bluuebunny/crossref_metadata_2025_split huggingface dataset:
Red-flag signs and symptoms for earlier diagnosis of early-onset colorectal cancer
Authors: Fritz Cassandra D L , Otegbeye Ebunoluwa E , Zong Xiaoyu , Demb Joshua , Nickel Katelin B , Olsen Margaret A , Mutch Matthew , Davidson Nicholas O , Gupta Samir , Cao Yin 
Published: May 2023

Abstract

Background
Prompt detection of colorectal cancer (CRC) among individuals younger than age 50 years (early-onset CRC) is a clinical priority because of its alarming rise.

Methods
We conducted a matched case-control study of 5075 incident early-onset CRC among US commercial insurance beneficiaries (113 million adults aged 18-64 years) with 2 or more years of continuous enrollment (2006-2015) to identify red-flag signs and symptoms between 3 months to 2 years before the index date among 17 prespecified signs and symptoms. We assessed diagnostic intervals according to the presence of these signs and symptoms before and within 3 months of diagnosis.

Results
Between 3 months and 2 years before the index date, 4 red-flag signs and symptoms (abdominal pain, rectal bleeding, diarrhea, and iron deficiency anemia) were associated with an increased risk of early-onset CRC, with odds ratios (ORs) ranging from 1.34 to 5.13. Having 1, 2, or at least 3 of these signs and symptoms were associated with a 1.94-fold (95% confidence interval [CI] = 1.76 to 2.14), 3.59-fold (95% CI = 2.89 to 4.44), and 6.52-fold (95% CI = 3.78 to 11.23) risk (Ptrend &lt; .001), respectively, with stronger associations for younger ages (Pinteraction &lt; .001) and rectal cancer (Pheterogenity = .012). The number of different signs and symptoms was predictive of early-onset CRC beginning 18 months before diagnosis. Approximately 19.3% of patients had their first sign or symptom occur between 3 months and 2 years before diagnosis (median diagnostic interval = 8.7 months), and approximately 49.3% had the first sign or symptom within 3 months of diagnosis (median diagnostic interval = 0.53 month).

Conclusions
Early recognition of red-flag signs and symptoms (abdominal pain, rectal bleeding, diarrhea, and iron-deficiency anemia) may improve early detection and timely diagnosis of early-onset CRC.
Local phytochrome signalling limits root growth in light by repressing auxin biosynthesis
Authors: Spaninks Kiki , Offringa Remko 
Published: May 2023

Abstract
In nature, plant shoots are exposed to light whereas the roots grow in relative darkness. Surprisingly, many root studies rely on in vitro systems that leave the roots exposed to light whilst ignoring the possible effects of this light on root development. Here, we investigated how direct root illumination affects root growth and development in Arabidopsis and tomato. Our results show that in light-grown Arabidopsis roots, activation of local phytochrome A and B by far-red or red light inhibits respectively PHYTOCHROME INTERACTING FACTORS 1 or 4, resulting in decreased YUCCA4 and YUCCA6 expression. As a result, auxin levels in the root apex become suboptimal, ultimately resulting in reduced growth of light-grown roots. These findings highlight once more the importance of using in vitro systems where roots are grown in darkness for studies that focus on root system architecture. Moreover, we show that the response and components of this mechanism are conserved in tomato roots, thus indicating its importance for horticulture as well. Our findings open up new research possibilities to investigate the importance of light-induced root growth inhibition for plant development, possibly by exploring putative correlations with responses to other abiotic signals, such as temperature, gravity, touch, or salt stress.
Redefining Possible: Combining Phylogenomic and Supersparse Data in Frogs
Authors: Portik Daniel M , Streicher Jeffrey W , Blackburn David C , Moen Daniel S , Hutter Carl R , Wiens John J 
Published: May 2023

