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| Open AccessAccurate spike estimation from noisy calcium signals for ultrafast three-dimensional imaging of large neuronal populations in vivo
Two-photon laser scanning microscopy allows functional calcium imaging of large neuronal populations in vivo, but the recorded signals typically suffer from low signal to noise. Here the authors develop an algorithm, MLspike, which estimates action potentials from noisy calcium signals, and benchmark it against existing methods.
- Thomas Deneux
- , Attila Kaszas
- & Ivo Vanzetta
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Article
| Open AccessThe ER membrane-anchored ubiquitin ligase Hrd1 is a positive regulator of T-cell immunity
Hrd1 is an E3 ubiquitin ligase involved in ER-associated degradation and MHC I turnover. Here the authors use T-cell-specific ko mice and a mouse model of multiple sclerosis to show that Hrd1 also drives pro-inflammatory T helper cell responses and contributes to pathogenesis of autoimmune disease.
- Yuanming Xu
- , Fang Zhao
- & Deyu Fang
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| Open AccessTreatment of ongoing autoimmune encephalomyelitis with activated B-cell progenitors maturing into regulatory B cells
Evidence of how functional Bregs develop in vivo has been lacking. Here the authors show that proB cells exposed in vivoto CpG differentiate into distinct Breg subsets that inhibit autoimmunity by arresting T cells in the lymph nodes via CCL19 and by producing IL-10 at the site of immunopathology.
- Sarantis Korniotis
- , Christophe Gras
- & Flora Zavala
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| Open AccessHigh-throughput dual-colour precision imaging for brain-wide connectome with cytoarchitectonic landmarks at the cellular level
High-throughput imaging methods for brain-wide connectome mapping with precise location reference have been lacking. Here authors report a method that allows simultaneous acquisition of fluorescently labelled neurons and cytoarchitectural landmarks in the same mouse brain at the single-cell resolution.
- Hui Gong
- , Dongli Xu
- & Qingming Luo
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Article
| Open AccessA peptide for targeted, systemic delivery of imaging and therapeutic compounds into acute brain injuries
Accurate treatment of traumatic brain injuries, a leading cause of neurological disability and death in young people, is hampered by poor accumulation of drugs in the brain. Here, the authors describe a tetrapeptide that can efficiently target brain injuries and deliver therapeutic or diagnostic payload.
- Aman P. Mann
- , Pablo Scodeller
- & Erkki Ruoslahti
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| Open AccessPACAP suppresses dry eye signs by stimulating tear secretion
Dry eye disease is a complex condition with limited treatments. Here the authors show that mice lacking a multi-functional peptide PACAP develop dry eye-like signs that can be topically treated with PACAP peptide that stimulates tearing in mice, suggesting a possible therapy in humans with dry eyes.
- Tomoya Nakamachi
- , Hirokazu Ohtaki
- & Seiji Shioda
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Article
| Open AccessA key genetic factor for fucosyllactose utilization affects infant gut microbiota development
The factors shaping the development of infants' gut microbiota are poorly understood. Here, the authors show that alterations in gut microbiota development in infants are associated with the presence of bifidobacteria having a gene for utilisation of human milk oligosaccharides.
- Takahiro Matsuki
- , Kana Yahagi
- & Ken Kurokawa
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Article
| Open AccessEndothelial to mesenchymal transition is common in atherosclerotic lesions and is associated with plaque instability
Endothelial to mesenchymal transition (EndMT) is a crucial developmental process that also plays a role in the pathogenesis of some diseases. Here the authors show that EndMT contributes to the development of atherosclerosis in mice and humans, and is associated with complex human plaques that may be prone to rupture.
- Solene M. Evrard
- , Laura Lecce
- & Jason C. Kovacic
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Article
| Open AccessMicroRNA-125b-5p mimic inhibits acute liver failure
miR125b-5p has been associated with acute liver failure. Here the authors show that this miRNA targets Keap1 and activates Nrf2 to inhibit liver cell death after APAP or FAS toxicity, plus they show that a miR125b-5p mimic can inhibit ALF in mice.
- Dakai Yang
- , Qinggong Yuan
- & Amar Deep Sharma
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Article
| Open AccessRare disruptive mutations and their contribution to the heritable risk of colorectal cancer
The genetic factors that predispose individuals to familial colorectal cancer are poorly understood. In this study, the authors use whole exome sequencing of 1,006 patients and 1,609 healthy controls and show it is unlikely that further major high-penetrance susceptibility genes exist.
