Τρίτη 29 Αυγούστου 2017
The Organization of Working Memory Networks is Shaped by Early Sensory Experience
Abstract
Early deafness results in crossmodal reorganization of the superior temporal cortex (STC). Here, we investigated the effect of deafness on cognitive processing. Specifically, we studied the reorganization, due to deafness and sign language (SL) knowledge, of linguistic and nonlinguistic visual working memory (WM). We conducted an fMRI experiment in groups that differed in their hearing status and SL knowledge: deaf native signers, and hearing native signers, hearing nonsigners. Participants performed a 2-back WM task and a control task. Stimuli were signs from British Sign Language (BSL) or moving nonsense objects in the form of point-light displays. We found characteristic WM activations in fronto-parietal regions in all groups. However, deaf participants also recruited bilateral posterior STC during the WM task, independently of the linguistic content of the stimuli, and showed less activation in fronto-parietal regions. Resting-state connectivity analysis showed increased connectivity between frontal regions and STC in deaf compared to hearing individuals. WM for signs did not elicit differential activations, suggesting that SL WM does not rely on modality-specific linguistic processing. These findings suggest that WM networks are reorganized due to early deafness, and that the organization of cognitive networks is shaped by the nature of the sensory inputs available during development.http://ift.tt/2wRKDmi
Denser Growing Fiber Connections Induce 3-hinge Gyral Folding
Abstract
Recent studies have shown that quantitative description of gyral shape patterns offers a novel window to examine the relationship between brain structure and function. Along this research line, this paper examines a unique and interesting type of cortical gyral region where 3 different gyral crests meet, termed 3-hinge gyral region. We extracted 3-hinge gyral regions in macaque/chimpanzee/human brains, quantified and compared the relevant DTI-derived fiber densities in 3-hinge and 2-hinge gyral regions. Our observations consistently showed that DTI-derived fiber densities in 3-hinge regions are much higher than those in 2-hinge regions. Therefore, we hypothesize that besides the cortical expansion, denser fiber connections can induce the formation of 3-hinge gyri. To examine the biomechanical basis of this hypothesis, we constructed a series of 3-dimensional finite element soft tissue models based on continuum growth theory to investigate fundamental biomechanical mechanisms of consistent 3-hinge gyri formation. Our computational simulation results consistently showed that during gyrification gyral regions with higher concentrations of growing axonal fibers tend to form 3-hinge gyri. Our integrative approach combining neuroimaging data analysis and computational modeling appears effective in probing a plausible theory of 3-hinge gyri formation and providing new insights into structural and functional cortical architectures and their relationship.http://ift.tt/2xLUCWu
Structural Connections of Functionally Defined Human Insular Subdivisions
Abstract
The organization of the human insular cortex has traditionally been considered as an anterior–posterior dichotomy, where anterior and posterior subdivisions have unique structural and functional connections. However, recent functional neuroimaging research proposes a tripartite organization where insular subdivisions have both unique and overlapping functional profiles. Studies examining unique profiles show that the dorsal anterior insula (dAI) has connections with frontal areas supporting higher-level cognitive processes, the ventral anterior insula (vAI) has connections with limbic areas supporting affective processes, and the posterior insula (PI) has connections with sensorimotor areas supporting interoceptive processes. Studies examining overlapping profiles demonstrate that all 3 subdivisions can also have similar functional profiles. The structural organization supporting a functional tripartite insula organization presenting with overlapping and unique connections is currently unknown. We used a large HARDI diffusion magnetic resonance imaging (MRI) dataset (n = 199) to demonstrate novel visualizations of insula white matter tracts supporting a tripartite structure–function insula organization. Overlapping connections of all 3 insula subdivisions consisted of association pathways (inferior fronto-occipital fasciculus, uncinate fasciculus, arcuate fasciculus) while unique connections included the corona radiata, subcortical-cortical tracts, and horizontal and u-shaped tracts. These results generally support a tripartite structure–function organization of the insular cortex, with subdivisions that exhibit both overlapping and unique connectivity profiles.http://ift.tt/2gowOVr
Cerebral Vein Malformations Result from Loss of Twist1 Expression and BMP Signaling from Skull Progenitor Cells and Dura
Publication date: Available online 30 August 2017
Source:Developmental Cell
Author(s): Max A. Tischfield, Caroline D. Robson, Nicole M. Gilette, Shek Man Chim, Folasade A. Sofela, Michelle M. DeLisle, Alon Gelber, Brenda J. Barry, Sarah MacKinnon, Linda R. Dagi, Jeremy Nathans, Elizabeth C. Engle
Dural cerebral veins (CV) are required for cerebrospinal fluid reabsorption and brain homeostasis, but mechanisms that regulate their growth and remodeling are unknown. We report molecular and cellular processes that regulate dural CV development in mammals and describe venous malformations in humans with craniosynostosis and TWIST1 mutations that are recapitulated in mouse models. Surprisingly, Twist1 is dispensable in endothelial cells but required for specification of osteoprogenitor cells that differentiate into preosteoblasts that produce bone morphogenetic proteins (BMPs). Inactivation of Bmp2 and Bmp4 in preosteoblasts and periosteal dura causes skull and CV malformations, similar to humans harboring TWIST1 mutations. Notably, arterial development appears normal, suggesting that morphogens from the skull and dura establish optimal venous networks independent from arterial influences. Collectively, our work establishes a paradigm whereby CV malformations result from primary or secondary loss of paracrine BMP signaling from preosteoblasts and dura, highlighting unique cellular interactions that influence tissue-specific angiogenesis in mammals.
Graphical abstract
Teaser
By characterizing dural cerebral vein malformations in TWIST1 mutation-positive humans and mouse models with craniosynostosis, Tischfield et al. report that cerebral vein angiogenesis requires paracrine BMP signaling from skull preosteoblasts and periosteal dura. The effects are independent from arterial influences and highlight unique cellular interactions that pattern tissue-specific vascular networks.http://ift.tt/2goVzR9
Beyond editing to writing large genomes
Nature Reviews Genetics. doi:10.1038/nrg.2017.59
Authors: Raj Chari & George M. Church
http://ift.tt/2vDvq3S
Range expansion potential of two co-occurring invasive vines to marginal habitats in Turkey
Source:Acta Oecologica, Volume 84
Author(s): Shahid Farooq, Sonnur Tad, Huseyin Onen, Hikmet Gunal, Ugur Caldiran, Cumali Ozaslan
Niche distribution models accurately predict the potential distribution range of invasive plants into new habitats based on their climatic requirements in the native regions. However, these models usually ignore the marginal habitats which can limit the distribution of exotic plants. We therefore tested the seedling survival, growth and nutrient acquisition capabilities of two co-occurring invasive vines [Persicaria perfoliata (L.) H. Gross and Sicyos angulatus L.] in three different manipulative greenhouse experiments to infer their range expansion potential to marginal habitats in Turkey. First experiment included five different moisture availability regimes (100, 75, 50, 25 and 12.5% available water), second experiment consisted of four different salinity levels (0, 3, 6 and 12 dSm−1 soil salinity) and third experiment had four different soil textures (clay-1, clay-2, sandy loam and silt-clay-loam). Seedling mortality was only observed under extreme moisture deficiency in both plant species, while most of the transplanted seedlings of both species did not survive under 6 and 12 dSm−1 salinity levels. Soil textures had no effect on seedling survival. POLPE better tolerated low moisture availability and high salinity compared to SIYAN. Biomass production in both plant species was linearly reduced with increasing salinity and moisture deficiency. SIYAN invested more resources towards shoot, accumulated higher K and P, whereas POLPE maintained higher root-to-shoot ratio under all experimental conditions. Both plant species employed different strategies to cope with adverse environmental conditions, but failed to persist under high soil salinity and moisture deficiency. Our study suggest that both plant species have limited potential of range expansion to marginal habitats and will be limited to moist and humid areas only. Therefore, further research activities should be concentrated in these regions to develop effective management strategies against both species.
http://ift.tt/2xwzOCW
Dopaminergic dysfunction in neurodevelopmental disorders: recent advances and synergistic technologies to aid basic research
Publication date: February 2018
Source:Current Opinion in Neurobiology, Volume 48
Author(s): J Elliott Robinson, Viviana Gradinaru
Neurodevelopmental disorders (NDDs) represent a diverse group of syndromes characterized by abnormal development of the central nervous system and whose symptomatology includes cognitive, emotional, sensory, and motor impairments. The identification of causative genetic defects has allowed for creation of transgenic NDD mouse models that have revealed pathophysiological mechanisms of disease phenotypes in a neural circuit- and cell type-specific manner. Mouse models of several syndromes, including Rett syndrome, Fragile X syndrome, Angelman syndrome, Neurofibromatosis type 1, etc., exhibit abnormalities in the structure and function of dopaminergic circuitry, which regulates motivation, motor behavior, sociability, attention, and executive function. Recent advances in technologies for functional circuit mapping, including tissue clearing, viral vector-based tracing methods, and optical readouts of neural activity, have refined our knowledge of dopaminergic circuits in unperturbed states, yet these tools have not been widely applied to NDD research. Here, we will review recent findings exploring dopaminergic function in NDD models and discuss the promise of new tools to probe NDD pathophysiology in these circuits.
