bluuebunny/crossref_metadata_2025_split huggingface dataset:
Meat intake and cancer risk: prospective analyses in UK Biobank
Authors: Knuppel Anika , Papier Keren , Fensom Georgina K. , Appleby Paul N. , Schmidt Julie A. , Tong Tammy Y. N. , Travis Ruth C. , Key Timothy J. , Perez-Cornago Aurora 
Published: August 2019

AbstractBackgroundRed and processed meat has been consistently associated with risk for colorectal cancer, but evidence for other cancer sites is limited and few studies have examined the association between poultry intake and cancer risk. We examined associations between total meat, red meat, processed meat and poultry intake and incidence for 20 common cancer sites.Methods and FindingsWe analysed data from 475,023 participants (54% women) in UK Biobank. Participants were aged 37-73 years and cancer free at baseline. Information on meat consumption was based on a touchscreen questionnaire completed at baseline covering type and frequency of meat intake. Diet intake was re-measured a minimum of three times in a subsample (15%) using a web-based 24h dietary recall questionnaire. Multivariable-adjusted Cox proportional hazards models were used to determine the association between baseline meat intake and cancer incidence. Trends in risk across baseline meat intake categories were calculated by assigning a mean value to each category using estimates from the re-measured meat intakes. During a mean follow-up of 6.9 years, 28,955 participants were diagnosed with a malignant cancer. Total, red and processed meat intakes were each positively associated with risk of colorectal cancer (e.g. hazard ratio (HR) per 70 g/day higher intake of red and processed meat combined 1.31, 95%-confidence interval (CI) 1.14-1.52).Red meat intake was positively associated with breast cancer (HR per 50 g/day higher intake 1.12, 1.01-1.24) and prostate cancer (1.15, 1.03-1.29). Poultry intake was positively associated with risk for cancers of the lymphatic and hematopoietic tissues (HR per 30g/day higher intake 1.16, 1.03-1.32). Only the associations with colorectal cancer were robust to Bonferroni correction for multiple comparisons. Study limitations include unrepresentativeness of the study sample for the UK population, low case numbers for less common cancers and the possibility of residual confounding.ConclusionsHigher intakes of red and processed meat were associated with a higher risk of colorectal cancer. The observed positive associations of red meat consumption with breast and prostate cancer, and poultry intake with cancers of the lymphatic and hematopoietic tissues, require further investigation.
Enhance genome editing efficiency and specificity by a quick CRISPR/Cas9 system
Authors: Hu Yingying , Luo Zhou , Li Jing , Wang Dan , Sun Hai-Xi , Xiao An , Liu Da , Cheng Zhenchao , Wu Jun , Shen Yue , Xu Xun , Zhang Bo , Wang Jian , Gu Ying , Yang Huanming 
Published: August 2019

AbstractCRISPR/Cas9 is a powerful genome editing tool that has been successfully applied to a variety of species, including zebrafish. However, targeting efficiencies vary greatly at different genomic loci, the underlying causes of which were still elusive. Here we report a quick CRISPR/Cas9 system, designated as qCas9, which exhibits accelerated turnover of Cas9 protein in zebrafish. Our data showed that qCas9 significantly improved targeting efficiency, including both knock-out and knock-in in F0embryos, and yielded higher germline transmission rate in founder screen. Importantly, qCas9 showed little to no off-target editing in zebrafish and profoundly reduced off-target effect in HEK293T cell line. In summary, our findings demonstrate that qCas9 is a simple, economic and highly effective method to improve genome editing efficiency in zebrafish embryos and also holds great potential in reducing off-target effect in mammalian cell lines.
A visualizable hepatitis A virus and hepatitis C virus coinfection model in vitro: coexistence of two hepatic viruses under limited competition in viral RNA synthesis
Authors: Jiang Wang , Ma Pengjuan , Long Gang 
Published: August 2019

