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Genome-wide association study reveals two new risk loci for bipolar disorder
Bipolar disorder (BD) is a severe mood disorder, which has been shown to have a large genetic component. Here the authors identify two previously unreported BD risk loci and provide further insights into the biological mechanisms underlying BD development.
- Thomas W. Mühleisen
- , Markus Leber
- & Sven Cichon
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| Open AccessHACE1-dependent protein degradation provides cardiac protection in response to haemodynamic stress
HACE1 is an E3 ubiquitin ligase known to regulate various cell biological processes. Here, Zhang et al.identify HACE1 as a protective factor in the heart, demonstrating that HACE1 inhibits the development of heart failure in response to haemodynamic stress by regulating protein degradation pathways.
- Liyong Zhang
- , Xin Chen
- & Peter P. Liu
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Mutations in Alström protein impair terminal differentiation of cardiomyocytes
Cardiomyocyte cell cycle arrest is important for mammalian heart maturation, but the process is poorly understood. Here, the authors use exome sequencing to identify compound heterozygous ALMS1mutations associated with cardiomyocyte replication and provide evidence that Alström protein deficiency impairs postnatal cardiomyocyte cell cycle arrest.
- Lincoln T. Shenje
- , Peter Andersen
- & Daniel P. Judge
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HDL-transferred microRNA-223 regulates ICAM-1 expression in endothelial cells
Lipoproteins such as HDL can bind and transport microRNAs throughout the body. Here the authors provide a new mechanism contributing to the anti-inflammatory effects of HDL by which HDL-associated miR-223 is transferred to endothelial cells, where it inhibits expression of the adhesion molecule ICAM-1.
- Fatiha Tabet
- , Kasey C. Vickers
- & Kerry-Anne Rye
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Decreased CALM expression reduces Aβ42 to total Aβ ratio through clathrin-mediated endocytosis of γ-secretase
CALM is an adaptor protein required for clathrin-mediated endocytosis, and is a protective factor in Alzheimer’s disease. Here, Kanatsu et al.show that CALM can reduce the production of toxic Aß42 protein by driving clathrin-mediated endocytosis of γ-secretase.
- Kunihiko Kanatsu
- , Yuichi Morohashi
- & Takeshi Iwatsubo
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| Open AccessDelayed bactericidal response of Mycobacterium tuberculosis to bedaquiline involves remodelling of bacterial metabolism
The delayed onset of bactericidal activity of the anti-tuberculosis antibiotic bedaquiline is puzzling. Here, Koul and colleagues show, using a multi-omics approach, that the drug triggers a metabolic remodelling in Mycobacterium tuberculosisthat enables the pathogen’s transient survival.
- Anil Koul
- , Luc Vranckx
- & Dirk Bald
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| Open AccessHistamine H3 receptors aggravate cerebral ischaemic injury by histamine-independent mechanisms
Histamine H3 receptor dysregulation is a hallmark of pathological conditions in the central nervous system, and H3 receptor antagonism is neuroprotective. Here Chen et al.show that histamine-independent H3 receptor activation can enhance neuronal cell death during cerebral ischaemia by suppressing autophagy.
- Haijing Yan
- , Xiangnan Zhang
- & Zhong Chen
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NF-Y inactivation causes atypical neurodegeneration characterized by ubiquitin and p62 accumulation and endoplasmic reticulum disorganization
Nuclear transcription factor-Y is a cell cycle regulator that remains active in differentiated neurons. Here, Yamanaka et al.show that nuclear transcription factor-Y activity in neurons is required for the proper organization of the endoplasmic reticulum.
- Tomoyuki Yamanaka
- , Asako Tosaki
- & Nobuyuki Nukina
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African origin of the malaria parasite Plasmodium vivax
Plasmodium vivax, the leading cause of human malaria in Asia and Latin America, is thought to have an Asian origin. Here, the authors show that wild chimpanzees and gorillas in Africa are infected with parasites that are closely related to P. vivax, indicating an African origin for this species.
- Weimin Liu
- , Yingying Li
- & Paul M. Sharp
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Notch2 activation ameliorates nephrosis
The Notch signalling pathway is normally inactive in adult kidneys, but reactivated in kidney diseases. Here the authors show that activation of Notch2 receptors protects renal podocytes from apoptosis, which contrasts with the known detrimental effects of Notch1 signalling on the progression of kidney disease.
