bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating Associations Between Nonclinical Cardiovascular Functional Endpoints and Repeat-dose Cardiovascular Toxicity in the Beagle Dog: A Cross-company Initiative
Authors: Milliken Philip , Aylott Mike , Edmunds Nick , Engle Steven , Ewart Lorna , Fleurance Renaud , Guffroy Magali , Hargreaves Adam , Heinz-Taheny Kathleen , Kirk Sarah , Leishman Derek , Leong Louise , McMahon Nick , Valentin Jean-Pierre , Watson David , Wallis Rob , Clements Peter
Published: April 2020

Integrating nonclinical in vitro, in silico, and in vivo datasets holistically can improve hazard characterization and risk assessment. In pharmaceutical development, cardiovascular liabilities are a leading cause of compound attrition. Prior to clinical studies, functional cardiovascular data are generated in single-dose safety pharmacology telemetry studies, with structural pathology data obtained from repeat-dose toxicology studies with limited concurrent functional endpoints, eg, electrocardiogram via jacketed telemetry. Relationships between datasets remain largely undetermined. To address this gap, a cross-pharma collaboration collated functional and structural data from 135 compounds. Retrospective functional data were collected from good laboratory practice conscious dog safety pharmacology studies: effects defined as hemodynamic blood pressure or heart rate changes. Morphologic pathology findings (mainly degeneration, vacuolation, inflammation) from related toxicology studies in the dog (3–91 days repeat-dosing) were reviewed, harmonized, and location categorized: cardiac muscle (myocardium, epicardium, endocardium, unspecified), atrioventricular/aortic valves, blood vessels. The prevalence of cardiovascular histopathology changes was 11.1% of compounds, with 53% recording a functional blood pressure or heart rate change. Correlations were assessed using the Mantel-Haenszel Chi-square trend test, identifying statistically significant associations between cardiac muscle pathology and (1) decreased blood pressure, (2) increased heart rate, and between cardiovascular vessel pathology and increased heart rate. Negative predictive values were high, suggesting few compounds cause repeat-dose cardiovascular structural change in the absence of functional effects in single-dose safety pharmacology studies. Therefore, observed functional changes could prompt moving (sub)chronic toxicology studies forward, to identify cardiovascular liabilities earlier in development, and reduce late-stage attrition.
Efficacy and Safety of Single and Multiple Doses of a Fixed-dose Combination of Ibuprofen and Acetaminophen in the Treatment of Postsurgical Dental Pain
Authors: Searle Shawn , Muse Derek , Paluch Ed , Leyva Rina , DePadova Elizabeth , Cruz-Rivera Mario , Kellstein David
Published: April 2020

Objectives:

A previous pilot study demonstrated that various fixed-dose combinations (FDCs) of ibuprofen (IBU) and acetaminophen (APAP) provided analgesic efficacy comparable to a higher dose of IBU, with the same safety profile. These studies further evaluated the chosen FDC IBU/APAP 250/500 mg formulation.

Materials and Methods:

Two phase 3 dental pain studies enrolled healthy young patients with ≥moderate pain after ≥3 third molar extractions who received single-dose FDC IBU/APAP 250/500 mg, IBU 250 mg, APAP 650 mg, or placebo evaluated over 12 hours (study 1) or multiple-dose FDC or placebo every 8 hours, evaluated over 48 hours (study 2). Time-weighted sum of pain intensity differences over 8 (SPID[11]0-8) and 24 (SPID[11]0-24) hours were primary outcomes, respectively. Time to meaningful pain relief and duration of pain relief were assessed; tolerability was evaluated by adverse events.

Results:

Five hundred sixty-eight patients were randomized in study 1; 123 in study 2. Study 1: SPID[11]0-8 favored FDC significantly over placebo, IBU, and APAP (P<0.001, P=0.008, and P<0.001, respectively); study 2: SPID[11]0-24 significantly favored FDC over placebo (P<0.001), with sustained efficacy during multiple dosing. Time to meaningful pain relief occurred within 1 hour; pain relief duration was >8 hours in both studies. Adverse event rates were lowest with the FDC.

Discussion:

FDC IBU/APAP 250/500 mg provides superior analgesic efficacy to individual monocomponents (IBU 250 mg and APAP 650 mg), a rapid onset of action, >8-hour duration of pain relief, is generally well tolerated, and may provide an additional nonopioid treatment option for acute pain.
Stereotactic Navigation for Rectal Surgery: Comparison of 3-Dimensional C-Arm−Based Registration to Paired-Point Registration
Authors: Okada Tomoaki , Kawada Kenji , Sumii Atsuhiko , Itatani Yoshiro , Hida Koya , Hasegawa Suguru , Sakai Yoshiharu
Published: April 2020

BACKGROUND:

Stereotactic navigation enables surgeons to use the preoperative CT or MRI images as a real-time “navigation map.” Although stereotactic navigation has been established in neurosurgery and orthopedic surgery, whether this technology is applicable to GI tract surgery remains challenging because of tissue deformation and organ motion. A critical component of this technology is the registration that links the patient’s actual body to the preoperative imaging data.

OBJECTIVE:

The objective was to assess the applicability of stereotactic navigation in rectal surgery, focusing on the registration method.

DESIGN:

This study was based on a prospective case series.

SETTING:

The study was conducted in a single university hospital.

