bluuebunny/crossref_metadata_2025_split huggingface dataset:
Concurrent targeting of BMI1 and CDK4/6 abrogates tumor growth in vitro and in vivo
Authors: Elango Ramesh , Vishnubalaji Radhakrishnan , Manikandan Muthurangan , Binhamdan Sarah Ibrahim , Siyal Abdul-Aziz , Alshawakir Yasser A. , Alfayez Musaad , Aldahmash Abdullah , Alajez Nehad M. 
Published: September 2019

AbstractDespite recent advances in cancer management and therapy, resistance to cytotoxic medications remains a major clinical challenge; hence, combination-based anti-cancer treatment regimens are currently gaining momentum. PTC-209 reduced BMI1 protein expression, while palbociclib inhibited CDK4, Rb, and pRbSer795 protein expression in MDA-MB-231 cells. PTC-209 and palbociclib exhibited dose-dependent cytotoxic effects against MDA-MB-231 (breast), HCT116 (colon), and PC-3 (prostate) models, which was more profound in the combination group. Transcriptome and pathway analyses revealed inhibition of insulin signaling, focal adhesion, DNA damage response, and Wnt/pluripotency signaling pathways as well as cell proliferation, and cellular movement functional categories by PTC-209. Transcriptome and pathway analyses revealed palbociclib to mainly affect cell cycle progression and survival. Upstream analysis identified several networks affected by PTC-209 (EZH2, IFNB1, TRIB3, EGFR, SREBF1, IL1A, ERG, TGFB1, MAX, MNT) and palbociclib (RABL6, MITF, RARA, TAL1, AREG, E2F3, FOXM1, ESR1, ERBB2, and E2F). PTC-209 and palbociclib reduced colony and sphere formation, cell migration, and cell viability, which was further enhanced in the combination group. Concordantly, combination of PTC-209 and palbociclib exhibited more profound effects on MDA-MB-231 tumor formation in vivo. Our data suggest concurrent targeting of BMI1 and CDK4/CDK6 might provide novel therapeutic opportunity for breast, colon, and prostate cancer.
Characterization of drug resistance and genetic diversity of Plasmodium falciparum parasites from Tripura, Northeast India
Authors: Patgiri S. J. , Sarma K. , Sarmah N. , Bhattacharyya N. , Sarma D. K. , Nirmolia T. , Bhattacharyya D. R. , Mohapatra P. K. , Bansal D. , Bharti P. K. , Sehgal R. , Mahanta J. , Sultan A. A. 
Published: September 2019

AbstractMonitoring of anti-malarial drug resistance is vital in Northeast India as this region shares its international border with Southeast Asia. Genetic diversity of Plasmodium parasites regulates transmission dynamics, disease severity and vaccine efficacy. P. falciparum chloroquine resistance transporter (Pfcrt), multidrug resistance-1 (Pfmdr-1) and kelch 13 propeller (PfK-13) genes which govern antimalarial drug resistance and three genetic diversity markers, merozoite surface protein 1 and 2 (Pfmsp-1, Pfmsp-2) and glutamate rich protein (Pfglurp) were evaluated from Tripura, Northeast India using molecular tools. In the Pfcrt gene, 87% isolates showed triple mutations at codons M74I, N75E and K76T. 12.5% isolates in Pfmdr-1 gene showed mutation at N86Y. No polymorphism in PfK-13 propeller was found. Polyclonal infections were observed in 53.85% isolates and more commonly in adults (p = 0.0494). In the Pfmsp-1 locus, the K1 allelic family was predominant (71.2%) followed by the 3D7/IC family (69.2%) in the Pfmsp-2 locus. RII region of Pfglurp exhibited nine alleles with expected heterozygosity of 0.85. The multiplicity of infection for Pfmsp-1, Pfmsp-2 and Pfglurp were 1.56, 1.31 and 1.06 respectively. Overall, the study demonstrated a high level of chloroquine resistance and extensive parasite diversity in the region, necessitating regular surveillance in this population group.
Circulation of low pathogenic avian influenza (LPAI) viruses in wild birds and poultry in the Netherlands, 2006–2016
Authors: Bergervoet Saskia A. , Pritz-Verschuren Sylvia B. E. , Gonzales Jose L. , Bossers Alex , Poen Marjolein J. , Dutta Jayeeta , Khan Zenab , Kriti Divya , van Bakel Harm , Bouwstra Ruth , Fouchier Ron A. M. , Beerens Nancy 
Published: September 2019

