bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chemokine positioning determines mutually exclusive roles for their receptors in extravasation of pathogenic human T cells
Authors: Parween Farhat , Singh Satya P. , Zhang Hongwei H , Kathuria Nausheen , Otaizo-Carrasquero Francisco A. , Shamsaddini Amirhossein , Gardina Paul J. , Ganesan Sundar , Kabat Juraj , Lorenzi Hernan A. , Myers Timothy G. , Farber Joshua M. 
Published: January 2023

AbstractPro-inflammatory T cells co-express multiple chemokine receptors, but the distinct functions of individual receptors on these cells are largely unknown. Human Th17 cells uniformly express the chemokine receptor CCR6, and we discovered that the subgroup of CD4+CCR6+cells that co-express CCR2 possess a pathogenic Th17 signature, can produce inflammatory cytokines independent of TCR activation, and are unusually efficient at transendothelial migration (TEM). The ligand for CCR6, CCL20, was capable of binding to activated endothelial cells (ECs) and inducing firm arrest of CCR6+CCR2+cells under conditions of flow - but CCR6 could not mediate TEM. By contrast, CCL2 and other ligands for CCR2, despite being secreted from both luminal and basal sides of ECs, failed to bind to the EC surfaces - and CCR2 could not mediate arrest. Nonetheless, CCR2 was required for TEM. To understand if CCR2’s inability to mediate arrest was due solely to an absence of EC-bound ligands, we generated a CCL2-CXCL9 chimeric chemokine that could bind to the EC surface. Although display of CCL2 on the ECs did indeed lead to CCR2-mediated arrest of CCR6+CCR2+cells, activating CCR2 with surface-bound CCL2 blocked TEM. We conclude that mediating arrest and TEM are mutually exclusive activities of chemokine receptors and/or their ligands that depend, respectively, on chemokines that bind to the EC luminal surfaces versus non-binding chemokines that form transendothelial gradients under conditions of flow. Our findings provide fundamental insights into mechanisms of lymphocyte extravasation and may lead to novel strategies to block or enhance their migration into tissue.
Ageing impairs the regenerative capacity of regulatory T cells in central nervous system remyelination
Authors: de la Fuente Alerie Guzman , Dittmer Marie , Heesbeen Elise , de la Vega Gallardo Nira , White Jessica , Young Andrew , McColgan Tiree , Dashwood Amy , Mayne Katie , Cabeza-Fernández Sonia , Falconer John , Rodriguez-Baena Francisco Javier , McMurran Christopher E. , Innayatullah Mohammed , Rawji Khalil S. , Franklin Robin J.M. , Dooley James , Liston Adrian , Ingram Rebecca , Tiwari Vijay K. , Penalva Rosana , Dombrowski Yvonne , Fitzgerald Denise C. 
Published: January 2023

AbstractMyelin regeneration (remyelination) is essential to prevent neurodegeneration in demyelinating diseases such as Multiple Sclerosis, however, its efficiency declines with age. Regulatory T cells (Treg) recently emerged as critical players in tissue regeneration, including remyelination. However, the effect of ageing on Treg-mediated regenerative processes is poorly understood. Here, we show that expansion of aged Treg does not rescue age-associated remyelination impairment due to an intrinsically diminished capacity of aged Treg to promote oligodendrocyte differentiation and myelination. This decline in regenerative Treg functions can be rescued by a young environment. We identified Melanoma Cell Adhesion Molecule 1 (MCAM1) and Integrin alpha 2 (ITGA2) as novel candidates of Treg-mediated oligodendrocyte differentiation that decrease with age. Our findings demonstrate that ageing limits the neuroregenerative capacity of Treg, likely limiting their remyelinating therapeutic potential in aged patients, and describe two novel mechanisms implicated in Treg-driven remyelination that may be targetable to overcome this limitation.
Gigantic Macroraptorial Sperm Whale Tooth (cf.Livyatan) from the Miocene of Orange County, California
Authors: Watmore Kristin I. , Prothero Donald R. 
Published: January 2023

