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| Open AccessA rapid bioluminescence assay for measuring myeloperoxidase activity in human plasma
Levels of the enzyme myeloperoxidase in the blood are considered a biomarker for the severity of cardiovascular disease. Here the authors report a rapid and inexpensive method for measuring myeloperoxidase activity in human plasma by luminescence, after adsorption of the enzyme to a polymer surface.
- Reece J. Goiffon
- , Sara C. Martinez
- & David Piwnica-Worms
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MnSOD upregulation sustains the Warburg effect via mitochondrial ROS and AMPK-dependent signalling in cancer
Tumour cells sustain high levels of glycolysis even in presence of oxygen, which is known as the Warburg effect. Here the authors show that MnSOD contributes to the Warburg effect by increasing the levels of H2O2released from mitochondria, which sustains glycolysis by activating AMPK.
- Peter C. Hart
- , Mao Mao
- & Marcelo G. Bonini
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Article
| Open AccessThe sperm of aging male bustards retards their offspring’s development
Sperm from aging males may decline in quality, but it is unclear how aging affects the ability of males to produce successful offspring. Here, the authors show that paternal aging of captive long-lived houbara bustards reduces both the likelihood that eggs hatch and the rate at which chicks grow.
- Brian T. Preston
- , Michel Saint Jalme
- & Gabriele Sorci
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Article
| Open AccessFumarate induces redox-dependent senescence by modifying glutathione metabolism
Fumarate hydratase (FH) mutations are associated with renal cancer. Here, Zheng et al. use metabolomic and analytical chemistry approaches to reveal that fumarate accumulated due to FH loss covalently modifies intracellular glutathione, leading to oxidative stress and senescence.
- Liang Zheng
- , Simone Cardaci
- & Eyal Gottlieb
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The 40-residue insertion in Vibrio cholerae FadR facilitates binding of an additional fatty acyl-CoA ligand
FadR is a regulator of fatty acid metabolism in bacteria, and contains a binding site for acyl-CoA. Here, Shi et al. present a structure of V. cholerae FadR and show that a unique C-terminal extension comprises a second acyl-CoA binding site, perhaps rendering V. choleraeFadR a more efficient regulator.
- Wei Shi
- , Gabriela Kovacikova
- & F. Jon Kull
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The mitochondrial uniporter controls fight or flight heart rate increases
Animals react to threats by increasing their heart rate. Wu et al. show that mitochondrial calcium uptake via a highly selective ion channel, the mitochondrial calcium uniporter, stimulates metabolism in cardiac pacemaker cells and is essential for physiological pulse acceleration but not resting heart rate.
- Yuejin Wu
- , Tyler P. Rasmussen
- & Mark E. Anderson
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Increased atrial arrhythmia susceptibility induced by intense endurance exercise in mice requires TNFα
Endurance exercise is associated with an increased risk of atrial fibrillation. Here, the authors show the adipokine TNFα is a crucial mediator of exercise-induced atrial fibrillation and irreversible atrial remodelling characterized by fibrosis and inflammation.
- Roozbeh Aschar-Sobbi
- , Farzad Izaddoustdar
- & Peter H. Backx
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Exercise at depth alters bradycardia and incidence of cardiac anomalies in deep-diving marine mammals
Deep-sea diving mammals routinely undergo extreme physiological challenges not experienced by their terrestrial counterparts. Using high-resolution electrocardiographic recorders fitted to seals and dolphins, Williams et al. report an increased frequency of cardiac arrhythmias at greater exercise intensity and dive depth.
- Terrie M. Williams
- , Lee A. Fuiman
- & Randall W. Davis
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Article
| Open AccessA subcutaneous adipose tissue–liver signalling axis controls hepatic gluconeogenesis
The drug amlexanox is known to improve obesity-related metabolic dysfunction in mice. Here the authors show that this effect is mediated by interleukin-6 secreted from subcutaneous adipocytes, which then inhibits gluconeogenesis in the liver by phosphorylating the hepatic transcription factor Stat3.
- Shannon M. Reilly
- , Maryam Ahmadian
- & Alan R. Saltiel
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Article
| Open AccessInsulin resistance and white adipose tissue inflammation are uncoupled in energetically challenged Fsp27-deficient mice
Fsp27 mediates ‘fusion’ of lipid droplets in mouse adipose tissue. Here, the authors investigate the physiological consequences of loss of Fsp27 in three different mouse models of ‘energetic overload’, and observe hepatic steatosis and insulin resistance but reduced adipose tissue inflammation.
