bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bipolar-associated miR-499-5p controls neuroplasticity by downregulating the Cav1.2 L-type voltage gated calcium channel subunit CACNB2
Authors: H.C. Martins , A.Ö. Sungur , C. Gilardi , M. Pelzl , S. Bicker , F. Gross , J. Winterer , T.M. Kisko , N. Malikowska-Racia , M.D. Braun , K. Brosch , I. Nenadic , F. Stein , S. Meinert , R.K.W. Schwarting , U. Dannlowski , T. Kircher , M. Wöhr , G. Schratt 
Published: June 2021

ABSTRACTBipolar disorder (BD) is a chronic mood disorder characterized by alternating manic and depressive episodes, often in conjunction with cognitive deficits. Dysregulation of neuroplasticity and calcium homeostasis as a result of complex genetic environment interactions are frequently observed in BD patients, but the underlying molecular mechanisms are largely unknown. Here, we show that a BD-associated microRNA, miR-499-5p, regulates neuronal dendrite development and cognitive function by downregulating the BD risk gene CACNB2. miR-499-5p expression is increased in peripheral blood of BD patients and healthy subjects at risk of developing the disorder due to a history of childhood maltreatment. This up-regulation is paralleled in the hippocampus of rats which underwent juvenile social isolation. Elevating miR-499-5p levels in rat hippocampal pyramidal neurons impairs dendritogenesis and reduces surface expression and activity of the voltage-gated L-type calcium channel Cav1.2. We further identified CACNB2, which encodes a regulatory β-subunit of Cav1.2, as a direct target of miR-499-5p in neurons. CACNB2 downregulation is required for the miR-499-5p dependent impairment of dendritogenesis, suggesting that CACNB2 is an important downstream target of miR-499-5p in the regulation of neuroplasticity. Finally, elevating miR-499-5p in the hippocampus in vivo is sufficient to induce short-term memory impairments in rats haploinsufficient for the Cav1.2 pore forming subunit Cacna1c. Taken together, we propose that stress-induced upregulation of miR-499-5p contributes to dendritic impairments and deregulated calcium homeostasis in BD, with specific implications for the neurocognitive dysfunction frequently observed in BD patients.
Loss of Elp1 disrupts trigeminal ganglion neurodevelopment in a model of Familial Dysautonomia
Authors: Leonard Carrie E. , Lefcort Frances , Taneyhill Lisa A. 
Published: June 2021

AbstractFamilial Dysautonomia (FD) is a sensory and autonomic neuropathy caused by a mutation in Elongator complex protein 1 (ELP1). FD patients have small trigeminal nerves and impaired perception of facial pain and temperature. These signals are relayed by nociceptive neurons in the trigeminal ganglion, a structure comprised of both neural crest- and placode-derived cells. Mice lacking Elp1 in neural crest derivatives (“Elp1 CKO”) are born with smaller trigeminal ganglia, suggesting Elp1 is important for trigeminal ganglion development, yet the function of Elp1 in this context is unknown. We demonstrate Elp1 expression in both neural crest- and placode-derived trigeminal neurons, which our data suggest give rise to primarily TrkA- and TrkB/C-expressing neurons, respectively. While Elp1 is not required for initial trigeminal ganglion formation, Elp1 CKO trigeminal neurons exhibit abnormal axon outgrowth and decreased target innervation. Developing nociceptors that express the receptor TrkA are especially vulnerable to Elp1 loss. TrkA expression is decreased in Elp1 CKO trigeminal nerve endings, coinciding with increased cell death. Subsequently, fewer TrkA neurons are present in the Elp1 CKO trigeminal ganglion, indicating Elp1 supports the target innervation and survival of trigeminal nociceptors. These findings explain the loss of facial pain and temperature sensation in FD.
Optimizing Network Propagation for Multi-Omics Data Integration
Authors: Charmpi Konstantina , Chokkalingam Manopriya , Johnen Ronja , Beyer Andreas 
Published: June 2021

