bluuebunny/crossref_metadata_2025_split huggingface dataset:
The ATR inhibitor elimusertib exhibits anti-lymphoma activity and synergizes with the PI3K inhibitor copanlisib
Authors: Sartori Giulio , Tarantelli Chiara , Spriano Filippo , Gaudio Eugenio , Cascione Luciano , Mascia Michele , Barreca Marilia , Arribas Alberto J. , Licenziato Luca , Golino Gaetanina , Ferragamo Adele , Pileri Stefano , Damia Giovanna , Zucca Emanuele , Stathis Anastasios , Politz Oliver , Wengner Antje M. , Bertoni Francesco 
Published: February 2023

ABSTRACTPurposeThe DNA damage response (DDR) is the cellular process devoted to the preservation of an intact genome. The DDR is often deregulated in lymphoma cells due to high levels of DNA damage, tumor suppressor inactivation, increased replication stress observed after oncogene activation, or high amounts of reactive oxygen species. The ataxia telangiectasia and Rad3-related (ATR) kinase is a crucial factor of DDR in the response to DNA single strand breaks. ATR inhibitors are a class of agents that have shown considerable clinical potential in this context.Experimental DesignWe characterized the activity of the ATR inhibitor elimusertib (BAY 1895344) in a panel of lymphoma cell lines. Furthermore, we evaluated the activity of elimusertib in combination with the clinically approved PI3K inhibitor copanlisib inin vitroandin vivolymphoma models.ResultsElimusertib exhibitedin vitroactivity across a variety of lymphoma subtypes which was associated with expression of genes related to replication stress. Elimusertib also demonstrated wide-spread anti-tumor activity that was stronger compared to ceralasertib, another ATR inhibitor, in several tumor models. This activity was present in both DDR-proficient and DDR-deficient lymphoma models. Furthermore, elimusertib had synergistic antitumor activity in combination with copanlisib.ConclusionsPotent antitumor activity of elimusertib was demonstrated in several lymphoma models which is associated with high expression of gene transcripts coding for proteins that are involved in DDR and cell cycle regulation. Combination of ATR and PI3K inhibition by treatment with elimusertib and copanlisib had synergistic efficacy providing a potential new treatment option for lymphoma patients.Translational relevanceThe DNA damage response (DDR) is often deregulated in lymphoma cells. Here, we characterized the activity of elimusertib, an inhibitor of the ataxia telangiectasia and Rad3-related kinase (ATR) that is involved in the DDR. Elimusertib was demonstrated to exhibit anti-lymphoma activity across several lymphoma cell lines and tumor models. Copanlisib is an inhibitor of PI3K kinase family which has also shown activity in various lymphomas. Combined treatment with elimusertib and copanlisib resulted in a synergistic antitumor effect in lymphoma models. The combination of elimusertib and copanlisib could potentially constitute a new chemotherapy-free treatment option for lymphomas.
Parallel mechanisms detect different photoperiods to independently control seasonal flowering and growth in plants
Authors: Wang Qingqing , Liu Wei , Leung Chun Chung , Tartè Daniel A. , Gendron Joshua M. 
Published: February 2023

AbstractFor nearly 100 years, we have known that both growth and flowering in plants are seasonally regulated by the length of the day (photoperiod). Intense research focus and powerful genetic tools have propelled studies of photoperiodic flowering, but far less is known about photoperiodic growth, in part because tools were lacking. Here, using a new genetic tool that visually reports on photoperiodic growth, we identified a seasonal growth regulation pathway, from photoperiod detection to gene expression. Surprisingly, this pathway functions in long days but is distinct from the canonical long day photoperiod flowering mechanism. This is possible because the two mechanisms detect the photoperiod in different ways: flowering relies on measuring photoperiod by directly detecting duration of light intensity while the identified growth pathway relies on measuring photosynthetic period indirectly by detecting the duration of photosynthetic metabolite production. In turn, the two pathways then control expression of genes required for flowering or growth independently. Finally, our tools allow us to show that these two types of photoperiods, and their measurement systems, are dissociable. Our results constitute a new view of seasonal timekeeping in plants by showing that two parallel mechanisms measure different photoperiods to control plant growth and flowering, allowing these processes to be coordinated independently across seasons.
GILEA: GAN Inversion-enabled latent eigenvalue analysis for phenome profiling and editing
Authors: Wu Jiqing , Koelzer Viktor H. 
Published: February 2023

