bluuebunny/crossref_metadata_2025 huggingface dataset:
Validation of the Mayo-Portland Adaptability Inventory-4 (MPAI-4) and reference norms in a French-Canadian population with traumatic brain injury receiving rehabilitation
Authors: Guerrette Marie-Claude , McKerral Michelle
Published: October 2020

Objective

To validate the factor structure and establish internal consistency reliability of the French-Canadian version of the Mayo-Portland Adaptability Inventory (MPAI-4), using a Canadian sample of adults with traumatic brain injury (TBI) receiving post-acute rehabilitation services.

Design

Psychometric analysis of prospectively collected French-Canadian MPAI-4 data.

Setting

Inpatient and outpatient TBI rehabilitation programs.

Participants

Adults (N = 1012) with a mild, moderate or severe TBI who received inpatient or outpatient rehabilitation interventions and for whom a first French-Canadian MPAI-4 measure was completed between 2016 and 2020.

Interventions

Not applicable.

Main Outcome Measure

French-Canadian MPAI-4 questionnaire.

Results

To evaluate the factor structure of the French-Canadian MPAI-4, an exploratory factor analysis using a varimax rotation method was conducted on z-scores for all items. The final and best solution was a three-factor solution, which accounted for 48.68% of the variance. The internal consistency of the French-Canadian MPAI-4 was determined using Cronbach’s alpha and all three subscales showed good internal consistency (all .70 ≤ α ≤ .89). Reference norms for the TBI sample are provided in the form of T scores for subscales and total score, as well as descriptive raw data according to sex, age, TBI severity and rehabilitation setting.

Conclusions

The three factors extracted using data from the French-Canadian MPAI-4 are similar, but not entirely identical to the three subscales of the original MPAI-4. Overall, the French-Canadian MPAI-4 factor structure is validated. The questionnaire shows good psychometric properties and represents a suitable tool to measure functional evolution and social participation of TBI adults receiving rehabilitation services in a French-Canadian context. The provided reference norms will also help guide the clinical use of the MPAI-4 in French-Canadian TBI populations.
Vaccine hesitancy and non-vaccination in an Irish paediatric outpatient population
Authors: Whelan SO , Moriarty F , Lawlor L , Gorman K , Beamish J
Published: October 2020

Objective

To administer the Parent Attitudes Childhood Vaccines (PACV) questionnaire to assess vaccine hesitancy and its relationship with non-vaccination.

Design

A cross-sectional study using the 15-item PACV questionnaire, with sociodemographic questions.

Setting

Outpatient department in a tertiary paediatric hospital, Dublin, Ireland.

Participants

Parents/caregivers of children attending general paediatric clinics.

Main outcome measures

PACV score and reported non-vaccination. We assessed sociodemographic factors associated with PACV score and accuracy of the PACV in predicting non-vaccination.

Results

In total, 436 participants completed the questionnaire. 5.5% of our population reported non-vaccination. HPV and MMR vaccines were the most commonly cited vaccines of concern (11.5% and 6.7% respectively) and autism spectrum disorder was the most commonly side effect of concern (4.3%). Mean PACV score was 26.9 (SD 19.1), with a significant difference between non-vaccinators and vaccinators (53.2 vs 25.3, p<0.001). Safety and efficacy concerns were the major contributor to non-vaccination. 14.4% of our population were vaccine-hesitant using the conventional cut-off score, which increased to 22% when using an optimal cut-off which maximised sensitivity and specificity. The accuracy of the PACV score to identify non-vaccination was good (area under the ROC curve = 0.827) and the optimal cut-off had a high negative predictive value (98.5%).

Conclusions

PACV identified non-vaccination with high accuracy in our population. It may be useful to screen vaccine hesitant parents who could benefit from interventions to improve uptake.
Genome-wide interaction study implicates VGLL2 and alcohol exposure and PRL and smoking in orofacial cleft risk
Authors: Carlson Jenna C. , Shaffer John R. , Deleyiannis Fred , Hecht Jacqueline T. , Wehby George L. , Christensen Kaare , Feingold Eleanor , Weinberg Seth M. , Marazita Mary L. , Leslie Elizabeth J.
Published: October 2020

Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect, affecting approximately 1 in 700 births. NSCL/P has complex etiology including several known genes and environmental factors; however, known genetic risk variants only account for a small fraction of the heritability of NSCL/P. It is commonly suggested that gene-by-environment (G×E) interactions may help explain some of the “missing” heritability of NSCL/P. We conducted a genome-wide G×E interaction study in European cases and controls with three common maternal exposures during pregnancy: alcohol, smoking, and vitamin use using a two-stage design. After selecting 127 loci with suggestive 2df tests for gene and G x E effects, 40 loci showed significant G x E effects after correcting for multiple tests. Notable interactions included SNPs of 6q22 near VGLL2 with alcohol and 6p22.3 near PRL with smoking. These interactions could provide new insights into the etiology of CL/P and new opportunities to modify risk through behavioral changes.
Mieap forms membrane-less organelles to compartmentalize and facilitate cardiolipin metabolism
Authors: Ikari Naoki , Honjo Katsuko , Sagami Yoko , Nakamura Yasuyuki , Arakawa Hirofumi
Published: October 2020

