bluuebunny/crossref_metadata_2025_split huggingface dataset:
RNA aptamers specific for transmembrane p24 trafficking protein 6 and Clusterin for the targeted delivery of imaging reagents and RNA therapeutics to human β cells
Authors: Van Simaeys Dimitri , De La Fuente Adriana , Zilio Serena , Zoso Alessia , Kuznetsova Victoria , Alcazar Oscar , Buchwald Peter , Grilli Andrea , Caroli Jimmy , Bicciato Silvio , Serafini Paolo 
Published: April 2022

AbstractThe ability to detect and target β cells in vivo can substantially refine how diabetes is studied and treated. However, the lack of specific probes still hampers a precise characterization of human β cell mass and the delivery of therapeutics in clinical settings. Here, we report the identification of two RNA aptamers that specifically and selectively recognize mouse and human β cells. The putative targets of the two aptamers are transmembrane p24 trafficking protein 6 (TMED6) and clusterin (CLUS). When given systemically in immune deficient mice, these aptamers recognize the human islet graft producing a fluorescent signal proportional to the number of human islets transplanted. These aptamers cross-react with endogenous mouse β cells and allow monitoring the rejection of mouse islet allografts. Finally, once conjugated to saRNA specific for X-linked inhibitor of apoptosis (XIAP), they can efficiently transfect non-dissociated human islets, prevent early graft loss, and improve the efficacy of human islet transplantation in immunodeficient in mice.
Integrative analysis of non-small cell lung cancer patient-derived xenografts identifies distinct proteotypes associated with patient outcomes
Authors: Mirhadi Shideh , Tam Shirley , Li Quan , Moghal Nadeem , Pham Nhu-An , Tong Jiefei , Golbourn Brian J. , Krieger Jonathan R. , Taylor Paul , Li Ming , Weiss Jessica , Martins-Filho Sebastiao N. , Raghavan Vibha , Mamatjan Yasin , Khan Aafaque A. , Cabanero Michael , Sakashita Shingo , Huo Kugeng , Agnihotri Sameer , Ishizawa Kota , Waddell Thomas K. , Zadeh Gelareh , Yasufuku Kazuhiro , Liu Geoffrey , Shepherd Frances A. , Moran Michael F. , Tsao Ming-Sound 
Published: April 2022

AbstractNon-small cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide. Only a fraction of NSCLC harbor actionable driver mutations and there is an urgent need for patient-derived model systems that will enable the development of new targeted therapies. NSCLC and other cancers display profound proteome remodeling compared to normal tissue that is not predicted by DNA or RNA analyses. Here, we generate 137 NSCLC patient-derived xenografts (PDXs) that recapitulate the histology and molecular features of primary NSCLC. Proteome analysis of the PDX models reveals 3 adenocarcinoma and 2 squamous cell carcinoma proteotypes that are associated with different patient outcomes, protein-phosphotyrosine profiles, signatures of activated pathways and candidate targets, and in adenocarcinoma, stromal immune features. These findings portend proteome-based NSCLC classification and treatment and support the PDX resource as a viable model for the development of new targeted therapies.
Integrated silicon carbide electro-optic modulator
Authors: Powell Keith , Li Liwei , Shams-Ansari Amirhassan , Wang Jianfu , Meng Debin , Sinclair Neil , Deng Jiangdong , Lončar Marko , Yi Xiaoke 
Published: April 2022

AbstractOwing to its attractive optical and electronic properties, silicon carbide is an emerging platform for integrated photonics. However an integral component of the platform is missing—an electro-optic modulator, a device which encodes electrical signals onto light. As a non-centrosymmetric crystal, silicon carbide exhibits the Pockels effect, yet a modulator has not been realized since the discovery of this effect more than three decades ago. Here we design, fabricate, and demonstrate a Pockels modulator in silicon carbide. Specifically, we realize a waveguide-integrated, small form-factor, gigahertz-bandwidth modulator that operates using complementary metal-oxide-semiconductor (CMOS)-level voltages on a thin film of silicon carbide on insulator. Our device is fabricated using a CMOS foundry compatible fabrication process and features no signal degradation, no presence of photorefractive effects, and stable operation at high optical intensities (913 kW/mm2), allowing for high optical signal-to-noise ratios for modern communications. Our work unites Pockels electro-optics with a CMOS foundry compatible platform in silicon carbide.
Mapping SP-C co-chaperone binding sites reveals molecular consequences of disease-causing mutations on protein maturation
Authors: Pobre-Piza Kristine F. R. , Mann Melissa J. , Flory Ashley R. , Hendershot Linda M. 
Published: April 2022

