bluuebunny/crossref_metadata_2025_split huggingface dataset:
Crystal structures of a β-trefoil lectin from Entamoeba histolytica in monomeric and a novel disulfide bond-mediated dimeric forms
Authors: Khan Farha , Kurre Devanshu , Suguna K 
Published: January 2020

Abstractβ-Trefoil lectins are galactose/N-acetyl galactosamine specific lectins, which are widely distributed across all kingdoms of life and are known to perform several important functions. However, there is no report available on the characterization of these lectins from protozoans. We have performed structural and biophysical studies on a β-trefoil lectin from Entamoeba histolytica (EntTref), which exists as a mixture of monomers and dimers in solution. Further, we have determined the affinities of EntTref for rhamnose, galactose and different galactose-linked sugars. We obtained the crystal structure of EntTref in a sugar-free form (EntTref_apo) and a rhamnose-bound form (EntTref_rham). A novel Cys residue-mediated dimerization was revealed in the crystal structure of EntTref_apo while the structure of EntTref_rham provided the structural basis for the recognition of rhamnose by a β-trefoil lectin for the first time. To the best of our knowledge, this is the only report of the structural, functional and biophysical characterization of a β-trefoil lectin from a protozoan source and the first report of Cys-mediated dimerization in this class of lectins.
Calpain-1 ablation partially rescues disease-associated hallmarks in models of Machado-Joseph disease
Authors: Weber Jonasz J , Haas Eva , Maringer Yacine , Hauser Stefan , Casadei Nicolas L P , Chishti Athar H , Riess Olaf , Hübener-Schmid Jeannette 
Published: January 2020

Abstract
Proteolytic fragmentation of polyglutamine-expanded ataxin-3 is a concomitant and modifier of the molecular pathogenesis of Machado–Joseph disease (MJD), the most common autosomal dominant cerebellar ataxia. Calpains, a group of calcium-dependent cysteine proteases, are important mediators of ataxin-3 cleavage and implicated in multiple neurodegenerative conditions. Pharmacologic and genetic approaches lowering calpain activity showed beneficial effects on molecular and behavioural disease characteristics in MJD model organisms. However, specifically targeting one of the calpain isoforms by genetic means has not yet been evaluated as a potential therapeutic strategy. In our study, we tested whether calpains are overactivated in the MJD context and if reduction or ablation of calpain-1 expression ameliorates the disease-associated phenotype in MJD cells and mice. In all analysed MJD models, we detected an elevated calpain activity at baseline. Lowering or removal of calpain-1 in cells or mice counteracted calpain system overactivation and led to reduced cleavage of ataxin-3 without affecting its aggregation. Moreover, calpain-1 knockout in YAC84Q mice alleviated excessive fragmentation of important synaptic proteins. Despite worsening some motor characteristics, YAC84Q mice showed a rescue of body weight loss and extended survival upon calpain-1 knockout. Together, our findings emphasize the general potential of calpains as a therapeutic target in MJD and other neurodegenerative diseases.
Genome-wide scan identifies novel genetic loci regulating salivary metabolite levels
Authors: Nag Abhishek , Kurushima Yuko , Bowyer Ruth C E , Wells Philippa M , Weiss Stefan , Pietzner Maik , Kocher Thomas , Raffler Johannes , Völker Uwe , Mangino Massimo , Spector Timothy D , Milburn Michael V , Kastenmüller Gabi , Mohney Robert P , Suhre Karsten , Menni Cristina , Steves Claire J 
Published: January 2020

