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Article
| Open AccessPhotocatalysis-mediated drug-free sustainable cancer therapy using nanocatalyst
Nanoparticles have been used to reduce the toxicity associated with chemotherapeutic agents. Here, the authors report a Z-scheme SnS1.68-WO2.41 nanocatalyst for photocatalytic generation of oxidative holes and hydrogen molecules for drug-free therapeutic strategy.
- Bin Zhao
- , Yingshuai Wang
- & Qianjun He
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Article
| Open AccessCAR-T cell-mediated depletion of immunosuppressive tumor-associated macrophages promotes endogenous antitumor immunity and augments adoptive immunotherapy
Several strategies have been attempted to target immune suppressive populations in the tumor microenvironment. Here the authors show that folate receptor β-targeted CAR-T cells eliminate immunosuppressive tumor associated macrophages, promoting endogenous antitumor immune responses and adoptive T-cell therapy in pre-clinical models.
- Alba Rodriguez-Garcia
- , Rachel C. Lynn
- & Daniel J. Powell Jr.
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Article
| Open AccessGranzyme B inhibition reduces disease severity in autoimmune blistering diseases
Pemphigoid diseases involve autoimmune mediated blistering and immunopathology of the upper dermis. Here, the authors implicate granzyme B in the immunopathology in multiple in vivo models of pemphigoid diseases and utilise a topical granzyme B inhibitor that attenuates disease phenotypes in vivo.
- Sho Hiroyasu
- , Matthew R. Zeglinski
- & David J. Granville
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Article
| Open AccessA pragmatic randomized controlled trial reports lack of efficacy of hydroxychloroquine on coronavirus disease 2019 viral kinetics
The use of hydroxychloroquine therapy for the treatment of Covid-19 is controversial. In this study, Lyngbakken and colleagues present a randomized controlled trial and show that the drug has no antiviral effects in humans infected with SARS-CoV-2.
- Magnus Nakrem Lyngbakken
- , Jan-Erik Berdal
- & Olav Dalgard
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Article
| Open AccessTreatment of MRSA-infected osteomyelitis using bacterial capturing, magnetically targeted composites with microwave-assisted bacterial killing
Deep tissue infections can be difficult to treat due to limited light penetration associated with phototherapies. Here, the authors report on a bacterial capture system for antibiotic delivery and microwave-assisted killing of MRSA in osteomyelitis and demonstrate application in vivo.
- Yuqian Qiao
- , Xiangmei Liu
- & Shuilin Wu
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Article
| Open AccessA lung tropic AAV vector improves survival in a mouse model of surfactant B deficiency
Surfactant protein B (SP-B) deficiency is a genetic lung disease that results in lethal respiratory distress within months of birth. Here, the authors describe a gene therapy strategy using a rationally designed AAV6 capsid that restores surfactant homeostasis, prevents lung injury, and improves survival in a mouse model of SP-B deficiency.
- Martin H. Kang
- , Laura P. van Lieshout
- & Bernard Thébaud
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Article
| Open AccessPost-surgical adhesions are triggered by calcium-dependent membrane bridges between mesothelial surfaces
Surgical adhesions are organ-joining bands of scar tissue that remain clinically untreatable. Here, the authors show that adhesions are formed through expansive mesothelial membrane bridges, and that blocking these with small molecules prevents formation of adhesions in mice.
- Adrian Fischer
- , Tim Koopmans
- & Yuval Rinkevich
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Article
| Open AccessExercise enhances skeletal muscle regeneration by promoting senescence in fibro-adipogenic progenitors
Some exercises exacerbate chronic inflammation and muscle fibrosis in chronic myopathy. Here, the authors show that senescence of fibro-adipogenic progenitors (FAPs) in response to exercise induces muscle regeneration, and impaired FAP senescence worsens inflammation and fibrosis in chronic myopathy in mice.
- Yuki Saito
- , Takako S. Chikenji
- & Mineko Fujimiya
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Article
| Open AccessMicrochannel network hydrogel induced ischemic blood perfusion connection
Restoration of blood flow to damaged sites has commonly involved treatment with pro-angiogenic molecules but these have undesired side effects. Here the authors present a microchannel-patterned gelatin hydrogel that is able to rescue mouse and porcine models of hindlimb ischemia.
