bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gold nanorod based delivery system could bring about superior therapy effect of Ramucirumab through direct cytotoxicity to cancer cell mediated by differential regulation of phagocytosis in gastric cancer cell
Authors: Fan Linyang , Zhao Minzhi 
Published: December 2019

AbstractGastric Cancer (GC) is one of the most serious cancers with high incidence and mortality all over the world. Chemotherapy hadn’t led to desirable effect and targeted therapy brings about a new stage to cancer treatment. Ramucirumab is the first FDA-approved therapy for advanced gastric cancer. It is well known that gold nanorod, a nontoxic biocompatible nanomaterial, is an especially promising candidate for cancer theranostic. In this study, Ramucirumab (Ab) were first modified by gold nanoparticles to enhance uptake efficiency. The simple Nano-delivery system had taken perfect aggregation effect in vivo even better than 5-fold Ab treatment. Gold nanomaterials, especially gold nanorod (AuNR), could induce direct cytotoxic effect to cancer cell in the presence of Ab, while Ab or gold nanoparticle themselves couldn’t lead to such direct killing effect even at an extremely high concentration. Proteomic and transcriptomic analyses revealed this direct cytotoxicity derived predominantly from Ab-mediated phagocytose, and the high affinity receptor for Fc gamma CD64 showed differential up-regulation only in gastric cancer cell treated by these nanodrugs compared with Ab, especially for AuNR group. This was the first time to discover that nanoparticle could induce regulation of immune related pathways and Fcγ receptor in the target cancer cell. Simplified and powerful designs of smart nanoparticles are highly desired for clinical. The dramatic enhancement of Ab accumulation with simple composition, combined with direct cytotoxic effect specific to cancer cells brought perfect therapeutic effects in vivo than Ab, which would promote further clinical application of gold nanorod in the diagnosis and therapeutics of gastric cancer.Abstract Figure
The history of measles: from a 1912 genome to an antique origin
Authors: Düx Ariane , Lequime Sebastian , Patrono Livia Victoria , Vrancken Bram , Boral Sengül , Gogarten Jan F. , Hilbig Antonia , Horst David , Merkel Kevin , Prepoint Baptiste , Santibanez Sabine , Schlotterbeck Jasmin , Suchard Marc A. , Ulrich Markus , Widulin Navena , Mankertz Annette , Leendertz Fabian H. , Harper Kyle , Schnalke Thomas , Lemey Philippe , Calvignac-Spencer Sébastien 
Published: December 2019

AbstractMany infectious diseases are thought to have emerged in humans after the Neolithic revolution. While it is broadly accepted that this also applies to measles, the exact date of emergence for this disease is controversial. Here, we sequenced the genome of a 1912 measles virus and used selection-aware molecular clock modeling to determine the divergence date of measles virus and rinderpest virus. This divergence date represents the earliest possible date for the establishment of measles in human populations. Our analyses show that the measles virus potentially arose as early as the 4thcentury BCE, rekindling the recently challenged hypothesis of an antique origin of this disease.One Sentence SummaryMeasles virus diverged from rinderpest virus in the 4thcentury BCE, which is compatible with an emergence of measles during Antiquity.
Disrupted neural synchrony mediates the relationship between white matter integrity and cognitive performance in older adults
Authors: Hinault T. , Kraut M. , Bakker A. , Dagher A. , Courtney S.M. 
Published: December 2019

AbstractOur main goal was to determine the influence of white matter integrity on the dynamic coupling between brain regions and the individual variability of cognitive performance in older adults. EEG was recorded while participants performed a task specifically designed to engage working memory and inhibitory processes, and the associations among functional activity, structural integrity, and cognitive performance were assessed. We found that the association between white matter microstructural integrity and cognitive functioning with aging is mediated by time-varying alpha and gamma phase-locking value (PLV). Specifically, older individuals with better preservation of the inferior fronto-occipital fasciculus showed greater task-related modulations of alpha and gamma long-range PLV between the inferior frontal gyrus and occipital lobe, lower local phase-amplitude coupling in occipital lobes, and better cognitive control performance. Our results help delineate the role of individual variability of white matter microstructure in dynamic synchrony and cognitive performance during normal aging, and show that even small reductions in white matter integrity can lead to altered communications between brain regions, which in turn can result in reduced efficiency of cognitive functioning.Significance statementCognitive aging is associated with large individual differences, as some individuals maintain cognitive performance similar to that of young adults while others are significantly impaired. We hypothesized that individual differences in white matter integrity would influence the functional synchrony between frontal and posterior brain regions, and cognitive performance in older adults. We found that the association between reduced tract integrity and worse cognitive performance in older adults was mediated by task-related modulations of coupling synchrony in the alpha and gamma bands. Results offer a mechanistic explanation for the neural basis of the variability of cognitive performance in older adults who do not have any clinically diagnosable neuropathology, and for the association between structural network integrity and cognition in older adults.
When to wake up? The optimal waking-up strategies for starvation-induced persistence
Authors: Himeoka Yusuke , Mitarai Namiko 
Published: December 2019