AbstractHepatitis A virus (HAV) and hepatitis C virus (HCV) coinfection in patients usually leads to HCV suppression or clearance. Whether this suppression/clearance is caused by direct virus-virus interaction or indirect interactions is still unknown. Here, we present a robust and visualizable HAV/HCV coinfection model for investigating their interactions in vitro. We find that HAV super infects HCV-persistently-infected Huh-7.5.1 cells without obvious virus-virus exclusion and vice versa, while there is a mild reciprocal viral interference in coinfection. Through single-cell scale confocal microscopy analysis and treating co-infected cells with rNTPs or antivirals e.g. Sofosbuvir, Simeprevir, and Ledipasvir, we find that HAV and HCV exploit cellular machinery in a compatible manner, but with reciprocal competition for rNTPs in their RNA synthesis. In conclusion, our findings reveal the absence of direct HAV-HCV interaction but the presence of indirect interaction, which may be due to limited competition in viral RNA synthesis. Therefore, we propose that suppression/clearance of HCV in HAV/HCV coinfected patients is probably due to indirect interactions e.g. viral competition or immunological interactions.Author summaryVirus-virus interactions could usually be categorized in three aspects: (1) direct interaction induced by interaction of viral gene or gene products; (2) indirect interaction mediated by immune response or (3) host environmental alteration. Hepatitis A virus (HAV) and hepatitis C virus (HCV) are two important causatives of human hepatitis. In patients, their coinfection often induces HCV suppression/clearance, and sometimes may lead to fulminant hepatitis. In this study, we find that a limited reciprocal viral interference occurs in HAV/HCV coinfection in vitro, which results from a viral competition of rNTPs in viral RNA synthesis. Our study provides a new paradigm of studying virus-virus interactions in single-cell scale. To our knowledge, we identify the rNTPs competition in virus coinfection for the first time by experiment, though several mathematical modelings have predicted the resource competition in virus coinfection.
ALS Motor Neurons Exhibit Hallmark Metabolic Defects That Are Rescued by Nicotinamide and SIRT3 Activation
Authors: Hor Jin-Hui , Santosa Munirah Mohamad , Lim Valerie Jing Wen , Xuan Ho Beatrice , Taylor Amy , Khong Zi Jian , Ravits John , Fan Yong , Liou Yih-Cherng , Soh Boon-Seng , Ng Shi-Yan 
Published: August 2019

SUMMARYMotor neurons (MNs) are highly energetic cells and recent studies suggest that altered energy metabolism precede MN loss in Amyotrophic Lateral Sclerosis (ALS), an age-onset neurodegenerative disease. However, clear mechanistic insights linking altered metabolism and MN death are still missing. In this study, induced pluripotent stem cells (iPSCs) from healthy controls, familial ALS and sporadic ALS patients were differentiated towards spinal MNs, cortical neurons and cardiomyocytes. Metabolic flux analyses reveal a MN-specific deficiency in mitochondrial respiration in ALS. Intriguingly, all forms of familial and sporadic ALS MNs tested in our study exhibited similar defective metabolic profiles, which were attributed to hyper-acetylation of mitochondrial proteins. In the mitochondria, SIRT3 functions as a mitochondrial deacetylase to maintain mitochondrial function and integrity. We found that activating SIRT3 using nicotinamide or a small molecule activator reversed the defective metabolic profiles in all our ALS MNs, as well as correct a constellation of ALS-associated phenotypes.
Chemotaxis and swarming in differentiated HL60 neutrophil-like cells
Authors: Babatunde Kehinde Adebayo , Wang Xiao , Hopke Alex , Mantel Pierre-Yves , Irimia Daniel 
Published: August 2019

ABSTRACTHuman leukemia cell line (HL-60) is an alternative to primary neutrophils in research studies. However, because HL-60 cells proliferate in an incompletely differentiated state, they must undergo differentiation before they acquire the functional properties of neutrophils. Here we provide evidence of swarming and chemotaxis in HL-60 neutrophil-like cells using precision microfluidic assays. We found that dimethyl sulfoxide (DMSO) differentiated HL-60 cells have larger size, increased length, and lower ability to squeeze through narrow channels compared to primary neutrophils. They migrate through tapered microfluidic channels slower than primary neutrophils, but faster than HL60s differentiated by other protocols, e.g. using all-trans retinoic acid. We found that differentiated HL-60 can swarm toward zymosan particle clusters, though they display disorganized migratory patterns and produce swarms of smaller size compared to primary neutrophils.
Impact of second-generation antipsychotics on white matter microstructure in adolescent-onset psychosis
Authors: Barth Claudia , Lonning Vera , Gurholt Tiril Pedersen , Andreassen Ole A. , Myhre Anne M. , Agartz Ingrid 
Published: August 2019