Biomolecular condensates (BCs) are formed by proteins with intrinsically disordered regions (IDRs) via liquid–liquid phase separation. Mieap/Spata18, a p53-inducible protein, participates in suppression of colorectal tumors by promoting mitochondrial quality control. However, the regulatory mechanism involved remains unclear. Here, we report that Mieap is an IDR-containing protein that drives formation of BCs involved in cardiolipin metabolism. Mieap BCs specifically phase separate the mitochondrial phospholipid, cardiolipin. Mieap directly binds to cardiolipinin vitro. Lipidomic analysis of cardiolipin suggests that Mieap promotes enzymatic reactions in cardiolipin biosynthesis and remodeling. Accordingly, four cardiolipin biosynthetic enzymes, TAMM41, PGS1, PTPMT1, and CRLS1, and two remodeling enzymes, PLA2G6 and TAZ, are phase-separated by Mieap BCs. Mieap-deficient cells exhibit altered crista structure, leading to decreased respiration activity and ATP production in mitochondria. These results suggest that Mieap may form membrane-less organelles to compartmentalize and facilitate cardiolipin metabolism, thus potentially contributing to mitochondrial quality control.
Symbiont-Screener: a reference-free filter to automatically separate host sequences and contaminants for long reads or co-barcoded reads by unsupervised clustering
Authors: Xu Mengyang , Guo Lidong , Shi Chengcheng , Liu Xiaochuan , Chen Jianwei , Liu Xin , Fan Guangyi
Published: October 2020

Decontamination is necessary for eliminating the effect of foreign genomes on the symbiont studies and biomedical discoveries. However, direct extraction of host sequencing reads with no references remains challenging. Here, we present a triobased method to classify the host error-prone long reads or sparse co-barcoded reads prior to assembly, free of any alignments against DNA or protein references. This method first identifies high-confident host reads by haplotype-specifick-mers inherited from parents, and then groups remaining host reads by the unsupervised clustering. Experimental results demonstrated that this approach successfully classified up to 97.38% of the host human long reads with the precision rate of 99.9999%, and 79.95% host co-barcoded reads with the precision rate of 98.36% using an artificially mixed data. Moreover, the tool also exhibited a good performance on the decontamination of the real algae data. The purified reads reconstructed two haplotypes and improved the assembly with larger contig NGA50 value and less misassemblies. Symbiont-Screener can be freely downloaded athttps://github.com/BGI-Qingdao/Symbiont-Screener.
Associative learning in larval and adult Drosophila is impaired by the dopamine-synthesis inhibitor 3-Iodo-L-tyrosine
Authors: Thoener Juliane , König Christian , Weiglein Aliće , Toshima Naoko , Mancini Nino , Amin Fatima , Schleyer Michael
Published: October 2020

Across the animal kingdom, dopamine plays a crucial role in conferring reinforcement signals that teach animals about the causal structure of the world. In the fruit flyDrosophila melanogaster, the dopamine system has largely been studied using a rich genetic toolbox. Here, we suggest a complementary pharmacological approach applying the dopamine-synthesis inhibitor 3-Iodo-L-tyrosine (3IY), which causes acute systemic inhibition of dopamine signaling. Using Pavlovian conditioning, across developmental stages (3rdinstar larva versus adult), valence domains (reward versus punishment), and types of reinforcement (natural versus optogenetically induced), we find that 3IY feeding specifically impairs associative learning, whereas additional feeding of L-3,4-dihydroxyphenylalanine (L-DOPA), a precursor of dopamine, rescues this impairment. This study establishes a simple, quick, and comparably low-cost approach that can be combined with the available genetic tools to manipulate and clarify the functions of the dopaminergic system – inD. melanogasterand other animals.
Roughness and dynamics of proliferating cell fronts as a probe of cell-cell interactions
Authors: Rapin Guillaume , Caballero Nirvana , Gaponenko Iaroslav , Ziegler Benedikt , Rawleigh Audrey , Moriggi Ermanno , Giamarchi Thierry , Brown Steven A. , Paruch Patrycja
Published: October 2020

Juxtacellular interactions play an essential but still not fully understood role in both normal tissue development and tumour invasion. Using proliferating cell fronts as a model system, we explore the effects of cell-cell interactions on the geometry and dynamics of these one-dimensional biological interfaces. We observe two distinct scaling regimes of the steady state roughness ofin-vitropropagating Rat1 fibroblast cell fronts, suggesting different hierarchies of interactions at sub-cell lengthscales and at a lengthscale of 2–10 cells. Pharmacological modulation significantly affects the proliferation speed of the cell fronts, and those modulators that promote cell mobility or division also lead to the most rapid evolution of cell front roughness. By comparing our experimental observations to numerical simulations of elastic cell fronts with purely short-range interactions, we demonstrate that the interactions at few-cell lengthscales play a key role. Our methodology provides a simple framework to measure and characterise the biological effects of such interactions, and could be useful in tumour phenotyping.