Graphical abstract
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Chromatin-remodeling enzymes in control of Schwann cell development, maintenance and plasticity
Source:Current Opinion in Neurobiology, Volume 47
Author(s): Claire Jacob
Gene regulation is essential for cellular differentiation and plasticity. Schwann cells (SCs), the myelinating glia of the peripheral nervous system (PNS), develop from neural crest cells to mature myelinating SCs and can at early developmental stage differentiate into various cell types. After a PNS lesion, SCs can also convert into repair cells that guide and stimulate axonal regrowth, and remyelinate regenerated axons. What controls their development and versatile nature? Several recent studies highlight the key roles of chromatin modifiers in these processes, allowing SCs to regulate their gene expression profile and thereby acquire or change their identity and quickly react to their environment.
http://ift.tt/2x3da7E
Mechanisms of Müller glial cell morphogenesis
Publication date: December 2017
Source:Current Opinion in Neurobiology, Volume 47
Author(s): Ryan B MacDonald, Mark Charlton-Perkins, William A Harris
Müller Glia (MG), the radial glia cells of the retina, have spectacular morphologies subserving their enormous functional complexity. As early as 1892, the great neuroanatomist Santiago Ramon y Cajal studied the morphological development of MG, defining several steps in their morphogenesis [1,2]. However, the molecular cues controlling these developmental steps remain poorly understood. As MG have roles to play in every cellular and plexiform layer, this review discusses our current understanding on how MG morphology may be linked to their function, including the developmental mechanisms involved in MG patterning and morphogenesis. Uncovering the mechanisms governing glial morphogenesis, using transcriptomics and imaging, may provide shed new light on the pathophysiology and treatment of human neurological disorders.
Graphical abstract
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Quantifying behavior to solve sensorimotor transformations: advances from worms and flies
Source:Current Opinion in Neurobiology, Volume 46
Author(s): Adam J Calhoun, Mala Murthy
The development of new computational tools has recently opened up the study of natural behaviors at a precision that was previously unachievable. These tools permit a highly quantitative analysis of behavioral dynamics at timescales that are well matched to the timescales of neural activity. Here we examine how combining these methods with established techniques for estimating an animal's sensory experience presents exciting new opportunities for dissecting the sensorimotor transformations performed by the nervous system. We focus this review primarily on examples from Caenorhabditis elegans and Drosophila melanogaster—for these model systems, computational approaches to characterize behavior, in combination with unparalleled genetic tools for neural activation, silencing, and recording, have already proven instrumental for illuminating underlying neural mechanisms.
http://ift.tt/2vDnhw9
From the statistics of connectivity to the statistics of spike times in neuronal networks
Source:Current Opinion in Neurobiology, Volume 46
Author(s): Gabriel Koch Ocker, Yu Hu, Michael A Buice, Brent Doiron, Krešimir Josić, Robert Rosenbaum, Eric Shea-Brown
An essential step toward understanding neural circuits is linking their structure and their dynamics. In general, this relationship can be almost arbitrarily complex. Recent theoretical work has, however, begun to identify some broad principles underlying collective spiking activity in neural circuits. The first is that local features of network connectivity can be surprisingly effective in predicting global statistics of activity across a network. The second is that, for the important case of large networks with excitatory-inhibitory balance, correlated spiking persists or vanishes depending on the spatial scales of recurrent and feedforward connectivity. We close by showing how these ideas, together with plasticity rules, can help to close the loop between network structure and activity statistics.
http://ift.tt/2x2GECq
Digit ratio 2D:4D is a possible indicator for androgenetic alopecia in males
Summary
Background
Androgenetic alopecia (AGA) is the most common hair loss. The 2D:4D digit ratio refers to the ratio of the length of the second finger to that of the fourth finger and is thought as a marker of prenatal androgen exposure.
Objectives
There are many studies which have examined the relationship between 2D:4D ratio and some other diseases. In this study, we evaluated the relationship between digit ratio 2D:4D and AGA.
Methods
The study group was composed of a male with AGA and healthy controls. The lengths of patients' second and fourth fingers were measured using a digital caliper with a resolution of 0.01 mm. Finger length was measured on the palmar side of the hand from the basal metacarpophalangeal crease. The 2D:4D ratio was obtained by dividing the length of the second finger by the length of the fourth finger.
Results
A total of 99 males who have androgenetic alopecia with a score of grade III or more and 90 controls were included. The mean age of AGA group was 29.72 ± 5.53, and the mean age of control group was 19.63 ± 5.05. The left-hand 2D:4D ratios of AGA group (0.893 ± 0.267) were significantly lower than healthy controls (0.971 ± 0.028). No significant relationships were found between AGA severity, age of onset,and digit ratios.
Conclusions
The left-hand digit ratio 2D:4D is lower in AGA patients, and therefore, left-hand digit ratio 2D:4D can be used as an estimation tool for AGA development in future. There is not any correlation between digit ratio and age of onset. Also, there is no correlation between digit ratio 2D:4D and AGA severity.
http://ift.tt/2wgXvRm
Tumor Lysis Syndrome in Chronic Lymphocytic Leukemia with Novel Targeted Agents
AbstractTumor lysis syndrome (TLS) is an uncommon but potentially life‐threatening complication associated with the treatment of some cancers. If left untreated, TLS may result in acute renal failure, cardiac dysrhythmia, neurologic complications, seizures, or death. Tumor lysis syndrome is most commonly observed in patients with hematologic malignancies with a high proliferation rate undergoing treatment with very effective therapies. In chronic lymphocytic leukemia (CLL), historically, TLS has been observed less often, owing to a low proliferation rate and slow response to chemotherapy. New targeted therapies have recently been approved in the treatment of CLL, including the oral kinase inhibitors, idelalisib and ibrutinib, and the B‐cell lymphoma‐2 protein inhibitor, venetoclax. Several others are also under development, and combination strategies of these agents are being explored. This review examines the diagnosis, prevention, and management of TLS and summarizes the TLS experience in CLL clinical trials with newer targeted agents. Overall, the risk of TLS is small, but the consequences may be fatal; therefore, patients should be monitored carefully. Therapies capable of eliciting rapid response and combination regimens are increasingly being evaluated for treatment of CLL, which may pose a higher risk of TLS. For optimal management, patients at risk for TLS require prophylaxis and close monitoring with appropriate tests and appropriate management to correct laboratory abnormalities, which allows for safe and effective disease control.Implications for Practice.Tumor lysis syndrome (TLS) is a potentially fatal condition observed with hematologic malignancies, caused by release of cellular components in the bloodstream from rapidly dying tumor cells. The frequency and severity of TLS is partly dependent upon the biology of the disease and type of therapy administered. Novel targeted agents highly effective at inducing rapid cell death in chronic lymphocytic leukemia (CLL) may pose a risk for TLS in patients with tumors characterized by rapid growth, high tumor burden, and/or high sensitivity to treatment. In this review, prevention strategies and management of patients with CLL who develop TLS are described.
http://ift.tt/2wH5t7k
PCAF/GCN5-Mediated Acetylation of RPA1 Promotes Nucleotide Excision Repair
Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Meimei Zhao, Rui Geng, Xiang Guo, Ruoshi Yuan, Xiao Zhou, Yanyan Zhong, Yanfei Huo, Mei Zhou, Qinjian Shen, Yinglu Li, Weiguo Zhu, Jiadong Wang
The RPA complex can integrate multiple stress signals into diverse responses by activating distinct DNA repair pathways. However, it remains unclear how RPA1 elects to activate a specific repair pathway during different types of DNA damage. Here, we report that PCAF/GCN5-mediated K163 acetylation of RPA1 is crucial for nucleotide excision repair (NER) but is dispensable for other DNA repair pathways. Mechanistically, we demonstrate that the acetylation of RPA1 is critical for the steady accumulation of XPA at damaged DNA sites and preferentially activates the NER pathway. DNA-PK phosphorylates and activates PCAF upon UV damage and consequently promotes the acetylation of RPA1. Moreover, the acetylation of RPA1 is tightly regulated by HDAC6 and SIRT1. Together, our results demonstrate that the K163 acetylation of RPA1 plays a key role in the repair of UV-induced DNA damage and reveal how the specific RPA1 modification modulates the choice of distinct DNA repair pathways.