ABSTRACTNetwork propagation refers to a class of algorithms that integrate information from input data across connected nodes in a given network. These algorithms have wide applications in systems biology, protein function prediction, inferring condition-specifically altered sub-networks, and prioritizing disease genes. Despite the popularity of network propagation, there is a lack of comparative analyses of different algorithms on real data and little guidance on how to select and parameterize the various algorithms. Here, we address this problem by analyzing different combinations of network normalization and propagation methods and by demonstrating schemes for the identification of optimal parameter settings on real proteome and transcriptome data. Our work highlights the risk of a ‘topology bias’ caused by the incorrect use of network normalization approaches. Capitalizing on the fact that network propagation is a regularization approach, we show that minimizing the bias-variance tradeoff can be utilized for selecting optimal parameters. The application to real multi-omics data demonstrated that optimal parameters could also be obtained by either maximizing the agreement between different omics layers (e.g. proteome and transcriptome) or by maximizing the consistency between biological replicates. Furthermore, we exemplified the utility and robustness of network propagation on multi-omics datasets for identifying ageing-associated genes in brain and liver tissues of rats and for elucidating molecular mechanisms underlying prostate cancer progression. Overall, this work compares different network propagation approaches and it presents strategies for how to use network propagation algorithms to optimally address a specific research question at hand.
Parasitic helminth infections in humans modulate Trefoil Factor levels in a manner dependent on the species of parasite and age of the host
Authors: Adewale Babatunde , Pastore Christopher F. , Rossi Heather L. , Hung Li-Yin , Bethony Jeff , Diemert David , Babatunde James Ayorinde , Herbert De’Broski. R. 
Published: June 2021

AbstractHelminth infections, including hookworms and Schistosomes, can cause severe disability and death. Infection management and control would benefit from identification of biomarkers for early detection and prognosis. While animal models suggest that Trefoil Factor Family proteins (TFF2 and TFF3) and interleukin-33 (IL-33) -driven type 2 immune responses are critical mediators of tissue repair and worm clearance in the context of hookworm infection, very little is known about how they are modulated in the context of human helminth infection. We measured TFF2, TFF3, and IL-33 levels in serum from patients in Brazil infected with Hookworm and/or Schistosomes, and compared them to endemic and non-endemic controls. TFF2 was specifically elevated by Hookworm infection, not Schistosoma or co-infection. This elevation was more strongly correlated with age than with worm burden. To determine if this might apply more broadly to other species or regions, we measured TFFs and cytokine levels in both the serum and urine of Nigerian school children infected with S. haematobium. We found that serum levels of TFF2 and 3 were reduced by infection, but urine cytokine levels were increased (IL-1β, TNFα, IL-13, and IL-10). Finally, to determine if TFF2 and 3 might have immunosuppressive effects, we treated stimulated or unstimulated PMBCs with recombinant human TFF2 or TFF3 and measured proinflammatory cytokine levels. We found that rhTFF2, but not rhTFF3, was able to suppress TNF alpha and IFN gamma release from stimulated human PMBCs. Taken together, these data support a role for TFF proteins in human helminth infection.Author SummaryBillions of people are infected with parasitic helminths across the globe, especially in resource poor regions. These infections can result in severe developmental delay, disability, and death. Adequate management of helminth infection would benefit from the identification of host biomarkers in easily obtained samples (e.g. serum or urine) that correlate to infection state. Our goal was to determine if specific proteins involved in tissue repair and immune modulation are altered by infection with specific helminth species in Brazil (hookworm) or Nigeria (blood fluke). One of these proteins, Trefoil Factor 2 (TFF2), was elevated in the serum of hookworm infected individuals, and decreased in the serum of blood fluke infected children. In the blood fluke-infected children, there were also significant increases in pro-inflammatory cytokines in the urine, where the eggs burst from host tissue. Further, in laboratory experiments, Trefoil Factor 2 reduced the release of pro-inflammatory cytokines from human blood cells. This suggests that at high levels TFF2 may suppress inflammation and could serve as a biomarker for infection or treatment efficacy.
The Role of the Nucleus Reuniens in Regulating Contextual Conditioning with the Predator Odor TMT
Authors: Ornelas Laura C. , Van Voorhies Kalynn , Besheer Joyce 
Published: June 2021

