bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular mechanisms of tubulogenesis revealed in the sea star hydro-vascular organ
Authors: Perillo Margherita , Swartz S. Zachary , Pieplow Cosmo , Wessel Gary M. 
Published: August 2022

AbstractA fundamental goal in the organogenesis field is to understand how cells organize into tubular shapes. Toward this aim, we have established the hydro-vascular organ in the sea star Patiria miniata as a model for tubulogenesis. In this animal, bilateral tubes grow out from the tip of the developing gut, and precisely extend to specific sites in the larva. This growth requires cell migration coupled with mitosis in distinct zones. Cell proliferation requires FGF signaling, whereas the three-dimensional orientation of the organ depends on Wnt signaling. Specification and maintenance of tube cell fate requires Delta/Notch signaling. Moreover, we identify target genes of the FGF pathway that contribute to tube morphology, revealing molecular mechanisms for tube outgrowth. Finally, we report that FGF activates the Six1/2 transcription factor, which serves as an evolutionarily ancient regulator of branching morphogenesis. This study uncovers novel mechanisms of tubulogenesis in vivo and we propose that cellular dynamics in the sea star hydro-vascular organ represents a key comparison for understanding the evolution of vertebrate organs.Highlights❖ The hydro-vascular organ of the sea star presents a valuable model of tubulogenesis❖ In this organ tube extension is driven by cell migration coupled with cell proliferation at specific growth zones❖ The Wnt pathway controls directional outgrowth❖ The FGF pathway promotes regionalized cell proliferation❖ The Notch/Delta pathway is essential in cell fate repression in tubulogenesis❖ A screen of FGF function revealed essential target gene expression, including the transcription factor Six1/2❖ Within a sister group to chordates, the sea star will reveal ancient mechanisms of tubulogenesis
Modulation of motor vigour by expectation of reward probability trial-by-trial is preserved in healthy ageing and Parkinson’s disease patients
Authors: Tecilla Margherita , Grossbach Michael , Gentile Giovanni , Holland Peter , Antonini Angelo , Ruiz Maria Herrojo 
Published: August 2022

ABSTRACTMotor improvements, such as faster movement times or increased velocity, have been consistently associated with reward magnitude in deterministic contexts. Yet whether individual inferences on reward probability influence motor vigour dynamically remains undetermined. Here we investigated how dynamically inferring volatile action-reward contingencies modulated motor performance trial-by-trial in healthy younger (HYA, 37) and older adults (HOA, 37), and in medicated Parkinson’s Disease patients (PD, 20). We conducted an online study that coupled a standard one-armed bandit decision-making paradigm with a motor sequence task and used a validated hierarchical Bayesian model to fit trial-by-trial data. Our results showed that stronger predictions about the tendency of the action-reward contingency led to faster performance tempo on a trial-by-trial basis without modulating reaction times (RT). Using Bayesian linear mixed models, we demonstrated in HYA, HOA and PD a similar sensitivity (slope) of execution tempo to inferences about the reward probabilities, despite HOA and PD being generally slower than HYA (intercept). In a second experiment in HYA (39), we additionally showed that subjective inferences about credit assignment – whether lack of reward is associated with an incorrect decision or execution error – led to a similar modulation of motor vigour by reward expectation. Our study is the first to reveal that the dynamic updating of beliefs about volatile action-reward contingencies positively biases motor performance through faster execution tempo, without affecting RT. We also provide novel evidence for a preserved sensitivity of motor vigour to inferences about the action-reward mapping in ageing and medicated PD.SIGNIFICANCE STATEMENTNavigating a world rich in uncertainty relies on updating beliefs about the probability that our actions lead to reward. Here we investigated how inferring the action-reward contingencies in a volatile environment modulated motor vigour trial-by-trial in healthy younger and older adults, and in Parkinson’s Disease patients on medication. We found an association between trial- by-trial predictions about the tendency of the action-reward contingency and performance tempo, with stronger expectations speeding performance. We additionally provided evidence for a similar sensitivity of performance tempo to the strength of these predictions in all groups. Thus, dynamic beliefs about the changing relationship between actions and their outcome invigorated motor performance. This positive bias was not compromised by age or Parkinson’s disease.
Inaccurate fossil placement does not compromise tip-dated divergence times
Authors: Koch Nicolas Mongiardino , Garwood Russell J , Parry Luke A 
Published: August 2022