- Eriko Tanaka
- , Katsuhiko Asanuma
- & Yasuhiko Tomino
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A sensitive two-photon probe to selectively detect monoamine oxidase B activity in Parkinson’s disease models
Monoamine oxidase B is an enzyme that is unusually active in Parkinson’s disease, a feature that makes it an ideal diagnostic biomarker. Here, Li et al. create a highly specific fluorogenic probe that can selectively detect monoamine oxidase B activity in vivoto effectively diagnose Parkinson’s disease.
- Lin Li
- , Cheng-Wu Zhang
- & Shao Q. Yao
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| Open AccessEstimates of the changing age-burden of Plasmodium falciparum malaria disease in sub-Saharan Africa
Reduction in malaria transmission has changed the age pattern of malaria incidence. This study brings insights into the changes in age distributions of clinical malaria across Africa, with importance for improving within-population targeting of malaria control interventions.
- Jamie T. Griffin
- , Neil M. Ferguson
- & Azra C. Ghani
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A novel allosteric mechanism in the cysteine peptidase cathepsin K discovered by computational methods
Allosteric sites are an increasingly used target for drug design. Here, the authors computationally predict an allosteric site in cathepsin K and subsequently identify a small-molecule allosteric modifier.
- Marko Novinec
- , Matevž Korenč
- & Antonio Baici
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Functional analysis of a de novo GRIN2A missense mutation associated with early-onset epileptic encephalopathy
N-methyl-D-aspartate receptors (NMDARs) are key regulators of neuronal excitability in the brain and NMDAR mutations are implicated in epilepsy. Here, the authors identify a NMDAR subunit mutation in a child with epileptic encephalopathy, and show that this mutation increases the activity of NMDAR channels.
- Hongjie Yuan
- , Kasper B. Hansen
- & Stephen F. Traynelis
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Gene co-expression network analysis reveals common system-level properties of prognostic genes across cancer types
Many studies provide evidence of genes that are associated with cancer prognosis but a global view of these genes is lacking. Using data from ‘The Cancer Genome Atlas’, Yang et al.investigate the network properties of prognostic genes and show that these genes tend to be within highly interconnected groups but not the most connected nodes in the gene co-expression network.
- Yang Yang
- , Leng Han
- & Han Liang
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Structure-based discovery of Middle East respiratory syndrome coronavirus fusion inhibitor
MERS-CoV is a novel human coronavirus that has recently caused outbreaks of respiratory illness with high case fatality rate. Here the authors characterize the membrane fusion apparatus of MERS-CoV and develop a peptide that can inhibit virus fusion and replication in vitro.
- Lu Lu
- , Qi Liu
- & Shibo Jiang
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Dynamic reassortments and genetic heterogeneity of the human-infecting influenza A (H7N9) virus
H7N9 influenza A viruses capable of infecting humans have recently emerged in China. Here, the authors show that these viruses remain genetically diverse, suggesting that they are still in the process of adapting to human hosts.
- Lunbiao Cui
- , Di Liu
- & George F. Gao
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Autotransporters but not pAA are critical for rabbit colonization by Shiga toxin-producing Escherichia coli O104:H4
An outbreak of diarrhoea and haemolytic uraemic syndrome in Germany in 2011 was caused by a Shiga toxin-producing enteroaggregative E. coli, which carried the aggregative adherence plasmid pAA. Here, the authors show that autotransporters, but not pAA, are required for intestinal colonization in an infant rabbit model.
- Diana Munera
- , Jennifer M. Ritchie
- & Matthew K. Waldor
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MafB promotes atherosclerosis by inhibiting foam-cell apoptosis
In the early stages of atherosclerosis, macrophages in the vessel wall convert into foam cells, which promote the rise of atherosclerotic plaques. Here Hamada et al. show that the macrophage transcription factor MafB inhibits foam-cell apoptosis, and that its absence promotes atherosclerosis development in mice.
- Michito Hamada
- , Megumi Nakamura
- & Satoru Takahashi
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Antibiotic-induced shifts in the mouse gut microbiome and metabolome increase susceptibility to Clostridium difficile infection
Antibiotics alter the intestinal microbiota and facilitate colonization of pathogens such as Clostridium difficile. Here, the authors show that antibiotic-induced shifts in the mouse gut microbiome are correlated with changes in levels of certain metabolites that C. difficilecan use for germination and growth.
