bluuebunny/crossref_metadata_2025_split huggingface dataset:
Segmentor: A tool for manual refinement of 3D microscopy annotations
Authors: Borland David , McCormick Carolyn M. , Patel Niyanta K. , Krupa Oleh , Mory Jessica T. , Beltran Alvaro A. , Farah Tala M. , Escobar-Tomlienovich Carla F. , Olson Sydney S. , Kim Minjeong , Wu Guorong , Stein Jason L. 
Published: January 2021

AbstractBackgroundRecent advances in tissue clearing techniques, combined with high-speed image acquisition through light sheet microscopy, enable rapid three-dimensional (3D) imaging of biological specimens, such as whole mouse brains, in a matter of hours. Quantitative analysis of such 3D images can help us understand how changes in brain structure lead to differences in behavior or cognition, but distinguishing features of interest, such as nuclei, from background can be challenging. Recent deep learning-based nuclear segmentation algorithms show great promise for automated segmentation, but require large numbers of manually and accurately labeled nuclei as training data.ResultsWe present Segmentor, an open-source tool for reliable, efficient, and user-friendly manual annotation and refinement of objects (e.g., nuclei) within 3D light sheet microscopy images. Segmentor employs a hybrid 2D-3D approach for visualizing and segmenting objects and contains features for automatic region splitting, designed specifically for streamlining the process of 3D segmentation of nuclei. We show that editing simultaneously in 2D and 3D using Segmentor significantly decreases time spent on manual annotations without affecting accuracy.ConclusionsSegmentor is a tool for increased efficiency of manual annotation and refinement of 3D objects that can be used to train deep learning segmentation algorithms, and is available athttps://www.nucleininja.org/andhttps://github.com/RENCI/Segmentor.
Clinical evaluation of BCL-2/XL levels pre- and post- HER2-targeted therapy
Authors: Zoeller Jason J. , Press Michael F. , Selfors Laura M. , Dering Judy , Slamon Dennis J. , Hurvitz Sara A. , Brugge Joan S. 
Published: January 2021

ABSTRACTOur previous pre-clinical work defined BCL-2 induction as a critical component of the adaptive response to lapatinib-mediated inhibition of HER2. To determine whether a similar BCL-2 upregulation occurs in lapatinib-treated patients, we evaluated gene expression within tumor biopsies, collected before and after lapatinib or trastuzumab treatment, from the TRIO-B-07 clinical trial (NCT#00769470). We detected BCL-2 mRNA upregulation in both HER2+/ER- as well as HER2+/ER+ patient tumors treated with lapatinib or trastuzumab. To address whether mRNA expression correlated with protein expression, we evaluated pre- and post-treatment tumors for BCL-2 via immunohistochemistry. Despite BCL-2 mRNA upregulation within HER2+/ER- tumors, BCL-2 protein levels were undetectable in most of the lapatinib- or trastuzumab-treated HER2+/ER- tumors. BCL-2 upregulation was evident within the majority of lapatinib-treated HER2+/ER+ tumors and was often coupled with increased ER expression and decreased proliferation. Comparable BCL-2 upregulation was not observed within the trastuzumab-treated HER2+/ER+ tumors. Together, these results provide clinical validation of the BCL-2 induction associated with the adaptive response to lapatinib and support evaluation of BCL-2 inhibitors within the context of lapatinib and other HER2-targeted receptor tyrosine kinase inhibitors.
Immune response to SARS-CoV-2 in the nasal mucosa in children and adults
Authors: Koch Clarissa M , Prigge Andrew D , Anekalla Kishore R , Shukla Avani , Do-Umehara Hanh Chi , Setar Leah , Chavez Jairo , Abdala-Valencia Hiam , Politanska Yuliya , Markov Nikolay S , Hahn Grant R , Heald-Sargent Taylor , Sanchez-Pinto L Nelson , Muller William J , Misharin Alexander V , Ridge Karen M , Coates Bria M 
Published: January 2021

