bluuebunny/crossref_metadata_2025_split huggingface dataset:
Yellow fever vaccine safety in immunocompromised individuals: a systematic review and meta-analysis
Authors: Wigg de Araújo Lagos Letícia , de Jesus Lopes de Abreu Ariane , Caetano Rosângela , Braga José Ueleres 
Published: August 2022

AbstractBackgroundYellow fever (YF) is an arbovirus with variable severity, including severe forms with high mortality. The vaccination is the most effective measure to protect against the disease. Non-serious and serious adverse events have been described in immunocompromised individuals, but previous studies have failed to demonstrate this association. This systematic review assessed the risk of adverse events after YF vaccination in immunocompromised individuals compared with its use in non-immunocompromised individuals.MethodsA search was conducted in the MEDLINE, LILACS, EMBASE, SCOPUS, DARE, Toxiline, Web of Science and grey literature databases for publications until February 2021. Randomized and quasi-randomized clinical trials and observational studies that included immunocompromised participants (individuals with HIV infection, organ transplants, with cancer, who used immunosuppressive drugs for rheumatologic diseases and those on immunosuppressive therapy for other diseases) were selected. The methodological quality of observational or non-randomized studies was assessed by the ROBINS-I tool. Two meta-analyses were performed, proportion and risk factor analyses, to identify the summary measure of relative risk (RR) in the studies that had variables suitable for combination.ResultsTwenty-five studies were included, most with risk of bias classified as critical. Thirteen studies had enough data to carry out the proposed meta-analyses. Seven studies without a comparator group had their results aggregated in the proportion meta-analysis, identifying an 8.5% [95% confidence interval (CI) 0.07–21.8] risk of immunocompromised individuals presenting adverse events after vaccination. Six cohort studies were combined, with an RR of 1.00 (95% CI 0.78–1.29). Subgroup analysis was performed according to the aetiology of immunosuppression and was also unable to identify an increased risk of adverse events following vaccination.ConclusionsIt is not possible to affirm that immunocompromised individuals, regardless of aetiology, have a higher risk of adverse events after receiving the YF vaccine.
X-ray properties of early-type stars in the Tarantula Nebula from T-ReX
Authors: Crowther Paul A , Broos Patrick S , Townsley Leisa K , Pollock Andy M T , Tehrani Katie A , Gagné Marc 
Published: August 2022

ABSTRACT
We reassess the historical LX/LBol relation for early-type stars from a comparison between T-ReX, the Chandra ACIS X-ray survey of the Tarantula Nebula in the Large Magellanic Cloud (LMC), and contemporary spectroscopic analysis of massive stars obtained primarily from VLT/FLAMES, VLT/MUSE, and HST/STIS surveys. For 107 sources in common (some host to multiple stars), the majority of which are bolometrically luminous (40 per cent exceed 106L⊙), we find an average log LX/LBol = −6.90 ± 0.65. Excluding extreme systems Mk 34 (WN5h+WN5h), R140a (WC4+WN6+), and VFTS 399 (O9 IIIn+?), plus four WR sources with anomalously hard X-ray components (R130, R134, R135, Mk 53) and 10 multiple sources within the spatially crowded core of R136a, log LX/LBol = −7.00 ± 0.49, in good agreement with Galactic OB stars. No difference is found between single and binary systems, nor between O, Of/WN, and WR stars, although there does appear to be a trend towards harder X-ray emission from O dwarfs, through O (super)giants, Of/WN stars, and WR stars. The majority of known OB stars in the Tarantula are not detected in the T-ReX point source catalogue, so we have derived upper limits for all undetected OB stars for which log LBol/L⊙ ≥ 5.0. A survival analysis using detected and upper limit log LX/LBol values indicates no significant difference between luminous O stars in the LMC and the Carina Nebula. This analysis suggests that metallicity does not strongly influence LX/LBol. Plasma temperatures for single, luminous O stars in the Tarantula ($\overline{kT_{m}}=1.0$ keV) are higher than counterparts in Carina ($\overline{kT_{m}}=0.5$ keV).
Reddening and the shape of the variable component of the continua of active galactic nuclei from the optical to the far-ultraviolet – I
Authors: Heard Clio Z P , Gaskell C Martin 
Published: August 2022

