bluuebunny/crossref_metadata_2025_split huggingface dataset:
Peripheral macrophages causally contribute to disease onset and progression in theNdufs4(KO) model of Leigh syndrome
Authors: Hanaford Allison R , Khanna Asheema , James Katerina , Chen Yihan , Mulholland Michael , Kayser Bernhard , Truong Vivian , Sedensky Margaret , Morgan Phil , Kalia Vandana , Baerchst Nathan , Sarkar Surojit , Johnson Simon C 
Published: January 2023

AbstractSubacute necrotizing encephalopathy, or Leigh syndrome (LS), is the most common paediatric presentation of genetic mitochondrial disease. LS is a multi-system disorder with severe neurologic, metabolic, and musculoskeletal symptoms. The presence of progressive, symmetric, necrotizing lesions in the brainstem are a defining feature of the disease, and the major cause of morbidity and mortality, but the mechanisms underlying their pathogenesis have been elusive. Recently, we demonstrated that high-dose pexidartinib, a CSF1R inhibitor, prevents LS CNS lesions and systemic disease in theNdufs4(-/-) mouse model of LS. While the dose-response in this study implicated peripheral immune cells, the immune populations involved have not yet been elucidated. Here, we used a targeted genetic tool, deletion of the colony stimulating factor 1 receptor (CSF1R) macrophage super-enhancer FIRE (Csf1rΔFIRE), to specifically deplete microglia and define the role of microglia in the pathogenesis of LS. Homozygosity for theCsf1rΔFIRE allele ablates microglia in both control andNdufs4(-/-) animals, but onset of CNS lesions and sequalae in theNdufs4(-/-), including mortality, are only marginally impacted by microglia depletion. The overall development of necrotizing CNS lesions is not altered, though microglia remain absent. Finally, histologic analysis of brainstem lesions provides direct evidence of a causal role for peripheral macrophages in the characteristic CNS lesions. These data demonstrate that peripheral macrophages play a key role in the pathogenesis disease in theNdufs4(-/-) model.
Mycobacterium tuberculosisSecA2-dependent activation of host Rig-I/MAVs signaling is not conserved inMycobacterium marinum
Authors: Serene Lindsay G. , Champion Patricia A. , Schorey Jeffrey S. 
Published: January 2023

ABSTRACTRetinoic acid inducible gene I (Rig-I) is a cytosolic pattern recognition receptor canonically described for its important role in sensing viral RNAs. Increasingly, bacterially-derived RNA from intracellular bacteria such asMycobacterium tuberculosis, have been shown to activate the same host Rig-I/Mitochondrial antiviral sensing protein (MAVS) signaling pathway to drive a type-I interferon response that contributes to bacterial pathogenesisin vivo. InM. tuberculosis, this response is mediated by the protein secretion system SecA2, but little is known about whether this process is conserved in other pathogenic mycobacteria or the mechanism by which these nucleic acids gain access to the host cytoplasm. Because theM. tuberculosisandM. marinumSecA2 protein secretion systems share a high degree of genetic and functional conservation, we hypothesized that Rig-I/MAVS activation and subsequent induction of IFN-β secretion by host macrophages will also be conserved between these two mycobacterial species. To test this, we generated a ΔsecA2 M. marinumstrain along with complementation strains expressing either theM. marinumorM. tuberculosis secA2genes. Our results suggest that the ΔsecA2strain has a growth defectin vitrobut not in host macrophages. These intracellular growth curves also suggested that the calculation applied to estimate the number of bacteria added to macrophage monolayers in infection assays underestimates bacterial inputs for the ΔsecA2strain. Therefore, to better examine secreted IFN-β levels when bacterial infection levels are equal across strains, we plated bacterial CFUs at 2hpi alongside our ELISA based infections. This enabled us to normalize secreted levels of IFN-β to a standard number of bacteria. Applying this approach to both WT and MAVS-/-bone marrow derived macrophages we observed equal or higher levels of secreted IFN-β from macrophages infected with the ΔsecA2 M. marinumstrain as compared to WT. Together our findings suggest that activation of host Rig-I/MAVS cytosolic sensors and subsequent induction of IFN-β response in a SecA2-dependent manner is not conserved inM. marinumunder the conditions tested.
An adult stem-like cell population generates germline and neurons in the sea anemoneNematostella vectensis
Authors: Miramón-Puértolas Paula , Steinmetz Patrick R.H. 
Published: January 2023