- Jung Bok Lee
- , Dae-Hyun Kim
- & Hak-Joon Sung
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Article
| Open AccessKetamine can reduce harmful drinking by pharmacologically rewriting drinking memories
Memories linking environmental cues to alcohol reward are involved in the development and maintenance of heavy drinking. Here, the authors show that a single dose of ketamine, given after retrieval of alcohol-reward memories, disrupts the reconsolidation of these memories and reduces drinking in humans.
- Ravi K. Das
- , Grace Gale
- & Sunjeev K. Kamboj
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Article
| Open AccessVastly extended drug release from poly(pro-17β-estradiol) materials facilitates in vitro neurotrophism and neuroprotection
Currently there are no therapeutics for long lasting central nervous system injuries, that can address the complex injury cascade that develops over years. Here the authors report biomaterial scaffolds that release 17β-estradiol (E2) at nanomolar concentrations over the course of 1–10 years via slow hydrolysis in vitro.
- Anthony R. D’Amato
- , Devan L. Puhl
- & Edmund F. Palermo
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Article
| Open AccessPerioperative use of renin-angiotensin system inhibitors and outcomes in patients undergoing cardiac surgery
Renin-angiotensin system inhibitors (RASi) are beneficial in several classes of cardiovascular patients. However, whether their perioperative use is beneficial and/or safe in cardiac surgery is unclear. Here the authors perform a multicenter retrospective cohort study showing that preoperative and postoperative use of RASi is associated with reduction of mortality in patients undergoing cardiac surgery.
- Qian Ding
- , Zugui Zhang
- & Jianzhong Sun
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Article
| Open AccessA zwitterionic near-infrared fluorophore for real-time ureter identification during laparoscopic abdominopelvic surgery
Iatrogenic injury of the ureters is a feared complication of laparoscopic abdominal surgery. Here the authors present the NIR fluorophore ZW800-1 as an intraoperative imaging agent for ureter mapping, showing its safety, pharmacokinetic properties, and efficacy in healthy volunteers and patients undergoing abdominopelvic surgery.
- Kim S. de Valk
- , Henricus J. Handgraaf
- & Alexander L. Vahrmeijer
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Article
| Open AccessRegeneration of severely damaged lungs using an interventional cross-circulation platform
Gastric aspiration severely injures donor lungs, frequently making them unacceptable for transplantation. Here the authors show that an interventional cross-circulation platform enables the regeneration of severely damaged lungs in a swine model of gastric aspiration injury.
- Brandon A. Guenthart
- , John D. O’Neill
- & Matthew Bacchetta
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Article
| Open AccessDeep brain stimulation of the internal capsule enhances human cognitive control and prefrontal cortex function
Deep brain stimulation (DBS) is a promising treatment for psychiatric disorders, but its mechanism in relieving symptoms is unclear. Here, the authors show that DBS of ventral internal capsule/ventral striatum (VCVS) may act by enhancing prefrontal cortex oscillations that in turn enhance cognitive control.
- A. S. Widge
- , S. Zorowitz
- & D. D. Dougherty
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Article
| Open AccessTargeting of dermal myofibroblasts through death receptor 5 arrests fibrosis in mouse models of scleroderma
Dermal myofibroblasts are responsible for fibrosis development in scleroderma. Here the authors show that a bioengineered recombinant human TRAIL ligand reverses established fibrosis in mouse models of scleroderma by targeting the death receptor 5 and inducing apoptosis of myofibroblasts.
- Jong-Sung Park
- , Yumin Oh
- & Seulki Lee
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Article
| Open AccessOptimal dosing of dihydroartemisinin-piperaquine for seasonal malaria chemoprevention in young children
Seasonal malaria chemoprevention provides substantial benefit for young children, but resistance to used drugs will likely develop. Here, Chotsiri et al. evaluate the use of dihydroartemisinin-piperaquine as a regimen in 179 children, and population-based simulations suggest that small children would benefit from a higher and extended dosage.
- Palang Chotsiri
- , Issaka Zongo
- & Joel Tarning
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Article
| Open AccessInactivating hepatitis C virus in donor lungs using light therapies during normothermic ex vivo lung perfusion
Organs from donors with transmissible viral infections, such as hepatitis C virus (HCV), are not offered for transplantation due to a high risk of transmission. Here, Galasso et al. develop a method for treatment of HCV-infected human donor lungs that is safe and prevents HCV transmission in the pig model.