ABSTRACT
We analyse the photometric variability of 4611 active galactic nuclei (AGNs) from the Sloan Digital Sky Survey (SDSS) Stripe 82. We recover the spectral energy distribution (SED) of the variable flux as a function of wavelength. For rest wavelengths longer than ∼2200 Å, we find that the SED of the variable component of the bluest AGNs is consistent with the Fν ∝ ν+1/3 spectrum predicted for an externally illuminated accretion disc. We confirm there is some residual variable emission corresponding to the ‘small blue bump’ and other broad-line region variability. We interpret steeper optical spectra of the variable component as being due to intrinsic reddening. This is supported by the correlation of the Balmer decrement with the colour excess of the variable component. We find the median internal reddening of SDSS AGNs in Stripe 82 with z &lt; 0.4 to be E(B − V) ≈ 0.10 in agreement with the reddening derived from the Balmer decrement. Individual AGNs in the sample can have E(B − V) &gt; 0.4.
Enhanced exon skipping and prolonged dystrophin restoration achieved by TfR1-targeted delivery of antisense oligonucleotide using FORCE conjugation in mdx mice
Authors: Desjardins Cody A , Yao Monica , Hall John , O’Donnell Emma , Venkatesan Reshmii , Spring Sean , Wen Aiyun , Hsia Nelson , Shen Peiyi , Russo Ryan , Lan Bo , Picariello Tyler , Tang Kim , Weeden Timothy , Zanotti Stefano , Subramanian Romesh , Ibraghimov-Beskrovnaya Oxana 
Published: August 2022

Abstract
Current therapies for Duchenne muscular dystrophy (DMD) use phosphorodiamidate morpholino oligomers (PMO) to induce exon skipping in the dystrophin pre-mRNA, enabling the translation of a shortened but functional dystrophin protein. This strategy has been hampered by insufficient delivery of PMO to cardiac and skeletal muscle. To overcome these limitations, we developed the FORCETM platform consisting of an antigen-binding fragment, which binds the transferrin receptor 1, conjugated to an oligonucleotide. We demonstrate that a single dose of the mouse-specific FORCE–M23D conjugate enhances muscle delivery of exon skipping PMO (M23D) in mdx mice, achieving dose-dependent and robust exon skipping and durable dystrophin restoration. FORCE–M23D-induced dystrophin expression reached peaks of 51%, 72%, 62%, 90% and 77%, of wild-type levels in quadriceps, tibialis anterior, gastrocnemius, diaphragm, and heart, respectively, with a single 30 mg/kg PMO-equivalent dose. The shortened dystrophin localized to the sarcolemma, indicating expression of a functional protein. Conversely, a single 30 mg/kg dose of unconjugated M23D displayed poor muscle delivery resulting in marginal levels of exon skipping and dystrophin expression. Importantly, FORCE–M23D treatment resulted in improved functional outcomes compared with administration of unconjugated M23D. Our results suggest that FORCE conjugates are a potentially effective approach for the treatment of DMD.
B-to-A transition in target DNA during retroviral integration
Authors: Jóźwik Ilona K , Li Wen , Zhang Da-Wei , Wong Doris , Grawenhoff Julia , Ballandras-Colas Allison , Aiyer Sriram , Cherepanov Peter , Engelman Alan N , Lyumkis Dmitry 
Published: August 2022