AbstractMost genetic research animals (e.g., vertebrates, insects, nematodes) segregate germline and soma during early embryogenesis. In contrast, some highly regenerative bilaterian (e.g., planarians) and non-bilaterian animals (e.g., hydrozoan cnidarians) retain adult stem cells with both germinal and somatic potentials. As these cells have been studied in only few phyla, their biology and evolution remain mostly enigmatic. Here, we aimed to identify and characterize adult stem cells and their cell lineages in the sea anemoneNematostella vectensisby combining gene expression analysis, immunostainings, and meganuclease-mediated and CRISPR/Cas9-mediated knock-in reporter lines of conserved germline and multipotency genes (e.g.,vasa2,piwi1). We found a small population ofvasa2+/piwi1+ cells in the gastrodermal folds of juvenile and adult sea anemones that generates germline and a diversity of somatic, mostly proliferative cells. Using a combination ofsoxB(2)neural progenitor andpiwi1reporter lines, we found that the somatic progeny fromvasa2+/piwi1+ cells includessoxB(2)+ neural progenitors. Our results strongly support the existence of an adult Vasa2+/Piwi1+ multipotent stem-like cell population that derives both germline and somatic lineages inNematostella. The similarities of lineages and gene expression profiles betweenNematostellaVasa2+/Piwi1+ stem-like cells and hydrozoan interstitial stem cells support their evolutionary conservation among cnidarians.
Control of gastruloid patterning and morphogenesis by the Erk and Akt signaling pathways
Authors: Underhill Evan J. , Toettcher Jared E. 
Published: January 2023

AbstractFibroblast growth factor (FGF) dependent elongation along an anterior-posterior (A-P) axis is a conserved feature of vertebrate embryogenesis. A-P axis elongation can also be reproduced in 3D cell culture models termed gastruloids, enabling dissection of this process in a controlled, minimal context. Here, we set out to determine how gastruloid posterior elongation depends on the Erk and Akt pathways, canonical downstream effectors of FGF signaling. We find that gastruloids exhibit reproducible posterior-to-anterior gradients in Erk and Akt phosphorylation that are generated independently and correlate with distinct zones of tissue movement, cell proliferation, and expression of cell motility and adhesion regulators. Pharmacological inhibition of FGFR, Erk, or Akt signaling impairs gastruloid elongation, and quantification of signaling gradients reveals how these patterns interact and scale with A-P axis length. Using global inhibitors and activators of each pathway, we find that a gradient of Ras/Erk signaling is required for the establishment of appropriately localized domains of E-cadherin, Snail, and Brachyury expression, whereas perturbing PI3K/Akt signaling alters proliferation but not patterning. Taken together, our data demonstrate that graded PI3K/Akt and Ras/Erk signaling provide spatial information to control proliferation and cell-cell adhesion during gastruloid elongation.
Molecular basis of RanGTP-activated nucleosome assembly with Histones H2A-H2B bound to Importin-9
Authors: Shaffer Joy M. , Jiou Jenny , Tripathi Kiran , Olaluwoye Oladimeji S. , Fung Ho Yee Joyce , Chook Yuh Min , D’Arcy Sheena 
Published: January 2023