Proliferating cell fronts underpin wound healing, tumour invasion, and morphogenesis, and are governed by a complex and still not fully understood interplay of multiple mechanical and chemical factors. From a physics perspective, these cell fronts can be described as elastic interfaces in disordered media. Thus, analysing their geometric properties and dynamics can reveal the characteristic lengthscales of the dominant interactions, and point towards the underlying biological pathways. Here, we show that the roughness of proliferating fronts of Rat1 fibroblasts is governed by two different hierarchies of interactions, with distinct behaviour at sub-cell and few-cell lengthscales. Using in-vitro scratch assays, we find moreover that pharmacological modulators significantly affect the proliferation speed of the cell fronts as well as the evolution of their roughness, increased when cell-cell communication via gap junctions is perturbed, and decreased when cell division is repressed. We determine that our experimental observations cannot be reproduced by numerical simulations of elastic cell fronts with purely short-range interactions, demonstrating the key role of juxtacellular interactions at few-cell lengthscales. Our approach provides a simple framework to measure and characterise the biological effects of such interactions, and could be useful in tumour phenotyping.
Microtubules and Gαo-signaling independently regulate the preferential secretion of newly synthesized insulin granules in pancreatic islet β cells
Authors: Hu Ruiying , Zhu Xiaodong , Yuan Mingyang , Ho Kung-Hsien , Kaverina Irina , Gu Guoqiang
Published: October 2020

For sustainable function, each pancreatic islet β cell maintains thousands of insulin granules (IGs) at all times. Glucose stimulation induces the secretion of a small portion of these IGs and simultaneously triggers IG biosynthesis to sustain this stock. The failure of these processes, often induced by sustained high-insulin output, results in type 2 diabetes. Intriguingly, newly synthesized IGs are more likely secreted during glucose-stimulated insulin secretion. The older IGs tend to lose releasability and be degraded, which represents a futile metabolic load that can sensitize β cells to workload-induced dysfunction and even death. Here, we examine the factor(s) that allows the preferential secretion of younger IGs. We show that β cells without either microtubules (MTs) or Gαo signaling secrete a bigger portion of older IGs, which is associated with increased IG docking on plasma membrane. Yet Gαo inactivation does not alter the β-cell MT network. These findings suggest that Gαo and MT regulate the preferential release of newer IGs via parallel pathways and provide two potential models to further explore the underlying mechanisms and physiological significance of this regulation in functional β cells.
The effect of basal core promoter and pre-core mutations on HBV replication and persistence in mice
Authors: Chen Yi , Xu Zhiwei , Zeng Yanli , Liu Junping , Tian Yongjun , Kang Yi
Published: October 2020

The appearance of the BCP or Pre-C mutations, which reduce or abolish HBeAg production, could increase HBV replication. The remove of the HBeAg often lead to a vigorous immune response, which has an important role in HBV related fulminant outcome. In this study, BCP mutations and Pre-C mutations were separately introduced by site-directed mutagenesis in the same genetic background of an HBV infectious clone, to determine the effect of these mutations per se on replication. BCP and Pre-C mutations increased HBV replication both invitroandin vivo. HBV could persist in mice injected with wild type HBV infectious clone for about 7 weeks. However, HBV could persist about 5 weeks in mice injected with BCP HBV infectious clone, and 3 weeks only in mice injected with Pre-C HBV infectious clone. HBV related CD8+ CTL response in BCP HBV infectious clone injected mice only slightly increased, but significantly increased in Pre-C HBV infectious clone injected mice compared with that in wild type HBV infectious clone injected mice. The population of Tregs significantly increased in liver but not in spleen of mice injected with Pre-C HBV infectious clone. In summary, we demonstrate that HBeAg plays an important role in suppressing the CTL response, which is related with increasing the frequency of Tregs in mouse. Lack of HBeAg expression leads to the partial loss of immune tolerance.
SDF-1/CXCR4 inhibition prevents paradoxical generation of cisplatin-induced pro-metastatic niches
Authors: Bertolini Giulia , Cancila Valeria , Milione Massimo , Russo Giuseppe Lo , Fortunato Orazio , Zaffaroni Nadia , Tortoreto Monica , Centonze Giovanni , Chiodoni Claudia , Facchinetti Federica , Giovinazzo Francesca , Moro Massimo , Camisaschi Chiara , De Toma Alessandro , D’Alterio Crescenzo , Pastorino Ugo , Tripodo Claudio , Scala Stefania , Sozzi Gabriella , Roz Luca
Published: October 2020

Platinum-based chemotherapy remains widely used in advanced non-small cell lung cancer (NSCLC) despite its ineffectiveness in long-term control of metastasis.

Here, we uncover the interconnected pathways subtending cisplatin-induced metastasis promotion.

We report that cisplatin treatment of tumor-free mice results in bone-marrow expansion of CCR2+CXCR4+Ly6Chighinflammatory monocytes (IM) concomitantly with increased levels in the lungs of stromal SDF-1, the CXCR4 ligand. In experimental metastasis assays, cisplatin-induced IM favor tumor cells extravasation and expansion of CD133+CXCR4+ metastasis initiating cells (MICs), facilitating lung metastasis formation. At the primary tumor, cisplatin reduces tumor size but induces tumor release of SDF-1 triggering MICs expansion and recruitment of pro-invasive CXCR4+ macrophages. Co-recruitment of MICs and CCR2+CXCR4+ IM at SDF-1-enriched distant sites also promotes spontaneous metastasis. Combination treatment with a CXCR4 inhibitor prevents cisplatin-induced IM/MICs recruitment and interaction thus precluding metastasis overgrowth. Finally, we observe in NSCLC patients’ specimens that SDF-1 levels are higher in platinum-treated samples and correlate with worse outcome.