Abstract
Integration into host target DNA (tDNA), a hallmark of retroviral replication, is mediated by the intasome, a multimer of integrase (IN) assembled on viral DNA (vDNA) ends. To ascertain aspects of tDNA recognition during integration, we have solved the 3.5 Å resolution cryo-EM structure of the mouse mammary tumor virus (MMTV) strand transfer complex (STC) intasome. The tDNA adopts an A-like conformation in the region encompassing the sites of vDNA joining, which exposes the sugar-phosphate backbone for IN-mediated strand transfer. Examination of existing retroviral STC structures revealed conservation of A-form tDNA in the analogous regions of these complexes. Furthermore, analyses of sequence preferences in genomic integration sites selectively targeted by six different retroviruses highlighted consistent propensity for A-philic sequences at the sites of vDNA joining. Our structure additionally revealed several novel MMTV IN-DNA interactions, as well as contacts seen in prior STC structures, including conserved Pro125 and Tyr149 residues interacting with tDNA. In infected cells, Pro125 substitutions impacted the global pattern of MMTV integration without significantly altering local base sequence preferences at vDNA insertion sites. Collectively, these data advance our understanding of retroviral intasome structure and function, as well as factors that influence patterns of vDNA integration in genomic DNA.
TGS1 impacts snRNA 3′-end processing, ameliorates survival motor neuron-dependent neurological phenotypes in vivo and prevents neurodegeneration
Authors: Chen Lu , Roake Caitlin M , Maccallini Paolo , Bavasso Francesca , Dehghannasiri Roozbeh , Santonicola Pamela , Mendoza-Ferreira Natalia , Scatolini Livia , Rizzuti Ludovico , Esposito Alessandro , Gallotta Ivan , Francia Sofia , Cacchione Stefano , Galati Alessandra , Palumbo Valeria , Kobin Marie A , Tartaglia Gian Gaetano , Colantoni Alessio , Proietti Gabriele , Wu Yunming , Hammerschmidt Matthias , De Pittà Cristiano , Sales Gabriele , Salzman Julia , Pellizzoni Livio , Wirth Brunhilde , Di Schiavi Elia , Gatti Maurizio , Artandi Steven E , Raffa Grazia D 
Published: August 2022

Abstract
Trimethylguanosine synthase 1 (TGS1) is a highly conserved enzyme that converts the 5′-monomethylguanosine cap of small nuclear RNAs (snRNAs) to a trimethylguanosine cap. Here, we show that loss of TGS1 in Caenorhabditis elegans, Drosophila melanogaster and Danio rerio results in neurological phenotypes similar to those caused by survival motor neuron (SMN) deficiency. Importantly, expression of human TGS1 ameliorates the SMN-dependent neurological phenotypes in both flies and worms, revealing that TGS1 can partly counteract the effects of SMN deficiency. TGS1 loss in HeLa cells leads to the accumulation of immature U2 and U4atac snRNAs with long 3′ tails that are often uridylated. snRNAs with defective 3′ terminations also accumulate in Drosophila Tgs1 mutants. Consistent with defective snRNA maturation, TGS1 and SMN mutant cells also exhibit partially overlapping transcriptome alterations that include aberrantly spliced and readthrough transcripts. Together, these results identify a neuroprotective function for TGS1 and reinforce the view that defective snRNA maturation affects neuronal viability and function.
Strand switching mechanism of Pif1 helicase induced by its collision with a G-quadruplex embedded in dsDNA
Authors: Valle-Orero Jessica , Rieu Martin , Tran Phong Lan Thao , Joubert Alexandra , Raj Saurabh , Allemand Jean-François , Croquette Vincent , Boulé Jean-Baptiste 
Published: August 2022

Abstract
G-rich sequences found at multiple sites throughout all genomes may form secondary structures called G-quadruplexes (G4), which act as roadblocks for molecular motors. Among the enzymes thought to process these structures, the Pif1 DNA helicase is considered as an archetypical G4-resolvase and its absence has been linked to G4-related genomic instabilities in yeast. Here we developed a single-molecule assay to observe Pif1 opening a DNA duplex and resolving the G4 in real time. In support of former enzymological studies, we show that the helicase reduces the lifetime of G4 from hours to seconds. However, we observe that in the presence of a G4, Pif1 exhibits a strong strand switching behavior, which can lead to Pif1 escaping G4 resolution, depending on the structural context surrounding the substrate. This behavior is also detected in the presence of other roadblocks (LNA or RNA). We propose that the efficiency of Pif1 to remove a roadblock (G4 or other) is affected by its strand switching behavior and depends on the context surrounding the obstacle. We discuss how this switching behavior may explain several aspects of Pif1 substrate preference and affect its activity as a G4 resolvase in vivo.
Molecular dynamics of DNA translocation by FtsK
Authors: Pajak Joshua , Arya Gaurav 
Published: August 2022

