bluuebunny/crossref_metadata_2025_split huggingface dataset:
ObLiGaRe doxycycline Inducible (ODIn) Cas9 system driving pre-clinical drug discovery, from design to cancer treatment
Authors: Lundin Anders , Porritt Michelle J. , Jaiswal Himjyot , Seeliger Frank , Johansson Camilla , Bidar Abdel Wahad , Badertscher Lukas , Davies Emma J. , Hardaker Elizabeth , Martins Carla P. , Admyre Therese , Taheri-Ghahfarokhi Amir , Bradley Jenna , Schantz Anna , Alaeimahabadi Babak , Clausen Maryam , Xu Xiufeng , Mayr Lorenz M. , Nitsch Roberto , Bohlooly-Y Mohammad , Barry Simon T. , Maresca Marcello 
Published: April 2020

ABSTRACTThe CRISPR-Cas9 system has increased the speed and precision of genetic editing in cells and animals. However, model generation for drug development is still expensive and time-consuming, demanding more target flexibility and faster turnaround times with high reproducibility. We have generated a tightly controlled ObLiGaRe doxycycline inducible SpCas9 (ODInCas9) transgene. Targeted ObLiGaRe resulted in functional integration into both human and mouse cells culminating in the generation of the ODInCas9 mouse. Genomic editing can be performed in cells of various tissue origins without any detectable gene editing in the absence of doxycycline. Somaticin vivoediting can model non-small cell lung cancer (NSCLC) adenocarcinomas, enabling treatment studies to validate the efficacy of candidate drugs. The ODInCas9 mouse can be utilized for robust and tunable genome editing allowing for flexibility, speed and uniformity at reduced cost, leading to high throughput and practical preclinicalin vivotherapeutic testing.
Diabetic phenotype in mouse and humans with β-amyloid pathology reduces the number of microglia around β-amyloid plaques
Authors: Natunen Teemu , Martiskainen Henna , Marttinen Mikael , Gabbouj Sami , Koivisto Hennariikka , Kemppainen Susanna , Kaipainen Satu , Takalo Mari , Svobodová Helena , Leppänen Luukas , Kemiläinen Benjam , Ryhänen Simo , Kuulasmaa Teemu , Rahunen Eija , Juutinen Sisko , Mäkinen Petra , Miettinen Pasi , Rauramaa Tuomas , Pihlajamäki Jussi , Haapasalo Annakaisa , Leinonen Ville , Tanila Heikki , Hiltunen Mikko 
Published: April 2020

AbstractType 2 diabetes (T2D) increases the risk of Alzheimer’s disease (AD). Even though these two diseases share common molecular pathways, the mechanisms remain elusive. To shed light into these mechanisms, mice with different AD- and/or tauopathy-linked genetic backgrounds were utilized; APPswe/PS1dE9 (A+Tw), Tau P301L (AwT+), and APPswe/PS1dE9/Tau P301L (A+T+). Feeding these mice with typical Western diet (TWD) led to obesity and diabetic phenotype as compared to respective mice with a standard diet. TWD also exacerbated memory and learning impairment in A+Tw and AwT+, but not in A+T+ mice. Furthermore, RNA sequencing of mouse hippocampal samples revealed altered responses to AD-related pathologies in A+Tw and A+T+ mice upon TWD, pointing specifically towards aberrant microglial functionality and PI3K-Akt signaling. Accordingly, fewer microglia alongside an increased number of dystrophic neurites around β-amyloid plaques, and impaired PI3K-Akt signaling, were discovered in the hippocampus of TWD mice. Mechanistic elucidation revealed that disruption of the PI3K-Akt signaling pathway by pharmacological or genetic approaches significantly decreased the phagocytic uptake and proinflammatory response as well as increased the activity of Syk-kinase upon ligand-induced activation of Trem2/Dap12 signaling in mouse microglia. Finally, characterization of microglial pathology in cortical biopsies of idiopathic normal pressure hydrocephalus (iNPH) patients harboring β-amyloid plaques revealed a significant decrease in the number of microglia per β-amyloid plaque in obese iNPH patients with T2D as compared to both normal weight and obese iNPH patients without T2D. Collectively, these results suggest that the peripheral diabetic phenotype in mice and humans associates with reduced microglial response to β-amyloid pathology.
Ontogenesis of the tear drainage system requires Prickle 1-controlled polarized basement membrane (BM) deposition
Authors: Guo Dianlei , Ru Jiali , Mao Fuxiang , Wu Kaili , Ouyang Hong , Liu Yizhi , Liu Chunqiao 
Published: April 2020