AbstractIn this study, we explore the circulation of low pathogenic avian influenza (LPAI) viruses in wild birds and poultry in the Netherlands. Surveillance data collected between 2006 and 2016 was used to evaluate subtype diversity, spatiotemporal distribution and genetic relationships between wild bird and poultry viruses. We observed close species-dependent associations among hemagglutinin and neuraminidase subtypes. Not all subtypes detected in wild birds were found in poultry, suggesting transmission to poultry is selective and likely depends on viral factors that determine host range restriction. Subtypes commonly detected in poultry were in wild birds most frequently detected in mallards and geese. Different temporal patterns in virus prevalence were observed between wild bird species. Virus detections in domestic ducks coincided with the prevalence peak in wild ducks, whereas virus detections in other poultry types were made throughout the year. Genetic analysis of the surface genes demonstrated that most poultry viruses were related to locally circulating wild bird viruses, but no direct spatiotemporal link was observed. Results indicate prolonged undetected virus circulation and frequent reassortment events with local and newly introduced viruses within the wild bird population. Increased knowledge on LPAI virus circulation can be used to improve surveillance strategies.
The importance of the quaternary structure to represent conformational ensembles of the major Mycobacterium tuberculosis drug target
Authors: Tarabini Renata Fioravanti , Timmers Luís Fernando Saraiva Macedo , Sequeiros-Borja Carlos Eduardo , Norberto de Souza Osmar 
Published: September 2019

AbstractFlexibility is a feature intimately related to protein function, since conformational changes can be used to describe environmental changes, chemical modifications, protein-protein and protein-ligand interactions. In this study, we have investigated the influence of the quaternary structure of 2-trans-enoyl-ACP (CoA) reductase or InhA, from Mycobacterium tuberculosis, to its flexibility. We carried out classical molecular dynamics simulations using monomeric and tetrameric forms to elucidate the enzyme’s flexibility. Overall, we observed statistically significant differences between conformational ensembles of tertiary and quaternary structures. In addition, the enzyme’s binding site is the most affected region, reinforcing the importance of the quaternary structure to evaluate the binding affinity of small molecules, as well as the effect of single point mutations to InhA protein dynamics.
Insights on the evolution of the living Great Amazon Reef System, equatorial West Atlantic
Authors: de Mahiques Michel Michaelovitch , Siegle Eduardo , Francini-Filho Ronaldo Bastos , Thompson Fabiano Lopes , de Rezende Carlos Eduardo , Gomes José Diego , Asp Nils Edvin 
Published: September 2019

AbstractThe Great Amazon Reef (GARS) is an extensive mesophotic reef ecosystem between Brazil and the Caribbean. Despite being considered as one of the most important mesophotic reef ecosystems of the South Atlantic, recent criticism on the existence of a living reef in the Amazon River mouth was raised by some scientists and politicians. The region is coveted for large-scale projects for oil and gas exploration. Here, we add to the increasing knowledge about the GARS by exploring evolutionary aspects of the reef using primary and secondary information on radiocarbon dating from carbonate samples. The results obtained demonstrate that the reef is alive and growing, with living organisms inhabiting the GARS in its totality. Additional studies on net reef growth, habitat diversity, and associated biodiversity are urgently needed to help reconcile economic activities and biodiversity conservation.
Leucine 232 and hydrophobic residues at the ribosomal P stalk binding site are critical for biological activity of ricin
Authors: Zhou Yijun , Li Xiao-Ping , Kahn Jennifer N. , McLaughlin John E. , Tumer Nilgun E. 
Published: September 2019

Abstract
Ricin interacts with the ribosomal P stalk to cleave a conserved adenine from the α-sarcin/ricin loop (SRL) of the rRNA. Ricin toxin A chain (RTA) uses Arg235 as the most critical arginine for binding to the P stalk through electrostatic interactions to facilitate depurination. Structural analysis showed that a P2 peptide binds to a hydrophobic pocket on RTA and the last two residues form hydrogen bonds with Arg235. The importance of hydrophobic residues relative to Arg235 in the interaction with the P stalk in vivo and on the toxicity of RTA is not known. Here, we mutated residues in the hydrophobic pocket to analyze their contribution to toxicity and depurination activity in yeast and in mammalian cells. We found that Leu232, Tyr183 and Phe240 contribute cumulatively to toxicity, with Leu232 being the most significant. A quadruple mutant, Y183A/L232A/R235A/F240A, which combined mutations in critical hydrophobic residues with R235A completely abolished the activity of RTA, indicating that Arg235 and hydrophobic residues are required for full biological activity. Y183A and F240A mutants had reduced activity on RNA, but higher activity on ribosomes compared with R235A in vitro, suggesting that they could partially regain activity upon interaction with ribosomes. These results expand the region of interaction between RTA and the P stalk critical for cellular activity to include the hydrophobic pocket and provide the first evidence that interaction of P stalk with the hydrophobic pocket promotes a conformational rearrangement of RTA to correctly position the active site residues for catalytic attack on the SRL.
A novel antimicrobial polymer efficiently treats multidrug-resistant MRSA-induced bloodstream infection
Authors: Chen Xu , Lou Weiyang , Liu Jingxing , Ding Bisha , Fan Weimin , Hong Jun 
Published: September 2019