AbstractThe bacterial FtsK motor harvests energy from ATP to translocate double-stranded DNA during cell division. Here, we probe the molecular mechanisms underlying coordinated DNA translocation in FtsK by performing long timescale simulations of its hexameric assembly and individual subunits. From these simulations we predict signaling pathways that connect the ATPase active site to DNA-gripping residues, which allows the motor to coordinate its translocation activity with its ATPase activity. Additionally, we utilize well-tempered metadynamics simulations to compute free-energy landscapes that elucidate the extended-to-compact transition involved in force generation. We show that nucleotide binding promotes a compact conformation of a motor subunit, whereas the apo subunit is flexible. Together, our results support a mechanism whereby each ATP-bound subunit of the motor conforms to the helical pitch of DNA, and ATP hydrolysis/product release causes a subunit to lose grip of DNA. By ordinally engaging and disengaging with DNA, the FtsK motor unidirectionally translocates DNA.
Biochemical and structural characterization of hepatitis A virus 2C reveals an unusual ribonuclease activity on single-stranded RNA
Authors: Chen Pu , Wojdyla Justyna Aleksandra , Colasanti Ombretta , Li Zhijian , Qin Bo , Wang Meitian , Lohmann Volker , Cui Sheng 
Published: August 2022

Abstract
The HAV nonstructural protein 2C is essential for virus replication; however, its precise function remains elusive. Although HAV 2C shares 24–27% sequence identity with other 2Cs, key motifs are conserved. Here, we demonstrate that HAV 2C is an ATPase but lacking helicase activity. We identified an ATPase-independent nuclease activity of HAV 2C with a preference for polyuridylic single-stranded RNAs. We determined the crystal structure of an HAV 2C fragment to 2.2 Å resolution, containing an ATPase domain, a region equivalent to enterovirus 2C zinc-finger (ZFER) and a C-terminal amphipathic helix (PBD). The PBD of HAV 2C occupies a hydrophobic pocket (Pocket) in the adjacent 2C, and we show the PBD–Pocket interaction is vital for 2C functions. We identified acidic residues that are essential for the ribonuclease activity and demonstrated mutations at these sites abrogate virus replication. We built a hexameric-ring model of HAV 2C, revealing the ribonuclease-essential residues clustering around the central pore of the ring, whereas the ATPase active sites line up at the gaps between adjacent 2Cs. Finally, we show the ribonuclease activity is shared by other picornavirus 2Cs. Our findings identified a previously unfound activity of picornavirus 2C, providing novel insights into the mechanisms of virus replication.
Tacrolimus induces a pro-fibrotic response in donor-derived human proximal tubule cells dependent on common variants of theCYP3A5andABCB1genes
Authors: Knops Noël , Ramazani Yasaman , De Loor Henriëtte , Goldschmeding Roel , Nguyen Tri Q , van den Heuvel Lambert P , Levtchenko Elena , Kuypers Dirk J 
Published: August 2022