AbstractA fossil tooth from the middle-upper Miocene Monterey or Capistrano Formation in the Orange County Cooper Center Paleontology Collection shows that a gargantuan sperm whale once inhabited the Miocene seas of southern California. Though difficult to diagnose to genus level based on a single, incomplete tooth, comparisons with known Miocene physeteroid whales provide key insight into the affinities of this fossil. Even though the tip is broken, the entire tooth is over 250 mm long and 86 mm in diameter. It has enamel only on the tip of the broken crown and there is no enamel coating over the rest of the tooth. Instead, the tooth consists mostly of layers of cementum over a core of ossified dentin. It is slightly smaller than the largest teeth of the largest known physeteroid, the South American MioceneLivyatan melvillei, a genus that has not been found outside of the Southern Hemisphere besides one record from northern Europe. It is also just slightly smaller than similar gigantic teeth reported from South Africa and Australia from the middle-late Miocene through the early Pliocene. We compared it to other Miocene members of the family such asHoplocetus,Scaldicetus, andZygophyseter, but none have teeth as large as this one. It is bigger than all known specimens of all other North American Miocene physeteroid whales, including another whale from the Monterey Formation,Albicetus oxymycterus. This fossil suggests that giant physeteroid whales closely related toLivyatanlived in the North Pacific. It represents a substantial geographic range extension for giant physeteroid whales, previously known only from the Miocene of the Southern Hemisphere and northern Europe.
Rapid and Highly Efficient Morphogenic Gene-Mediated Hexaploid Wheat Transformation
Authors: Johnson Kari , Chu Uyen Cao , Anthony Geny , Wu Emily , Che Ping , Jones Todd J. 
Published: January 2023

ABSTRACTThe successful employment of morphogenic regulator genes,Zm-Baby Boom(ZmBbm) andZm-Wuschel2(ZmWus2), forAgrobacterium-mediated transformation of maize (Zea maysL.) and sorghum (Sorghum bicolorL.) has been reported to improve transformation by inducing rapid somatic embryo formation. Here, we report two morphogenic gene-mediated wheat transformation methods, either with or without morphogenic and marker gene excision. These methods yield independent-transformation efficiency up to 58% and 75%, respectively. In both cases, the tissue culture duration for generating transgenic plants was significantly reduced from 80 to nearly 50 days. In addition, the transformation process was significantly simplified to make the procedure less labor-intensive, higher-throughput and more cost-effective, by eliminating the requirement for embryonic axis excision, bypassing the necessity for prolonged dual-selection steps for callus formation, and obviating the prerequisite of cytokinin for shoot regeneration. Furthermore, we have demonstrated the flexibility of the methods and generated high-quality transgenic events across multiple genotypes using herbicide (phosphinothricin, ethametsulfuron)- and antibiotic (G418)-based selections.
Distinct nonlinear spectrotemporal integration in primary and secondary auditory cortices
Authors: Kline Amber M. , Aponte Destinee A. , Kato Hiroyuki K. 
Published: January 2023

AbstractAnimals sense sounds through hierarchical neural pathways that ultimately reach higher-order cortices to extract complex acoustic features, such as vocalizations. Elucidating how spectrotemporal integration varies along the hierarchy from primary to higher-order auditory cortices is a crucial step in understanding this elaborate sensory computation. Here we used two-photon calcium imaging and two-tone stimuli with various frequency-timing combinations to compare spectrotemporal integration between primary (A1) and secondary (A2) auditory cortices in mice. Individual neurons showed mixed supralinear and sublinear integration in a frequency-timing combination-specific manner, and we found unique integration patterns in these two areas. Temporally asymmetric spectrotemporal integration in A1 neurons enabled their discrimination of frequency-modulated sweep directions. In contrast, temporally symmetric and coincidence-preferring integration in A2 neurons made them ideal spectral integrators of concurrent multifrequency sounds. Moreover, the ensemble neural activity in A2 was sensitive to two-tone timings, and coincident two-tones evoked distinct ensemble activity patterns from the linear sum of component tones. Together, these results demonstrate distinct roles of A1 and A2 in encoding complex acoustic features, potentially suggesting parallel rather than sequential information extraction between these regions.
Remapping in a recurrent neural network model of navigation and context inference
Authors: Low Isabel I.C. , Giocomo Lisa M. , Williams Alex H. 
Published: January 2023