Abstract
The present study aimed to ascertain if polymer 2a, a novel synthesized antimicrobial polyionene, could treat methicillin-resistant Staphylococcus aureus (MRSA)-induced bloodstream infection. The minimum inhibitory concentration (MIC) of polymer 2a against MRSA was detected. A time-kill assay was employed to determine the killing kinetic of polymer 2a. Potential antimicrobial mechanisms of polymer 2a, including membrane disruption and programmed cell death (PCD), were explored. A resistance development assay was introduced to determine the propensity of polymer 2a toward resistance against MRSA. A mouse model of MRSA bacteremia was established to assess in vivo efficacy of polymer 2a. Furthermore, in vivo toxicity of polymer 2a was also evaluated through injection by tail vein. Polymer 2a exhibited more superior antimicrobial activity and faster killing kinetic than the control antibiotics against clinically isolated MRSA strains. Polymer 2a resulted in an obvious leakage of cellular components (concentration more than 1× MIC). mRNA expression of PCD pathway-related gene (recA) was significantly up-regulated in the presence of polymer 2a with low concentration (concentration less than 1× MIC). Repeated use of polymer 2a did not lead to drug resistance. In a MRSA-induced bloodstream infection mouse model, polymer 2a displayed superior therapeutic efficacy with negligible systemic toxicity. Moreover, polymer 2a treatment by tail vein could evidently reduce MRSA counts in blood and major organs and markedly improve living conditions. In conclusion, all these findings presented in this work convincingly suggested that polymer 2a may be a promising therapeutic alternative for treating MRSA-induced infections, especially bloodstream infection.
Nature of a shell of young stars in the outskirts of the Small Magellanic Cloud
Authors: Martínez-Delgado David , Katherina Vivas Anna , Grebel Eva K. , Gallart Carme , Pieres Adriano , Bell Cameron P. M. , Zivick Paul , Lemasle Bertrand , Clifton Johnson Lent , Carballo-Bello Julio A. , Noël Noelia E. D. , Cioni Maria-Rosa L. , Choi Yumi , Besla Gurtina , Schmidt Judy , Zaritsky Dennis , Gruendl Robert A. , Seibert Mark , Nidever David , Monteagudo Laura , Monelli Mateo , Hubl Bernhard , van der Marel Roeland , Ballesteros Fernando J. , Stringfellow Guy , Walker Alistair , Blum Robert , Bell Eric F. , Conn Blair C. , Olsen Knut , Martin Nicolas , Chu You-Hua , Inno Laura , Boer Thomas J. L. , Kallivayalil Nitya , De Leo Michele , Beletsky Yuri , Neyer Fabian , Muñoz Ricardo R. 
Published: September 2019

Context. Understanding the evolutionary history of the Magellanic Clouds requires an in-depth exploration and characterization of the stellar content in their outer regions, which ultimately are key to tracing the epochs and nature of past interactions.
Aims. We present new deep images of a shell-like overdensity of stars in the outskirts of the Small Magellanic Cloud (SMC). The shell, also detected in photographic plates dating back to the fifties, is located at ∼1.9° from the center of the SMC in the north-east direction.
Methods. The structure and stellar content of this feature were studied with multiband, optical data from the Survey of the MAgellanic Stellar History (SMASH) carried out with the Dark Energy Camera on the Blanco Telescope at Cerro Tololo Inter-American Observatory. We also investigate the kinematic of the stars in the shell using the Gaia Data Release 2.
Results. The shell is composed of a young population with an age ∼150 Myr, with no contribution from an old population. Thus, it is hard to explain its origin as the remnant of a tidally disrupted stellar system. The spatial distribution of the young main-sequence stars shows a rich sub-structure, with a spiral arm-like feature emanating from the main shell and a separated small arc of young stars close to the globular cluster NGC 362. We find that the absolute g-band magnitude of the shell is Mg, shell = −10.78 ± 0.02, with a surface brightness of μg, shell = 25.81 ± 0.01 mag arcsec−2.
Conclusion. We have not found any evidence that this feature is of tidal origin or a bright part of a spiral arm-like structure. Instead, we suggest that the shell formed in a recent star formation event, likely triggered by an interaction with the Large Magellanic Cloud and or the Milky Way, ∼150 Myr ago.
Challenges of achieving accreditation to ISO 6789-2:2017 – for the calibration of hand torque tools
Authors: Gypps Matthew 
Published: September 2019

