bluuebunny/crossref_metadata_2025_split huggingface dataset:
The lysosomal disease caused by mutant VPS33A
Authors: Pavlova Elena V , Shatunov Aleksey , Wartosch Lena , Moskvina Alena I , Nikolaeva Lena E , Bright Nicholas A , Tylee Karen L , Church Heather J , Ballabio Andrea , Luzio J Paul , Cox Timothy M 
Published: April 2019

AbstractA rare lysosomal disease resembling a mucopolysaccharidosis with unusual systemic features, including renal disease and platelet dysfunction, caused by the defect in a conserved region of the VPS33A gene on human chromosome 12q24.31, occurs in Yakuts—a nomadic Turkic ethnic group of Southern Siberia. VPS33A is a core component of the class C core vacuole/endosome tethering (CORVET) and the homotypic fusion and protein sorting (HOPS) complexes, which have essential functions in the endocytic pathway. Here we show that cultured fibroblasts from patients with this disorder have morphological changes: vacuolation with disordered endosomal/lysosomal compartments and—common to sphingolipid diseases—abnormal endocytic trafficking of lactosylceramide. Urine glycosaminoglycan studies revealed a pathological excess of sialylated conjugates as well as dermatan and heparan sulphate. Lipidomic screening showed elevated β-D-galactosylsphingosine with unimpaired activity of cognate lysosomal hydrolases. The 3D crystal structure of human VPS33A predicts that replacement of arginine 498 by tryptophan will de-stabilize VPS33A folding. We observed that the missense mutation reduced the abundance of full-length VPS33A and other components of the HOPS and CORVET complexes. Treatment of HeLa cells stably expressing the mutant VPS33A with a proteasome inhibitor rescued the mutant protein from degradation. We propose that the disease is due to diminished intracellular abundance of intact VPS33A. Exposure of patient-derived fibroblasts to the clinically approved proteasome inhibitor, bortezomib, or inhibition of glucosylceramide synthesis with eliglustat, partially corrected the impaired lactosylceramide trafficking defect and immediately suggest therapeutic avenues to explore in this fatal orphan disease.
A 45-year experience with the Fontan procedure: tachyarrhythmia, an important sign for adverse outcome
Authors: Rijnberg Friso M , Blom Nico A , Sojak Vladimir , Bruggemans Eline F , Kuipers Irene M , Rammeloo Lukas A J , Jongbloed Monique R M , Bouma Berto J , Hazekamp Mark G 
Published: April 2019

AbstractOBJECTIVESThis study aims to evaluate our 45-year experience with the Fontan procedure and to identify risk factors for late mortality and morbidity.METHODSDemographic, preoperative, perioperative and postoperative characteristics were retrospectively collected for all patients who underwent a Fontan procedure in a single centre between 1972 and 2016.RESULTSThe study included 277 Fontan procedures (44 atriopulmonary connections, 28 Fontan-Björk, 42 lateral tunnels and 163 extracardiac conduits). Early failure occurred in 17 patients (6.1%). Median follow-up of the study cohort was 11.9 years (Q1–Q3 7.6–17.5). Longest survival estimates were 31% [95% confidence intervals (CI) 18–44%] at 35 years for atriopulmonary connection/Björk, 87% (95% CI 63–96%) at 20 years for lateral tunnel and 99% (95% CI 96–100%) at 15 years for extracardiac conduit. Estimated freedom from Fontan failure (death, heart transplant, take-down, protein-losing enteropathy, New York Heart Association III–IV) at 15 years was 65% (95% CI 52–76%) for atriopulmonary connection/Björk, 90% (95% CI 73–97%) for lateral tunnel and 90% (95% CI 82–94%) for extracardiac conduit. The development of tachyarrhythmia was an important predictor of Fontan failure [hazard ratio (HR) 2.6, 95% CI 1.2–5.8; P = 0.017], thromboembolic/neurological events (HR 3.6, 95% CI 1.4–9.4; P = 0.008) and pacemaker for sinus node dysfunction (HR 3.7, 95% CI 1.4–9.6; P = 0.008). Prolonged pleural effusion (>21 days) increased the risk of experiencing protein-losing enteropathy (HR 4.7, 95% CI 2.0–11.1; P < 0.001).CONCLUSIONSWith modern techniques, survival and freedom from Fontan failure are good. However, Fontan patients remain subject to general attrition. Tachyarrhythmia is an important sign for an adverse outcome. Prevention and early treatment of tachyarrhythmia may, therefore, be paramount in improving the long-term outcome.
Complete Minors in Graphs Without Sparse Cuts
Authors: Krivelevich Michael , Nenadov Rajko 
Published: April 2019