- Daniel Chubb
- , Peter Broderick
- & Richard S. Houlston
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Article
| Open AccessEarly role of vascular dysregulation on late-onset Alzheimer’s disease based on multifactorial data-driven analysis
Late-onset Alzheimer's disease (LOAD) is a complex multi-factorial disorder. Here, the authors perform a data-driven analysis of LOAD progression, including multimodal brain imaging, plasma and CSF biomarkers, and find vascular dysfunction is among the earliest and strongest altered events.
- Y. Iturria-Medina
- , R. C. Sotero
- & Ansgar J. Furst
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| Open AccessEarly synaptic deficits in the APP/PS1 mouse model of Alzheimer’s disease involve neuronal adenosine A2A receptors
Hippocampal synaptic dysfunctions are an early symptom of Alzheimer’s disease. Here, the authors find adenosine A2A receptors are up-regulated in APP/PS1 model mice and that deleting or blocking receptor activity helps alleviate plasticity and memory impairments.
- Silvia Viana da Silva
- , Matthias Georg Haberl
- & Christophe Mulle
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| Open AccessA multigene mutation classification of 468 colorectal cancers reveals a prognostic role for APC
APC is a well-known tumour suppressor that is frequently inactivated in colorectal cancer. Here, the authors sequence more than 1000 cancer genes in 468 colorectal cancers and show that mutation signatures can be used to classify the tumours and that multiple mutations in APCare associated with a poor prognosis.
- Michael J. Schell
- , Mingli Yang
- & Timothy J. Yeatman
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Article
| Open AccessHigh-throughput automated home-cage mesoscopic functional imaging of mouse cortex
Functional imaging in awake head-fixed mice is a widely used technique to study neural responses. Here the authors report on an open source, fully automated unsupervised system for training mice to self initiate head fixation to enable stable mesoscopic functional imaging of cortical functional connectivity.
- Timothy H. Murphy
- , Jamie D. Boyd
- & Jeff M. LeDue
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| Open AccessSURVIV for survival analysis of mRNA isoform variation
Clinical RNA-seq datasets can predict clinical outcomes. Here, Shen et al. report a statistical method for survival analysis of mRNA isoform variation using clinical RNA-seq datasets, and the identified isoform based survival predictors outperform gene expression based survival predictors using TCGA data on six cancer types.
- Shihao Shen
- , Yuanyuan Wang
- & Yi Xing
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| Open AccessUbiqutination via K27 and K29 chains signals aggregation and neuronal protection of LRRK2 by WSB1
Mutations in LRRK2 are linked to Parkinson’s Disease. Here, the authors identify WSB1 as a LRRK2 interacting protein and find that it promotes LRRK2 aggregation in primary neurons and drosophila models via ubiquitin K27 and K29 linkages.
- Frederick C. Nucifora Jr
- , Leslie G. Nucifora
- & Christopher A. Ross
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Article
| Open AccessTenascin-C drives persistence of organ fibrosis
Systemic sclerosis (SSc) is a fibrotic disease affecting multiple organs. Here the authors use patient samples plus mouse studies to show a central role for tenascin C as a TLR4 activator responsible for persistence of fibrosis in the context of SSc and SSc-like disease.
- Swati Bhattacharyya
- , Wenxia Wang
- & John Varga
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Article
| Open AccessA bispecific antibody targeting sclerostin and DKK-1 promotes bone mass accrual and fracture repair
Antibodies that block the Wnt inhibitors sclerostin and DKK- 1 enhance bone formation and fracture repair. Here the authors show these monospecific antibodies induce compensatory mechanisms that limit efficacy, and have designed a sclerostin/DKK-1 bispecific antibody that promotes superior fracture repair in rodents and bone formation in primates.
- Monica Florio
- , Kannan Gunasekaran
- & Michael S. Ominsky
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Article
| Open AccessKCNQ channel openers reverse depressive symptoms via an active resilience mechanism
Potassium channels in the ventral tegmental area are known to regulate resilience against stress-induced depression. Here, the authors show over expression of KCNQ3 channels in VTA dopaminergic neurons or treatment with KCNQ channel openers normalizes depressive behaviours in mouse models.
- Allyson K. Friedman
- , Barbara Juarez
- & Ming-Hu Han
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Article
| Open AccessStructural basis of omalizumab therapy and omalizumab-mediated IgE exchange
Omalizumab is an antibody against IgE that is used to treat patients with asthma and chronic idiopathic urticaria. Here, the authors report the structure of omalizumab in complex with an IgE fragment and develop an approach to exchange rather than deplete IgE on human basophils to block their activation.