AbstractPadavannil et al. 2019 show that Importin-9 (Imp9) transports Histones H2A-H2B from the cytoplasm to the nucleus using a non-canonical mechanism whereby binding of a GTP-bound Ran GTPase (RanGTP) fails to evict the H2A-H2B cargo. Instead, a stable complex forms, comprised of equimolar RanGTP, Imp9, and H2A-H2B. Unlike the binary Imp9•H2A-H2B complex, this RanGTP•Imp9•H2A-H2B ternary complex can release H2A-H2B to an assembling nucleosome. Here, we define the molecular basis for this RanGTP-activated nucleosome assembly by Imp9. We use hydrogen-deuterium exchange coupled with mass spectrometry and compare the dynamics and interfaces of the RanGTP•Imp9•H2A-H2B ternary complex to those in the Imp9•H2A-H2B or Imp9•RanGTP binary complexes. Our data are consistent with the Imp9•H2A-H2B structure by Padavannil et al. 2019 showing that Imp9 HEAT repeats 4-5 and 18-19 contact H2A-H2B, as well as many homologous importin•RanGTP structures showing that importin HEAT repeats 1 and 3, and the h8 loop, contact RanGTP. We show that Imp9 stabilizes H2A-H2B beyond the direct binding site, similar to other histone chaperones. Importantly, we reveal that binding of RanGTP releases H2A-H2B interaction at Imp9 HEAT repeats 4-5, but not 18-19. This exposes DNA- and histone-binding surfaces of H2A-H2B, thereby facilitating nucleosome assembly. We also reveal that RanGTP has a weaker affinity for Imp9 when H2A-H2B is bound. This may ensure that H2A-H2B is only released in high RanGTP concentrations near chromatin. We delineate the molecular link between the nuclear import of H2A-H2B and its deposition into chromatin by Imp9.SignificanceImp9 is the primary importin for shuttling H2A-H2B from the cytoplasm to the nucleus. It employs an unusual mechanism where the binding of RanGTP alone is insufficient to release H2A-H2B. The resulting stable RanGTP•Imp9•H2A-H2B complex gains nucleosome assembly activity as H2A-H2B can be deposited onto an assembling nucleosome. We show that H2A-H2B is allosterically stabilized via interactions with both N- and C-terminal portions of Imp9, reinforcing its chaperone-like behavior. RanGTP binding causes H2A-H2B release from the N-terminal portion of Imp9 only. The newly-exposed H2A-H2B surfaces can interact with DNA or H3-H4 in nucleosome assembly. Imp9 thus plays a multi-faceted role in histone import, storage, and deposition regulated by RanGTP, controlling histone supply in the nucleus and to chromatin.
Multi-omics analysis identifies LBX1 and NHLH1 as central regulators of human midbrain dopaminergic neuron differentiation
Authors: Ramos Borja Gomez , Ohnmacht Jochen , de Lange Nikola , Ginolhac Aurélien , Valceschini Elena , Rakovic Aleksandar , Halder Rashi , Massart François , Klein Christine , Krause Roland , Schulz Marcel H. , Sauter Thomas , Krüger Rejko , Sinkkonen Lasse 
Published: January 2023

AbstractMidbrain dopaminergic neurons (mDANs) control voluntary movement, cognition, and reward behavior under physiological conditions and are implicated in human diseases such as Parkinson’s disease (PD). Many transcription factors (TFs) controlling human mDAN differentiation during development have been described, but much of the regulatory landscape remains undefined. Using a tyrosine hydroxylase (TH) iPSC reporter line, we have generated time series transcriptomic and epigenomic profiles of purified mDANs during differentiation. Integrative analysis predicted novel central regulators of mDAN differentiation and super-enhancers were used to prioritize key TFs. We find LBX1, NHLH1 and NR2F1/2 to be necessary for mDAN differentiation and show that overexpression of either LBX1 or NHLH1 can also improve mDAN specification. NHLH1 is necessary for the induction of neuronal miR-124, while LBX1 regulates cholesterol biosynthesis, possibly through mTOR signaling. Consistently, rapamycin treatment led to an inhibition of mDAN differentiation. Thus, our work reveals novel regulators of human mDAN differentiation.
Expanding the repertoire of the plant infecting ophioviruses
Authors: Debat Humberto , García María Laura , Bejerman Nicolás 
Published: January 2023

AbstractOphioviruses (genusOphiovirus, familyAspiviridae) are plant-infecting viruses with non-enveloped, filamentous, naked nucleocapsid virions. Members of genusOphiovirushave a segmented single-stranded negative-sense RNA genome (ca. 11.3-12.5 kb), encompassing three or four linear segments. These segments encode in total four to seven proteins in sense and antisense orientation, both in the viral and complementary strands. The genusOphiovirusincludes seven species with viruses infecting both monocots and dicots, mostly trees, shrubs and some ornamentals. From a genomic perspective, as of today, there are complete genomes available for only four species. Here, by exploring large metatranscriptomics publicly available datasets, we report the identification and molecular characterization of 33 novel viruses with genetic and evolutionary cues of ophioviruses. Genetic distance and evolutionary insights suggest that all the detected viruses could correspond to members of novel species, which expand ca. 4.5-fold the current diversity of ophioviruses. The detected viruses increase the tentative host range of ophioviruses for the first time to mosses, liverwort and ferns. In addition, viruses were linked to severalAsteraceae, OrchidaceaeandPoaceaecrops/ornamental plants. Phylogenetic analyses showed a novel clade of mosses, liverworts and fern ophioviruses, characterized by long branches suggesting still plenty unsampled hidden diversity within the genus. This study represents a significant expansion of genomics of ophioviruses, opening the grounds to future works on the molecular and evolutionary peculiarity of this virus genus.
scMultiome analysis identifies embryonic hindbrain progenitors with mixed rhombomere identities
Authors: Kim Yong-Il , O’Rourke Rebecca , Sagerström Charles G. 
Published: January 2023