AbstractBiP co-chaperones ERdj4, ERdj5, and GRP170 associate in cells with peptides predicted to be aggregation prone. Here, extending these findings to a full-length protein, we examine two Interstitial Lung Disease-associated mutants (ILD) of surfactant protein C (SP-C). The TANGO algorithm, which identifies sequences prone to formation of β strand aggregates, found three such regions in SP-C: the N-terminal transmembrane (TM) domain and two sites in the intermolecular chaperone BRICHOS domain. We show the ILD mutants disrupt di-sulfide bond formation in the BRICHOS domain and expose the aggregation-prone peptides leading to binding of ERdj4, ERdj5, and GRP170. The destabilized mutant BRICHOS domain fails to properly insert its TM region in the ER membrane, exposing part of the N-terminal TM domain site. Our studies with ILD-associated mutant proteins provide insights into the specificity of ERdj4, ERdj5, and GRP170, identify context-dependent differences in their binding, and reveal molecular consequences of disease-associated mutants on folding.
Porcine gut microbiota in mediating host metabolic adaptation to cold stress
Authors: Zhang Yu , Sun Lan , Zhu Run , Zhang Shiyu , Liu Shuo , Wang Yan , Wu Yinbao , Xing Sicheng , Liao Xindi , Mi Jiandui 
Published: April 2022

AbstractThe gut microbiota plays a key role in host metabolic ﻿thermogenesis by activating UCP1 and increasing the browning process of white adipose tissue (WAT), especially in cold environments. However, the crosstalk between the gut microbiota and the host, which lacks functional UCP1, making them susceptible to cold stress, has rarely been illustrated. We used male piglets as a model to evaluate the host response to cold stress via the gut microbiota (four groups: room temperature group, n = 5; cold stress group, n = 5; cold stress group with antibiotics, n = 5; room temperature group with antibiotics, n = 3). We found that host thermogenesis and insulin resistance increased the levels of serum metabolites such as glycocholic acid (GCA) and glycochenodeoxycholate acid (GCDCA) and altered the compositions and functions of the cecal microbiota under cold stress. The gut microbiota was characterized by increased levels of Ruminococcaceae, Prevotellaceae, and Muribaculaceae under cold stress. We found that piglets subjected to cold stress had increased expression of genes related to bile acid and short-chain fatty acid (SCFA) metabolism in their liver and fat lipolysis genes in their fat. In addition, the fat lipolysis genes CLPS, PNLIPRP1, CPT1B, and UCP3 were significantly increased in the fat of piglets under cold stress. However, the use of antibiotics showed a weakened or strengthened cold tolerance phenotype, indicating that the gut microbiota plays important role in host thermogenesis. Our results demonstrate that the gut microbiota-blood-liver and fat axis may regulate thermogenesis during cold acclimation in piglets.
The effects of microgravity on bone structure and function
Authors: Man Joey , Graham Taylor , Squires-Donelly Georgina , Laslett Andrew L. 
Published: April 2022

AbstractHumans are spending an increasing amount of time in space, where exposure to conditions of microgravity causes 1–2% bone loss per month in astronauts. Through data collected from astronauts, as well as animal and cellular experiments conducted in space, it is evident that microgravity induces skeletal deconditioning in weight-bearing bones. This review identifies contentions in current literature describing the effect of microgravity on non-weight-bearing bones, different bone compartments, as well as the skeletal recovery process in human and animal spaceflight data. Experiments in space are not readily available, and experimental designs are often limited due to logistical and technical reasons. This review introduces a plethora of on-ground research that elucidate the intricate process of bone loss, utilising technology that simulates microgravity. Observations from these studies are largely congruent to data obtained from spaceflight experiments, while offering more insights behind the molecular mechanisms leading to microgravity-induced bone loss. These insights are discussed herein, as well as how that knowledge has contributed to studies of current therapeutic agents. This review also points out discrepancies in existing data, highlighting knowledge gaps in our current understanding. Further dissection of the exact mechanisms of microgravity-induced bone loss will enable the development of more effective preventative and therapeutic measures to protect against bone loss, both in space and possibly on ground.
Dopamine-induced changes to thalamic GABA concentration in impulsive Parkinson disease patients
Authors: Trujillo Paula , Song Alexander K. , Hay Kaitlyn R. , Aumann Megan , Yan Yan , Kang Hakmook , Donahue Manus J. , Claassen Daniel O. 
Published: April 2022