AbstractProlonged lag time can be induced by starvation contributing to the antibiotic tolerance of bacteria. We analyze the optimal lag time to survive and grow the iterative and stochastic application of antibiotics. A simple model shows that the optimal lag time can exhibit a discontinuous transition when the severeness of the antibiotic application, such as the probability to be exposed the antibiotic, the death rate under the exposure, and the duration of the exposure, is increased. This suggests the possibility of reducing tolerant bacteria by controlled usage of antibiotics application. When the bacterial populations are able to have two phenotypes with different lag times, the fraction of the second phenotype that has different lag time shows a continuous transition. We then present a generic framework to investigate the optimal lag time distribution for total population fitness for a given distribution of the antibiotic application duration. The obtained optimal distributions have multiple peaks for a wide range of the antibiotic application duration distributions, including the case where the latter is monotonically decreasing. The analysis supports the advantage in evolving multiple, possibly discrete phenotypes in lag time for bacterial long-term fitness.Author summaryBacteria grow exponentially consuming nutrients, and then starve until the next nutrient is added. During the starvation, the cells enter dormancy and the cells become tolerant not only to starvation but also to other stressors. When nutrients are given to the starved cells, it takes some time before the cells fully “wake-up” and proliferate again. At first sight, it appears that the shorter this lag time the better for the bacteria. However, if the environment may contain another deadly stressor such as antibiotics, it may be better to “over-sleep” until the stressor is gone. Thus, they need to evolve to optimize their waking up strategy in the fluctuating environment. Here we have developed a theory for the optimal strategy for the repeated grow-and-starvation cycles with a fluctuating application of antibiotics. The optimal lag time exhibits a steep transition from immediate wake-up to over-sleep when the severeness of the antibiotics exceeds the threshold. The proposed general framework provides a way to predict the optimal distribution of lag time for various environmental fluctuation, and it may open for possible applications in administrating drug usage for interventions of pathogenic bacteria as well as cancer therapies where drug tolerance of dormant cells are observed.
NanoCaller for accurate detection of SNPs and indels in difficult-to-map regions from long-read sequencing by haplotype-aware deep neural networks
Authors: Ahsan Mian Umair , Liu Qian , Fang Li , Wang Kai 
Published: December 2019

AbstractLong-read sequencing enables variant detection in genomic regions that are considered difficult-to-map by short-read sequencing. To fully exploit the benefits of longer reads, here we present a deep-learning method NanoCaller, which detects SNPs using long-range haplotype information, then phases long reads with called SNPs and calls indels with local realignment. Evaluation on 8 human genomes demonstrated that NanoCaller generally achieves better performance than competing approaches. We experimentally validated 41 novel variants in a widely-used benchmarking genome, which cannot be reliably detected previously. In summary, NanoCaller facilitates the discovery of novel variants in complex genomic regions from long- read sequencing.
Learning temporal integration from internal feedback
Authors: Nygren Erik , Ramirez Alexandro , McMahan Brandon , Aksay Emre , Senn Walter 
Published: December 2019

