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| Open AccessMyc targeted CDK18 promotes ATR and homologous recombination to mediate PARP inhibitor resistance in glioblastoma
PARP inhibitors are mainly used to treat BRCA1/2 mutated cancers. Here, the authors show that MYC amplified glioblastomas are sensitive to PARP inhibition due to CDK18 repression, which impairs ATR regulated homologous recombination repair, and that ATR inhibition sensitises glioblastomas to PARP inhibition.
- Jian-Fang Ning
- , Monica Stanciu
- & Samuel D. Rabkin
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Article
| Open AccessSequential LASER ART and CRISPR Treatments Eliminate HIV-1 in a Subset of Infected Humanized Mice
Here, the authors show that sequential treatment with long-acting slow-effective release ART and AAV9- based delivery of CRISPR-Cas9 results in undetectable levels of virus and integrated DNA in a subset of humanized HIV-1 infected mice. This proof-of-concept study suggests that HIV-1 elimination is possible.
- Prasanta K. Dash
- , Rafal Kaminski
- & Howard E. Gendelman
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Article
| Open AccessThe deubiquitylase OTUD3 stabilizes GRP78 and promotes lung tumorigenesis
The deubiquitylase OTUD3 can function as a tumour-suppressor by stabilizing PTEN. Here, the authors show that OTUD3 also has an oncogenic role in lung cancer by stabilizing the glucose-regulated protein GRP78.
- Tongde Du
- , Hongchang Li
- & Lingqiang Zhang
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Article
| Open AccessTransient drug-tolerance and permanent drug-resistance rely on the trehalose-catalytic shift in Mycobacterium tuberculosis
Trehalose metabolism has been linked to Mycobacterium tuberculosis (Mtb) virulence and biofilm formation. Here, using a model of drug-tolerant persisters and metabolomics, the authors dissect the role of trehalose metabolism in Mtb persister formation, linking trehalose-catalytic shift to antibiotic resistance.
- Jae Jin Lee
- , Sun-Kyung Lee
- & Hyungjin Eoh
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Article
| Open AccessMolecular tuning of farnesoid X receptor partial agonism
The ligand-activated transcription factor farnesoid X receptor (FXR) acts as a cellular sensor for bile acids and is of interest as a drug target. Here the authors employ X-ray crystallography and NMR to characterize the molecular determinants of FXR agonists, antagonists and a partial agonist that drive FXR activation and antagonism.
- Daniel Merk
- , Sridhar Sreeramulu
- & Harald Schwalbe
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Article
| Open AccessActivating an anterior nucleus gigantocellularis subpopulation triggers emergence from pharmacologically-induced coma in rodents
The reticular activating system (RAS) of the brainstem regulates wakefulness, and stimulation of RAS areas can reverse effects of anaesthesia. Here, the authors show that stimulation of a particular RAS area, the anterior portion of nucleus gigantocellularis, can produce arousal from deep coma.
- S. Gao
- , A. Proekt
- & D. W. Pfaff
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Article
| Open AccessInherent biomechanical traits enable infective filariae to disseminate through collecting lymphatic vessels
Stimuli affecting migration of filaria in host tissues are unclear. Using in situ imaging, Kilarski et al. here show that universal adaptations of nematodes allow Litomosoides sigmodontis infective larvae to mechanically break into pre-collecting lymphatics and follow the direction of flow towards the lymph node.
- Witold W. Kilarski
- , Coralie Martin
- & Melody A. Swartz
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Article
| Open AccessConserved transcriptomic profile between mouse and human colitis allows unsupervised patient stratification
Clinical and molecular heterogeneity of ulcerative colitis presents unresolved challenges to identify predictive biomarkers of response to therapies. Here, the authors combine mouse colitis time course with patient biopsy transcriptomes, achieving unsupervised clustering of UC patients correlating with therapeutic outcomes in independent data sets.
