...
August 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28810912/inhibition-of-trpm7-suppresses-cell-proliferation-of-colon-adenocarcinoma-in-vitro-and-induces-hypomagnesemia-in-vivo-without-affecting-azoxymethane-induced-early-colon-cancer-in-mice
#6
Junhao Huang, Hideki Furuya, Malika Faouzi, Zheng Zhang, Mahealani Monteilh-Zoller, F Kelly Galbraith Kawabata, David Horgen, Toshihiko Kawamori, Reinhold Penner, Andrea Fleig
BACKGROUND: Magnesium (Mg(2+)) is an essential cation implicated in carcinogenesis, solid tumor progression and metastatic potential. The Transient Receptor Potential Melastatin Member 7 (TRPM7) is a divalent ion channel involved in cellular and systemic Mg(2+) homeostasis. Abnormal expression of TRPM7 is found in numerous cancers, including colon, implicating TRPM7 in this process. METHODS: To establish a possible link between systemic magnesium (Mg(2+)) status, the Mg(2+) conducting channel TRPM7 in colon epithelial cells, and colon carcinogenesis, in vitro whole-cell patch clamp electrophysiology, qPCR, and pharmacological tools were used probing human colorectal adenocarcinoma HT-29 as well as normal primary mouse colon epithelial cells...
August 15, 2017: Cell Communication and Signaling: CCS
https://www.readbyqxmd.com/read/28809985/a-magnetic-micropore-chip-for-rapid-1-hour-unbiased-circulating-tumor-cell-isolation-and-in-situ-rna-analysis
#7
Jina Ko, Neha Bhagwat, Stephanie S Yee, Taylor Black, Colleen Redlinger, Janae Romeo, Mark O'Hara, Arjun Raj, Erica L Carpenter, Ben Z Stanger, David Issadore
The use of microtechnology for the highly selective isolation and sensitive detection of circulating tumor cells has shown enormous promise. One challenge for this technology is that the small feature sizes - which are the key to this technology's performance - can result in low sample throughput and susceptibility to clogging. Additionally, conventional molecular analysis of CTCs often requires cells to be taken off-chip for sample preparation and purification before analysis, leading to the loss of rare cells...
August 15, 2017: Lab on a Chip
https://www.readbyqxmd.com/read/28809028/lifting-the-veil-on-reptile-embryology-the-veiled-chameleon-chamaeleo-calyptratus-as-a-model-system-to-study-reptilian-development
#8
Raul E Diaz, Federica Bertocchini, Paul A Trainor
Living amniotes comprise three major phylogenetic lineages: mammals, birds, and non-avian reptiles. Mouse and avian embryos continue to be the primary species used in experimental settings to further our knowledge and understanding of the genetics and embryology of amniotes. In comparison, non-avian reptiles, which constitute up to 40% of all living amniotes, have played a comparatively minor role. Studies of non-avian reptiles are, however, paramount for providing insights into the evolutionary changes that occurred in the transition from reptilian-like amniote ancestors to derived mammalian and avian species...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28808928/regulation-of-survival-motor-neuron-protein-by-the-nuclear-factor-kappa-b-pathway-in-mouse-spinal-cord-motoneurons
#9
Saravanan Arumugam, Stefka Mincheva-Tasheva, Ambika Periyakaruppiah, Sandra de la Fuente, Rosa M Soler, Ana Garcera
Survival motor neuron (SMN) protein deficiency causes the genetic neuromuscular disorder spinal muscular atrophy (SMA), characterized by spinal cord motoneuron degeneration. Since SMN protein level is critical to disease onset and severity, analysis of the mechanisms involved in SMN stability is one of the central goals of SMA research. Here, we describe the role of several members of the NF-κB pathway in regulating SMN in motoneurons. NF-κB is one of the main regulators of motoneuron survival and pharmacological inhibition of NF-κB pathway activity also induces mouse survival motor neuron (Smn) protein decrease...
August 14, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28808293/targeting-apolipoprotein-e-amyloid-%C3%AE-binding-by-peptoid-cpo_a%C3%AE-17-21%C3%A2-p-ameliorates-alzheimer-s-disease-related-pathology-and-cognitive-decline
#10
Shan Liu, Shinae Park, Grant Allington, Frances Prelli, Yanjie Sun, Mitchell Martá-Ariza, Henrieta Scholtzova, Goutam Biswas, Bernard Brown, Philip B Verghese, Pankaj D Mehta, Yong-Uk Kwon, Thomas Wisniewski
Inheritance of the apolipoprotein E4 (apoE4) genotype has been identified as the major genetic risk factor for late onset Alzheimer's disease (AD). Studies have shown that apoE, apoE4 in particular, binds to amyloid-β (Aβ) peptides at residues 12-28 of Aβ and this binding modulates Aβ accumulation and disease progression. We have previously shown in several AD transgenic mice lines that blocking the apoE/Aβ interaction with Aβ12-28 P reduced Aβ and tau-related pathology, leading to cognitive improvements in treated AD mice...
