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| Open AccessCOVA1-18 neutralizing antibody protects against SARS-CoV-2 in three preclinical models
Monoclonal antibodies show great promise in treating Covid-19 patients. Here, Maisonnasse, Aldon and colleagues report pre-clinical results for COVA1-18 and demonstrate that it reduces viral infectivity in three animal models with over 95% efficacy in macaques upper respiratory tract.
- Pauline Maisonnasse
- , Yoann Aldon
- & Roger Le Grand
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Article
| Open AccessPreclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19
The 3CL protease of SARS-CoV-2 is inhibited by PF-00835231 in vitro. Here, the authors show that the prodrug PF-07304814 has broad spectrum activity, inhibiting SARS-CoV and SARS-CoV-2 in mice and its ADME and safety profile support clinical development.
- Britton Boras
- , Rhys M. Jones
- & Charlotte Allerton
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Article
| Open AccessInhibiting endocytosis in CGRP+ nociceptors attenuates inflammatory pain-like behavior
The authors show the endocytotic adaptor subunit called AP2A2 is differentially expressed in CGRP+ nociceptors. Locally inhibiting nociceptor endocytosis with a lipidated AP2 inhibitor peptide reduces acute and chronic pain-like behaviour in mice and rats, indicating prolonged analgesia.
- Rasheen Powell
- , Violet A. Young
- & Arin Bhattacharjee
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Article
| Open AccessC3 complement inhibition prevents antibody-mediated rejection and prolongs renal allograft survival in sensitized non-human primates
Donor-specific antibodies in sensitized recipients may cause kidney transplant rejection. Here the authors show that complement component C3 inhibition prolongs graft survival by inhibiting T and B cell proliferation/activation and hence tissue injury, despite antibody levels remaining unaffected.
- Robin Schmitz
- , Zachary W. Fitch
- & Stuart J. Knechtle
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Article
| Open AccessSmall-molecule polymerase inhibitor protects non-human primates from measles and reduces shedding
Measles virus is highly contagious and outbreaks occur worldwide. Here the authors show that the orally bioavailable small-molecule polymerase inhibitor ERDRP-0519 prevents measles disease in squirrel monkeys and reduces virus shedding.
- Kevin Wittwer
- , Danielle E. Anderson
- & Veronika von Messling
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| Open AccessTargeting SARS-CoV-2 receptor-binding domain to cells expressing CD40 improves protection to infection in convalescent macaques
In this study, Marlin et al. provide insights into the potential use of subunit vaccines that induce a high level of protection against SARS-CoV-2 in animal models.
- Romain Marlin
- , Veronique Godot
- & Roger Le Grand
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Article
| Open AccessLactate sensing mechanisms in arterial chemoreceptor cells
Lactate levels in blood change during hypoxia or exercise, however whether this variable is sensed to evoke adaptive responses is unknown. Here the authors show that oxygen-sensing carotid body cells stimulated by hypoxia are also activated by lactate to potentiate a compensatory ventilatory response.
- Hortensia Torres-Torrelo
- , Patricia Ortega-Sáenz
- & José López-Barneo
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Article
| Open Accessβ-Arrestin-1 is required for adaptive β-cell mass expansion during obesity
During insulin-resistance, the compensatory expansion of beta-cell mass is able to delay or the onset of overt type 2 diabetes. Here, the authors report that beta-arrestin-1, an intracellular protein known to regulate signalling through G protein-coupled receptors, is essential for beta-cell replication and function in insulin-resistant mice.
- Luiz F. Barella
- , Mario Rossi
- & Jürgen Wess
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Article
| Open AccessMolecular landscape and subtype-specific therapeutic response of nasopharyngeal carcinoma revealed by integrative pharmacogenomics
Nasopharyngeal carcinoma (NPC) is a malignant cancer type with high morbidity in Asia, and its current molecular classification is insufficient to predict therapy outcomes. Here the authors explore NPC subtype-specific response to therapy with a pharmacogenomics strategy integrating genomics and drug response of patient-derived organoids.
