bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and safety of biologic, biosimilars and targeted synthetic DMARDs in moderate-to-severe rheumatoid arthritis with inadequate response to methotrexate: a systematic review and network meta-analysis
Authors: Budtarad Nuttakarn , Prawjaeng Juthamas , Leelahavarong Pattara , Pilasant Songyot , Chanjam Chonticha , Narongroeknawin Pongthorn , Kitumnuaypong Tasanee , Katchamart Wanruchada 
Published: January 2023

AbstractObjectiveTo assess the comparative efficacy and safety of approved biologic disease-modifying antirheumatic drugs (bDMARDs), biosimilars, and targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) for patients with rheumatoid arthritis (RA) who had inadequate responses to methotrexate (MTX).Results53 eligible studies were identified and 44 studies were included in a network meta-analysis. Using Surface Under the Cumulative Ranking Curve (SUCRA), tofacitinib (10 mg bid) with MTX [Relative risk (RR) 95% confidence interval (CI) 4.65 (2.98-7.27)] and tofacitinib (10 mg bid) [RR (95%CI)1.96 (1.27-3.03)] were ranked highest among tsDMARDs for increasing remission rate at 24-26 weeks and 48-52 weeks, respectively. For bDMARDs, tocilizumab (8 mg/kg) with MTX was ranked with highest treatment effect for remission at both 24-26 and 48-52 weeks [RR (95%CI) 3.06 (2.27-4.12); RR (95%CI) 2.52 (1.94-3.28)]. For safety, baricitinib (4 mg) and tofacitinib (5 mg bid) with MTX likely showed an increased risk of HZ with statistical significance [for baricitinib, RR (95%CI) 3.52 (1.38-9.02) at 24-26 weeks, and RR (95%CI) 4.20 (1.22-14.48) at 48-52 weeks, and for tofacitinib, RR (95%CI) 5.38 (1.00-28.91) at 48-52 weeks]. No statistically significant safety concerns for serious infection, tuberculosis (TB), cancer, and cardiovascular (CV) events were identified.ConclusionsFor RA patients who failed MTX, bDMARDs, biosimilars, and tsDMARDs monotherapy and combination therapy with MTX provided better treatment outcomes than MTX monotherapy with modest safety concerns within 24-52 weeks. A scarcity of longer-term effects and post-market surveillance necessitates further analyses using long-term patient-level data to improve the medication profile.Rheumatology key messagesFor RA patients who failed MTX and other conventional DMARDs, different types of DMARDs are available.At dose- and time point-specific levels, tofacitinib (10 mg bd) showed the highest probability to be the most effective in achieving remission at 24-26 weeks.An increased risk of herpes zoster was found for baricitinib (4 mg) and tofacitinib (5 mg bid) with MTX.
Chiral Graphene Quantum Dots Enhanced Drug Loading into Exosomes
Authors: Zhang Youwen , Zhu Yini , Kim Gaeun , Wang Ceming , Zhu Runyao , Lu Xin , Chang Hsueh-Chia , Wang Yichun 
Published: January 2023

ABSTRACTAs nanoscale extracellular vesicles secreted by cells, exosomes have enormous potential as safe and effective vehicles to deliver drugs into lesion locations. Despite promising advances with exosome-based drug delivery systems, there are still challenges to drug loading into exosome, which hinder the clinical applications of exosomes. Herein, we report an exogenous drug-agnostic chiral graphene quantum dots (GQDs) exosome-loading platform, based on chirality matching with the exosome lipid bilayer. Both hydrophobic and hydrophilic chemical and biological drugs can be functionalized or adsorbed onto GQDs by π–π stacking and van der Waals interactions. By tuning the ligands and GQD size to optimize its chirality, we demonstrate drug loading efficiency of 66.3% and 64.1% for Doxorubicin and siRNA, which is significantly higher than other reported exosome loading techniques.
Ralstonia solanacearumpandemic lineage strain UW551 overcomes inhibitory xylem chemistry to break tomato bacterial wilt resistance
Authors: Hamilton Corri D. , Zaricor Beatriz , Dye Carolyn Jean , Dresserl Emma , Michaels Renee , Allen Caitilyn 
Published: January 2023