Abstract
The data available for reconstructing molecular phylogenies have become wildly disparate. Phylogenomic studies can generate data for thousands of genetic markers for dozens of species, but for hundreds of other taxa, data may be available from only a few genes. Can these two types of data be integrated to combine the advantages of both, addressing the relationships of hundreds of species with thousands of genes? Here, we show that this is possible, using data from frogs. We generated a phylogenomic data set for 138 ingroup species and 3,784 nuclear markers (ultraconserved elements [UCEs]), including new UCE data from 70 species. We also assembled a supermatrix data set, including data from 97% of frog genera (441 total), with 1–307 genes per taxon. We then produced a combined phylogenomic–supermatrix data set (a “gigamatrix”) containing 441 ingroup taxa and 4,091 markers but with 86% missing data overall. Likelihood analysis of the gigamatrix yielded a generally well-supported tree among families, largely consistent with trees from the phylogenomic data alone. All terminal taxa were placed in the expected families, even though 42.5% of these taxa each had &gt;99.5% missing data and 70.2% had &gt;90% missing data. Our results show that missing data need not be an impediment to successfully combining very large phylogenomic and supermatrix data sets, and they open the door to new studies that simultaneously maximize sampling of genes and taxa.
Kinetic principles of ParA2-ATP cycling guide dynamic subcellular localizations inVibrio cholerae
Authors: Chodha Satpal S , Brooks Adam C , Davis Peter J , Ramachandran Revathy , Chattoraj Dhruba K , Hwang Ling Chin 
Published: May 2023

AbstractDynamic protein gradients are exploited for the spatial organization and segregation of replicated chromosomes. However, mechanisms of protein gradient formation and how that spatially organizes chromosomes remain poorly understood. Here, we have determined the kinetic principles of subcellular localizations of ParA2 ATPase, an essential spatial regulator of chromosome 2 segregation in the multichromosome bacterium, Vibrio cholerae. We found that ParA2 gradients self-organize in V. cholerae cells into dynamic pole-to-pole oscillations. We examined the ParA2 ATPase cycle and ParA2 interactions with ParB2 and DNA. In vitro, ParA2-ATP dimers undergo a rate-limiting conformational switch, catalysed by DNA to achieve DNA-binding competence. This active ParA2 state loads onto DNA cooperatively as higher order oligomers. Our results indicate that the midcell localization of ParB2-parS2 complexes stimulate ATP hydrolysis and ParA2 release from the nucleoid, generating an asymmetric ParA2 gradient with maximal concentration toward the poles. This rapid dissociation coupled with slow nucleotide exchange and conformational switch provides for a temporal lag that allows the redistribution of ParA2 to the opposite pole for nucleoid reattachment. Based on our data, we propose a ‘Tug-of-war’ model that uses dynamic oscillations of ParA2 to spatially regulate symmetric segregation and positioning of bacterial chromosomes.
Faster, broader, and deeper! Suggested directions for research on net-zero transitions
Authors: Andersen Allan Dahl , Geels Frank W , Coenen Lars , Hanson Jens , Korsnes Marius , Linnerud Kristin , Makitie Tuukka , Nordholm Amber , Ryghaug Marianne , Skjolsvold Tomas , Steen Markus , Wiebe Kirsten 
Published: May 2023

Abstract
The growing attention to the political goal of achieving net-zero emissions by mid-century reflects past failures to alter the trajectory of increasing greenhouse gas (GHG) emissions. As a consequence, the world now needs to decarbonize all systems and sectors at an unprecedented pace. This commentary discusses how the net-zero challenge presents transition scholarship with four enhanced research challenges that merit more attention: (1) the speed, (2) breadth and (3) depth of transitions as well as (4) tensions and interactions between these.
Petrology and Tectonic Significance of Epidote Blueschist-Facies Rocks from the Northern Margin of the Pelagonian Unit in the Republic of North Macedonia
Authors: Altherr Rainer , Hanel Michael , Soder Christian G , Peters Daniel , Bahl Chiara 
Published: May 2023