Graphical abstract
Teaser
RPA complex is a central player in multiple DNA repair pathways. Zhao et al. show that PCAF/GCN5-mediated acetylation of RPA1 is crucial for NER repair by promoting stable RPA1/XPA complex.http://ift.tt/2xwujnW
UV-Induced RPA1 Acetylation Promotes Nucleotide Excision Repair
Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Hanqing He, Jiajia Wang, Ting Liu
Replication protein A (RPA) is a multifunctional, single-stranded DNA-binding protein complex and plays a critical role in DNA replication and damage response. Herein, we show that the 70-kDa subunit of RPA (RPA1) is acetylated on lysine 163 by the acetyltransferases GCN5 and PCAF and that such acetylation is reversed principally via the action of the deacetylase HDAC6. UV irradiation promotes cytoplasmic translocation of HDAC6, thereby disrupting the interaction of HDAC6 with RPA1 and increasing RPA1 acetylation. Mutation of the acetylation site of RPA1 specifically impairs the ability of the protein to interact with the key nucleotide excision repair (NER) protein XPA, reduces XPA retention at sites of DNA damage caused by UV, compromises NER, and renders the cell hypersensitive to UV irradiation. Our data suggest that the acetylation status of RPA1 played a crucial role in repair of DNA damage via NER.
Graphical abstract
Teaser
He et al. find that the RPA1 protein becomes acetylated at lysine 163 in response to UV irradiation. Such acetylation specifically enhances interaction between RPA1 and the key NER protein XPA and promotes XPA retention at DNA damage sites. These findings suggest that RPA1 acetylation is a unique NER-related event.http://ift.tt/2xwaKfA
Multilayered Reprogramming in Response to Persistent DNA Damage in C. elegans
Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Diletta Edifizi, Hendrik Nolte, Vipin Babu, Laia Castells-Roca, Michael M. Mueller, Susanne Brodesser, Marcus Krüger, Björn Schumacher
DNA damage causally contributes to aging and age-related diseases. Mutations in nucleotide excision repair (NER) genes cause highly complex congenital syndromes characterized by growth retardation, cancer susceptibility, and accelerated aging in humans. Orthologous mutations in Caenorhabditis elegans lead to growth delay, genome instability, and accelerated functional decline, thus allowing investigation of the consequences of persistent DNA damage during development and aging in a simple metazoan model. Here, we conducted proteome, lipidome, and phosphoproteome analysis of NER-deficient animals in response to UV treatment to gain comprehensive insights into the full range of physiological adaptations to unrepaired DNA damage. We derive metabolic changes indicative of a tissue maintenance program and implicate an autophagy-mediated proteostatic response. We assign central roles for the insulin-, EGF-, and AMPK-like signaling pathways in orchestrating the adaptive response to DNA damage. Our results provide insights into the DNA damage responses in the organismal context.
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Teaser
Edifizi et al. provide a comprehensive proteomics, phosphoproteomics, and lipidomics analysis of the response to persistent DNA damage in a metazoan organism. Proteostasis shifts toward autophagy, fatty acid metabolism is attenuated, and the insulin-, EGF-, and AMPK-like signaling pathways form the center of the response network.http://ift.tt/2xw4LqY
NEIL3 Repairs Telomere Damage during S Phase to Secure Chromosome Segregation at Mitosis
Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Jia Zhou, Jany Chan, Marie Lambelé, Timur Yusufzai, Jason Stumpff, Patricia L. Opresko, Markus Thali, Susan S. Wallace
Oxidative damage to telomere DNA compromises telomere integrity. We recently reported that the DNA glycosylase NEIL3 preferentially repairs oxidative lesions in telomere sequences in vitro. Here, we show that loss of NEIL3 causes anaphase DNA bridging because of telomere dysfunction. NEIL3 expression increases during S phase and reaches maximal levels in late S/G2. NEIL3 co-localizes with TRF2 and associates with telomeres during S phase, and this association increases upon oxidative stress. Mechanistic studies reveal that NEIL3 binds to single-stranded DNA via its intrinsically disordered C terminus in a telomere-sequence-independent manner. Moreover, NEIL3 is recruited to telomeres through its interaction with TRF1, and this interaction enhances the enzymatic activity of purified NEIL3. Finally, we show that NEIL3 interacts with AP Endonuclease 1 (APE1) and the long-patch base excision repair proteins PCNA and FEN1. Taken together, we propose that NEIL3 protects genome stability through targeted repair of oxidative damage in telomeres during S/G2 phase.
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Teaser
NEIL3 DNA glycosylase activity is critical in highly proliferating cells including cancer cells. Zhou et al. show that NEIL3 is specifically active at telomeres during S/G2, and that depletion of NEIL3 causes telomere dysfunction and thus mitotic defects, revealing its involvement in telomere repair, which prevents genome instability.http://ift.tt/2xwegGN
SMC Progressively Aligns Chromosomal Arms in Caulobacter crescentus but Is Antagonized by Convergent Transcription
Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Ngat T. Tran, Michael T. Laub, Tung B.K. Le
The structural maintenance of chromosomes (SMC) complex plays an important role in chromosome organization and segregation in most living organisms. In Caulobacter crescentus, SMC is required to align the left and the right arms of the chromosome that run in parallel down the long axis of the cell. However, the mechanism of SMC-mediated alignment of chromosomal arms remains elusive. Here, using genome-wide methods and microscopy of single cells, we show that Caulobacter SMC is recruited to the centromeric parS site and that SMC-mediated arm alignment depends on the chromosome-partitioning protein ParB. We provide evidence that SMC likely tethers the parS-proximal regions of the chromosomal arms together, promoting arm alignment. Furthermore, we show that highly transcribed genes near parS that are oriented against SMC translocation disrupt arm alignment, suggesting that head-on transcription interferes with SMC translocation. Our results demonstrate a tight interdependence of bacterial chromosome organization and global patterns of transcription.
Graphical abstract
Teaser
Tran et al. investigate the mechanism and function of SMC in the global organization of the Caulobacter chromosome. The findings suggest that SMC functions as a tether to actively cohese the chromosomal arms together and show that head-on transcription profoundly interferes with SMC translocation from the centromeric parS site.http://ift.tt/2xwgru4
Feeling Stressed under the Sun? RPA1 Acetylation to the Rescue
Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Debabrata Chakravarti, Tapas K. Hazra
Nucleotide excision repair (NER) requires replication protein A (RPA), among others, to respond to DNA damaging agents. In this issue of Cell Reports, He et al. (2017) and Zhao et al. (2017) show acetylation of RPA1 regulates the UV-induced DNA damage response.
Teaser
Nucleotide excision repair (NER) requires replication protein A (RPA), among others, to respond to DNA damaging agents. In this issue of Cell Reports, He et al. (2017) and Zhao et al. (2017) show acetylation of RPA1 regulates the UV-induced DNA damage response.http://ift.tt/2xwaw8a
Lysophosphatidic Acid Receptor 4 Activation Augments Drug Delivery in Tumors by Tightening Endothelial Cell-Cell Contact
Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Kazuhiro Takara, Daisuke Eino, Koji Ando, Daisuke Yasuda, Hisamichi Naito, Yohei Tsukada, Tomohiro Iba, Taku Wakabayashi, Fumitaka Muramatsu, Hiroyasu Kidoya, Shigetomo Fukuhara, Naoki Mochizuki, Satoshi Ishii, Haruhiko Kishima, Nobuyuki Takakura
Vascular normalization in tumors may improve drug delivery and anti-tumor immunity. Angiogenesis inhibitors induce hypoxia, which may facilitate malignant progression; therefore, we investigated other methods to promote vascular maturation. Here, we show that lysophosphatidic acid (LPA) enhances blood flow by promoting fine vascular networks, thereby improving vascular permeability and suppressing tumor growth when combined with anti-cancer drug treatment. Six different G protein-coupled receptors have been identified as LPA receptors (LPA1–6). In studies using mutant mice, we found that LPA4 is involved in vascular network formation. LPA4 activation induces circumferential actin bundling beneath the cell membrane and enhances linear adherens junction formation by VE-cadherin in endothelial cells. Therefore, we conclude that activation of LPA4 is a promising approach for vascular regulation.