- Casey M. Theriot
- , Mark J. Koenigsknecht
- & Vincent B. Young
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Kinase fusions are frequent in Spitz tumours and spitzoid melanomas
Spitzoid neoplasms constitute a spectrum of melanocytic tumours, characterized by distinct clinical, pathological and genetic features. Here, Wiesner et al. show that kinase fusions represent the majority of oncogenic aberrations in spitzoid neoplasms and may serve as therapeutic targets for metastatic spitzoid melanoma.
- Thomas Wiesner
- , Jie He
- & Boris C. Bastian
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A statin-loaded reconstituted high-density lipoprotein nanoparticle inhibits atherosclerotic plaque inflammation
Inflammatory processes in atherosclerotic lesions promote disease progression and plaque rupture. Here the authors load the drug statin into nanoparticles made of recombinant high-density lipoprotein and show that these accumulate in atherosclerotic plaques and reduce plaque inflammation in mice.
- Raphaël Duivenvoorden
- , Jun Tang
- & Willem J. M. Mulder
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| Open AccessTRPA1 channels mediate acute neurogenic inflammation and pain produced by bacterial endotoxins
Gram-negative bacterial infections can often cause inflammation and pain. Meseguer et al. show that the inflammation and pain result from the direct activation of nociceptor TRPA1 channels by lipopolysaccharide, a major component of the outer membrane of Gram-negative bacteria.
- Victor Meseguer
- , Yeranddy A. Alpizar
- & Félix Viana
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Genome-scale metabolic modelling of hepatocytes reveals serine deficiency in patients with non-alcoholic fatty liver disease
Alterations in hepatocyte metabolism can lead to disorders such as non-alcoholic steatohepatitis (NASH). Here the authors create a comprehensive model of hepatocyte metabolism and use it to identify metabolic pathways altered in disease, revealing that serine levels are reduced in patients with NASH.
- Adil Mardinoglu
- , Rasmus Agren
- & Jens Nielsen
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Wafer-scale design of lightweight and transparent electronics that wraps around hairs
Realising flexible, lightweight and transparent electronics is a continuous challenge. Here, the authors report a process to create such transistor devices, which can be transferred onto various flexible substrates, and continue to function when wrapped around human hairs.
- Giovanni A. Salvatore
- , Niko Münzenrieder
- & Gerhard Tröster
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Two new susceptibility loci 1q24.2 and 11p11.2 confer risk to severe acne
Severe acne is a common skin disease characterized by chronic inflammation and potential scarring. Here, the authors have identified genetic variants at two loci associated with severe acne and provide insight into the genetic architecture and biological pathways underlying the disease.
- Li He
- , Wen-Juan Wu
- & Ya-Ping Zhang
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The MHF complex senses branched DNA by binding a pair of crossover DNA duplexes
The conserved MHF1/MHF2 DNA-processing complex is essential for DNA repair in response to genotoxic stress. Here, Zhao et al.report the crystal structure of a human MHF–DNA complex that provides insight into how MHF recognizes branched DNA—a feature important for cellular resistance to DNA damage.
- Qi Zhao
- , Dorina Saro
- & Yong Xiong
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Transcription factors FOXG1 and Groucho/TLE promote glioblastoma growth
Glioblastoma cancers contain brain tumour-initiating cells and targeting these specific cells is an attractive opportunity for therapy. In this study, the authors show that FOXG1 and Groucho/TLE transcription factors are important for glioblastoma growth and might be useful therapeutic targets.
- Federica Verginelli
- , Alessandro Perin
- & Stefano Stifani
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Indoleamides are active against drug-resistant Mycobacterium tuberculosis
New classes of antitubercular drugs are in constant demand as drug-resistant strains of Mycobacterium tuberculosis become more prevalent. Here, the authors characterize a class of drugs that are active against various M. tuberculosisstrains, including those resistant to currently used antituberculars.
- Shichun Lun
- , Haidan Guo
- & William R. Bishai
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The atypical mechanosensitive microRNA-712 derived from pre-ribosomal RNA induces endothelial inflammation and atherosclerosis
Gene expression in the vascular endothelium is sensitive to shear forces exerted by the circulation. Here the authors identify miR-712 as a mechanosensitive microRNA expressed in endothelial cells and show that miR-712 inhibits pro-atherogenic processes by downregulating tissue inhibitor of metalloproteinase 3.