AbstractRationaleDespite similar viral load and infectivity rates between children and adults infected with SARS-CoV-2, children rarely develop severe illness. Differences in the host response to the virus at the primary infection site are among the proposed mechanisms.ObjectivesTo investigate the host response to SARS-CoV-2, respiratory syncytial virus (RSV), and influenza virus (IV) in the nasal mucosa in children and adults.MethodsClinical outcomes and gene expression in the nasal mucosa were analyzed in 36 children hospitalized with SARS-CoV-2 infection, 24 children with RSV infection, 9 children with IV infection, 16 adults with mild to moderate SARS-CoV-2 infection, and 7 healthy pediatric and 13 healthy adult controls.ResultsIn both children and adults, infection with SARS-CoV-2 leads to an interferon response in the nasal mucosa. The magnitude of the interferon response correlated with the abundance of viral reads and was comparable between symptomatic children and adults infected with SARS-CoV-2 and symptomatic children infected with RSV and IV. Cell type deconvolution identified an increased abundance of immune cells in the samples from children and adults with a viral infection. Expression of ACE2 and TMPRSS2 – key entry factors for SARS-CoV-2 – did not correlate with age or presence or absence of viral infection.ConclusionsOur findings support the hypothesis that differences in the immune response to SARS-CoV-2 determine disease severity, independent of viral load and interferon response at the primary infection primary site.
The Addiction Risk Factor: A Unitary Genetic Vulnerability Characterizes Substance Use Disorders and Their Associations with Common Correlates
Authors: Hatoum Alexander S. , Johnson Emma C. , Colbert Sarah M.C. , Polimanti Renato , Zhou Hang , Walters Raymond , Gelernter Joel , Edenberg Howard J. , Bogdan Ryan , Agrawal Arpana 
Published: January 2021

AbstractSubstance use disorders commonly co-occur with one another and with other psychiatric disorders. They share common features including high impulsivity, negative affect, and lower executive function. We tested whether a common genetic factor undergirds liability to problematic alcohol use (PAU), problematic tobacco use (PTU), cannabis use disorder (CUD), and opioid use disorder (OUD) by applying genomic structural equation modelling to genome-wide association study summary statistics for individuals of European ancestry (Total N = 1,019,521; substance specific Ns range: 82,707-435,563), while adjusting for the genetics of substance use (Ns = 184,765-632,802). We also tested whether shared liability across SUDs is associated with behavioral constructs (risk taking, executive function, neuroticism; Ns = 328,339-427,037) and non-substance use psychopathology (psychotic, compulsive, and early neurodevelopmental disorders). Shared genetic liability to PAU, PTU, CUD, and OUD was characterized by a unidimensional addiction risk factor (termed The Addiction-Risk-Factor, independent of substance use. OUD and CUD demonstrated the largest loadings, while problematic tobacco use showed the lowest loading. The Addiction-Risk-Factor was associated with risk taking, neuroticism, executive function, and non-substance psychopathology, but retained specific variance before and after accounting for genetics of substance use. Thus, a common genetic factor partly explains susceptibility for alcohol, tobacco, cannabis, and opioid use disorder. The Addiction-Risk-Factor has a unique genetic architecture that is not shared with normative substance use or non-substance psychopathology, suggesting that addiction is not the linear combination of substance use and psychopathology.
Prevalence of chronic kidney disease in the general population in Latin America and the Caribbean: Protocol for a systematic review and meta-analysis
Authors: Sequeiros-Buendia Diego A , Villa-Ato Camila S , Weiss-Carlini Marlies , Carrillo-Larco Rodrigo M 
Published: January 2021

ABSTRACTBackgroundChronic kidney disease (CKD) is a global health issue with a general prevalence of 9%. Although the most affected populations are in low- and middle-income countries, the epidemiology of CKD in these countries remains poorly understood and prevalence estimates come from global efforts informed by data from high-income countries; these prevalence estimates need to be compared –and if needed updated–with local estimates.ObjectiveTo estimate the prevalence of CKD in adults in Latin America and the Caribbean (LAC).MethodsSystematic review and meta-analysis. We will search Embase, Medline, Global Health (these three through Ovid), Scopus and LILACS. No date or language restrictions will be set. We seek observational studies with a random sample of the general population. We will screen titles and abstracts, we will then study the selected reports. Both phases will be done by two reviewers independently. Data extraction will be performed by two researchers independently using a pre-specified Excel form. We will evaluate the risk of bias with the scale proposed by Hoy et al. for prevalence studies. We will conduct a meta-analysis of prevalence estimates, if there are at least three reports homogeneous enough to be pooled; we will use a random-effects model.ConclusionsThis systematic review and meta-analysis will provide the prevalence of CKD in adults in countries of LAC. Currently, information regarding CKD in the region is limited. This work will provide evidence to elucidate the magnitude of CKD prevalence in LAC. In so doing, we will provide evidence to inform the scientific community about the burden of CKD in LAC so that research, policies and health interventions can be planned accordingly.
Foveal vision at the time of microsaccades
Authors: Mostofi Naghmeh , Intoy Janis , Rucci Michele 
Published: January 2021