AbstractWe show that if $G$ is a graph on $n$ vertices, with all degrees comparable to some $d = d(n)$, and without a sparse cut, for a suitably chosen notion of sparseness, then it contains a complete minor of order $$\begin{equation*} \Omega\left( \sqrt{\frac{n d}{\log d}} \right). \end{equation*}$$As a corollary we determine the order of a largest complete minor one can guarantee in $d$-regular graphs for which the 2nd largest eigenvalue is bounded away from $d/2$, in $(d/n, o(d))$-jumbled graphs, and in random $d$-regular graphs, for almost all $d = d(n)$.
Persistence of Antibodies to 2 Virus-Like Particle Norovirus Vaccine Candidate Formulations in Healthy Adults: 1-Year Follow-up With Memory Probe Vaccination
Authors: Atmar Robert L , Baehner Frank , Cramer Jakob P , Lloyd Eric , Sherwood James , Borkowski Astrid , Mendelman Paul M ,   NOR-201 Study Group, Al-Ibrahim Mohamed S , Bernstein David L , Brandon Donald M , Chu Laurence , Davis Matthew G , Epstein Robert J , Frey Sharon E , Rosen Jeffrey B , Treanor John J 
Published: April 2019

AbstractBackgroundWe previously reported the tolerability and immunogenicity 1 month after intramuscular administration of 2 bivalent virus-like particle (VLP)–based candidate norovirus vaccine formulations in adults. We now describe the persistence of immunity and responses to a memory probe vaccination 1 year later.MethodsA total of 454 healthy men and women aged 18–49 years in 3 equal groups received placebo (saline) or 15/50 or 50/50 vaccine formulations (ie, 15 or 50 µg of GI.1 genotype VLPs, respectively, and 50 µg of GII.4c VLPs) with MPL and Al(OH)3. Immunogenicity and safety were assessed up to day 365, when 351 participants received a memory probe vaccination of 15 µg each of GI.1 and GII.4c VLPs with Al(OH)3.ResultsNo safety signals were detected up to 1 year after the first vaccination. Pan-immunoglobulin, immunoglobulin A, and histo-blood group antigen–blocking (HBGA) antibody levels among vaccinees waned but remained higher than levels before vaccination and levels in placebo recipients on days 180 and 365. Memory probe vaccination increased all antibody titers. Levels of HBGA antibodies to GI.1 but not GII.4c were higher after the first vaccination in candidate vaccine groups, compared with those in the placebo group.ConclusionLevels of antibodies to both candidate norovirus VLP formulations persisted above baseline levels for at least 1 year after primary vaccination. HBGA-blocking responses to the memory probe for GI.1 but not GII.4c displayed characteristics of immune memory.Clinical Trials RegistrationNCT02142504.
Hepatitis E Virus (HEV) Open Reading Frame 2 Antigen Kinetics in Human-Liver Chimeric Mice and Its Impact on HEV Diagnosis
Authors: Sayed Ibrahim M , Verhoye Lieven , Montpellier Claire , Abravanel Florence , Izopet Jacques , Cocquerel Laurence , Meuleman Philip 
Published: April 2019

AbstractBackgroundHepatitis E virus infection (HEV) is an emerging problem in developed countries. Diagnosis of HEV infection is based on the detection of HEV-specific antibodies, viral RNA, and/or antigen (Ag). Humanized mice were previously reported as a model for the study of HEV infection, but published data were focused on the quantification of viral RNA. However, the kinetics of HEV Ag expression during infection remains poorly understood.MethodsPlasma specimens and suspensions of fecal specimens from HEV-infected and ribavirin-treated humanized mice were analyzed using HEV antigen–specific enzyme-linked immunosorbent assay, reverse transcription–quantitative polymerase chain reaction analysis, density gradient analysis, and Western blotting.ResultOpen reading frame 2 (ORF2) Ag was detected in both plasma and stool from HEV-infected mice, and levels increased over time. Contrary to HEV RNA, ORF2 Ag levels were higher in mouse plasma than in stool. Interestingly, ORF2 was detected in plasma from mice that tested negative for HEV RNA in plasma but positive for HEV RNA in stool and was detected after viral clearance in mice that were treated with ribavirin. Plasma density gradient analysis revealed the presence of the noninfectious glycosylated form of ORF2.ConclusionORF2 Ag can be used as a marker of active HEV infection and for assessment of the effect of antiviral therapy, especially when fecal samples are not available or molecular diagnostic tests are not accessible.
Structure of the periplasmic domain of SflA involved in spatial regulation of the flagellar biogenesis of Vibrio reveals a TPR/SLR-like fold
Authors: Sakuma Mayuko , Nishikawa Shoji , Inaba Satoshi , Nishigaki Takehiko , Kojima Seiji , Homma Michio , Imada Katsumi 
Published: April 2019