- Dong Ju Son
- , Sandeep Kumar
- & Hanjoong Jo
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| Open AccessA rare functional cardioprotective APOC3 variant has risen in frequency in distinct population isolates
Isolated populations may empower genetic association studies of complex traits. Here, the authors identify a rare cardioprotective APOC3variant in a Greek population isolate and highlight the value of using population isolates to detect rare variants that confer disease risk.
- Ioanna Tachmazidou
- , George Dedoussis
- & Eleftheria Zeggini
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| Open AccessRETRACTED ARTICLE: Pericyte loss influences Alzheimer-like neurodegeneration in mice
Pericytes are cells in the blood–brain barrier that degenerate with the onset of Alzheimer's disease. Here, Sagare et al. show that pericyte loss contributes to disease onset by promoting amyloid-beta accumulation, tau pathology and early loss of neuronal cells.
- Abhay P. Sagare
- , Robert D. Bell
- & Berislav V. Zlokovic
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The smooth muscle-selective RhoGAP GRAF3 is a critical regulator of vascular tone and hypertension
Variants of the gene encoding the RhoGAP GRAF3 are associated with hypertension; however, the molecular basis for this association is unclear. Here, Bai et al.show that GRAF3 is strongly and specifically expressed in vascular smooth muscle cells, where it regulates blood pressure by inhibiting the GTPase RhoA.
- Xue Bai
- , Kaitlin C. Lenhart
- & Joan M. Taylor
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| Open AccessInfluenza A(H7N9) virus gains neuraminidase inhibitor resistance without loss of in vivo virulence or transmissibility
Some clinical isolates of influenza A(H7N9) virus encode a mutation within neuraminidase that could confer resistance to the only class of drugs active against H7N9. Here, the authors show that this mutation does not affect viral replication and pathogenicity while mediating resistance to antivirals in vivo.
- Rong Hai
- , Mirco Schmolke
- & Nicole M. Bouvier
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| Open AccessMicroRNA-33 regulates sterol regulatory element-binding protein 1 expression in mice
The micro-RNA miR-33 is encoded by an intron of the gene encoding sterol regulatory-binding protein 2 (SREBP-2) and controls cholesterol homoeostasis. Here, Horie et al.identify SREBP-1 as a target of miR-33 and show that deletion of miR-33 promotes diet-induced obesity and liver steatosis in mice.
- Takahiro Horie
- , Tomohiro Nishino
- & Koh Ono
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Real-time influenza forecasts during the 2012–2013 season
Our ability to accurately predict the spread of infectious diseases is still in its infancy. Here, Shamanet al.develop a model framework that produces accurate real-time forecasts of influenza peak timing for over a hundred cities in the USA.
- Jeffrey Shaman
- , Alicia Karspeck
- & Marc Lipsitch
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Cyclin D1 induction of Dicer governs microRNA processing and expression in breast cancer
Whether microRNA processing mediated by Dicer is regulated in a cell-cycle-dependent manner is unknown. Here, Chen et al.show that Cyclin D1, which is important in the control of the cell cycle, regulates the expression of Dicer, and that Cyclin D1 and Dicer expression levels correlate in breast cancer.
- Zuoren Yu
- , Liping Wang
- & Richard G. Pestell
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| Open AccessTRAF1 is a critical regulator of cerebral ischaemia–reperfusion injury and neuronal death
TRAF1 is an intracellular signalling molecule that has diverse biological functions. In this study, the authors show that TRAF1 is expressed in mice soon after they have suffered a stroke and that increased TRAF1 expression increases susceptibility to ischaemia-induced apoptosis and brain injury.
- Yan-Yun Lu
- , Zuo-Zhi Li
- & Hongliang Li
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| Open AccessA closed-loop synthetic gene circuit for the treatment of diet-induced obesity in mice
Designer gene circuits allow the controlled expression of proteins in response to specific stimuli. Here, Rössger et al.use synthetic biology approaches to create a fatty-acid biosensor that controls the production of a satiety hormone and use it to control diet-induced obesity in mice.
- Katrin Rössger
- , Ghislaine Charpin-El-Hamri
- & Martin Fussenegger
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Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology
Myofibroblasts drive fibrogenesis in the liver but their cellular origins remain unclear. Here Mederacke et al. use the Lratgene to label hepatic stellate cells (HSCs) in transgenic mice and reveal HSCs as the major source of myofibroblasts in models of toxic, biliary and fatty liver fibrosis.
