bluuebunny/crossref_metadata_2025_split huggingface dataset:
CK2α-dependent regulation of Wnt activity governs white matter development and repair
Authors: Wang Chih-Yen , Zuo Zhongyuan , Kim Kyoung In , Bellen Hugo J. , Lee Hyun Kyoung 
Published: April 2023

AbstractWnt signaling plays an essential role in developmental and regenerative myelination in the CNS. The Wnt signaling pathway is comprised of multiple regulatory layers; thus, how these processes are coordinated to orchestrate oligodendrocyte development remains unclear. Here we show CK2α, a Wnt/β-catenin signaling Ser/Thr kinase, phosphorylates Daam2, inhibiting its function and Wnt-activity during oligodendrocyte development. Intriguingly, we found Daam2 phosphorylation differentially impacts distinct stages of oligodendrocyte development, accelerating early differentiation followed by decelerating maturation and myelination. Application towards white matter injury revealed CK2α-mediated Daam2 phosphorylation plays a protective role for developmental and behavioral recovery after neonatal hypoxia, while promoting myelin repair following adult demyelination. Together, our findings identify a novel regulatory node in the Wnt pathway that regulates oligodendrocyte development via protein phosphorylation-induced signaling complex instability and highlights a new biological mechanism for myelin restoration.SignificanceWnt signaling plays a vital role in OL development and has been implicated as an adverse event for myelin repair after white matter injury. Emerging studies have shed light on multi-modal roles of Wnt effectors in the OL lineage, but the underlying molecular mechanisms and modifiable targets in OL remyelination remain unclear. Using genetic mouse development and injury model systems, we delineate a novel stage-specific function of Daam2 in Wnt signaling and OL development via a S704/T7-5 phosphorylation mechanism, and determine a new role of the kinase CK2α in contributing to OL development. In-depth understanding of CK2α-Daam2 pathway regulation will allow us to precisely modulate its activity in conjunction with Wnt signaling and harness its biology for white matter pathology.
Flowers are leakier than leaves but cheaper to build
Authors: Roddy Adam B. , Guilliams C. Matt , Fine Paul V.A. , Mambelli Stefania , Dawson Todd E. , Simonin Kevin A. 
Published: April 2023

Summary-Producing and maintaining flowers is essential for reproduction in most angiosperms, underpinning population persistence and speciation. Although the physiological costs of flowers often oppose pollinator selection, these physiological costs have rarely been quantified.-We measured a suite of physiological traits quantifying the water and carbon costs and drought tolerance on flowers and leaves of over 100 phylogenetically diverse species, including water and dry mass contents, minimum epidermal conductance to water vapor (gmin), vein density, and dry mass per area.-Although there was substantial variation among species, flowers had significantly highergminand water content per unit area than leaves, but significantly lower vein density and dry mass per area than leaves. Both leaves and flowers exhibited similarly strong scaling between dry mass investment and water content.-The highergminof flowers offset their higher water content, suggesting that flowers may desiccate more rapidly than leaves during drought. The coordination between dry mass and water investment suggests that flowers rely on a hydrostatic skeleton to remain upright rather than on a carbon-based skeleton. For short-lived structures like flowers, water may be relatively cheaper than carbon, particularly given the relatively high amount of water loss per unit of carbon synthesized in photosynthesis.
Improved interpretability of bacterial genome-wide associations using gene cluster centric k-mers
Authors: Neubauer Hannes , Galardini Marco 
Published: April 2023

