bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neighborhood Poverty and Sex Differences in Live Donor Kidney Transplant Outcomes in the United States
Authors: Purnell Tanjala S. , Luo Xun , Crews Deidra C. , Bae Sunjae , Ruck Jessica M. , Cooper Lisa A. , Grams Morgan E. , Henderson Macey L. , Waldram Madeleine M. , Johnson Morgan , Segev Dorry L. 
Published: February 2019

Background.
Neighborhood poverty has been associated with worse outcomes after live donor kidney transplantation (LDKT), and prior work suggests that women with kidney disease may be more susceptible to the negative influence of poverty than men. As such, our goal was to examine whether poverty differentially affects women in influencing LDKT outcomes.

Methods.
Using data from the Scientific Registry of Transplant Recipients and US Census, we performed multivariable Cox regression to compare outcomes among 18 955 women and 30 887 men who received a first LDKT in 2005–2014 with follow-up through December 31, 2016.

Results.
Women living in poor (adjusted hazard ratio [aHR], 1.30; 95% confidence interval [CI], 1.13-1.50) and middle-income (aHR, 1.26; 95% CI, 1.14-1.40) neighborhoods had higher risk of graft loss than men, but there were no differences in wealthy areas (aHR, 1.07; 95% CI, 0.88-1.29). Women living in wealthy (aHR, 0.71; 95% CI, 0.59-0.87) and middle-income (aHR, 0.82; 95% CI, 0.74-0.92) neighborhoods incurred a survival advantage over men, but there were no statistically significant differences in mortality in poor areas (aHR, 0.85; 95% CI, 0.72-1.01).

Conclusions.
Given our findings that poverty is more strongly associated with graft loss in women, targeted efforts are needed to specifically address mechanisms driving these disparities in LDKT outcomes.
High Intrapatient Variability in Tacrolimus Exposure Is Not Associated With Immune-mediated Graft Injury After Liver Transplantation
Authors: van der Veer Marlotte A.A. , Nangrahary Negina , Hesselink Dennis A. , Erler Nicole S. , Metselaar Herold J. , van Gelder Teun , Darwish Murad Sarwa 
Published: February 2019

Background.
A high intrapatient variability (IPV) in tacrolimus exposure is associated with impaired long-term clinical outcome after kidney transplantation. It remains to be determined if this is equally detrimental for liver transplant recipients. The objective of this study was to investigate the association between IPV in tacrolimus exposure and immune-mediated graft injury after liver transplantation.

Methods.
For 326 liver transplant recipients, transplanted between 2000 and 2015, tacrolimus IPV was calculated from at least 5 tacrolimus trough samples obtained between months 6 and 18 after liver transplantation and expressed as the coefficient of variation. Primary composite endpoint consisted of immune-mediated graft injury (chronic rejection, biopsy proven, and suspected late acute rejection) after month 6. Secondary outcomes were the association between tacrolimus IPV on (1) loss of renal function per year of follow-up and (2) cytomegalovirus viremia after month 6.

Results.
Of the 326 included liver transplant recipients, 70 patients (21.5%) reached the primary endpoint. Median tacrolimus coefficient of variation was 28%. There was no significant difference in reaching the primary composite endpoint between the low- and high-IPV groups (P = 0.068). Model for End-Stage Liver Disease score pretransplantation and the number of acute rejections were identified as independent predictors for immune-mediated graft injury (P = 0.049 and 0.016). A higher IPV in combination with a low kidney function at baseline (estimated glomerular filtration rate < 40 mL/min) was associated with greater loss of renal function per year of follow-up (P = 0.007). Tacrolimus variability was not associated with late cytomegalovirus viremia.

Conclusions.
High IPV in tacrolimus exposure beyond month 6 postliver transplantation was not associated with immune-mediated graft injury.
Corneal Stromal Transplantation With Human-derived Acellular Dermal Matrix for Pellucid Marginal Corneal Degeneration: A Nonrandomized Clinical Trial
Authors: Jiang Xiaodan , Wang Yuexin , Qiu Weiqiang , Huang Chen , Liu Ziyuan , Ding Tong , Shi Danna , Li Xuemin 
Published: February 2019

Background.
To investigate the transparency, biocompatibility, and safety of human-derived acellular dermal matrix for application in corneal stromal transplantation.