AbstractImpulsivity is inherent to behavioral disorders such as substance abuse and binge eating. While the role of dopamine in impulse behavior is well established, γ-aminobutyric acid (GABA) therapies have promise for the treatment of maladaptive behaviors. In Parkinson disease (PD), dopaminergic therapies can result in the development of impulsive and compulsive behaviors, and this clinical syndrome shares similar pathophysiology to that seen in addiction, substance abuse, and binge-eating disorders. We hypothesized that impulsive PD patients have a reduced thalamic GABAergic response to dopamine therapy. To test this hypothesis, we employed GABA magnetic resonance spectroscopy, D2-like receptor PET imaging, and clinical and quantitative measures of impulsivity in PD patients (n = 33), before and after dopamine agonist administration. We find a blunted thalamic GABA response to dopamine agonists in patients with elevated impulsivity (p = 0.027). These results emphasize how dopamine treatment differentially augments thalamic GABA concentrations, which may modify behavioral impulsivity.
Evolution patterns of probable REM sleep behavior disorder predicts Parkinson’s disease progression
Authors: Ye Guanyu , Xu Xiaomeng , Zhou Liche , Zhao Aonan , Zhu Lin , Liu Jun 
Published: April 2022

AbstractThe course of REM sleep behavior disorder (RBD) variates in the early stage of Parkinson’s disease. We aimed to delineate the association between the evolution pattern of probable RBD (pRBD) and the progression of Parkinson’s disease (PD). 281 de novo PD patients from the Parkinson’s Progression Markers Initiative database were included. Patients were followed up for a mean of 6.8 years and were classified into different groups according to the evolution patterns of pRBD. Disease progression was compared among groups using survival analysis, where the endpoint was defined as progression to Hoehn-Yahr stage 3 or higher for motor progression and progression to mild cognitive impairment for cognitive decline. At the 4th year of follow-up, four types of pRBD evolution patterns were identified: (1) non-RBD-stable (55.5%): patients persistently free of pRBD; (2) late-RBD (12.1%): patients developed pRBD during follow-up; (3) RBD-stable (24.9%): patients showed persistent pRBD, and (4) RBD-reversion (7.5%): patients showed pRBD at baseline which disappeared during follow-up. The RBD-reversion type showed the fastest motor progression while the RBD-stable type showed the fastest cognitive decline. At baseline, the RBD-reversion type showed the most severe gray matter atrophy in the middle frontal gyrus, while the RBD-stable type showed gray matter atrophy mainly in the para-hippocampal gyrus. Four types of early pRBD evolution patterns featured different brain lesions and predicted different courses of motor and cognitive decline in PD.
Intravitreal antisense oligonucleotide sepofarsen in Leber congenital amaurosis type 10: a phase 1b/2 trial
Authors: Russell Stephen R. , Drack Arlene V. , Cideciyan Artur V. , Jacobson Samuel G. , Leroy Bart P. , Van Cauwenbergh Caroline , Ho Allen C. , Dumitrescu Alina V. , Han Ian C. , Martin Mitchell , Pfeifer Wanda L. , Sohn Elliott H. , Walshire Jean , Garafalo Alexandra V. , Krishnan Arun K. , Powers Christian A. , Sumaroka Alexander , Roman Alejandro J. , Vanhonsebrouck Eva , Jones Eltanara , Nerinckx Fanny , De Zaeytijd Julie , Collin Rob W. J. , Hoyng Carel , Adamson Peter , Cheetham Michael E. , Schwartz Michael R. , den Hollander Wilhelmina , Asmus Friedrich , Platenburg Gerard , Rodman David , Girach Aniz 
Published: April 2022

AbstractCEP290-associated Leber congenital amaurosis type 10 (LCA10) is a retinal disease resulting in childhood blindness. Sepofarsen is an RNA antisense oligonucleotide targeting the c.2991+1655A>G variant in the CEP290 gene to treat LCA10. In this open-label, phase 1b/2 (NCT03140969), 12-month, multicenter, multiple-dose, dose-escalation trial, six adult patients and five pediatric patients received ≤4 doses of intravitreal sepofarsen into the worse-seeing eye. The primary objective was to evaluate sepofarsen safety and tolerability via the frequency and severity of ocular adverse events (AEs); secondary objectives were to evaluate pharmacokinetics and efficacy via changes in functional outcomes. Six patients received sepofarsen 160 µg/80 µg, and five patients received sepofarsen 320 µg/160 µg. Ten of 11 (90.9%) patients developed ocular AEs in the treated eye (5/6 with 160 µg/80 µg; 5/5 with 320 µg/160 µg) versus one of 11 (9.1%) in the untreated eye; most were mild in severity and dose dependent. Eight patients developed cataracts, of which six (75.0%) were categorized as serious (2/3 with 160 µg/80 µg; 4/5 with 320 µg/160 µg), as lens replacement was required. As the 160-µg/80-µg group showed a better benefit–risk profile, higher doses were discontinued or not initiated. Statistically significant improvements in visual acuity and retinal sensitivity were reported (post hoc analysis). The manageable safety profile and improvements reported in this trial support the continuation of sepofarsen development.
SLEAP: A deep learning system for multi-animal pose tracking
Authors: Pereira Talmo D. , Tabris Nathaniel , Matsliah Arie , Turner David M. , Li Junyu , Ravindranath Shruthi , Papadoyannis Eleni S. , Normand Edna , Deutsch David S. , Wang Z. Yan , McKenzie-Smith Grace C. , Mitelut Catalin C. , Castro Marielisa Diez , D’Uva John , Kislin Mikhail , Sanes Dan H. , Kocher Sarah D. , Wang Samuel S.-H. , Falkner Annegret L. , Shaevitz Joshua W. , Murthy Mala 
Published: April 2022