AbstractHumans use rapid eye movements (saccades) to inspect stimuli with the foveola, the region of the retina where receptors are most densely packed. It is well established that visual sensitivity is generally attenuated during these movements, a phenomenon known as saccadic suppression. This effect is commonly studied with large, often peripheral, stimuli presented during instructed saccades. However, little is known about how saccades modulate the foveola and how the resulting dynamics unfold during natural visual exploration. Here we measured the foveal dynamics of saccadic suppression in a naturalistic high-acuity task, a task designed after primate’s social grooming, which—like most explorations of fine patterns—primarily elicits minute saccades (microsaccades). Leveraging on recent advances in gaze-contingent display control, we were able to systematically map the peri-saccadic time-course of sensitivity across the foveola. We show that contrast sensitivity is not uniform across this region and that both the extent and dynamics of saccadic suppression vary within the foveola. Suppression is stronger and faster in the most central portion, where sensitivity is generally higher and selectively rebounds at the onset of a new fixation. These results shed new light on the modulations experienced by foveal vision during the saccade-fixation cycle and explain some of the benefits of microsaccades.
Nonlinear visuoauditory integration in the mouse superior colliculus
Authors: Ito Shinya , Si Yufei , Litke Alan M. , Feldheim David A. 
Published: January 2021

AbstractSensory information from different modalities is processed in parallel, and then integrated in associative brain areas to improve object identification and the interpretation of sensory experiences. The Superior Colliculus (SC) is a midbrain structure that plays a critical role in integrating visual, auditory, and somatosensory input to assess saliency and promote action. Although the response properties of the individual SC neurons to visuoauditory stimuli have been characterized, little is known about the spatial and temporal dynamics of the integration at the population level. Here we recorded the response properties of SC neurons to spatially restricted visual and auditory stimuli using large-scale electrophysiology. We then created a general, population-level model that explains the spatial, temporal, and intensity requirements of stimuli needed for sensory integration. We found that the mouse SC contains topographically organized visual and auditory neurons that exhibit nonlinear multisensory integration. We show that nonlinear integration depends on properties of auditory but not visual stimuli. We also find that a heuristically derived nonlinear modulation function reveals conditions required for sensory integration that are consistent with previously proposed models of sensory integration such as spatial matching and the principle of inverse effectiveness.
A trigger phosphodiesterase modulates the global c-di-GMP pool, motility and biofilm formation inVibrio parahaemolyticus
Authors: Martínez-Méndez Raquel , Camacho-Hernández Diego A. , Sulvarán-Guel Elizabeth , Zamorano-Sánchez David 
Published: January 2021

AbstractVibrio parahaemolyticuscells transit from free swimming to surface adapted lifestyles, such as swarming colonies and three-dimensional biofilms. These transitions are regulated by sensory modules and regulatory networks that involve the second messenger cyclic dimeric guanosine monophosphate (c-di-GMP). In this work, we show that a previously uncharacterized c-di-GMP phosphodiesterase (VP1881) fromV. parahaemolyticusplays an important role in modulating the c-di-GMP pool. We found that the product of VP1881 promotes its own expression when the levels of c-di-GMP were low or when the phosphodiesterase was catalytically inactive. This behavior has been observed in a class of c-di-GMP receptors called Trigger phosphodiesterases, hence we named the product of VP1881 TpdA, for Trigger phosphodiesterase A. The absence oftpdAshowed a negative effect on swimming motility while its overexpression from an IPTG inducible promoter showed a positive effect on both swimming and swarming motility, and a negative effect on biofilm formation. Changes in TpdA abundance altered the expression of representative polar and lateral flagellar genes as well as the biofilm related genecpsA. Our results also revealed that autoactivation of the native PtpdApromoter is sufficient to alter c-di-GMP signaling responses such as swarming and biofilm formation inV. parahaemolyticus, an observation that could have important implications in the dynamics of this social behaviors.ImportanceC-di-GMP trigger phosphodiesterases (PDEs) could play a key role in controlling the heterogeneity of biofilm-matrix composition, a property that endows characteristics that are potentially relevant for sustaining integrity and functionality of biofilms in a variety of natural environments. Trigger PDEs are not always easy to identify based on their sequence, hence not many examples of these type of signaling proteins have been reported in the literature. Here we report on the identification of a novel trigger PDE inV. parahaemolyticusand provide evidence suggesting that its autoactivation could play an important role in the progression of swarming motility and biofilm formation, multicellular behaviors that are important for the survival and dissemination of this environmental pathogen.
TheGASAGene Family inTheobroma cacao: Genome wide Identification and Expression Analysis
Authors: Abdullah  , Faraji Sahar , Mehmood Furrukh , Malik Hafiz Muhammad Talha , Ahmed Ibrar , Heidari Parviz , Poczai Peter 
Published: January 2021

