bluuebunny/crossref_metadata_2025_split huggingface dataset:
Engineered red blood cells as an off-the-shelf allogeneic anti-tumor therapeutic
Authors: Zhang Xuqing , Luo Mengyao , Dastagir Shamael R. , Nixon Mellissa , Khamhoung Annie , Schmidt Andrea , Lee Albert , Subbiah Naren , McLaughlin Douglas C. , Moore Christopher L. , Gribble Mary , Bayhi Nicholas , Amin Viral , Pepi Ryan , Pawar Sneha , Lyford Timothy J. , Soman Vikram , Mellen Jennifer , Carpenter Christopher L. , Turka Laurence A. , Wickham Thomas J. , Chen Tiffany F. 
Published: May 2021

AbstractCheckpoint inhibitors and T-cell therapies have highlighted the critical role of T cells in anti-cancer immunity. However, limitations associated with these treatments drive the need for alternative approaches. Here, we engineer red blood cells into artificial antigen-presenting cells (aAPCs) presenting a peptide bound to the major histocompatibility complex I, the costimulatory ligand 4-1BBL, and interleukin (IL)-12. This leads to robust, antigen-specific T-cell expansion, memory formation, additional immune activation, tumor control, and antigen spreading in tumor models in vivo. The presence of 4-1BBL and IL-12 induces minimal toxicities due to restriction to the vasculature and spleen. The allogeneic aAPC, RTX-321, comprised of human leukocyte antigen-A*02:01 presenting the human papilloma virus (HPV) peptide HPV16 E711-19, 4-1BBL, and IL-12 on the surface, activates HPV-specific T cells and promotes effector function in vitro. Thus, RTX-321 is a potential ‘off-the-shelf’ in vivo cellular immunotherapy for treating HPV + cancers, including cervical and head/neck cancers.
Comprehensive cell type decomposition of circulating cell-free DNA with CelFiE
Authors: Caggiano Christa , Celona Barbara , Garton Fleur , Mefford Joel , Black Brian L. , Henderson Robert , Lomen-Hoerth Catherine , Dahl Andrew , Zaitlen Noah 
Published: May 2021

AbstractCirculating cell-free DNA (cfDNA) in the bloodstream originates from dying cells and is a promising noninvasive biomarker for cell death. Here, we propose an algorithm, CelFiE, to accurately estimate the relative abundances of cell types and tissues contributing to cfDNA from epigenetic cfDNA sequencing. In contrast to previous work, CelFiE accommodates low coverage data, does not require CpG site curation, and estimates contributions from multiple unknown cell types that are not available in external reference data. In simulations, CelFiE accurately estimates known and unknown cell type proportions from low coverage and noisy cfDNA mixtures, including from cell types composing less than 1% of the total mixture. When used in two clinically-relevant situations, CelFiE correctly estimates a large placenta component in pregnant women, and an elevated skeletal muscle component in amyotrophic lateral sclerosis (ALS) patients, consistent with the occurrence of muscle wasting typical in these patients. Together, these results show how CelFiE could be a useful tool for biomarker discovery and monitoring the progression of degenerative disease.
Anomalous normal fluid response in a chiral superconductor UTe2
Authors: Bae Seokjin , Kim Hyunsoo , Eo Yun Suk , Ran Sheng , Liu I-lin , Fuhrman Wesley T. , Paglione Johnpierre , Butch Nicholas P. , Anlage Steven M. 
Published: May 2021

AbstractChiral superconductors have been proposed as one pathway to realize Majorana normal fluid at its boundary. However, the long-sought 2D and 3D chiral superconductors with edge and surface Majorana normal fluid are yet to be conclusively found. Here, we report evidence for a chiral spin-triplet pairing state of UTe2 with surface normal fluid response. The microwave surface impedance of the UTe2 crystal was measured and converted to complex conductivity, which is sensitive to both normal and superfluid responses. The anomalous residual normal fluid conductivity supports the presence of a significant normal fluid response. The superfluid conductivity follows the temperature behavior predicted for an axial spin-triplet state, which is further narrowed down to a chiral spin-triplet state with evidence of broken time-reversal symmetry. Further analysis excludes trivial origins for the observed normal fluid response. Our findings suggest that UTe2 can be a new platform to study exotic topological excitations in higher dimension.
Photon quantum entanglement in the MeV regime and its application in PET imaging
Authors: Watts D. P. , Bordes J. , Brown J. R. , Cherlin A. , Newton R. , Allison J. , Bashkanov M. , Efthimiou N. , Zachariou N. A. 
Published: May 2021