- Luke F. Pennington
- , Svetlana Tarchevskaya
- & Theodore S. Jardetzky
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| Open AccessGlobally prevalent PfMDR1 mutations modulate Plasmodium falciparum susceptibility to artemisinin-based combination therapies
Antimalarial chemotherapy relies on combination therapies (ACTs) consisting of an artemisinin derivative and a partner drug. Here, the authors study the effects of globally prevalent mutations in a multidrug resistance transporter (PfMDR1) on the parasite’s susceptibility to ACT drugs.
- M. Isabel Veiga
- , Satish K. Dhingra
- & David A. Fidock
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| Open AccessHeterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant
Fulvestrant degrades the oestrogen receptor. Here, the authors report on a clinical trial using fulvestrant and show that mutations in the oestrogen receptor alpha gene are prevalent in circulating tumour DNA and do not influence the clinical outcome of patients to fulvestrant.
- Jill M. Spoerke
- , Steven Gendreau
- & Mark R. Lackner
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Article
| Open AccessCaloric restriction blocks neuropathology and motor deficits in Machado–Joseph disease mouse models through SIRT1 pathway
SIRTs have been reported to provide neuroprotective actions in polyglutamine diseases, and are linked to the beneficial effects of caloric restrictive diets. Here, the authors show caloric restriction improves behavioural and neuropathological deficits in MJD model mice, an effect dependent on SIRT1 activity.
- Janete Cunha-Santos
- , Joana Duarte-Neves
- & Cláudia Cavadas
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| Open AccessThe somatic mutation profiles of 2,433 breast cancers refine their genomic and transcriptomic landscapes
Much effort has recently been devoted to understanding the genomics of breast cancer. In this study, the authors integrate somatic mutation data with previously published copy number aberration and gene expression information for nearly 2,500 breast cancer samples.
- Bernard Pereira
- , Suet-Feung Chin
- & Carlos Caldas
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Article
| Open AccessAn inhibitor of chondroitin sulfate proteoglycan synthesis promotes central nervous system remyelination
Chondroitin sulfate proteoglycans (CSPGs) secreted by astrocytes are known to inhibit OPC differentiation and remyelination. Here, the authors identify a novel CSPG synthesis inhibitor and find it can rescue OPC differentiation in vitroand accelerate remyelination in mice following focal demyelination.
- Michael B. Keough
- , James A. Rogers
- & V. Wee Yong
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Article
| Open AccessA small number of abnormal brain connections predicts adult autism spectrum disorder
Autism spectrum disorder (ASD) is manifested by subtle but significant changes in the brain. Here, Yahata and colleagues devise a novel machine learning algorithm and develop a reliable ASD classifier based on brain functional connectivity, with which they quantitatively measure neuroimaging dimensions between ASD and other mental disorders.
- Noriaki Yahata
- , Jun Morimoto
- & Mitsuo Kawato
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| Open AccessT-cell activation is an immune correlate of risk in BCG vaccinated infants
BCG vaccine confers only partial protection against tuberculosis. Here the authors show that the risk of tuberculosis infection and progression to disease in BCG-immunized children positively correlates with the frequency of activated HLA-DR+CD4+T cells.
- Helen A. Fletcher
- , Margaret A. Snowden
- & Helen McShane
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Article
| Open AccessParathyroid hormone receptor signalling in osterix-expressing mesenchymal progenitors is essential for tooth root formation
How the parathyroid hormone-related protein receptor (PPR) and its ligand act in root formation and tooth eruption is unclear. Here, the authors identify osterix-expressing dental mesenchymal cells as progenitors for root formation and that PPR signalling mediates their differentiation and tooth eruption.
- Wanida Ono
- , Naoko Sakagami
- & Henry M. Kronenberg
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| Open Access4D Visualization of replication foci in mammalian cells corresponding to individual replicons
Whether replication happens at individual replicons or in replication factories is a controversial debate. Here the authors use super-resolution microscopy and analysis of replication fork speed to present evidence in favour of replicons.
- V. O. Chagin
- , C. S. Casas-Delucchi
- & M. C. Cardoso
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Article
| Open AccessChimeric 2C10R4 anti-CD40 antibody therapy is critical for long-term survival of GTKO.hCD46.hTBM pig-to-primate cardiac xenograft
Tweaking immune characteristics of donors and recipients could allow for successful cross-species organ transplantation. Here, the authors show that an anti-CD40 antibody therapy of baboons that received heart transplants from genetically modified pigs is key to their long-term survival.