Abstract
Bacteria have evolved various types of flagellum, an organella for bacterial motility, to adapt to their habitat environments. The number and the spatial arrangement of the flagellum are precisely controlled to optimize performance of each type of the flagellar system. Vibrio alginolyticus has a single sheathed flagellum at the cell pole for swimming. SflA is a regulator protein to prevent peritrichous formation of the sheathed flagellum, and consists of an N-terminal periplasmic region, a transmembrane helix, and a C-terminal cytoplasmic region. Whereas the cytoplasmic region has been characterized to be essential for inhibition of the peritrichous growth, the role of the N-terminal region is still unclear. We here determined the structure of the N-terminal periplasmic region of SflA (SflAN) at 1.9-Å resolution. The core of SflAN forms a domain-swapped dimer with tetratricopeptide repeat (TPR)/Sel1-like repeat (SLR) motif, which is often found in the domains responsible for protein–protein interaction in various proteins. The structural similarity and the following mutational analysis based on the structure suggest that SflA binds to unknown partner protein by SflAN and the binding signal is important for the precise control of the SflA function.
PCR-Based Bloodmeal Analysis of Aedes aegypti and Culex quinquefasciatus (Diptera: Culicidae) in St. George Parish, Grenada
Authors: Fitzpatrick Daniel M , Hattaway Lindsey M , Hsueh Andy N , Ramos-Niño Maria E , Cheetham Sonia M 
Published: April 2019

Abstract
Blood-feeding patterns of mosquitoes affect the transmission and maintenance of arboviral diseases. In the Caribbean, Aedes aegypti (L.) and Culex quinquefasciatus Say mosquitoes are the dominant mosquito species in developed areas. However, no information is available on the bloodmeal hosts of these invasive vectors in Grenada, where arboviral pathogens such as dengue, chikungunya, and Zika viruses cause significant human suffering. To this end, Ae. aegypti and Cx. quinquefasciatus mosquitoes were investigated from five semirural locations near houses in St. George’s Parish, from 2017 to 2018. Polymerase chain reaction was conducted on DNA extracted from individual blood-fed mosquitoes using vertebrate-specific cytochrome b primers. The 32 Ae. aegypti bloodmeals included humans (70%), mongooses (18%), domestic dogs (6%), a domestic cat (3%), and an unidentified bird (3%). Thirty-seven Cx. quinquefasciatus mosquitoes took bloodmeals from seven species of birds (51%), humans (27%), domestic cats (8%), iguanas (5%), a domestic dog (3%), a rat (3%), and a common opossum (3%). The high percentage of human bloodmeal hosts in our study, especially by the normally anthropophilic Ae. aegypti, is expected. The bloodmeal sources and the percentage of nonhuman bloodmeals (30%) taken by Ae. aegypti are comparable to other studies. The large range of hosts may be explained in part by the semirural nature of most local housing. Accordingly, this may contribute to an exchange of pathogens between domestic, peridomestic, and sylvatic transmission cycles.
Challenging the Welfare System and Forcing Policy Innovation? Unaccompanied Asylum-seeking Children in Sweden and Germany
Authors: Aflaki Inga Narbutaité , Freise Matthias 
Published: April 2019