ABSTRACTModeling heterogeneous disease states by data-driven methods has great potential to advance biomedical research. However, a comprehensive analysis of phenotypic heterogeneity is often challenged by the complex nature of biomedical datasets and emerging imaging methodologies. Here, we propose a novel GAN Inversion-enabled Latent Eigenvalue Analysis (GILEA) framework and apply it to phenome profiling and editing. As key use cases for fluorescence and natural imaging, we demonstrate the power of GILEA using publicly available SARS-CoV-2 datasets stained with the multiplexed fluorescence cell-painting protocol as well as real-world medical images of common skin lesions captured by dermoscopy. The quantitative results of GILEA can be biologically supported by editing latent representations and simulating dynamic phenotype transitions between physiological and pathological states. In conclusion, GILEA represents a new and broadly applicable approach to the quantitative and interpretable analysis of biomedical image data. The GILEA code and video demos are publicly available athttps://github.com/CTPLab/GILEA.
Pervasive environmental chemicals impair oligodendrocyte development
Authors: Cohn Erin F. , Clayton Benjamin L.L. , Madhavan Mayur , Yacoub Sara , Federov Yuriy , Paul-Friedman Katie , Shafer Timothy J. , Tesar Paul J. 
Published: February 2023

ABSTRACTExposure to environmental chemicals can impair neurodevelopment1–4. Oligodendrocytes that wrap around axons to boost neurotransmission may be particularly vulnerable to chemical toxicity as they develop throughout fetal development and into adulthood5,6. However, few environmental chemicals have been assessed for potential risks to oligodendrocyte development. Here, we utilized a high-throughput developmental screen and human cortical brain organoids, which revealed environmental chemicals in two classes that disrupt oligodendrocyte development through distinct mechanisms. Quaternary compounds, ubiquitous in disinfecting agents, hair conditioners, and fabric softeners, were potently and selectively cytotoxic to developing oligodendrocytes through activation of the integrated stress response. Organophosphate flame retardants, commonly found in household items such as furniture and electronics, were non-cytotoxic but prematurely arrested oligodendrocyte maturation. Chemicals from each class impaired human oligodendrocyte development in a 3D organoid model of prenatal cortical development. In analysis of epidemiological data from the CDC’s National Health and Nutrition Examination Survey, adverse neurodevelopmental outcomes were associated with childhood exposure to the top organophosphate flame retardant identified by our oligodendrocyte toxicity platform. Collectively, our work identifies toxicological vulnerabilities specific to oligodendrocyte development and highlights common household chemicals with high exposure risk to children that warrant deeper scrutiny for their impact on human health.
Meta-analysis and Open-source Database for In Vivo Brain Magnetic Resonance Spectroscopy in Health and Disease
Authors: Gudmundson Aaron T. , Koo Annie , Virovka Anna , Amirault Alyssa L. , Soo Madelene , Cho Jocelyn H. , Oeltzschner Georg , Edden Richard A.E. , Stark Craig 
Published: February 2023

AbstractProton (1H) Magnetic Resonance Spectroscopy (MRS) is a non-invasive tool capable of quantifying brain metabolite concentrationsin vivo. Prioritization of standardization and accessibility in the field has led to the development of universal pulse sequences, methodological consensus recommendations, and the development of open-source analysis software packages. One on-going challenge is methodological validation with ground-truth data. As ground-truths are rarely available forin vivomeasurements, data simulations have become an important tool. The diverse literature of metabolite measurements has made it challenging to define ranges to be used within simulations. Especially for the development of deep learning and machine learning algorithms, simulations must be able to produce accurate spectra capturing all the nuances ofin vivodata. Therefore, we sought to determine the physiological ranges and relaxation rates of brain metabolites which can be used both in data simulations and as reference estimates. Using the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, we’ve identified relevant MRS research articles and created an open-source database containing methods, results, and other article information as a resource. Using this database, expectation values and ranges for metabolite concentrations and T2relaxation times are established based upon a meta-analyses of healthy and diseased brains.
Alpaca Single B Cell Interrogation and Heavy-Chain-Only Antibody Discovery on an Optofluidic Platform
Authors: Shapiro Mariya B , Boucher Jacqueline , Brousseau Anna , Dehkharghani Amin , Gabriel Justin , Kamat Vishal , Patil Ketan , Gao Feng , Walker Jennifer , Kelly Ryan , Souders Colby A 
Published: February 2023