- Linkang Zhou
- , Shi-Young Park
- & Peng Li
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A non-conserved miRNA regulates lysosomal function and impacts on a human lysosomal storage disorder
Multiple sulfatase deficiency is a lysosomal storage disorder arising from mutations in the sulfatase modifying factor 1 (SUMF1) gene. Here Frankel et al. show that targeting a microRNA, miR-95, can increase residual SUMF1 expression and restore sulfatase activity in patient cells.
- Lisa B. Frankel
- , Chiara Di Malta
- & Anders H. Lund
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Telomerase expression confers cardioprotection in the adult mouse heart after acute myocardial infarction
Short telomeres are risk factors for age-associated diseases such as cardiopathies. Here the authors show that cardiac reactivation of telomerase, the telomere-elongating enzyme whose expression is normally silenced postnatally, mitigates the consequences of myocardial infarction in adult mice.
- Christian Bär
- , Bruno Bernardes de Jesus
- & Maria A. Blasco
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Article
| Open AccessFunctionally reciprocal mutations of the prolactin signalling pathway define hairy and slick cattle
The hormone prolactin is a known modulator of mammalian lactation and hair growth. Here, the authors describe two dominant mutations in bovine prolactin and its receptor, demonstrating antagonistic effects on these traits and highlighting a role for this pathway in sweat gland function and thermoregulation.
- Mathew D. Littlejohn
- , Kristen M. Henty
- & Stephen R. Davis
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Article
| Open AccessThe switching role of β-adrenergic receptor signalling in cell survival or death decision of cardiomyocytes
The contribution of signal strength on cell fate decisions is often not reflected in signalling networks. By combining mathematical simulation and biochemical experiments in cultured adult cardiomyocytes, Shin et al. show that the concentration of a β-adrenergic receptor agonist affects the expression of Bcl-2, influencing the balance between cell survival and death.
- Sung-Young Shin
- , Taeyong Kim
- & Do Han Kim
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Somatic mutations in arachidonic acid metabolism pathway genes enhance oral cancer post-treatment disease-free survival
Chemical inhibitors of the tumour-progression promoting arachidonic acid metabolism pathway prolong post-treatment survival of cancer patients. Here the authors analyse sequence variation in oral cancer patients and show that loss-of-function mutations in this pathway prolong survival.
- Nidhan K. Biswas
- , Subrata Das
- & Partha P. Majumder
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Article
| Open AccessSerotonergic neurons respond to nutrients and regulate the timing of steroid hormone biosynthesis in Drosophila
Steroidal hormones play a major role in the transition from juvenile-to-adult stages of development. Here, Shimada-Niwa and Niwa show that production of one such hormone in the prothoracic gland of Drosophila melanogaster, is regulated by a subset of serotonergic neurons innervating the prothoracic gland.
- Yuko Shimada-Niwa
- & Ryusuke Niwa
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The long-chain alkane metabolism network of Alcanivorax dieselolei
The ability to degrade hydrocarbons, such as alkanes, is common among marine microbes but many details of this process are unclear. Here, Wang & Shao identify genes and proteins involved in alkane sensing, uptake and degradation in the marine bacterium Alcanivorax dieselolei.
- Wanpeng Wang
- & Zongze Shao
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Article
| Open AccessTRPA1 is essential for the vascular response to environmental cold exposure
Blood flow in the skin of mammals changes in response to cold, but the mechanisms driving this response are unclear. Aubdool et al. show that the non-selective cation channel, TRPA1, is a vascular cold sensor and required for the vascular protective response to local cold exposure.
- Aisah A. Aubdool
- , Rabea Graepel
- & Susan D. Brain
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Article
| Open AccessResponse-dependent dynamics of cell-specific inhibition in cortical networks in vivo
Inhibitory neurons in the visual cortex alter the computations of target cells by exerting division or subtraction effects, but what determines these different functions is not clear. Here the authors use visual stimuli and optogenetics to show that the effects mediated by somatostatin-expressing and parvalbumin-expressing neurons are driven by their response mode and timing.
- Sami El-Boustani
- & Mriganka Sur
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Large arteriolar component of oxygen delivery implies a safe margin of oxygen supply to cerebral tissue
Capillaries are thought to be the main suppliers of oxygen to tissues. Here the authors challenge this view by showing that, at baseline brain activity, half of blood oxygen is extracted from arterioles, whereas capillaries supply an oxygen reserve when neuronal activity is high or cerebral blood flow is decreased.