SUMMARYRhombomeres serve to position neural progenitors in the embryonic hindbrain, thereby ensuring appropriate neural circuit formation, but the molecular identities of individual rhombomeres and the mechanism whereby they form have not been fully established. Here we apply scMultiome analysis in zebrafish to molecularly resolve all rhombomeres for the first time. We find that rhombomeres become molecularly distinct between 10hpf (end of gastrulation) and 13hpf (early segmentation). While the mature hindbrain consists of alternating odd- versus even-type rhombomeres, our scMultiome analyses do not detect extensive odd versus even characteristics in the early hindbrain. Instead, we find that each rhombomere displays a unique gene expression and chromatin profile. Prior to the appearance of distinct rhombomeres, we detect three hindbrain progenitor clusters (PHPDs) that correlate with the earliest visually observed segments in the hindbrain primordium and that represent prospective rhombomere r2/r3 (possibly including r1), r4 and r5/r6, respectively. We further find that the PHPDs form in response to Fgf and RA morphogens and that individual PHPD cells co-express markers of multiple mature rhombomeres. We propose that the PHPDs contain mixed-identity progenitors and that their subdivision into individual mature rhombomeres requires resolution of mixed transcription and chromatin states.
Dendritic spine neck plasticity controls synaptic expression of long-term potentiation
Authors: Gupta Rahul , O’Donnell Cian 
Published: January 2023

AbstractDendritic spines host glutamatergic excitatory synapses and compartmentalize biochemical signalling underlying synaptic plasticity. The narrow spine neck that connects the spine head with its parent dendrite is the crucial structural element of this compartmentalization. Both neck morphology and its molecular composition differentially regulate exchange of molecular signals between the spine and rest of the neuron. Although these spine neck properties themselves show activity-dependent plasticity, it remains unclear what functional role spine neck plasticity plays in synaptic plasticity expression. To address this, we built a data-constrained biophysical computational model of AMPA receptor (AMPAR) trafficking and intracellular signalling involving Ca2+/calmodulin-dependent kinase II (CaMKII) and the phosphatase calcineurin in hippocampal CA1 neurons, which provides new mechanistic insights into spatiotemporal AMPAR dynamics during long-term potentiation (LTP). Using the model, we tested how plasticity of neck morphology and of neck septin7 barrier, which specifically restricts membrane protein diffusion, affect LTP. We found that spine neck properties control LTP by regulating the balance between AMPAR and calcineurin escape from the spine. Neck plasticity that increases spine-dendrite coupling reduces LTP by allowing more AMPA receptors to diffuse away from the synapse. Surprisingly, neck plasticity that decreases spine-dendrite coupling can also reduce LTP by trapping calcineurin, which dephosphorylates AMPARs. Further simulations showed that the precise timescale of neck plasticity, relative to AMPAR and enzyme diffusion and phosphorylation dynamics, critically regulates LTP. These results suggest a new mechanistic and experimentally-testable theory for how spine neck plasticity regulates synaptic plasticity.
Elevated glucocorticoid alters the developmental dynamics of hypothalamic neurogenesis
Authors: Eachus Helen , Choi Min-Kyeung , Tochwin Anna , Kaspareit Johanna , Ho May , Ryu Soojin 
Published: January 2023

AbstractExposure to excess glucocorticoid (GC) during early development is implicated in adult dysfunctions. Reduced adult hippocampal neurogenesis is a well-known consequence of exposure to early life stress or elevated GC, however the effects on neurogenesis during development and effects on other brain regions are not well understood. Using an optogenetic zebrafish model, here we analysed the effects of GC exposure on neurogenesis during development in the whole brain. We identify that the hypothalamus is a highly GC-sensitive region where elevated GC causes precocious development. This is followed by failed maturation and early decline accompanied by impaired feeding, growth, and longevity. In GC-exposed animals, the developmental trajectory of hypothalamic progenitor cells is strikingly altered, potentially mediated by direct regulation of transcription factors such asrx3by GC. Our data provide cellular and molecular level insight into GC-induced alteration of the hypothalamic development trajectory, a process crucial for health across the life-course.
Design of stimulus-responsive two-state hinge proteins
Authors: Praetorius Florian , Leung Philip J. Y. , Tessmer Maxx H. , Broerman Adam , Demakis Cullen , Dishman Acacia F. , Pillai Arvind , Idris Abbas , Juergens David , Dauparas Justas , Li Xinting , Levine Paul M. , Lamb Mila , Ballard Ryanne K. , Gerben Stacey R. , Nguyen Hannah , Kang Alex , Sankaran Banumathi , Bera Asim K. , Volkman Brian F. , Nivala Jeff , Stoll Stefan , Baker David 
Published: January 2023