AbstractWhite matter abnormalities are well-established in adult patients with psychosis. Yet less is known about changes in early onset psychosis (EOP) during adolescence, especially whether antipsychotic medication might impact white matter microstructure in this sensitive phase. Here, we utilized Magnetic Resonance Imaging (MRI) in unmedicated and medicated adolescent EOP patients in comparison to healthy controls to examine the impact of antipsychotic medication status on indices of white matter microstructure. Twenty-two EOP patients (11 unmedicated) and 33 healthy controls, aged between 12-18 years, underwent 3T diffusion-weighted MRI. Using Tract-based Spatial Statistics, we calculate case-control differences in scalar diffusion measures, i.e. fractional anisotropy (FA), axial diffusion (AD) and radial diffusion (RD), and investigated their association with antipsychotic medication. We found significantly lower mean FA and AD in largely overlapping areas, particularly in left anterior corona radiata (ACR), in EOP patients relative to healthy controls. Mean FA in the left ACR was significantly associated with antipsychotic medication status (t = 2.991, p = 0.008, R2 = 0.298), showing higher FA values in medicated compared to unmedicated EOP patients. The present study is the first to link antipsychotic medication status to altered regional FA in the left ACR, a region being discussed to contribute to the etiology of psychosis. Yet, further work with larger samples is needed to draw firm conclusions about putatively enhancing effects of antipsychotic medication on white matter microstructure early in the disease process.
Heterogeneity in human hippocampal CaMKII transcripts reveals allosteric hub-dependent regulation
Authors: Sloutsky Roman , Dziedzic Noelle , Dunn Matthew J. , Bates Rachel M. , Torres-Ocampo Ana P. , Boopathy Sivakumar , Page Brendan , Weeks John G. , Chao Luke H. , Stratton Margaret M. 
Published: August 2019

AbstractCa2+-calmodulin dependent protein kinase II (CaMKII) plays a central role in Ca2+signaling throughout the body. Specifically in the hippocampus, CaMKII is required for learning and memory. CaMKII is encoded by four highly conserved genes in vertebrates: α, β, γ, and δ. AllCaMKIIs are comprised of a kinase domain, regulatory segment, variable linker region, and hub domain responsible for oligomerization. The four genes differ primarily in linker length and composition due to extensive alternative splicing. Here, we unambiguously report the heterogeneity of CaMKII transcripts in 3 complex samples of human hippocampus using Illumina sequencing. Our results show that hippocampal cells contain a diverse collection of 70 CaMKII transcripts from all four CaMKII genes. We characterized the Ca2+/CaM sensitivity of hippocampal CaMKII variants spanning a broad range of linker lengths and compositions. We demonstrate that the effect of the variable linker on Ca2+/CaM sensitivity is conditional on kinase and hub domains. Moreover, we reveal a novel role for the hub domain as an allosteric regulator of kinase activity, which may provide a new pharmacological target for modulating CaMKII activity. Using small angle X-ray scattering and single-particle electron cryo-microscopy, we present evidence for extensive interaction between the kinase and the hub domain, even in the presence of a 30-residue linker. Taken together, we propose that Ca2+/CaM sensitivity in CaMKII is gene-dependent and includes significant contributions from the hub. Our sequencing approach combined with biochemistry provides new insights into understanding the complex pool of endogenous CaMKII.One Sentence SummaryCaMKII is a well-conserved protein that is essential for learning and memory. When CaMKII is mutated in a mouse, this mouse has difficulty learning and remembering how to get through a maze. The hippocampus is the part of the brain required for memory. Here, we used a specific experiment to determine every type of CaMKII that is in a human hippocampus. We found 70 different types and then asked how these differences affect CaMKII function. These data provide evidence that an assembly domain of CaMKII plays an unexpected role regulating its activity. This new finding helps us better understand endogenous CaMKII in the brain and provides a new mechanism for modulating CaMKII activity.
Immune Profiling of Atherosclerotic Plaques Identifies Innate and Adaptive Dysregulations Associated with Ischemic Cerebrovascular Events
Authors: Fernandez Dawn M. , Rahman Adeeb H. , Fernandez Nicolas , Chudnovskiy Aleksey , Amir El-ad David , Amadori Letizia , Khan Nayaab S. , Wong Christine , Shamailova Roza , Hill Christopher , Wang Zichen , Remark Romain , Li Jennifer R. , Pina Christian , Faries Christopher , Awad Ahmed J. , Moss Noah , Bjorkegren Johan L.M. , Kim-Schulze Seunghee , Gnjatic Sacha , Ma’ayan Avi , Mocco J. , Faries Peter , Merad Miriam , Giannarelli Chiara 
Published: August 2019