- Paulo Czarnewski
- , Sara M. Parigi
- & Eduardo J. Villablanca
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Article
| Open AccessDeath effector domain-containing protein induces vulnerability to cell cycle inhibition in triple-negative breast cancer
The use of of CDK4/6 inhibitors to treat patients with TNBC is limited by loss of Rb. Here, the authors show that a combination of CDK4/6 inhibitor and EGFR inhibitor is effective against DEDD-overexpressing TNBC, independent of Rb status.
- Yingjia Ni
- , Keon R. Schmidt
- & Siyuan Zhang
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Article
| Open AccessImproving the diagnostic yield of exome- sequencing by predicting gene–phenotype associations using large-scale gene expression analysis
A genetic diagnosis remains unattainable for many individuals with a rare disease because of incomplete knowledge about the genetic basis of many diseases. Here, the authors present the web-based tool GADO (GeneNetwork Assisted Diagnostic Optimization) that uses public RNA-seq data for prioritization of candidate genes.
- Patrick Deelen
- , Sipko van Dam
- & Lude Franke
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Article
| Open AccessA frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy
Genetic variants in RP1 can cause hereditary retinal degeneration (HRD). Here, in a genomic screen of 331 Japanese HRD patients, the authors identify a near-polymorphic RP1 variant that causes Mendelian HRD in trans with an Alu insertion and otherwise is associated with HRD according to a complex model of inheritance.
- Konstantinos Nikopoulos
- , Katarina Cisarova
- & Carlo Rivolta
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Article
| Open AccessThe microRNAs miR-204 and miR-211 maintain joint homeostasis and protect against osteoarthritis progression
Osteoarthritis involves whole-joint tissue degeneration. Here, the authors show that miR-204 and miR-211 in mesenchymal joint cells regulate their proliferation, catabolic and osteogenic responses, and that disease progression is ameliorated by intra-articular miR-204 delivery in mice.
- Jian Huang
- , Lan Zhao
- & Di Chen
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Article
| Open AccessA neurotoxin that specifically targets Anopheles mosquitoes
So far identified clostridial neurotoxins target vertebrates. Here, Contreras et al. isolate the clostridial-like neurotoxin PMP1 from Paraclostridium bifermentans strains and show that it selectively targets anopheline mosquitoes by targeting mosquito syntaxin.
- Estefania Contreras
- , Geoffrey Masuyer
- & Sarjeet S. Gill
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Article
| Open AccessMacrophage hypoxia signaling regulates cardiac fibrosis via Oncostatin M
Fibrosis is a hallmark of several cardiac pathologies and its underlying mechanisms are still poorly defined. Here the authors show that macrophage hypoxia signaling following transverse aortic constriction in mice suppresses the activation of cardiac fibroblasts by secreting oncostatin M.
- Hajime Abe
- , Norihiko Takeda
- & Issei Komuro
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Article
| Open AccessIdentification of a potent benzoxaborole drug candidate for treating cryptosporidiosis
Cryptosporidium infection can cause severe diarrhea with limited treatment options available. Here, Lunde et al. perform a drug repositioning screen with a library of benzoxaboroles and identify AN7973 as potent inhibitor of intracellular parasite development with good efficacy in murine and neonatal dairy calf disease models.
- Christopher S. Lunde
- , Erin E. Stebbins
- & Christopher D. Huston
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Article
| Open AccessBioinspired extracellular vesicles embedded with black phosphorus for molecular recognition-guided biomineralization
Bone regeneration is of interest for treating a wide range of medical conditions. Here, the authors report on bioinspired matrix vesicles loaded with black phosphorus nanosheets and cell-specific aptamers for bone regeneration and demonstrate bone defect repair in vivo.
- Yingqian Wang
- , Xiaoxia Hu
- & Quan Yuan
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Article
| Open AccessSTING induces early IFN-β in the liver and constrains myeloid cell-mediated dissemination of murine cytomegalovirus
Innate immune signaling pathways sense different microbial features and can elicit distinct yet overlapping immune responses. Here the authors dissect the contribution of these pathways to the response to MCMV infection and find that STING signaling is dispensable for host survival but crucial to restrict viral replication and dissemination via myeloid cells.