Our findings suggest a possible novel combination therapy based on CXCR4 blockade to control metastatic disease, paradoxically promoted by cisplatin.
Structural basis of ribosomal frameshifting during translation of the SARS-CoV-2 RNA genome
Authors: Bhatt Pramod R. , Scaiola Alain , Loughran Gary , Leibundgut Marc , Kratzel Annika , McMillan Angus , O’ Connor Kate M. , Bode Jeffrey W. , Thiel Volker , Atkins John F. , Ban Nenad
Published: October 2020

Programmed ribosomal frameshifting is the key event during translation of the SARS-CoV-2 RNA genome allowing synthesis of the viral RNA-dependent RNA polymerase and downstream viral proteins. Here we present the cryo-EM structure of the mammalian ribosome in the process of translating viral RNA paused in a conformation primed for frameshifting. We observe that the viral RNA adopts a pseudoknot structure lodged at the mRNA entry channel of the ribosome to generate tension in the mRNA that leads to frameshifting. The nascent viral polyprotein that is being synthesized by the ribosome paused at the frameshifting site forms distinct interactions with the ribosomal polypeptide exit tunnel. We use biochemical experiments to validate our structural observations and to reveal mechanistic and regulatory features that influence the frameshifting efficiency. Finally, a compound previously shown to reduce frameshifting is able to inhibit SARS-CoV-2 replication in infected cells, establishing coronavirus frameshifting as target for antiviral intervention.
Bombesin-like peptide recruits disinhibitory cortical circuits and enhances fear memories
Authors: Melzer Sarah , Newmark Elena , Mizuno Grace Or , Hyun Minsuk , Philson Adrienne C. , Quiroli Eleonora , Righetti Beatrice , Gregory Malika R. , Huang Kee Wui , Levasseur James , Tian Lin , Sabatini Bernardo L.
Published: October 2020

Disinhibitory neurons throughout the mammalian cortex are powerful enhancers of circuit excitability and plasticity. The differential expression of neuropeptide receptors in disinhibitory, inhibitory and excitatory neurons suggests that each circuit motif is controlled by distinct neuropeptidergic systems. Here, we reveal that a bombesin-like neuropeptide, gastrin-releasing peptide (GRP), recruits disinhibitory cortical microcircuits through selective targeting and activation of vasoactive intestinal peptide (VIP)-expressing cells. Using a newly-developed genetically-encoded GRP sensor and trans-synaptic tracing we reveal that GRP regulates VIP cells via extrasynaptic diffusion from several putative local and long-range sources.In vivophotometry and CRISPR/Cas9-mediated knockout of the GRP receptor (GRPR) in auditory cortex indicate that VIP cells are strongly recruited by novel sounds and aversive shocks, and that GRP-GRPR signaling enhances auditory fear memories. Our data establish peptidergic recruitment of selective disinhibitory cortical microcircuits as a mechanism to regulate fear memories.
Transfer learning from simulations improves the classification of OCT images of glandular epithelia
Authors: Ostvar Sassan , Truong Han , Silver Elisabeth R. , Lightdale Charles J. , Hur Chin , Tatonetti Nicholas P.
Published: October 2020

Esophageal adenocarcinoma (EAC) is a rare but lethal cancer with rising incidence in several global hotspots including the United States. The five-year survival rate for patients diagnosed with advanced disease can be as low as 5% in EAC, making early detection and preventive intervention crucial. The current standard of care for EAC targets patients with Barrett’s esophagus (BE), the main precursor to EAC and a relatively common condition in adults with chronic acid reflux disease. Preventive care for EAC requires repeated surveillance endoscopies of BE patients with biopsy sampling, and can be intrusive, error-prone, and costly. The integration of minimally-invasive subsurface tissue imaging in the current standard of care can reduce the need for exhaustive tissue sampling and improve the quality of life in BE patients. Effective adoption of subsurface imaging in EAC care can be facilitated by computer-aided detection (CAD) systems based on deep learning. Despite their recent successes in lung and breast cancer imaging, the development of deep neural networks for rare conditions like EAC remains challenging due to data scarcity, heavy bias in existing datasets toward non-cases, and uncertainty in image labels. Here we explore the use of synthetic datasets–specifically data derived from simulations of optical back-scattering during imaging– in the development of CAD systems based on deep learning. As a proof of concept, we studied the binary classification of esophageal OCT into normal squamous and glandular mucosae, typical of BE. We found that deep convolutional networks trained on synthetic data had improved performance over models trained on clinical datasets with uncertain labels. Model performance also improved with dataset size during training on synthetic data. Our findings demonstrate the utility of transfer from simulations to real data in the context of medical imaging, especially in the severely data-poor regime and when significant uncertainty in labels are present, and motivate further development of transfer learning from simulations to aid the development of CAD for rare malignancies.
Evolutionary dynamics of neutral phenotypes under DNA substitution models
Authors: Zabad Shadi , Moses Alan M
Published: October 2020