AbstractThere has been much focus on the mechanisms of temporal integration, but little on how circuits learn to integrate. In the adult oculomotor system, where a neural integrator maintains fixations, changes in integration dynamics can be driven by visual error signals. However, we show through dark-rearing experiments that visual inputs are not necessary for initial integrator development. We therefore propose a vision-independent learning mechanism whereby a recurrent network learns to integrate via a ‘teaching’ signal formed by low-pass filtered feedback of its population activity. The key is the segregation of local recurrent inputs onto a dendritic compartment and teaching inputs onto a somatic compartment of an integrator neuron. Model instantiation for oculomotor control shows how a self-corrective teaching signal through the cerebellum can generate an integrator with both the dynamical and tuning properties necessary to drive eye muscles and maintain gaze angle. This bootstrap learning paradigm may be relevant for development and plasticity of temporal integration more generally.Highlights- A neuronal architecture that learns to integrate saccadic commands for eye position.- Learning is based on the recurrent dendritic prediction of somatic teaching signals.- Experiment and model show that no visual feedback is required for initial integrator learning.- Cerebellum is an internal teacher for motor nuclei and integrator population.
Enhancing Intracellular Accumulation and Target Engagement of PROTACs with Reversible Covalent Chemistry
Authors: Guo Wen-Hao , Qi Xiaoli , Yu Xin , Liu Yang , Chung Chan-I , Bai Fang , Lin Xingcheng , Lu Dong , Wang Lingfei , Chen Jianwei , Su Lynn Hsiao , Nomie Krystle J. , Li Feng , Wang Meng C. , Shu Xiaokun , Onuchic José N. , Woyach Jennifer A. , Wang Michael L. , Wang Jin 
Published: December 2019

AbstractCurrent efforts in the proteolysis targeting chimera (PROTAC) field mostly focus on choosing an appropriate E3 ligase for the target protein, improving the binding affinities towards the target protein and the E3 ligase, and optimizing the PROTAC linker. However, due to the large molecular weights of PROTACs, their cellular uptake remains an issue. Through comparing how different warhead chemistry, reversible noncovalent (RNC), reversible covalent (RC), and irreversible covalent (IRC) binders, affects the degradation of Bruton’s Tyrosine Kinase (BTK), we serendipitously discover that cyano-acrylamide-based reversible covalent chemistry can significantly enhance the intracellular accumulation and target engagement of PROTACs and develop RC-1 as a reversible covalent BTK PROTAC with a high target occupancy as its corresponding kinase inhibitor and effectiveness as a dual functional inhibitor and degrader, a different mechanism-of-action for PROTACs. Importantly, this reversible covalent strategy is generalizable to improve other PROTACs, opening a path to enhance PROTAC efficacy.
Large-scale nuclear remodeling and transcriptional deregulation occur on both derivative chromosomes after Mantle Cell Lymphoma chromosomal translocation
Authors: Sall Fatimata Bintou , Pichugin Andrei , Iarovaia Olga , Barat Ana , Tsfasman Tatyana , Brossas Caroline , Prioleau Marie-Noëlle , Sheval Eugeny V. , Zharikova Anastasiya A. , Lazarovici Julien , Camara-Clayette Valérie , Ribrag Vincent , Lipinski Marc , Vassetzky Yegor , Germini Diego 
Published: December 2019

ABSTRACTRecurrent chromosomal translocations are found in many blood and solid cancers. Balanced translocations, frequent in lymphoid malignancies, lead to the formation of two aberrant derivative (der) chromosomes. This event often leads to overexpression of an oncogene. In many cases, the expression of an oncogene is not enough to produce a malignant phenotype; however, most part of the studies focus on the events involving the chromosome where the oncogene is located, but rarely the other der chromosome where other oncogenic alterations may potentially arise. Mantle cell lymphoma (MCL), an aggressive B-cell non-Hodgkin lymphoma, is a perfect example of this. In 85% of the cases, it is characterized by the translocation t(11;14), which leads to the overexpression of cyclin D1 (CCND1) gene which results juxtaposed to the immunoglobulin heavy chain (IGH) gene on the der14 chromosome. This feature alone is not sufficient to induce oncogenesis. Here we focused on the der11 chromosome. We demonstrated that expression of 88 genes located in a 15mb region close to the translocation breakpoint on the der11 was deregulated both in the GRANTA-519 MCL cell line and in B-cells from MCL patients. We found that a large segment of der11containing deregulated genes was relocated from its normal position in the nuclear periphery towards the center of the nucleus in close proximity to the nucleolus where the abundant nucleolar protein nucleolin binds a subset of genes located close to the breakpoint and activates their expression. This finding allowed to identify new potential oncogenes involved in MCL and the mechanisms of their upregulation.
Calcium induced calcium release in proximity to hair cell BK channels revealed by PKA activation
Authors: Bai Jun-ping , Xue Na , Lawal Omolara , Nyati Anda , Santos-Sacchi Joseph , Navaratnam Dhasakumar 
Published: December 2019