AbstractSaliva, as a biofluid, is inexpensive and non-invasive to obtain, and provides a vital tool to investigate oral health and its interaction with systemic health conditions. There is growing interest in salivary biomarkers for systemic diseases, notably cardiovascular disease. Whereas hundreds of genetic loci have been shown to be involved in the regulation of blood metabolites, leading to significant insights into the pathogenesis of complex human diseases, little is known about the impact of host genetics on salivary metabolites. Here we report the first genome-wide association study exploring 476 salivary metabolites in 1419 subjects from the TwinsUK cohort (discovery phase), followed by replication in the Study of Health in Pomerania (SHIP-2) cohort. A total of 14 distinct locus-metabolite associations were identified in the discovery phase, most of which were replicated in SHIP-2. While only a limited number of the loci that are known to regulate blood metabolites were also associated with salivary metabolites in our study, we identified several novel saliva-specific locus-metabolite associations, including associations for the AGMAT (with the metabolites 4-guanidinobutanoate and beta-guanidinopropanoate), ATP13A5 (with the metabolite creatinine) and DPYS (with the metabolites 3-ureidopropionate and 3-ureidoisobutyrate) loci. Our study suggests that there may be regulatory pathways of particular relevance to the salivary metabolome. In addition, some of our findings may have clinical significance, such as the utility of the pyrimidine (uracil) degradation metabolites in predicting 5-fluorouracil toxicity and the role of the agmatine pathway metabolites as biomarkers of oral health.
Statistical inference in matched case–control studies of recurrent events
Authors: Cheung Yin Bun , Ma Xiangmei , Lam K F , Li Jialiang , Yung Chee Fu , Milligan Paul , Mackenzie Grant 
Published: January 2020

Abstract

Background
The concurrent sampling design was developed for case–control studies of recurrent events. It involves matching for time. Standard conditional logistic-regression (CLR) analysis ignores the dependence among recurrent events. Existing methods for clustered observations for CLR do not fit the complex data structure arising from the concurrent sampling design.

Methods
We propose to break the matches, apply unconditional logistic regression with adjustment for time in quintiles and residual time within each quintile, and use a robust standard error for observations clustered within persons. We conducted extensive simulation to evaluate this approach and compared it with methods based on CLR. We analysed data from a study of childhood pneumonia to illustrate the methods.

Results
The proposed method and CLR methods gave very similar point estimates of association and showed little bias. The proposed method produced confidence intervals that achieved the target level of coverage probability, whereas the CLR methods did not, except when disease incidence was low.

Conclusions
The proposed method is suitable for the analysis of case–control studies with recurrent events.
Evaluation of a community pharmacy-led test-and-treat service for women with uncomplicated lower urinary tract infection in England
Authors: Thornley Tracey , Kirkdale Charlotte L , Beech Elizabeth , Howard Philip , Wilson Peter 
Published: January 2020

Abstract

Background
Uncomplicated lower urinary tract infections (UTIs) are common in women consulting primary healthcare, taking up GP resources. Delayed consultation can increase the risk of serious infections such as pyelonephritis or bacteraemia.

Objectives
To evaluate the effectiveness and uptake of a lower UTI test-and-treat service for women presenting with urinary symptoms within a community pharmacy in supporting self-care and appropriate use of antibiotics and reducing demand on other NHS resources.

Methods
The service was aligned to national guidelines to diagnose and treat lower UTI in women aged 16–64 years and used national resources to provide safety-netting and self-care advice. Consultation included clinical assessment and a urine dipstick test alongside a novel smartphone app, with diagnosis informed by test results. Women were provided with safety-netting advice and either advised on self-care, supplied with antibiotics or referred to their GP.

Results
Data were analysed for 764 women who presented to 23 pharmacies during December 2018 to April 2019. Lower UTI was found to be likely in 372/496 (75.0%) women, most of whom purchased antibiotics on the same day. Had the service not been available, approximately three-quarters of women who had completed the service and responded to the question would have visited their GP (214/301) and more than one-third would have used self-care with or without going to see their GP (116/301).

