bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human papillomavirus intermittence, redetections, and associated risk of cytological abnormalities in the Ludwig-McGill cohort study of adult women
Authors: Malagón Talía , Trottier Helen , El-Zein Mariam , Villa Luisa L , Franco Eduardo ,   the Ludwig-McGill Cohort Study
Published: October 2022

AbstractIntroductionWe assessed the incidence of redetection with the same human papillomavirus (HPV) genotype, predictors of first HPV detections and redetections, and prevalence of cytological lesions during HPV redetections.MethodsThe Ludwig-McGill cohort study followed women aged 18-60 years from São Paulo, Brazil in 1993-1997 for up to 10 years. Women provided cervical samples for cytology testing and HPV DNA testing at each visit. A redetection was defined as a recurring genotype-specific HPV positive result after one or more intervening negative visits. Predictors of genotype-specific redetection were assessed using adjusted hazard ratios (aHR) with Cox regression modeling.Results2184 women contributed 2368 incident HPV genotype-specific first detections and 308 genotype-specific redetections over a median follow-up of 6.5 years. The cumulative incidence of redetection with the same genotype was 7% at 1 year and 15% at 5 years after the loss of positivity of the first detection. Neither age (aHR 0.90, 95%CI 0.54-1.47 for ≥45y vs. <25y) nor new sexual partner acquisition (aHR 0.98, 95%CI 0.70-1.35) were statistically associated with genotype-specific redetection. High-grade squamous intraepithelial lesion prevalence was similar during first HPV detections (2.9%) and redetection (3.2%).ConclusionsOur findings suggest many HPV redetections were likely reactivations of latent recurring infections.
Benchtop evaluation of a double stent retriever thrombectomy technique for acute ischemic stroke treatment
Authors: Hofmeister Jeremy , Bernava Gianmarco , Rosi Andrea , Reymond Philippe , Brina Olivier , Muster Michel , Lovblad Karl-Olof , Machi Paolo 
Published: October 2022

AbstractBackgroundA mechanical thrombectomy technique using a double stent retriever (DSR) approach has been reported for the treatment of patients with acute ischemic stroke. The purpose of this study was to perform a benchtop evaluation of the mechanism of action and efficacy of a DSR approach compared to a single stent retriever approach.MethodsIn vitromechanical thrombectomy procedures were performed in a vascular phantom reproducing a M1-M2 occlusion with two different clot analog consistencies (soft and hard). We compared the DSR approach to the single stent retriever approach and recorded the recanalisation rate, distal embolization, and retrieval forces of each mechanical thrombectomy procedure.ResultsThe DSR approach achieved a higher recanalization rate and lower embolic complications compared to the single stent retriever approach. This seems to stem from two facts: the greater probability of targeting the correct artery with two stents in the case of bifurcation occlusion, and an improved clot capture mechanism using the DSR approach. However, the DSR was associated with an increased initial retrieval force.ConclusionIn vitroevaluation of the mechanism of action of the DSR provided explanations that appear to support the high efficacy of such an approach in patient cohorts and could help operators when selecting the optimal mechanical thrombectomy strategy in cases of arterial occlusions difficult to treat with a single stent retriever.
Global neuropathologic severity of Alzheimer’s disease and locus coeruleus vulnerability influences plasma phosphorylated tau levels
Authors: Murray Melissa E. , Moloney Christina M. , Kouri Naomi , Syrjanen Jeremy A. , Matchett Billie J. , Rothberg Darren M. , Tranovich Jessica F. , Hicks Sirmans Tiffany N. , Wiste Heather J. , Boon Baayla D. C. , Nguyen Aivi T. , Reichard R. Ross , Dickson Dennis W. , Lowe Val J. , Dage Jeffrey L , Petersen Ronald C. , Jack Clifford R. , Knopman David S. , Vemuri Prashanthi , Graff-Radford Jonathan , Mielke Michelle M. 
Published: October 2022