We study the evolution of quantitative molecular traits in the absence of selection. Using Felsenstein’s 1981 DNA substitution model, we predict a linear restoring force on the mean of an additive phenotype. Remarkably, the mean dynamics are independent of the effect sizes and genotype and are similar to those predicted by the widely-used OU model for stabilizing selection and the house-of-cards model for phenotype evolution. We confirm the predictions empirically using additive molecular phenotypes calculated from ancestral reconstructions of putatively unconstrained DNA sequences in primate genomes. We predict and confirm empirically that the dynamics of the variance are more complicated than those predicted by the OU model, and show that our results for the restoring force of mutation hold even for nonadditive phenotypes, such as number of transcription factor binding sites, longest encoded peptide and folding propensity of the encoded peptide. Our results have implications for efforts to infer selection based on quantitative phenotype dynamics as well as to understand long-term trends in evolution of quantitative molecular traits.
The genomic epidemiology of SARS-CoV-2 in Palestine
Authors: Qutob Nouar , Salah Zaidoun , Richard Damien , Darwish Hisham , Sallam Husam , Shtayeh Issa , Najjar Osama , Ruzayqat Mahmoud , Najjar Dana , Balloux François , van Dorp Lucy
Published: October 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the novel coronavirus responsible for the COVID-19 pandemic, continues to cause significant public health burden and disruption globally. Genomic epidemiology approaches point to most countries in the world having experienced many independent introductions of SARS-CoV-2 during the early stages of the pandemic. However, this situation may change with local lockdown policies and restrictions on travel leading to the emergence of more geographically structured viral populations and lineages transmitting locally. Here, we report the first SARS-CoV-2 genomes from Palestine sampled from early March, when the first cases were observed, through to August of 2020. SARS-CoV-2 genomes from Palestine fall across the diversity of the global phylogeny, consistent with at least nine independent introductions into the region. We identify one locally predominant lineage in circulation represented by 50 Palestinian SARS-CoV-2, grouping with isolated viral samples from patients in Israel and the UK. We estimate the age of introduction of this lineage to 05/02/2020 (16/01/2020 - 19/02/2020), suggesting SARS-CoV-2 was already in circulation in Palestine predating its first detection in Bethlehem in early March. Our work highlights the value of ongoing genomic surveillance and monitoring to reconstruct the epidemiology of COVID-19 at both local and global scales.
Modifying adaptive therapy to enhance competitive suppression
Authors: Hansen Elsa , Read Andrew F.
Published: October 2020

Adaptive therapy is a promising new approach to cancer treatment. It is designed to leverage competition between drug-sensitive and drug-resistant cells in order to suppress resistance and maintain tumor control for longer. Prompted by encouraging results from a recent pilot clinical trial, we evaluate the design of this initial test of adaptive therapy and identify three simple modifications that should improve performance. These modifications are designed to increase competition and are easy to implement. Using the mathematical model that supported the recent adaptive therapy trial, we show that the suggested modifications further delay time to tumor progression and also increase the range of patients who can benefit from adaptive therapy.
Synergistic Combination of Cytotoxic Chemotherapy and Cyclin Dependent Kinase 4/6 Inhibitors in Biliary Tract Cancers
Authors: Arora Mansi , Bogenberger James M. , Abdelrahman Amro M. , Yonkus Jennifer , Alva-Ruiz Roberto , Leiting Jennifer L. , Chen Xianfeng , Junior Pedro Luiz Serrano Uson , Dumbauld Chelsae R. , Baker Alexander T. , Gamb Scott I. , Egan Jan B. , Zhou Yumei , Nagalo Bolni Marius , Meurice Nathalie , Eskelinen Eeva-Liisa , Salomao Marcela A. , Kosiorek Heidi E. , Braggio Esteban , Barrett Michael T. , Buetow Kenneth H. , Sonbol Mohamad B. , Mansfield Aaron S. , Roberts Lewis R. , Bekaii-Saab Tanios S. , Ahn Daniel H. , Truty Mark J. , Borad Mitesh J.
Published: October 2020

Biliary tract cancers (BTCs) are uncommon but highly lethal gastrointestinal malignancies. Gemcitabine/cisplatin is a standard-of-care (SOC) systemic therapy, but has a modest impact on survival and harbor toxicities including myelosuppression, nephropathy, neuropathy and ototoxicity. While BTCs are characterized by aberrations activating the cyclinD1-CDK4/6-CDKN2A-RB pathway, clinical use of CDK4/6 inhibitors as monotherapy is limited by lack of validated biomarkers, diffident pre-clinical efficacy and development of acquired drug resistance. Emerging studies have explored therapeutic strategies to enhance the anti-tumor efficacy of CDK4/6 inhibitors by combination with chemotherapy-regimens but their mechanism of action remains elusive. Here, we reportin vitroandin vivosynergy in BTC models, showing enhanced efficacy, reduced toxicity and better survival with a combination comprising gemcitabine/cisplatin and CDK4/6 inhibitors. Furthermore, we demonstrated that abemaciclib monotherapy had only modest efficacy due to autophagy induced resistance. Notably, triplettherapy was able to potentiate efficacy through elimination of the autophagic flux. Correspondingly, abemaciclib potentiated RRM1 reduction, resulting in sensitization to gemcitabine. Conclusions: As such, these data provide robust pre-clinical mechanistic evidence of synergy between gemcitabine/cisplatin and CDK4/6 inhibitors, and delineate a path forward for translation of these findings to preliminary clinical studies in advanced BTC patients.
Dinucleotides as simple models of the base stacking-unstacking component of DNA ‘breathing’ mechanisms
Authors: Beyerle Eric R. , Dinpajooh Mohammadhasan , Ji Huiying , von Hippel Peter H. , Marcus Andrew H. , Guenza Marina G.
Published: October 2020