AbstractTime-scaled phylogenies underpin the interrogation of evolutionary processes across deep timescales, as well as attempts to link these to Earth’s history. By inferring the placement of fossils and using their ages as temporal constraints, tip dating under the fossilised-birth death (FBD) process provides a coherent prior on divergence times. At the same time, it also links topological and temporal accuracy, as incorrectly placed fossil terminals should misinform divergence times. This could pose serious issues for obtaining accurate node ages, yet the interaction between topological and temporal error has not been thoroughly explored. We simulate phylogenies and associated morphological datasets using methodologies that incorporate evolution under selection, and are benchmarked against empirical datasets. We find that datasets of moderate sizes (300 characters) and realistic levels of missing data generally succeed in inferring the correct placement of fossils on a constrained extant backbone topology, and that true node ages are usually contained within Bayesian posterior distributions. While increased fossil sampling improves the accuracy of inferred ages, topological and temporal errors do not seem to be linked: analyses in which fossils resolve less accurately do not exhibit elevated errors in node age estimates. At the same time, divergence times are systematically biased, a pattern that stems from a mismatch between the FBD prior and the shape of our simulated trees. While these results are encouraging, suggesting even fossils with uncertain affinities can provide useful temporal information, they also emphasise that paleontological information cannot overturn discrepancies between model priors and the true diversification history.
Beet curly top Iran virus Rep and V2 gene work as suppressors of post-transcriptional gene silencing through separate mechanisms
Authors: Ebrahimi Saeideh , Eini Omid , Baßler Alexandra , Yildirim Zeynep , Wassenegger Michael , Krczal Gabi , Uslu Veli Vural 
Published: August 2022

ABSTRACTBeet curly top Iran Virus (BCTIV) is a yield-limiting geminivirus belonging to the becurtovirus genus. The genome organization of BCTIV is unique such that the complementary strand of BCTIV resembles mastreviruses, whereas the virion strand organization is close to curtoviruses. Geminiviruses are known to avoid the plant defense system by suppressing the RNA interference mechanisms both at the transcriptional gene silencing (TGS) and post-transcriptional gene silencing (PTGS) level. Multiple geminivirus genes have been identified as viral suppressors of RNA silencing (VSR) but VSR activity remains elusive in becurtoviruses. By screening all verified open reading frames in the BCTIV genome, we found that only V2 and Rep were able to suppress specific PTGS mechanisms, triggered by the expression of a partial or full-length sense-strand transcript of the target gene (S-PTGS). BCTIV-V2 could suppress S-PTGS more efficiently than BCTIV-Rep when then the target GFP gene is transiently expressed. On the other hand, S-PTGS is suppressed by Rep but not V2 when target GFP is only stably expressed. Deletional mutagenesis of BCTIV-Rep implicated that multiple domains are required for its VSR activity. Furthermore, neither V2 nor Rep could fully suppress local PTGS induced by inverted repeat targeting GFP (GFP-IR). Also, in a closer look at the spread of local silencing by GFP-IR, we observed that V2 or Rep are not able to suppress the movement of sRNAs. Nevertheless, Rep suppressed the systemic silencing induced by GFP-IR in 16C plants. Northern blot analyses showed that BCTIV-Rep inhibits silencing by mitigating sRNA production, whereas BCTIV-V2 does not alter sRNA levels. In summary, both the silencing phenotype and the molecular signatures of silencing implicate distinct modes of VSR activity of BCTIV-Rep and -V2.
Stimulation of the catalytic activity of the tyrosine kinase Btk by the adaptor protein Grb2
Authors: Nocka Laura M. , Groves Jay T. , Kuriyan John 
Published: August 2022