AbstractRationaleExperiencing intrusive distressing memories of a traumatic event(s) is a prominent symptom profile for post-traumatic stress disorder (PTSD). Understanding the neurobiological mechanisms associated with this symptom profile can be invaluable for effective treatment for PTSD.ObjectivesHere, we investigated the functional role of the nucleus reuniens (RE), a midline thalamic in modulating stressor-related memory.MethodsFemale Long Evans rats were implanted with a cannula aimed at the RE. The RE was pharmacologically inactivated via muscimol (0.5 mM) prior to exposure to the predator odor stressor trimethylthiazoline (TMT; synthetically derived fox feces component) or water (controls) in a distinct context with bedding material (Experiment 1) or no bedding (Experiment 2). To measure context reactivity, the index of the contextual memory, 2 weeks following exposure to TMT, rats were re-exposed to the TMT-paired context (in the absence of TMT).ResultsIn Experiment 1, during context re-exposure (with bedding), inactivation of the RE had no effect on context reactivity. In Experiment 2, during context re-exposure (no bedding), rats previous exposed to TMT showed decreased immobility compared to controls, indicating reactivity to the context and likely related to increased exploration of the environment. Rats in the TMT group that received RE inactivation showed increased immobility relative to rats that received aCSF, suggesting that muscimol pre-treatment blunted context reactivity.ConclusionIn conclusion, recruitment of the RE in stressor-related contextual memory appears to be dependent on the contextual environment and whether the animal is able to engage in different stress coping strategies.
Biosynthesis of cannabinoid precursor olivetolic acid by overcoming rate-limiting steps in genetically engineered Yarrowia lipolytica
Authors: Ma Jingbo , Gu Yang , Xu Peng 
Published: June 2021

AbstractNatural products acting on our central nervous systems are in utmost demand to fight against pain and mental disorders. Cannabinoids (CBDs) are proven neuroactive agents to treat anxiety, depression, chronic pain diseases, seizure, strokes and neurological disorders. The scarcity of the hemp-sourced CBD products and the prohibitive manufacturing cost limit the wide application of CBDs. Yeast metabolic engineering offers the flexibility to meet the ever-increasing market demand. In this work, we took a retrosynthetic approach and sequentially identified the rate-limiting steps to improve the biosynthesis of the CBD precursor olivetolic acid (OLA) in Yarrowia lipolytica. We debottlenecked the critical enzymatic steps to overcome the supply of hexanoyl-CoA, malonyl-CoA, acetyl-CoA, NADPH and ATPs to redirect carbon flux toward OLA. Implementation of these strategies led to an 83-fold increase in OLA titer in shaking flask experiment. This work may serve as a baseline for engineering CBD biosynthesis in oleaginous yeast species.
Right Temporoparietal Junction Encodes Mental Experience of Others More Than Evaluating False Versus True Belief
Authors: Bio Branden J. , Guterstam Arvid , Pinsk Mark , Wilterson Andrew I. , Graziano Michael S. A. 
Published: June 2021

AbstractWhen people make inferences about other people’s minds, called theory of mind (ToM), a network in the cerebral cortex becomes active. ToM experiments sometimes use the false belief task, in which subjects decide whether a story character believes A or B. The “false” belief occurs if the character believes A when B is true. We devised a version in which subjects judged whether a cartoon head “believed” a ball to be in box 1 or box 2. The task was a visual, reaction-time version of a ToM task. We proposed two alternative hypotheses. In hypothesis 1, cortical regions of interest within the ToM network should distinguish between false and true belief trials, reflecting outside information that the subjects have about the cartoon character. In hypothesis 2, the ToM network should distinguish between conditions only if the subjects think that the cartoon character can distinguish between the conditions, thus reflecting a model of the internal contents of the cartoon character’s mind. The results supported hypothesis 2. Events that the cartoon could not “see” did not affect activity in the ToM network; the same events, when the cartoon could apparently “see” them, significantly affected activity in the right temporoparietal junction (TPJ). The results support the view that the right TPJ participates in modeling the mental states of others, rather than in evaluating the accuracy of the beliefs of others, and may help explain why previous experiments showed mixed results when directly comparing false belief to true belief conditions.Significance statementHow do we understand the minds of others? A specific network of areas in the human brain is known to emphasize building models of other people’s minds. In one traditional hypothesis, this network helps us distinguish whether someone else’s beliefs are true or false. Here we show that the network is relatively insensitive to one’s own, outside knowledge about whether someone else’s beliefs are true or false. Instead, at least one node in the network appears to limit itself mainly to reconstructing the other person’s point of view. This social cognition network may be more about empathy than about critical evaluation.ClassificationSocial Sciences - Psychological and Cognitive Sciences
Ovule siRNAs methylate protein-coding genes intrans
Authors: Burgess Diane , Chow Hiu Tung , Grover Jeffrey W. , Freeling Michael , Mosher Rebecca A. 
Published: June 2021