- Muhammad M. Mohiuddin
- , Avneesh K. Singh
- & Keith A. Horvath
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Article
| Open AccessRepression of GSK3 restores NK cell cytotoxicity in AML patients
Natural killer cells of acute myeloid leukaemia patients lack cytotoxic activity. Here the authors show that these cells have elevated GSK3β, and that its inhibition prolongs survival of mice transplanted with human AML and stimulates NK cytotoxicity via increased adhesion of NK cells to their targets.
- Reshmi Parameswaran
- , Parameswaran Ramakrishnan
- & David N. Wald
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Article
| Open AccessTherapeutic activity of modified U1 core spliceosomal particles
Modification of the spliceosome is being tested as a potential therapy for exon-skipping diseases, such as spinal muscular atrophy (SMA). Here the authors show that 70K and stem loop IV structural elements of a modified U1 particle are essential for splicing enhancement and effective treatment of SMA mice.
- Malgorzata Ewa Rogalska
- , Mojca Tajnik
- & Franco Pagani
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Article
| Open AccessPterosin B prevents chondrocyte hypertrophy and osteoarthritis in mice by inhibiting Sik3
Therapies are needed for the prevention of chondrocyte hypertrophy and thinning of articular cartilage, features of osteoarthritic joint destruction. Here, the authors show that interfering with Sik3 signalling can increase the size of the chondrocyte population and reduce severity of a surgically induced mouse model of osteoarthritis.
- Yasuhito Yahara
- , Hiroshi Takemori
- & Noriyuki Tsumaki
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| Open AccessGenome-wide DNA methylation levels and altered cortisol stress reactivity following childhood trauma in humans
Exposure to childhood trauma is a major risk factor for the development of almost all psychiatric disorders. By epigenome-wide studies, here, Houtepen et al. show that DNA methylation at a locus in the Kit ligand gene (KITLG) mediates the relationship between childhood trauma and cortisol stress reactivity.
- Lotte C. Houtepen
- , Christiaan H. Vinkers
- & Marco P. M. Boks
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| Open AccessGeneration and transplantation of reprogrammed human neurons in the brain using 3D microtopographic scaffolds
Human pluripotent stem cell derived neurons have the potential for cell replacement therapy for brain injury and disease but problems on transplantation need to be overcome. Here, the authors use a microtopographic scaffold to graft neurons into both hippocampal organoids and the mouse brain striatum.
- Aaron L. Carlson
- , Neal K. Bennett
- & Prabhas V. Moghe
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| Open AccessTherapeutic targeting and rapid mobilization of endosteal HSC using a small molecule integrin antagonist
Mobilizing haematopoietic stem cells to the peripheral blood has largely replaced bone marrow transplants as a strategy in the clinic. Here, Cao et al. report the use of an α9β1/α4β1integrin antagonist to induce rapid mobilization of blood stem cells from the bone marrow in a humanized mouse model.
- Benjamin Cao
- , Zhen Zhang
- & Susan K. Nilsson
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Article
| Open AccessIL-17-producing γδ T cells enhance bone regeneration
γδ T cells are innate-like lymphocytes that regulate immune responses by producing IL-17A or IFN-γ, but have no known role in bone healing. Here the authors show a nonimmune bone-regenerative function of IL-17A produced by the Vγ6+ subset in mice.
- Takehito Ono
- , Kazuo Okamoto
- & Hiroshi Takayanagi
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Article
| Open AccessThe Gq signalling pathway inhibits brown and beige adipose tissue
Brown and beige adipose tissues contribute to organismal energy expenditure by generating heat. Here, Klepac et al. survey G protein-coupled receptors in brown fat and show that Gq-coupled receptors inhibit expression of thermogenic proteins in mice and in human adipocytes.
- Katarina Klepac
- , Ana Kilić
- & Alexander Pfeifer
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Article
| Open AccessStructural basis of allosteric and synergistic activation of AMPK by furan-2-phosphonic derivative C2 binding
AMPK regulates the metabolism and so drugs that activate AMPK might have potential for the treatment of metabolic disease. Here, the authors report the structure of AMPK bound to an activating compound, revealing two binding sites and indicating that dual therapy might be a good drug strategy.
- Christopher G. Langendorf
- , Kevin R. W. Ngoei
- & Bruce E. Kemp
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Article
| Open AccessAntibody-based PET imaging of amyloid beta in mouse models of Alzheimer’s disease
Imaging tools for evaluating progression of Alzheimer’s disease have been lacking. Here the authors develop a blood brain barrier-permeable Aß probe based on a radiolabelled, anti-Aß antibody, and report age-dependent brain uptake visualized in vivo with PET in mouse models of the disease.