Methods.
Twenty-four patients (24 eyes) with pellucid marginal corneal degeneration were enrolled, and intrastromal keratoplasty was performed with human-derived acellular dermal matrix. The ocular symptoms and signs as well as graft characteristics were evaluated at baseline and at 1 day, 1 week, and 1, 3, and 6 months postoperatively. Photography by a slit lamp, topography by Pentacam, anterior segment-optical coherence tomography, and corneal confocal microscopy were conducted at baseline and during the follow-up period.

Results.
Postoperative discomfort was relieved during the follow-up period. No abnormal ocular signs were observed at 6 months, indicating the safety of the procedure. Desirable and improved transparency of the grafts was demonstrated, and all the grafts healed without dissolution or fall at 6 months postoperatively. Reepithelization was completed, and confocal microscopy revealed that keratocytes and nerves repopulated in all the grafts at 6 months postoperatively. The thinning of the marginal corneal stroma was eliminated following the transplantation, and the curvature and corneal regularity remained stable at 6 months compared with baseline.

Conclusions.
The present study demonstrated the transparency, biocompatibility, and safety of human-derived acellular dermis matrix in intrastromal keratoplasty. With further improvements, human-derived acellular dermis matrix could be applied in central lamellar keratoplasty and ultimately solve the shortage of donor grafts.
The Abnormal Oswald Ripening of Protein Nanofiber in Myofibrillar Protein Solution
Authors: Niu Fuge , Zhang Rui , Fan Jiamei , Pan Weichun 
Published: February 2019

AbstractIn solutions of myofibrillar protein extracted from giant squid (Dosidicus gigas), the size-coarsening process of protein nanofiber is complex. At high temperature (25°C), nanofiber keeps growth but with two distinguishable patterns, slow rate at the initial stage with t0.2 and the fast one at the late stage with t2.3. The intersection of these two slopes is around 300 min. Meanwhile, protein concentration in solution enhances as well. These behaviors contradict to the prediction of Ostwald ripening. Thus, we call this process as abnormal. These abnormal behaviors come from the conformation change of some types of constitution protein molecules with chemical potential reduction when they dissolve from nanofiber to solution. On the other hand, low temperature (10°C) depresses this size growth. This observation suggests that temperature regulates protein molecule conformation change in nanofiber. The consequence of this abnormal Ostwald ripening process is that all protein molecules in nanofiber are redistributed. Protein molecules with the absence of conformation change in dissolution accumulate in nanofiber to cause it growing, while the rest concentrates in solution.
Rapid and dynamic nucleic acid hybridization enables enzymatic oligonucleotide synthesis by cyclic reversible termination
Authors: Hoff K. , Halpain M. , Garbagnati G. , Edwards J. , Zhou W. 
Published: February 2019

AbstractEnzymatic oligonucleotide synthesis (EOS) has been attempted in many iterations for more than forty years, but chemical synthesis remains the industry standard despite hazardous waste produced, time restrictions, and length limitations of approximately 200 bases. Herein, we demonstrate that single-stranded oligos on a solid surface can transiently hybridize to neighboring strands and these structures can be recognized and extended by DNA polymerases and reverse transcriptases through a mechanism we describe as “bend and extend.” Additionally, we show that the sequence of the newly synthesized fragment can be controlled to create custom oligonucleotides. We used this enzymatic approach to synthesize 20 bases on a solid surface through a two-step cyclic reversible termination process with stepwise efficiency over 98%. In our approach, a nascent DNA strand that serves as both primer and template is extended through polymerase-controlled sequential addition of 3’-reversibly blocked nucleotides followed by subsequent cleavage of the 3’-capping group. This process enables oligonucleotide synthesis in an environment not permitted by traditional phosphoramidite methods, eliminates the need for hazardous chemicals, has the potential to provide faster and higher yield results, and synthesizes DNA on a solid support with a free 3’ end.
Mouse Model Systems of Autism Spectrum Disorder: Replicability and Informatics Signature
Authors: Kabitzke Patricia , Morales Diana , He Dansha , Cox Kimberly , Sutphen Jane , Thiede Lucinda , Sabath Emily , Hanania Taleen , Biemans Barbara , Brunner Daniela 
Published: February 2019