ABSTRACTBackgroundCommon genetic variants of the enzymes and efflux pump involved in tacrolimus disposition have been associated with calcineurin inhibitor nephrotoxicity, but their importance is unclear because of the multifactorial background of renal fibrosis. This study explores the pro-fibrotic response of tacrolimus exposure in relation to the differential capacity for tacrolimus metabolism in proximal tubule cells (PTCs) with a variable (pharmaco)genetic background.MethodsPTCs were obtained from protocol allograft biopsies with different combinations of CYP3A5 and ABCB1 variants and were incubated with tacrolimus within the concentration range found in vivo. Gene and protein expression, CYP3A5 and P-glycoprotein function, and tacrolimus metabolites were measured in PTC. Connective tissue growth factor (CTGF) expression was assessed in protocol biopsies of kidney allograft recipients.ResultsPTCs produce CTGF in response to escalating tacrolimus exposure, which is approximately 2-fold higher in cells with the CYP3A5*1 and ABCB1 TT combination in vitro. Increasing tacrolimus exposure results in relative higher generation of the main tacrolimus metabolite {13-O-desmethyl tacrolimus [M1]} in cells with this same genetic background. Protocol biopsies show a larger increase in in vivo CTGF tissue expression over time in TT vs. CC/CT but was not affected by the CYP3A5 genotype.ConclusionsTacrolimus exposure induces a pro-fibrotic response in a PTC model in function of the donor pharmacogenetic background associated with tacrolimus metabolism. This finding provides a mechanistic insight into the nephrotoxicity associated with tacrolimus treatment and offers opportunities for a tailored immunosuppressive treatment.
Tenofovir-Diphosphate in Dried Blood Spots vs Tenofovir in Urine/Plasma for Oral Preexposure Prophylaxis Adherence Monitoring
Authors: Niu Xin , Kubiak Rachel W , Siriprakaisil Oraphan , Klinbuyaem Virat , Sukrakanchana Pra ornsuda , Cressey Ratchada , Okochi Hideaki , Gandhi Monica , Cressey Tim R , Drain Paul K 
Published: August 2022

Abstract

Background
Tenofovir-diphosphate (TFV-DP) measured in dried blood spots (DBS) and tenofovir (TFV) measured in urine/plasma have been used to measure TFV-based oral pre-exposure prophylaxis (PrEP) adherence. However, there are limited data comparing these 3 metrics and their appropriate use for PrEP adherence monitoring.

Methods
We collected DBS, urine, and plasma samples from HIV-negative adults randomized to a low (2 doses/week), moderate (4 doses/week), or perfect (7 doses/week) adherence group (via directly observed therapy) of tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for 6 weeks, followed by a 4-week washout phase. Drug concentrations were measured using liquid chromatography tandem mass spectrometry. Linear mixed-effects modeling was used to examine associations between drug concentrations and dosing time.

Results
Among 28 participants, the median age was 33 years, and 12 (43%) were female. At steady state, 25th percentile TFV-DP concentrations were 466, 779, and 1375 fmol/3 mm punch in the low, moderate, and perfect adherence group, respectively. Correlation was stronger between quantifiable TFV-DP and plasma TFV (r = 0.65; P &lt; .01) than between TFV-DP and urine TFV (r = 0.50; P &lt; .01). Among all participants, each additional week of cumulative dosing on average led to a mean increase of 158 fmol/3 mm punch (P &lt; .001) in TFV-DP during the dosing phase. Each additional day after the last dose was associated with 43 fmol/3 mm punch lower TFV-DP (P = .07).

Conclusions
TFV-DP levels in DBS provide valuable insight into both dosing recency and cumulative doses from variable adherence patterns. Our observed benchmark TFV-DP concentrations were slightly higher than prior predicted estimates based on convenience samples.
Comparing the Efficacy and Safety of Gemcitabine plus Nab-Paclitaxel versus Gemcitabine Alone in Older Adults with Unresectable Pancreatic Cancer
Authors: Kobayashi Satoshi , Suzuki Motoko , Ueno Makoto , Maruki Yuta , Okano Naohiro , Todaka Akiko , Ozaka Masato , Tsuji Kunihiro , Shioji Kazuhiko , Doi Keitaro , Kojima Yasushi , Tsumura Hidetaka , Tanaka Kazunari , Higuchi Hajime , Kawabe Ken , Imaoka Hiroshi , Yamashita Tatsuya , Miwa Haruo , Nagano Hiroaki , Arima Shiho , Hayashi Hideyuki , Naganuma Atsushi , Yamaguchi Hironori , Hisano Terumasa , Umemoto Kumiko , Ishii Shuji , Nakashima Koji , Suzuki Rei , Kitano Yohei , Misumi Toshihiro , Furuse Junji , Ishii Hiroshi 
Published: August 2022