- Pia-Katharina Tegtmeyer
- , Julia Spanier
- & Ulrich Kalinke
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Article
| Open AccessA single-nucleus RNA-sequencing pipeline to decipher the molecular anatomy and pathophysiology of human kidneys
Single-cell studies in solid tissues remain challenging and have benefited from the development of single-nuclei RNA sequencing strategies. Here Lake et al. apply single-nucleus RNA sequencing to human kidney tissues to provide a comprehensive molecular and cellular atlas of the human kidney, with potential implications for the understanding of kidney physiology and disease.
- Blue B. Lake
- , Song Chen
- & Sanjay Jain
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Article
| Open AccessTargeting a therapeutic LIF transgene to muscle via the immune system ameliorates muscular dystrophy
A number of therapeutic agents aimed at reducing pathology in Duchenne muscular dystrophy have been developed, but may have off-target effects when delivered systemically. Here, the authors express the therapeutic LIF transgene in leukocytes, and show this results in targeting to inflamed dystrophic muscle and reduced fibrosis by suppressing type 2 immunity.
- Steven S. Welc
- , Ivan Flores
- & James G. Tidball
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Article
| Open AccessTGFβ-induced degradation of TRAF3 in mesenchymal progenitor cells causes age-related osteoporosis
Increased inflammation during ageing promotes osteoporosis by activating osteoclast function and inhibiting osteoblasts. Here, the authors show that TGFβ1 release from bone matrix during ageing induces degradation of TRAF3 in mesenchymal progenitor cells, leading to reduced osteoblast differentiation and increased osteoclast formation, and suggesting that pharmacological stabilization of TRAF3 could ameliorate age-related osteoporosis.
- Jinbo Li
- , Akram Ayoub
- & Brendan F. Boyce
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Article
| Open AccessDOT1L inhibition reveals a distinct subset of enhancers dependent on H3K79 methylation
Histone 3 lysine 79 is mono (me1), di (me2), or tri (me3) methylated by the methyltransferase DOT1L. Here the authors reveal a group of enhancers defined by H3K79me2/3 which regulates enhancer-promoter interactions and other key enhancer features in MLL-AF4 leukemia cells.
- Laura Godfrey
- , Nicholas T. Crump
- & Thomas A. Milne
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Article
| Open AccessA shape-memory and spiral light-emitting device for precise multisite stimulation of nerve bundles
Optogenetic stimulation of damaged peripheral nerves has advantages over electrical stimulation but it’s limited to single-site stimulation. Here the authors develop a spiral-shaped LED implant for precise optogenetic stimulation of peripheral nerve bundles at multiple sites and use it to induce distinct limb movements in mice.
- Hao Zheng
- , Zhitao Zhang
- & Jiayi Zhang
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Article
| Open AccessA 3,2-Hydroxypyridinone-based Decorporation Agent that Removes Uranium from Bones In Vivo
In vivo decorporation of U(VI) from bones is an unsolved challenge because of the formation of stable uranium phosphate complexes. Here, the authors develop a hydroxypyridonone-based ligand with strong uranium complexation and low cytotoxicity. They find this ligand effectively removes uranium from kidney and bones in mice, and is suitable for oral administration.
- Xiaomei Wang
- , Xing Dai
- & Shuao Wang
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Article
| Open AccessGenome-wide analysis of dental caries and periodontitis combining clinical and self-reported data
Dental caries and periodontitis are among the most common medical conditions. Here, the authors report a GWAS for measures of oral health that reveals 47 risk loci for caries, find genetic correlation with 31 other complex traits and use Mendelian randomization analyses to explore potential causal relationships.