AbstractPlant pathogenicRalstoniastrains cause bacterial wilt disease by colonizing xylem vessels of many crops, including tomato. Host resistance is the best control for bacterial wilt, but resistance mechanisms of the widely used Hawaii7996 tomato breeding line are unknown. Using growth inex vivoxylem sap as a proxy for host xylem, we found thatRalstoniastrain GMI1000 grows in sap from both healthy plants andRalstonia-infected susceptible plants. However, sap fromRalstonia-infected Hawaii7996 plants inhibitedRalstoniagrowth, suggesting that in response toRalstoniainfection, resistant plants increase inhibitors in their xylem sap. Consistent with this, reciprocal grafting and defense gene expression experiments indicated that Hawaii7996 wilt resistance acts both above- and belowground. Concerningly, Hawaii7996 resistance is broken byRalstoniastrain UW551 of the pandemic lineage that threatens highland tropical agriculture. Unlike otherRalstoniastrains, UW551 grew well in sap fromRalstonia-infected Hawaii7996 plants. Moreover, otherRalstoniastrains could grow in sap from Hawaii7996 plants previously infected by UW551. Thus, UW551 overcomes Hawaii7996 resistance in part by detoxifying inhibitors in xylem sap. Testing a panel of xylem sap compounds identified by metabolomics revealed that no single chemical differentially inhibitsRalstoniastrains that cannot infect Hawaii7996. However, sap fromRalstonia-infected Hawaii7996 contained more phenolic compounds, which are known plant antimicrobial defenses. Culturing UW551 in this sap reduced total phenolic levels, indicating that the resistance-breakingRalstoniastrain degrades these chemical defenses. Together, these results suggest that Hawaii7996 tomato wilt resistance depends at least in part on inducible phenolic compounds in xylem sap.
Developmental changes in individual alpha frequency: Recording EEG data during public engagement events
Authors: Turner Christopher , Baylan Satu , Bracco Martina , Cruz Gabriela , Hanzal Simon , Keime Marine , Kuye Isaac , McNeill Deborah , Ng Zika , van der Plas Mircea , Ruzzoli Manuela , Thut Gregor , Trajkovic Jelena , Veniero Domenica , Wale Sarah P , Whear Sarah , Learmonth Gemma 
Published: January 2023

AbstractStatistical power in cognitive neuroimaging experiments is often very low. Low sample size can reduce the likelihood of detecting real effects (false negatives) and increase the risk of detecting non-existing effects by chance (false positives). Here we document our experience of leveraging a relatively unexplored method of collecting a large sample size for simple electroencephalography (EEG) studies: by recording EEG in the community during public engagement and outreach events. We collected data from 346 participants (189 females, age range 6-76 years) over 6 days, totalling 29 hours, at local science festivals. Alpha activity (6-15 Hz) was filtered from 30 seconds of signal, recorded from a single electrode placed between the occipital midline (Oz) and inion (Iz) while participants rested with their eyes closed. A total of 289 good quality datasets were obtained. Using this community-based approach, we were able to replicate controlled, lab-based findings: IAF increased during childhood, reaching a peak frequency of 10.28 Hz at 28.1 years old, and slowed again in middle and older age. Total alpha power decreased linearly, but the aperiodic-adjusted alpha power did not change over the lifespan. Aperiodic slopes and intercepts were highest in the youngest participants. There were no associations between these EEG indexes and self-reported fatigue, measured by the Multidimensional Fatigue Inventory. Finally, we present a set of important considerations for researchers who wish to collect EEG data within public engagement and outreach environments.
poolHelper: an R package to help in designing Pool-Seq studies
Authors: Carvalho João , Faria Rui , Butlin Roger K. , Sousa Vítor C. 
Published: January 2023

AbstractNext-generation sequencing of pooled samples (Pool-seq) is an important tool in population genomics and molecular ecology. In Pool-seq, the relative number of reads with an allele reflects the allele frequencies in the sample. However, unequal individual contributions to the pool and sequencing errors can lead to inaccurate allele frequency estimates. When designing Pool-seq studies, researchers need to decide the pool size (number of individuals) and average depth of coverage (sequencing effort). An efficient sampling design should maximize the accuracy of allele frequency estimates while minimizing the sequencing effort. We introduce an R package,poolHelper, enabling users to simulate Pool-seq data under different combinations of average depth of coverage, pool sizes and number of pools, accounting for unequal individual contribution and sequencing errors, modelled by parameters that users can modify.poolHelpercan be used to assess how different combinations of those parameters influence the error of sample allele frequencies and expected heterozygosity. The mean absolute error is computed by comparing the sample allele frequencies obtained based on individual genotypes with the frequency estimates obtained with Pool-seq. Using simulations under a single population model, we illustrate that increasing the depth of coverage does not necessarily lead to more accurate estimates, reinforcing that finding the best Pool-seq study design is not straightforward. Moreover, we show that simulations can be used to identify different combinations of parameters with similarly low mean absolute errors. ThepoolHelperpackage provides tools for performing simulations with different combinations of parameters before sampling and generating data, allowing users to define sampling schemes that minimize the sequencing effort.
Using RNASeq to investigate the involvement of theOphiocordycepsclock in ant host infection and behavioral manipulation
Authors: Das Biplabendu , Will Ian , Brouns Roos , Brachmann Andreas , de Bekker Charissa 
Published: January 2023