ABSTRACTIn vivodiscovery approaches for single domain antibodies such as VHH have been limited by the lack of methodologies available for camelid B cell interrogation. Here, we report a novel application of the Berkeley Lights Beacon® optofluidic platform to the discovery of heavy-chain-only antibodies by screening single B cells from alpacas immunized with two different targets. Custom methods for alpaca B cell enrichment, culture, on-Beacon IgG2/3 detection, and sequencing were developed and used to discover target-specific VHH candidates from an alpaca immunized with either human prostate specific membrane antigen (PSMA) or a second blinded target, in a proof-of-concept study. PSMA-specific VHH hits discovered on the Beacon were recombinantly expressed as VHH-Fc, purified, and characterized using label-free techniques. All but one VHH-Fc bound PSMA with a single-digit nanomolar affinity, and four candidates were successfully humanizedin silicousing a rapid bulk humanization approach. In addition, next-generation repertoire sequencing was performed at longitudinal timepoints after immunization, uncovering additional variants within the clonal lineages of the validated hits discovered on the Beacon platform. The establishment of this single B cell VHH discovery workflow extends the powerful Beacon technology to enable rapid discovery of VHH directly from natural camelid immune repertoires.
Continuous Prediction of Leg Kinematics during Walking using Inertial Sensors, Smart Glasses, and Embedded Computing
Authors: Tsepa Oleksii , Burakov Roman , Laschowski Brokoslaw , Mihailidis Alex 
Published: February 2023

AbstractUnlike traditional hierarchical controllers for robotic leg prostheses and exoskeletons, continuous systems could allow persons with mobility impairments to walk more naturally in real-world environments without requiring high-level switching between locomotion modes. To support these next-generation controllers, we developed a new system calledKIFNet(Kinematics and Image Fusing Network) that uses lightweight and efficient deep learning models to continuously predict the leg kinematics during walking. We tested different sensor fusion methods to combine kinematics data from inertial sensors and computer vision data from smart glasses and found that adaptive instance normalization achieved the lowest RMSE predictions for knee and ankle joint kinematics. We also deployed our model on an embedded device. Without inference optimization, our model was 20 times faster than the previous state-of-the-art and achieved 20% higher prediction accuracies, and during some locomotor activities like stair descent, decreased RMSE up to 300%. With inference optimization, our best model achieved 125 FPS on an NVIDIA Jetson Nano. These results demonstrate the potential to build fast and accurate deep learning models for continuous prediction of leg kinematics during walking based on sensor fusion and embedded computing, therein providing a foundation for real-time continuous controllers for robotic leg prostheses and exoskeletons.
Encoding of predictive associations in human prefrontal and medial temporal neurons during Pavlovian conditioning
Authors: Aquino Tomas G. , Courellis Hristos , Mamelak Adam N. , Rutishauser Ueli , O’Doherty John P. 
Published: February 2023

AbstractPavlovian conditioning is thought to involve the formation of learned associations between stimuli and values, and between stimuli and specific features of outcomes. Here we leveraged human single neuron recordings in ventromedial prefrontal, dorsomedial frontal, hippocampus and amygdala neurons while patients performed a sequential Pavlovian conditioning task containing both stimulus-value and stimulus-stimulus associations. Neurons in the ventromedial prefrontal cortex encoded predictive value along with the amygdala, but also encoded predictions about the identity of stimuli that would subsequently be presented, suggesting a role for neurons in this region in encoding predictive information beyond value. Unsigned error signals were found in dorsomedial prefrontal areas and hippocampus, potentially supporting learning of non-value related outcome features. Our findings implicate distinct human prefrontal and medial temporal neuronal populations in mediating predictive associations which could partially support model-based mechanisms during Pavlovian conditioning.Significance statementPavlovian conditioning is a fundamental form of learning, allowing organisms to associate stimuli and outcomes. Recent Pavlovian work suggests that phenomena such as devaluation sensitivity and sensory preconditioning can be explained by a model-based learning framework. How human neurons perform model-based learning during Pavlovian conditioning is still an open question. We recorded single neurons from epilepsy patients during a two-step Pavlovian conditioning task and found that ventromedial prefrontal neurons encoded expected rewards along with amygdala neurons, but also predicted the identity of upcoming stimuli as required for model-based cognition. Additionally, medial frontal neurons were found to encode error signals that could be used for stimulus-outcome learning. This is the first study mapping model-based computations during Pavlovian conditioning in human neurons.
CaV3.1 Channels Facilitate Calcium Wave Generation and Myogenic Tone Development in Mouse Mesenteric Arteries
Authors: El-Lakany Mohammed A. , Haghbin Nadia , Arora Naman , Hashad Ahmed M. , Mironova Galina Yu. , Sancho Maria , Welsh Donald G. 
Published: February 2023