AbstractIn terrestrial animals, lacrimal drainage apparatus evolved to serve as conduits for tear flow. Little is known about the ontogenesis of this system. Here, we investigated tear duct origin, developmental course, genetic and cellular determinants in mouse. We report that primordial tear duct (PTD) originates from junction epithelium of the joining maxillary and lateral nasal processes, which reshapes into future tear duct branches. We identified Prickle 1 as a hallmark for tear duct outgrowth, ablation of which stalled duct elongation. In particular, the disruption of basement membrane (BM) with cytoplasmic accumulation of laminin suggests aberrant protein trafficking. Mutant embryoid bodies (EBs) derived from iPSCs recapitulate BM phenotype of the PTD exhibiting defective visceral endoderm (VE), which normally expresses high level of Prickle 1. Furthermore, replenishing mutant VE with Prickle 1 completely rescued BM but not cell polarity. Taken together, our results reveal a distinct role of Prickle 1 in regulating polarized BM secretion and deposition in precedently uncharacterized tear drainage system and VE, which is independent of apicobasal polarity establishment.
Effects of the selective dopamine D3receptor antagonist PG01037 on morphine-induced hyperactivity and antinociception in mice
Authors: Botz-Zapp Christian A. , Foster Stephanie L. , Pulley Desta M. , Hempel Briana , Bi Guo-Hua , Xi Zheng-Xiong , Newman Amy Hauck , Weinshenker David , Manvich Daniel F. 
Published: April 2020

ABSTRACTRecent preclinical studies have reported that pretreatment with the novel and highly-selective dopamine D3receptor (D3R) antagonists R-VK4-40 or VK4-116 attenuates the abuse-related behavioral effects of oxycodone while enhancing its analgesic properties. However, whether these observed effects are generalizable to the broad class of D3R antagonists and/or extend to opioids other than oxycodone has not been extensively explored. The present study sought to assess the impact of pretreatment with another selective D3R antagonist, PG01037, on several behavioral effects of morphine in mice. C57Bl/6J mice were pretreated with PG01037 (0 – 10 mg/kg) and tested for 1) hyperlocomotion induced by acute morphine (5.6 – 56 mg/kg), 2) locomotor sensitization following repeated morphine (56 mg/kg), 3) antinociception following acute morphine (18 mg/kg), and 4) catalepsy following administration of PG01037 alone or in combination with morphine (56 mg/kg). PG01037 dose-dependently attenuated morphine-induced hyperlocomotion and morphine-induced antinociception at doses that did not alter basal locomotion or nociception alone, but did not prevent the induction of locomotor sensitization following repeated morphine administration. Moreover, PG01037 did not induce catalepsy either alone or in combination with morphine. These results suggest that attenuation of acute opioid-induced hyperlocomotion may be a behavioral effect shared among D3R-selective antagonists, thus supporting continued investigations into their use as potential treatments for opioid use disorder. However, PG01037 is unlike newer, highly-selective D3R antagonists in its capacity to reduce opioid-induced antinociception, indicating that modulation of opioid analgesia may vary across different D3R antagonists.
A meta-analysis of transformational leadership in hospitality research
Authors: Gui Chenglin , Luo Anqi , Zhang Pengcheng , Deng Aimin 
Published: April 2020