In recent years hand torque tools have been manufactured and calibrated in accordance with the standard BS EN ISO 6789:2003. A number of flaws were identified with this standard and therefore a revised version BS EN ISO 6789:2017 was released.
The new standard required a significant increase in the number of measurements to be made which in turn created a risk to engineers, from repetitive strain injuries and a potential increase in cost to customers.
As the market leader for calibration with a high demand for accredited calibration, Trescal set the following objectives: minimise risk to Engineers, maintain a cost effective service and be the first non-manufacturer to obtain accreditation to the revised standard.
Significant investment in automated equipment not only reduced the risk of injury to engineers but also reduced calibration times and therefore cost. However the use of automated solutions for calibration of mechanical devices, created a number of challenges when trying to achieve accreditation.
Differences in the interpretation of the ISO standard by national assessment bodies resulted in variations of requirements and timescales for achieving accreditation throughout Europe.
Our presentation will highlight some of these issues.
Long-term Outcome of Subacute Thyroiditis
Authors: Görges Julia , Ulrich Jan , Keck Christoph , Müller-Wieland Dirk , Diederich Sven , Janssen Onno E. 
Published: September 2019

Abstract
Background Subacute thyroiditis (SAT) is a rare inflammatory disease that presents diagnostic challenges. The underlying pathophysiology and prediction of outcomes are elusive. We investigated the long-term follow-up of SAT for up to 30 years and determined predictors for later hypothyroidism.
Methods SAT outcome data from 127 patients (age: 47.6 ± 11.0 yrs., BMI: 24.7±4.8 kg/m²) were analyzed retrospectively. Patients with pre-existing and known causes of hypothyroidism unrelated to SAT were excluded. We also excluded patients without an accelerated erythrocyte sedimentation rate. SAT outcome parameters included anterior neck pain or tenderness of the thyroid, inflammation markers, hypoechoic areas in thyroid ultrasound, hyperthyroidism, fine-needle aspiration, and thyroid scan. Pre-treatment TSH-levels, gender, age, ultrasound findings, anti-thyroid antibodies and markers of inflammation were considered as possible predictors of SAT outcome.
Results More than 26.8% of SAT patients developed permanent hypothyroidism within 3 years of treatment. The patient groups later developing hypothyroidism did not differ in age, BMI, pre-treatment TSH levels or initial dosage of prednisolone treatment. However, high cumulative doses of prednisolone were associated with a higher prevalence of hypothyroidism. Also, women were more likely to develop hypothyroidism (OR: 3.18 (95% CI: 1.14–8.65); p=0.0176).
Conclusions Our study suggests that one-quarter of patients with SAT develop hypothyroidism in the long-term. Hypothyroidism was predicted by high cumulative doses of prednisolone treatment and female gender. The reported lower prevalence of hypothyroidism in other countries may represent the faster establishment of diagnosis, different treatment protocols, or lower susceptibility to loss of thyroid function. Swift establishment of the diagnosis and rapid tapering of steroids may result in a higher proportion of patients with euthyroidism.
Clinical Impact of the TCF7L2 Gene rs7903146 Type 2 Diabetes
Mellitus Risk Polymorphism in Women with Gestational Diabetes Mellitus: Impaired
Glycemic Control and Increased Need of Insulin Therapy
Authors: Potasso Laura , Perakakis Nikolaos , Lamprinou Apostolia , Polyzou Elektra , Kassanos Dimitrios , Peter Andreas , Päth Günter , Seufert Jochen , Laubner Katharina 
Published: September 2019

Abstract
Background The single nucleotide polymorphism in TCF7L2 rs7903146 is
associated with an increased risk of type 2 diabetes mellitus and gestational
diabetes mellitus. Mechanisms by which this mutation acts, and its impact on the
clinical course of the diseases remain unclear. Here we investigated the
clinical impact of the T risk allele in women with gestational diabetes
mellitus.
Methods We genotyped the C/T polymorphism in 164 Caucasian women
with GDM (German n=114; Greek n=50). The impact of the T allele
on the results of the 75g oral-glucose-tolerance-test, and on the required
therapy (diet/lifestyle or insulin) was investigated.
Results During oral-glucose-tolerance-test, women harboring the T allele
displayed significantly higher glucose values at 60 min (p=0.034) and
were more likely to require insulin therapy even after adjusting for
confounders, such as BMI and age.
Conclusion These results provide evidence that the T risk allele in
TCF7L2 rs7903146 is associated with failure in early postprandial glycemic
control and requirement of insulin therapy in women with gestational diabetes
mellitus, even after adjusting for confounding factors such BMI and age.
Microsurgical Treatment of Anterior Communicating Artery Aneurysms: A 20-year Single-institution Experience
Authors: Pietrantonio Andrea , Trungu Sokol , Delfini Roberto , Raco Antonino 
Published: September 2019