PATIENTS:

Four patients who underwent laparoscopic rectal surgery were included.

INTERVENTIONS:

Paired-point registration was performed for 2 cases, whereas 3-dimensional C-arm−based registration was performed for the other 2 cases. In addition, 3-dimensional C-arm−based registration was performed twice during the operation.

MAIN OUTCOME MEASURE:

Navigation accuracy was evaluated by measuring target registration error at 8 anatomical landmarks.

RESULTS:

Target registration error of the 3-dimensional C-arm−based registration group was significantly smaller than that of the paired-point registration group (median, 19.5 mm vs 54.1 mm; p < 0.001). In particular, the error of Z-axis (cranial-to-caudal direction) was significantly smaller in 3-dimensional C-arm−based registration (median, 12.4 mm vs 48.8 mm; p < 0.001). In one case in the 3-dimensional C-arm−based registration group, target registration error of the second registration became significantly smaller than that of the first registration (p = 0.008).

LIMITATIONS:

This was an observational study with small sample size.

CONCLUSION:

Three-dimensional C-arm−based registration could be performed with the patient in a lithotomy position with head down and lateral tilt without being affected by positional changes. Three-dimensional C-arm−based registration resulted in significantly higher navigation accuracy than paired-point registration, and its accuracy could be further improved by intraoperative re-registration.
Clinically significant pseudophakic cystoid macular edema after bag-in-the-lens implantation
Authors: Scheers Dorothée , Van Os Luc , Ní Dhubhghaill Sorcha , Wouters Kristien , Tassignon Marie-José
Published: April 2020

Purpose:

To determine the incidence of clinically significant pseudophakic cystoid macular edema (CSPME) after phacoemulsification using the bag-in-the-lens intraocular lens (BIL IOL) implantation technique and to examine the influence of associated risk factors, both ocular and systemic.

Setting:

Monocentric, Antwerp University Hospital, Belgium.

Design:

Retrospective.

Methods:

This study included 1 077 first-operated eyes of 1 077 adults who underwent phaco-emulsification cataract surgery using the BIL IOL implantation technique between January 2013 and December 2015.

Results:

The 3-month incidence of CSPME in the subgroup without risk factors was 0% (95% CI, 0.0-0.0). The 3-month incidence of CSPME in the subgroup with risk factors was 2.8% (95% CI, 1.3-4.3). The 3-month incidence of CSPME in the total group of 1077 patients was 1.4% (95% CI, 0.6-2.1). The risk factors most significantly associated with CSPME included diabetes (hazard ratio [HR]: 5.37; 95% CI, 1.5-19.3; P = .019), exudative age-related macular degeneration (HR: 121; 95% CI, 36.1-409; P < .001), and macular traction (HR: 6.47; 95% CI, 1.9-22.1; P < .009).

Conclusions:

The incidence of CSPME was zero in eyes without risk factors. The incidence was consistent with previous reports in the literature regarding the lens-in-the-bag IOL implantation technique in eyes with risk factors. This indicates that the BIL IOL implantation technique is a safe procedure and does not confer a higher risk for developing cystoid macular edema after cataract surgery compared with the lens-in-the-bag IOL implantation technique, despite the requirement of a primary posterior continuous curvilinear capsulorhexis.
A risk score based on simple angiographic characteristics to aid in choosing the optimal revascularization strategy for patients with multivessel disease presenting with ST-elevation myocardial infarction
Authors: Schamroth Pravda Nili , Witberg Guy , Zusman Oren , Landes Uri , Bental Tamir , Assali Abid , Vaknin Assa Hana , Greenberg Gabriel , Codner Pablo , Perl Leor , Kornowski Ran
Published: April 2020

Background:

The optimal revascularization strategy is not clearly defined for patients with ST-elevation myocardial infarction with multivessel disease (MV-STEMI). We aimed to develop a simple angiographic risk score for identifying patients with MV-STEMI that might benefit from a multivessel percutaneous coronary intervention (MV-PCI), compared to a PCI for only the infarct-related artery (IRA-PCI).

Methods and results:

This retrospective study acquired data from a single-center STEMI registry on 841 consecutive patients with MV-STEMI (645 IRA-PCI and 196 MV-PCI). Patients were stratified according to high- and low-risk scores. We devised a score based on three characteristics of non-culprit lesions previously reported to predict overall mortality (proximal left anterior descending artery involvement, maximal % stenosis, and number of involved vessels). The primary endpoint was major adverse cardiac events (MACEs: a composite of death/MI/urgent repeat revascularization). After a median follow-up of 1909 days, MACE occurred in 205/841 (24.4%) patients. MACE risk was higher in the high-risk than in the low-risk group (HR 1.43, P < 0.001). In comparing the IRA-PCI and MV-PCI approaches within each risk group, we found that these revascularization strategies had differential effects on outcome. Compared to the MV-PCI, IRA-PCI was associated with less MACE in the low-risk group (HR 0.597, P = 0.033), and more MACE in the high-risk group (HR 3.14, P < 0.001).