PurposeThough the effect of transformational leadership (TFL) on followers has been largely examined in hospitality, the findings are rather inconsistent. This paper aims to provide a quantitative review for the relationship between TFL and follower outcomes in hospitality and a detailed analysis of the moderating variables (cultural differences, measurement instrument, rating sources and time lag).Design/methodology/approachTo explore the effect sizes of TFL on followers, this study conducted a quantitative meta-analysis based on 62 primary studies, including 66 independent samples (N= 23,037). The outcomes of TFL were categorized into subordinates’ attitudinal outcomes, relational perceptions and behavioral outcomes.FindingsThe results indicate that TFL has the strongest impact on relational perceptions, followed by subordinates’ attitudinal and behavioral outcomes. The results also show that cultural differences, rating sources and time lag partially moderate the relationships between TFL and follower outcomes.Research limitations/implicationsTFL generally has a high level of validity for explaining attitudinal, behavioral and relational perception outcomes of followers in the field of hospitality. Given that, there have been a large number of studies investigating TFL with follower attitudinal and behavioral outcomes, it might not be necessary to continue applying identical frameworks to investigate the effect of TFL. Instead, future research on TFL is expected to explore the relationship between TFL and followers’ relational perceptions and consider cultural and methodological factors.Originality/valueTo the best of authors’ knowledge, this is the first meta-analysis to clear theoretical links between TFL and its outcomes in the hospitality context. This study further investigates several moderators that can influence the effects of TFL and helps better understand the influence of TFL in the area of hospitality. The study also provides future research directions for leadership research in the hospitality context.
WER IST HIER DER FEIND? VERBÜNDETE UND GEGNER IN ALEXANDER SOLSCHENIZYNS DARSTELLUNG VON DEUTSCHLAND
Authors: Kriza Elisa 
Published: April 2020

AbstractThe prominent Russian writer and Nobel Prize Laureate Alexander Solzhenitsyn (1918–2008) was known mainly for his work on the Soviet prison camps. In many of his fictional and non‐fiction works, however, Solzhenitsyn dealt with the subject of Germany. This article analyses Solzhenitsyn's depiction of Germany in the works August 1914, The Gulag Archipelago, and shorter non‐fiction texts. The aim is to assess Solzhenitsyn's interpretation of Germany in the context of the two World Wars and the Cold War. Complex opposites and friend‐foe paradigms characterise the portrayal of Germany and its relation to Russia in Solzhenitsyn's work. Solzhenitsyn suggests a bond of fate between Russia and Germany. Yet it was his trivialising discussion of Nazi crimes that became particularly relevant to his German reception, as well as his benevolent interpretation of the denazification process. Solzhenitsyn's admiration for German troops in the First World War and his views on Nazism are examined here in the context of the author's anti‐communism, nationalism, and anti‐Semitism. A discussion of paradigmatic texts from his (West) German reception during the Cold War illustrates the complexity of Solzhenitsyn's historical interpretations and the different responses to them.
Pharmacokinetics and tissue concentrations of firocoxib in sows following oral administration
Authors: Kleinhenz Michael D. , Odland Carissa , Williams Todd E. , Zhang Yuntao , Fitzgerald Alyson H. , Sidhu Pritam K. , Wulf Larry W. , Coetzee Johann F. 
Published: April 2020