Regulatory protein access to the DNA duplex ‘interior’ depends on local DNA ‘breathing’ fluctuations, and the most fundamental of these are thermally-driven base stacking-unstacking interactions. The smallest DNA unit that can undergo such transitions is the dinucleotide, whose structural and dynamic properties are dominated by stacking, while the ion condensation, cooperative stacking and inter-base hydrogen-bonding, present in duplex DNA are not involved. We use dApdA to study stacking-unstacking at the dinucleotide level because the fluctuations observed are likely to resemble those of larger DNA molecules, but in the absence of constraints introduced by cooperativity are likely to be more pronounced, and thus more accessible to measurement. We study these fluctuations with a combination of Molecular Dynamics simulations on the microsecond timescale and Markov State Model analyses, and validate our results by calculations of circular dichroism (CD) spectra, with results that agree well with experiments. Our analyses show that the CD spectrum of dApdA is defined by two distinct chiral conformations that correspond, respectively, to a Watson-Crick form and a hybrid form with one base in a Hoogsteen configuration. We find also that ionic structure and water orientation around dApdA play important roles in controlling its breathing fluctuations.
Timing variability and midfrontal ~4 Hz rhythms correlate with cognition in Parkinson’s disease
Authors: Singh Arun , Cole Rachel C. , Espinoza Arturo I. , Evans Aron , Cao Scarlett , Cavanagh James F. , Narayanan Nandakumar S.
Published: October 2020

Patients with Parkinson’s disease (PD) can have significant cognitive dysfunction; however, the mechanisms for these cognitive symptoms are unknown. Here, we used scalp electroencephalography (EEG) to investigate the cortical basis for PD-related cognitive impairments during interval timing, which requires participants to estimate temporal intervals of several seconds. Time estimation is an ideal task demand for investigating cognition in PD because it is simple, requires medial frontal cortical areas, and recruits basic executive processes such as working memory and attention.

However, interval timing has never been systematically studied in PD patients with cognitive impairments. We report three main findings. First, 71 PD patients had increased temporal variability compared to 37 demographically-matched controls, and this variability correlated with cognitive dysfunction as measured by the Montreal Cognitive Assessment (MOCA). Second, PD patients had attenuated ~4 Hz EEG oscillatory activity at midfrontal electrodes in response to the interval-onset cue, which was also predictive of MOCA. Finally, trial-by-trial linear mixed-effects modeling demonstrated that cue-triggered ~4 Hz power predicted subsequent temporal estimates as a function of PD and MOCA. Our data suggest that impaired cue-evoked midfrontal ~4 Hz activity predicts increased timing variability that is indicative of cognitive dysfunction in PD. These findings link PD-related cognitive dysfunction with cortical mechanisms of cognitive control, which could advance novel biomarkers and neuromodulation for PD.
Sex-specific predictive values of biomarkers for immunotherapy efficacy in lung adenocarcinoma
Authors: Jia Mingming , Chi Tian
Published: October 2020

It remains a challenge to accurately predict patient responses to tumor immunotherapy, although various biomarkers have been proposed to predict patient responses to anti-PD-1 therapy. Here by integrating genomic, transcriptomic, proteomic and clinical phenotype data from three immunotherapeutic cohorts and a multiple-dimensional dataset of The Cancer Genome Atlas (TCGA) project, we uncovered a profound effect of Sex on the predictive values of conventional biomarkers in lung adenocarcinoma (LUAD): only in females were nonsynonymous mutation burden (TMB), neoantigen burden, smoking signature, KRAS mutations (especially G12C and G12V) or tumor microenvironment robustly correlated with anti-PD-1 efficacy; the correlations in males were either absent or weaker. We propose that Sex be considered in conjunction with conventional biomarkers when predicting immunotherapy efficacy, and conversely, conventional biomarkers be carefully controlled for when attempting to dissect the impact of Sex on immunotherapy efficacy.
DNA-loop extruding SMC complexes can traverse one anotherin vivo
Authors: Brandão Hugo B. , Ren Zhongqing , Karaboja Xheni , Mirny Leonid A. , Wang Xindan
Published: October 2020

The spatial organization of chromosomes by structural maintenance of chromosomes (SMC) complexes is vital to organisms from bacteria to humans1,2. SMC complexes were recently found to be motors that extrude DNA loops3–11. It remains unclear, however, what happens when multiple SMC complexes encounter one anotherin vivoon the same DNA, how encounters are resolved, or how interactions help organize an active genome12. Here, we set up a “crash-course track” system to study what happens when SMC complexes encounter one another. Using theparS/ParB system, which loads SMC complexes in a targeted manner13–17, we engineered theBacillus subtilischromosome to have multiple SMC loading sites. Chromosome conformation capture (Hi-C) analyses of over 20 engineered strains show an amazing variety of never-before-seen chromosome folding patterns. Polymer simulations indicate these patterns require SMC complexes to traverse past each otherin vivo, contrary to the common assumption that SMC complexes mutually block each other’s extrusion activity18. Our quantitative model of bypassing predicted that increasing the numbers of SMCs on the chromosome could overwhelm the bypassing mechanism, create SMC traffic jams, and lead to major chromosome reorganization. We validated these predictions experimentally. We posit that SMC complexes traversing one another is part of a larger phenomenon of bypassing large steric barriers which enables these loop extruders to spatially organize a functional and busy genome.
Co-infection in critically ill patients with COVID-19: An observational cohort study from England
Authors: Baskaran Vadsala , Lawrence Hannah , Lansbury Louise , Webb Karmel , Safavi Shahideh , Zainuddin Izzah , Huq Tausif , Eggleston Charlotte , Ellis Jayne , Thakker Clare , Charles Bethan , Boyd Sara , Williams Tom , Phillips Claire , Redmore Ethan , Platt Sarah , Hamilton Eve , Barr Andrew , Venyo Lucy , Wilson Peter , Bewick Tom , Daniel Priya , Dark Paul , Jeans Adam R , McCanny Jamie , Edgeworth Jonathan D , Llewelyn Martin J , Schmid Matthias L , McKeever Tricia M , Beed Martin , Lim Wei Shen
Published: October 2020

Objective

To describe the incidence and nature of co-infection in critically ill adults with COVID-19 infection in England.