ABSTRACT24-nt small interfering siRNAs maintain asymmetric DNA methylation at thousands of euchromatic transposable elements in plant genomes in a process call RNA-directed DNA Methylation (RdDM). RdDM is dispensable for growth and development in Arabidopsis, but is required for reproduction in other plant species, such asBrassica rapa.24-nt siRNAs are particularly abundant in maternal reproductive tissue, due largely to overwhelming expression from a small number of loci in the ovule and developing seed coat, termed siren loci. Recently it was shown that abundantly expressed 24-nt siRNAs produced in the tapetal tissue of anthers can methylate male meiocyte genesin trans(Long et al., 2021). Here we show that a similar process takes place in female tissue. siRNAs are produced from gene fragments embedded in some siren loci, and these siRNAs can trigger methylation intransat related protein-coding genes. Thistrans-methylation is associated with silencing of some target genes and may be responsible for seed abortion in RdDM mutants. Furthermore, we demonstrate that a consensus sequence in at least two families of DNA transposons is associated with abundant siren expression, most likely through recruitment of the CLSY3 putative chromatin remodeller. This research describes a new mechanism whereby RdDM influences gene expression and sheds light on the role of RdDM during plant reproduction.
Profiling Human CMV-specific T cell responses reveals novel immunogenic ORFs
Authors: Dhanwani Rekha , Dhanda Sandeep Kumar , Pham John , Williams Gregory P. , Sidney John , Grifoni Alba , Picarda Gaelle , Lindestam Arlehamn Cecilia S. , Sette Alessandro , Benedict Chris A 
Published: June 2021

AbstractDespite the prevalence and medical significance of human cytomegalovirus (HCMV) infections, a systematic analysis of the targets of T cell recognition in humans that spans the entire genome and includes recently described potential novel ORFs is not available. Here, we screened a library of epitopes predicted to bind HLA class II that spans over 350 different HCMV ORFs and includes ∼150 previously described and ∼200 recently described potential novel ORFs using an ex vivo IFNγ fluorospot assay. We identified 235 unique HCMV specific epitopes derived from 100 ORFs, some previously described as immunodominant and others that were not previously described to be immunogenic. Of those, 41 belong to the set of recently reported novel ORFs, thus providing evidence that at least some of these are actually expressed in vivo in humans. These data reveal that the breadth of the human T cell response to HCMV is much greater than previously thought. The ORFs and epitopes identified will help elucidate how T cell immunity relates to HCMV pathogenesis and instruct ongoing HCMV vaccine research.ImportanceTo understand the crucial role of adaptive immunity in controlling cytomegalovirus infection and disease, we systematically analyzed the CMV ’ORFeome’ to identify new CMV epitopes targeted primarily by CD4 T cells in humans. Our study identified >200 new T cell epitopes derived from both canonical and novel ORFs, highlighting the substantial breadth of anti-CMV T cell response and providing new targets for vaccine design.
Essential role of hyperacetylated microtubules in innate immunity escape orchestrated by the EBV-encoded BHRF1 protein
Authors: Glon Damien , Vilmen Géraldine , Perdiz Daniel , Hernandez Eva , Beauclair Guillaume , Quignon Frédérique , Berlioz-Torrent Clarisse , Maréchal Vincent , Poüs Christian , Lussignol Marion , Esclatine Audrey 
Published: June 2021