AbstractAdvances in ultrasensitive detection of phosphorylated tau (p-tau) in plasma has enabled the use of blood tests to measure Alzheimer’s disease (AD) biomarker changes. Examination of postmortem brains of participants with antemortem plasma p-tau levels remains critical to understanding comorbid and AD-specific contribution to these biomarker changes. We analyzed 35 population-based Mayo Clinic Study of Aging participants with plasma p-tau at threonine181 and threonine217 (p-tau181, p-tau217) available within 3 years of death. Autopsied participants included cognitively unimpaired, mild cognitive impairment, AD dementia, and non-AD neurodegenerative disorders. Global neuropathologic scales of tau, amyloid-β, TDP-43, and cerebrovascular disease were examined. Regional digital pathology measures of tau (phosphorylated threonine181 and 217 [pT181, pT217]) and amyloid-β (6F/3D) were quantified in hippocampus and parietal cortex. Neurotransmitter hubs reported to influence development of tangles (nucleus basalis of Meynert) and amyloid-β plaques (locus coeruleus) were evaluated. The strongest regional associations were with parietal cortex for tau burden (p-tau181 R=0.55, p=0.003; p-tau217 R=0.66, p<0.001) and amyloid-β burden (p-tau181 R=0.59, p<0.001; p-tau217 R=0.71, p<0.001). Linear regression analysis of global neuropathologic scales explained 31% of variability in plasma p-tau181 (R2=0.31) and 59% in plasma p-tau217 (R2=0.59). Neither TDP-43 nor cerebrovascular disease global scales independently contributed to variability. Global scales of tau pathology (β-coefficient=0.060, p=0.016) and amyloid-β pathology (β-coefficient=0.080, p<0.001) independently predicted plasma p-tau217 when modeled together with co-pathologies, but only amyloid-β (β-coefficient=0.33, p=0.021) significantly predicted plasma p-tau181. While nucleus basalis of Meynert neuron count/mm2was not associated with plasma p-tau levels, a lower locus coeruleus neuron count/mm2was associated with higher plasma p-tau181 (R=-0.50, p=0.007) and higher plasma p-tau217 (R=-0.55, p=0.002). Cognitive scores (R2=0.31-0.34) were predicted by the global tau scale, but not by the global amyloid-β scale or plasma p-tau when modeled simultaneously. Higher soluble plasma p-tau levels may be the result of an intersection between insoluble deposits of amyloid-β and tau accumulation in brain and may be associated with locus coeruleus degeneration.
Risk factors for suicide following treatment with electroconvulsive therapy: A nationwide study of 11,780 patients
Authors: Spanggård Anders , Rohde Christopher , Østergaard Søren Dinesen 
Published: October 2022

ABSTRACTObjectivesDespite the well-established anti-suicidal effect of electroconvulsive therapy (ECT), patients receiving ECT remain at high risk of dying from suicide. In the present study, we aimed to quantify this risk and identify risk factors for suicide among patients receiving ECT.MethodsWe used nationwide Danish registers to identify all patients that initiated ECT between 2006 and 2016. These patients were matched on sex and age to 10 reference individuals from the general Danish population. First, we compared 2-year suicide risk between patients initiating ECT and the matched reference individuals. Second, we investigated if any patient characteristics were associated with suicide following ECT via Cox proportional-hazards regression.ResultsA total of 11,780 patients receiving ECT and 117,800 reference individuals were included in the analyses. Among the patients receiving ECT, 161 (1.4%) died from suicide within two years. Compared to the reference individuals, patients receiving ECT had a substantially elevated suicide rate (Hazard rate ratio (HRR)=44.5, 95%CI=31.1-63.6). Among those receiving ECT, we identified the following risk factors for suicide: Male sex (HRR=2.3, 95%CI=1.7-3.1), age 60-70 years (HRR=1.6, 95%CI=1.0-2.6), Medium-term higher education (HRR=1.5, 95%CI=1.0-2.2); Long-term higher education (HRR=1.9, 95%CI=1.1-3.1), history of substance use disorder (HRR=2.0, 95%CI=1.4-2.8) and history of intentional self-harm/suicide attempt (HRR=4.0, 95%CI=2.8-5.8).ConclusionAmong patients receiving ECT, those who are male, aged 60-70 years, have mediumterm to long-term higher education, or have a history of substance use disorder or intentional self-harm/suicide attempt, are at particularly elevated risk of suicide. These findings may guide initiatives to reduce the risk of suicide.
WITHDRAWN: Post-acute symptoms four months after SARS-CoV-2 infection during the Omicron period: a nationwide Danish questionnaire study
Authors: Spiliopoulos Lampros , Sørensen Anna Irene Vedel , Bager Peter , Nielsen Nete Munk , Hansen Jørgen Vinsløv , Koch Anders , Meder Inger Kristine , Videbech Poul , Ethelberg Steen , Hviid Anders 
Published: October 2022