AbstractPositron Emission Tomography (PET) is a widely-used imaging modality for medical research and clinical diagnosis. Imaging of the radiotracer is obtained from the detected hit positions of the two positron annihilation photons in a detector array. The image is degraded by backgrounds from random coincidences and in-patient scatter events which require correction. In addition to the geometric information, the two annihilation photons are predicted to be produced in a quantum-entangled state, resulting in enhanced correlations between their subsequent interaction processes. To explore this, the predicted entanglement in linear polarisation for the two photons was incorporated into a simulation and tested by comparison with experimental data from a cadmium zinc telluride (CZT) PET demonstrator apparatus. Adapted apparati also enabled correlation measurements where one of the photons had undergone a prior scatter process. We show that the entangled simulation describes the measured correlations and, through simulation of a larger preclinical PET scanner, illustrate a simple method to quantify and remove the unwanted backgrounds in PET using the quantum entanglement information alone.
Tanc2-mediated mTOR inhibition balances mTORC1/2 signaling in the developing mouse brain and human neurons
Authors: Kim Sun-Gyun , Lee Suho , Kim Yangsik , Park Jieun , Woo Doyeon , Kim Dayeon , Li Yan , Shin Wangyong , Kang Hyunjeong , Yook Chaehyun , Lee Minji , Kim Kyungdeok , Roh Junyeop Daniel , Ryu Jeseung , Jung Hwajin , Um Seung Min , Yang Esther , Kim Hyun , Han Jinju , Heo Won Do , Kim Eunjoon 
Published: May 2021

AbstractmTOR signaling, involving mTORC1 and mTORC2 complexes, critically regulates neural development and is implicated in various brain disorders. However, we do not fully understand all of the upstream signaling components that can regulate mTOR signaling, especially in neurons. Here, we show a direct, regulated inhibition of mTOR by Tanc2, an adaptor/scaffolding protein with strong neurodevelopmental and psychiatric implications. While Tanc2-null mice show embryonic lethality, Tanc2-haploinsufficient mice survive but display mTORC1/2 hyperactivity accompanying synaptic and behavioral deficits reversed by mTOR-inhibiting rapamycin. Tanc2 interacts with and inhibits mTOR, which is suppressed by mTOR-activating serum or ketamine, a fast-acting antidepressant. Tanc2 and Deptor, also known to inhibit mTORC1/2 minimally affecting neurodevelopment, distinctly inhibit mTOR in early- and late-stage neurons. Lastly, Tanc2 inhibits mTORC1/2 in human neural progenitor cells and neurons. In summary, our findings show that Tanc2 is a mTORC1/2 inhibitor affecting neurodevelopment.
Posterior subthalamic nucleus (PSTh) mediates innate fear-associated hypothermia in mice
Authors: Liu Can , Lee Chia-Ying , Asher Greg , Cao Liqin , Terakoshi Yuka , Cao Peng , Kobayakawa Reiko , Kobayakawa Ko , Sakurai Katsuyasu , Liu Qinghua 
Published: May 2021

AbstractThe neural mechanisms of fear-associated thermoregulation remain unclear. Innate fear odor 2-methyl-2-thiazoline (2MT) elicits rapid hypothermia and elevated tail temperature, indicative of vasodilation-induced heat dissipation, in wild-type mice, but not in mice lacking Trpa1–the chemosensor for 2MT. Here we report that Trpa1−/− mice show diminished 2MT-evoked c-fos expression in the posterior subthalamic nucleus (PSTh), external lateral parabrachial subnucleus (PBel) and nucleus of the solitary tract (NTS). Whereas tetanus toxin light chain-mediated inactivation of NTS-projecting PSTh neurons suppress, optogenetic activation of direct PSTh-rostral NTS pathway induces hypothermia and tail vasodilation. Furthermore, selective opto-stimulation of 2MT-activated, PSTh-projecting PBel neurons by capturing activated neuronal ensembles (CANE) causes hypothermia. Conversely, chemogenetic suppression of vGlut2+ neurons in PBel or PSTh, or PSTh-projecting PBel neurons attenuates 2MT-evoked hypothermia and tail vasodilation. These studies identify PSTh as a major thermoregulatory hub that connects PBel to NTS to mediate 2MT-evoked innate fear-associated hypothermia and tail vasodilation.
A high-entropy manganite in an ordered nanocomposite for long-term application in solid oxide cells
Authors: Baiutti F. , Chiabrera F. , Acosta M. , Diercks D. , Parfitt D. , Santiso J. , Wang X. , Cavallaro A. , Morata A. , Wang H. , Chroneos A. , MacManus-Driscoll J. , Tarancon A. 
Published: May 2021