AbstractThe desire to understand how the brain generates and patterns behavior has driven rapid methodological innovation in tools to quantify natural animal behavior. While advances in deep learning and computer vision have enabled markerless pose estimation in individual animals, extending these to multiple animals presents unique challenges for studies of social behaviors or animals in their natural environments. Here we present Social LEAP Estimates Animal Poses (SLEAP), a machine learning system for multi-animal pose tracking. This system enables versatile workflows for data labeling, model training and inference on previously unseen data. SLEAP features an accessible graphical user interface, a standardized data model, a reproducible configuration system, over 30 model architectures, two approaches to part grouping and two approaches to identity tracking. We applied SLEAP to seven datasets across flies, bees, mice and gerbils to systematically evaluate each approach and architecture, and we compare it with other existing approaches. SLEAP achieves greater accuracy and speeds of more than 800 frames per second, with latencies of less than 3.5 ms at full 1,024 × 1,024 image resolution. This makes SLEAP usable for real-time applications, which we demonstrate by controlling the behavior of one animal on the basis of the tracking and detection of social interactions with another animal.
Exome sequencing of individuals with Huntington’s disease implicates FAN1 nuclease activity in slowing CAG expansion and disease onset
Authors: McAllister Branduff , Donaldson Jasmine , Binda Caroline S. , Powell Sophie , Chughtai Uroosa , Edwards Gareth , Stone Joseph , Lobanov Sergey , Elliston Linda , Schuhmacher Laura-Nadine , Rees Elliott , Menzies Georgina , Ciosi Marc , Maxwell Alastair , Chao Michael J. , Hong Eun Pyo , Lucente Diane , Wheeler Vanessa , Lee Jong-Min , MacDonald Marcy E. , Long Jeffrey D. , Aylward Elizabeth H. , Landwehrmeyer G. Bernhard , Rosser Anne E. ,   REGISTRY Investigators of the European Huntington’s disease network, Paulsen Jane S. ,   PREDICT-HD Investigators of the Huntington Study Group, Williams Nigel M. , Gusella James F. , Monckton Darren G. , Allen Nicholas D. , Holmans Peter , Jones Lesley , Massey Thomas H. 
Published: April 2022

AbstractThe age at onset of motor symptoms in Huntington’s disease (HD) is driven byHTTCAG repeat length but modified by other genes. In this study, we used exome sequencing of 683 patients with HD with extremes of onset or phenotype relative to CAG length to identify rare variants associated with clinical effect. We discovered damaging coding variants in candidate modifier genes identified in previous genome-wide association studies associated with altered HD onset or severity. Variants in FAN1 clustered in its DNA-binding and nuclease domains and were associated predominantly with earlier-onset HD. Nuclease activities of purified variants in vitro correlated with residual age at motor onset of HD. Mutating endogenous FAN1 to a nuclease-inactive form in an induced pluripotent stem cell model of HD led to rates of CAG expansion similar to those observed with completeFAN1knockout. Together, these data implicate FAN1 nuclease activity in slowing somatic repeat expansion and hence onset of HD.
Datasets for characterizing extreme events relevant to hydrologic design over the conterminous United States
Authors: Sun Ning , Yan Hongxiang , Wigmosta Mark S. , Coleman Andre M. , Leung L. Ruby , Hou Zhangshuan 
Published: April 2022