Methods

A retrospective cohort study of adults with COVID-19 admitted to seven intensive care units (ICUs) in England up to 18 May 2020, was performed. Patients with completed ICU stays were included. The proportion and type of organisms were determined at <48 and >48 hours following hospital admission, corresponding to community and hospital-acquired co-infections.

Results

Of 254 patients studied (median age 59 years (IQR 49-69); 64.6% male), 139 clinically significant organisms were identified from 83(32.7%) patients. Bacterial co-infections were identified within 48 hours of admission in 14(5.5%) patients; the commonest pathogens were Staphylococcus aureus (four patients) and Streptococcus pneumoniae (two patients). The proportion of pathogens detected increased with duration of ICU stay, consisting largely of Gram-negative bacteria, particularly Klebsiella pneumoniae and Escherichia coli. The co-infection rate >48 hours after admission was 27/1000 person-days (95% CI 21.3-34.1). Patients with co-infections were more likely to die in ICU (crude OR 1.78,95% CI 1.03-3.08, p=0.04) compared to those without co-infections.

Conclusion

We found limited evidence for community-acquired bacterial co-infection in hospitalised adults with COVID-19, but a high rate of Gram-negative infection acquired during ICU stay.
Decline in mortality among hospitalised covid-19 patients in Sweden: a nationwide observational study
Authors: Strålin Kristoffer , Wahlström Erik , Walther Sten , Bennet-Bark Anna M , Heurgren Mona , Lindén Thomas , Holm Johanna , Hanberger Håkan
Published: October 2020

OBJECTIVE

It is important to know if mortality among hospitalised covid-19 patients has changed as the pandemic has progressed. The aim of this study was to describe the dynamics of mortality among patients hospitalised for covid-19 in a nationwide study.

DESIGN

Nationwide observational cohort study of all patients hospitalised in Sweden 1 March to 30 June 2020 with SARS-CoV-2 RNA positivity 14 days before to 5 days after admission, and a discharge code for covid-19.

SETTING

All hospitals in Sweden.

PARTICIPANTS

15 761 hospitalised patients with covid-19, with data compiled by the Swedish National Board of Health and Welfare.

MAIN OUTCOME MEASURES

Outcome was 60-day all-cause mortality. Patients were stratified according to month of hospital admission. Poisson regression was used to estimate the relative risk of death by month of admission, adjusting for pre-existing conditions, age, sex, care dependency, and severity of illness (Simplified Acute Physiology, version 3), for patients in intensive care units (ICU).

RESULTS

The overall 60-day mortality was 17.8% (95% confidence interval (CI), 17.2% to 18.4%), and it decreased from 24.7% (95% CI, 23.0% to 26.5%) in March to 13.3% (95% CI, 12.1% to 14.7%) in June. Adjusted relative risk (RR) of death was 0.56 (95% CI, 0.51 to 0.63) for June, using March as reference. Corresponding RR for patients not admitted to ICU and those admitted to ICU were 0.60 (95% CI, 0.53 to 0.67) and 0.61 (95% CI, 0.48 to 0.79), respectively. The proportion of patients admitted to ICU decreased from 19.5% (95% CI, 17.9% to 21.0%) in the March cohort to 11.0% (95% CI, 9.9% to 12.2%) in the June cohort.

CONCLUSIONS

There was a gradual decline in mortality from March to June 2020 in Swedish hospitalised covid-19 patients, which was independent of pre-existing conditions, age, and sex. Future research is needed to explain the reasons for this decline. The changing covid-19 mortality should be taken into account when management and results of studies from the first pandemic wave are evaluated.
The effect of China factor on Taiwan's elections: how has it changed across generations from 2008 to 2014?
Authors: Weng Dennis Lu-Chung , Chen Lu-Huei , Wang Ching-Hsing
Published: October 2020

Purpose

The main purpose of this study is to reveal how the China factor influences Taiwan voters' evaluations of the two major parties across elections and generations. We contend that 1) elderly Taiwan voters may take the China factor more seriously than younger cohorts, and 2) China factor may be weighted differently depending on the levels of elections. More importantly, we argue that the China factor is tangled with voters' partisanship.

Design/methodology/approach

Data gathered from 2008 to 2014 Taiwan's Election and Democratization Study (TEDS) enable in investigating the influence of the China factor on Taiwan people's vote choices in the two local and two presidential elections. To answer the research question, this study applies issue voting theory and the seemingly unrelated regression (SUR) employed for empirical investigations.

Findings

The findings of this study provide empirical evidence on how political generations have changed their reactions to China in Taiwan's elections. The fundamental variables, party identification and the China issue are still very important and cannot be disregarded. Specifically, the China factor played a quite influential role in the Democratic Progressive Party (DPP) supporters' voting decisions regardless of their generations, whereas its effect on the Kuomintang (KMT) supporters' voting decisions varies depending on electoral contexts and generations.