ABSTRACTIntroductionParasites can modify host behavior to ensure their own growth and transmission. Multiple species of the fungiOphiocordycepsinfect ants, but in a species-specific manner; one fungal species co-evolved to successfully modify the behavior of one ant species. However, several characteristics of the behavioral modification seem to be similar across differentOphiocordyceps-ant systems, including a preference for the time of the day for manipulating host behavior. In this study, we explored the various mechanisms via which the circadian clock ofOphiocordycepsmight be playing a role in modifying host behavior. We studiedO. camponoti-floridanithat modifies the behavior of its ant hostCamponotus floridanus. To separate the role of the clock in behavior manipulation, from its role in growth and survival, we compared the daily gene expression profile ofO. camponoti-floridanito a generalist, non-manipulating fungal parasite,Beauveria bassiana, which also successfully infects the same ant host.ResultsMajority of the 24h rhythmicO. camponoti-floridanigenes show peak expression before or at the transitions between light and dark. Rhythmic genes inO. camponoti-floridani, for whichB. bassianalacks an ortholog, were overrepresented for enterotoxin genes. Around half of all genes that show 24h rhythms in eitherO. camponoti-floridaniorB. bassianashowed a consistent difference in their temporal pattern of daily expression. At the halfway mark inO. camponoti-floridaniinfections, when diseased ants show a loss of 24h rhythms in daily foraging, several fungal clock genes, includingFrequency, showed differential expression. Network analyses revealed a single gene cluster, containingWhite Collar 1and2, that showed overrepresentation for genes oscillating every 24h in liquid culture as well as genes differentially expressed while growing inside the ant head.ConclusionThis study identifies several sets of putatively clock-controlled genes and biological processes inO. camponoti-floridanithat likely plays a role in modifying the behavior of its ant host. Differential expression ofO. camponoti-floridaniclock genes or 24h-rhythmic genes during infection is suggestive of either a loss of daily rhythm or a change in the amplitude of rhythmic gene expression. Both possibilities would suggest that a disease-associated change occurs to the functioning of theO. camponoti-floridaniclock, and its output, while the fungi grows inside the ant head.
Functional characterization ofSalmonellaTyphimurium encoded YciF, a domain of unknown function (DUF892) family protein, and its role in protection during bile and oxidative stress
Authors: Singh Madhulika , Penmatsa Aravind , Nandi Dipankar 
Published: January 2023

AbstractYciF (STM14_2092) is a member of domain of unknown function (DUF892) family. It is an uncharacterized protein, involved in stress responses inSalmonellaTyphimurium. In this study, we investigated the significance of YciF and its DUF892 domain during bile and oxidative stress responses ofS. Typhimurium. Purified wild type YciF forms higher order oligomers, binds to iron and displays ferroxidase activity. Studies on the site-specific mutants revealed that the ferroxidase activity of YciF is dependent on the two metal binding sites present within the DUF892 domain. Transcriptional analysis displayed that the ΔcspE strain, which has compromised expression of YciF, encounters iron toxicity due to dysregulation of iron homeostasis in presence of bile. Utilizing this observation, we demonstrate that the bile mediated iron toxicity in ΔcspE causes lethality, primarily through the generation of reactive oxygen species (ROS). Expression of wild type YciF, but not the three mutants of the DUF892 domain, in ΔcspE alleviate ROS in presence of bile. Our results establish the role of YciF as a ferroxidase that can sequester excess iron in the cellular milieu to counter ROS-associated cell death. In fact, pre-treatment with an iron chelator mitigates the hypersensitivity of ΔcspE to bile.ImportanceThe DUF892 domain has a wide taxonomic distribution encompassing several bacterial pathogens. This domain belongs to the ferritin-like superfamily; however, it has not been biochemically and functionally characterized. This is the first report of characterization of a member of this family. In this study, we demonstrate thatS. Typhimurium YciF is an iron binding protein with ferroxidase activity, which is dependent on the metal binding sites present within the DUF892 domain. It combats iron toxicity and oxidative damage caused due to exposure to bile. The functional characterization of YciF delineates the significance of the DUF892 domain in bacteria. In addition, our studies onS. Typhimurium bile stress response divulged the importance of comprehensive iron homeostasis in bacteria in presence of bactericidal compounds that tend to generate ROS irrespective of their primary targets.
Rectus FemorisMuscle Elasticity and Stiffness Correlates with Maximal Oxygen Consumption in Triathletes
Authors: Gavronski Georg , Reimets Ain , Talts Jaak , Koovit Indrek , Mandel Tõnis , Viir Ragnar , Vasar Eero , Veraksitš Alar 
Published: January 2023