- Sava Sakadžić
- , Emiri T. Mandeville
- & David A. Boas
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Review Article |
The role of protein clearance mechanisms in organismal ageing and age-related diseases
Proteins are subject to continuous and complex quality-control mechanisms, which ensure integrity of the proteome. Vilchez et al.review how a demise in these processes, collectively referred to as proteostasis, is linked to organismal ageing and the development of age-associated diseases.
- David Vilchez
- , Isabel Saez
- & Andrew Dillin
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Hepatic miR-378 targets p110α and controls glucose and lipid homeostasis by modulating hepatic insulin signalling
PI3K is a central component of the insulin signalling pathway. Here, the authors reveal that miR-378 expression in the liver changes dynamically in response to fasting or refeeding, and show that miR-378 regulates hepatic insulin signalling by targeting the P110a subunit of PI3K.
- Wei Liu
- , Hongchao Cao
- & Hao Ying
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Article
| Open AccessDNA methylation signatures link prenatal famine exposure to growth and metabolism
The long-term effect of prenatal nutrition on gene regulation is largely unknown. Here the authors identify differentially methylated regions in whole blood from individuals exposed to famine early after conception, and show that these epigenetic changes may have adverse metabolic consequences later in life.
- Elmar W. Tobi
- , Jelle J. Goeman
- & Bastiaan T. Heijmans
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| Open AccessTRF2 and lamin A/C interact to facilitate the functional organization of chromosome ends
The shortening of telomeres—a structure that protects chromosome ends—is associated with cellular aging. Here, Wood et al.present evidence that interaction between the telomere-binding protein TRF2 and lamin A/C facilitates the formation of interstitial t-loops and stabilizes telomeres.
- Ashley M. Wood
- , Jannie M. Rendtlew Danielsen
- & Steven T. Kosak
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A glutamatergic reward input from the dorsal raphe to ventral tegmental area dopamine neurons
Glutamatergic neurons project from the dorsal raphe to the ventral tegmental area, two brain areas strongly associated with addictive behaviour, however the functional significance of this connection remains unclear. Qi et al.show that optogenetic activation of this pathway conveys reward in mice.
- Jia Qi
- , Shiliang Zhang
- & Marisela Morales
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S-nitrosothiols regulate nitric oxide production and storage in plants through the nitrogen assimilation pathway
Assimilation of nitrate by plant roots leads to the generation of the signalling molecule, nitric oxide. Here Frungillo et al.show that nitric oxide fine-tunes nitrate homeostasis by feedback regulating nitrate transporters and reductases, while also promoting its own storage.
- Lucas Frungillo
- , Michael J. Skelly
- & Ione Salgado
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Article
| Open AccessCotton cytochrome P450 CYP82D regulates systemic cell death by modulating the octadecanoid pathway
Oxylipin signalling is known to play important roles in plant growth, development and defence against pathogens. Here Sun et al.identify a novel cytochrome P450 in cotton and show that its suppression leads to activation of plant defence responses and alteration of oxylipin metabolism.
- Longqing Sun
- , Longfu Zhu
- & Xianlong Zhang
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Regulation of the NaV1.5 cytoplasmic domain by calmodulin
Voltage-gated sodium channels (Nav) are transmembrane proteins that underlie action potentials in excitable tissues. Here, Gabelli et al. suggest a novel mechanism for the cytoplasmic control of switching from the inactivated to the non-inactivated form of the Nav1.5 channel that involves dimerization.
- Sandra B. Gabelli
- , Agedi Boto
- & L. Mario Amzel
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Functional reconstitution of mitochondrial Fe/S cluster synthesis on Isu1 reveals the involvement of ferredoxin
The action of iron–sulphur proteins has been found in many important biological processes. Here, the authors present a reconstituted in vitrosystem for the characterization of a ferredoxin–ferredoxin reductase pair as an electron transfer chain in the initial step of iron–sulphur protein biogenesis.
- Holger Webert
- , Sven-Andreas Freibert
- & Roland Lill
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Cell type-specific plasticity of striatal projection neurons in parkinsonism and L-DOPA-induced dyskinesia
Parkinson’s disease and L-DOPA-induced dyskinesia are both associated with imbalances in activity between populations of spiny projection neurons. Fieblinger et al.show that homeostatic adaptations in excitability are engaged by these disease states, but synaptic strengths are not scaled accordingly.