Conclusion:

For patients with MV-STEMI that undergo primary PCI, a simple risk score based on three angiographic characteristics could identify patients at high risk of future adverse events. This score might facilitate choosing the optimal revascularization strategy.
Bilateral internal thoracic artery grafting in patients with left main disease: a single-center experience
Authors: Gordon Amit , Nesher Nachum , Mohr Raphael , Pevni Dmitry , Kramer Amir , Ziv-Baran Tomer , Paz Yosef , Ben-Gal Yanai
Published: April 2020

Objective

We compared early and long-term outcomes between bilateral internal thoracic artery (BITA) grafting and single internal thoracic artery (SITA) grafting in patients with LM disease.

Methods

We evaluated the outcomes of all patients with LM disease who underwent revascularization in our center during 1996–2011. Variables that were adjusted for in a multivariate analysis and in propensity matching included age, sex, comorbid diseases, repeat operation, the number of diseased vessels, other conduits used, the use of sequential grafting, the number of grafts constructed, and the operative era (1996–2000 vs. 2001–2011).

Results

In total, 949 patients with LM disease underwent BITA grafting and 564 underwent SITA grafting during the study period. SITA patients were more often female and more likely to have comorbidities such as chronic obstructive pulmonary disease, ejection fraction <30%, recent myocardial infarction, diabetes, congestive heart failure, chronic renal failure, and peripheral vascular disease, and to have undergone an emergency operation. We found no statistically significant difference between the SITA and BITA groups in 30-day mortality (4.8% vs. 3.3%, P = 0.136), sternal wound infection (2.0% vs. 2.4%, P = 0.548), and stroke (3.2% vs. 4.4%, P = 0.234). BITA patients had improved long-term survival (70.1% vs. 52.0% p<0.001), median follow-up of 15 years. In multivariate analysis, after propensity score matching (477 matched pairs), this finding was not statistically significant (P = 0.135).

Conclusion

This study did not demonstrate a clear benefit of BITA grafts among patients with LM disease.
Supporting African American Mothers during Nurse Home Visits in Adopting Safe Sleep Practices
Authors: Stiffler Deborah , Matemachani Sherry Mukasa , Crane Lisa
Published: April 2020

Background:

Nurses providing home visits were concerned that some mothers were not routinely using safe sleep practices for their newborns and infants.

Purpose:

The purpose of this study was to listen to how home visit nurses offer education to their African American clients about the safe to sleep guidelines during the prenatal and postpartum periods and discuss ways nurses could support mothers to be more successful in using safe sleep practices.

Study Design and Methods:

A focus group was conducted with home visit nurses who partner with pregnant mothers and follow them through the first 2 years of their child's life. We asked the nurses to discuss how they offer information and education to their African American clients about safe sleep practices and what could be done to support adoption of the guidelines. A qualitative narrative approach was used for data analysis.

Results:

Seventeen home visit nurses participated in the focus group. We identified two overall themes with eight subthemes. The first theme focused on nurses' perceptions about challenges some mothers have in following the recommendations. The second theme included nurses' perspectives on how to better promote the safe sleep message and educating mothers within their cultural context.

Clinical Implications:

Expectant and new mothers need advice and knowledge about the Safe to Sleep® guidelines that provide ways to decrease risk of infant death. Nurses must be aware of their clients' culture and beliefs so they can offer support and information on infant safety within that context.
Hybrid origin ofPopulus tomentosaCarr. identified through genome sequencing and phylogenomic analysis
Authors: An Xinmin , Gao Kai , Chen Zhong , Li Juan , Yang Xiong , Yang Xiaoyu , Zhou Jing , Guo Ting , Zhao Tianyun , Huang Sai , Miao Deyu , Khan Wasif Ullah , Rao Pian , Ye Meixia , Lei Bingqi , Liao Weihua , Wang Jia , Ji Lexiang , Li Ying , Guo Bing , Mustafa Nada Siddig , Li Shanwen , Yun Quanzheng , Keller Stephen R. , Mao Jianfeng , Zhang Rengang , Strauss Steven H.
Published: April 2020

Populus tomentosais widely distributed and cultivated in the Northern and Central China, where it is of great economic and ecological importance. However, the origin ofP. tomentosaremains controversial. Here, we used a PacBio+Hi-C+Illumina strategy to sequence and assemble its 740.2 Mb (2n) genome. The assembly accounts for greater than 92.1% of the 800-megabase genome, comprises 38 chromosomes, and contains 59,124 annotated protein-coding genes. Phylogenomic analyses elucidated dynamic genome evolution events among its closely related white poplars, and revealed thattomentosais comprised of two subgenomes, which we deomonstrate is likely to have resulted from hybridization betweenPopulus adenopodaas the female, andPopulus albavar.pyramidalisas the male, around 3.93 Mya. We also detected structural variations and allele-indels across genome. Our study presents a high quality and well assembled genome, unveils the origin of the widely distributed and plantedP. tomentosa, and provides a powerful resource for comparative plant biology, breeding, and biotechnology.
Cognitive Flexibility Deficits in Rats with Dorsomedial Striatal 6-OHDA Lesions Tested Using a 3-Choice Serial Reaction Time Task with Reversal Learning
Authors: Wang Zhuo , Flores Ilse , Donahue Erin K. , Lundquist Adam J. , Guo Yumei , Jakowec Michael W. , Holschneider Daniel P.
Published: April 2020