AbstractThe wide adoption of bacterial genome sequencing and encoding both core and accessory genome variation using k-mers has allowed bacterial genome wide association studies (GWAS) to identify genetic variants associated with relevant phenotypes such as those linked to infection. Significant limitations still remain as far as the interpretation of association results is concerned, which affects the wider adoption of GWAS methods on microbial data sets. We have developed a simple computational method (panfeed) that explicitly links each k-mer to their gene cluster at base resolution level, which allows us to avoid biases introduced by a global de Bruijn graph as well as more easily map and annotate associated variants. We tested panfeed on two independent data sets, correctly identifying previously characterized causal variants, which demonstrates the precision of the method, as well as its scalable performance. panfeed is a command line tool written in the python programming language and available athttps://github.com/microbial-pangenomes-lab/panfeed.
In situ structures from relaxed cardiac myofibrils reveal the organization of the muscle thick filament
Authors: Tamborrini Davide , Wang Zhexin , Wagner Thorsten , Tacke Sebastian , Stabrin Markus , Grange Michael , Kho Ay Lin , Rees Martin , Bennett Pauline , Gautel Mathias , Raunser Stefan 
Published: April 2023

AbstractThe thick filament is a key component of sarcomeres, the basic force-generating and load-bearing unit of striated muscle1. Mutations in thick filament proteins are associated with familial hypertrophic cardiomyopathy and other heart and muscle diseases2, 3. Despite this central importance for sarcomere force generation, it remains unclear how thick filaments are structurally organized and how its components interact with each other and with thin filaments to enable highly regulated muscle contraction. Here, we present the molecular architecture of native cardiac sarcomeres in the relaxed state, determined by electron cryo-tomography. Our reconstruction of the thick filament reveals the three-dimensional organization of myosin heads and tails, myosin-binding protein C (MyBP-C) and titin, elucidating the structural basis for their interaction during muscle contraction. The arrangement of myosin heads is variable depending on their position along the filament, suggesting that they have different capacities in terms of strain susceptibility and activation. Myosin tails exhibit a distinct arrangement and pattern of interactions. These are likely orchestrated by three alpha and three beta titin chains that are arranged like a spring, suggesting the existence of specialized roles of thick filament segments in length-dependent activation and contraction. Surprisingly, while the three titin alpha chains run along the entire length of the thick filament, titin beta does not. The structure also demonstrates that the C-terminal region of MyBP-C binds myosin tails and unexpectedly also directly interacts with the myosin heads, suggesting a previously undescribed direct role in the preservation of the myosin OFF state. Furthermore, we visualize how MyBP-C forms links between thin and thick filaments. These findings establish a robust groundwork for forthcoming research endeavors aiming to explore muscle disorders that involve sarcomeric structural components.
Identification of 1600 replication origins inS. cerevisiae
Authors: Foss Eric J. , Lichauco Carmina , Gatbonton-Schwager Tonibelle , Gonske Sara J. , Lofts Brandon , Lao Uyen , Bedalov Antonio 
Published: April 2023

AbstractThere are approximately 500 known origins of replication in the yeast genome, and the process by which DNA replication initiates at these locations is well understood. In particular, these sites are made competent to initiate replication by loading of the Mcm replicative helicase prior to the start of S phase; thus, “a site to which MCM is bound in G1” might be considered to provide an operational definition of a replication origin. By fusing a subunit of Mcm to micrococcal nuclease, a technique referred to as “Chromatin Endogenous Cleavage”, we previously showed that known origins are typically bound by a single Mcm double hexamer, loaded adjacent to the ARS consensus sequence (ACS). Here we extend this analysis from known origins to the entire genome, identifying candidate Mcm binding sites whose signal intensity varies over at least 3 orders of magnitude. Published data quantifying the production of ssDNA during S phase showed clear evidence of replication initiation among the most abundant 1600 of these sites, with replication activity decreasing in concert with Mcm abundance and disappearing at the limit of detection of ssDNA. Three other hallmarks of replication origins were apparent among the most abundant 5,500 sites. Specifically, these sites (1) appeared in intergenic nucleosome-free regions that were flanked on one or both sides by well-positioned nucleosomes; (2) were flanked by ACSs; and (3) exhibited a pattern of GC skew characteristic of replication initiation. Furthermore, the high resolution of this technique allowed us to demonstrate a strong bias for detecting Mcm double-hexamers downstream rather than upstream of the ACS, which is consistent with the directionality of Mcm loading by Orc that has been observedin vitro. We conclude that, if sites at which Mcm double-hexamers are loaded can function as replication origins, then DNA replication origins are at least 3-fold more abundant than previously assumed, and we suggest that replication may occasionally initiate in essentially every intergenic region. These results shed light on recent reports that as many as 15% of replication events initiate outside of known origins, and this broader distribution of replication origins suggest that S phase in yeast may be less distinct from that in humans than is widely assumed.
Adhesion-induced cortical flows pattern E-cadherin-mediated cell contacts
Authors: Arslan Feyza Nur , Hannezo Édouard , Merrin Jack , Loose Martin , Heisenberg Carl-Philipp 
Published: April 2023