- Ren-Bo Ding
- , Ping Chen
- & Chu-Xia Deng
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Article
| Open AccessSex differences in fear memory consolidation via Tac2 signaling in mice
The Tachykinin 2 (Tac2) pathway in the central amygdala is sufficient and necessary for modulating fear memory consolidation. The authors show that silencing Tac2 neurons in the amygdala of male mice reduces fear expression, while fear expression in female mice is increased when manipulations are made during proestrus.
- A. Florido
- , E. R. Velasco
- & R. Andero
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Article
| Open AccessCell barrier function of resident peritoneal macrophages in post-operative adhesions
Peritoneal adhesions are a major cause of complications after abdominal surgery. Here the authors use a post-operative abdominal adhesion model in mice to show that resident F4/80HighCD206− macrophages form a protective barrier that can be enhanced by IL-4 administration or adoptive transfer of these cells.
- Tomoya Ito
- , Yusuke Shintani
- & Ken Suzuki
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Article
| Open AccessCombination therapy protects macaques against advanced Marburg virus disease
Extending the therapeutic window for acute viral infections could save lives. Here, the authors show that combination treatment with a human monoclonal antibody and remdesivir initiated at 6 days post infection with Marburg virus provides 80% protection in non-human primates.
- Robert W. Cross
- , Zachary A. Bornholdt
- & Thomas W. Geisbert
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Article
| Open AccessImplication of TIGIT+ human memory B cells in immune regulation
Regulatory B cells have been shown to play critical roles in the modulation of the immune system. Here, the authors implicate TIGIT expression in B cells with the process of immuno-regulation.
- Md Mahmudul Hasan
- , Sumi Sukumaran Nair
- & SangKon Oh
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Article
| Open AccessIdentification of CD318, TSPAN8 and CD66c as target candidates for CAR T cell based immunotherapy of pancreatic adenocarcinoma
There is an unmet clinical need to identify therapeutic options for the treatment of pancreatic cancer (PDAC). Here the authors present a systematic screening approach for the identification of potential PDAC cell surface target candidates for CAR-T cell based immunotherapy, followed by their functional validation in preclinical models.
- Daniel Schäfer
- , Stefan Tomiuk
- & Olaf Hardt
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Article
| Open AccessImmunogenicity and protective efficacy of inactivated SARS-CoV-2 vaccine candidate, BBV152 in rhesus macaques
SARS-CoV-2 vaccines are needed to fight the pandemic. Here, authors show protective efficacy and immunogenicity of the inactivated SARS-CoV-2 vaccine BBV152 in rhesus macaques. This vaccine is currently in clinical development.
- Pragya D. Yadav
- , Raches Ella
- & Balram Bhargava
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Article
| Open AccessDual targeting of polyamine synthesis and uptake in diffuse intrinsic pontine gliomas
Diffuse intrinsic pontine glioma (DIPG) is an almost incurable malignant childhood brain tumor. Here, the authors show that the polyamine synthetic pathway is activated in DIPG and that the dual targeting of polyamine synthesis and uptake results in prolonged survival in animal models.
- Aaminah Khan
- , Laura D. Gamble
- & David S. Ziegler
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Article
| Open AccessA COVID-19 vaccine candidate using SpyCatcher multimerization of the SARS-CoV-2 spike protein receptor-binding domain induces potent neutralising antibody responses
Vaccines for SARS-COV-2 are needed in the ongoing pandemic. Here the authors characterize a vaccine candidate that presents the receptor-binding domain (RBD) of SARS-CoV-2 spike protein on a synthetic VLP platform using SpyTag/SpyCatcher technology and show immunogenicity of a prime-boost regimen in mice and pigs.