Abstract
The article examines from a comparative perspective how Sweden and Germany reacted to the unprecedented increase in unaccompanied asylum-seeking children (UASC) in 2015. Concretely, it analyses on the basis of Windrum’s taxonomy of public-sector innovation what kinds of generic and context-specific policy instruments have been developed for this particularly vulnerable group and discusses whether and to what extent prevailing welfare-service organizational arrangements have changed in the two countries since 2015. By illustrating the reactions of two countries, the study shows that an unprecedented wave of refugees/asylum seekers can trigger both more incremental, adaptive and drastic transformative policy changes. The policy systems of both countries indicate not only some resilience, but also overburdened government capacity and more drastic changes that led to reduction of the legal rights of UASC.
Low S-adenosylmethionine/ S-adenosylhomocysteine Ratio in Urine is Associated with Chronic Kidney Disease
Authors: Kruglova Maria Petrovna , Grachev Sergej Vital’evich , Bulgakova Polina Olegovna , Ivanov Alexander Vladimirovich , Virus Edward Danielevich , Nikiforova Ksenya Alexandrovna , Fedoseev Anatolij Nikolaevich , Savina Galina Dmitrievna , Kubatiev Aslan Amirkhanovich 
Published: April 2019

Abstract

Objective
To evaluate the association of S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) in urine with chronic kidney disease (CKD).

Methods
Case-control study including 50 patients with CKD and 20 healthy volunteers.

Results
SAM level and SAM/SAH ratio in urine were significantly lower in patients than in control individuals (P &lt;.001 and P = .01, respectively). The estimated glomerular filtration rate was associated with the SAM level (P = .04) and the SAM/SAH ratio in urine (P = .01).

Conclusion
CKD is associated not only with the decline in the SAM level but also with the decrease in the SAM/SAH ratio in urine. Thus, use of the urinary SAM/SAH ratio as a noninvasive diagnostic indicator of renal function seems promising.
Foxr2 promotes formation of CNS-embryonal tumors in a Trp53-deficient background
Authors: Poh Boonmin , Koso Hideto , Momota Hiroyuki , Komori Takashi , Suzuki Yutaka , Yoshida Nobuaki , Ino Yasushi , Todo Tomoki , Watanabe Sumiko 
Published: April 2019

AbstractBackgroundEmbryonal tumors in the central nervous system (CNS) are primary, aggressive, and poorly differentiated pediatric brain tumors. We identified forkhead box R2 (Foxr2) as an oncogene for medulloblastoma through a transposon-based insertional mutagenesis screen. Foxr2 translocation has been identified in a subset of human embryonal tumors of the CNS, designated as CNS neuroblastoma with Foxr2 activation (CNS NB-Foxr2); however, the in vivo functions of Foxr2 remain elusive.MethodsWe analyzed the effect of Foxr2 overexpression in the mouse brain by generating a transgenic strain that expresses Foxr2 in the entire brain under a transformation related protein 53 (Trp53)–deficient background. We performed histological analysis of tumors and characterized tumor-derived sphere-forming cells. We investigated gene expression profiles of tumor-derived cells.ResultsFoxr2 and Trp53 loss promoted tumor formation in the olfactory bulb (OB) and brainstem (BS). The tumors showed the common morphological features of small round blue cell tumors, exhibiting divergent, mainly neuronal and glial, patterns of differentiation, which corresponds to the definition of CNS-embryonal tumors. Importantly, all mice developed CNS-embryonal tumors. In the OB, early proliferative lesions consisting of oligodendrocyte transcription factor 2 (Olig2+) cells were observed, indicating that Foxr2 expression expanded Olig2+ cells in the OB. Tumor-derived cells formed spheres in vitro and induced tumors that recapitulated the parental tumor upon transplantation, indicating the presence of tumor-initiating cells. Gene expression profiling revealed that OB and BS tumor cells were enriched for the expression of the genes specific to CNS NB-Foxr2.ConclusionOur data demonstrate that Foxr2 plays a causative role in the formation of CNS-embryonal tumors.
Heat Stress Suppresses Brassica napus Seed Oil Accumulation by Inhibition of Photosynthesis and BnWRI1 Pathway
Authors: Huang Ruizhi , Liu Zhihong , Xing Meiqing , Yang Yong , Wu Xuelong , Liu Heqin , Liang Weifang 
Published: April 2019