AbstractMetazoan development relies on the formation and remodeling of cell-cell contacts. Dynamic reorganization of adhesion receptors and the actomyosin cell cortex in space and time play a central role in cell-cell contact formation and maturation. Yet, how this process is mechanistically achieved remains unclear. Here, by building a biomimetic assay composed of progenitor cells adhering to supported lipid bilayers functionalized with E-cadherin ectodomains, we show that cortical Actin flows, driven by the depletion of Myosin-2 at the cell contact center, mediate the dynamic reorganization of adhesion receptors and cell cortex at the contact. E-cadherin-dependent downregulation of the small GTPase RhoA at the forming contact leads to both a depletion of Myosin-2 and a decrease of F-actin at the contact center. This depletion of Myosin-2 causes centrifugal F-actin flows, leading to further accumulation of F-actin at the contact rim and the progressive redistribution of E-cadherin from the contact center to the rim. Eventually, this combination of actomyosin downregulation and flows at the contact determine the characteristic molecular organization, with E-cadherin and F-actin accumulating at the contact rim, where they are needed to mechanically link the contractile cortices of the adhering cells.
Highly specific σ2R/TMEM97 ligand alleviates neuropathic pain and inhibits the integrated stress response
Authors: Yousuf Muhammad Saad , Sahn James J. , Yang Hongfen , David Eric T. , Shiers Stephanie , Mancilla Moreno Marisol , Iketem Jonathan , Royer Danielle M. , Garcia Chelsea D. , Zhang Jennifer , Hong Veronica M. , Mian Subhaan M. , Ahmad Ayesha , Kolber Benedict J. , Liebl Daniel J , Martin Stephen F. , Price Theodore J. 
Published: April 2023

AbstractThe Sigma 2 receptor (σ2R) was described pharmacologically more than three decades ago, but its molecular identity remained obscure until recently when it was identified as transmembrane protein 97 (TMEM97). We and others have shown that σ2R/TMEM97 ligands alleviate mechanical hypersensitivity in mouse neuropathic pain models with a time course wherein maximal anti-nociceptive effect is approximately 24 hours following dosing. We sought to understand this unique anti-neuropathic pain effect by addressing two key questions: do these σ2R/TMEM97 compounds act selectively via the receptor, and what is their downstream mechanism on nociceptive neurons? Using male and female conventional knockout (KO) mice forTmem97,we find that a new σ2R/TMEM97 binding compound, FEM-1689, requires the presence of the gene to produce anti-nociception in the spared nerve injury model in mice. Using primary mouse dorsal root ganglion (DRG) neurons, we demonstrate that FEM-1689 inhibits the integrated stress response (ISR) and promotes neurite outgrowth via a σ2R/TMEM97-specific action. We extend the clinical translational value of these findings by showing that FEM-1689 reduces ISR and p-eIF2α levels in human sensory neurons and that it alleviates the pathogenic engagement of ISR by methylglyoxal. We also demonstrate that σ2R/TMEM97 is expressed in human nociceptors and satellite glial cells. These results validate σ2R/TMEM97 as a promising target for further development for the treatment of neuropathic pain.Significance StatementNeuropathic pain is a major medical problem that is poorly treated with existing therapeutics. Our findings demonstrate that targeting σ2R/TMEM97 with a newly described modulator reduces pain hypersensitivity in a mouse model with exquisite selectivity. We also identify integrated stress response (ISR) inhibition as a potential mechanism of action that links the receptor to cellular signaling events that have preclinical and clinical validation for pain relief. Our work suggests that σ2R/TMEM97 can be selectively engaged by specific small molecules to produce ISR inhibition in a subset of cells that are critical for neuropathic pain. σ2R/TMEM97-targeted therapeutics thus have the potential to offer effective pain relief without engagement of opioid receptors.
Polycomb safeguards imaginal disc specification through control of the Vestigial-Scalloped complex
Authors: Brown Haley E. , Weasner Brandon P. , Weasner Bonnie M. , Kumar Justin P. 
Published: April 2023