3.AbstractBackgroundPhenotyping mouse model systems of human disease has proven to be a difficult task, with frequent poor inter- and intra-laboratory replicability and translatability, particularly in behavioral domains such as social and verbal function. However, establishing robust animal model systems with strong construct validity is of fundamental importance as they are central tools for understanding disease pathophysiology and developing therapeutics. To complete our studies of mouse model systems relevant to autism spectrum disorder (ASD), we present a replication of the main findings from our two published studies comprising five genetic mouse model systems of ASD.MethodsTo assess the robustness of our previous results, we chose the two model systems that showed the greatest phenotypic differences, theShank3/FandCntnap2, and repeated assessments of general health, activity, and social behavior. We additionally explored all five model systems in the same framework, comparing all results obtained in this three-yearlong effort using informatics techniques to look for commonalities and differences.ResultsResults in the current study were very similar to our previously published results. The informatics signatures of the two model systems chosen for the replication showed that they were most distinguished by activity levels. Although the two model systems were opposite in this regard, those aspects of their social behavior not confounded by activity (vocalizations) were similar.ConclusionsOur results showed high intra-laboratory replicability of results, even for those with effect sizes that were not particularly large, suggesting that discrepancies in the literature may be dependent on subtle differences in testing conditions, housing enrichment, or background strains and not so much on the variability of the behavioral phenotypes. The overall informatics analysis suggests two main classes of model systems that in some aspects lie on opposite ends of the behavioral spectrum, supporting the view that autism is not a unitary concept.
Stochastic Single Cell Behaviour Leads to Robust Horizontal Cell Layer Formation in the Vertebrate Retina
Authors: Amini Rana , Labudina Anastasia , Norden Caren 
Published: February 2019

ABSTRACTDevelopmental programs that arrange cells and tissues into patterned organs are remarkably robust. In the developing vertebrate retina for example, neurons reproducibly assemble into distinct layers giving the mature organ its overall structured appearance. This stereotypic neuronal arrangement, termed lamination, is important for efficient neuronal connectivity. While retinal lamination is conserved in many vertebrates including humans, how it emerges from single cell behaviour is not fully understood. To shed light on this question, we here investigated the formation of the retinal horizontal cell layer. Using in vivo light sheet imaging of the developing zebrafish retina, we generated a comprehensive quantitative analysis of horizontal single cell behaviour from birth to final positioning. Interestingly, we find that all parameters analyzed including cell cycle dynamics, migration paths and kinetics as well as sister cell dispersal are very heterogeneous. Thus, horizontal cells show individual non-stereotypic behaviour before final positioning. Yet, these initially stochastic cell dynamics always generate the correct laminar pattern. Consequently, our data shows that lamination of the vertebrate retina contains a yet underexplored extent of single cell stochasticity.
The effect of cathodal tDCS on fear extinction: a cross-measures study
Authors: Ganho-Ávila Ana , Gonçalves Óscar F. , Guiomar Raquel , Boggio Paulo Sérgio , Asthana Manish Kumar , Krypotos Angelos-Miltiadis , Almeida Jorge 
Published: February 2019

AbstractExtinction-based procedures are often used to inhibit maladaptive fear responses. However, because extinction procedures show efficacy limitations, transcranial direct current stimulation (tDCS) has been suggested as a promising add-on enhancer. In this study, we tested the effect of cathodal tDCS over extinction, to unveil the processes at play that boost the effectiveness of extinction procedures and its translational potential to the treatment of anxiety disorders.We implemented a fear conditioning procedure whereby 41 healthy women (mean age = 20.51 ± 5.0) were assigned to either cathodal tDCS (n=27) or sham tDCS (n=16). Fear responses were measured with self-reports, autonomic responses, and implicit avoidance tendencies.Cathodal tDCS shows no statistically significant effect in extinction, according to self-reports, and seems to even negatively affect fear conditioned skin conductance responses. However, implicit avoidance tendencies, assessed one-to-three months after the tDCS session and extinction, reveal a group difference in the avoidance tendencies towards the neutral stimuli (F(1, 41) = 12.04,p= .001,ηp2= .227), with the active cathodal tDCS groups showing a positive bias but not the sham group. This suggests a decreased generalization effect in the tDCS group with a moderate effect size. That is, cathodal tDCS may have enhanced long-term distinctiveness between threatening cues and perceptively similar neutral cues through a disambiguation process of the value of the neutral stimuli – a therapeutic target in anxiety disorders. Future studies should confirm these results and extend the study of cathodal tDCS effect on short term avoidance tendencies.
The Tug1 Locus is Essential for Male Fertility
Authors: Lewandowski Jordan P. , Dumbović Gabrijela , Watson Audrey R. , Hwang Taeyoung , Jacobs-Palmer Emily , Chang Nydia , Much Christian , Turner Kyle , Kirby Christopher , Schulz Jana Felicitas , Müller Clara-Louisa , Rubinstein Nimrod D. , Groff Abigail F. , Liapis Steve C. , Gerhardinger Chiara , Hubner Norbert , van Heesch Sebastiaan , Hoekstra Hopi E. , Sauvageau Martin , Rinn John L. 
Published: February 2019