Withdrawal StatementThis manuscript has been removed because it included data obtained through a copyrighted questionnaire. The survey described in the manuscript was launched in haste during the pandemic and the authors were not aware of the copyright protection and acted in good faith. Attempts to obtain permission to use the questionnaire retrospectively were rejected by the copyright holders. The first author was not involved in the decision to include the copyrighted questionnaire, in any other aspects of the design of the survey or in the data collection and therefore bears no responsibility for this mishap. The senior author Anders Hviid takes full responsibility.
CRISPR-Cas phage defense systems and prophages inCandidatusAccumulibacter
Authors: Deng Xuhan , Yuan Jing , Chen Liping , Chen Hang , Wei Chaohai , Nielsen Per H. , Wuertz Stefan , Qiu Guanglei 
Published: October 2022

AbstractCandidatusAccumulibacter is a key genus of polyphosphate-accumulating organisms (PAOs) found in laboratory- and full-scale wastewater treatment systems, mediating enhanced biological phosphorus removal (EBPR). However, little is known about their ability to resist phage infection. We conducted a systematic analysis of the occurrence and characteristics of clustered regularly interspaced short palindromic repeats and associated proteins (CRISPR-Cas) systems and prophages in diverseCa.Accumulibacter taxa (43 in total, including 10 newly recovered genomes). Fourty complete CRISPR loci were identified in 28 genomes, falling into 6 subtypes. The occurrence and distribution of CRISPR-Cas systems did not follow a vertical evolutionary relationship. Phylogenetic analyses of thecasgenes and direct repeats (DRs) suggested that the CRISPR-Cas systems were likely acquired via horizontal gene transfer, with acquisition rates higher than those of speciation, rendering differentCa.Accumulibacter distinct adaptivity to phage predations. 2448 spacers were identified, 67 of them matched to known phages. Major differences were observed among the numbers of spacers for differentCa.Accumulibacter, showing unique phages that could be resisted by different members. A comparison of the spacers in genomes having the samecasgene but from distinct geographical locations indicated that habitat isolation may have resulted in the acquisition of different spacers by differentCa. Accumulibacter. Metagenomic analysis allowed the identification of 26 viral contigs (18 are Caudovirales members) in 6 metagenomic datasets from three lab-scale enrichment reactors, matching to 73 spacers in 10Ca.Accumulibacter genomes in these reactors, showing the specific immunity of theseCa.Accumulibacter. Metatranscriptomic analyses showed the activity of the CRISPR-Cas system under both anaerobic and aerobic conditions. Extra efforts were made to identify prophages inCa.Accumulibacter genomes. In total, 133 prophage regions were identified. Twenty-seven of them were classified as potentially active prophages. Three prophages (all are Caudovirales members, in DS2011, SCELSE-7IIH and SCELSE-5IIH, respectively) are readily activable. Differences in the occurrence of CRISPR-Cas systems and prophages inCa.Accumulibacter will lead to their distinct responses under phage predation. This study represents the first systematic analysis of CRISPR-Cas systems and prophages with combined experimental and bioinformatic methods in theCa.Accumulibacter lineage, providing new perspectives on the potential impacts of phages onCa.Accumulibacter and EBPR systems.
Permeation Across the Mycomembrane in Live Mycobacteria
Authors: Liu Zichen , Lepori Irene , Dalesandro Brianna E. , Chordia Mahendra D. , Guo Taijie , Sharpless Karl Barry , Dong Jiajia , Siegrist M. Sloan , Pires Marcos M. 
Published: October 2022