AbstractNeurons in navigational brain regions provide information about position, orientation, and speed relative to environmental landmarks. These cells also change their firing patterns (“remap”) in response to changing contextual factors such as environmental cues, task conditions, and behavioral state, which influence neural activity throughout the brain. How can navigational circuits preserve their local computations while responding to global context changes? To investigate this question, we trained recurrent neural network models to track position in simple environments while at the same time reporting transiently-cued context changes. We show that these combined task constraints (navigation and context inference) produce activity patterns that are qualitatively similar to population-wide remapping in the entorhinal cortex, a navigational brain region. Furthermore, the models identify a solution that generalizes to more complex navigation and inference tasks. We thus provide a simple, general, and experimentally-grounded model of remapping as one neural circuit performing both navigation and context inference.
The actin depolymerizing factor StADF2 alters StREM1.3 plasma membrane nanodomains to inhibit thePotato Virus X
Authors: Jolivet Marie-Dominique , Gouguet Paul , Legrand Anthony , Xhelilaj Kaltra , Faiss Natalie , Massoni-Laporte Aurélie , Robbe Terezinha , Sagot Isabelle , Boudsocq Marie , German-Retana Sylvie , Üstün Suayib , Loquet Antoine , Habenstein Birgit , Germain Véronique , Mongrand Sébastien , Gronnier Julien 
Published: January 2023

ABSTRACTThe dynamic regulation of the plasma membrane (PM) organization at the nanoscale emerged as a key element shaping the outcome of host-microbe interactions. Protein organization into nanodomains (ND) is often assumed to be linked to the activation of cellular processes. In contrast, we have previously shown that the phosphorylation of theSolanum tuberosumREM1.3 (StREM1.3) N-terminal domain disperses its native ND organization and promotes its inhibitory effect onPotato Virus X(PVX) cell-to-cell movement. Here, we show that the phosphorylation of StREM1.3 modify the chemical environment of numerous residues in its intrinsically-disordered N-terminal domain. We leveraged exploratory screens to identify potential phosphorylation-dependent interactors of StREM1.3. Herewith, we uncovered uncharacterized regulators of PVX cell-to-cell movement, linking StREM1.3 to autophagy, water channels and the actin cytoskeleton. We show that theSolanum tuberosumactin depolymerizing factors 2 (StADF2) alters StREM1.3 NDs and limits PVX cell-to-cell movement in a REMORIN-dependent manner. Mutating a conserved single residue reported to affect ADFs affinity to actin inhibits StADF2 effect on StREM1.3 ND organization and PVX cell-to-cell movement. These observations provide functional links between the organization of plant PM and the actin cytoskeleton and suggests that the alteration of StREM1.3 ND organization promotes plant anti-viral responses. We envision that analogous PM re-organization applies for additional signaling pathways in plants and in other organisms.
Development of a conceptual framework to guide description and evaluation of social interventions for people with serious mental health conditions
Authors: Appleton Rebecca , Barnett Phoebe , Chipp Beverley , Clark Michael , Goldblatt Peter , Jeffreys Stephen , Machin Karen , Needle Justin J , Shah Prisha , Thompson Georgina , Trevillion Kylee , Webber Martin , Worden Minnie , Johnson Sonia , Lloyd-Evans Brynmor 
Published: January 2023

AbstractPeople with serious mental health conditions face social exclusion and have poorer social outcomes compared to the general population in several areas of life. Social exclusion also negatively impacts mental health. Promising models of support to improve social outcomes for people with serious mental health conditions have been described in the literature and proliferate in practice, but typologies of support are not clearly established and a robust evidence base for effective approaches is lacking in many areas. We conducted a scoping review of relevant literature and consulted with experts in the field to identify models to improve social circumstances across eight life domains, with the aim of developing a conceptual framework to distinguish the main broad approaches to improving the social circumstances of people with serious mental health conditions. We also sought to explore which approaches have been used in models within each life domain, and to detect any preliminary indications of which approaches are most promising, based on evaluations of identified models of support. This work was conducted in collaboration with a group of expert stakeholders, including people with lived experience of accessing mental health services. We developed a conceptual framework which distinguishes sources and types of support, allowing description of complex interventions to improve the social circumstances of people with serious mental health problems, and providing a framework to guide future service development and evaluation.
Rate of tuberculosis screening and isoniazid prophylaxis treatment among human immunodeficiency virus patients in Obio/Akpor Local Government Area: A retrospective study
Authors: Edoja Precious Ruth , Apugo Uchechukwu Ifeanyichukwu , Anekwe Ekenedilichukwu Chukwudubem 
Published: January 2023