AbstractA fundamental goal of developmental biology is to understand how cell and tissue fates are specified. The imaginal discs ofDrosophilaare excellent model systems for addressing this paradigm as their fate can be redirected when discs regenerate after injury or when key selector genes are mis-regulated. Here, we show that whenPolycombexpression is reduced, the wing selector genevestigialis ectopically activated. This leads to the inappropriate formation of the Vestigial-Scalloped complex which forces the eye to transform into a wing. We further demonstrate that disrupting this complex does not simply block wing formation or restore eye development. Instead, immunohistochemistry and high throughput genomic analysis show that the eye-antennal disc unexpectedly undergoes hyperplastic growth with multiple domains being organized into other imaginal discs and tissues. These findings provide insight into the complex developmental landscape that tissues must navigate before adopting their final fate.Summary StatementHere we describe a novel mechanism by which Pc promotes an eye fate during normal development and how the eye is reprogrammed into a wing in its absence.
Construction of the ETECFinder database for the characterisation of enterotoxigenicEscherichia coli(ETEC) and revision of theVirulenceFinderwebtool at the CGE website
Authors: Scheutz Flemming , Nielsen Camilla Hald , von Mentzer Astrid 
Published: April 2023

ABSTRACTThe identification of pathogens is essential for effective surveillance and outbreak detection, which has been facilitated by the decreasing cost of whole-genome sequencing (WGS). However, extracting relevant virulence genes from WGS data remains a challenge. In this study, we developed a web-based tool to predict virulence-associated genes in enterotoxigenicEscherichia coli(ETEC), including heat-labile toxin (LT) genes (eltAandeltB), heat-stable enterotoxin (ST) genes (est) for both human and animal, enterotoxin (espC), colonization factors CS1 through 30, F4, F5, F6, F17, F18, and F41, and toxigenic invasion and adherence loci (tia, tibAC, etpBAC, eatA, yghJ, andtleA).To construct the database, we revised the existing ETEC nomenclature and used the VirulenceFinder webtool at the CGE website (https://cge.cbs.dtu.dk/services/VirulenceFinder/). The database was tested on 1,083 preassembled ETEC genomes and the ETEC reference sequence for strain H10407. We added 455 new alleles, replaced or renamed 50 alleles, and removed two.Overall, our tool has the potential to greatly facilitate ETEC identification and improve the accuracy of WGS analysis. The revised nomenclature and expanded gene repertoire provide a better understanding of the genetic diversity of ETEC. Additionally, the user-friendly interface makes it accessible to users with limited bioinformatics experience.
Catalytic reactor for operando spatially resolved structure–activity profiling using high-energy X-ray diffraction
Authors: Wollak Birte , Espinoza Diego , Dippel Ann-Christin , Sturm Marina , Vrljic Filip , Gutowski Olof , Nielsen Ida G. , Sheppard Thomas L. , Korup Oliver , Horn Raimund 
Published: April 2023