AbstractVO2max is considered single best indicator of cardiovascular fitness and aerobic endurance. We analyzed retrospectively, are there any relationships between muscle parameters and oxygen consumption in a study where the myoton equipment was used to establish muscle biomechanical properties, such as elasticity, stiffness, and tension (measured as oscillation frequency) in triathletes. Eight muscles were studied in 14 male triathletes over three years. Relaxed and contracted states of muscles were measured. VO2max was recorded in these athletes up to four times during this period. Average values were calculated for each athlete and High (max 71.8–min 62.3 ml/kg/min) and Low (59.1–51.3) oxygen consumption groups were formed. Higher oxygen consumption correlated significantly (r=−0.58; p=0.029) with improved elasticity (represented by smaller decrement values) of therectus femorismuscle in a contracted state. Also, in the High VO2max group, this muscle (in a relaxed state) was significantly more elastic and stiffer at the same time compared to the Low group. An ultrasound registration was also conducted to observe the depth of the device’s impact in the posterior crural muscles. It was confirmed that deep and substantial tissue disturbances were caused by this impact. According to our findings, myotonometry is an adequate method to establish muscle parameters. Elasticity and stiffness of therectus femorismuscle may determine success in triathlon.
Spatial determination and prognostic impact of the fibroblast transcriptome in pancreatic ductal adenocarcinoma
Authors: Croft Wayne , Pearce Hayden , Margielewska-Davies Sandra , Lim Lindsay , Nicol Samantha M. , Zayou Fouzia , Blakeway Daniel , Marcon Francesca , Powell-Brett Sarah , Mahon Brinder , Merard Reena , Zuo Jianmin , Middleton Gary , Roberts Keith , Brown Rachel M. , Moss Paul 
Published: January 2023

AbstractPancreatic ductal adenocarcinoma has a poor clinical outcome and responses to immunotherapy are suboptimal. Stromal fibroblasts are a dominant but heterogenous population within the tumor microenvironment and therapeutic targeting of stromal subsets may have therapeutic utility. Here we combined spatial transcriptomics and scRNA-Seq to define the transcriptome of tumor-proximal and tumor-distal cancer-associated fibroblasts (CAFs) and linked this to clinical outcome. Tumor-proximal fibroblasts comprised large populations of myofibroblasts, strongly expressed podoplanin, and were enriched for Wnt ligand signaling. In contrast, inflammatory CAFs were dominant within tumor-distal subsets and expressed complement components and the Wnt-inhibitor SFRP2. Poor clinical outcome was correlated with elevated HIF-1α and podoplanin whilst high level expression of inflammatory and complement genes was predictive of extended survival. These findings demonstrate the extreme transcriptional heterogeneity of CAFs and its determination by apposition to tumor. Selective targeting of tumor-proximal subsets, potentially combined with HIF-1α inhibition and immune stimulation, may offer a multimodal therapeutic approach for this disease.Graphical Abstract
LACK OF INTERACTIONS BETWEEN PRENATAL IMMUNE ACTIVATION AND Δ9-TETRAHYDROCANNABINOL EXPOSURE DURING ADOLESCENCE IN BEHAVIOURS RELEVANT TO SYMPTOM DIMENSIONS OF SCHIZOPHRENIA IN RATS
Authors: Moreno-Fernández Mario , Ucha Marcos , Reis-de-Paiva Raquel , Marcos Alberto , Ambrosio Emilio , Higuera-Matas Alejandro 
Published: January 2023