Abstract
Heat stress during Brassica napus seed filling severely impairs yield and oil content. However, the mechanisms underlying heat-stress effects on B. napus seed photosynthesis and oil accumulation remain elusive. In this study, we showed that heat stress resulted in reduction of seed oil accumulation, whereas the seed sugar content was enhanced, which indicated that incorporation of carbohydrates into triacylglycerols was impaired. Photosynthesis and respiration rates, and the maximum quantum yield of photosystem II in developing seeds were inhibited by heat stress. Transcriptome analysis revealed that heat stress led to up-regulation of genes associated with high light response, providing evidence that photoinhibition was induced by heat stress. BnWRI1 and its downstream genes, including genes involved in de novo fatty acid biosynthesis pathway, were down-regulated by heat stress. Overexpression of BnWRI1 with a seed-specific promoter stabilized both oil accumulation and photosynthesis under the heat-stress condition, which suggested BnWRI1 plays an important role in mediating the effect of heat stress on fatty acid biosynthesis. A number of sugar transporter genes were inhibited by heat stress, resulting in defective integration of carbohydrates into triacylglycerols units. The results collectively demonstrated that disturbances of the seed photosynthesis machinery, impairment of carbohydrates incorporation into triacylglycerols and transcriptional deregulation of the BnWRI1 pathway by heat stress might be the major cause of decreased oil accumulation in the seed.
Assessing Reality Testing in Mice Through Dopamine-Dependent Associatively Evoked Processing of Absent Gustatory Stimuli
Authors: Fry Benjamin R , Russell Nicollette , Gifford Ryan , Robles Cindee F , Manning Claire E , Sawa Akira , Niwa Minae , Johnson Alexander W 
Published: April 2019

Abstract
Impairments in reality testing are core features of numerous neuropsychiatric conditions. However, relatively few animal models have been developed to assess this critical facet of neuropsychiatric illness, thus impeding our understanding of the underlying central systems and circuits. Using mice in which dominant-negative Disrupted-in-Schizophrenia-1 is expressed throughout central nervous system circuitry (DN-DISC1-PrP), the capacity for an auditory conditioned stimulus (CS) to evoke perceptual processing of an absent sucrose solution was examined. At test, during CS presentations, DN-DISC1-PrP mice consumed more water and displayed a licking profile that is more typically revealed while ingesting a sweet-tasting solution. DN-DISC1-PrP mice also displayed greater c-fos expression in the insular (gustatory) cortex when consuming water in the presence of the CS. This capacity for the CS to more readily substitute for the taste features of the absent sucrose solution in DN-DISC1-PrP mice was attenuated following systemic treatment with the antipsychotic haloperidol. Conversely, social isolation during adolescence promoted the manifestation of these effects. These results provide strong validation for using associative learning procedures to examine dopamine-mediated reality testing associated with insular cortex activation.
Massachusetts' Parental Consent Law and Procedural Timing Among Adolescents Undergoing Abortion
Authors: Janiak Elizabeth , Fulcher Isabel R. , Cottrill Alischer A. , Tantoco Nicole , Mason Ashley H. , Fortin Jennifer , Sabino Jamie , Goldberg Alisa B. 
Published: April 2019

OBJECTIVE:
To describe individual-level delay in obtaining abortion associated with use of the Massachusetts judicial bypass system, which legal minors (aged 17 years or younger) use to obtain abortion without consent of a parent or legal guardian in the setting of Massachusetts' parental consent law for abortion.

METHODS:
We conducted a retrospective cohort study of 2,026 abortions among minors at a large, statewide network of abortion clinics between 2010 and 2016. Delay was defined as the number of calendar days between the minor's first call to the clinic to schedule an abortion, and the day the abortion was received.

RESULTS:
In the study population, 1,559 (77%) abortions were obtained with parental consent and 467 (23%) using judicial bypass. Abortions after judicial bypass were more common among minors identifying as Hispanic, non-Hispanic black, or other race, those of low socioeconomic status (as indicated by having Medicaid insurance) and those with a prior birth or prior abortion (all P<.05). Minors with parental consent received their abortion a mean of 8.6 days after initial contact, compared with 14.8 days for minors with judicial bypass, for an unadjusted difference of 6.1 days. In multivariable linear regression modeling adjusting for demographic differences between groups, this difference persisted: minors who obtained abortions after judicial bypass had a significantly greater delay compared with those with parental consent (adjusted mean difference = 5.2 days; 95% CI 4.3 to 6.2). Using multivariable logistic regression modeling, minors with judicial bypass also had higher odds of becoming ineligible for medication abortion between the day of first call and the day of procedure (adjusted odds ratio 1.57; 95% CI 1.09 to 2.26).

CONCLUSION:
Massachusetts' parental consent law for abortion is associated with delay among minors and thereby may constrain the clinical options available to them.