AbstractBackgroundThe myogenic response is the mechanism whereby intraluminal pressure elicits arterial constriction pursuant to the maintenance of tissue perfusion. Smooth muscle [Ca2+] is a key determinant of constriction, a process intimately tied to L-type (CaV1.2) Ca2+channels. While important, other Ca2+channels, in particular T-type, are expressed and could contribute to pressure regulation within defined voltage ranges. This study examined the role of one T-type Ca2+channel using mesenteric arteries from C57BL/6 wild type and CaV3.1-/-mice.MethodsPatch-clamp electrophysiology, pressure myography, non-invasive blood pressure measurements and rapid Ca2+imaging were employed to define the CaV3.1-/-phenotype relative to C57BL/6. Proximity ligation assay tested the closeness of CaV3.1 channels to inositol triphosphate receptors (IP3R). Nifedipine (0.3 μM) and 2-APB (50 μM) were used to block L-type Ca2+channels and IP3Rs, respectively.ResultsInitial experiments confirmed the absence of CaV3.1 expression and whole-cell current in global deletion mice, a change that coincided with a reduction in systemic blood pressure. Mesenteric arteries from CaV3.1-/-mice produced less myogenic tone than C57BL/6, particularly at lower pressures (20-60 mmHg) where membrane potential is more hyperpolarized. This reduction in myogenic tone correlated with diminished Ca2+wave generation in the CaV3.1-/-mice. These asynchronous events are dependent upon Ca2+release from the sarcoplasmic reticulum which is insensitive to L-type Ca2+channel blockade. A close physical association (<40 nm) between IP3R1 and CaV3.1 was confirmed by proximity ligation assay; blockade of IP3R in nifedipine-treated C57BL/6 arteries rendered a CaV3.1-/-contractile phenotype.ConclusionFindings indicate that Ca2+influx through CaV3.1 channels contributes to myogenic tone development at hyperpolarized voltages by triggering a Ca2+-induced Ca2+release mechanism tied to the sarcoplasmic reticulum. This study helps establish CaV3.1 as a potential therapeutic target in the control of blood pressure.
Complementary effects of above- and belowground biodiversity on ecosystem functions across global grasslands
Authors: Martins Catarina S. C. , Delgado-Baquerizo Manuel , Jayaramaiah Ramesha H. , Wang Jun-Tao , Sáez-Sandino Tadeo , Liu Hongwei , Maestre Fernando T. , Reich Peter B. , Singh Brajesh K. 
Published: February 2023

AbstractGrasslands are integral to maintaining biodiversity and key ecosystem services under climate change. Plant and soil biodiversity, and their interactions, support the provision of multiple ecosystem functions (multifunctionality). However, whether plant and soil biodiversity explain unique, or shared, contributions to supporting multifunctionality across global grasslands remains virtually unknown. Here, we combine results from a global survey of 101 grasslands with a novel microcosm study, controlling for both plant and soil microbial diversity to identify their individual and interactive contribution to support multifunctionality under aridity and experimental drought. We found that, plant and soil microbial diversity independently predict a unique portion of variation in above- and belowground functioning, suggesting both types of biodiversity complement each other. Interactions between plant and soil microbial diversity regulated primary productivity, nutrient storage, and plant productivity. Our findings were also context dependent, since soil fungal diversity was strongly associated to multifunctionality in less arid regions, while plant diversity was strongly linked to multifunctionality in more arid regions. Our results highlight the need to conserve both above- and belowground diversity to sustain grassland multifunctionality in a drier world and indicate climate change may shift the relative contribution of plant and soil biodiversity to multifunctionality across global grasslands.
Impact of COVID-19 Outbreak on Healthcare Workers in a Tertiary Healthcare Center in India - A cross sectional study
Authors: Mirza Shahzad , VR Arvinden , Rophina Mercy , Bhawalkar Jitendra , Chothani Bhavin , Khan Uzair , Singh Shivankur , Sharma Tanya , Dwivedi Aryan , Pandey Ellora , Garg Shivam , Sadrudin Mukhida Sahjid , Sange Zeeshan Shabbir Ahmed , Bhaumik Shalini , Varughese Jessin , Devkar Vishwamohini Yallappa , Singh Jyoti , mol V K Anju , K Veena , Mandviwala Husen Shabbir Husen , Scaria Vinod , Gupta Aayush 
Published: February 2023