- Tiong Kit Tan
- , Pramila Rijal
- & Alain R. Townsend
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Article
| Open AccessPreclinical assessment of the efficacy and specificity of GD2-B7H3 SynNotch CAR-T in metastatic neuroblastoma
Antibodies targeting a tumor antigen, GD2, show some efficacy for neuroblastoma but induce severe neuropathic pain and peripheral neuropathy. Here the authors design a gated chimeric antigen receptor (CAR), using GD2 as the gate and another tumor antigen, B7H3, as the target, to find this GD2-B7H3 CAR capable of suppressing neuroblastoma in mouse models with little adverse effects.
- Babak Moghimi
- , Sakunthala Muthugounder
- & Shahab Asgharzadeh
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Article
| Open AccessCapsid-like particles decorated with the SARS-CoV-2 receptor-binding domain elicit strong virus neutralization activity
Here the authors generate a capsid-like particle based vaccine candidate displaying the receptor-binding domain of the SARS-CoV-2 spike protein and show induction of neutralizing antibodies after intramuscular prime-boost immunization in mice.
- Cyrielle Fougeroux
- , Louise Goksøyr
- & Adam F. Sander
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Article
| Open AccessDistinct populations of cortical pyramidal neurons mediate drug reward and aversion
The anterior cingulate plays a role in addiction, but studies have not examined the role of its two types of glutamatergic projection neurons, pyramidal tract (PT) and intratelencephalic (IT). Here we demonstrate that these two populations regulate distinct features of a drug experience, its positive and negative aspects, respectively.
- A. F. Garcia
- , E. A. Crummy
- & S. M. Ferguson
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Article
| Open AccessEpigenetic activation of a RAS/MYC axis in H3.3K27M-driven cancer
Histone H3 at lysine 27 (H3K27M) is often mutated in cancer but its role in tumour initiation is unclear. Here, the authors generated a transgenic model expressing H3.3K27M from the Fabp7 gene promoter, demonstrating that H3.3K27M can initiate diverse tumorigesis on its own, acting through a RAS/MYC transcriptomic programme.
- Sanja Pajovic
- , Robert Siddaway
- & Cynthia Hawkins
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Article
| Open AccessTumor evolutionary trajectories during the acquisition of invasiveness in early stage lung adenocarcinoma
Invasive early stage lung adenocarcinoma has a heterogeneous prognosis. Here, the authors microdissect malignant pulmonary nodules to invasive and preinvasive components and study the mutations that are common or private between the lesions, allowing them to understand the evolutionary path of the tumours.
- Siwei Wang
- , Mulong Du
- & Rong Yin
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Article
| Open AccessShortwave-infrared meso-patterned imaging enables label-free mapping of tissue water and lipid content
Quantifying lipid and water content in tissues non-invasively is difficult, and no method exists to quantify lipids in blood non-invasively. Here the authors develop an imaging approach called shortwave infrared meso-patterned imaging (SWIR-MPI) to detect and spatially map tissue water and lipids in preclinical models.
- Yanyu Zhao
- , Anahita Pilvar
- & Darren Roblyer
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Article
| Open AccessCardio-centric hemodynamic management improves spinal cord oxygenation and mitigates hemorrhage in acute spinal cord injury
Clinical neuroprotective strategies for acute spinal cord injury (SCI) have largely overlooked the heart. Here the authors show cardiac contractility is immediately impaired in a porcine model of T2 SCI, and cardio-centric treatment with dobutamine optimizes cord oxygenation and mitigates haemorrhage.
- Alexandra M. Williams
- , Neda Manouchehri
- & Christopher R. West
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Article
| Open AccessRepurposing anti-inflammasome NRTIs for improving insulin sensitivity and reducing type 2 diabetes development
Inflammasome activation may contribute to type 2 diabetes, but whether targeting inflammasome is beneficial is unclear. Here the authors show that repurposing nucleoside reverse transcriptase inhibitors for inhibiting inflammasome activation is associated with reduced diabetes development in people and improves insulin sensitivity in experimental settings.