Conclusions
A community pharmacy-led UTI test-and-treat service for women aged 16–64 years presenting with urinary symptoms provided accessible and timely care aligned to national guidance, with 75.0% of consultations requiring antibiotic treatment.
Impact of added copper, alone or in combination with chlortetracycline, on growth performance and antimicrobial resistance of fecal enterococci of weaned piglets
Authors: Capps Kaylen M , Amachawadi Raghavendra G , Menegat Mariana B , Woodworth Jason C , Perryman Kurt , Tokach Mike D , Dritz Steve S , DeRouchey Joel M , Goodband Robert D , Bai Jianfa , Apley Mike D , Lubbers Brian V , Nagaraja Tiruvoor G 
Published: January 2020

AbstractStudies suggest a link between added copper (Cu) and co-selection of antimicrobial resistance (AMR) in Enterococcus spp., but data are inconsistent. This study aimed to assess the impact of added Cu, alone or with a feed-grade antimicrobial, on growth performance, transferable Cu resistance gene (tcrB) prevalence, abundance of tcrB in fecal community DNA, and AMR in fecal enterococci in weaned piglets. A total of 320 barrows (DNA 200 × 400, DNA Genetics) weaned at approximately 21 d of age with 7.4 kg (7.4 ± 0.06 kg) BW were used in a 28-d study. Piglets were fed a common non-medicated diet for 7 d of acclimation. Treatments were arranged in a 2 × 2 factorial design with main effects of added Cu (0 vs. 200 mg/kg Cu from Cu sulfate) and chlortetracycline (0 vs. 440 mg/kg CTC). Growth performance and fecal samples were obtained on days 0, 14, and 28. There was no evidence (P &gt; 0.05) for Cu and CTC interaction in growth performance. Pigs fed diets with added Cu had increased (P &lt; 0.05) ADG and ADFI from days 0 to 14, with no evidence for differences (P &gt; 0.05) from days 15 to 28 and 0 to 28. Pigs fed diets with CTC had improved (P &lt; 0.01) ADG, ADFI, and G:F from days 0 to 28. Prevalence of tcrB-positive enterococci was not affected by the addition of Cu and/or CTC (P &gt; 0.05). Prevalence of tcrB-positive enterococci was higher on day 14 than other sampling days (P = 0.002). Prevalence of tetracycline resistance gene [tet(M)]-positive enterococci was not affected by treatments or day (P &gt; 0.05). Prevalence of macrolide resistance gene [erm(B)]-positive enterococci had a significant treatment and sampling day interaction (P = 0.021). The abundance of the tcrB gene in feces, quantified by PCR, was not affected by Cu treatment. The median Cu minimum inhibitory concentrations (MIC) of tcrB-negative and -positive isolates were 3 and 20 mM, respectively (P &lt; 0.001). For day 0 and day 28, all Enterococcus isolates were susceptible to gentamicin, kanamycin, streptomycin, daptomycin, and tigecycline, with a majority of isolates resistant to chloramphenicol, erythromycin, lincomycin, linezolid, tetracycline, tylosin tartrate, and Synercid. In conclusion, 200 mg/kg added Cu or 440 mg/kg CTC in nursery diets improved growth performance of nursery pigs. Added Cu, with or without a selection pressure of CTC, did not increase Cu-resistant enterococci and did not co-select resistance to antibiotics.
Neuropathology of Speech Network Distinguishes Bulbar From Nonbulbar Amyotrophic Lateral Sclerosis
Authors: Shellikeri Sanjana , Keith Julia , Black Sandra E , Zinman Lorne , Yunusova Yana 
Published: January 2020