Abstract
In the Republic of North Macedonia, the northern marginal part of the Pelagonian Unit comprises several isolated slivers of low-grade blueschist-facies rocks. These rocks were metamorphosed at conditions of the epidote-blueschist facies with rare transitions to the lawsonite-epidote blueschist facies. If present, lawsonite occurs as relic inclusions in albite, suggesting a local metasomatic enrichment of Na. No aragonite or fibrous calcite was detected, suggesting that the rocks were equilibrated at pressures below the aragonite-calcite boundary. When present, calcite + quartz coexist with glaucophane, epidote, and titanite suggesting the presence of a metamorphic H2O-rich fluid phase with very low XCO2 values (&lt; 0.002). Most samples contain chlorite and only some have garnet, which is nearly free of Mg, but contains an andradite component. Albite only occurs in garnet-free rocks. A core-to-rim decrease of Fe3+/(Fe3++Al3++Cr + Mn3+) in epidote, VIFe3+/VI(Fe3++Al) in blue Na-rich amphibole, and Fe3+/(Fe2++Fe3+) in garnet grains suggest a decrease of ƒO2 during metamorphism. The general absence of magnetite and the presence of very small amounts of hematite in some samples suggest that the hematite–magnetite buffer curve was probably not crossed. It is thought that the investigated blueschist-facies rocks were part of the once highly oxidized sedimentary cover of the subducting oceanic plate. The underlying basaltic crust and oceanic mantle, however, were probably relatively reduced. Aqueous fluids which left this part of the lithosphere during subduction (dehydration) partially reduced the overlying oxidized metasediments. Concerning metamorphic P–T conditions, a pressure range of 0.7–0.9 GPa is defined by the presence of glaucophane + epidote + quartz at the lower boundary and the absence of aragonite at the higher boundary. The temperature range of 320–420°C is defined by the absence of Fe-Mg-pumpellyite at the lower side and the presence of lawsonite + albite at the higher side. These conditions can be narrowed down by using calculated equilibrium mineral assemblage diagrams (pseudosections) for three different bulk-rock compositions, resulting in P = 0.74–0.85 GPa and T = 340–370°C. It must, however, be emphasized that many phases (garnet, glaucophane, epidote, and phengite) show significant chemical zonation, which makes the use of pseudosections problematic.
Suppression of the Arabidopsis cinnamoyl-CoA reductase 1-6 intronic T-DNA mutation by epigenetic modification
Authors: Wouters Marlies , Bastiaanse Héloïse , Rombauts Stephane , de Vries Lisanne , De Pooter Tim , Strazisar Mojca , Neutelings Godfrey , Vanholme Ruben , Boerjan Wout 
Published: May 2023

Abstract
Arabidopsis (Arabidopsis thaliana) transfer DNA (T-DNA) insertion collections are popular resources for fundamental plant research. Cinnamoyl-CoA reductase 1 (CCR1) catalyzes an essential step in the biosynthesis of the cell wall polymer lignin. Accordingly, the intronic T-DNA insertion mutant ccr1-6 has reduced lignin levels and shows a stunted growth phenotype. Here, we report restoration of the ccr1-6 mutant phenotype and CCR1 expression levels after a genetic cross with a UDP-glucosyltransferase 72e1 (ugt72e1),-e2,-e3 T-DNA mutant. We discovered that the phenotypic recovery was not dependent on the UGT72E family loss of function but due to an epigenetic phenomenon called trans T-DNA suppression. Via trans T-DNA suppression, the gene function of an intronic T-DNA mutant was restored after the introduction of an additional T-DNA sharing identical sequences, leading to heterochromatinization and splicing out of the T-DNA–containing intron. Consequently, the suppressed ccr1-6 allele was named epiccr1-6. Long-read sequencing revealed that epiccr1-6, not ccr1-6, carries dense cytosine methylation over the full length of the T-DNA. We showed that the SAIL T-DNA in the UGT72E3 locus could trigger the trans T-DNA suppression of the GABI-Kat T-DNA in the CCR1 locus. Furthermore, we scanned the literature for other potential cases of trans T-DNA suppression in Arabidopsis and found that 22% of the publications matching our query report on double or higher-order T-DNA mutants that meet the minimal requirements for trans T-DNA suppression. These combined observations indicate that intronic T-DNA mutants need to be used with caution since methylation of intronic T-DNA might derepress gene expression and can thereby confound results.
Financial Crises and the Transmission of Monetary Policy to Consumer Credit Markets
Authors: Indarte Sasha 
Published: May 2023