- Jayakrishna Ambati
- , Joseph Magagnoli
- & Bradley D. Gelfand
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Article
| Open AccessGlioma-initiating cells at tumor edge gain signals from tumor core cells to promote their malignancy
Intratumoural spatial heterogeneity is crucial to enhance therapeutic resistance in glioblastoma. Here, the authors show a paracrine signaling mechanism where glioblastoma-initiating cells located in the tumour edge elevate their malignancy by interaction with core-located tumour cells.
- Soniya Bastola
- , Marat S. Pavlyukov
- & Ichiro Nakano
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Comment
| Open AccessEmerging preclinical evidence does not support broad use of hydroxychloroquine in COVID-19 patients
There is an urgent need for drugs, therapies and vaccines to be available to protect the human population against COVID-19. One of the first approaches taken in the COVID-19 global response was to consider repurposing licensed drugs. This commentary highlights an extraordinary international collaborative effort of independent researchers who have recently all come to the same conclusion—that chloroquine or hydroxchloroquine are unlikely to provide clinical benefit against COVID-19.
- S. G. P. Funnell
- , W. E. Dowling
- & C. M. Coleman
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Article
| Open AccessOptogenetic restoration of retinal ganglion cell activity in the living primate
Non-human primate models are important for the development of high quality vision restoration therapies for blindness. Here, the authors demonstrate restoration of light responses in foveal retinal ganglion cells of the living macaque following optogenetic gene therapy.
- Juliette E. McGregor
- , Tyler Godat
- & William H. Merigan
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Article
| Open AccessMonitoring spatiotemporal changes in chaperone-mediated autophagy in vivo
Chaperone mediated autophagy (CMA) is selective but its activity in different tissue types has been unclear due to a lack of tools. Here, the authors generate transgenic mice expressing a CMA reporter that provides spatial and temporal in vivo data, uncovering differences in CMA in distinct tissues.
- S. Dong
- , C. Aguirre-Hernandez
- & A. M. Cuervo
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Article
| Open AccessTissue pO2 distributions in xenograft tumors dynamically imaged by Cherenkov-excited phosphorescence during fractionated radiation therapy
Hypoxia in solid tumors is an important factor in radiation therapy resistance, but partial pressures of oxygen in the tissue are heterogenous and difficult to measure. Here the authors develop Cherenkov excited phosphorescence imaging using oxygen probe Oxyphor PtG4 to spatially track oxygen distributions in tumors during fractionated radiotherapy.
- Xu Cao
- , Srinivasa Rao Allu
- & Brian W. Pogue
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Article
| Open AccessPHD1 controls muscle mTORC1 in a hydroxylation-independent manner by stabilizing leucyl tRNA synthetase
mTORC1 is an important regulator of muscle mass. Here, the authors show that the PHD1 controls muscle mass in a hydroxylation-independent manner. PHD1 prevents the degradation of leucine sensor LRS during oxygen and amino acid depletion to ensure effective mTORC1 activation in response to leucine.
- Gommaar D’Hulst
- , Inés Soro-Arnaiz
- & Katrien De Bock
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Article
| Open AccessYAP1 mediates survival of ALK-rearranged lung cancer cells treated with alectinib via pro-apoptotic protein regulation
Relapse is a limitation for the efficacy of the anaplastic lymphoma kinase (ALK)-inhibitor alectinib in ALK-rearranged lung cancer. Here, the authors show that YAP1 activation upon alectinib treatment leads to therapy resistance and that inhibiting both YAP1 and ALK leads to longer tumor remission in mice.
- Takahiro Tsuji
- , Hiroaki Ozasa
- & Toyohiro Hirai
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Article
| Open AccessDescending motor circuitry required for NT-3 mediated locomotor recovery after spinal cord injury in mice
Neurotrophin-3 (NT-3) plays a key role in the growth, development, and function of the nervous system. Here the authors show that NT-3-induced propriospino-motoneuron circuit reorganization is critical for locomotor recovery in mice following spinal cord injury.