Lesions of the dorsomedial striatum elicit deficits in cognitive flexibility that are an early feature of Parkinson’s disease (PD), and presumably reflect alterations in frontostriatal processing. The current study aimed to examine deficits in cognitive flexibility in rats with bilateral 6-hydroxydopamine (6-OHDA) lesions in the dorsomedial striatum. While deficits in cognitive flexibility have previously been examined in rodent PD models using the cross-maze, T-maze, and a food-digging task, the current study is the first to examine such deficits using a 3-choice serial reaction time task (3-CSRT) with reversal learning (3-CSRT-R). Although the rate of acquisition in 3-CSRT was slower in lesioned compared to control rats, lesioned animals were able to acquire a level of accuracy comparable to that of control animals following 16 days of training. In contrast, substantial and persistent deficits were apparent during the reversal learning phase. Our results demonstrate that deficits in cognitive flexibility can be robustly unmasked by reversal learning in the 3-CSRT-R paradigm, which can be a useful test for evaluating effects of dorsomedial striatal deafferentation.
New Insights Into the Effect of Residue Mutation on the Rotavirus VP1 Function Using Molecular Dynamic Simulations
Authors: Abid Nabil , Salemi Marco , Chillemi Giovanni
Published: April 2020

Rotavirus group A remains a major cause of diarrhea in infants and young children worldwide. The permanently emergence of new genotypes puts the potential effectiveness of vaccines under serious question. Thirteen VP1 mutants were analyzed using molecular dynamic simulations and the results were combined with the experimental findings, reported previously. The results revealed structural fluctuations and secondary structure change of VP1 protein that may alter its function during viral replication/transcription. Altogether, the structural analysis of VP1 may boost efforts to develop antivirals, as they might complement the available vaccines.
Metabolic pathway alterations in microvascular endothelial cells in response to hypoxia
Authors: Cohen Emily B. , Geck Renee C. , Toker Alex
Published: April 2020

The vasculature within a tumor is highly disordered both structurally and functionally. Endothelial cells that comprise the vasculature are poorly connected causing vessels to be leaky and exposing the endothelium to a hypoxic microenvironment. Therefore, most anti-angiogenic therapies are generally inefficient and result in acquired resistance to increased hypoxia due to elimination of the vasculature. Recent studies have explored the efficacy of targeting metabolic pathways in tumor cells in combination with anti-angiogenic therapy. However, the metabolic alterations of endothelial cells in response to hypoxia has been relatively unexplored. Here, we measured polar metabolite levels in microvascular endothelial cells exposed to short- and long-term hypoxia with the goal of identifying metabolic vulnerabilities that can be targeted to normalize tumor vasculature and improve drug delivery. Many amino acid-related metabolites were altered by hypoxia exposure, especially within alanine-aspartate-glutamate, serine-threonine, and cysteine-methionine metabolism. Additionally, there were significant changes inde novopyrimidine synthesis as well as glutathione and taurine metabolism. These results provide key insights into the metabolic alterations that occur in endothelial cells in response to hypoxia, which serve as a foundation for future studies to develop therapies that lead to vessel normalization and more efficient drug delivery.
Assessments of hepatitis B virus-like particles and Crm197 as carrier proteins in melioidosis glycoconjugate vaccines
Authors: Bayliss Marc , Donaldson Matthew I. , Pergolizzi Giulia , Scott Andrew E. , Nepogodiev Sergey A. , Beales Lucy , Whelan Michael , Rosenberg William , Peyret Hadrien , Lomonossoff George P. , Harmer Nicholas J. , Atkins Tim , Field Robert A. , Prior Joann L.
Published: April 2020

The Tier 1 select agentBurkholderia pseudomalleiis the causative agent of melioidosis, a global pathogen and a major cause of pneumonia and sepsis for which no licensed vaccines currently exist. Previous work has shown the potential forBurkholderiacapsular polysaccharide (CPS) to be used as a vaccine antigen but the T-cell independent nature of the immune response to this molecule requires the use of this polysaccharide as a glycoconjugate for vaccination. Recent studies have focussed on the use of Crm197 (a non-toxic mutant protein derived from diphtheria toxin) as the carrier but there are concerns regarding its potential to cause interference with other vaccines containing Crm197. Therefore research with alternative carrier proteins would be beneficial. In this study, CPS was isolated from the non-pathogenicB. thailandensisstrain E555. This was chemically conjugated to Crm197, or Tandem Core™ virus-like particles (TCVLP) consisting of hepatitis B core protein, which is the first documented use of VLPs in melioidosis vaccine development. Analysis of CPS-specific IgG antibody titres showed that mice vaccinated with the Crm197 conjugate generated significantly higher titres than the mice that received TCVLP-CPS but both conjugate vaccines were able to protect mice against intraperitonealB. pseudomalleistrain K96243 challenges of multiple median lethal doses.
Complete representation of a tapeworm genome reveals chromosomes capped by centromeres, necessitating a dual role in segregation and protection
Authors: Olson Peter D. , Tracey Alan , Baillie Andrew , James Katherine , Doyle Stephen R. , Buddenborg Sarah K. , Rodgers Faye H. , Holroyd Nancy , Berriman Matt
Published: April 2020

Background

Chromosome-level assemblies are indispensable for accurate gene prediction, synteny assessment and understanding higher-order genome architecture. Reference and draft genomes of key helminth species have been published but little is yet known about the biology of their chromosomes. Here we present the complete genome of the tapewormHymenolepis microstoma,providing a reference-quality, end-to-end assembly that represents the first fully assembled genome of a spiralian/lophotrochozoan, revealing new insights into chromosome evolution.