- Dmitry Shungin
- , Simon Haworth
- & Ingegerd Johansson
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Article
| Open AccessPathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure
The genetic and pathogenetic basis of heart failure is incompletely understood. Here, the authors present a high-fidelity tissue collection from rapidly preserved failing and non-failing control hearts which are used for eQTL mapping and network analysis, resulting in the prioritization of PPP1R3A as a heart failure gene.
- Pablo Cordero
- , Victoria N. Parikh
- & Euan A. Ashley
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Article
| Open AccessReduced subcutaneous adipogenesis in human hypertrophic obesity is linked to senescent precursor cells
Adipose tissue hypertrophy in obesity is associated with insulin resistance and other metabolic complications. Here, the authors analyze subcutaneous adipose tissue from patients with hypertrophic obesity and insulin resistance and find that adipocyte progenitor cells show features of senescence and have poor differentiation capacity.
- Birgit Gustafson
- , Annika Nerstedt
- & Ulf Smith
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Article
| Open AccessLugdunin amplifies innate immune responses in the skin in synergy with host- and microbiota-derived factors
Lugdunin is a peptide antibiotic produced by the skin commensal Staphylococcus lugdunensis. Here, the authors show that lugdunin reduces Staphylococcus aureus colonization in human keratinocytes and mouse skin by inducing the expression of human LL-37 and recruitment of monocytes and neutrophils.
- Katharina Bitschar
- , Birgit Sauer
- & Birgit Schittek
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Article
| Open AccessIdentification of HIV transmitting CD11c+ human epidermal dendritic cells
Composition and function of immune populations at barrier surfaces is crucial for response to infection. Here, the authors identify a population of dendritic cells in human epidermis, abundant in anogenital epithelia and distinct from Langerhans cells by surface phenotype and by high capacity for HIV infection and transmission.
- Kirstie M. Bertram
- , Rachel A. Botting
- & Andrew N. Harman
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Perspective
| Open AccessLessons from the reestablishment of Public Health Laboratory activities in Puerto Rico after Hurricane Maria
Hurricane Maria hit Puerto Rico in 2017 and resulted in a complete loss of activity of the Public Health Laboratories. Here, the authors discuss the approach taken and tools developed to re-establish activity in these laboratories using a quality management system and the lessons learned in this process.
- Margaret C. Hardy
- , Rita C. Stinnett
- & Eduardo O’Neill
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Article
| Open AccessIL-33 drives group 2 innate lymphoid cell-mediated protection during Clostridium difficile infection
Here, Frisbee et al. show that hypervirulent Clostridium difficile induces IL-33 expression in the gut and IL-33 reduces mortality and morbidity via group 2 innate lymphoid cells. Furthermore, serum levels of the soluble IL-33 decoy receptor, sST2, are associated with enhanced disease severity in human C. difficile patients.
- Alyse L. Frisbee
- , Mahmoud M. Saleh
- & William A. Petri Jr.
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Article
| Open AccessP2X7 receptor induces mitochondrial failure in monocytes and compromises NLRP3 inflammasome activation during sepsis
Systemic sepsis is a potentially life-threatening illness and immunocompromised individuals are especially vulnerable. Here, using a cohort of patients with intra-abdominal origin sepsis, the authors show an important role for the NLRP3 inflammasome in establishing a host response, and NLRP3 dysfunction is a common feature of sepsis mortality.
- Juan José Martínez-García
- , Helios Martínez-Banaclocha
- & Pablo Pelegrin
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Article
| Open AccessFOXF2 reprograms breast cancer cells into bone metastasis seeds
Bone metastasis in breast cancer patients causes major skeletal-related complications. Here, the authors show that FOXF2/BMP/SMAD pathway plays a major role in bone metastasis and suggest targeting this axis to manage bone metastasis.
- Shuo Wang
- , Gui-Xi Li
- & Yu-Mei Feng
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Article
| Open AccessCD46 facilitates entry and dissemination of human cytomegalovirus
Human cytomegalovirus (CMV) infects a wide range of host cells. Here, using a high throughput antibody screening platform, the authors identify the cell surface receptor CD46 to be required for CMV infection of epithelial cells and trophoblast-derived cells, the latter critical for congenital CMV infection.