- Qi Han
- , Josue D. Ordaz
- & Xiao-Ming Xu
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Article
| Open AccessThe ALFA-tag is a highly versatile tool for nanobody-based bioscience applications
Epitope tags are widely used in various applications, but often lack versatility. Here, the authors introduce a small, alpha helical tag, which is recognized by a high affinity nanobody and can be used in a range of different applications, from protein purification to super-resolution imaging and in vivo detection of proteins.
- Hansjörg Götzke
- , Markus Kilisch
- & Steffen Frey
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Article
| Open AccessNon-classical tissue monocytes and two functionally distinct populations of interstitial macrophages populate the mouse lung
Functional diversity of tissue-resident macrophages and signals governing their ontogeny and turnover remain unknown for the majority of tissues. Here the authors describe two phenotypically and functionally distinct long-lived populations of lung interstitial macrophages and their putative blood-derived monocytic precursor.
- Joey Schyns
- , Qiang Bai
- & Thomas Marichal
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Article
| Open AccessCollagen-rich airway smooth muscle cells are a metastatic niche for tumor colonization in the lung
Collagen is a dynamic component of both the tumor and metastatic niche. Here, the authors show that airway smooth muscle cells are a collagen III rich niche bladder cancer cells expressing CD167a, and Stat3 is a downstream target for abrogating these collagen III/CD167a-driven metastatic foci.
- Yu-Cheng Lee
- , Antonina V. Kurtova
- & Keith Syson Chan
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Article
| Open AccessSynthetic TRuC receptors engaging the complete T cell receptor for potent anti-tumor response
Supraphysiological T cell activation by chimeric antigen receptor (CAR) contributes to T cell exhaustion and adverse events in CAR T cell therapies. Here the authors engineer a synthetic antigen receptor that integrates into the endogenous TCR complex, preserving natural regulatory circuits and achieving improved performance in mouse tumor models.
- Patrick A. Baeuerle
- , Jian Ding
- & Robert Hofmeister
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Article
| Open AccessNear physiological spectral selectivity of cochlear optogenetics
Cochlear implant spectral resolution is limited by current spread from each stimulation electrode. Here the authors compare optogenetic, electric and acoustic stimulation in gerbils and demonstrate improved spectral resolution of optogenetic over conventional electric stimulation.
- Alexander Dieter
- , Carlos J. Duque-Afonso
- & Tobias Moser
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Article
| Open AccessOrganoid-derived C-Kit+/SSEA4− human retinal progenitor cells promote a protective retinal microenvironment during transplantation in rodents
Stem cell transplantation to treat retinal degeneration could be limited by the degenerative microenvironment. Here, the authors show that C-Kit+/SSEA4– progenitor cells enriched from human embryonic stem cell derived retinal organoids protect retinal structure, suppress microglial activation, gliosis and inflammation.
- Ting Zou
- , Lixiong Gao
- & Zheng Qin Yin
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Article
| Open AccessSympathetic nervous system controls resolution of inflammation via regulation of repulsive guidance molecule A
Diverse interactions between the nervous and immune systems have been shown, but specific mechanistic insights are still lacking. Here the authors show, using both mouse inflammation models and clinical correlation, that adrenergic nerve may ameliorate inflammation by inducing repulsive guidance molecule A signalling.
- Andreas Körner
- , Martin Schlegel
- & Valbona Mirakaj
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Article
| Open AccessPlasma redox imbalance caused by albumin oxidation promotes lung-predominant NETosis and pulmonary cancer metastasis
Neutrophil extracellular traps (NETs) are known to promote metastasis in mouse models. Here the authors show plasma redox imbalance caused by albumin oxidation to induce inflammation-independent NETosis and lung metastasis, and albumin oxidation and reduced plasma free thiol to be associated with lung metastasis in a cohort of head and neck cancer patients.