AbstractInnate immunity constitutes the first line of defense against viruses, in which mitochondria play an important role in the induction of the interferon (IFN) response. BHRF1, a multifunctional viral protein expressed during Epstein-Barr virus reactivation, modulates mitochondrial dynamics and disrupts the IFN signaling pathway. Mitochondria are mobile organelles that move through the cytoplasm thanks to the cytoskeleton and in particular the microtubule (MT) network. MTs undergo various post-translational modifications, among them tubulin acetylation. In this study, we demonstrated that BHRF1 induces MT hyperacetylation to escape innate immunity. Indeed, the expression of BHRF1 induces the clustering of shortened mitochondria next to the nucleus. This “mito-aggresome” is organized around the centrosome and its formation is MT-dependent. We also observed that the α-tubulin acetyltransferase ATAT1 interacts with BHRF1. Using ATAT1 knockdown or a non-acetylatable α-tubulin mutant, we demonstrated that this hyperacetylation is necessary for the mito-aggresome formation. Similar results were observed during EBV reactivation. We investigated the mechanism leading to the clustering of mitochondria, and we identified dyneins as motors that are required for mitochondrial clustering. Finally, we demonstrated that BHRF1 needs MT hyperacetylation to block the induction of the IFN response. Moreover, the loss of MT hyperacetylation blocks the localization of autophagosomes close to the mito-aggresome, impeding BHRF1 to initiate mitophagy, which is essential to inhibiting the signaling pathway. Therefore, our results reveal the role of the MT network, and its acetylation level, in the induction of a pro-viral mitophagy.
Mechanical stress in pancreatic cancer: Signaling pathway adaptation activates cytoskeletal remodeling and enhances cell migration
Authors: Kalli Maria , Li Ruxuan , Mills Gordon B. , Stylianopoulos Triantafyllos , Zervantonakis Ioannis K. 
Published: June 2021

AbstractNew treatments for patients with advanced or metastatic pancreatic cancers are urgently needed due to their resistance to all current therapies. Current studies focus on alternative treatment approaches that target or normalize the abnormal microenvironment of pancreatic tumors, which among others, is responsible for elevated mechanical stress in the tumor interior. Nevertheless, the underlying mechanisms by which mechanical stress regulates pancreatic cancer metastatic potential remain elusive. Herein, we used a large-scale proteomic assay to profile mechanical stress-induced signaling cascades that drive the motility of pancreatic cancer cells. Proteomic analysis, together with selective protein inhibition and siRNA treatments, revealed that mechanical stress enhances cell migration through activation of the p38 MAPK/HSP27 and JNK/c-Jun signaling axes, and activation of the actin cytoskeleton remodelers: Rac1, cdc42, and Myosin II. Our results highlight targeting aberrant signaling in cancer cells that are adapted to the mechanical tumor microenvironment as a novel approach to effectively limit pancreatic cancer cell migration.
Evaluation of traditional foods from a consumer's perspective: a review of methods and highlights
Authors: García-Barrón Sergio Erick , Leyva-Trinidad Doris Arianna , Carmona-Escutia Rosa Pilar , Romero-Medina Angélica , Villanueva-Rodríguez Socorro Josefina 
Published: June 2021

PurposeThis review aims to summarize some of the relevant methodologies used to study traditional foods evaluated from the consumers' perspective. The analysis provided in this review will shed light on the methods as a valuable tool to stimulate research in traditional to promote cultural and nutritional revaluation of these products.Design/methodology/approachA systematic literature review was performed on 60 articles related to the study of traditional foods from the consumer's perspective.FindingsTen methodologies were found that address the study of this product category. European countries lead the research in traditional foods while research in Latin America, Africa and Asia is still incipient.Practical implicationsThis review shows the potential of each method to be applied in the study of traditional foods as well as the positive implications that research about these products could bring to regions/countries with a great diversity of traditional products.Originality/valueThis review reveals the need to approach the study of traditional foods and encourage future research on them, which in turn, will contribute to the cultural and integral development of local communities, even to the recovery of ingredients and local raw materials.
Apps within apps: predicting government WeChat mini-program adoption from trust–risk perspective and innovation diffusion theory
Authors: Tang Zhenya , Zhou Zhongyun , Xu Feng , Warkentin Merrill 
Published: June 2021

PurposeThe WeChat mini-program is a new channel for the delivery of online and mobile services, including electronic government services. Given the distinguishing characteristics and new business model of WeChat mini-programs, additional studies of mini-program-based government services are warranted. The purpose of this paper is to identify the factors that determine user adoption and usage of government WeChat mini-programs (GWMPs).Design/methodology/approachAn empirical study was conducted through an online survey of Chinese GWMPs users. The proposed model was tested by analyzing the collected data using the covariance-based structural equation modeling approach.FindingsThe findings show that trust in government, trust in WeChat, trust in GWMPs and perceived convenience have significant effects on the usage of GWMPs.Originality/valueThis study contributes to the understanding of the GWMPs and mini-program-based government phenomenon. Theoretical implications for future e-government research as well as practical suggestions for GWMPs operators are also discussed.