AbstractThe implementation of nano-engineered composite oxides opens up the way towards the development of a novel class of functional materials with enhanced electrochemical properties. Here we report on the realization of vertically aligned nanocomposites of lanthanum strontium manganite and doped ceria with straight applicability as functional layers in high-temperature energy conversion devices. By a detailed analysis using complementary state-of-the-art techniques, which include atom-probe tomography combined with oxygen isotopic exchange, we assess the local structural and electrochemical functionalities and we allow direct observation of local fast oxygen diffusion pathways. The resulting ordered mesostructure, which is characterized by a coherent, dense array of vertical interfaces, shows high electrochemically activity and suppressed dopant segregation. The latter is ascribed to spontaneous cationic intermixing enabling lattice stabilization, according to density functional theory calculations. This work highlights the relevance of local disorder and long-range arrangements for functional oxides nano-engineering and introduces an advanced method for the local analysis of mass transport phenomena.
Expression of FoxP2 in the basal ganglia regulates vocal motor sequences in the adult songbird
Authors: Xiao Lei , Merullo Devin P. , Koch Therese M. I. , Cao Mou , Co Marissa , Kulkarni Ashwinikumar , Konopka Genevieve , Roberts Todd F. 
Published: May 2021

AbstractDisruption of the transcription factor FoxP2, which is enriched in the basal ganglia, impairs vocal development in humans and songbirds. The basal ganglia are important for the selection and sequencing of motor actions, but the circuit mechanisms governing accurate sequencing of learned vocalizations are unknown. Here, we show that expression of FoxP2 in the basal ganglia is vital for the fluent initiation and termination of birdsong, as well as the maintenance of song syllable sequencing in adulthood. Knockdown of FoxP2 imbalances dopamine receptor expression across striatal direct-like and indirect-like pathways, suggesting a role of dopaminergic signaling in regulating vocal motor sequencing. Confirming this prediction, we show that phasic dopamine activation, and not inhibition, during singing drives repetition of song syllables, thus also impairing fluent initiation and termination of birdsong. These findings demonstrate discrete circuit origins for the dysfluent repetition of vocal elements in songbirds, with implications for speech disorders.
Lying in wait: the resurgence of dengue virus after the Zika epidemic in Brazil
Authors: Brito Anderson Fernandes , Machado Lais Ceschini , Oidtman Rachel J. , Siconelli Márcio Junio Lima , Tran Quan Minh , Fauver Joseph R. , Carvalho Rodrigo Dias de Oliveira , Dezordi Filipe Zimmer , Pereira Mylena Ribeiro , de Castro-Jorge Luiza Antunes , Minto Elaine Cristina Manini , Passos Luzia Márcia Romanholi , Kalinich Chaney C. , Petrone Mary E. , Allen Emma , España Guido Camargo , Huang Angkana T. , Cummings Derek A. T. , Baele Guy , Franca Rafael Freitas Oliveira , da Fonseca Benedito Antônio Lopes , Perkins T. Alex , Wallau Gabriel Luz , Grubaugh Nathan D. 
Published: May 2021

AbstractAfter the Zika virus (ZIKV) epidemic in the Americas in 2016, both Zika and dengue incidence declined to record lows in many countries in 2017–2018, but in 2019 dengue resurged in Brazil, causing ~2.1 million cases. In this study we use epidemiological, climatological and genomic data to investigate dengue dynamics in recent years in Brazil. First, we estimate dengue virus force of infection (FOI) and model mosquito-borne transmission suitability since the early 2000s. Our estimates reveal that DENV transmission was low in 2017–2018, despite conditions being suitable for viral spread. Our study also shows a marked decline in dengue susceptibility between 2002 and 2019, which could explain the synchronous decline of dengue in the country, partially as a result of protective immunity from prior ZIKV and/or DENV infections. Furthermore, we performed phylogeographic analyses using 69 newly sequenced genomes of dengue virus serotype 1 and 2 from Brazil, and found that the outbreaks in 2018–2019 were caused by local DENV lineages that persisted for 5–10 years, circulating cryptically before and after the Zika epidemic. We hypothesize that DENV lineages may circulate at low transmission levels for many years, until local conditions are suitable for higher transmission, when they cause major outbreaks.
A Stat1 bound enhancer promotes Nampt expression and function within tumor associated macrophages
Authors: Huffaker Thomas B. , Ekiz H. Atakan , Barba Cindy , Lee Soh-Hyun , Runtsch Marah C. , Nelson Morgan C. , Bauer Kaylyn M. , Tang William W. , Mosbruger Timothy L. , Cox James E. , Round June L. , Voth Warren P. , O’Connell Ryan M. 
Published: May 2021