AbstractThe Tec-family kinase Btk contains a lipid-binding Pleckstrin homology and Tec homology (PH-TH) module connected by a proline-rich linker to a “Src module”, an SH2-SH3-kinase unit also found in Src-family kinases and Abl. We showed previously that Btk is activated by PH-TH dimerization, which is triggered on membranes by the phosphatidyl inositol phosphate PIP3, or in solution by hexakisinositol phosphate (IP6) (Wang et al. 2015, https://doi.org/10.7554/eLife.06074). We now report that the ubiquitous adaptor protein growth-factor-receptor-bound protein 2 (Grb2) binds to and substantially increases the activity of PIP3-bound Btk on membranes. Using reconstitution on supported-lipid bilayers, we find that Grb2 can be recruited to membrane-bound Btk through interaction with the proline-rich linker in Btk. This interaction requires intact Grb2, containing both SH3 domains and the SH2 domain, but does not require that the SH2 domain be able to bind phosphorylated tyrosine residues – thus Grb2 bound to Btk is free to interact with scaffold proteins via the SH2 domain. We show that the Grb2-Btk interaction recruits Btk to scaffold-mediated signaling clusters in reconstituted membranes. Our findings indicate that PIP3-mediated dimerization of Btk does not fully activate Btk, and that Btk adopts an autoinhibited state at the membrane that is released by Grb2.
The Behaviour of F-statistics over Time
Authors: Li Song , Wiuf Carsten 
Published: August 2022

AbstractWe study the behaviour of the F2-statistic and Fst-statistic, respectively, over time in a Wright-Fisher model with mutation and migration. We give precise conditions for when the F2-statistic is non-monotonic, that is, increases over time until a certain point and then starts decreasing. We show that even for small population sizes, the two statistics are well approximated by population size scaled expressions.
Understanding the effects of mesenchymal stromal cell therapy for treating osteoarthritis using an in vitro co-culture model
Authors: Shang Vivian , Li Jiarong , Little Christopher B. , Li Jiao Jiao 
Published: August 2022

AbstractOsteoarthritis (OA) is a leading cause of chronic pain and disability, for which there is no cure. Mesenchymal stromal cells (MSCs) have been used in clinical trials for treating OA due to their unique functions to send paracrine anti-inflammatory and trophic signals. Interestingly, these studies have shown mainly short-term effects of MSCs in improving pain and joint function, rather than sustained and consistent benefits. This may reflect a change or loss in the therapeutic effects of MSCs after intra-articular injection. This study aimed to unravel the reasons behind the variable efficacy of MSC injections for OA using an in vitro co-culture model. Osteoarthritic human synovial fibroblasts (OA-HSFs) exposed to MSCs showed short-term downregulation of pro-inflammatory and pro-catabolic genes, but the MSCs showed upregulation of pro-inflammatory genes and impaired ability to undergo osteogenesis and chondrogenesis in the presence of OA-HSFs. Moreover, short-term exposure of OA-HSFs to MSCs was insufficient for inducing sustained changes to their diseased behaviour. These findings suggest MSCs may not provide long-term effects in correcting the OA joint environment due to adopting the diseased phenotype of the surrounding tissues, which have important implications in the future development of effective stem cell-based OA treatments with long-term therapeutic efficacy.
CXCL12 in late-stage osteoblasts and osteocytes is required for load-induced bone formation in mice
Authors: Cabahug-Zuckerman Pamela , Liu Chao , Atria Pablo , Cai Cinyee , Fang Emily , Qureshi Shahar , Rooklin Rikki , Ponce Cesar , Morocho Camila , Castillo Alesha B. 
Published: August 2022