- Tim Fieblinger
- , Steven M. Graves
- & D. James Surmeier
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Platelets promote tumour metastasis via interaction between TLR4 and tumour cell-released high-mobility group box1 protein
Factors affecting the fate of disseminating tumour cells in the circulation play a critical role in metastasis. Here the authors show that TLR4 on platelets promotes their adhesion to tumour cells and enhances metastasis.
- Le-Xing Yu
- , Lei Yan
- & Hong-Yang Wang
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Identification of the phytosphingosine metabolic pathway leading to odd-numbered fatty acids
Most cellular fatty acids contain even-numbered chains, and the origin of the small fraction of odd-numbered fatty acids remains unclear. Kondo et al.show that odd-numbered fatty acids are generated by metabolism of the long-chain base phytosphingosine in yeast and mammalian cells.
- Natsuki Kondo
- , Yusuke Ohno
- & Akio Kihara
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Article
| Open AccessSuperficial layer pyramidal cells communicate heterogeneously between multiple functional domains of cat primary visual cortex
Pyramidal cells in superficial layers of neocortex form a lateral network of synaptic bouton clusters, but its functional implication remains unclear. Here the authors overlaid activity maps of orientation preference in cat visual cortex with single-cell anatomy and observed projections to multiple functional domains.
- Kevan A. C. Martin
- , Stephan Roth
- & Elisha S. Rusch
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Oestrogen signalling in white adipose progenitor cells inhibits differentiation into brown adipose and smooth muscle cells
Oestrogen has various metabolic and physiological effects. Here the authors show that oestrogen receptor alpha signalling determines lineage commitment of murine adipose progenitor cells, regulating their differentiation into white adipocytes, beige adipocytes or smooth muscle cells.
- Kfir Lapid
- , Ajin Lim
- & Jonathan M. Graff
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Article
| Open AccessInterferon regulatory factor 9 is critical for neointima formation following vascular injury
Blood vessels respond to injury by thickening the supportive smooth muscle layer in a process known as neointima formation. Here the authors describe a novel regulatory pathway of neointima formation that involves a transcription factor, Interferon Regulating Factor 9, and its downstream target, the deacetylase SIRT1.
- Shu-Min Zhang
- , Li-Hua Zhu
- & Hongliang Li
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Integrated control of hepatic lipogenesis versus glucose production requires FoxO transcription factors
The transcription factors FoxoO1 and Srebp-1 control hepatic glucose and lipid production, respectively. Here, Haeusler et al.propose a model that integrates glucose and lipid regulation in the normal and diabetic liver under the unifying control of FoxO transcription factors.
- Rebecca A. Haeusler
- , Kirsten Hartil
- & Domenico Accili
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Article
| Open AccessSKN-1 and Nrf2 couples proline catabolism with lipid metabolism during nutrient deprivation
The coordinated metabolism of cellular nutrients is important to maintain energy homeostasis, particularly if nutrients are scarce. Here, the authors report that the sensor protein SKN-1/Nrf2 links catabolism of the amino acid proline with lipid metabolism in C. elegansand in cultured human cells.
- Shanshan Pang
- , Dana A. Lynn
- & Sean P. Curran
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Regulated spatial organization and sensitivity of cytosolic protein oxidation in Caenorhabditis elegans
Cells respond to redox changes by shifting their protein thiol–disulfide balance. Here, the authors show that this balance is spatially regulated and varies widely across individuals, challenging the concept that glutathione acts as the main cellular redox buffer.
- Catalina Romero-Aristizabal
- , Debora S. Marks
- & Javier Apfeld
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The tumour suppressor LKB1 regulates myelination through mitochondrial metabolism
Myelination of peripheral axons by Schwann cells is essential for proper transmission of nerve signals but the underlying mechanisms are not completely understood. Here the authors show that metabolic changes are required to ensure Schwann cell differentiation and proper myelination, and involve the tumour suppressor Lkb1 in regulating this process.
- Shabnam Pooya
- , Xiaona Liu
- & Biplab Dasgupta
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Hypothalamic S1P/S1PR1 axis controls energy homeostasis
Sphingosine-1-phosphate is a bioactive lipid with various physiological roles. Here, Silva et al. show that sphingosine-1-phosphate signalling in the hypothalamic arcuate nucleus regulates food intake of rodents, and that this process is altered in animal models of obesity and cancer anorexia.