SUMMARYAtherosclerosis is driven by multifaceted contributions of the immune system within the circulation and at vascular focal sites. Yet the specific immune dysregulations within the atherosclerotic lesions that lead to clinical cerebro- and cardiovascular complications (i.e. ischemic stroke and myocardial infarction) are poorly understood. Here, using single-cell mass cytometry with Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) we found that atherosclerotic plaques were enriched in activated, differentiated, and exhausted subsets of T cells vs. blood. Next, using single-cell proteomic, transcriptomic, and cell-to-cell interaction analyses we found unique functional dysregulations of both T cells and macrophages in plaques of patients with clinically symptomatic (SYM; recent stroke of TIA) or asymptomatic (ASYM, no recent stroke) carotid artery disease. SYM plaques were enriched with a distinct CD4+T cell subset, and T cells were activated, differentiated and presented subset specific exhaustion. SYM macrophages presented alternatively activated phenotypes including subsets associated with plaque vulnerability. In ASYM plaques, T cells and macrophages were activated and displayed a strong IL-1β signaling across cell types, that was absent in SYM plaques. The identification of plaque-specific innate and adaptive immune dysregulations associated with cerebrovascular events provides the basis for the design of precisely tailored cardiovascular immunotherapies.
Pathogenic Role of Delta 2 Tubulin in Bortezomib Induced Peripheral Neuropathy
Authors: Pero Maria Elena , Meregalli Cristina , Qu Xiaoyi , Kumar Atul , Shorey Matthew , Rolls Melissa , Tanji Kurenai , Brannagan Thomas H. , Alberti Paola , Fumagalli Giulia , Monza Laura , Cavaletti Guido , Bartolini Francesca 
Published: August 2019

ABSTRACTThe pathogenesis of chemotherapy induced peripheral neuropathy (CIPN) is still poorly understood. Herein, we found that the CIPN-causing drug, bortezomib (Bort), induces delta 2 tubulin (D2) while affecting MT stability and dynamics in sensory neurons, and that accumulation of D2 is a hallmark of Bort-induced peripheral neuropathy in humans. Furthermore, while induction of D2 was sufficient to cause axonopathy and inhibit mitochondria motility, reducing D2 alleviated both axonal degeneration and loss of mitochondria motility promoted by Bort. Altogether, our data demonstrate that Bort, structurally unrelated to tubulin poisons, can affect the tubulin cytoskeleton in sensory neurons in vitro, in vivo and in humans, indicating that the pathogenic mechanisms of seemingly unrelated CIPN drugs may converge on tubulin damage. They further reveal a previously unrecognized pathogenic role for D2 in bortezomib-causing CIPN through its regulation of mitochondria dynamics.
NAD+repletion rescues female fertility during reproductive ageing
Authors: Bertoldo Michael J. , Listijono Dave R. , Ho Wing-Hong Jonathan , Riepsamen Angelique H. , Jin Xing L. , Selesniemi Kaisa , Goss Dale M. , Mahbub Saabah , Campbell Jared M. , Habibalahi Abbas , Loh Wei-Guo Nicholas , Youngson Neil A. , Maniam Jayanthi , Wong Ashley S.A. , Richani Dulama , Li Catherine , Zhao Yiqing , Marinova Maria , Kim Lynn-Jee , Lau Laurin , Wu Rachael M , Mikolaizak A. Stefanie , Araki Toshiyuki , Le Couteur David G. , Turner Nigel , Morris Margaret J. , Walters Kirsty A. , Goldys Ewa , O’Neill Christopher , Gilchrist Robert B. , Sinclair David A. , Homer Hayden A. , Wu Lindsay E. 
Published: August 2019

AbstractFemale infertility is a common and devastating condition with life-long health, emotional and social consequences. There is currently no pharmacological therapy for preserving oocyte quality during aging, which is the strongest risk factor for infertility. This leads to an age dependent decline in natural conception and IVF success rates (1). Here, we show that this is due in part to declining levels of the metabolic cofactor nicotinamide adenine dinucleotide (NAD+), and that restoring NAD+levels with its metabolic precursor nicotinamide mononucleotide (NMN) rejuvenates oocyte quality and quantity in aged animals, leading to improved fertility. These benefits extend to the developing embryo, where NMN supplementation in embryo culture media following IVF enhances blastocyst formation in older mice. The NAD+dependent deacylase SIRT2 is sufficient, but not essential, to recapitulate the benefits ofin vivoNMN treatment, and transgenic overexpression of SIRT2 maintains oocyte spindle assembly, accurate chromosome segregation, decreased oxidative stress and overall fertility with ageing. Pharmacological elevation of NAD+may be an effective, non-invasive strategy for restoring and maintaining female fertility during ageing, and for improving the success of IVF.
PredictingN-strain coexistence from co-colonization interactions: epidemiology meets ecology and the replicator equation
Authors: Madec Sten , Gjini Erida 
Published: August 2019