Results

Long-read sequencing and optical mapping data were added to previous short-read data enabling complete re-assembly into six chromosomes, consistent with karyology. Small genome size (169 Mb) and lack of haploid variation (1 SNP/3.2 Mb) contributed to exceptionally high contiguity with only 85 gaps remaining in regions of low complexity sequence. Resolution of repeat regions reveals novel gene expansions, micro-exon genes, and spliced leader transsplicing, and illuminates the landscape of transposable elements, explaining observed length differences in sister chromatids. Syntenic comparison with other parasitic flatworms shows conserved ancestral linkage groups indicating that theH. microstomakaryotype evolved through fusion events. Strikingly, the assembly reveals that the chromosomes terminate in centromeric arrays, indicating that these motifs play a role not only in segregation, but also in protecting the linear integrity and full lengths of chromosomes.

Conclusions

Despite strong conservation of canonical telomeres, our results show that they can be substituted by more complex, species-specific sequences, as represented by centromeres. The assembly provides a robust platform for investigations that require complete genome representation.
The effect of recombination on the evolution of a population ofNeisseria meningitidis
Authors: MacAlasdair Neil , Pesonen Maiju , Brynildsrud Ola , Eldholm Vegard , Kristiansen Paul A. , Corander Jukka , Caugant Dominique A. , Bentley Stephen D
Published: April 2020

Neisseria meningitidis(the meningococcus) is a major human pathogen with a history of high invasive disease burden, particularly in sub-Saharan Africa. Our current understanding of the evolution of meningococcal genomes is limited by the rarity of large-scale genomic population studies and lack of in-depth investigation of the genomic events associated with routine pathogen transmission. Here we fill this knowledge gap by a detailed analysis of 2,839 meningococcal genomes obtained through a carriage study of over 50,000 samples collected systematically in Burkina Faso, West Africa, before, during, and after the serogroup A vaccine rollout, 2009-2012. Our findings indicate that the meningococcal genome is highly dynamic, with recombination hotspots and frequent gene sharing across deeply separated lineages in a structured population. Furthermore, our findings illustrate the profound effect of population structure on genome flexibility, with some lineages in Burkina Faso being orders of magnitude more recombinant than others. We also examine the effect of selection on the population, in particular how it is correlated with recombination. We find that recombination principally acts to prevent the accumulation of deleterious mutations, although we do also find an example of recombination acting to speed the adaptation of a gene. In general, we show the importance of recombination in the evolution of a geographically expansive population with deep population structure in a short timescale. This has important consequences for our ability to both foresee the outcomes of vaccination programmes and, using surveillance data, predict when lineages of the meningococcus are likely to become a public health concern.
Targeted Eicosanoid Profiling Reveals MicroRNA-155 Shifts PGE2/PGD2 Balance Towards Oncogenic State
Authors: Kim Sinae , Lee Eun Sung , Lee Eun ji , Jung Jae Yun , Lee Sae Byul , Lee Hee Jin , Kim Jisun , Kim Hee Jung , Lee Jong Won , Son Byung Ho , Gong Gyungyub , Ahn Sei Hyun , Chang Suhwan
Published: April 2020

microRNA-155 is a strong oncogenic microRNAs with multiple functions. To reveal its novel function in cancer metabolism, we performed a targeted metabolomic analysis of icosanoids, the key metabolites of inflammation-related carcinogenesis. We found miR-155-depleted cells expressed unbalanced prostaglandins, especially in PGE2 and PGD2. Subsequent analysis of primary cancer cells and 20 TNBC specimen indicated a positive correlation between miR-155 and PGE2/PGD2 ratio. Mechanistically, miR-155 controls the prostaglandin shift by up-regulating PGE2-producing enzymes PTGES/PTGES2 and down-regulating PGD2-producing enzyme PTGDS. Further analysis showed that the up-regulation ofPTGES2is driven by miR-155-cMYC axis whereasPTGESis transactivated by miR-155-KLF4 axis, indicating a dual-regulatory mode for the metabolic enzyme expression drives a shift in PGE2/PGD2 balance. Lastly, we show the miR-155-driven cellular proliferation is significantly restored by the siRNA of PTGES1/2, of which expression also correlates with patients’ survival. Taken altogether, our study reveals an unprecedented oncogenic function of miR-155 on prostaglandin regulation.
Clathrin adaptor AP-1 and Stratum act in parallel pathways to control Notch activation inDrosophilaSensory Organ Precursor Cells
Authors: Bellec Karen , Pinot Mathieu , Gicquel Isabelle , Le Borgne Roland
Published: April 2020