ABSTRACTBackgroundSeveral long noncoding RNAs (lncRNAs) have been shown to function as central components of molecular machines that play fundamental roles in biology. While the number of annotated lncRNAs in mammalian genomes has greatly expanded, their functions remain largely uncharacterized. This is compounded by the fact that identifying lncRNA loci that have robust and reproducible phenotypes when mutated has been a challenge.ResultsWe previously generated a cohort of 20 lncRNA loci knockout mice. Here, we extend our initial study and provide a more detailed analysis of the highly conserved lncRNA locus, Taurine Upregulated Gene 1 (Tug1). We report that Tug1 knockout male mice are sterile with complete penetrance due to a low sperm count and abnormal sperm morphology. Having identified a lncRNA loci with a robust phenotype, we wanted to determine which, if any, potential elements contained in the Tug1 genomic region (DNA, RNA, protein, or the act of transcription) have activity. Using engineered mouse models and cell-based assays, we provide evidence that the Tug1 locus harbors three distinct regulatory activities – two noncoding and one coding: (i) a cis DNA repressor that regulates many neighboring genes, (ii) a lncRNA that can regulate genes by a trans-based function, and finally (iii) Tug1 encodes an evolutionary conserved peptide that when overexpressed impacts mitochondrial membrane potential.ConclusionsOur results reveal an essential role for the Tug1 locus in male fertility and uncover three distinct regulatory activities in the Tug1 locus, thus highlighting the complexity present at lncRNA loci.
Thyroid hormone coordinates developmental trajectories but does not underlie developmental truncation in Danionins
Authors: Hu Yinan , Mauri Angela , Donahue Joan , Singh Rajendra , Acosta Benjamin , McMenamin Sarah 
Published: February 2019

ABSTRACTBackgroundChanges in post-embryonic developmental trajectories can profoundly alter adult phenotypes and life history transitions. In vertebrate clades with complex, biphasic life cycles, thyroid hormone (TH) regulates metamorphosis, and alterations to TH metabolism underlie famous cases of paedomorphosis. We tested the requirement for TH in multiple post-embryonic developmental processes in the zebrafish, and asked if TH loss was associated with paedomorphosis in miniaturizedDanionellas.ResultsWe found that TH regulates the relative growth of different body parts in zebrafish, inhibiting head growth at juvenile stages. The lateral line also showed sensitivity to the hormone: head neuromasts were inhibited by TH, while trunk neuromasts required TH for their proliferation. While several aspects ofDanionellamorphology resembled that of larval zebrafish, these species did not resemble hypothyroid zebrafish in their shape or lateral line, and these fish showed functional thyroid follicles.ConclusionsAlthough zebrafish do not undergo a discrete ecological transformation, we found that multiple tissues go through a protracted metamorphosis, and that TH ushers in growth patterns and processes typical of juveniles. We found no evidence that compromised TH metabolism is responsible for paedomorphosis inDanionellas.Nonetheless, modulations to TH-sensitive pathways affect evolutionarily-relevant traits, and are likely important targets for adaptation.Bullet PointsThyroid hormone regulates shifts in relative growth trajectories in different zebrafish tissuesThyroid hormone inhibits head growth in juvenile zebrafish, and regulates juvenile growth patternsThyroid hormone stimulates formation of neuromast canals in the head and ‘stitches’ on the trunk of zebrafishDanionella, the miniaturized sister group toDaniomorphologically resemble larval zebrafish and do not form neuromast canalsHypothyroidism is not the cause of paedomorphosis inDanionellaGrant SponsorsNIH R00GM105874NIH R03HD091634Burroughs Wellcome Collaborative Research Travel Grant 1017439
Biological insights from multi-omic analysis of 31 genomic risk loci for adult hearing difficulty
Authors: Kalra Gurmannat , Milon Beatrice , Casella Alex M. , Song Yang , Herb Brian R. , Rose Kevin , Hertzano Ronna , Ament Seth A. 
Published: February 2019