AbstractThe objectives of this study were to describe the pharmacokinetics of firocoxib following oral (PO) dosing and intravenous (IV) injection in sows. Seven healthy sows were administered 0.5 mg firocoxib/kg IV. Following a 23‐d washout period, sows were administered firocoxib at 4.0 mg firocoxib/kg PO. Blood samples were collected at predetermined times for 72 hr after IV and 120 hr after PO administration. Plasma firocoxib concentration was measured using UPLC‐MS/MS, and pharmacokinetic analysis was performed using noncompartmental procedures. Tissue firocoxib concentrations were determined at 5, 10 (n = 2/time point), and 21 d (n = 3) after PO administration. The geometric mean half‐life following IV and PO administration was 16.6 and 22.5 hr, respectively. A mean peak plasma concentration (Cmax) of 0.06 µg/ml was recorded at 7.41 hr (Tmax) after oral administration. Mean oral bioavailability was determined to be 70.3%. No signs of NSAID toxicity were observed on macroscopic and microscopic investigation. Firocoxib was detected in the skin with subcutaneous fat (0.02 µg/g) of one of three sows at 21 days postadministration. Additional work to establish appropriate meat withhold intervals in sows is required. Firocoxib was readily absorbed following PO administration. Further work is needed to better understand the analgesic effects for sows and piglets nursing sows administered firocoxib.
A Multibody Model for Predicting Spatial Distribution of Human Brain Deformation Following Impact Loading
Authors: Gabrieli David , Vigilante Nicholas F. , Scheinfeld Rich , Rifkin Jared A. , Schumm Samantha N. , Wu Taotao , Gabler Lee F. , Panzer Matthew B. , Meaney David F. 
Published: April 2020

Abstract
With an increasing focus on long-term consequences of concussive brain injuries, there is a new emphasis on developing tools that can accurately predict the mechanical response of the brain to impact loading. Although finite element models (FEM) estimate the brain response under dynamic loading, these models are not capable of delivering rapid (∼seconds) estimates of the brain's mechanical response. In this study, we develop a multibody spring-mass-damper model that estimates the regional motion of the brain to rotational accelerations delivered either about one anatomic axis or across three orthogonal axes simultaneously. In total, we estimated the deformation across 120 locations within a 50th percentile human brain. We found the multibody model (MBM) correlated, but did not precisely predict, the computed finite element response (average relative error: 18.4 ± 13.1%). We used machine learning (ML) to combine the prediction from the MBM and the loading kinematics (peak rotational acceleration, peak rotational velocity) and significantly reduced the discrepancy between the MBM and FEM (average relative error: 9.8 ± 7.7%). Using an independent sports injury testing set, we found the hybrid ML model also correlated well with predictions from a FEM (average relative error: 16.4 ± 10.2%). Finally, we used this hybrid MBM-ML approach to predict strains appearing in different locations throughout the brain, with average relative error estimates ranging from 8.6% to 25.2% for complex, multi-axial acceleration loading. Together, these results show a rapid and reasonably accurate method for predicting the mechanical response of the brain for single and multiplanar inputs, and provide a new tool for quickly assessing the consequences of impact loading throughout the brain.
Effective containment explains subexponential growth in recent confirmed COVID-19 cases in China
Authors: Maier Benjamin F. , Brockmann Dirk 
Published: April 2020

Containment works
National governments have taken different approaches in response to the coronavirus disease 2019 (COVID-19) pandemic, ranging from draconian quarantines to laissez-faire mitigation strategies. In data from China collected in February 2020, Maier and Brockmann noticed that, unexpectedly, the epidemic did not take off exponentially. Nonexponential spread occurs when the supply of susceptible individuals is depleted on a time scale comparable to the infectious period of the virus. The results of the authors' modeling approach indicate that the public response to the epidemic plus containment policies were becoming effective despite the initial increase in confirmed cases.