- Marcos Galasso
- , Jordan J. Feld
- & Marcelo Cypel
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Article
| Open AccessIndustrial scale high-throughput screening delivers multiple fast acting macrofilaricides
Parasitic nematodes causing onchocerciasis and lymphatic filariasis rely on a bacterial endosymbiont, Wolbachia, which is a validated therapeutic target. Here, Clare et al. perform a high-throughput screen of 1.3 million compounds and identify 5 chemotypes with faster kill rates than existing anti-Wolbachia drugs.
- Rachel H. Clare
- , Catherine Bardelle
- & Stephen A. Ward
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Article
| Open AccessA biomimetic nanoreactor for synergistic chemiexcited photodynamic therapy and starvation therapy against tumor metastasis
Photodynamic therapy is usually ineffective against deeply seated metastatic tumors due to poor penetration of the excitation light. Here, the authors design a biomimetic nanoreactor which can convert nutriment glucose into toxic singlet oxygen via chemiluminescence resonance energy transfer with no light excitation and demonstrate its high efficacy in a mouse lung metastatic model.
- Zhengze Yu
- , Ping Zhou
- & Bo Tang
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Comment
| Open AccessFrom petri dishes to politics – a multi-pronged approach is essential for saving endangered species
- Terri L. Roth
- & William F. Swanson
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Article
| Open AccessEmbryos and embryonic stem cells from the white rhinoceros
The Southern (SWR) and Northern (NWR) are two subspecies of the White Rhinoceros with the NWR being almost extinct. Here, using assisted reproduction technology, the authors produce and cryopreserve SWR purebred and NWR-SWR hybrid embryos developed to the blastocyst stage, and also generate embryonic stem cell lines, in an attempt to save genes of the NWR.
- Thomas B. Hildebrandt
- , Robert Hermes
- & Cesare Galli
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Article
| Open AccessInhibition of Y1 receptor signaling improves islet transplant outcome
Islet transplantation is considered one of the potential treatments for T1DM but limited islet survival and their impaired function pose limitations to this approach. Here Loh et al. show that the Y1 receptor is expressed in β- cells and inhibition of its signalling, both genetic and pharmacological, improves mouse and human islet function.
- Kim Loh
- , Yan-Chuan Shi
- & Herbert Herzog
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Article
| Open AccessHollow boron nitride nanospheres as boron reservoir for prostate cancer treatment
Use of soluble boron compounds in prostate cancer therapy is hampered by their short half-life time and low effectiveness. Here, the authors show that boron nitride nanospheres with controlled boron release can reduce proliferation of prostate cancer cells and inhibit tumour growth in animal models.
- Xia Li
- , Xiupeng Wang
- & Dmitri Golberg
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Article
| Open AccessAdditives for vaccine storage to improve thermal stability of adenoviruses from hours to months
Keeping viral vaccines cold from the manufacturers to patients is problematic and costly. Here, Krol and others show additives that can significantly improve at very low concentrations the storage of adenovirus type 5 at ambient and elevated temperature.
- Maria Pelliccia
- , Patrizia Andreozzi
- & Silke Krol
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Article
| Open AccessControl of diabetic hyperglycaemia and insulin resistance through TSC22D4
TSC22D4 regulates hepatic lipoprotein production, but has so far mainly been studied in the context of cancer cachexia. Here, the authors show TSC22D4 inhibition improves insulin sensitivity in several mouse models of diabetes, which they attribute at least in part to the induction of secreted LCN13.
- Bilgen Ekim Üstünel
- , Kilian Friedrich
- & Stephan Herzig
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Article
| Open AccessFenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer’s disease in rodent models
NSAID-induced analgesia is typically induced by inhibition of COX enzymes. Here the authors show instead that fenamate NSAIDs inhibit the Nlrp3 inflammasome via an effect on volume-regulated anion channel function and also repurpose these drugs for therapeutic effect in rodent models of Alzheimer disease.
- Michael J. D. Daniels
- , Jack Rivers-Auty
- & David Brough
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Article
| Open AccessExosome engineering for efficient intracellular delivery of soluble proteins using optically reversible protein–protein interaction module
Exosomes have been identified as promising vehicles for the in vivodelivery of therapeutic molecules. Here the authors design a system to load protein cargos into exosomes during their biogenesis using optogenetic control of protein-protein interactions between the cargo and an exosome-localized partner.
- Nambin Yim
- , Seung-Wook Ryu
- & Chulhee Choi
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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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Article
| 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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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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Article
| 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 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 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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Article
| 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 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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Article
| 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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Article
| 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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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 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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Article
| 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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Article
| 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 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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