Drosophilasensory organ precursors divide asymmetrically to generate pIIa/pIIb cells whose identity relies on the differential activation of Notch at cytokinesis. While Notch is present apically and basally relative to the midbody at the pIIa-pIIb interface, only the basal pool of Notch is reported to contribute to Notch activation in the pIIa cell. Correct intra-lineage signalling requires appropriate apico-basal targeting of Notch, its ligand Delta and its trafficking partner Sanpodo. We previously reported that AP-1 and Stratum regulate the intracellular trafficking of Notch and Sanpodo from thetrans-Golgi network to the basolateral membrane. Loss of AP-1 or Stratum caused mildNotchgain-of-function phenotypes. Here, we report that the concomitant loss of AP-1 and Stratum results in a much more penetrantNotchgain-of-function phenotype indicating that AP-1 and Strat control two parallel pathways. While unequal partitioning of cell fate determinants and cell polarity were unaffected, Numb-mediated symmetry breaking is impaired. We further observed increased amounts of signaling competent Notch as well as Delta and Sanpodo at the apical pIIa-pIIb interface and the loss of the basal pool of Notch. We propose that AP-1 and Stratum operate in two parallel pathways to ensure the correct apico-basal localization of Notch controlling where receptor activation takes place.
Addressable Nanoantennas with Cleared Hotspots for Single-Molecule Detection on a Portable Smartphone Microscope
Authors: Trofymchuk Kateryna , Glembockyte Viktorija , Grabenhorst Lennart , Steiner Florian , Vietz Carolin , Close Cindy , Pfeiffer Martina , Richter Lars , Schütte Max L. , Selbach Florian , Yaadav Renukka , Zähringer Jonas , Wei Qingshan , Ozcan Aydogan , Lalkens Birka , Acuna Guillermo P. , Tinnefeld Philip
Published: April 2020

The advent of highly sensitive photodetectors1,2and the development of photostabilization strategies3made detecting the fluorescence of a single molecule a routine task in many labs around the world. However, to this day, this process requires cost-intensive optical instruments due to the truly nanoscopic signal of a single emitter. Simplifying single-molecule detection would enable many exciting applications,e.g.in point-of-care diagnostic settings, where costly equipment would be prohibitive.4Here, we introduce addressable NanoAntennas with Cleared HOtSpots (NACHOS) that are scaffolded by DNA origami nanostructures and can be specifically tailored for the incorporation of bioassays. Single emitters placed in the NACHOS emit up to 461-fold brighter enabling their detection with a customary smartphone camera and an 8-US-dollar objective lens. To prove the applicability of our system, we built a portable, battery-powered smartphone microscope and successfully carried out an exemplary single-molecule detection assay for DNA specific to antibiotic-resistantKlebsiella pneumonia"on the road “.
Requirement of DNMT1 to orchestrate epigenomic reprogramming during NPM-ALK driven T cell lymphomagenesis
Authors: Redl Elisa , Sheibani-Tezerji Raheleh , Hamminger Patricia , Timelthaler Gerald , Hassler Melanie Rosalia , Lagger Sabine , Dillinger Thomas , Hofbauer Lorena , Zrimšek Maša , Tiefenbacher Andreas , Kothmayer Michael , Dietz Charles H. , Ramsahoye Bernard H. , Kenner Lukas , Bock Christoph , Seiser Christian , Ellmeier Wilfried , Schweikert Gabriele , Egger Gerda
Published: April 2020

Malignant transformation depends on genetic and epigenetic events that result in a burst of deregulated gene expression and chromatin changes. To dissect the sequence of events in this process, we used a T cell-specific lymphoma model based on the human oncogenic NPM-ALK translocation. We find that transformation of T cells shifts thymic cell populations to an undifferentiated immunophenotype, which occurs only after a period of latency, accompanied by induction of the MYC-NOTCH1 axis and deregulation of key epigenetic enzymes. We discover aberrant DNA methylation patterns, overlapping with regulatory regions, plus a high degree of epigenetic heterogeneity between individual tumors. In addition, ALK positive tumors show a loss of collaborative methylation patterns of neighboring CpG sites. Notably, deletion of the maintenance DNA methyltransferase DNMT1 completely abrogates lymphomagenesis in this model, despite oncogenic signaling through NPM-ALK, suggesting that faithful maintenance of tumor-specific methylation through DNMT1 is essential for sustained proliferation and tumorigenesis.

STATEMENT OF SIGNIFICANCE

Epigenetic alterations are causally involved in tumorigenesis. Here we show that induction of a single human oncogene in murine T cells induces specific deregulation of epigenetic enzymes resulting in epigenomic alterations similar to human tumors. Our findings are of broader implication to understand how epigenomic processes are shaped by oncogene induced transformation.
Numerical analysis of dynamic properties of wrinkled thin membranes
Authors: Wang Xiaofeng , Chu Haoyue , Yang Qingshan
Published: April 2020

Purpose

This paper aims to numerically study the effects of boundary conditions, pre-stress, material constants and thickness on the dynamic performance of a wrinkled thin membrane.

Design/methodology/approach

Based on the stability theory of plates and shells, the dynamic equations of a wrinkled thin membrane were developed, and they were solved with the Lanczos method

Findings

The effects of wrinkle-influencing factors on the dynamic performance of a wrinkled membrane are determined by the wrinkling stage. The effects are prominent when wrinkling deformation is evolving, but they are very small and can hardly be observed when wrinkling deformation is stable. Mode shapes of a wrinkled membrane are sensitive to boundary conditions, pre-stress and Poisson’s ratio, but its natural frequencies are sensitive to all these five factors.

Practical implications

The research work in this paper is expected to help understand the dynamic behavior of a wrinkled membrane and present access to ensuring its dynamic stability by controlling the wrinkle-influencing factors.