AbstractIncreased physical loading of the skeleton activates new bone formation ensuring its ability to meet mechanical demands over time; however, the capacity of bone to respond to mechanical stimulation diminishes with age. Osteocytes, the cells embedded and dispersed throughout mineralized bone matrix, are master regulators of mechanoadaptation through recruitment of new bone-forming cells, the osteoblasts, via signaling to osteoprogenitors located on bone surfaces. We previously demonstrated that in vivo and in vitro mechanical stimulation significantly upregulated the chemokine C-X-C Motif Chemokine Ligand 12 (CXCL12) and its receptor, CXCR4, in osteocytes and bone lining cells, and that CXCR4 antagonism with AMD3100 attenuated in vivo load-induced bone formation. Here, we extended this work by showing that ablation of CXCL12+ cells and deletion of cxcl12 in late-stage osteoblasts and osteocytes significantly attenuated in vivo load-induced bone formation in the mouse tibia. This bone loading phenotype was rescued by treatment with recombinant CXCL12. To address mechanism, we showed that in vitro deletion of cxcl12 and cxcr4, separately, in bone marrow stromal cells resulted in significantly reduced osteogenic differentiation. Furthermore, CXCL12 treatment enhanced GSK-3b phosphorylation and β-catenin translocation to the nucleus, the former of which was partially blocked by AMD3100. Finally, CXCL12 synergized Wnt signaling leading to significantly increased total β-catenin protein and Axin2 expression, a Wnt signaling target gene. These findings together demonstrate that CXCL12 expression in late-stage osteoblasts and osteocytes is essential for load-induced bone formation, in part, by regulating osteogenic differentiation through activation of the Wnt signaling pathway.SignificanceSkeletal adaptation to mechanical loading is contingent on the recruitment of new osteoblasts to bone surfaces. CXCL12, a chemokine expressed by osteolineage cells, targets effector cells expressing its receptor CXCR4, including osteoprogenitors. Exogenous mechanical loading of mouse hind limbs upregulates CXCL12 in osteocytes, bone lining cells and marrow cells, while antagonizing CXCR4 led to significantly attenuated load-induced bone formation. Here, we show that CXCL12 expression in late-stage osteoblasts and osteocytes is required for load-induced bone formation. Treatment with recombinant CXCL12 rescued the bone loading phenotype suggesting that the CXCL12/CXCR4 signaling pathway may be a feasible drug target for promoting load-induced bone formation when exercise alone is insufficient to counteract low bone mass and osteoporosis.
Myxococcus xanthus, a nonpathogenic bacterium, eliminates Cryptococcus neoformans, a fungal pathogen of human, independent of cell-cell contact
Authors: Zhang Huan , Pettibon Joshua D. , Patel Raj , Nan Beiyan 
Published: August 2022

AbstractEach year an estimated 1.2 billion people suffer from fungal diseases and 1.5 - 2 million die from fungal infections - surpassing the loss from malaria and tuberculosis1-3. Due to the similarities between fungal and human cells, the lack of fungal-specific targets has become the major hurdle for antifungal discovery. Many fungi, including the deadly human pathogen Cryptococcus neoformans, are found in soil, where they compete with other microorganisms, including bacteria. However, most bacteria that inhibit fungal growth are pathogens and their antifungal effects strictly rely on cell-cell contact. Here we show that Myxococcus xanthus, a nonpathogenic, soil-dwelling bacterium, efficiently eliminates C. neoformans and strongly inhibits the production of fungal virulence factors. Remarkably, these antifungal activities do not require cell-cell contact. Using fluorescence microscopy, we found that M. xanthus increases the permeability of C. neoformans cells. Our results on the cross-kingdom interaction between M. xanthus and C. neoformans will reveal fundamental mechanisms for bacterial-fungal interactions and suggest novel strategies for antifungal therapies.
Using deep learning predictions of inter-residue distances for model validation
Authors: Rodríguez Filomeno Sánchez , Chojnowski Grzegorz , Keegan Ronan M. , Rigden Daniel J. 
Published: August 2022

AbstractDetermination of protein structures typically entails building a model that satisfies the collected experimental observations and its deposition in the Protein Data Bank (PDB). Experimental limitations can lead to unavoidable uncertainties during the process of model building, which result in the introduction of errors into the deposited model. Many metrics are available for model validation, but most are limited to the consideration of the physico-chemical aspects of the model or its match to the map. The latest advances in the field of deep learning have enabled the increasingly accurate prediction of inter-residue distances, an advance which has played a pivotal role in the recent improvements observed in the field of protein ab initio modelling. Here we present new validation methods based on the use of these precise inter-residue distance predictions, which are compared with the distances observed in the protein model. Sequence register errors are particularly clearly detected, and the register shifts required for their correction can be reliably determined. The method is available in the package ConKit (www.conkit.org).
A search for “perio-probiotics” by longitudinal dissection of oral bacterial community shifts during the onset and resolution of gingivitis
Authors: Hall Michael W , Wellappuli Nimali C , Huang Ruo Chen , Wu Kay , Lam David K , Glogauer Michael , Beiko Robert G , Senadheera Dilani B 
Published: August 2022