AbstractDespite the close linkage between extreme floods and snowmelt, particularly through rain-on-snow (ROS), hydrologic infrastructure is mostly designed based on standard precipitation Intensity-Duration-Frequency curves (PREC-IDF) that neglect snow processes in runoff generation. For snow-dominated regions, such simplification could result in substantial errors in estimating extreme events and infrastructure design risk. To address this long-standing problem, we applied the Next Generation IDF (NG-IDF) technique to estimate design basis extreme events for different durations and return periods in the conterminous United States (CONUS) to distinctly represent the contribution of rain, snowmelt, and ROS events to the amount of water reaching the land surface. A suite of datasets were developed to characterize the magnitude, trend, seasonality, and dominant mechanism of extreme events for over 200,000 locations. Infrastructure design risk associated with the use of PREC-IDF was estimated. Accuracy of the model simulations used in the analyses was confirmed by long-term snow data at over 200 Snowpack Telemetry stations. The presented spatially continuous datasets are readily usable and instrumental for supporting site-specific infrastructure design.
DarkCideS 1.0, a global database for bats in karsts and caves
Authors: Tanalgo Krizler C. , Tabora John Aries G. , de Oliveira Hernani Fernandes Magalhães , Haelewaters Danny , Beranek Chad T. , Otálora-Ardila Aída , Bernard Enrico , Gonçalves Fernando , Eriksson Alan , Donnelly Melissa , González Joel Monzón , Ramos Humberto Fernández , Rivas Alberto Clark , Webala Paul W. , Deleva Stanimira , Dalhoumi Ridha , Maula Jaycelle , Lizarro Dennis , Aguirre Luis F. , Bouillard Nils , Quibod Ma. Niña Regina M. , Barros Jennifer , Turcios-Casco Manfredo Alejandro , Martínez Marcio , Ordoñez-Mazier Diego Iván , Orellana José Alejandro Soler , Ordoñez-Trejo Eduardo J. , Ordoñez Danny , Chornelia Ada , Lu Jian Mei , Xing Chen , Baniya Sanjeev , Muylaert Renata L. , Dias-Silva Leonardo Henrique , Ruadreo Nittaya , Hughes Alice Catherine 
Published: April 2022

AbstractUnderstanding biodiversity patterns as well as drivers of population declines, and range losses provides crucial baselines for monitoring and conservation. However, the information needed to evaluate such trends remains unstandardised and sparsely available for many taxonomic groups and habitats, including the cave-dwelling bats and cave ecosystems. We developed the DarkCideS 1.0 (https://darkcides.org/), a global database of bat caves and species synthesised from publicly available information and datasets. The DarkCideS 1.0 is by far the largest database for cave-dwelling bats, which contains information for geographical location, ecological status, species traits, and parasites and hyperparasites for 679 bat species are known to occur in caves or use caves in part of their life histories. The database currently contains 6746 georeferenced occurrences for 402 cave-dwelling bat species from 2002 cave sites in 46 countries and 12 terrestrial biomes. The database has been developed to be collaborative and open-access, allowing continuous data-sharing among the community of bat researchers and conservation biologists to advance bat research and comparative monitoring and prioritisation for conservation.
Lipid phosphate phosphatase 3 in smooth muscle cells regulates angiotensin II-induced abdominal aortic aneurysm formation
Authors: Van Hoose Patrick M. , Yang Liping , Kraemer Maria , Ubele Margo , Morris Andrew J. , Smyth Susan S. 
Published: April 2022

AbstractGenetic variants that regulate lipid phosphate phosphatase 3 (LPP3) expression are risk factors for the development of atherosclerotic cardiovascular disease. LPP3 is dynamically upregulated in the context of vascular inflammation with particularly heightened expression in smooth muscle cells (SMC), however, the impact of LPP3 on vascular pathology is not fully understood. We investigated the role of LPP3 and lysophospholipid signaling in a well-defined model of pathologic aortic injury and observed Angiotensin II (Ang II) increases expression of PLPP3 in SMCs through nuclear factor kappa B (NF-κB) signaling Plpp3 global reduction (Plpp3+/−) or SMC-specific deletion (SM22-Δ) protects hyperlipidemic mice from AngII-mediated aneurysm formation. LPP3 expression regulates SMC differentiation state and lowering LPP3 levels promotes a fibroblast-like phenotype. Decreased inactivation of bioactive lysophosphatidic acid (LPA) in settings of LPP3 deficiency may underlie these phenotypes because deletion of LPA receptor 4 in mice promotes early aortic dilation and rupture in response to AngII. LPP3 expression and LPA signaling influence SMC and vessel wall responses that are important for aortic dissection and aneurysm formation. These findings could have important implications for therapeutics targeting LPA metabolism and signaling in ongoing clinical trials.