ABSTRACTThe causality in the association between cannabis use and the risk of developing schizophrenia has been the subject of intense debate in the last years. The development of animal models recapitulating several aspects of the disease is crucial for shedding light on this issue. Maternal infections are a known risk for schizophrenia. Here, we used the maternal immune activation (MIA) model combined with THC exposure during adolescence to examine several behaviours in rats (working memory in the Y maze, sociability in the three-chamber test, sucrose preference as a measure, prepulse inhibition and formation of incidental associations) that are similar to the different symptom clusters of the disease. To this end, we administered LPS to pregnant dams and when the offspring reached adolescence, we exposed them to a mild dose of THC to examine their behaviour in adulthood. We also studied several parameters in the dams, including locomotor activity in the open field, elevated plus maze performance and their response to LPS, that could predict symptom severity of the offspring, but found no evidence of any predictive value of these variables. In the adult offspring, MIA was associated with impaired working memory and sensorimotor gating, but surprisingly, it increased sociability, social novelty and sucrose preference. THC, on its own, impaired sociability and social memory, but there were no interactions between MIA and THC exposure. These results suggest that, in this model, THC during adolescence does not trigger or aggravate symptoms related to schizophrenia in rats.
Computational Analysis of Maize Enhancer Regulatory Elements Using ATAC-STARR-seq
Authors: Marand Alexandre P. 
Published: January 2023

AbstractThe blueprints to development, response to the environment, and cellular function are largely the manifestation of distinct gene expression programs controlled by the spatiotemporal activity ofcis-regulatory elements. Although biochemical methods for identifying accessible chromatin – a hallmark of activecis-regulatory elements – have been developed, approaches capable of measuring and quantifyingcis-regulatory activity are only beginning to be realized. Massively Parallel Reporter Assays coupled to chromatin accessibility profiling present a high-throughput solution for testing the transcription-activating capacity of millions of putatively regulatory DNA sequences in parallel.However, clear computational pipelines for analyzing these high-throughput sequencing-based reporter assays are lacking. In this protocol, I layout and rationalize a computational framework for the processing and analysis of Assay for Transposase Accessible Chromatin profiling followed by Self-Transcribed Active Regulatory Region sequencing (ATAC-STARR-seq) data from a recent study inZea mays. The approach described herein can be adapted to other sequencing-based reporter assays and is largely agnostic to the model organism with the appropriate input substitutions.
YAP and TAZ couple osteoblast precursor mobilization to angiogenesis and mechanoregulated bone development
Authors: Collins Joseph M. , Lang Annemarie , Parisi Cristian , Moharrer Yasaman , Nijsure Madhura P. , Kim Jong Hyun (Thomas) , Szeto Greg L. , Qin Ling , Gottardi Riccardo L. , Dyment Nathanial A. , Nowlan Niamh C. , Boerckel Joel D. 
Published: January 2023

AbstractEndochondral ossification requires coordinated mobilization of osteoblast precursors with blood vessels. During adult bone homeostasis, vessel adjacent osteoblast precursors respond to and are maintained by mechanical stimuli; however, the mechanisms by which these cells mobilize and respond to mechanical cues during embryonic development are unknown. Previously, we found that deletion of the mechanoresponsive transcriptional regulators, YAP and TAZ, from Osterix-expressing osteoblast precursors and their progeny caused perinatal lethality. Here, we show that embryonic YAP/TAZ signaling couples vessel-associated osteoblast precursor mobilization to angiogenesis in developing long bones. Osterix-conditional YAP/TAZ deletion impaired endochondral ossification in the primary ossification center but not intramembranous osteogenesis in the bone collar. Single-cell RNA sequencing revealed YAP/TAZ regulation of the angiogenic chemokine, Cxcl12, which was expressed uniquely in vessel-associated osteoblast precursors. YAP/TAZ signaling spatially coupled osteoblast precursors to blood vessels and regulated vascular morphogenesis and vessel barrier function. Further, YAP/TAZ signaling regulated vascular loop morphogenesis at the chondro-osseous junction to control hypertrophic growth plate remodeling. In human cells, mesenchymal stromal cell co-culture promoted 3D vascular network formation, which was impaired by stromal cell YAP/TAZ depletion, but rescued by recombinant CXCL12 treatment. Lastly, YAP and TAZ mediated mechanotransduction for load-induced osteogenesis in embryonic bone.