AbstractMulti-type spreading processes are ubiquitous in ecology, epidemiology and social systems, but remain hard to model mathematically and to understand on a fundamental level. Here, we describe and study a multi-typesusceptible-infected-susceptible(SIS) model that allows for up to two co-infections of a host. Fitness differences betweenNinfectious agents are mediated through altered susceptibilities to secondary infections that depend on colonizer- co-colonizer interactions. By assuming small differences between such pairwise traits (and other infection parameters equal), we derive a model reduction framework using separation of timescales. This ‘quasi-neutrality’ in strain space yields a fast timescale where all types behave as neutral, and a slow timescale where non-neutral dynamics take place. On the slow timescale,Nequations govern strain frequencies and accurately approximate the dynamics of the full system withO(N2) variables. We show that this model reduction coincides with a special case of the replicator equation, which, in our system, emerges in terms of the pairwise invasion fitnesses among strains. This framework allows to build the multi-type community dynamics bottom-up from only pairwise outcomes between constituent members. We find that mean fitness of the multi-strain system, changing with individual frequencies, acts equally upon each type, and is a key indicator of system resistance to invasion. Besides efficient computation and complexity reduction, these results open new perspectives into high-dimensional community ecology, detection of species interactions, and evolution of biodiversity, with applications to other multi-type biological contests. By uncovering the link between an epidemiological system and the replicator equation, we also show our co-infection model relates to Fisher’s fundamental theorem and to conservative Lotka-Volterra systems.
A role for DIS3L2 over human nonsense-mediated mRNA decay targets
Authors: da Costa Paulo J. , Menezes Juliane , Saramago Margarida , García-Moreno Juan F. , Santos Hugo A. , Gama-Carvalho Margarida , Arraiano Cecília M. , Viegas Sandra C. , Romão Luísa 
Published: August 2019

ABSTRACTThe nonsense-mediated decay (NMD) pathway selectively degrades mRNAs carrying a premature translation-termination codon but also regulates the abundance of a large number of physiological mRNAs that encode full-length proteins. In human cells, NMD-targeted mRNAs are degraded by endonucleolytic cleavage and exonucleolytic degradation from both 5’ and 3’ ends. This is done by a process not yet completely understood that recruits decapping and 5’-to-3’ exonuclease activities, as well as deadenylating and 3’-to-5’ exonuclease exosome activities. In yeast, DIS3/Rrp44 protein is the catalytic subunit of the exosome, but in humans, there are three known paralogues of this enzyme: DIS3, DIS3L1, and DIS3L2. DIS3L1 and DIS3L2 exoribonucleases localize in the same compartment where NMD occurs, but little is known about their role in this process. In order to unveil the role of DIS3L2 in NMD, here we show that some NMD-targets accumulate in DIS3L2-depleted cells. mRNA half-life analysis further supports that these NMD-targets are in fact DIS3L2 substrates. Besides, we observed that DIS3L2 acts over full-length transcripts, through a process that also involves UPF1. Moreover, DIS3L2-mediated decay is dependent on the activity of the terminal uridylyl transferases Zcchc6/11 (TUT7/4). Together, our findings establish a role for DIS3L2 and uridylation in NMD.
Anterior cingulate cortex differently modulates fronto-parietal functional connectivity between resting-state and working memory tasks
Authors: Di Xin , Zhang Heming , Biswal Bharat B 
Published: August 2019

AbstractThe brain fronto-parietal regions and the functional communications between them are critical in supporting working memory and other executive functions. The functional connectivity between fronto-parietal regions are modulated by working memory loads, and are shown to be modulated by a third brain region in resting-state. However, it is largely unknown that whether the third-region modulations remain the same during working memory tasks or were largely modulated by task demands. In the current study, we collected functional MRI (fMRI) data when the subjects were performing n-back tasks and in resting-state. We first used a block-designed localizer to define the fronto-parietal regions that showed higher activations in the 2-back than the 1-back condition. Next, we performed physiophysiological interaction (PPI) analysis using left and right middle frontal gyrus (MFG) and superior parietal lobule (SPL) regions, respectively, in three continuous-designed runs of resting-state, 1-back, and 2-back conditions. No regions showed consistent modulatory interactions with the seed pairs in the three conditions. Instead, the anterior cingulate cortex (ACC) showed different modulatory interactions with the right MFG and SPL among the three conditions. While increased activity of the ACC was associated with decreased functional coupling between the right MFG and SPL in resting-state, it was associated with increased functional coupling in the 2-back condition. The observed task modulations support the functional significance of the modulations of the ACC on fronto-parietal connectivity.