AbstractThe gibberellic acid-stimulatedArabidopsis(GASA/GAST) gene family is widely distributed in plants. The role of theGASAgene family has been reported previously in various physiological and biological processes, such as cell division, root and seed development, stem growth, and fruit ripening. These genes also provide resistance to abiotic and biotic stresses including antimicrobial, antiviral, and antifungal. Here, we report 17tcGASAgenes inTheobroma cacaoL. distributed on six chromosomes. The gene structure, promoter-region sequences, protein structure, and biochemical properties, expression, and phylogenetics of alltcGASAs were analyzed. Phylogenetic analyses divided tcGASA proteins into five groups. The nine segmentally duplicating genes form four pairs and cluster together in phylogenetic tree. Purifying selection pressure was recorded ontcGASA, including duplicated genes. Several stress/hormone-responsive cis-regulatory elements were also recognized in the promoter region oftcGASAs.Differential expression analyses revealed that most of thetcGASAgenes showed elevated expression in the seeds (cacao food), implying their role in seed development. The black rod disease of genusPhytophthoracaused up to 20–25% loss (700,000 metric tons) in world cacao production. The role oftcGASAgenes in conferring fungal resistance was also explored based on RNAseq data againstPhytophthora megakarya. The differential expression oftcGASAgenes was recorded between the tolerant and susceptible cultivars of cacao plants, which were inoculated with the fungus for 24h and 72h. This differential expression indicating possible role oftcGASAgenes to fungal resistant in cacao. Our findings provide new insight into the function, evolution, and regulatory system of theGASAfamily genes inT.cacao and provide new target genes for development of fungi-resistant cacao varieties in breeding programs.
Unique Protein Interaction Networks Define The Chromatin Remodeling Module of The NuRD Complex
Authors: Tabar Mehdi Sharifi , Giardina Caroline , Feng Yue Julie , Francis Habib , Sani Hakimeh Moghaddas , Low Jason K. K. , Mackay Joel P. , Bailey Charles G. , Rasko John E.J. 
Published: January 2021

AbstractThe combination of four proteins and their paralogues including MBD2/3, GATAD2A/B, CDK2AP1, and CHD3/4/5, which we refer to as the MGCC module, form the chromatin remodeling module of the Nucleosome Remodeling and Deacetylase (NuRD) complex, a gene repressor complex. Specific paralogues of the MGCC subunits such as MBD2 and CHD4 are amongst the key repressors of adult-stage fetal globin and provide important targets for molecular therapies in beta (β)-thalassemia. However, mechanisms by which the MGCC module acquires paralogue-specific function and specificity have not been addressed to date. Understanding the protein-protein interaction (PPI) network of the MGCC subunits is essential in defining underlying mechanisms and developing treatment strategies. Therefore, using pulldown followed by mass spectrometry analysis (PD-MS) we report a proteome-wide interaction network of the MGCC module in a paralogue-specific manner. Our data also demonstrate that the disordered C-terminal region of CHD3/4/5 is a gateway to incorporate remodeling activity into both the ChAHP (CHD4, ADNP, HP1γ) and NuRD complexes in a mutually exclusive manner. We define a short aggregation prone region (APR) within the C-terminal segment of GATAD2B that is essential for the interaction of CHD4 and CDK2AP1 with the NuRD complex. Finally, we also report an association of CDK2AP1 with the Nuclear Receptor Co-Repressor (NCOR) complex. Overall, this study provides insight into the possible mechanisms through which the MGCC module can achieve specificity and diverse biological functions.
Arabidopsis inositol polyphosphate kinases IPK1 and ITPK1 modulate crosstalks between SA-dependent immunity and phosphate-starvation responses
Authors: Gulabani Hitika , Goswami Krishnendu , Walia Yashika , Noor Jewel Jameeta , Ingole Kishor D. , Roy Abhisha , Laha Debabrata , Schaaf Gabriel , Bhattacharjee Saikat 
Published: January 2021