Abstract
How does creditor health affect the pass-through of monetary policy to households? Using data on the universe of U.S. credit unions, I document that creditor asset losses increase the sensitivity of consumer credit to monetary policy. Identification exploits plausibly exogenous variation in asset losses and high-frequency identification of monetary policy shocks. Weaker lenders can respond more if they face financial frictions that easing alleviates. The estimates imply constraints on monetary policy become more costly in financial crises featuring creditor asset losses and that an additional benefit of monetary easing is that it weakens the causal, contractionary effect of asset losses.
Authors have furnished an Internet Appendix, which is available on the Oxford University Press Web site next to the link to the final published paper online
Ten-year safety and clinical benefit from open-label etanercept treatment in children and young adults with juvenile idiopathic arthritis
Authors: Vojinović Jelena , Foeldvari Ivan , Dehoorne Joke , Panaviene Violeta , Susic Gordana , Horneff Gerd , Stanevicha Valda , Kobusinska Katarzyna , Zuber Zbigniew , Dobrzyniecka Bogna , Akikusa Jonathan , Avcin Tadej , Borlenghi Cecilia , Arthur Edmund , Tatulych Svitlana Y , Zang Chuanbo , Tsekouras Vassilis , Vlahos Bonnie , Martini Alberto , Ruperto Nicolino 
Published: May 2023

Abstract

Objectives
CLIPPER2 was an 8-year, open-label extension of the phase 3b, 2-year CLIPPER study on the safety and efficacy of etanercept in patients with JIA, categorized as extended oligoarticular arthritis (eoJIA), enthesitis-related arthritis (ERA) or PsA.

Methods
Participants with eoJIA (2–17 years old), ERA or PsA (each 12–17 years old) who received ≥1 etanercept dose (0.8 mg/kg weekly; maximum 50 mg) in CLIPPER could enter CLIPPER2. Primary end point was occurrence of malignancy. Efficacy assessments included proportions achieving JIA ACR 30/50/70/90/100 criteria and ACR inactive disease criteria, and clinical remission (ACR criteria) or Juvenile Arthritis DAS (JADAS) ≤1.

Results
Overall, 109/127 (86%) CLIPPER participants entered CLIPPER2 [n = 55 eoJIA, n = 31 ERA, n = 23 PsA; 99 (78%) on active treatment]; 84 (66%) completed 120 months’ follow-up [32 (25%) on active treatment]. One malignancy (Hodgkin’s disease in 18-year-old patient with eoJIA treated with methotrexate for 8 years) was reported; there were no cases of active tuberculosis or deaths. Numbers and incidence rates (events per 100 patient-years) of TEAEs (excluding infections/ISRs) decreased from 193 (173.81) in Year 1 to 9 (27.15) in Year 10; TE infections and serious infections also decreased. Over 45% of participants (n = 127) achieved JIA ACR50 responses from Month 2 onwards; 42 (33%) and 34 (27%) participants achieved JADAS and ACR clinical remission, respectively.

Conclusions
Etanercept treatment up to 10 years was well tolerated, consistent with the known safety profile, with durable response in the participants still on active treatment. The benefit–risk assessment of etanercept in these JIA categories remains favourable.