Originality/value

While some scholars might suspect that the single item is not sufficient to be an effective predictor of vote choice, we contend that the China factor is definitely the most significant component in Taiwan's elections, especially when it is tangled with partisanship. The SUR approach in this study confirms that partisanship and the China factor cannot be viewed separately.
Implementation of age-friendly initiatives in smart cities: probing the barriers through a systematic review
Authors: Torku Alex , Chan Albert P.C. , Yung Esther H.K.
Published: October 2020

Purpose

The purpose of this study is to identify the barriers that hinder the implementation of age-friendly initiatives in smart cities.

Design/methodology/approach

A systematic review of the literature was conducted using Scopus search engine. Relevant keywords were used to discover 81 publications in academic journals. The titles, abstracts, keywords and full texts of the publications were examined to select 39 publications that were relevant for identifying the barriers that hinder the implementation of age-friendly initiatives in smart cities. The contents of the 39 relevant publications were analysed to ascertain the key barriers. A system thinking approach was adopted to understand the interaction among the barriers.

Findings

The study identified five key groups of barriers – namely physical barriers and environmental characteristics, technological barriers, social barriers, financial barriers and political barriers – that smart cities encountered or are likely to encounter in implementing age-friendly initiatives. Moreover, practical examples of good age-friendly implementation practices were highlighted.

Research limitations/implications

A limitation of this study is in the number of publications reviewed. Despite the comprehensive review, the number of publications reviewed may not be exhaustive. This is justified by the inapplicability of considering all possible keywords in one review study.

Practical implications

The systemic perspective of the barriers that hinder the implementation of age-friendly initiatives in smart cities would support policymakers in formulating policy recommendations to improve age-friendliness in cities.

Originality/value

This study underscores the variable and dynamic nature of developing age-friendly smart cities and forms novel basis for gaining insights into the multiple factors that can promote the integration of age-friendly initiatives within smart cities.
Same talk, different reaction? Communication, emergent leadership and gender
Authors: Schlamp Sofia , Gerpott Fabiola H. , Voelpel Sven C.
Published: October 2020

Purpose

We investigate the role of gender in linking communicative acts that occur in the interactions of self-managed teams to emergent leadership. Specifically, this study presents a framework that differentiates between agentic and communal task- and relations-oriented communication as predictors of emergent leadership, and it hypothesizes that men and women do not differ in what they say but do differ in how they are rewarded (i.e. ascribed informal leadership responsibilities) for their statements.

Design/methodology/approach

Interaction coding was used to capture the meeting communication of 116 members of 41 self-managed teams.

Findings

Men and women exhibited the same amount of agentic and communal task- and relations-oriented communication and were equally likely to emerge as leaders. However, men experienced an emergent leadership advantage when engaging in agentic and communal task-oriented behaviors. Agentic and communal relations-oriented behaviors did not predict emergent leadership.

Research limitations/implications

The findings imply that theories could be more precise in differentiating between objective behaviors (i.e. actor perspective) and perceptions thereof (i.e. observer perspective) to understand why women experience a disadvantage in assuming leadership roles.

Practical implications

Although women displayed the same verbal behaviors as men, they experienced different consequences. Organizations can provide unconscious bias training programs, which help increase employees' self-awareness of a potential positive assessment bias toward men's communication.

Originality/value

This research utilizes an innovative, fine-grained coding approach to gather data that add to previous studies showing that, unlike men, women experience a disadvantage in terms of emergent leadership ascriptions when they deviate from stereotypically expected behavior.
Customer brand engagement during service lockdown
Authors: Hollebeek Linda D. , Smith Dale L.G. , Kasabov Edward , Hammedi Wafa , Warlow Alexander , Clark Moira K.
Published: October 2020

Purpose

While the customer brand engagement (CBE) research has advanced important insight, most studies to date explore CBE under regular, free-market conditions, yielding an important knowledge gap regarding its manifestation under less regular conditions, including disaster/pandemics. This study, therefore, aims to explore CBE with essential/non-essential service during COVID-19-prompted citizen lockdown.

Design/methodology/approach

Based on a review, the authors develop a framework of lockdown-based CBE with essential/non-essential service interactions, which are conceptualized by their respective capacity to meet differing needs in Maslow’s hierarchy. The authors view lockdown-based essential/non-essential service interactions to differentially impact CBE, as summarized in a set of propositions.

Findings

The framework depicts lockdown-based essential/non-essential service interactions and their respective impact on CBE. The authors propose two essential service modes (i.e. socially distant/platform-mediated interactions) and two non-essential service modes (i.e. service closure/platform-mediated interactions), which the authors hypothesize to differently affect CBE. Moreover, the authors view the associations between our lockdown-based service modes and CBE to be moderated by customers’ regulatory focus (i.e. promotion/prevention), as formalized in the propositions.

Research limitations/implications

Given the authors’ focus on lockdown-based CBE, this paper adds unique insight to the literature. It also raises ample opportunities for further study, as outlined.

Practical implications

This study yields important managerial implications, including the suggested adoption of differing tactics/strategies to leverage promotion/prevention-focused customers’ brand engagement during lockdown.

Originality/value

By exploring the effects of lockdown-based essential/non-essential service modes on promotion/prevention-focused customers’ brand engagement, this paper adds novel insight.