Science
, this issue p.
742
Cytotoxic Necrotizing Factor Type 2 Produced by Pathogenic
Escherichia coli
Deamidates a Gln Residue in the Conserved G-3 Domain of the Rho Family and Preferentially Inhibits the GTPase Activity of RhoA and Rac1
Authors: Sugai Motoyuki , Hatazaki Kiyotaka , Mogami Akira , Ohta Hiroyuki , Pérès Sylvie Y. , Hérault Fredéric , Horiguchi Yasuhiko , Masuda Minako , Ueno Yoko , Komatsuzawa Hitoshi , Suginaka Hidekazu , Oswald Eric 
Published: April 2020

ABSTRACT

Cytotoxic necrotizing factor types 1 and 2 (CNF1 and -2) produced by pathogenic
Escherichia coli
strains have 90% conserved residues over 1,014-amino-acid sequences. Both CNFs are able to provoke a remarkable increase in F-actin structures in cultured cells and covalently modify the RhoA small GTPases. In this study, we demonstrated that CNF2 reduced RhoA GTPase activity in the presence and absence of P122
RhoGAP
. Subsequently, peptide mapping and amino acid sequencing of CNF2-modified FLAG-RhoA produced in
E. coli
revealed that CNF2 deamidates Q63 of RhoA-like CNF1. In vitro incubation of the C-terminal domain of CNF2 with FLAG-RhoA resulted also in deamidation of the FLAG-RhoA, suggesting that this region contains the enzymatic domain of CNF2. An oligopeptide antibody (anti-E63) which specifically recognized the altered G-3 domain of the Rho family reacted with glutathione
S
-transferase (GST)-RhoA and GST-Rac1 but not with GST-Cdc42 when coexpressed with CNF2. In addition, CNF2 selectively induced accumulation of GTP form of FLAG-RhoA and FLAG-Rac1 but not of FLAG-Cdc42 in Cos-7 cells. Taken together, these results indicate that CNF2 preferentially deamidates RhoA Q63 and Rac1 Q61 and constitutively activates these small GTPases in cultured cells. In contrast, anti-E63 reacted with GST-RhoA and GST-Cdc42 but not with GST-Rac1 when coexpressed with CNF1. These results indicate that CNF2 and CNF1 share the same catalytic activity but have distinct substrate specificities, which may reflect their differences in toxic activity in vivo.
Continuous neurally adjusted ventilation: a feasibility study in preterm infants
Authors: Rochon Marie-Eve , Lodygensky Gregory , Tabone Laurence , Essouri Sandrine , Morneau Sylvain , Sinderby Christer , Beck Jennifer , Emeriaud Guillaume 
Published: April 2020

ObjectivesTo assess the feasibility and tolerance of NeuroPAP, a new non-invasive ventilation mode which continuously adjusts (during both inspiration and expiration) the pressure support proportionally to the diaphragm electrical activity (Edi), in preterm infants and to evaluate the impact on ventilation pressure and Edi.DesignProspective cross-over single-centre feasibility study.SettingOne level 3 neonatal intensive care unit in Canada.PatientsStable preterm infants ventilated with non-invasive positive pressure ventilation (NIPPV).InterventionsSubjects were successively ventilated in NIPPV with prestudy settings (30 min), in NeuroPAP with minimal pressure similar to NIPPV PEEP (positive end-expiratory pressure) (60 min), in NeuroPAP with minimal pressure reduced by 2 cmH20 (60 min), in continuous positive airway pressure (15 min) and again in NIPPV (30 min). Main outcome measures included tolerance, ventilation pressure, Edi and patient-ventilator synchrony.ResultsTwenty infants born at 28.0±1.0 weeks were included. NeuroPAP was well tolerated and could be delivered during 100% of planned period. During NeuroPAP, the PEEP was continuously adjusted proportionally to tonic diaphragm Edi, although the average PEEP value was similar to the set minimal pressure. During NeuroPAP, 83 (78–86)% breaths were well synchronised vs 9 (6–12)% breaths during NIPPV (p<0.001).ConclusionsNeuroPAP is feasible and well tolerated in stable preterm infants, and it allows transient adaptation in PEEP in response to tonic diaphragm electrical activity changes. Further studies are warranted to determine the impact of these findings on clinical outcomes.Trial registration numberNCT02480205.
Prognostic value of intermediate age-related macular degeneration phenotypes for geographic atrophy progression
Authors: Thiele Sarah , Nadal Jennifer , Pfau Maximilian , Saßmannshausen Marlene , Fleckenstein Monika , Holz Frank G , Schmid Matthias , Schmitz-Valckenberg Steffen 
Published: April 2020