- Vagner R. R. Silva
- , Thayana O. Micheletti
- & Eduardo R. Ropelle
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Dynamic GATA4 enhancers shape the chromatin landscape central to heart development and disease
Transcription factors (TFs) drive spatiotemporal patterns of gene expression that control organ development and disease responses. Here, He et al.show that chromatin occupancy of GATA4 varies between fetal, adult and hypertrophic heart to direct developmental stage- and disease-specific transcriptional programs.
- Aibin He
- , Fei Gu
- & William T. Pu
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SIRT6 represses LINE1 retrotransposons by ribosylating KAP1 but this repression fails with stress and age
Retrotransposons are repetitive sequences in the genome that can amplify themselves and whose activity has been linked to age-related pathologies. Here, Van Meter et al.report that the histone deacetylase SIRT6 represses activity of the L1 retrotransposon by ribosylating the nuclear corepressor protein, KAP1.
- Michael Van Meter
- , Mehr Kashyap
- & Vera Gorbunova
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Article
| Open AccessGlucose substitution prolongs maintenance of energy homeostasis and lifespan of telomere dysfunctional mice
Shortened telomeres and reduced mitochondrial biogenesis are cellular hallmarks of ageing. Here, Missios et al.show that old mice with telomere dysfunction have an increased energetic demand that cannot be met unless mice are fed a glucose-rich diet, which improves energy metabolism and extends lifespan.
- Pavlos Missios
- , Yuan Zhou
- & K. Lenhard Rudolph
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Metabolic properties in stroked rats revealed by relaxation-enhanced magnetic resonance spectroscopy at ultrahigh fields
1H magnetic resonance can detect endogenous metabolites at physiological concentrations but its application in animal models is challenged by low sensitivity. Here the authors focus ultrahigh magnetic fields on metabolites whose spectral signatures are selectively excited, and achieve microarchitectural insight of rat brains after a stroke.
- Noam Shemesh
- , Jens T. Rosenberg
- & Lucio Frydman
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Lifespan maturation and degeneration of human brain white matter
White matter in the human brain is known to change its properties during an individual's lifespan. Here, Yeatman et al. use quantitative imaging measurements of the living human brain to model changes in white mater structure based on tissue development and decline between the ages of 7–85 years.
- Jason D. Yeatman
- , Brian A. Wandell
- & Aviv A. Mezer
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Steroid hormone signalling links reproduction to lifespan in dietary-restricted Caenorhabditis elegans
Dietary restriction increases the lifespan of many species, but often at the cost of reduced fertility. Here, Thondamal et al. show that the dietary restriction-mediated increase in lifespan in Caenorhabditis elegansdepends on the production of a steroid hormone and its inhibition of germline plasticity.
- Manjunatha Thondamal
- , Michael Witting
- & Hugo Aguilaniu
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Insights into mitochondrial fatty acid synthesis from the structure of heterotetrameric 3-ketoacyl-ACP reductase/3R-hydroxyacyl-CoA dehydrogenase
3-Ketoacyl-ACP reductase is required for mitochondrial fatty acid synthesis. Venkatesan et al.present structures of this enzyme, show that the β-subunit is involved in fatty acid synthesis and propose a role for the α-subunit in routing unsaturated fatty acids into β-oxidation.
- Rajaram Venkatesan
- , Shiv K. Sah-Teli
- & Zhijun Chen
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Megakaryocyte-specific Profilin1-deficiency alters microtubule stability and causes a Wiskott–Aldrich syndrome-like platelet defect
Patients with mutations in the gene encoding the cytoskeleton regulator WAS have platelet defects. Here the authors show that the WAS-binding protein, Profilin1, is essential for platelet formation in mice, and that its deficiency reproduces the bleeding disorder of patients with WAS mutations.
- Markus Bender
- , Simon Stritt
- & Bernhard Nieswandt
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MicroRNA-378 controls classical brown fat expansion to counteract obesity
Brown fat tissue contributes to organismal energy expenditure due to its thermogenic capacity. Here, the authors identify miR-378 as a specific regulator of brown fat tissue expansion, and suggest that physiological crosstalk between adipose tissue depots leads to a reduction in white fat mass.
- Dongning Pan
- , Chunxiao Mao
- & Yong-Xu Wang