ABSTRACTAge-related hearing impairment (ARHI), one of the most common medical conditions, is strongly heritable, yet its genetic causes remain largely unknown. We conducted a meta-analysis of GWAS summary statistics from multiple hearing-related traits in the UK Biobank (n = up to 323,978) and identified 31 genome-wide significant risk loci for self-reported hearing difficulty (p < 5e-8), of which 30 have not been reported previously in the peer-reviewed literature at genome-wide significance. We investigated the regulatory and cell specific expression for these loci by generating mRNA-seq, ATAC-seq, and single-cell RNA-seq from cells in the mouse cochlea. Risk-associated genes were most strongly enriched for expression in cochlear epithelial cells, as well as for genes related to sensory perception and known Mendelian deafness genes, supporting their relevance to auditory function. Regions of the human genome homologous to open chromatin in sensory epithelial cells from the mouse were strongly enriched for heritable risk for hearing difficulty, even after adjusting for baseline effects of evolutionary conservation and cell-type nonspecific regulatory regions. Epigenomic and statistical fine-mapping most strongly supported 50 putative risk genes. Of these, at least 39 were expressed robustly in mouse cochlea and 16 were enriched specifically in sensory hair cells. These results reveal new risk loci and risk genes for hearing difficulty and suggest an important role for altered gene regulation in the cochlear sensory epithelium.
Allosteric Structural Alterations and Auto-regulation of Rab5 GEF Activity in Rabex5
Authors: Lauer Janelle , Cezanne Alice , Guaitoli Giambattista , Raimondi Francesco , Gentzel Marc , Alva Vikram , Habeck Michael , Ueffing Marius , Lupas Andrei , Gloeckner Christian Johannes , Zerial Marino 
Published: February 2019

AbstractIntracellular trafficking depends on the function of Rab GTPases, whose activation is regulated by guanine exchange factors (GEFs). The Rab5 GEF, Rabex5, was previously proposed to be autoinhibited by its C-terminus. Here, we studied full-length Rabex5 and Rabaptin5 proteins as well as domain deletion Rabex5 mutants using hydrogen deuterium exchange mass spectrometry. We generated a structural model of Rabex5, using chemical crosslinking mass spectrometry and integrative modeling techniques. Our results are inconsistent with the previous model of autoinhibition. By correlating structural changes with nucleotide exchange activity for each construct, we uncovered new auto-regulatory roles for the Ubiquitin binding domains and the Linker connecting those domains to the catalytic core of Rabex5. Our results suggest a more complex auto-regulation mechanism than previously thought and imply that Ubiquitin binding serves not only to position Rabex5 but to also control its Rab5 GEF activity through allosteric structural alterations.
Androgen deprivation upregulates SPINK1 expression and potentiates cellular plasticity in prostate cancer
Authors: Tiwari Ritika , Manzar Nishat , Bhatia Vipul , Yadav Anjali , Carskadon Shannon , Gupta Nilesh , Zoubeidi Amina , Palanisamy Nallasivam , Ateeq Bushra 
Published: February 2019

AbstractThe Serine Peptidase Inhibitor, Kazal type 1 (SPINK1) overexpression represents ~10-25% of the prostate cancer (PCa) cases associated with shorter recurrence-free survival and poor prognosis. Nonetheless, androgen-deprivation therapy (ADT) remains the mainstay treatment for locally advanced and metastatic PCa patients. However, majority of these individuals eventually progress to castration-resistant stage, and a subset of these patients develop ADT-induced neuroendocrine PCa. Despite adverse effects of ADT, possible role of androgen signaling in SPINK1-mediated prostate oncogenesis remains unexplored. Here, we show that androgen receptor (AR) and its corepressor, the RE1-silencing transcription factor (REST), occupySPINK1promoter and functions as a direct transcriptional repressor ofSPINK1, thus blocking AR signaling via ADT relieves its repression, leading to SPINK1 upregulation. In agreement, an inverse association between SPINK1 levels and AR expression was observed across multiple PCa cohorts, and in neuroendocrine differentiated cells. While, lineage reprogramming factor SOX2 in turn binds toSPINK1promoter leading to its transactivation in androgen-deprived conditions with concomitant increase in neuroendocrine markers. Additionally, we also confirm the role ofSPINK1in epithelial-mesenchymal transition, drug resistance, stemness and cellular plasticity. Moreover, we show that Casein Kinase 1 inhibitor stabilizes the REST levels, which in cooperation with AR, conjures transcriptional repression ofSPINK1expression, and impedes SPINK1-mediated oncogenesis. Collectively, our findings provide a plausible explanation to the paradoxical clinical outcomes of ADT, possibly due to increased SPINK1 levels. This study highlights the need to take a well-informed decision prior to ADT and develop alternative therapeutic strategies for castrate-resistant PCa patients.