AbstractThe general lack of permeability of small molecules observed forMycobacterium tuberculosis(Mtb) is most commonly ascribed to its unique cell envelope. More specifically, the outer mycomembrane is hypothesized to be the principal determinant for access of antibiotics to their molecular targets. Nonetheless, there is limited information on the types of molecular scaffolds that can readily permeate past the mycomembrane of mycobacteria. To address this, we describe a novel assay that combines metabolic tagging of the peptidoglycan scaffold, which sits directly beneath the mycomembrane, and a fluorescent labeling chase step, to measure the permeation of small molecules. We showed that the assay workflow was robust and compatible with high-throughput analysis inMycobacterium smegmatisandMtb. A small panel of molecules was tested and we found a large range in the permeability profile of molecules. Interestingly, the general trend is similar across the two types of mycobacteria, with some notable exceptions. We anticipate that this assay platform will lay the foundation for medicinal chemistry efforts to understand and improve uptake of both existing drugs and newly-discovered compounds into mycobacteria. The methods described, which do not require genetic manipulation, can be generally adopted to other species for which envelope permeability is treatment-limiting.
IGFBP2 expressing midlobular hepatocytes preferentially contribute to liver homeostasis and regeneration
Authors: Lin Yu-Hsuan , Wei Yonglong , Wang Yunguan , Pagani Chase A. , Li Lin , Zhu Min , Wang Zixi , Hsieh Meng-Hsiung , Zhang Yu , Sharma Tripti , Wang Tao , Zhu Hao 
Published: October 2022

AbstractWhile midlobular hepatocytes in zone 2 are a recently identified cellular source for liver homeostasis and regeneration, these cells have not been exclusively fate mapped. We generated aIgfbp2-CreERknockin strain, which specifically labels midlobular hepatocytes. During homeostasis over 1 year, zone 2 hepatocytes increased in abundance from occupying 21% to 41% of the lobular area. After either pericentral injury with carbon tetrachloride or periportal injury with DDC, IGFBP2+ cells replenished lost hepatocytes in zones 3 and 1, respectively. IGFBP2+ cells also preferentially contributed to regeneration after 70% partial hepatectomy, as well as liver growth during pregnancy. Because IGFBP2 labeling increased substantially with fasting, we used single nuclear transcriptomics to explore zonation as a function of nutrition, revealing that the zonal division of labor shifts dramatically with fasting. These studies demonstrate the contribution of IGFBP2-labeled zone 2 hepatocytes to liver homeostasis and regeneration.HighlightsLineage tracing showed that midlobular hepatocytes proliferate during homeostasis.Zone 2 cells were protected from portal and centrilobular injuries and replaced lost hepatocytes.Fasting induced significant changes in liver zonation.eTOC statementThe liver consists of different zones with spatial heterogeneity in their metabolic functions. Here, a newIgfbp2-CreERline enabled direct tracing of midlobular hepatocytes, which showed that IGFBP2+ cells serve as a source of new hepatocytes during normal homeostasis and regeneration.
mTORC2 Interactome and Localization Determine Aggressiveness of High-Grade Glioma Cells through Association with Gelsolin
Authors: Chantaravisoot Naphat , Wongkongkathep Piriya , Kalpongnukul Nuttiya , Pacharakullanon Narawit , Kaewsapsak Pornchai , Ariyachet Chaiyaboot , Loo Joseph A. , Tamanoi Fuyuhiko , Pisitkun Trairak 
Published: October 2022