- Ingmar Mederacke
- , Christine C. Hsu
- & Robert F. Schwabe
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| Open AccessGenome-wide association study implicates NDST3 in schizophrenia and bipolar disorder
Schizophrenia and bipolar disorder are important psychiatric disorders with overlapping genetic components. Here, the authors identify and replicate a genome-wide significant risk locus for the two disorders, and suggest a role for NDST3in severe psychiatric disease.
- Todd Lencz
- , Saurav Guha
- & Ariel Darvasi
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| Open AccessPlatelet-targeted gene therapy with human factor VIII establishes haemostasis in dogs with haemophilia A
Haemophilia is a genetic bleeding disorder associated with a deficiency in the coagulation factor VIII. Here, the authors use gene therapy to achieve stable overexpression of factor VIII in platelets of dogs with haemophilia A, preventing the occurrence of severe bleeding episodes for over 2.5 years.
- Lily M. Du
- , Paquita Nurden
- & David A. Wilcox
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Lysosomal NEU1 deficiency affects amyloid precursor protein levels and amyloid-β secretion via deregulated lysosomal exocytosis
The enzyme NEU1 negatively regulates lysosomal exocytosis in various cell types. Annunziata et al.show that mice deficient in NEU1 display Alzheimer’s disease-like pathology and that direct brain administration of NEU1 reduces pathology in an Alzheimer’s disease mouse model.
- Ida Annunziata
- , Annette Patterson
- & Alessandra d’Azzo
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Heat-shock protein dysregulation is associated with functional and pathological TDP-43 aggregation
Misfolding and aggregation of TAR DNA-binding protein 43 is implicated in various neurodegenerative diseases. Chang et al. show that aggregation of this protein is regulated by heat-shock proteins, which act to reduce the amount of pathological protein aggregates.
- Hsiang-Yu Chang
- , Shin-Chen Hou
- & I-Fan Wang
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Mechanism of inhibition of Mycobacterium tuberculosis antigen 85 by ebselen
As drug-resistant strains of Mycobacterium tuberculosis continue to emerge, antitubercular drugs with novel mechanisms of action are in high demand. Here, the authors show that ebselen is an inhibitor of M. tuberculosisantigen 85 and reveal the mechanism of inhibition.
- Lorenza Favrot
- , Anna E. Grzegorzewicz
- & Donald R. Ronning
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Mepenzolate bromide displays beneficial effects in a mouse model of chronic obstructive pulmonary disease
Chronic obstructive pulmonary disease (COPD) is a serious respiratory disease that is resistant to many forms of treatment. Tanake et al.screen compounds from a library of medicines and find that mepenzolate bromide reduces inflammatory responses and improves respiration in a mouse model of COPD.
- Ken-Ichiro Tanaka
- , Tomoaki Ishihara
- & Tohru Mizushima
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| Open AccessAnti-ghrelin immunoglobulins modulate ghrelin stability and its orexigenic effect in obese mice and humans
Obesity is often associated with increased appetite and food intake, despite normal blood levels of the hunger hormone ghrelin. Here the authors show that ghrelin-reactive antibodies in the blood of obese mice and humans enhance the orexigenic effect of ghrelin by protecting it from degradation.
- Kuniko Takagi
- , Romain Legrand
- & Sergueï O. Fetissov
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Polycystin-1 binds Par3/aPKC and controls convergent extension during renal tubular morphogenesis
Loss-of-function mutations in PKD1, the gene encoding the plasma membrane receptor Polycystin-1, lead to renal cyst formation in polycystic kidney disease. Here, Castelli et al. show that Polycystin-1 interacts with the Par3 polarity complex and has a role in the morphogenesis of kidney tubules during mouse development.
- Maddalena Castelli
- , Manila Boca
- & Alessandra Boletta
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Selection on haemagglutinin imposes a bottleneck during mammalian transmission of reassortant H5N1 influenza viruses
Mutations in the haemagglutinin of H5N1 avian influenza viruses confer transmissibility in ferrets. Here, Wilker et al. show that while within host variability is high, transmitted virus diversity is low suggesting a genetic bottleneck acts during transmission, driven by selection on haemagglutinin genes.
- Peter R. Wilker
- , Jorge M. Dinis
- & Thomas C. Friedrich
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