Abstract

Background
Gemcitabine plus nab-paclitaxel (GnP) has been a standard treatment for unresectable pancreatic cancer (uPC); however, the current treatment status and usefulness in older adults with uPC remain unclear. Therefore, we aimed to investigate the patient background and compare the efficacy and safety of GnP versus other treatments in older adults with uPC.

Patients and Methods
In this prospective observational study, we enrolled 233 eligible patients aged ≥76 years with pathologically proven, clinically uPC, and no history of chemotherapy from 55 Japanese centers during September 2018-September 2019. The main endpoints were overall survival (OS), progression-free survival (PFS), and safety. Geriatric assessments were performed upon registration and after 3 months. To adjust for confounders, we conducted propensity score-matched analyses.

Results
GnP, gemcitabine alone (Gem), best supportive care, and other therapies were administered to 116, 72, 16, and 29 patients, respectively. In the propensity score-matched analysis, 42 patients each were selected from the GnP and Gem groups. The median OS was longer in the GnP group than in the Gem group (12.2 vs. 9.4 months; hazard ratio [HR], 0.65; 95% CI, 0.37-1.13). The median PFS was significantly longer in the GnP group than in the Gem group (9.2 vs. 3.7 months; HR, 0.38; 95% CI, 0.23-0.64). The incidence of severe adverse events was higher with GnP than with Gem; however, the difference was not significant.

Conclusion
GnP is more efficacious than Gem in patients aged ≥76 years with uPC despite demonstrating a higher incidence of severe adverse events.
Serum biomarkers in prednisolone-treated hand osteoarthritis patients
Authors: van de Stadt Lotte A , Kroon Féline P B , Thudium Christian F , Bay-Jensen Anne C , Kloppenburg Margreet 
Published: August 2022

AbstractObjectivesTo investigate whether biomarkers are modulated by prednisolone treatment in patients with hand OA and whether they can predict response to prednisolone.MethodsBiomarkers reflecting tissue turnover and inflammation [aggrecanase-derived neoepitope of arggecan (ARGS), MMP-derived neoepitope of type I collagen (C1M), MMP-derived neoepitope of type III collagen (C3M), marker of true type V collagen formation (PROC5), MMP-derived neoepitope of CRP (CRPM), citrullinated vimentin fragment (VICM), high-sensitivity (hsCRP)] were measured in sera from 78 patients with painful inflammatory hand OA, who were randomized between prednisolone or placebo treatment. Association of baseline biomarker levels with disease characteristics [visual analogue scale (VAS) pain, synovial thickening ultrasonography sum score and erosive OA] and OMERACT-Osteoarthritis Research Society International (OARSI) response after 6 weeks were analysed with linear or logistic regression and adjusted for age, BMI and sex. Change in biomarker levels after 6 weeks was assessed with linear regression adjusted for baseline biomarker levels, age, BMI and sex.ResultsFor all patients (mean age 64 years, 79% female), there were no associations between biomarker levels and VAS finger pain or synovial thickening score at baseline. Patients with erosive hand OA had higher levels of C1M and hsCRP [adjusted geometric mean ratio 1.24 (95% CI 1.03, 1.49) and 1.91 (1.19, 3.06), respectively]. Biomarker levels did not decrease over time. There was no association between baseline biomarkers levels and OARSI response, except for CRPM [geometric mean ratio of 0.88 (0.77, 1.00)].ConclusionErosive disease was associated with higher levels of C1M and hsCRP. Biomarker levels were not influenced by treatment with prednisolone. Current biomarkers were not associated with response to prednisolone in hand OA.