AbstractTumor associated macrophage responses are regulated by distinct metabolic states that affect their function. However, the ability of specific signals in the local tumor microenvironment to program macrophage metabolism remains under investigation. Here, we identify NAMPT, the rate limiting enzyme in NAD salvage synthesis, as a target of STAT1 during cellular activation by interferon gamma, an important driver of macrophage polarization and antitumor responses. We demonstrate that STAT1 occupies a conserved element within the first intron of Nampt, termed Nampt-Regulatory Element-1 (NRE1). Through disruption of NRE1 or pharmacological inhibition, a subset of M1 genes is sensitive to NAMPT activity through its impact on glycolytic processes. scRNAseq is used to profile in vivo responses by NRE1-deficient, tumor-associated leukocytes in melanoma tumors through the creation of a unique mouse strain. Reduced Nampt and inflammatory gene expression are present in specific myeloid and APC populations; moreover, targeted ablation of NRE1 in macrophage lineages results in greater tumor burden. Finally, elevated NAMPT expression correlates with IFNγ responses and melanoma patient survival. This study identifies IFN and STAT1-inducible Nampt as an important factor that shapes the metabolic program and function of tumor associated macrophages.
Selective inhibition of cullin 3 neddylation through covalent targeting DCN1 protects mice from acetaminophen-induced liver toxicity
Authors: Zhou Haibin , Lu Jianfeng , Chinnaswamy Krishnapriya , Stuckey Jeanne A. , Liu Liu , McEachern Donna , Yang Chao-Yie , Bernard Denzil , Shen Hong , Rui Liangyou , Sun Yi , Wang Shaomeng 
Published: May 2021

AbstractCullin-RING E3 ligases (CRLs) regulate the turnover of approximately 20% of mammalian cellular proteins. Neddylation of individual cullin proteins is essential for the activation of each CRL. We report herein the discovery of DI-1548 and DI-1859 as two potent, selective and covalent DCN1 inhibitors. These inhibitors selectively inhibit neddylation of cullin 3 in cells at low nanomolar concentrations and are 2–3 orders of magnitude more potent than our previously reported reversible DCN1 inhibitor. Mass spectrometric analysis and co-crystal structures reveal that these compounds employ a unique mechanism of covalent bond formation with DCN1. DI-1859 induces a robust increase of NRF2 protein, a CRL3 substrate, in mouse liver and effectively protects mice from acetaminophen-induced liver damage. Taken together, this study demonstrates the therapeutic potential of selective inhibition of cullin neddylation.
A SARS-CoV-2 neutralizing antibody with extensive Spike binding coverage and modified for optimal therapeutic outcomes
Authors: Guo Yu , Huang Lisu , Zhang Guangshun , Yao Yanfeng , Zhou He , Shen Shu , Shen Bingqing , Li Bo , Li Xin , Zhang Qian , Chen Mingjie , Chen Da , Wu Jia , Fu Dan , Zeng Xinxin , Feng Mingfang , Pi Chunjiang , Wang Yuan , Zhou Xingdong , Lu Minmin , Li Yarong , Fang Yaohui , Lu Yun-Yueh , Hu Xue , Wang Shanshan , Zhang Wanju , Gao Ge , Adrian Francisco , Wang Qisheng , Yu Feng , Peng Yun , Gabibov Alexander G. , Min Juan , Wang Yuhui , Huang Heyu , Stepanov Alexey , Zhang Wei , Cai Yan , Liu Junwei , Yuan Zhiming , Zhang Chen , Lou Zhiyong , Deng Fei , Zhang Hongkai , Shan Chao , Schweizer Liang , Sun Kun , Rao Zihe 
Published: May 2021

AbstractCOVID-19 pandemic caused by SARS-CoV-2 constitutes a global public health crisis with enormous economic consequences. Monoclonal antibodies against SARS-CoV-2 can provide an important treatment option to fight COVID-19, especially for the most vulnerable populations. In this work, potent antibodies binding to SARS-CoV-2 Spike protein were identified from COVID-19 convalescent patients. Among them, P4A1 interacts directly with and covers majority of the Receptor Binding Motif of the Spike Receptor-Binding Domain, shown by high-resolution complex structure analysis. We further demonstrate the binding and neutralizing activities of P4A1 against wild type and mutant Spike proteins or pseudoviruses. P4A1 was subsequently engineered to reduce the potential risk for Antibody-Dependent Enhancement of infection and to extend its half-life. The engineered antibody exhibits an optimized pharmacokinetic and safety profile, and it results in complete viral clearance in a rhesus monkey model of COVID-19 following a single injection. These data suggest its potential against SARS-CoV-2 related diseases.
Critical role of interferons in gastrointestinal injury repair
Authors: McElrath Constance , Espinosa Vanessa , Lin Jian-Da , Peng Jianya , Sridhar Raghavendra , Dutta Orchi , Tseng Hsiang-Chi , Smirnov Sergey V. , Risman Heidi , Sandoval Marvin J. , Davra Viralkumar , Chang Yun-Juan , Pollack Brian P. , Birge Raymond B. , Galan Mark , Rivera Amariliz , Durbin Joan E. , Kotenko Sergei V. 
Published: May 2021