AbstractBackgroundThe co-occurrence of Tuberculosis (TB) and Human Immunodeficiency Virus (HIV) has been recognised as a global public health problem with considerable mutual interaction and a leading cause of death worldwide.AimTo determine the rate of TB screening among People Living with HIV (PLWH) and treatment with isoniazid (INH) prophylaxis in directly observed treatment short course (DOTS) clinics in Primary Healthcare centres (PHCs) in Obio/Akpor Local Government Area of Rivers state.Materials and MethodThis clinic-based, two-year retrospective cross-sectional study involved a complete review and abstraction of all records for HIV patients (18 years and above) who have been receiving HIV care and treatment for at least 6 months prior to the study in DOTS clinics in five selected PHCs in OBALGA. The data were extracted using a checklist while the statistical analysis of the study was carried out using SPSS version 23.ResultsThe proportion of HIV-positive patients screened for TB was 79.8% while those who had TB diagnostic evaluation among them was 38.6%, and 38.7% of the HIV/TB co-infected patients were placed on INH prophylaxis.ConclusionInsufficient attention is being paid to TB diagnostic evaluation and IPT. Hence, it is recommended that the PHCs in the LGA should be equipped with appropriate devices for TB diagnosis as well as engage the Healthcare Workers in sensitization workshops on the need for continuous screening of PLWH for TB.
Histone-organized chromatin in bacteria
Authors: Hocher Antoine , Laursen Shawn P. , Radford Paul , Tyson Jess , Lambert Carey , Stevens Kathryn M , Picardeau Mathieu , Sockett R. Elizabeth , Luger Karolin , Warnecke Tobias 
Published: January 2023

ABSTRACTHistones are the principal constituents of chromatin in eukaryotes and most archaea, while bacteria generally rely on an orthogonal set of proteins to organize their chromosomes. However, several bacterial genomes encode proteins with putative histone fold domains. Whether these proteins are structurally and functionally equivalent to archaeal and eukaryotic histones is unknown. Here, we demonstrate that histones are essential and are major components of chromatin in the bacteriaBdellovibrio bacteriovorusandLeptospira interrogans. Patterns of sequence evolution suggest important roles in several additional bacterial clades. Structural analysis of theB. bacteriovorushistone (Bd0055) dimer shows that histone fold topology is conserved between bacteria, archaea, and eukaryotes. Yet, unexpectedly, Bd0055 binds DNA end-on and forms a sheath of tightly packed histone dimers to encase straight DNA. This binding mode is in stark contrast to archaeal, eukaryotic, and viral histones, which invariably bend and wrap DNA around their outer surface. Our results demonstrate that histones are integral chromatin components across the tree of life and highlight organizational innovation in the domain Bacteria.
Insights into polyprotein processing and RNA-protein interactions in foot-and-mouth disease virus genome replication
Authors: Pierce Danielle M. , Rowlands David J. , Stonehouse Nicola J. , Herod Morgan R. 
Published: January 2023