Trial registration
ClinicalTrials.gov IDs: CLIPPER (NCT00962741); CLIPPER2 (NCT01421069)
A uniquein vivopharmacokinetic profile,in vitrometabolic stability and hepatic first-pass metabolism of garcinol, a promising novel anticancer phytoconstituent, by liquid chromatography–mass spectrometry
Authors: Rao Gajula Siva Nageswara , Talari Sasikala , Chilvery Shrilekha , Godugu Chandraiah , Sonti Rajesh 
Published: May 2023

AbstractObjectivesGarcinol exhibits promising potential anticancer activity in cancer cells by inhibiting several critical regulatory pathways. Despite its pharmacological activity, information regarding its pharmacokinetics and metabolism is unavailable. Hence, we aimed to systematically determine the in vivo pharmacokinetic parameters, in vitro metabolic stability and hepatic first-pass metabolism of garcinol.MethodsWe developed and validated a sensitive bioanalytical method for the quantitative determination of garcinol in rat plasma and human liver microsomes using liquid chromatography–tandem mass spectrometry (LC–MS/MS). The developed method was applied to assess the pharmacokinetic parameters, bioavailability and metabolic stability associated with metabolic half-life and intrinsic hepatic clearance. Further, we calculated the hepatic first-pass metabolism of garcinol from the metabolic stability data.Key findingsThe metabolic stability of garcinol in human liver microsomes demonstrated it as a medium clearance drug with a CLint value of 33.94 µL/min/mg microsomal protein and 94% of garcinol would escape the hepatic first-pass metabolism. Furthermore, a pharmacokinetics study of garcinol in Sprague Dawley rats showed 26.64 ± 0.23% and 35.72 ± 0.97% oral bioavailability at two doses, that is 22.5 and 45 mg/kg, respectively. The Cmax values at these two oral doses were 2317.69 ± 180.44 and 3446.14 ± 190.12 ng/mL.ConclusionsMetabolic stability data showed that garcinol is a medium clearance drug and less fraction of the drug undergoes hepatic first-pass metabolism. The determined pharmacokinetic parameters and metabolic stability data help to understand and optimise the dose and route of administration for designing clinical trials to further develop garcinol as an anticancer drug.
Mindfulness Combined With Exercise Online (MOVE) Compared With a Self-management Guide for Adults With Chronic Pain
Authors: Deegan Orla , Fullen Brona M. , Casey Maire-Brid , Segurado Ricardo , Hearty Conor , Doody Catherine 
Published: May 2023

Objective:
Limited studies exist combining mindfulness-based stress reduction (MBSR) and exercise in a pain management programme (PMP), with none thus far delivering a combined intervention as an online PMP. This study aimed to explore the acceptability and feasibility of a combined MBSR and exercise online PMP for adults with chronic pain and to examine the feasibility of conducting a randomized controlled trial (RCT) comparing MBSR and exercise delivered online with an online self-management guide.

Materials and Methods:
A feasibility RCT was conducted with participants randomized into the MOVE group (8-wk MBSR and exercise live online) or the self-management (SM) group (8-wk online self-management guide). Primary outcomes included recruitment, attrition, intervention adherence, and satisfaction. Participants wore a Fitbit watch during the study and completed patient-reported outcome measures at baseline, postintervention, and 12-week follow-up.

Results:
Ninety-six participants were randomized and 80 (83.3%) completed the interventions. Higher mean satisfaction (Client Satisfaction Questionnaire-8) was reported in the MOVE group 26.2 (±5.5) than the SM group 19.4 (±5.6). The Patient Global Impression of Change scale showed favourable changes in both groups; 65.1% of the MOVE group, 42.3% of the SM group reporting improvement. Seventy-three participants (76.3%) adhered to wearing the Fitbit for 8 weeks. Comparable improvements postintervention and at a 12-week follow-up were noted within both groups for Brief Pain Inventory, Pain Self-Efficacy Questionnaire, Pain Disability Index, Pain Catastrophising Scale, Fear Avoidance Belief Questionnaire and Short Form-36 Health Survey.