Abstract
Bulbar amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative subtype affecting speech and swallowing motor functions as well as associated with the burden of cognitive deficits. The neuroanatomical underpinnings of bulbar ALS are not well understood. The aim of this study was to compare neuropathology of the speech network (SpN) between 3 cases of bulbar-onset ALS (bALS), 3 cases of spinal-onset ALS (sALS) with antemortem bulbar ALS (sALSwB) against 3 sALS without antemortem bulbar ALS (sALSnoB) and 3 controls. Regional distribution and severity of neuronal loss, TDP-43 (transactive response DNA-binding protein of 43 kDa), and tau proteinopathy were examined. All 3 bALS cases showed marked neuronal loss and severe proteinopathy across most SpN regions; sALSwB cases showed no neuronal loss but mild and variable TDP-43 pathology in focal regions; sALSnoB cases demonstrated an absence of pathology. Two bALS cases had coexisting tauopathy in SpN regions, which was not noted in any sALS cases. The findings suggested that bALS may have a distinct neuropathological signature characterized by marked neuronal loss and polypathology in the SpN. Milder TDP-43 pathology in the SpN for sALSwB cases suggested a link between severity of bulbar ALS and SpN damage. Findings support a clinicopathologic link between bulbar symptoms and pathology in the SpN.
Linear Polyubiquitin Chain Modification of TDP-43-Positive Neuronal Cytoplasmic Inclusions in Amyotrophic Lateral Sclerosis
Authors: Nakayama Yoshiaki , Tsuji Kazumi , Ayaki Takashi , Mori Megumi , Tokunaga Fuminori , Ito Hidefumi 
Published: January 2020

Abstract
Neuronal cytoplasmic inclusions (NCIs) containing TAR DNA-binding protein of 43 kDa (TDP-43) are pathological hallmarks of amyotrophic lateral sclerosis (ALS) and are known to be ubiquitinated. Eight linkage types of polyubiquitin chains have been reported, each type of chain exerting different intracellular actions. The linkage type of polyubiquitin chain involved in the formation of NCIs in sporadic ALS (sALS), however, has not yet been elucidated. We performed immunohistochemical study of the spinal cords of 12 patients with sALS and on those of 6 control subjects. Virtually all ubiquitinated NCIs were immunolabeled with lysine 48-linked polyubiquitin chain (K48-Ub). Although the majority of NCIs were triple-immunoreactive for K48-Ub, linear polyubiquitin chain (L-Ub), and lysine 63-linked polyubiquitin chain (K63-Ub), thin parts of K48-Ub-immunopositive NCIs were not labeled for K63-Ub or L-Ub. We also detected HOIP and SHARPIN, components of linear ubiquitin chain assembly complex, colocalizing with L-Ub on NCIs. Moreover, the immunosignal of optineurin, an autophagy receptor working with L-Ub, and that of activated NF-κB p65, were observed to be colocalizing with L-Ub on certain parts of NCIs. The L-Ub modification of TDP-43-positive NCIs may function as an inducer of autophagic clearance of NCIs, neuroinflammation, and neurodegeneration in sALS.
Mutations in orthologous PETALOSA TOE-type genes cause a dominant double-flower phenotype in phylogenetically distant eudicots
Authors: Gattolin Stefano , Cirilli Marco , Chessa Stefania , Stella Alessandra , Bassi Daniele , Rossini Laura 
Published: January 2020

Abstract
The double-flower phenotype has been selected by humans for its attractiveness in various plant species and it is of great commercial value for the ornamental market. In this study we investigated the genetic determinant of the dominant double-flower trait in carnation, petunia, and Rosa rugosa, and identified mutant alleles of TARGET OF EAT (TOE)-type genes characterized by a disruption of the miR172 target sequence and of the C-terminal portion of the encoded protein. Despite the phylogenetic distance between these eudicots, which diverged in the early Cretaceous, the orthologous genes carrying these mutations all belong to a single TOE-type subgroup, which we name as PETALOSA (PET). Homology searches allowed us to identify PET sequences in various other species. To confirm the results from naturally occurring mutations, we used CrispR-Cas9 to induce lesions within the miR172 target site of Nicotiana tabacum PET genes, and this resulted in the development of supernumerary petaloid structures. This study describes pet alleles in economically important ornamental species and provides evidence about the possibility of identifying and engineering PET genes to obtain the desirable double-flower trait in different plants.
The WAGGS project-III. Discrepant mass-to-light ratios of Galactic globular clusters at high metallicity
Authors: Dalgleish H , Kamann S , Usher C , Baumgardt H , Bastian N , Veitch-Michaelis J , Bellini A , Martocchia S , Da Costa G S , Mackey D , Bellstedt S , Pastorello N , Cerulo P 
Published: January 2020