August 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28808160/incremental-contributions-of-fbaa-and-other-impetigo-associated-surface-proteins-to-fitness-and-virulence-of-a-classical-group-a-streptococcal-skin-strain
#11
Candace N Rouchon, Anhphan T Ly, John P Noto, Feng Luo, Sergio Lizano, Debra E Bessen
Group A streptococci (GAS) are highly prevalent human pathogens whose primary ecological niche is the superficial epithelial layers of the throat and/or skin. Many GAS strains having a strong tendency to cause pharyngitis are distinct from strains that tend to cause impetigo; thus, genetic differences between them may confer host tissue-specific virulence. In this study, the FbaA surface protein gene is found to be present in most skin specialist strains, but largely absent from a genetically-related subset of pharyngitis isolates...
August 14, 2017: Infection and Immunity
https://www.readbyqxmd.com/read/28808057/a-kidney-specific-genetic-control-module-in-mice-governs-endocrine-regulation-of-the-cytochrome-p450-gene-cyp27b1-essential-for-vitamin-d3-activation
#12
Mark B Meyer, Nancy A Benkusky, Martin Kaufmann, Seong Min Lee, Melda Onal, Glenville Jones, J Wesley Pike
The vitamin D endocrine system regulates mineral homeostasis through its activities in the intestine, kidney, and bone. Terminal activation of vitamin D3 to its hormonal form, 1,25(OH)2D3, occurs in the kidney via the cytochrome P450 enzyme CYP27B1. Despite its importance in vitamin D metabolism, the molecular mechanisms underlying the regulation of the gene for this enzyme, Cyp27b1, are unknown. Here, we identified a kidney-specific control module governed by a renal cell-specific chromatin structure located distal to Cyp27b1 that mediates unique basal and parathyroid hormone (PTH)-, fibroblast growth factor 23 (FGF23)-, and 1,25(OH)2D3-mediated regulation of Cyp27b1 expression...
August 14, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28808027/de-novo-mutations-in-inhibitors-of-wnt-bmp-and-ras-erk-signaling-pathways-in-non-syndromic-midline-craniosynostosis
#13
Andrew T Timberlake, Charuta G Furey, Jungmin Choi, Carol Nelson-Williams, Erin Loring, Amy Galm, Kristopher T Kahle, Derek M Steinbacher, Dawid Larysz, John A Persing, Richard P Lifton
Non-syndromic craniosynostosis (NSC) is a frequent congenital malformation in which one or more cranial sutures fuse prematurely. Mutations causing rare syndromic craniosynostoses in humans and engineered mouse models commonly increase signaling of the Wnt, bone morphogenetic protein (BMP), or Ras/ERK pathways, converging on shared nuclear targets that promote bone formation. In contrast, the genetics of NSC is largely unexplored. More than 95% of NSC is sporadic, suggesting a role for de novo mutations. Exome sequencing of 291 parent-offspring trios with midline NSC revealed 15 probands with heterozygous damaging de novo mutations in 12 negative regulators of Wnt, BMP, and Ras/ERK signaling (10...
August 14, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28807677/phosphodiesterase-4b-expression-plays-a-major-role-in-alcohol-induced-neuro-inflammation
#14
Diana V Avila, Scott A Myers, JingWen Zhang, Giorgi Kharebava, Craig J McClain, Hee-Yong Kim, Scott R Whittemore, Leila Gobejishvili, Shirish Barve
It is increasingly evident that alcohol-induced, gut-mediated peripheral endotoxemia plays a significant role in glial cell activation and neuro-inflammation. Using a mouse model of chronic alcohol feeding, we examined the causal role of endotoxin- and cytokine-responsive Pde4 subfamily b (Pde4b) expression in alcohol-induced neuro-inflammation. Both pharmacologic and genetic approaches were used to determine the regulatory role of Pde4b. In C57Bl/6 wild type (WT) alcohol fed (WT-AF) animals, alcohol significantly induced peripheral endotoxemia and Pde4b expression in brain tissue, accompanied by a decrease in cAMP levels...
August 11, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28807414/transient-receptor-potential-vanilloid-4-expressing-macrophages-and-keratinocytes-contribute-differentially-to-allergic-and-nonallergic-chronic-itch
#15
Jialie Luo, Jing Feng, Guang Yu, Pu Yang, Madison R Mack, Junhui Du, Weihua Yu, Aihua Qian, Yujin Zhang, Shenbin Liu, Shijin Yin, Amy Xu, Jizhong Cheng, Qingyun Liu, Roger G O'Neil, Yang Xia, Liang Ma, Susan M Carlton, Brian S Kim, Kenneth Renner, Qin Liu, Hongzhen Hu
BACKGROUND: Chronic itch is a highly debilitating symptom that underlies many medical disorders with no universally effective treatments. Although unique neuronal signaling cascades in the sensory ganglia and spinal cord have been shown to critically promote the pathogenesis of chronic itch, the role of skin-associated cells remains poorly understood. OBJECTIVE: We sought to examine the cutaneous mechanisms underlying transient receptor potential vanilloid 4 (TRPV4)-mediated allergic and nonallergic chronic itch...