Graphical abstract
Teaser
Takara et al. find that lysophosphatidic acid (LPA) promotes fine capillary network formation and improves drug delivery in tumors. LPA controls localization of VE-cadherin in endothelial cells through LPA receptor 4 (LPA4) signaling.http://ift.tt/2wghsaL
Spatiotemporal Control of Lipid Conversion, Actin-Based Mechanical Forces, and Curvature Sensors during Clathrin/AP-1-Coated Vesicle Biogenesis
Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Mihaela Anitei, Christoph Stange, Cornelia Czupalla, Christian Niehage, Kai Schuhmann, Pia Sala, Aleksander Czogalla, Theresia Pursche, Ünal Coskun, Andrej Shevchenko, Bernard Hoflack
Clathrin/adaptor protein-1-coated carriers connect the secretory and the endocytic pathways. Carrier biogenesis relies on distinct protein networks changing membrane shape at the trans-Golgi network, each regulating coat assembly, F-actin-based mechanical forces, or the biophysical properties of lipid bilayers. How these different hubs are spatiotemporally coordinated remains largely unknown. Using in vitro reconstitution systems, quantitative proteomics, and lipidomics, as well as in vivo cell-based assays, we characterize the protein networks controlling membrane lipid composition, membrane shape, and carrier scission. These include PIP5K1A and phospholipase C-beta 3 controlling the conversion of PI[4]P into diacylglycerol. PIP5K1A binding to RAC1 provides a link to F-actin-based mechanical forces needed to tubulate membranes. Tubular membranes then recruit the BAR-domain-containing arfaptin-1/2 guiding carrier scission. These findings provide a framework for synchronizing the chemical/biophysical properties of lipid bilayers, F-actin-based mechanical forces, and the activity of proteins sensing membrane shape during clathrin/adaptor protein-1-coated carrier biogenesis.
Graphical abstract
Teaser
Clathrin/adaptor protein-1 (AP-1) coats control the transport of specific cargoes between the biosynthetic and endocytic pathways. Anitei et al. illustrate the coordination of protein networks controlling the biophysical properties of lipid bilayers, actin-based mechanical forces, and membrane curvature during clathrin/AP-1-coated carrier biogenesis.http://ift.tt/2wgWwk7
Aberrant Compartment Formation by HSPB2 Mislocalizes Lamin A and Compromises Nuclear Integrity and Function
Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Federica F. Morelli, Dineke S. Verbeek, Jessika Bertacchini, Jonathan Vinet, Laura Mediani, Sandra Marmiroli, Giovanna Cenacchi, Milena Nasi, Sara De Biasi, Jeanette F. Brunsting, Jan Lammerding, Elena Pegoraro, Corrado Angelini, Rossella Tupler, Simon Alberti, Serena Carra
Small heat shock proteins (HSPBs) contain intrinsically disordered regions (IDRs), but the functions of these IDRs are still unknown. Here, we report that, in mammalian cells, HSPB2 phase separates to form nuclear compartments with liquid-like properties. We show that phase separation requires the disordered C-terminal domain of HSPB2. We further demonstrate that, in differentiating myoblasts, nuclear HSPB2 compartments sequester lamin A. Increasing the nuclear concentration of HSPB2 causes the formation of aberrant nuclear compartments that mislocalize lamin A and chromatin, with detrimental consequences for nuclear function and integrity. Importantly, phase separation of HSPB2 is regulated by HSPB3, but this ability is lost in two identified HSPB3 mutants that are associated with myopathy. Our results suggest that HSPB2 phase separation is involved in reorganizing the nucleoplasm during myoblast differentiation. Furthermore, these findings support the idea that aberrant HSPB2 phase separation, due to HSPB3 loss-of-function mutations, contributes to myopathy.
Graphical abstract
Teaser
Morelli et al. show that, in mammalian cells, HSPB2 forms liquid-like nuclear compartments that affect lamin A localization and mobility, with detrimental consequences for chromatin organization and nuclear integrity. Aberrant compartment formation by HSPB2 is regulated by HSPB3, but not by two identified HSPB3 mutants linked to myopathy.http://ift.tt/2wgeROc
Loss of Apela Peptide in Mice Causes Low Penetrance Embryonic Lethality and Defects in Early Mesodermal Derivatives
Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Laina Freyer, Chih-Wei Hsu, Sonja Nowotschin, Andrea Pauli, Junji Ishida, Keiji Kuba, Akiyoshi Fukamizu, Alexander F. Schier, Pamela A. Hoodless, Mary E. Dickinson, Anna-Katerina Hadjantonakis
Apela (also known as Elabela, Ende, and Toddler) is a small signaling peptide that activates the G-protein-coupled receptor Aplnr to stimulate cell migration during zebrafish gastrulation. Here, using CRISPR/Cas9 to generate a null, reporter-expressing allele, we study the role of Apela in the developing mouse embryo. We found that loss of Apela results in low-penetrance cardiovascular defects that manifest after the onset of circulation. Three-dimensional micro-computed tomography revealed a higher penetrance of vascular remodeling defects, from which some mutants recover, and identified extraembryonic anomalies as the earliest morphological distinction in Apela mutant embryos. Transcriptomics at late gastrulation identified aberrant upregulation of erythroid and myeloid markers in mutant embryos prior to the appearance of physical malformations. Double-mutant analyses showed that loss of Apela signaling impacts early Aplnr-expressing mesodermal populations independently of the alternative ligand Apelin, leading to lethal cardiac defects in some Apela null embryos.
Graphical abstract
Teaser
Apela (a.k.a. Elabela, Ende, and Toddler) is a key signaling peptide that activates APLNR in mouse development. Freyer et al. show that lethal developmental defects in Apela mutants may rely on sufficient blood circulation. They suggest that extraembryonic mesoderm derivatives, including endothelial and hematopoietic progenitors, may be the first cell populations impacted by the loss of Apela.http://ift.tt/2wgIyig
Folding of the Cerebral Cortex Requires Cdk5 in Upper-Layer Neurons in Gyrencephalic Mammals
Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Yohei Shinmyo, Yukari Terashita, Tung Anh Dinh Duong, Toshihide Horiike, Muneo Kawasumi, Kazuyoshi Hosomichi, Atsushi Tajima, Hiroshi Kawasaki
Folds in the cerebral cortex in mammals are believed to be key structures for accommodating increased cortical neurons in the cranial cavity. However, the mechanisms underlying cortical folding remain largely unknown, mainly because genetic manipulations for the gyrencephalic brain have been unavailable. By combining in utero electroporation and the CRISPR/Cas9 system, we succeeded in efficient gene knockout of Cdk5, which is mutated in some patients with classical lissencephaly, in the gyrencephalic brains of ferrets. We show that Cdk5 knockout in the ferret cerebral cortex markedly impaired cortical folding. Furthermore, the results obtained from the introduction of dominant-negative Cdk5 into specific cortical layers suggest that Cdk5 function in upper-layer neurons is more important for cortical folding than that in lower-layer neurons. Cdk5 inhibition induced severe migration defects in cortical neurons. Taken together, our findings suggest that the appropriate positioning of upper-layer neurons is critical for cortical folding.