BackgroundTo characterise early stages of geographic atrophy (GA) development in age-related macular degeneration (AMD) and to determine the prognostic value of structural precursor lesions in eyes with intermediate (i) AMD on the subsequent GA progression.MethodsStructural precursor lesions for atrophic areas (lesion size at least 0.5 mm² in fundus autofluorescence images) were retrospectively identified based on multimodal imaging and evaluated for association with the subsequent GA enlargement rates (square-root transformed, sqrt). A linear mixed-effects model was used to account for the hierarchical nature of the data with a Tukey post hoc test to assess the impact of the local precursor on the subsequent GA progression rate.ResultsA total of 39 eyes with GA of 34 patients with a mean age of 74.4±6.7 (±SD) years were included in this study. Five precursor lesions (phenotypes 1–5) preceding GA development were identified: large, sub-retinal pigment epithelial drusen (n=19), reticular pseudodrusen (RPD, n=10), refractile deposits (n=4), pigment epithelial detachment (n=4) and vitelliform lesions (n=2). Precursor lesions exhibited a significant association with the subsequent (sqrt) GA progression rates (p=0.0018) with RPD (phenotype 2) being associated with the fastest GA enlargement (2.29±0.52 (±SE) mm/year.ConclusionsThe results indicate the prognostic relevance of iAMD phenotyping for subsequent GA progression highlighting the role of structural AMD features across different AMD stages.
HPV types, cervical high-grade lesions and risk factors for oncogenic human papillomavirus infection among 3416 Tanzanian women
Authors: Mchome Bariki Lawrence , Kjaer Susanne Krüger , Manongi Rachel , Swai Patricia , Waldstroem Marianne , Iftner Thomas , Wu Chunsen , Mwaiselage Julius , Rasch Vibeke 
Published: April 2020

ObjectiveThe objective of the present study was to assess the prevalence and type-specific distribution of cervical high-risk (HR) human papillomavirus (HPV) among women with normal and abnormal cytology, and to describe risk factors for HR HPV among HIV-positive and HIV-negative women in Tanzania.MethodologyA cross-sectional study was conducted in existing cervical cancer screening clinics in Kilimanjaro and Dar es Salaam. Cervical specimens were obtained from women aged 25–60 years. Samples were shipped to Denmark for cytological examination, and to Germany for HR HPV testing (using Hybrid Capture 2) and genotyping (using LiPaExtra). Risk factors associated with HPV were assessed by multivariable logistic regression analysis.ResultAltogether, 4080 women were recruited with 3416 women contributing data for the present paper, including 609 HIV-positive women and 2807 HIV-negative women. The overall HR HPV prevalence was 18.9%, whereas the HR HPV prevalence in women with high-grade squamous intraepithelial lesions (HSILs) was 92.7%. Among HPV-positive women with HSIL, HPV16 (32.5%) and HPV58 (19.3%) were the the most common types followed by HPV18 (16.7%) and HPV52 (16.7%). Factors associated with HR HPV included younger age, increasing number of partners and early age at first intercourse. Similar risk factors were found among HIV-positive and HIV-negative women. In addition, among HIV-positive women, those with CD4 counts <200 cells/mm3had an increased risk of HR HPV (OR 2.2; 95% CI 1.2 to 4.8) compared with individuals with CD4 count ≥500 cells/mm3.ConclusionGiven the HPV distribution among Tanzanian women, the current HPV vaccination in Tanzania using quadrivalent vaccine may be considered replaced by the nonavalent vaccine in the future. In addition, appropriate antiretroviral treatment management including monitoring of viremia may decrease the burden of HR HPV in HIV-positive women.