ABSTRACTThe mTOR complex 2 (mTORC2) has been implicated as a key regulator of glioblastoma cell migration. However, the roles of mTORC2 in the migrational control process have not been entirely elucidated. Here we elaborate that active mTORC2 is crucial for GBM cell motility. Inhibition of mTORC2 impaired cell movement and negatively affected microfilaments and microtubules’ functions. We also aimed to characterize important players involved in the regulation of cell migration and other mTORC2-mediated cellular processes in GBM cells through the proteomic and bioinformatic analyses. Therefore, we quantitatively characterized the alteration of mTORC2 interactome under selective conditions using affinity-purification mass spectrometry (AP-MS) in glioblastoma. We demonstrated that changes in cell migration ability specifically altered mTORC2-associated proteins. Gelsolin (GSN) was identified as one of the most dynamic proteins. The mTORC2-GSN linkage was mostly highlighted in high-grade glioma cells and shown to connect functional mTORC2 to multiple proteins responsible for directional cell movement in GBM. GSN also mediated membrane localization of mTORC2. Loss of GSN disconnected mTORC2 from numerous cytoskeletal proteins but did not affect mTORC2 integrity. In addition, we reported 86 stable mTORC2 interactome involved with diverse molecular functions, predominantly cytoskeletal remodeling in GBM. Our findings help expand future opportunities for predicting the highly migratory phenotype of brain cancers in the clinical investigation.
Structural analysis of human papillomavirus E6 interactions with Scribble PDZ domains
Authors: Stewart Bryce Z. , Caria Sofia , Humbert Patrick O. , Kvansakul Marc 
Published: October 2022

ABSTRACTThe cell polarity regulator Scribble has been shown to be a critical regulator of the establishment and development of tissue architecture, and its dysregulation promotes or suppresses tumor development in a context dependent manner. Scribble activity is subverted by numerous viruses. This includes human papillomaviruses (HPVs), who target Scribble via the E6 protein. Binding of E6 from high-risk HPV strains to Scribble via a C-terminal PDZ binding motif leads to Scribble degradationin vivo. However, the precise molecular basis for Scribble-E6 interactions remains to be defined. We now show that Scribble PDZ1 and PDZ3 are the major interactors of HPV E6 from multiple high-risk strains, with each E6 protein displaying a unique interaction profile. We then determined crystal structures of Scribble PDZ1 and PDZ3 domains in complex with the PBM motifs of E6 from HPV strains 16, 18 and 66. Our findings reveal distinct interaction patterns for each E6 PBM motif from a given HPV strain, suggesting that a complex molecular interplay exists that underpins the overt Scribble-HPV E6 interaction and controls E6 carcinogenic potential.
Spatial expression of an mRNA encoding Tie2-agonist in the capillary endothelium of the lung prevents pulmonary vascular leakage
Authors: Radloff Katrin , Gutbier Birgitt , Dunne Charlotte Maeve , Moradian Hanieh , Schwestka Marko , Gossen Manfred , Ahrens Katharina , Kneller Laura , Wang Yadong , Moga Akanksha , Gkionis Leonidas , Keil Oliver , Fehring Volker , Tondera Daniel , Giese Klaus , Santel Ansgar , Kaufmann Jörg , Witzenrath Martin 
Published: October 2022