Graphical abstract
Teaser
Shinmyo et al. describe a highly efficient gene knockout method for the folded cerebral cortex of ferrets using the CRISPR/Cas9 system. Loss-of-function studies of the Cdk5 gene suggest that appropriate positioning of upper-layer neurons is crucial for cortical folding.http://ift.tt/2wgPUSO
A Fatty Acid Oxidation-Dependent Metabolic Shift Regulates Adult Neural Stem Cell Activity
Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Marlen Knobloch, Gregor-Alexander Pilz, Bart Ghesquière, Werner J. Kovacs, Thomas Wegleiter, Darcie L. Moore, Martina Hruzova, Nicola Zamboni, Peter Carmeliet, Sebastian Jessberger
Hippocampal neurogenesis is important for certain forms of cognition, and failing neurogenesis has been implicated in neuropsychiatric diseases. The neurogenic capacity of hippocampal neural stem/progenitor cells (NSPCs) depends on a balance between quiescent and proliferative states. Here, we show that the rate of fatty acid oxidation (FAO) regulates the activity of NSPCs. Quiescent NSPCs show high levels of carnitine palmitoyltransferase 1a (Cpt1a)-dependent FAO, which is downregulated in proliferating NSPCs. Pharmacological inhibition and conditional deletion of Cpt1a in vitro and in vivo leads to altered NSPC behavior, showing that Cpt1a-dependent FAO is required for stem cell maintenance and proper neurogenesis. Strikingly, manipulation of malonyl-CoA, the metabolite that regulates levels of FAO, is sufficient to induce exit from quiescence and to enhance NSPC proliferation. Thus, the data presented here identify a shift in FAO metabolism that governs NSPC behavior and suggest an instructive role for fatty acid metabolism in regulating NSPC activity.
Graphical abstract
Teaser
Controlled balance between proliferation and quiescence of neural stem/progenitor cells (NSPCs) is required for lifelong neurogenesis. Knobloch et al. identify a metabolic shift in fatty acid oxidation (FAO) that governs the proliferation of NSPCs. Further, their data suggest an instructive role for FAO in regulating NSPC activity. Thus, Knobloch et al. identify FAO as a key metabolic pathway to regulate NSPC activity.http://ift.tt/2wgz06N
Neto Auxiliary Subunits Regulate Interneuron Somatodendritic and Presynaptic Kainate Receptors to Control Network Inhibition
Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Megan S. Wyeth, Kenneth A. Pelkey, Xiaoqing Yuan, Geoffrey Vargish, April D. Johnston, Steven Hunt, Calvin Fang, Daniel Abebe, Vivek Mahadevan, André Fisahn, Michael W. Salter, Roderick R. McInnes, Ramesh Chittajallu, Chris J. McBain
Although Netos are considered auxiliary subunits critical for kainate receptor (KAR) function, direct evidence for their regulation of native KARs is limited. Because Neto KAR regulation is GluK subunit/Neto isoform specific, such regulation must be determined in cell-type-specific contexts. We demonstrate Neto1/2 expression in somatostatin (SOM)-, cholecystokinin/cannabinoid receptor 1 (CCK/CB1)-, and parvalbumin (PV)-containing interneurons. KAR-mediated excitation of these interneurons is contingent upon Neto1 because kainate yields comparable effects in Neto2 knockouts and wild-types but fails to excite interneurons or recruit inhibition in Neto1 knockouts. In contrast, presynaptic KARs in CCK/CB1 interneurons are dually regulated by both Neto1 and Neto2. Neto association promotes tonic presynaptic KAR activation, dampening CCK/CB1 interneuron output, and loss of this brake in Neto mutants profoundly increases CCK/CB1 interneuron-mediated inhibition. Our results confirm that Neto1 regulates endogenous somatodendritic KARs in diverse interneurons and demonstrate Neto regulation of presynaptic KARs in mature inhibitory presynaptic terminals.
Graphical abstract
Teaser
Netos are considered critical kainate receptor (KAR) auxiliary subunits in glutamatergic principal cells, but their roles in GABAergic interneurons remain unexplored. Wyeth et al. find that somatodendritic KARs within diverse interneurons require Neto1, whereas both Neto1 and Neto2 regulate presynaptic KAR-mediated suppression of inhibitory transmission.http://ift.tt/2wgD5b3
The Deacetylase HDAC6 Mediates Endogenous Neuritic Tau Pathology
Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Jui-Heng Tseng, Ling Xie, Sheng Song, Youmei Xie, Lauren Allen, Deepa Ajit, Jau-Shyong Hong, Xian Chen, Rick B. Meeker, Todd J. Cohen
The initiating events that promote tau mislocalization and pathology in Alzheimer's disease (AD) are not well defined, partly because of the lack of endogenous models that recapitulate tau dysfunction. We exposed wild-type neurons to a neuroinflammatory trigger and examined the effect on endogenous tau. We found that tau re-localized and accumulated within pathological neuritic foci, or beads, comprised of mostly hypo-phosphorylated, acetylated, and oligomeric tau. These structures were detected in aged wild-type mice and were enhanced in response to neuroinflammation in vivo, highlighting a previously undescribed endogenous age-related tau pathology. Strikingly, deletion or inhibition of the cytoplasmic shuttling factor HDAC6 suppressed neuritic tau bead formation in neurons and mice. Using mass spectrometry-based profiling, we identified a single neuroinflammatory factor, the metalloproteinase MMP-9, as a mediator of neuritic tau beading. Thus, our study uncovers a link between neuroinflammation and neuritic tau beading as a potential early-stage pathogenic mechanism in AD.
Graphical abstract
Teaser
Tau mislocalization and aggregation are implicated in the pathogenesis of Alzheimer's disease. Tseng et al. report that endogenous neuronal tau re-localizes to distinct neuritic foci, which are active sites of calcium deregulation, leading to aberrant tau accumulation. These findings provide insights into the early-stage tau dysfunction that occurs in vulnerable neurons.http://ift.tt/2wgIzCQ
Deletion of Nampt in Projection Neurons of Adult Mice Leads to Motor Dysfunction, Neurodegeneration, and Death
Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Xiaowan Wang, Qiao Zhang, Ruisi Bao, Nannan Zhang, Yingzhen Wang, Luis Polo-Parada, Andrew Tarim, Aidan Alemifar, Xianlin Han, Heather M. Wilkins, Russell H. Swerdlow, Xinglong Wang, Shinghua Ding
Intracellular nicotinamide phosphoribosyltransferase (iNAMPT) is the rate-limiting enzyme of the mammalian NAD+ biosynthesis salvage pathway. Using inducible and conditional knockout (cKO) mice, we show that Nampt gene deletion in adult projection neurons leads to a progressive loss of body weight, hypothermia, motor neuron (MN) degeneration, motor function deficits, paralysis, and death. Nampt deletion causes mitochondrial dysfunction, muscle fiber type conversion, and atrophy, as well as defective synaptic function at neuromuscular junctions (NMJs). When treated with nicotinamide mononucleotide (NMN), Nampt cKO mice exhibit reduced motor function deficits and prolonged lifespan. iNAMPT protein levels are significantly reduced in the spinal cord of amyotrophic lateral sclerosis (ALS) patients, indicating the involvement of NAMPT in ALS pathology. Our findings reveal that neuronal NAMPT plays an essential role in mitochondrial bioenergetics, motor function, and survival. Our study suggests that the NAMPT-mediated NAD+ biosynthesis pathway is a potential therapeutic target for degenerative MN diseases.
Graphical abstract
Teaser
Wang et al. find that projection neuron NAMPT is essential for mitochondrial bioenergetics, motor function, and survival of adult mice and that iNAMPT is reduced in ALS patients. NMN improves health and extends the lifespan of Nampt knockout mice. Their findings suggest therapeutic avenues for motor neuron degenerative diseases.http://ift.tt/2wgz1rn
Genomic Determinants of Protein Abundance Variation in Colorectal Cancer Cells
Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Theodoros I. Roumeliotis, Steven P. Williams, Emanuel Gonçalves, Clara Alsinet, Martin Del Castillo Velasco-Herrera, Nanne Aben, Fatemeh Zamanzad Ghavidel, Magali Michaut, Michael Schubert, Stacey Price, James C. Wright, Lu Yu, Mi Yang, Rodrigo Dienstmann, Justin Guinney, Pedro Beltrao, Alvis Brazma, Mercedes Pardo, Oliver Stegle, David J. Adams, Lodewyk Wessels, Julio Saez-Rodriguez, Ultan McDermott, Jyoti S. Choudhary
Assessing the impact of genomic alterations on protein networks is fundamental in identifying the mechanisms that shape cancer heterogeneity. We have used isobaric labeling to characterize the proteomic landscapes of 50 colorectal cancer cell lines and to decipher the functional consequences of somatic genomic variants. The robust quantification of over 9,000 proteins and 11,000 phosphopeptides on average enabled the de novo construction of a functional protein correlation network, which ultimately exposed the collateral effects of mutations on protein complexes. CRISPR-cas9 deletion of key chromatin modifiers confirmed that the consequences of genomic alterations can propagate through protein interactions in a transcript-independent manner. Lastly, we leveraged the quantified proteome to perform unsupervised classification of the cell lines and to build predictive models of drug response in colorectal cancer. Overall, we provide a deep integrative view of the functional network and the molecular structure underlying the heterogeneity of colorectal cancer cells.