- Dag Sehlin
- , Xiaotian T. Fang
- & Stina Syvänen
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Article
| Open AccessSelf-renewal of CD133hi cells by IL6/Notch3 signalling regulates endocrine resistance in metastatic breast cancer
ER+ breast cancer patients treated with endocrine therapies often acquire resistance and develop metastasis. In this study, the authors demonstrate that endocrine therapies can promote the self-renewal of CD133hi/ERlodrug resistant cells with metastatic potential driven through the IL6-Notch3 axis activation.
- Pasquale Sansone
- , Claudio Ceccarelli
- & Jacqueline Bromberg
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Article
| Open AccessTransplanted neurons integrate into adult retinas and respond to light
Replacing lost retinal ganglion cells is a potential treatment for optic neuropathies such as glaucoma. Here, the authors show that transplanted donor RGCs can successfully integrate into a mature host retina in vivo, projecting axons along the intact visual pathway and responding to light stimuli.
- Praseeda Venugopalan
- , Yan Wang
- & Jeffrey L. Goldberg
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Article
| Open AccessIntracellular mGluR5 plays a critical role in neuropathic pain
mGluR5 has been shown to play a role in chronic pain regulation. Here, the authors use membrane permeable and non-transported, impermeable mGluR5 antagonists to show that spinal analgesic effects in vivoare mediated by intracellular rather than cell surface mGluR5.
- Kathleen Vincent
- , Virginia M. Cornea
- & Terence J. Coderre
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Article
| Open AccessGWAS of 89,283 individuals identifies genetic variants associated with self-reporting of being a morning person
Circadian rhythms and related behaviours vary across individuals. Here, a large genome-wide association study reveals common single nucleotide variants influencing whether an individual reports as being a ‘morning person’ by identifying 15 significant loci, including 7 near known circadian genes.
- Youna Hu
- , Alena Shmygelska
- & David A. Hinds
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Article
| Open AccessIntestinal microbiome is related to lifetime antibiotic use in Finnish pre-school children
The impact of antibiotics on the microbiome and health of children is poorly understood. Here, Korpela et al. study the gut microbiome of 142 children and show that the use of macrolides, but not penicillins, is associated with long-lasting shifts in microbiota composition and increased risk of asthma and overweight.
- Katri Korpela
- , Anne Salonen
- & Willem M. de Vos
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Article
| Open AccessImaging tumour cell heterogeneity following cell transplantation into optically clear immune-deficient zebrafish
Direct visualisation of heterogeneous cell populations in live animals has been challenging. Here, the authors optimize cell transplantation into optically clear immune-deficient zebrafish, and use intravital imaging to track and to assess functional diversity of individual cancer cells in vivo.
- Qin Tang
- , John C. Moore
- & David M. Langenau
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Article
| Open AccessPrevention of Treacher Collins syndrome craniofacial anomalies in mouse models via maternal antioxidant supplementation
The TCOF1 gene is mutated in Treacher Collin's syndrome, a congenital craniofacial syndrome. Here, the authors show that Tcof1loss-of-function results in oxidative stress induced DNA damage and neuroepithelial cell death, and addition of antioxidants to pregnant mutant mice protected against these defects.
- Daisuke Sakai
- , Jill Dixon
- & Paul A. Trainor
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Article
| Open AccessRepetitive magnetic stimulation induces plasticity of inhibitory synapses
Repetitive transcranial magnetic stimulation (rTMS) is widely used as a therapeutic tool yet its effect on inhibitory networks in the brain has not been studied. Here, the authors demonstrate that 10Hz rTMS specifically reduces dendritic inhibition onto pyramidal neurons accompanied by remodeling of postsynaptic gephyrin clusters.
- Maximilian Lenz
- , Christos Galanis
- & Andreas Vlachos
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Article
| Open AccessA shear gradient-activated microfluidic device for automated monitoring of whole blood haemostasis and platelet function
The current hemostasis assays are unable to predict thrombotic or bleeding risk in clinics. Here, Jain et al. present a novel microfluidic device mimicking stenosed arterioles that determines clotting times in vitroand in extracorporeal circuits, offering a simple and reliable monitoring of blood homeostasis and platelet function.
- Abhishek Jain
- , Amanda Graveline
- & Donald E. Ingber