- Minoru Inoue
- , Ryota Nakashima
- & Scott V. Bratman
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Article
| Open AccessPreclinical development of a microRNA-based therapy for intervertebral disc degeneration
Intervertebral disk degeneration (IDD) is characterized by changes in the nucleus pulposus (NP) extra cellular matrix that compromise disk structural integrity. In a miRNA screen of human IDD patient NP tissue, the authors identify deregulated miR-141 and show that direct injection of nanoparticle-coupled miR-141 into the NP alleviates IDD in mice.
- Ming-liang Ji
- , Hua Jiang
- & Jun Lu
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Article
| Open AccessGriffithsin carrageenan fast dissolving inserts prevent SHIV HSV-2 and HPV infections in vivo
Safety and efficacy remain important challenges for non-antiretroviral-based microbicides. Here, Derby et al. show that a Griffithsin-Carrageenan fast dissolving vaginal insert provides on-demand protection against SHIV infections in macaques, paving the way for the development of pre-exposure prophylaxis on-demand products.
- Nina Derby
- , Manjari Lal
- & Thomas M. Zydowsky
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Article
| Open AccessAugmentation of vaccine-induced humoral and cellular immunity by a physical radiofrequency adjuvant
Vaccine adjuvants ensure sufficient engagement of the immune system in vaccination, however safety issues can be associated with novel chemical adjuvants. Here, Cao et al. report a physical radiofrequency adjuvant to simultaneously augment vaccine-induced humoral and cellular immune responses without potentially harmful adverse reactions.
- Yan Cao
- , Xiaoyue Zhu
- & Xinyuan Chen
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Article
| Open AccessAntifungal tolerance is a subpopulation effect distinct from resistance and is associated with persistent candidemia
The authors show that antifungal tolerance, defined as the fraction of growth of a fungal pathogen above the minimal inhibitory concentration, is due to the slow growth of subpopulations of cells that overcome drug stress, and that high tolerance is often associated with persistent infections.
- Alexander Rosenberg
- , Iuliana V. Ene
- & Judith Berman
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Article
| Open AccessTargetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models
T- and NK-cell lymphomas (TCL) are a group of lymphoid malignancies characterized by poor prognosis, but the absence of appropriate pre-clinical models has hampered the development of effective therapies. Here the authors establish several pre-clinical models and identify vulnerabilities that could be further exploited to treat patients afflicted by these diseases.
- Samuel Y. Ng
- , Noriaki Yoshida
- & Raphael Koch
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Article
| Open AccessRelease of Staphylococcus aureus extracellular vesicles and their application as a vaccine platform
Extracellular vesicles (EVs) influence host-pathogen interactions, but EV biogenesis in gram-positive bacteria remains elusive. Here authors characterize EVs from Staphylococcus aureus and show that phenol-soluble modulins and autolysins promote EV biogenesis by disrupting the membrane and cell wall.
- Xiaogang Wang
- , Christopher D. Thompson
- & Jean C. Lee
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Article
| Open AccessStructure-based design of native-like HIV-1 envelope trimers to silence non-neutralizing epitopes and eliminate CD4 binding
Eliciting broadly neutralizing antibodies (bnAbs) is a primary HIV vaccine goal, but available immunogens expose epitopes for development of non-nAbs. Here, the authors use computational and structure-guided design to develop improved native-like envelope trimers and analyze Ab response in animal models.
- Daniel W. Kulp
- , Jon M. Steichen
- & William R. Schief
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Article
| Open AccessDynamic contrast-enhanced photoacoustic imaging using photothermal stimuli-responsive composite nanomodulators
Photoacoustic imaging becomes an enabling technology that is designed for clinic diagnosis of disease. Here, Chenet al. report an imaging contrast agent—plasmonic nanoparticles caged in hydrogel subject to reversible volume change depending on temperature, which exhibits tunable photoacoustic signal.
- Yun-Sheng Chen
- , Soon Joon Yoon
- & Stanislav Emelianov