AbstractThe etiology of ulcerative colitis is poorly understood and is likely to involve perturbation of the complex interactions between the mucosal immune system and the commensal bacteria of the gut, with cytokines acting as important cross-regulators. Here we use IFN receptor-deficient mice in a dextran sulfate sodium (DSS) model of acute intestinal injury to study the contributions of type I and III interferons (IFN) to the initiation, progression and resolution of acute colitis. We find that mice lacking both types of IFN receptors exhibit enhanced barrier destruction, extensive loss of goblet cells and diminished proliferation of epithelial cells in the colon following DSS-induced damage. Impaired mucosal healing in double IFN receptor-deficient mice is driven by decreased amphiregulin expression, which IFN signaling can up-regulate in either the epithelial or hematopoietic compartment. Together, these data underscore the pleiotropic functions of IFNs and demonstrate that these critical antiviral cytokines also support epithelial regeneration following acute colonic injury.
Adjuvant oncolytic virotherapy for personalized anti-cancer vaccination
Authors: Roy D. G. , Geoffroy K. , Marguerie M. , Khan S. T. , Martin N. T. , Kmiecik J. , Bobbala D. , Aitken A. S. , de Souza C. T. , Stephenson K. B. , Lichty B. D. , Auer R. C. , Stojdl D. F. , Bell J. C. , Bourgeois-Daigneault M.-C. 
Published: May 2021

AbstractBy conferring systemic protection and durable benefits, cancer immunotherapies are emerging as long-term solutions for cancer treatment. One such approach that is currently undergoing clinical testing is a therapeutic anti-cancer vaccine that uses two different viruses expressing the same tumor antigen to prime and boost anti-tumor immunity. By providing the additional advantage of directly killing cancer cells, oncolytic viruses (OVs) constitute ideal platforms for such treatment strategy. However, given that the targeted tumor antigen is encoded into the viral genomes, its production requires robust infection and therefore, the vaccination efficiency partially depends on the unpredictable and highly variable intrinsic sensitivity of each tumor to OV infection. In this study, we demonstrate that anti-cancer vaccination using OVs (Adenovirus (Ad), Maraba virus (MRB), Vesicular stomatitis virus (VSV) and Vaccinia virus (VV)) co-administered with antigenic peptides is as efficient as antigen-engineered OVs and does not depend on viral replication. Our strategy is particularly attractive for personalized anti-cancer vaccines targeting patient-specific mutations. We suggest that the use of OVs as adjuvant platforms for therapeutic anti-cancer vaccination warrants testing for cancer treatment.
A coordinated progression of progenitor cell states initiates urinary tract development
Authors: Sanchez-Ferras Oraly , Pacis Alain , Sotiropoulou Maria , Zhang Yuhong , Wang Yu Chang , Bourgey Mathieu , Bourque Guillaume , Ragoussis Jiannis , Bouchard Maxime 
Published: May 2021

AbstractThe kidney and upper urinary tract develop through reciprocal interactions between the ureteric bud and the surrounding mesenchyme. Ureteric bud branching forms the arborized collecting duct system of the kidney, while ureteric tips promote nephron formation from dedicated progenitor cells. While nephron progenitor cells are relatively well characterized, the origin of ureteric bud progenitors has received little attention so far. It is well established that the ureteric bud is induced from the nephric duct, an epithelial duct derived from the intermediate mesoderm of the embryo. However, the cell state transitions underlying the progression from intermediate mesoderm to nephric duct and ureteric bud remain unknown. Here we show that nephric duct morphogenesis results from the coordinated organization of four major progenitor cell populations. Using single cell RNA-seq and Cluster RNA-seq, we show that these progenitors emerge in time and space according to a stereotypical pattern. We identify the transcription factors Tfap2a/b and Gata3 as critical coordinators of this progenitor cell progression. This study provides a better understanding of the cellular origin of the renal collecting duct system and associated urinary tract developmental diseases, which may inform guided differentiation of functional kidney tissue.