Originality/value

Very few documents investigated the dynamic properties of wrinkled membranes. No attention has yet been paid by the present literature to the global dynamic performance of a wrinkled membrane under the influences of the factors that play a pivotal role in the wrinkling deformation. In view of this, this paper numerically studied the global modes and corresponding frequencies of a wrinkled membrane and their variation with the wrinkle-influencing factors. The results indicate that the global dynamic properties of a wrinkled membrane are sensitive to these factors at the stage of wrinkling evolution.
Packaging strategies: knowledge outlook on consumer buying behaviour
Authors: Rambabu Lavuri , Porika Ramlal
Published: April 2020

Purpose

Packaging is a mantra for encountering a period of immense potential. It keeps on being seen as a key component in the buying decision, and also it is exhibited as a brand communication gadget that goes past the products and can interface with customers in both the physical and virtual forms. The research aspiration is to establish that the speculation of packaging approaches will influence on buyers’ purchasing mode. An attempt has been made to examine and present the results. This research facilitates to discern the perception of consumer in the direction of packaging strategies and to spot the power of packaging factors, elements and strategies of product packaging on purchasing mode of buyers.

Design/methodology/approach

Data were collected from 836 respondents from the four major cities of two states in India through structure questionnaire. Every age of the respondents was targeted in the this study to get their perception and buying mode of them, and the analysis was done by using analysis of variance, correlation and regression analysis by using 23.0 version of SPSS.

Findings

The consequence of research reveals that media exposures, packaging strategies and elements have better influence on the buyers’ buying mode. Business people must produce innovative bundling designs for their items to market. These allow the keeping and catching the new and existed customers, because packaging has superior influence and also helps in acquiring and retaining the new consumers for their new products.

Research limitations/implications

This study being at micro level considered that the city customers may not be similar to the rural customers. Hence, the perception of rural and urban may not be much different. A sample size is 836 drawn from the four major cities of two states in India; therefore, the sample may not represent the whole population of India. Hence, the limitation of generalization will be there. The elicited opinion of consumers may not be reliable all the times, and study considered only some of FMCG products.

Originality/value

The study theme is to establish the theory as stated earlier, and it's proved consumers are considering the packaging styles and designs while purchasing the products, which promotes to meet the expectations of the present and potential customers.
Changes in climate and land use interact to create an ecological trap in a migratory species
Authors: Buderman Frances E. , Devries Jim H. , Koons David N.
Published: April 2020

Anthropogenic landscape alteration and climate change can have multiscale and interrelated effects on ecological systems. Such changes to the environment can disrupt the connection between habitat quality and the cues that species use to identify quality habitat, which can result in an ecological trap. Ecological traps are typically difficult to identify without fine‐scale information on individual survival and fitness, but this information is rarely available over large temporal and spatial scales.

The Prairie Pothole Region (PPR) of the United States and Canada has undergone extensive changes in the latter half of the 20th century due to advancements in agricultural technologies, water management practices and climate change. Historically, the PPR has been a highly productive area for breeding waterfowl. While the overall trends for dabbling ducks in the PPR have exhibited increasing abundances since the late 1980s, some species, such as the northern pintail, have been declining in abundance.

We used a long‐term dataset of pintail counts across the PPR to separate count data into a demographic process and a habitat selection process using a hierarchical model. The hierarchical model provided an alternative way of identifying ecological traps in the absence of individual survival and fitness. Our model also allowed us to account for the indirect pathways by which climate and agriculture impact pintail through their additional contribution to wetland availability, which is a primary driver of pintail demography and habitat selection.

Decoupling these processes allowed us to identify an ecological trap related to increasing cropland land cover, in which pintail selected for cropland over alternative nesting habitat, likely due to the similarities with productive native mixed‐grass prairie. However, large proportions of cropland within a region resulted in fewer pintail the following year, likely due to nest failures from predation and agricultural practices. In addition, we identified several regions in Canada where this ecological trap is contributing significantly to mismatches between habitat selection and demographic processes.
Pleurisy and pulmonary embolism: physician sees through patient eyes
Authors: Cochrane Belinda
Published: April 2020

As a respiratory physician personally affected by pulmonary thromboembolism, I bring a unique perspective to managing this condition. It has made me realise that sometimes we do not see in detail the ways our colleagues practise, even working alongside them, although general management principles are the same. While banned from work, but permitted ‘as much paperwork as I like’ (the sole compromise that would ensure this patient's adherence), I sought to learn from my time as patient, hoping that other clinicians might gain from my experience in both roles. When it came to deciding which insights would be most useful to impart for the benefit of our patients, the leading concepts were not novel but important to emphasise in our current medical world, which prioritises both efficiency and quality of patient care.
Issue Conclusion: Sociology, Political Inequality, and Democracy Beyond 2020
Authors: Rosino Michael L.
Published: April 2020