ABSTRACT
Observed mass-to-light ratios (M/L) of metal-rich globular clusters (GCs) disagree with theoretical predictions. This discrepancy is of fundamental importance since stellar population models provide the stellar masses that underpin most of extragalactic astronomy, near and far. We have derived radial velocities for 1622 stars located in the centres of 59 Milky Way GCs – 12 of which have no previous kinematic information – using integral-field unit data from the WAGGS project. Using N-body models, we determine dynamical masses and M/LV for the studied clusters. Our sample includes NGC 6528 and NGC 6553, which extend the metallicity range of GCs with measured M/L up to [Fe/H] ∼ −0.1 dex. We find that metal-rich clusters have M/LV more than two times lower than what is predicted by simple stellar population models. This confirms that the discrepant M/L–[Fe/H] relation remains a serious concern. We explore how our findings relate to previous observations, and the potential causes for the divergence, which we conclude is most likely due to dynamical effects.
Multiplicity functions of quasars: predictions from the MassiveBlackII simulation
Authors: Bhowmick Aklant K , Di Matteo Tiziana , Myers Adam D 
Published: January 2020

ABSTRACT
We examine multiple active galactic nucleus (AGN) systems (triples and quadruples, in particular) in the MassiveBlackII simulation over a redshift range of 0.06 ≲ z ≲ 4. We identify AGN systems (with bolometric luminosity $L_{\mathrm{bol}}\gt 10^{42}~\mathrm{erg\, s}^{-1}$) at different scales (defined by the maximum distance between member AGNs) to determine the AGN multiplicity functions. This is defined as the volume/surface density of AGN systems per unit richness R, the number of AGNs in a system. We find that gravitationally bound multiple AGN systems tend to populate scales of ${\lesssim}0.7~\mathrm{cMpc}\, h^{-1}$; this corresponds to angular separations of ≲100 arcsec and a line-of-sight velocity difference ${\lesssim}200~\mathrm{km\, s}^{-1}$. The simulation contains ∼10 and ∼100 triples/quadruples per deg2 up to depths of DESI (g ≲ 24) and LSST (g ≲ 26) imaging, respectively; at least $20{{\ \rm per\ cent}}$ of these should be detectable in spectroscopic surveys. The simulated quasar ($L_{\mathrm{bol}}\gt 10^{44}~\mathrm{erg\, s}^{-1}$) triples and quadruples predominantly exist at 1.5 ≲ z ≲ 3. Their members have black hole masses $10^{6.5}\lesssim M_{\mathrm{ bh}}\lesssim 10^{9}~\mathrm{M}_{\odot }\, h^{-1}$ and live in separate (one central and multiple satellite) galaxies with stellar masses $10^{10}\lesssim M_{*}\lesssim 10^{12}~\mathrm{M}_{\odot }\, h^{-1}$. They live in the most massive haloes (e.g. ${\sim}10^{13}~\mathrm{M}_{\odot }\, h^{-1}$ at z = 2.5; ${\sim}10^{14}~\mathrm{M}_{\odot }\, h^{-1}$ at z = 1) in the simulation. Their detections provide an exciting prospect for understanding massive black hole growth and their merger rates in galaxies in the era of multimessenger astronomy.
A large, deep 3 deg2 survey of H α, [O iii], and [O ii] emitters from LAGER: constraining luminosity functions
Authors: Khostovan A A , Malhotra S , Rhoads J E , Jiang C , Wang J , Wold I , Zheng Z-Y , Barrientos L F , Coughlin A , Harish S , Hu W , Infante L , Perez L A , Pharo J , Valdes F , Walker A R , Yang H 
Published: January 2020