AimTo understand the spatiotemporal dynamics of bacterial succession during gingivitis, and to identify taxa with a critical role in gum health with prognostic value.Materials and methodsLongitudinal microbiome data were collected from 15 individuals after completely discontinuing all forms of oral hygiene, and subsequently reintroducing it for three and two weeks, respectively. Sequences from the 16S rRNA V4-V5 gene region from sub- and supra-gingival plaque, saliva, and tongue sites were annotated and mapped to a reference tree of Human Oral Microbiome Database sequences.ResultsSuspending oral hygiene induced gingivitis, which was resolved after its resumption to baseline. Most significant shifts in bacterial abundance were observed in dental plaque, but not in saliva and tongue sites. During gingivitis-induction, baseline microbiota dominated by Streptococcus, was superseded by increased Prevotella, Fusobacterium, Leptotrichia, and Porphyromonas genera. Converse to its decline during disease-induction, gum health restoration was accompanied by a significant increase in streptococci.ConclusionWe present the most comprehensive, spatiotemporal map of bacterial succession during gingivitis onset and resolution. We have identified taxa with potential as probiotic candidates for gum disease (i.e., perio-probiotics), and suggest tooth-associated plaque and not saliva or tongue plaque should be used in future prognostic tests.
Plasma Proteome Perturbation for CMV DNAemia in Kidney Transplantation
Authors: Sigdel Tara K. , Boada Patrick , Kerwin Maggie , Rashmi Priyanka , Gjertson David , Rossetti Maura , Sur Swastika , Munar Dane , Cimino James , Ahn Richard , Pickering Harry , Sen Subha , Parmar Rajesh , Fatou Benoit , Steen Hanno , Schaenman Joanna , Bunnapradist Suphamai , Reed Elaine F. , Sarwal Minnie M. ,   CMV Systems Immunobiology Group
Published: August 2022

AbstractBackgroundCytomegalovirus (CMV) infection, either de novo or as reactivation after allotransplantation and chronic immunosuppression, is recognized to cause detrimental alloimmune effects, inclusive of higher susceptibility to graft rejection and substantive impact on chronic graft injury and reduced transplant survival. To obtain further insights into the evolution and pathogenesis of CMV infection in an immunocompromised host we evaluated changes in the circulating host proteome serially, before and after transplantation, and during and after CMV DNA replication (DNAemia), as measured by quantitative polymerase chain reaction (QPCR).MethodsLC-MS-based proteomics was conducted on 168 serially banked plasma samples, from 62 propensity score-matched kidney transplant recipients. Patients were stratified by CMV replication status into 31 with CMV DNAemia and 31 without CMV DNAemia. Patients had blood samples drawn at protocol times of 3- and 12-months post-transplant. Additionally, blood samples were also drawn before and 1 week and 1 month after detection of CMV DNAemia. Plasma proteins were analyzed using an LCMS 8060 triple quadrupole mass spectrometer. Further, public transcriptomic data on time matched PBMCs samples from the same patients was utilized to evaluate integrative pathways. Data analysis was conducted using R and Limma.ResultsSamples were segregated based on their proteomic profiles with respect to their CMV Dnaemia status. A subset of 17 plasma proteins was observed to predict the onset of CMV at 3 months post-transplant enriching platelet degranulation (FDR, 4.83E-06), acute inflammatory response (FDR, 0.0018), blood coagulation (FDR, 0.0018) pathways. An increase in many immune complex proteins were observed at CMV infection. Prior to DNAemia the plasma proteome showed changes in the anti-inflammatory adipokine vaspin (SERPINA12), copper binding protein ceruloplasmin (CP), complement activation (FDR=0.03), and proteins enriched in the humoral (FDR=0.01) and innate immune responses (FDR=0.01).ConclusionPlasma proteomic and transcriptional perturbations impacting humoral and innate immune pathways are observed during CMV infection and provide biomarkers for CMV disease prediction and resolution. Further studies to understand the clinical impact of these pathways can help in the formulation of different types and duration of anti-viral therapies for management of CMV infection in the immunocompromised host.