AbstractNumerous speculations have continually emerged, trying to explore the association between COVID-19 infection and a varied range of demographic and clinical factors. Frontline healthcare workers have been at the forefront of this illness exposure. However, there is a paucity of large cohort-based association studies, performed among Indian health care professionals, exploring their potential risk and predisposing factors. This study aims to systematically utilize the demographic and clinical data of over 3000 healthcare workers from a tertiary hospital in India to gain significant insights on the associations between disease prevalence, severity, and post-infection symptoms.Article SummaryPotential associations between various demographic and clinical factors with disease severity and post COVID syndromes among a large cohort of healthcare workers in India suggest that Smokers were discovered to be more vulnerable to COVID-19 infection because of their immunocompromised lung health and Blood group B, like previous studies, was found to possess an increased risk of predisposition to long COVIDs
ADAM10 mediates macroglial cell fate decisions in the developing brain
Authors: Wang Yihui , Liang Yue , Ai Daosheng , Li Jun-Liszt , Feng Ziyan , Guo Zhibao , Chen Xing-jun , Zhang Tingting , Zou Xiaoxiao , Gao Jun-Li , Gao Xiaofei , Hu Xiao-Ling , Wu Long-Jun , Sun Wenzhi , Zhu Suiqiang , Duan Shumin , Wang Wei , Ge Woo-ping 
Published: February 2023

SummaryADAMs (a disintegrinandmetalloproteinase) are transmembrane proteins with cell adhesion and protease activities that contain disintegrin and metalloproteinase domains. ADAM10, a member of the ADAM family, is widely expressed in the brain. There are >40 substrates reported for ADAM10, including Notch, Delta-like ligand-1 (Dll1), and N-cadherin. To date, however, its function in the brain has been largely unknown. We used genetic manipulation to deleteAdam10specifically from glial progenitors in developing brains and observed that conditional knockout mice showed locomotor abnormalities. They all died within 4 months with apparent defects in the cerebellum. By comprehensively analyzing data from bulk RNA sequencing, single-cell RNA sequencing, and staining of the cerebellum, we found that ADAM10 promoted astrocyte generation under physiological conditions. Upon the removal ofAdam10in glial progenitors, the production of oligodendrocytes vastly increased, whereas the generation of astrocytes was substantially inhibited. Our results showed that ADAM10 plays a critical role in macroglial cell fate decisions during brain development.
Cold Comfort: metabolic rate and tolerance to low temperatures predict latitudinal distribution in ants
Authors: Willot Quentin , Ørsted Michael , Malte Hans , Overgaard Johannes 
Published: February 2023

AbstractMetabolic compensation has been proposed as a mean for ectotherms to cope with colder climates. For example, under the metabolic cold adaptation/metabolic homeostasis hypotheses (MCA/MHH), it has been formulated that cold-adapted ectotherms should display higher/more thermally sensitive metabolic rates (MRs) at lower temperatures. However, whether such compensation can truly be associated with distribution, and whether it interplays with cold-tolerance to support species’ climatic niches, remains largely unclear despite broad ecological implications thereof. Here, we teased apart the relationship between MRs, cold-tolerance, and distribution, to confront the MCA/MHH among 13 ant species. We report clear metabolic compensation effects, consistent with the MCA and MHH, where MR parameters strongly correlated with latitude and climatic factors across species’ distributions. The combination of both cold-tolerance and MR further upheld the best predictions of species’ climatic niches. To our knowledge, this is the first study showing that the association of metabolic data with cold-tolerance supports increased predictive value for biogeographical models in social insects. These results also highlight that adaptation to higher latitudes in ants involved adjustments of both cold-tolerance and MRs, potentially at the expense of metabolic performance at warmer temperatures, to allow this extremely successful group of insects to thrive under colder climates.