Graphical abstract
Teaser
Roumeliotis et al. use in-depth proteomics to assess the impact of genomic alterations on protein networks in colorectal cancer cell lines. Cell-line-specific network signatures are inferred de novo by protein quantification profiles and ultimately expose the collateral and transcript-independent effects of detrimental mutations on protein complexes.http://ift.tt/2whrU1X
The Functional Impact of Alternative Splicing in Cancer
Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Héctor Climente-González, Eduard Porta-Pardo, Adam Godzik, Eduardo Eyras
Alternative splicing changes are frequently observed in cancer and are starting to be recognized as important signatures for tumor progression and therapy. However, their functional impact and relevance to tumorigenesis remain mostly unknown. We carried out a systematic analysis to characterize the potential functional consequences of alternative splicing changes in thousands of tumor samples. This analysis revealed that a subset of alternative splicing changes affect protein domain families that are frequently mutated in tumors and potentially disrupt protein-protein interactions in cancer-related pathways. Moreover, there was a negative correlation between the number of these alternative splicing changes in a sample and the number of somatic mutations in drivers. We propose that a subset of the alternative splicing changes observed in tumors may represent independent oncogenic processes that could be relevant to explain the functional transformations in cancer, and some of them could potentially be considered alternative splicing drivers (AS drivers).
Graphical abstract
Teaser
Climente-González et al. show that alternative splicing (AS) changes in tumors are linked to a significant loss of functional domain families that are also frequently mutated in cancer. These domain losses happen independently of somatic mutations and lead to the remodeling of complexes and protein-protein interactions in cancer.http://ift.tt/2wgTgoL
Generation of Mouse Haploid Somatic Cells by Small Molecules for Genome-wide Genetic Screening
Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Zheng-Quan He, Bao-Long Xia, Yu-Kai Wang, Jing Li, Gui-Hai Feng, Lin-Lin Zhang, Yu-Huan Li, Hai-Feng Wan, Tian-Da Li, Kai Xu, Xue-Wei Yuan, Yu-Fei Li, Xin-Xin Zhang, Ying Zhang, Liu Wang, Wei Li, Qi Zhou
The recent success of derivation of mammalian haploid embryonic stem cells (haESCs) has provided a powerful tool for large-scale functional analysis of the mammalian genome. However, haESCs rapidly become diploidized after differentiation, posing challenges for genetic analysis. Here, we show that the spontaneous diploidization of haESCs happens in metaphase due to mitotic slippage. Diploidization can be suppressed by small-molecule-mediated inhibition of CDK1 and ROCK. Through ROCK inhibition, we can generate haploid somatic cells of all three germ layers from haESCs, including terminally differentiated neurons. Using piggyBac transposon-based insertional mutagenesis, we generated a haploid neural cell library harboring genome-wide mutations for genetic screening. As a proof of concept, we screened for Mn2+-mediated toxicity and identified the Park2 gene. Our findings expand the applications of mouse haploid cell technology to somatic cell types and may also shed light on the mechanisms of ploidy maintenance.
Graphical abstract
Teaser
He et al. show that CDK1 and ROCK inhibition can suppress the spontaneous diploidization of haploid embryonic stem cells (haESCs) and generate haploid somatic cells of all three germ layers for genome-wide genetic screening.http://ift.tt/2wgeNxW
Mass Cytometry and Topological Data Analysis Reveal Immune Parameters Associated with Complications after Allogeneic Stem Cell Transplantation
Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Tadepally Lakshmikanth, Axel Olin, Yang Chen, Jaromir Mikes, Erik Fredlund, Mats Remberger, Brigitta Omazic, Petter Brodin
Human immune systems are variable, and immune responses are often unpredictable. Systems-level analyses offer increased power to sort patients on the basis of coordinated changes across immune cells and proteins. Allogeneic stem cell transplantation is a well-established form of immunotherapy whereby a donor immune system induces a graft-versus-leukemia response. This fails when the donor immune system regenerates improperly, leaving the patient susceptible to infections and leukemia relapse. We present a systems-level analysis by mass cytometry and serum profiling in 26 patients sampled 1, 2, 3, 6, and 12 months after transplantation. Using a combination of machine learning and topological data analyses, we show that global immune signatures associated with clinical outcome can be revealed, even when patients are few and heterogeneous. This high-resolution systems immune monitoring approach holds the potential for improving the development and evaluation of immunotherapies in the future.
Graphical abstract
Teaser
Lakshmikanth et al. conduct a systems analysis of immune reconstitution after stem cell transplantation. Using topological data analysis, combinations of cells and proteins associated with CMV and graft-versus-host disease were revealed and illustrate the potential of systems immunomonitoring to improve the development and evaluation of cancer immunotherapies.http://ift.tt/2wgTeNF
Systems Vaccinology Identifies an Early Innate Immune Signature as a Correlate of Antibody Responses to the Ebola Vaccine rVSV-ZEBOV
Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Anne Rechtien, Laura Richert, Hadrien Lorenzo, Gloria Martrus, Boris Hejblum, Christine Dahlke, Rahel Kasonta, Madeleine Zinser, Hans Stubbe, Urte Matschl, Ansgar Lohse, Verena Krähling, Markus Eickmann, Stephan Becker, Rodolphe Thiébaut, Marcus Altfeld, Marylyn Addo
Predicting vaccine efficacy remains a challenge. We used a systems vaccinology approach to identify early innate immune correlates of antibody induction in humans receiving the Ebola vaccine rVSV-ZEBOV. Blood samples from days 0, 1, 3, 7, and 14 were analyzed for changes in cytokine levels, innate immune cell subsets, and gene expression. Integrative statistical analyses with cross-validation identified a signature of 5 early innate markers correlating with antibody titers on day 28 and beyond. Among those, IP-10 on day 3 and MFI of CXCR6 on NK cells on day 1 were independent correlates. Consistently, we found an early gene expression signature linked to IP-10. This comprehensive characterization of early innate immune responses to the rVSV-ZEBOV vaccine in humans revealed immune signatures linked to IP-10. These results suggest correlates of vaccine-induced antibody induction and provide a rationale to explore strategies for augmenting the effectiveness of vaccines through manipulation of IP-10.
Graphical abstract
Teaser
Rechtien et al. apply a systems vaccinology approach to examine the early innate immune responses elicited by the Ebola vaccine rVSV-ZEBOV. They find that early innate immune responses, with IP-10 as an independent soluble marker, correlate with EBOV-GP-specific antibody induction.http://ift.tt/2gopo4v
Blowing the Whistle; the Ethical, Professional and Legal Implications of Raising Concerns and Self-Regulation within Dentistry
Abstract
Whistle-blowers are a necessary part of any system; dentistry is no different. The role of whistle-blowers in dentistry has been enshrined in Australian law since 2010. Raising concerns has become a legal duty as well as an ethical and professional obligation. It is important that these different aspects of raising concerns are explored as each adds another layer of consideration to the issue. The health professional's duty to whistle-blow could be viewed as problematic; the observance of this duty is associated with being trapped between a rock and a hard place where any decision to engage or not may have negative consequences. For the obligation of raising concerns to gain acceptability within the dental profession, the concept requires reframing as being necessary for the profession's continued success. The stigma of mandatory reporting needs to be removed to allow this essential process to occur. This article will discuss the ethical, professional and legal imperatives for the dental profession to engage with whistle-blowing and the likely challenges that are likely to be met in doing so.
This article is protected by copyright. All rights reserved.
http://ift.tt/2wHdauk
Prosthodontic management of maxillofacial cases: a case series
Abstract
Maxillo-facial prosthetics is an important and recognised sub-discipline of prosthodontics that forms a key component of postgraduate training programs. General dentists have a role to play in the management of maxillo-facial defect patients even though treatment usually requires a multidisciplinary approach in an institutional environment. Maxillo-facial prosthetic cases frequently present with complex histories but simple patient goals. The conservatively managed implant-retained auricular prosthesis, speech aid prosthesis and orbital prosthesis cases described in this report were completed in a postgraduate clinical residency program and highlight the intrinsic complexities, challenges and ultimately satisfaction related to cases of this nature.