AbstractThe propensity for polyphosphorylation makesmyo-inositol derivatives, the inositol polyphosphates (InsPs), especially phytic acid or inositol hexakisphosphate (InsP6) the major form of phosphate storage in plants. Acts of pyrophosphorylation on InsP6generates InsP7or InsP8containing high-energy phosphoanhydride bonds that are harnessed during energy requirements of a cell. Also implicated as co-factors for several phytohormone signaling networks, InsP7/InsP8modulate key developmental processes. With recent identification as the common moeity for transducing both jasmonic acid (JA) and phosphate-starvation responses (PSR), InsP8is the classic example of a metabolite that may moonlight crosstalks to different cellular pathways during diverse stress adaptations. We show here thatArabidopsis thalianaINOSITOL PENTAKISPHOSPHATE 2-KINASE (IPK1), INOSITOL 1,3,4-TRISPHOSPHATE 5/6-KINASE 1 (ITPK1), and DIPHOSPHOINOSITOL PENTAKISPHOSPHATE KINASE 2 (VIH2), but not other InsP-kinases, suppress basal salicylic acid (SA)-dependent immunity. Inipk1, itpk1orvih2mutants, elevated endogenous SA levels and constitutive activation of defense signaling lead to enhanced resistance against the virulentPseudomonas syringae pvtomato DC3000 (PstDC3000) strain. Our data reveal that activated SA-signaling sectors in these mutants modulate expression amplitudes of phosphate-starvation inducible (PSI)-genes, reported earlier. In turn, via mutualism the heightened basal defenses in these mutants require upregulated PSI-gene expressions likely highlighting the increased demand of phosphates required to support immunity. We demonstrate that SA is induced in phosphate-deprived plants, however its defense-promoting functions are likely diverted to PSR-supportive roles. Overall, our investigations reveal selective InsPs as crosstalk mediators among diverse signaling networks programming stress-appropriate adaptations.
The Endoplasmic Reticulum pool of Bcl-xL dampens the Unfolded Protein Response through IP3R-dependent Calcium Release
Authors: Jabbour Lea , Nguyen Trang , Gadet Rudy , Lohez Olivier , Mikaelian Ivan , Gonzalo Philippe , Luyten Thomas , Chalabi-Dcha Mounira , Bultynck Geert , Rimokh Ruth , Gillet Germain , Popgeorgiev Nikolay 
Published: January 2021

AbstractApoptosis plays a role in cell homeostasis in both normal development and disease. Bcl-xL, a member of the Bcl-2 family of proteins, regulates the intrinsic mitochondrial pathway of apoptosis. It is overexpressed in several cancers. Bcl-xL has a dual subcellular localization and is found at the mitochondria as well as the endoplasmic reticulum (ER). However, the biological significance of its ER localization is unclear. In order to decipher the functional contributions of the mitochondrial and reticular pools of Bcl-xL, we generated genetically modified mice expressing exclusively Bcl-xL at the ER, referred to as ER-xL, or the mitochondria, referred to as Mt-xL. By performing cell death assays, we showed that ER-xL MEFs show increased vulnerability to apoptotic stimuli but are more resistant to ER stress. Furthermore, ER-xL MEFs demonstrated a reduced expression of the Unfolded Protein Response (UPR) markers upon ER stress and displayed reduced inositol trisphosphate receptor (IP3R)-mediated ER calcium release. Collectively, our data show that upon ER stress, Bcl-xL negatively regulates IP3R-mediated calcium flux from the ER, which prevents ER calcium depletion and maintains the UPR and subsequent cell death in check. This work reveals a moonlighting function of Bcl-xL at the ER, apart from its cliché regulation of apoptosis.