- Kathryn R. Stein
- , Thomas J. Gardner
- & Domenico Tortorella
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Article
| Open AccessMass cytometry reveals systemic and local immune signatures that distinguish inflammatory bowel diseases
Distinguishing clinical subtypes of IBD is critical for optimal treatments, outcome prediction, and better understanding of disease pathogenesis. Here the authors phenotype blood and intestinal immune cells by mass cytometry and identify signatures associated with distinct disease states.
- Samuel J. S. Rubin
- , Lawrence Bai
- & Aida Habtezion
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Article
| Open AccessSMPDL3b modulates insulin receptor signaling in diabetic kidney disease
Sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) is a lipid raft enzyme known to affect membrane lipid composition. Here, Mitrofanova et al. show that increased expression of SMPDL3b in diabetes impairs insulin signaling and ceramide-1-phosphate (C1P) availability in podocytes, and that C1P supplementation protects mice from diabetic kidney disease.
- A. Mitrofanova
- , S. K. Mallela
- & A. Fornoni
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Article
| Open AccessIAPP toxicity activates HIF1α/PFKFB3 signaling delaying β-cell loss at the expense of β-cell function
Type 2 diabetes is associated with islet amyloid deposits derived from islet amyloid polypeptide (IAPP) expressed by β-cells. Here the authors show that IAPP misfolded protein stress induces the hypoxia inducible factor 1 alpha injury repair pathway and activates survival metabolic changes mediated by PFKFB3.
- Chiara Montemurro
- , Hiroshi Nomoto
- & Slavica Tudzarova
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Article
| Open Accessβ-Cardiac myosin hypertrophic cardiomyopathy mutations release sequestered heads and increase enzymatic activity
Hypertrophic cardiomyopathy (HCM) leads to hyper-contractility of the heart and is often caused by mutations in human β-cardiac myosin. Here authors show that four separate β-cardiac myosin mutations can modulate myosin activity by disrupting intramolecular interactions.
- Arjun S. Adhikari
- , Darshan V. Trivedi
- & Kathleen M. Ruppel
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Article
| Open AccessGenomic structure and diversity of Plasmodium falciparum in Southeast Asia reveal recent parasite migration patterns
Understanding genomic variation in Plasmodium falciparum parasites and inferring migration patterns can guide malaria elimination strategies. Using genome-wide data for 1722 parasites collected from 54 districts, the authors use identity-by-descent approaches to estimate regional parasite migration and spread of artemisinin drug resistance.
- Amol C. Shetty
- , Christopher G. Jacob
- & Marie A. Onyamboko
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Article
| Open AccessCommunity assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen
Resistance to first line treatment is a major hurdle in cancer treatment, that can be overcome with drug combinations. Here, the authors provide a large drug combination screen across cancer cell lines to benchmark crowdsourced methods and to computationally predict drug synergies.
- Michael P. Menden
- , Dennis Wang
- & Julio Saez-Rodriguez
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Article
| Open AccessXX sex chromosome complement promotes atherosclerosis in mice
Men and women differ in their risk of developing coronary artery disease, in part due to differences in their levels of sex hormones. Here, AlSiraj et al. show that the XX sex genotype regulates lipid metabolism and promotes atherosclerosis independently of sex hormones in mice.
- Yasir AlSiraj
- , Xuqi Chen
- & Lisa A. Cassis
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Article
| Open AccessDeterministic processes structure bacterial genetic communities across an urban landscape
Disease transmission is particularly complex at the human-livestock-wildlife interface. Here the authors sample E. coli from wild birds near households in Nairobi and show that antimicrobial resistance gene diversity is correlated with human and lifestock density, while virulence gene diversity is correlated with avian species richness.