This article is protected by copyright. All rights reserved.
http://ift.tt/2wm6XRH
Oral health of community dwelling older Australian men: The Concord Health and Ageing in Men Project (CHAMP)
Abstract
Background
CHAMP is a cohort study of the health of a representative sample of Australian men aged 70 years and older. The aim of this report is to describe the oral health of these men.
Methods
Oral health was assessed when the men were all aged 78 years or older. Two calibrated examiners conducted a standardised intra-oral assessment. Descriptive data, with means and confidence intervals where appropriate, were analysed by statistical association tests. Participants were excluded from the collection of some periodontal assessments if they had a medical contraindication.
Results
Dental assessments of 614 participants revealed 90 (14.6%) were edentate. Men had a mean of 13.8 (CI 13.2-14.4) missing teeth and 10.3 (CI 9.8-10.8)teeth. Dentate participants had a mean of 1.1(CI 0.9-1.2) teeth with active coronal decay. Participants born in Italy had higher rates of sound teeth and lower rates of filled teeth, while those in the low income group had a higher rate of decayed teeth and lower rate of filled teeth. Thirty-four participants (5.5%) had one or more dental implants, and 66.3%relied on substitute natural teeth for functional occlusion. Of the 296 participants with full periodontal assessments, 90.9% (n=269) had one or more sites with pocket depths ≥3mm, 96.6% (n=286), had one or more sites with clinical attachment loss ≥ 5mm and 90.2% (n=267) had three or more sites with GI ≥ 2 scores.
Conclusions
There was a high prevalence of periodontal diseases and restorative burden of dentitions, which suggests that greater attention needs to be given to prevention and health maintenance in older Australian men.
This article is protected by copyright. All rights reserved.
http://ift.tt/2wHd7hW
Studying the human oral microbiome: challenges and the evolution of solutions
Abstract
Since the pioneering work of van Leeuwenhoek in 1684, subsequently built upon by other renowned microbiologists Robert Koch, Willoughby Miller and G.V. Black, oral microbiology has developed innovative techniques to study the oral microflora (now termed the "oral microbiome"). The advent of molecular techniques such as DNA-DNA hybridisation, polymerase chain reaction (PCR) and DNA sequencing has created an array of opportunities to construct a comprehensive picture of the diversity and composition of the oral microbiome. Approximately 700 oral bacterial species have been identified, of which 50% have yet to be cultivated, and some of these are known only by their signature DNA sequences. The synergism of ever-evolving culture-based and state-of-the-art culture-independent molecular techniques has facilitated in-depth understanding of the dynamics, acquisition and transfer of oral bacteria, along with their role in oral and general health and disease. Further research is needed to not only analyse but also to make sense of the ever-increasing volumes of data which these molecular techniques (especially high-throughput DNA sequencing) are generating, as well as why particular bacteria are present and what they are "actually doing" there. This review presents a comprehensive literature search of oral microbiology-related methods currently used to study the oral microbiome.
This article is protected by copyright. All rights reserved.
http://ift.tt/2wmq4er
In the Hunger Games, the Winner Takes Everything
Publication date: Available online 28 August 2017
Source:Trends in Biochemical Sciences
Author(s): Franziska Püschel, Cristina Muñoz-Pinedo
Entosis is an atypical form of cell death that occurs when a cell engulfs and kills another cell. A recent article by Overholtzer and colleagues indicates that glucose deprivation promotes entosis. AMP-activated protein kinase (AMPK) activation in the loser cells triggers their engulfment and elimination by winner cells, which endure starvation.
http://ift.tt/2wm2yOG
Effects of Cataract Opacity and Surgery on Sleep Quality
Rejuvenation Research , Vol. 0, No. 0.
http://ift.tt/2wf0ucS
Scholar : These new articles for Annals of the American Association of Geographers are available online
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Thyroid diseases and bone health
Abstract
Thyroid hormones are essential for skeletal development and are important regulators of bone maintenance in adults. Childhood hypothyroidism causes delayed skeletal development, retarded linear growth and impaired bone mineral accrual. Epiphyseal dysgenesis is evidenced by classic features of stippled epiphyses on X-ray. In severe cases, post-natal growth arrest results in a complex skeletal dysplasia. Thyroid hormone replacement stimulates catch-up growth and bone maturation, but recovery may be incomplete dependent on the duration and severity of hypothyroidism prior to treatment. A severe phenotype characteristic of hypothyroidism occurs in children with resistance to thyroid hormone due to mutations affecting THRA encoding thyroid hormone receptor α (TRα). Discovery of this rare condition recapitulated animal studies demonstrating that TRα mediates thyroid hormone action in the skeleton. In adults, thyrotoxicosis is well known to cause severe osteoporosis and fracture, but cases are rare because of prompt diagnosis and treatment. Recent data, however, indicate that subclinical hyperthyroidism is associated with low bone mineral density (BMD) and an increased risk of fracture. Population studies have also shown that variation in thyroid status within the reference range in post-menopausal women is associated with altered BMD and fracture risk. Thus, thyroid status at the upper end of the euthyroid reference range is associated with low BMD and increased risk of osteoporotic fragility fracture. Overall, extensive data demonstrate that euthyroid status is required for normal post-natal growth and bone mineral accrual, and is fundamental for maintenance of adult bone structure and strength.
http://ift.tt/2wgdYVX
Deiodinases and stem cells: an intimate relationship
Abstract
Thyroid hormone is a major determinant of tissue functions in vivo. The deiodinase family controls the tissue-specific activation or inactivation of intracellular thyroid hormones. Precise control of the T3-dependent transcriptional program is required by multiple cell systems, including the stem cell. In this context, the identification of a close connection between thyroid hormones and different signal pathways involved in the control of stem cell functions suggested that the deiodinases may play a role in the definition of stem cell biology and physiology. Stem cells have an unlimited self-renewal capacity and the potential to differentiate into different types of mature cells. Deciphering how all these events are achieved, how the T3 signal is controlled and integrated in stem cells and their niches, and how it can impact on them is essentially unknown and represents a challenge for coming years. In this review, I will explore the role played by the deiodinases in the modulation of the TH signal in stem cells of adult tissues, namely muscle and intestine, and how their actions control the delicate balance among self-renewal, proliferation and differentiation. Elucidation of the molecular mechanisms presiding thyroid hormone action in stem cells may reveal therapeutic potential, for example in the fields of regenerative diseases and cancer.
http://ift.tt/2xuHCFx
Dermoscopy prior to Mohs Micrographic surgery does not improve tumour margin assessment and lead to fewer Mohs stages
Abstract
Dermoscopy prior to Mohs Micrographic surgery does not improve tumour margin assessment for basal cell carcinoma of the head and neck and lead to fewer Mohs stages Mohs micrographic surgery (MMS) is a time consuming and expensive gold standard treatment for difficult to treat basal cell carcinoma (BCC). One factor that contributes significantly to the expense and duration is the number of stages required to obtain clear excision margins.
This article is protected by copyright. All rights reserved.
http://ift.tt/2wfgFqE
Scholar : These new articles for Archives and Records are available online
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Contribution of the ENT (Ear, Nose, and Throat) Surgeon's Clinical Evaluation to the Contouring of Target Volumes and Organs Eligible for Radiotherapy in Head and Neck Cancers
Conditions: Radiotherapy, Conformal (IMRT); Head and Neck Cancer; Otolaryngology; Surgeons; Radiation Oncologists
Intervention: Other: Systematic consideration of the advice of the ENT surgeon in the determination of the radiotherapy target volumes in head and neck cancers.
Sponsor: Fondation Ophtalmologique Adolphe de Rothschild
Not yet recruiting - verified July 2017
http://ift.tt/2xuQI4X
Intervention: Other: Systematic consideration of the advice of the ENT surgeon in the determination of the radiotherapy target volumes in head and neck cancers.