Discussion:
The findings suggest both interventions explored are acceptable and feasible. A fully powered RCT examining the effectiveness of MBSR combined with exercise, delivered live online is warranted.
Spatial and temporal epidemiological analysis on the mortality rate of female breast cancer in Suzhou, China: 2006–2020
Authors: Wang Linchi , Lu Yan , Huang Chunyan , Tang Jing 
Published: May 2023

Objective:
The epidemiological trend and spatial distribution of female breast cancer mortality in Suzhou were analyzed, so as to provide a scientific basis for the prevention and treatment of breast cancer.

Materials and Methods:
The annual trend of female breast cancer mortality data from 2006 to 2020 years was analyzed. The spatial autocorrelation analysis was carried out by Moran’s I method of GeoDa software to explore its regional aggregation.

Results:
The average annual crude mortality rate (CR) of breast cancer in Suzhou was 8.54 per 100 000 from 2006 to 2020, while the age-standardized mortality rate (ASMR) was 7.38 per100 000. The annual change percentage (APC) of CR in the recent 15 years was 1.98% (1.30–2.66%), which was statistically significant (P<0.001). The annual change trend of ASMR was decreased slightly (APC=−0.95%, P=0.04). Spatial analysis indicated that there was a certain clustering of breast cancer in Suzhou. The CR of female breast cancer in Suzhou showed an upward trend, but ASMR decreased slightly.

Conclusion:
Health promotion and education should be strengthened in the areas with a high incidence of female breast cancer death in Suzhou, and the participation rate of breast cancer screening should be further improved.
Role of SARS-CoV-2 mutations in the evolution of the COVID-19 pandemic
Authors: Colson Philippe , Chaudet Hervé , Delerce Jérémy , Pontarotti Pierre , Levasseur Anthony , Fantini Jacques , Scola Bernard LA , Devaux Christian , Raoult Didier 
Published: May 2023

ABSTRACTRNA viruses, including SARS-CoV-2, evolve by mutation acquisition, or by hybridization between viral genomes. The SARS-CoV-2 pandemic provided an exceptional opportunity to analyze the mutations that appeared over a three-year period.In this study, we analysed the type of mutations and their epidemic consequences on the thousands of genomes produced in our laboratory. These were obtained by next-generation sequencing from respiratory samples performed for genomic surveillance. The frequencies of mutations were calculated using Nextclade, Microsoft Excel, and an in-house Python script. In total, 61,397 genomes matching 483 Pangolin lineages were analyzed; 22,225 nucleotide mutations were identified, and of them 220 (1.0%) were each at the root of at least 836 genomes, a frequency threshold classifying mutations as “hyperfertile”. Two of these seeded the pandemic in Europe, namely a mutation in the RNA-dependent RNA polymerase associated with an increased mutation rate (P323L) and one in the spike protein (D614G), which plays a particular role in virus fitness. Most of these 220 “hyperfertile” mutations occurred in areas not predicted to be associated with increased virulence. Their number was 8±6 (0-22) per 1,000 nucleotides on average per gene. They were 3.7 times more frequent in accessory than informational genes (14 versus 4; p= 0.0037). Particularly, they were 4.1 times more frequent in ORF8 than in the gene encoding RNA polymerase. Interestingly, stop codons were present in 97 positions, almost only in six accessory genes including ORF7a (25 per 100 codons) and ORF8 (21). Furthermore, 1,661 mutations (16.3%) were associated with a lower number of “offspring” (50-835) and classified as “fertile”.In conclusion, except for two initial mutations that could predict a change in the dynamics of the epidemic (mutation rate and change in the virus attachment site), most of the “hyperfertile” mutations did not predict the emergence of a new epidemic form. Significantly, some mutations were in non-coding areas and some consisted of stop codons, indicating that some genes (particularly ORF7a and ORF8) were rather “non-virulence genes” at a given stage of the epidemic, which is an unusual concept for viruses.