AbstractFoot-and-mouth disease affects cloven hoofed animals and is caused by foot-and-mouth disease virus (FMDV), a picornavirus with a positive-sense RNA genome. The FMDV genome contains a single open reading frame, which is translated to produce a polyprotein that is cleaved by viral proteases to produce the viral structural and non-structural proteins. Initial processing of the polyprotein occurs at three main junctions to generate four primary products; Lproand the P1, P2 and P3 precursors (also termed 1ABCD, 2BC and 3AB1,2,3CD). The 2BC and 3AB1,2,3CD precursors undergo subsequent proteolysis to generate non-structural proteins that are required for viral replication, including the enzymes 2C, 3Cproand 3Dpol. These precursors can be processed through bothcisandtrans(i.e., intra- and inter-molecular proteolysis) pathways, which are thought to be important for controlling virus replication. Our previous studies suggested that a single residue in the 3B3-3C junction had an important role in controlling 3AB1,2,3CD processing. Here, we usein vitrobased assays to show that a single point mutation at the 3B3-3C boundary increases the rate of proteolysis to generate a novel 2C-containing precursor. Complementation assays showed that while this point mutation permitted production of some non-enzymatic non-structural proteins, those with enzymatic functions were inhibited. Interestingly, replication could only be supported by complementation with mutations incisacting RNA elements, providing genetic evidence for a functional interaction between replication enzymes and RNA elements.ImportanceFoot-and-mouth disease virus (FMDV) is an economically important pathogen of animals that is responsible for foot-and-mouth disease (FMD). FMD is endemic in many parts of the world and can results in major economic losses. Replication of the virus is a highly coordinated event that occurs within membrane-associated compartments in infected cells and requires the viral non-structural proteins. These are all initially produced as a polyprotein that undergoes proteolysis likely through bothcisandtranspathways (i.e., intra- and inter-molecular proteolysis). Alternative processing pathways can provide a mechanism to help coordinate viral replication by providing temporal control to protein production. Here, we analyse the consequences of mutations that change temporal control of FMDV polyprotein processing. Our data suggests that correct processing is required to produce key enzymes for replication in an environment in which they can interact with essential viral RNA elements. These data further the understanding of FMDV genome replication.
Assembly properties ofSpiroplasmaMreB involved in swimming motility
Authors: Takahashi Daichi , Miyata Makoto , Fujiwara Ikuko 
Published: January 2023

AbstractBacterial actin MreB forms filaments in which the unit of the structure is an antiparallel double strand. The wall-less helical bacteriumSpiroplasmahas five MreB homologs (MreB1–5), a part of which is composed of an intra-cellular ribbon for driving its swimming motility. The interaction modes of each ribbon component are unclear, although these are clues for understandingSpiroplasmaswimming. Here, we examined the assembly properties ofSpiroplasma eriocheirisMreB5 (SpeMreB5), which forms sheets and is a component protein of the ribbon. Electron microscopy (EM) revealed that sheet formation was inhibited under acidic conditions and paracrystal structures were formed under acidic and neutral conditions with low ionic strength. Solution assays found four properties of paracrystals as follows: (I) their formation followed sheet formation, (II) electrostatic interactions were required for their formation, (III) the positively charged and unstructured C-terminal region contributed to the nucleation of their formation, and (IV) their formation required Mg2+at neutral pH but was inhibited by divalent cations under acidic conditions. During these studies, we found two aggregation modes of SpeMreB5, with distinct responses to ATP. These properties will shed light on SpeMreB5 assembly dynamics at the molecular level.
Host cell cAMP-Epac pathway inhibition by hawthorn extract as a potential treatment for Chagas disease
Authors: Ferri Gabriel , Fernández Lucía R. , Di Mario Guillermo , Palermo Jorge A. , Edreira Martin M. 
Published: January 2023

AbstractBenznidazole (BNZ) and nifurtimox (NFX), drugs used in the treatment of Chagas disease (CD), are effective in acute and congenital cases. However, due to the high toxicity of both drugs, the long duration of the treatment, the high doses, and the low effectiveness during the chronic phase, new therapies are needed. Recently, there has been an increase in alternative medicine and natural products popularity. Medicinal herbs emerge as a promising alternative for the development of new therapies against CD. The development of new active drugs requires the identification of new molecular targets. Host cell cAMP-Epac pathway plays a key role duringTrypanosoma cruziinvasion. We have previously shown that Epac1 is required during the cAMP-mediated invasion of this parasite. Moreover, vitexin, a natural flavone that protects against ischemia-reperfusion damage, acts by inhibiting the expression of Epac and Rap1 proteins. Vitexin can be found in plants of the genusCrataegus spp., traditionally known as hawthorn, that are of great interest considering their highly documented use as cardio-protectors. In this work, using HPLC-HRMS and MS2, we could confirm the presence of vitexin in an extract ofC. oxyacantha(CO-EE). Interenstingly, treating cells with CO-EE, similar results forT. cruziinvasion than the ones observed for Epac1 specific inhibitor ESI-09 were observed. In addition, treated cells have a diminished activated Rap1b, suggesting that the extract could act through the cAMP-Epac signalling pathway. Most significantly, when using CO-EE in conjunction with NFX we observed an addition of the negative effects on the invasion, opening the possibility of decreasing the dosage/time currently used and thus alleviating the secondary side effects of available drugs, as well as theper capitatreatment cost of CD.