Sponsor: Fondation Ophtalmologique Adolphe de Rothschild
Not yet recruiting - verified July 2017
http://ift.tt/2xuQI4X
Familial Investigations of Childhood Cancer Predisposition
Conditions: Acute Leukemia; Adenomatous Polyposis; Adrenocortical Carcinoma; AML; BAP1 Tumor Predisposition Syndrome; Carney Complex; Choroid Plexus Carcinoma; Constitutional Mismatch Repair Deficiency Syndrome; Diamond-Blackfan Anemia; DICER1 Syndrome; Dyskeratosis Congenita; Emberger Syndrome; Familial Acute Myeloid Leukaemia; Familial Adenomatous Polyposis; Fanconi Anemia; Familial Cancer; Familial Wilms Tumor; Familial Neuroblastoma; GIST; Hereditary Breast and Ovarian Cancer; Hereditary Paraganglioma-Pheochromocytoma Syndrome; Hodgkin Lymphoma; Juvenile Polyposis; Li-Fraumeni Syndrome; Lynch Syndrome; MDS; Melanoma Syndrome; Multiple Endocrine Neoplasia Type 1; Multiple Endocrine Neoplasia Type 2; Neuroblastoma; Neurofibromatosis Type 1; Neurofibromatosis Type II; Nevoid Basal Cell Carcinoma Syndrome; Non Hodgkin Lymphoma; Noonan Syndrome and Other Rasopathy; Overgrowth Syndromes; Pancreatic Cancer; Peutz-Jeghers Syndrome; Pheochromocytoma/Paraganglioma; PTEN Hamartoma Tumor Syndrome; Retinoblastoma; Rhabdoid Tumor Predisposition Syndrome; Rhabdomyosarcoma; Rothmund-Thomson Syndrome; Tuberous Sclerosis; Von Hippel-Lindau Disease
Intervention:
Sponsor: St. Jude Children's Research Hospital
Recruiting - verified August 2017
http://ift.tt/2wf1Nss
Intervention:
Sponsor: St. Jude Children's Research Hospital
Recruiting - verified August 2017
http://ift.tt/2wf1Nss
Evaluation of Video Laryngoscopy in Patients With Head and Neck Pathology
Condition: Difficult Intubation
Intervention: Device: Indirect Laryngoscopy
Sponsor: Icahn School of Medicine at Mount Sinai
Recruiting - verified August 2017
http://ift.tt/2wffEz7
Intervention: Device: Indirect Laryngoscopy
Sponsor: Icahn School of Medicine at Mount Sinai
Recruiting - verified August 2017
http://ift.tt/2wffEz7
Expressing Personalized Tumor Antigens Study
Conditions: Colon Cancer Metastatic; Head and Neck Cancer Metastatic; Metastatic Non-Small Cell Lung Cancer
Intervention: Biological: ADXS-NEO
Sponsors: Advaxis, Inc.; Amgen
Not yet recruiting - verified August 2017
http://ift.tt/2xuF8qA
Intervention: Biological: ADXS-NEO
Sponsors: Advaxis, Inc.; Amgen
Not yet recruiting - verified August 2017
http://ift.tt/2xuF8qA
The role of radical radiotherapy in the management of malignant pleural mesothelioma: A systematic review
Source:Radiotherapy and Oncology
Author(s): Miranda Ashton, Noelle O'Rourke, Suzanne Currie, Andreas Rimner, Anthony Chalmers
Malignant pleural mesothelioma (MPM) is a devastating disease with limited treatment options and a dismal prognosis. Attempts to employ radical radiotherapy in this disease have been limited by the complex shape of the pleura and the dose restrictions necessitated by the close proximity of radiosensitive structures. Recent shifts towards a 'lung sparing' surgical approach in MPM have further heightened these challenges. The aim of this systematic review is to assess recent advances in radiotherapy planning and delivery, to ascertain how these developments have impacted on the feasibility of delivering photon-based, high-dose radiotherapy with radical intent in MPM. Three electronic databases were searched and a total of 249 articles reviewed. The challenge of generating high quality, practice-defining data for diseases such as MPM was highlighted by the identification of just two randomised studies. Much of the literature consisted of low quality, retrospective data with small cohorts and inconsistent reporting on radiotherapy techniques and dosimetry. Nevertheless, a number of prospective phase II studies were identified to suggest that radical doses of radiotherapy can be delivered safely after a lung sparing procedure in MPM, reporting encouraging survival data and acceptable levels of toxicity.
http://ift.tt/2vFTNgu
Evaluation of high dose volumetric CT to reduce inter-observer delineation variability and PTV margins for prostate cancer radiotherapy
Source:Radiotherapy and Oncology
Author(s): Hamideh Alasti, Young-Bin Cho, Charles Catton, Alejandro Berlin, Peter Chung, Andrew Bayley, Aaron Vandermeer, Vickie Kong, David Jaffray
PurposeThe aim was to determine whether the enhanced soft tissue contrast provided by high-dose volumetric CT (HDVCT) can reduce inter-observer variability in delineating prostate compared to helical conventional CT (CCT) scans and 3T MRI scans for patients undergoing radical prostate cancer radiotherapy. Secondly, to quantify the potential PTV reduction with decreased inter-observer variability.Materials and methodsA 320 slice volumetric CT scanner was used. The wide-detector coverage of 16cm enabled volumetric image acquisition of prostate gland in one rotation. Three imaging studies were performed on ten patients. CCT and HDVCT were performed consecutively at the same coordinate system followed by MRI. Five radiation oncologists delineated the prostate.ResultsThe inter-observer variability is 2.0±0.6, 1.9±0.4 and 1.8±0.4mm for CCT, HDVCT and MR respectively with the maximum at the apex region. Comparing inter-observer difference variability between CCT and HDVCT with MR indicates that observers have larger variations in contouring using CCT than HDVCT especially at apex. Jaccard index of HDVCT is significantly higher than CCT with a mean difference of 0.03 (p=0.011). Both MRI and HDVCT provide the opportunity for a 2mm PTV margin reduction at the apex compared to CCT.ConclusionInter-observer variability in delineation remains an important source of systematic error. HDCTV for treatment planning reduces this error without recourse to MRI and permits a PTV reduction of 2mm at the apex. The margins required to account for residual error with any imaging modality are still greater than are used in typical current practice.
http://ift.tt/2voJ2Uv
Developing a multidisciplinary rehabilitation package following hip fracture and testing in a randomised feasibility study: Fracture in the Elderly Multidisciplinary Rehabilitation (FEMuR).
A multidisciplinary rehabilitation package was developed for use following hip fracture and a feasibility randomised controlled trial identified methods for definitive evaluation.
http://ift.tt/2wlkEjS
Fentanyl (Fentora) [Internet].
The objective of this review was to perform a systematic review of the beneficial and harmful effects of Fentora for the management of breakthrough pain in cancer patients aged 18 years and older who are already receiving and who are tolerant to continuous opioid therapy for their persistent baseline cancer pain.
http://ift.tt/2wG9atW
Pilot of a randomised controlled trial of the selective serotonin reuptake inhibitor sertraline versus cognitive behavioural therapy for anxiety symptoms in people with generalised anxiety disorder who have failed to respond to low-intensity psychological treatments as defined by the National Institute for Health and Care Excellence guidelines.
Significant recruitment challenges led to premature closure of this trial for generalised anxiety disorder, and recruiting participants from primary care rather than psychological therapy services may be more successful.
http://ift.tt/2wlkDfO
Immunologic properties and therapeutic efficacy of a multivalent epitope-based vaccine against four Helicobacter pylori adhesins (urease, Lpp20, HpaA, and CagL) in Mongolian gerbils
Abstract
Background
Therapeutic vaccination is a desirable alternative for controlling Helicobacter pylori (H. pylori) infection. Attachment to the gastric mucosa is the first step in establishing bacterial colonization, and adhesins, which are on the surface of H. pylori, play a pivotal role in binding to human gastric mucosa.
Materials and Methods
In the present study, we constructed a multivalent epitope-based vaccine named CFAdE with seven carefully selected antigenic fragments from four H. pylori adhesins (urease, Lpp20, HpaA and CagL). The specificity, immunogenicity and ability to produce neutralizing antibodies of CFAdE were evaluated in BALB/c mice. After that, its therapeutic efficacy and protective immune mechanisms were explored in H. pylori-infected Mongolian gerbils.
Results
The results indicated that CFAdE could induce comparatively high levels of specific antibodies against urease, Lpp20, HpaA and CagL. Additionally, oral therapeutic immunization with CFAdE plus polysaccharide adjuvant (PA) significantly decreased H. pylori colonization compared with oral immunization with urease plus PA, and the protection was correlated with IgG and sIgA antibody and antigen-specific CD4+ T cells.
Conclusions
This study indicated that the multivalent epitope-based vaccine, which targeted multiple adhesins in adherence of H. pylori to the gastric mucosa, is more effective than the univalent vaccine targeting urease only. This multivalent epitope-based vaccine may be a promising therapeutic candidate vaccine against H. pylori infection.
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