AbstractAngiopoietin ligands Ang1 and Ang2 and the Tie2 receptor tyrosine kinases form an endothelial signaling pathway regulating vascular homeostasis and controlling vessel permeability, inflammation and angiogenic responses. Whereas Ang1-mediated Tie2 activation reduces inflammation and endothelial permeability, its antagonist, Ang2 increases it. Increased plasma Ang2 levels are associated with poor outcomes in patients with acute lung injury (ALI), as well as in acute respiratory distress syndrome (ARDS).In the study presented here we tested the effect of a novel synthetic, nucleoside-modified mRNA-76 encoding for a hyperactive Ang1 derived fusion protein (COMP-Ang1) on attenuating post-inflammation vascular leakage. COMP-Ang1 mRNA was formulated into a cationic lipid nanoparticle (cLNP) using an optimized mixture of three different lipids and a microfluidic mixing technology. After intravenous injection, the respective mRNA-loaded LNPs were found to be delivered predominantly to the endothelial cells of the lung, while sparing other vascular beds. Also, the specific multimeric folding of the COMP-Ang1 protein complex appeared to be pivotal for its activity in preventing vascular leakage and in restoring the alveolar-endothelial barrier function in the inflamed and injured pulmonary vasculature. The mode of action of mRNA-76, such as its activation of the Tie2 signal transduction pathway, was tested by pharmacological studiesin vitroandin vivoby systemic administration in respective mouse models. mRNA-76 was found to prevent lung vascular leakage/lung edema as well as neutrophil infiltration in an LPS-challenging model.
Endosomal Trafficking of Two Pore K+Efflux Channel TWIK2 to Plasmalemma Mediates NLRP3 Inflammasome Activation and Inflammatory Injury
Authors: Di Anke , Huang Long Shuang , Zhou Bisheng , Toth Peter T. , Krishnan Yamuna , Malik Asrar B. 
Published: October 2022

AbstractPotassium efflux via the two pore K+channel TWIK2 is a requisite step for the activation of the NLRP3 inflammasome, however it is unclear how the efflux is activated in response to cues. Here we report that during homeostasis, TWIK2 resides in endosomal compartments. TWIK2 is transported by endosomal fusion to the plasmalemma in response to increased extracellular ATP resulting in extrusion of K+ATP-induced endosomal TWIK2 plasmalemma translocation is regulated by Rab11a. Deleting Rab11a or ATP ligated purinergic receptor P2X7 prevented endosomal fusion with the plasmalemma and K+efflux and NLRP3 inflammasome activation in macrophages. Adoptive transfer of Rab11a-deleted macrophages into mouse lungs prevented NLRP3 inflammasome activation and inflammatory lung injury. Rab11a-mediated endosomal trafficking in macrophages thus regulates TWIK2 abundance and activity on the cell surface and downstream activation of the NLRP3 inflammasome. Endosomal trafficking of TWIK2 to the plasmalemma is therefore a potential therapy target in acute or chronic inflammatory states.
Structures of the holo CRISPR RNA-guided transposon integration complex
Authors: Park Jung-Un , Tsai Amy Wei-Lun , Rizo Alexandrea N. , Truong Vinh H. , Wellner Tristan X. , Schargel Richard D. , Kellogg Elizabeth H. 
Published: October 2022

AbstractCRISPR-associated transposons (CAST) are programmable mobile elements that insert large DNA cargo by an RNA-guided mechanism. Multiple conserved components act in concert at the target site through formation of an integration complex (transpososome). We reconstituted the type V-K CAST transpososome fromScytonema hofmannii(ShCAST) and determined the structure using cryo-EM. Transpososome architecture ensures orientation-specific association: AAA+ regulator TnsC has defined polarity and length, with dedicated interaction interfaces for other CAST components. Interestingly, transposase (TnsB)-TnsC interactions we observe contribute to stimulating TnsC’s ATP hydrolysis activity. TnsC deviates from previously observed helical configurations of TnsC, and target DNA does not track with TnsC protomers. Consequently, TnsC makes new, functionally important protein-DNA interactions throughout the transpososome. Finally, two distinct transpososome populations suggests that associations with the CRISPR effector are flexible. These ShCAST transpososome structures significantly enhances our understanding of CAST transposition systems and suggests avenues for improving CAST transposition for precision genome-editing applications.