ABSTRACT
We present our measurements of the H α, [O iii], and [O ii] luminosity functions as part of the Lyman Alpha Galaxies at Epoch of Reionization (LAGER) survey using our samples of 1577 z = 0.47 H α-, 3933 z = 0.93 [O iii]-, and 5367 z = 1.59 [O ii]-selected emission line galaxies in a 3 deg2 single, CTIO/Blanco DECam pointing of the COSMOS field. Our observations reach 5σ depths of 8.2 × 10−18 erg s−1 cm−2 and comoving volumes of (1−7) × 105 Mpc3 making our survey one of the deepest narrow-band surveys. We select our emission line galaxies via spectroscopic confirmation, photometric redshifts, and colour–colour selections. We measure the observed luminosity functions for each sample and find best fits of $\phi ^\star = 10^{-3.16^{+0.09}_{-0.09}}$ Mpc−3 and $L^\star = 10^{41.72^{+0.09}_{-0.09}}$ erg s−1 for H α, $\phi ^\star = 10^{-2.16^{+0.10}_{-0.12}}$ Mpc−3 and $L^\star = 10^{41.38^{+0.07}_{-0.06}}$ erg s−1 for [O iii], and $\phi ^\star = 10^{-1.97^{+0.07}_{-0.07}}$ Mpc−3 and $L^\star = 10^{41.66^{+0.03}_{-0.03}}$ erg s−1 for [O ii], with α fixed to −1.75, −1.6, and −1.3, respectively. An excess of bright &gt;1042 erg s−1 [O iii] emitters is observed and may be due to active galactic nucleus (AGN) contamination. Corrections for dust attenuation are applied assuming AHα = 1 mag. We also design our own empirical rest-frame g − r calibration using SDSS DR12 data, test it against our z = 0.47 H α emitters with zCOSMOS 1D spectra, and calibrate it for (g − r) between −0.8 and 1.3 mag. Dust and AGN-corrected star formation rate densities (SFRDs) are measured as log10ρSFR/(M⊙ yr−1 Mpc−3) = −1.63 ± 0.04, −1.07 ± 0.06, and −0.90 ± 0.10 for H α, [O iii], and [O ii], respectively. We find our [O iii] and [O ii] samples fully trace cosmic star formation activity at their respective redshifts in comparison to multiwavelength SFRDs, while the H α sample traces ∼70 per cent of the total z = 0.47 SFRD.
The identification of novel mutations in PLCZ1 responsible for human fertilization failure and a therapeutic intervention by artificial oocyte activation
Authors: Mu Jian , Zhang Zhihua , Wu Ling , Fu Jing , Chen Biaobang , Yan Zheng , Li Bin , Zhou Zhou , Wang Wenjing , Zhao Lin , Dong Jie , Kuang Yanping , Sun Xiaoxi , He Lin , Wang Lei , Sang Qing 
Published: January 2020

AbstractFertilization involves a series of molecular events immediately following egg–sperm fusion; Ca2+ oscillations are the earliest signaling event, and they initiate the downstream reactions including pronucleus formation. Successful human reproduction requires normal fertilization. In clinical IVF or ICSI attempts, some infertile couples suffer from recurrent fertilization failure. However, the genetic reasons for fertilization failure are largely unknown. Here, we recruited several couples diagnosed with fertilization failure even though their gametes are morphologically normal. Through whole-exome sequencing and Sanger sequencing, we identified biallelic mutations in gene-encoding phospholipase C zeta 1 (PLCZ1) in four independent males in couples diagnosed with fertilization failure. Western blotting showed that missense mutations decreased the level of PLCZ1 and that nonsense or frameshift mutations resulted in undetectable or truncated proteins. Expression of these mutations in mice significantly reduced the levels of oocyte activation. Artificial oocyte activation in patient oocytes could rescue the phenotype of fertilization failure and help establish pregnancy and lead to live birth. Our findings expand the spectrum of PLCZ1 mutations that are responsible for human fertilization failure and provide a potentially feasible therapeutic treatment for these patients.