Abstract
Background Anterior communicating artery (AComA) aneurysms are the most frequent intracranial aneurysms. They have a high risk of rupture, morbidity, and mortality following rupture. Surgical treatment is complex because of their deep location, proximity to the perforators, and their different projections and relations with the parent vessels. This retrospective study reports our experience in the surgical management of AComA aneurysms, describing how the microsurgical strategy is influenced by their projection and size, the orientation of the AComA complex, and the location and caliber of the parent vessels.
Methods We reviewed all the patients treated surgically at our institution from September 1995 to March 2015 for ruptured and unruptured AComA aneurysms. Operative reports, neuroimages, and intraoperative videos were analyzed, and the surgical technique was examined. Illustrative cases are also included.
Results A complete documentation was available for 223 (75.3%) of the 296 treated patients. Medium-size (55.1%) and superiorly projecting (31.8%) aneurysms were the most represented; 158 patients (70.9%) had different A1 diameters. A left- or right-sided pterional approach was performed in 85 patients (38.1%) and 138 patients (61.9%), respectively. A complete occlusion was documented in 185 patients (83%).
Conclusions Posterior and superior projections are the most complex to deal with because of the difficult dissection of the perforators and the contralateral A2, respectively. Approaching from the side of the dominant A1 ensures a prompt proximal control. Searching preoperatively for an eventual rotation of the AComA complex and for the location of the A2s can be very helpful for intraoperative orientation.
Progesterone's Serum Level and a New Ultrasonographic Parameter in the First Trimester Pregnancy – Prognostic Factors for Embryonic Demise
Authors: Bucuri Carmen Elena , Ciortea Razvan , Malutan Andrei Mihai , Berceanu Costin , Rada Maria Patricia , Mihu Dan 
Published: September 2019

Abstract
Objective The etiology of embryonic demise is multifactorial, with chromosomal abnormalities being the most common (40%). The purpose of the present study is to evaluate the correlation between a serum biomarker, progesterone, and an ultrasonographic parameter, the distance between yolk sac and embryo (DYSE) in assessing the prognosis of pregnancy outcome in the 1st trimester.
Methods The present study is a prospective case-control analysis that includes 2 groups of patients: 81 patients with first-trimester normal evolutive pregnancy and 89 patients with embryonic demise, all of the patients having between 6 and 11 weeks of amenorrhea. Endovaginal ultrasonographic exploration was performed to evaluate the distance between the lower pole of the embryo and the yolk sac. From each subject enrolled in the study, 20 ml of blood was collected for progesterone serum level measurement.
Results Regarding the DYSE in the case group, lower values were observed compared with the control group, the difference being statistically significant. In the statistical analysis of serum progesterone values, statistically significant differences were observed between the 2 groups (p < 0.05).
Conclusion The DYSE has a high positive predictive value in identifying pregnancies with potentially reserved outcome, with the present study demonstrating that a DYSE < 3 mm causes an unfavorable evolution of the pregnancy. Low serum levels of progesterone are associated with an increased rate of nonviable embryos. The correlation between these two parameters increases the effectiveness of screening methods in prenatal monitoring and improves the diagnostic methods for the first-trimester pregnancies whose outcome potential can be reserved.
A Prolonged Treatment Response in Acquired Von Willebrand Syndrome
Authors: Désage Stéphanie , Le Quellec Sandra , Karlin Lionel , Lienhart Anne , Meunier Sandrine , Rugeri Lucia 
Published: September 2019

AbstractAcquired von Willebrand syndrome (AVWS) is a rare bleeding disorder. We report herein a case of AVWS due to a monoclonal gammopathy of undetermined significance, in which a transient but prolonged response to a treatment by intravenous immunoglobulin (IVIG) was observed. The diagnosis was fortuitously made in a preoperative setting for neurosurgery, after biological exploration of an isolated prolonged activated partial thromboplastin time. AVWS was confirmed by an accelerated clearance of an infused plasma-derived von Willebrand factor (VWF) concentrate. High doses of IVIG were used to perform the neurosurgery. Fifty-four days after IVIG, the patient was still responding to treatment with normal levels of factor VIII and VWF.