In heterogeneous catalysis, operando measurements probe catalysts in their active state and are essential for revealing complex catalyst structure–activity relationships. The development of appropriate operando sample environments for spatially resolved studies has come strongly into focus in recent years, particularly when coupled to the powerful and multimodal characterization tools available at synchrotron light sources. However, most catalysis studies at synchrotron facilities only measure structural information about the catalyst in a spatially resolved manner, whereas gas analysis is restricted to the reactor outlet. Here, a fully automated and integrated catalytic profile reactor setup is shown for the combined measurement of temperature, gas composition and high-energy X-ray diffraction (XRD) profiles, using the oxidative dehydrogenation of C2H6 to C2H4 over MoO3/γ-Al2O3 as a test system. The profile reactor methodology was previously developed for X-ray absorption spectroscopy and is here extended for operando XRD. The profile reactor is a versatile and accessible research tool for combined spatially resolved structure–activity profiling, enabling the use of multiple synchrotron-based characterization methods to promote a knowledge-based optimization of a wide range of catalytic systems in a time- and resource-efficient way.
Infrastructure availability and disruption levels on performance of firms: a survey of Sub-Saharan Africa informal enterprises
Authors: Mbedzi Edson , Kapingura Forget Mingiri 
Published: April 2023

PurposeInfrastructure deficiency and supply disruption challenges are quite common among developing economies. While Sub-Saharan Africa is not unique to these challenges, it is the extent of levels of infrastructure deficiency and disruptions that affect the level of performance of small businesses. Literature on the performance of small businesses suggests both infrastructure availability and disruptions affect the performance of small businesses, but the effects on informal enterprises that operate from locations where the supply of infrastructure is weak are less documented. The paper, therefore, investigates the effects of four types of infrastructure supply in two dimensions of availability and disruption levels on the performance of informal enterprises in 12 Sub-Saharan African countries.Design/methodology/approachThe study uses data from World Bank informal enterprises surveys based on a sample of 3 735 informal enterprises. The study uses the multiple analysis of variance method based on the World Bank's Informal Enterprise Surveys (IFS) country-level cross-sectional data collected between 2009 and 2019.FindingsResults show infrastructure supply is quite low irrespective of the form of infrastructure. Infrastructure availability is associated with high supply disruptions. Infrastructure supply deficiency and disruption intensities are negatively associated with informal enterprises' performance. Finally, the effects of both infrastructure availability and supply disruptions are positively associated with informal enterprises' business activity levels.Research limitations/implicationsDue to data limitations, only four types of infrastructure are captured in the analysis. A wider variety of types of infrastructure could improve the analysis.Originality/valueGiven the deficiency level of infrastructure and its implications on informal enterprise development, therefore, policy interventions aiming at addressing informal enterprises' challenges should focus on improving infrastructure supply deficiencies and disruption challenges. This paper provides the link between infrastructure levels, infrastructure supply disruptions and performance of the informal enterprises which is an essential starting point for policy intervention in informal enterprise development.
Intellectual disability and autism in adults influence psychological treatments for mental health comorbidities
Authors: Mills Rachel , Nathan Rajan , Soper Paul , Michelet Felix , Stewart Alex G. , Jaydeokar Sujeet 
Published: April 2023

Purpose
The purpose of the study was to examine whether there were differences in the provision of non-pharmacological interventions based on the level of intellectual disability and the presence or absence of autism. Mental health conditions are often underdiagnosed in adults with intellectual disability and do not always receive psychological interventions as recommended by the National Institute for Health and Care Excellent guidelines. To realise the national UK programme’s aim of stopping the overuse of medications in people with intellectual disability, it is important that these individuals have access to appropriate non-pharmacological interventions. The authors examined the relationship between an individual’s level of intellectual disability and the presence or absence of autism with access to relevant non-pharmacological interventions from specialist community intellectual disability services.

Design/methodology/approach
A cross-sectional study of adults accessing four specialist intellectual disability services in North West England in 2019.

Findings
There was a high prevalence of mental health comorbidity, even higher for autistic adults. However, a relatively small percentage of the study population was receiving psychological interventions. The most frequent non-pharmacological intervention was a positive behaviour support plan, irrespective of comorbid mental illnesses.

Research limitations/implications
Not having access to psychological interventions for the treatment of mental illness could result in poor health outcomes and increasing health inequalities. The study highlights the need for developing psychological interventions, particularly for those with moderate to severe intellectual disability and for those with associated autism.

Originality/value
This large sample study examined the relationship between intellectual disability level and the presence of autism with accessing psychological interventions.