AbstractProteins that switch between two structural states as a function of environmental stimuli are widespread in nature. These proteins structurally transduce biochemical information in a manner analogous to how transistors control information flow in computing devices. Engineering challenges ranging from biological computing devices to molecular motors require such two-state switches, but designing these is an unsolved problem as it requires sculpting an energy landscape with two low-energy but structurally distinct conformations that can be modulated by external inputs. Here we describe a general design approach for creating “hinge” proteins that populate one distinct state in the absence of ligand and a second designed state in the presence of ligand. X-ray crystallography, electron microscopy, and double electron-electron resonance spectroscopy demonstrate that despite the significant structural differences, the two states are designed with atomic level accuracy. The kinetics and thermodynamics of effector binding can be finely tuned by modulating the free energy differences between the two states; when this difference becomes sufficiently small, we obtain bistable proteins that populate both states in the absence of effector, but collapse to a single state upon effector addition. Like the transistor, these switches now enable the design of a wide array of molecular information processing systems.
Paradoxical leader behavior and leader effectiveness: moderating role of structural and job-related uncertainty
Authors: Batool Uzma , Raziq Muhammad Mustafa , Sarwar Naukhez , Saleem Sharjeel , Obaid Asfia 
Published: January 2023

PurposeThe purpose of this study is to examine the impact of paradoxical leader behavior (PLB) on leader effectiveness (LE). The authors propose an underlying mechanism of this relationship and examine if the stated relationship is moderated by job-related and structural uncertainty in the organization.Design methodology approachThe authors draw on survey data from 127 employees working in public and privately owned organizations and analyze data using AMOS and SPSS.FindingsResults offer partial support to the authors’ hypotheses indicating that paradoxical leader behavior is positively associated to LE. As expected, the relationship is negatively moderated by structural uncertainty indicating that LE is weakened where there is structural uncertainty in the organization. However, in contrast to our other assumption, the authors find a positive (rather than negative) moderating role of job-related uncertainty in the PLB–LE relationship.Originality valueParadoxes are everywhere and inherently embedded in complex and dynamic organizational systems. To deal with paradoxes, organizational leaders often seek to act paradoxically. However, not every leader has a paradoxical mindset, and where a leader has such, it remains unclear if they will prove to be effective leaders. What can further influence the effectiveness of such leaders is the uncertainty that organizations face in the today’s dynamic environments. In this study, the authors contribute to paradox theory and the paradoxical leadership literature by unfolding the boundary conditions which can influence paradoxical leader’s effectiveness.
Relationship between Twitter activity and stock performance: evidence from Turkish airline industry
Authors: Ismayil Javid , Demir Oguz 
Published: January 2023

Purpose
The purpose of this paper is to analyze the correlation between the Twitter activity of two airline companies and their stock performance at the Istanbul Stock Exchange (BIST).

Design/methodology/approach
Overall, 113,018 tweets were divided into 34,152 semantic and 78,866 share tweets. Semantic tweets are tweets mentioning company’s products or services and were labeled manually and with deep learning models. Share tweets were divided into 13,618 relevant and 65,248 irrelevant tweets.

Findings
A positive correlation was found between share tweets and stock performance. Semantic tweets did not display a correlation with stock performance. Relevant share tweets displayed as a strong correlation as all share tweets for one company. Also, the manual labeling of 8,000 tweets led to the discovery of many insights related to service provision in the airway industry, management of digital support channels, management of reputation on social media and using Twitter as a customer support platform.

Practical implications
Relevant share tweets comprise only 20% of all share tweets for one company and show the same level of correlation with stock performance. This means that the efficiency of business intelligence solutions created to monitor Twitter activity can be improved five times by saving computational power, network bandwidth and data storage.

Originality/value
Previous research has analyzed all Twitter activity taken together. By dividing tweets into semantic and share tweets, this paper illustrates that it is, in fact, share tweets that are correlated with stock performance and not semantic tweets.