- J. M. Hassell
- , M. J. Ward
- & E. M. Fèvre
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Article
| Open AccessLarge-scale brain modes reorganize between infant sleep states and carry prognostic information for preterms
Patterns of brain activity during sleep in early stages of life influence brain development and behavior. Here, the authors reveal cortical dynamics underpinning quiet and active sleep states in pre- and full-term infants, and their links to neurodevelopmental outcomes.
- Anton Tokariev
- , James A. Roberts
- & Luca Cocchi
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Article
| Open AccessAn integrative cross-omics analysis of DNA methylation sites of glucose and insulin homeostasis
Our understanding of the functional link between differential DNA methylation and type 2 diabetes and obesity remains limited. Here the authors present a blood-based EWAS of fasting glucose and insulin among 4808 non-diabetic Europeans and identify nine CpGs not previously implicated in glucose, insulin homeostasis and diabetes.
- Jun Liu
- , Elena Carnero-Montoro
- & Cornelia M. van Duijn
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Article
| Open AccessLncRNA-p21 alters the antiandrogen enzalutamide-induced prostate cancer neuroendocrine differentiation via modulating the EZH2/STAT3 signaling
The induction of neuroendocrine differentiation occurs in enzalutamide treated castration resistant prostate cancer. Here, the authors show that lncRNA-21 mediates enzalutamide induced neuroendocrine differentiation through EZH2/STAT axis and EZH2 inhibition suppresses this differentiation.
- Jie Luo
- , Keliang Wang
- & Chawnshang Chang
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Article
| Open AccessPolymer-tetrodotoxin conjugates to induce prolonged duration local anesthesia with minimal toxicity
There is interest in developing long-lasting local anaesthetics for a range of applications. Here, the authors report on the application of tetrodotoxin conjugated to amphiphilic biodegradable polymer to reduce systemic toxicity, achieve sustained release and investigate application as a local anaesthetic.
- Chao Zhao
- , Andong Liu
- & Daniel S. Kohane
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Article
| Open AccessDRP1-mediated mitochondrial shape controls calcium homeostasis and muscle mass
Muscle loss is associated with altered expression of proteins involved in mitochondrial homeostasis, but whether this is causative remains unclear. Here, the authors show that genetic ablation of the pro-fission protein DRP1 leads to accumulation of abnormal mitochondria that induce muscle atrophy by altering Ca2+ homeostasis and cellular stress responses.
- Giulia Favaro
- , Vanina Romanello
- & Marco Sandri
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Article
| Open AccessTranslatome analysis reveals altered serine and glycine metabolism in T-cell acute lymphoblastic leukemia cells
The ribosomal protein RPL10 is frequently mutated in T-cell acute lymphoblastic leukemia (T-ALL). Here, the authors show that it promotes proliferation of T-ALL cells by upregulating the serine biosynthesis enzyme phosphoserine phosphatase which in turn modulates serine and glycine metabolism.
- Kim R. Kampen
- , Laura Fancello
- & Kim De Keersmaecker
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Article
| Open AccessLIF regulates CXCL9 in tumor-associated macrophages and prevents CD8+ T cell tumor-infiltration impairing anti-PD1 therapy
LIF is a pleiotropic cytokine that promotes an immunosuppressive microenvironment and has critical functions in embryonic development. Here, the authors show that LIF regulates CD8+ T cell tumor infiltration in cancer by repressing CXCL19 and promoting the presence of protumoral macrophages and thatLIF inhibition, via neutralizing antibodies, promotes T cell infiltration and synergizes with immune checkpoint inhbitors resulting in tumor regression and immunological memory.
- Mónica Pascual-García
- , Ester Bonfill-Teixidor
- & Joan Seoane
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Article
| Open AccessIntegrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns
Environmental influences during prenatal development may have implications for health and disease later in life. Here, Czamara et al. assess DNA methylation in cord blood from new-born under various models including environmental and genetic effects individually and their additive or interaction effects.
- Darina Czamara
- , Gökçen Eraslan
- & Elisabeth B. Binder