August 5, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28807034/exosomes-from-embryonic-mesenchymal-stem-cells-alleviate-osteoarthritis-through-balancing-synthesis-and-degradation-of-cartilage-extracellular-matrix
#16
Yafei Wang, Dongsheng Yu, Zhiming Liu, Fang Zhou, Jun Dai, Bingbing Wu, Jing Zhou, Boon Chin Heng, Xiao Hui Zou, Hongwei Ouyang, Hua Liu
BACKGROUND: Mesenchymal stem cell therapy for osteoarthritis (OA) has been widely investigated, but the mechanisms are still unclear. Exosomes that serve as carriers of genetic information have been implicated in many diseases and are known to participate in many physiological processes. Here, we investigate the therapeutic potential of exosomes from human embryonic stem cell-induced mesenchymal stem cells (ESC-MSCs) in alleviating osteoarthritis (OA). METHODS: Exosomes were harvested from conditioned culture media of ESC-MSCs by a sequential centrifugation process...
August 14, 2017: Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/28806762/a-becn1-mutation-mediates-hyperactive-autophagic-sequestration-of-amyloid-oligomers-and-improved-cognition-in-alzheimer-s-disease
#17
Altea Rocchi, Soh Yamamoto, Tabitha Ting, Yuying Fan, Katherine Sadleir, Yigang Wang, Weiran Zhang, Sui Huang, Beth Levine, Robert Vassar, Congcong He
Impairment of the autophagy pathway has been observed during the pathogenesis of Alzheimer's disease (AD), a neurodegenerative disorder characterized by abnormal deposition of extracellular and intracellular amyloid β (Aβ) peptides. Yet the role of autophagy in Aβ production and AD progression is complex. To study whether increased basal autophagy plays a beneficial role in Aβ clearance and cognitive improvement, we developed a novel genetic model to hyperactivate autophagy in vivo. We found that knock-in of a point mutation F121A in the essential autophagy gene Beclin 1/Becn1 in mice significantly reduces the interaction of BECN1 with its inhibitor BCL2, and thus leads to constitutively active autophagy even under non-autophagy-inducing conditions in multiple tissues, including brain...
August 14, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28804489/normalized-synergy-predicts-that-cd8-co-receptor-contribution-to-t-cell-receptor-tcr-and-pmhc-binding-decreases-as-tcr-affinity-increases-in-human-viral-specific-t-cells
#18
Chad M Williams, Alexandra A Schonnesen, Shu-Qi Zhang, Ke-Yue Ma, Chenfeng He, Tori Yamamoto, S Gail Eckhardt, Christopher A Klebanoff, Ning Jiang
The discovery of naturally occurring T cell receptors (TCRs) that confer specific, high-affinity recognition of pathogen and cancer-associated antigens remains a major goal in cellular immunotherapies. The contribution of the CD8 co-receptor to the interaction between the TCR and peptide-bound major histocompatibility complex (pMHC) has previously been correlated with the activation and responsiveness of CD8(+) T cells. However, these studies have been limited to model systems of genetically engineered hybridoma TCRs or transgenic mouse TCRs against either a single epitope or an array of altered peptide ligands...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28801578/basophils-contribute-to-pristane-induced-lupus-like-nephritis-model
#19
Barbara Dema, Yasmine Lamri, Christophe Pellefigues, Emeline Pacreau, Fanny Saidoune, Caroline Bidault, Hajime Karasuyama, Karim Sacré, Eric Daugas, Nicolas Charles
Lupus nephritis (LN), one of the most severe outcomes of systemic lupus erythematosus (SLE), is initiated by glomerular deposition of immune-complexes leading to an inflammatory response and kidney failure. Autoantibodies to nuclear antigens and autoreactive B and T cells are central in SLE pathogenesis. Immune mechanisms amplifying this autoantibody production drive flares of the disease. We previously showed that basophils were contributing to LN development in a spontaneous lupus-like mouse model (constitutive Lyn (-/-) mice) and in SLE subjects through their activation and migration to secondary lymphoid organs (SLOs) where they amplify autoantibody production...
August 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28800207/optically-derived-metabolic-and-hemodynamic-parameters-predict-hippocampal-neurogenesis-in-the-btbr-mouse-model-of-autism
#20
David Abookasis, Danit Lerman, Hava Roth, Mati Tfilin, Gadi Turgeman
In the present study, we made use of dual-wavelength laser speckle imaging (DW-LSI) to assess cerebral blood flow in the BTBR genetic mouse model of Autism Spectrum Disorder, as well as control (C57Bl/6J) mice. Since the deficits in social behavior demonstrated by BTBR mice are attributed to changes in neural tissue structure and function, we postulated that these changes can be detected optically using DW-LSI. BTBR mice demonstrated reductions in both cerebral blood flow (CBF) and cerebral oxygen metabolism (CMRO2 ), as suggested by studies using conventional neuroimaging technologies to reflect impaired neuronal activation and cognitive function...
August 11, 2017: Journal of Biophotonics
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