The articles in this special issue all contribute to a broader and richer understanding of racial and gender politics. They help reveal how racialized and gendered barriers to political participation reflect and reproduce intersecting racialized and gendered systems of domination. In doing so, they provide insights that can be applied to uncover political processes, cultivate political praxis, and draw our awareness to empowering modes of social and political transformation. Given all this, I propose a renewed sociology of political inequality that focuses on advancing democracy. This agenda includes (1) emphasizing the state of democracy over the state of political party competition, (2) highlighting how democratizing social change happens at various levels, (3) developing and practicing empirically grounded public advocacy, (4) seeing social and political structures are interconnected, and (5) employing sociology in the service of democracy.
Au-free recessed Ohmic contacts to AlGaN/GaN high electron mobility transistor: Study of etch chemistry and metal scheme
Authors: S Niranjan , Guiney Ivor , Humphreys Colin J. , Sen Prosenjit , Muralidharan Rangarajan , Nath Digbijoy N.
Published: April 2020

The authors study the effect of etch chemistry and metallization scheme on recessed Au-free Ohmic contacts to AlGaN/GaN heterostructures on silicon. The effect of variation in the recess etch chemistry on the uniformity of Ohmic contact resistance has been studied using two different etch chemistries (BCl3/O2 and BCl3/Cl2). Experiments to determine the optimum recess etch depth for obtaining a low value of contact resistance have been carried out, and it is shown that near-complete etching of the AlGaN barrier layer before metallization leads to the lowest value of contact resistance. Furthermore, two metal schemes, namely, Ti/Al and Ti/Al/Ti/W, are investigated, and it is found that the Ti/W cap layer on Ti/Al leads to low contact resistance with a smooth contact surface morphology. The effect of maintaining unequal mesa and contact pad widths on the extracted values of contact resistance and sheet resistance using the linear transfer length method (LTLM) has been studied. This is important as LTLM structures are used as monitors for process control during various steps of fabrication. It is shown that the extracted contact resistance and sheet resistance values are reliable when the mesa width is equal to the contact pad width. Finally, a possible mechanism for carrier transport in the Ohmic contacts formed using this process has been discussed, based on temperature dependent electrical characterization, and the field emission mechanism is found to be the dominant mechanism of carrier transport. A low Ohmic contact resistance of 0.56 Ω mm, which is one of the lowest reported values for identical metal schemes, and good contact surface morphology has been obtained with moderate post-metal annealing conditions of 600°C.
Ringing the Changes: How the Relationship between the International Gymnastics Federation and the International Olympic Committee Has Shaped Gymnastics Policy
Authors: Cervin Georgia
Published: April 2020

This paper examines the governing body of international gymnastics, the Fédération Internationale de Gymnastique (FIG) and its relationship with the International Olympic Committee (IOC). It outlines the nature of the relationship between the two bodies and how that relationship has historically impacted the resulting policy of both organizations. In particular, this research focuses on three main areas of policy. The first is economics and the shift from amateur to professional and commercial gymnastics. When the IOC began to develop commercial interests, the FIG feared losing its purity if it was to follow suit. Second, it explores policy surrounding gender. This is particularly relevant in a sport where each discipline is not only categorized by gender, but also contested on the basis of performance-gendered ideals. And finally, this research examines athlete welfare. Gymnastics is known for its young, docile participant base and, more recently, cases of sexual abuse in the United States. While a range of protective policies have since been created, what existed at an international level before then? I argue that the FIG has had to work within the confines of its Olympic remit in order to retain its relevance to the Olympic behemoth and its inclusion in the Games as gymnastics’ pinnacle event. At the same time, the FIG has mediated Olympic policy and exerted the will of the IOC over stakeholders in gymnastics. Moreover, this relationship is symbiotic: gymnastics is one of the top three most popular Olympic sports, attracting viewership and its attendant commercial benefits to the Games. This research is based on FIG bulletins and IOC correspondence, and it builds on a range of secondary works about the role of International Federations, their policies, and their rules in shaping the sports they govern.
Comorbidity phenotypes and risk of mortality in patients with ischaemic heart disease in the UK
Authors: Crowe Francesca , Zemedikun Dawit T , Okoth Kelvin , Adderley Nicola Jaime , Rudge Gavin , Sheldon Mark , Nirantharakumar Krishnarajah , Marshall Tom
Published: April 2020

Objectives

The objective of this study is to use latent class analysis of up to 20 comorbidities in patients with a diagnosis of ischaemic heart disease (IHD) to identify clusters of comorbidities and to examine the associations between these clusters and mortality.

Methods

Longitudinal analysis of electronic health records in the health improvement network (THIN), a UK primary care database including 92 186 men and women aged ≥18 years with IHD and a median of 2 (IQR 1–3) comorbidities.

Results

Latent class analysis revealed five clusters with half categorised as a low-burden comorbidity group. After a median follow-up of 3.2 (IQR 1.4–5.8) years, 17 645 patients died. Compared with the low-burden comorbidity group, two groups of patients with a high-burden of comorbidities had the highest adjusted HR for mortality: those with vascular and musculoskeletal conditions, HR 2.38 (95% CI 2.28 to 2.49) and those with respiratory and musculoskeletal conditions, HR 2.62 (95% CI 2.45 to 2.79). Hazards of mortality in two other groups of patients characterised by cardiometabolic and mental health comorbidities were also higher than the low-burden comorbidity group; HR 1.46 (95% CI 1.39 to 1.52) and 1.55 (95% CI 1.46 to 1.64), respectively.

Conclusions

This analysis has identified five distinct comorbidity clusters in patients with IHD that were differentially associated with risk of mortality. These analyses should be replicated in other large datasets, and this may help shape the development of future interventions or health services that take into account the impact of these comorbidity clusters.