AbstractLarge conductance calcium-activated potassium (BK) channels play a critical role in electrical resonance, a mechanism of frequency selectivity in chicken hair cells. We determine that BK currents are dependent on inward flow of Ca2+, and intracellular buffering of Ca2+. Entry of Ca2+is further amplified locally by Ca2+induced Ca2+release (CICR) in close proximity to plasma membrane BK channels. Ca2+imaging reveals peripheral clusters of high concentrations of Ca2+that are suprathreshold to that needed to activate BK channels. PKA activation increases BK currents likely by recruiting more BK channels due to spatial spread of high Ca2+concentrations in turn from increasing CICR. STORM imaging confirms the presence of nanodomains with ryanodine and IP3 receptors in close proximity to the Slo subunit of BK channels. Together, these data require a rethinking of how electrical resonance is brought about and suggest effects of CICR in synaptic release. Both genders were included in this study.
Activation of the hypothalamic-pituitary adrenal axis in response to a verbal fluency task and associations with task performance
Authors: Becker Linda , Schade Ursula , Rohleder Nicolas 
Published: December 2019

AbstractSpeech fluency can be impaired in stressful situations. The aim of the present study was to investigate whether a verbal fluency task without any further stress induction by itself induces responses of the hypothalamic-pituitary adrenal (HPA) axis and of the sympathetic nervous system (SNS).The sample consisted ofn= 85 participants (68.2% female; 33.3 ± 15.2 years, BMI = 23.7 ± 4.3 kg/m2) who performed two consecutive verbal fluency tasks for two minutes each. The categories were either ‘stress’ or ‘disease’ and ‘animals’ or ‘foods’ which were presented in a randomized order. Three saliva samples were collected, prior to the task (t0), immediately after (t1), and ten minutes after (t2). Salivary α-amylase and cortisol were assessed. Furthermore, blood pressure, heart rate, and subjective ratings of actual stress perception, level of effort, and tiredness were measured.The verbal fluency task induced an HPA axis response with a maximum cortisol level at t2(p< .001, ηp2= .19) which was independent of task performance. Furthermore, subjective stress and effort as well of tiredness increased immediately after the task (allp< .001; alld≥ 1.0). Tiredness immediately after the task was negatively correlated with task performance (p= .002). No α-amylase, blood pressure or heart rate responses were found.We conclude that a verbal fluency task acts like an acute stressor that induces a cortisol response without the need of further (e.g., social-evaluative) stress components. Therefore, it is a little time-consuming alternative to other stress tasks that can be used in field studies with little effort.
An instrument to assess HIV-related knowledge and adjustment to HIV+ status, and their association with anti-retroviral adherence
Authors: Laws M. Barton , Lee Yoojin , Rogers William S. , Taubin Tatiana , Wilson Ira B. 
Published: December 2019

ABSTRACTBackgroundFindings on the association between health literacy and anti-retroviral (ARV) adherence are inconsistent. Health literacy is usually operationalized with simple tests of basic literacy, but more complex conceptions of health literacy include content knowledge. People living with chronic illness also conceptualize and experience illness in ways other than biomedical or mechanistic models of disease.ObjectiveThere are no instruments that comprehensively assess knowledge of people living with HIV concerning HIV disease and treatment; or psychological adjustment to being HIV+. Little is known about the relationship between factual knowledge, or positive identification as HIV+, and anti-retroviral (ARV) adherence.MethodsFormative work with in-depth semi-structured interviews, and cognitive testing, to develop a structured instrument assessing HIV-related knowledge, and personal meanings of living with HIV. Pilot administration of the instrument to a convenience sample of 101 respondents.Key ResultsRespondents varied considerably in their expressed need for in-depth knowledge, the accuracy of their understanding of relevant scientific concepts and facts about ARV treatment, and psychological adjustment and acceptance of HIV+ status. Most knowledge domains were not significantly related to self-reported ARV adherence, but accurate knowledge specifically about ARV treatment was (r=0.25, p=.02), as was an adapted version of the Need for Cognition scale (r=.256, p=.012). Negative feelings about living with HIV (r=.33, p=.0012), and medication taking (r=.276, p=.008) were significantly associated with non-adherence.ConclusionThe instrument may be useful in diagnosing addressable reasons for non-adherence, as a component of psychoeducational interventions, and for evaluation of such interventions.PLAIN LANGUAGE SUMMARYWe developed a questionnaire for people with HIV. General knowledge about HIV wasn’t related to whether people took their medications, but specific information about treatment was. People with lots of bad feelings about living with HIV were less likely to take medications as prescribed. People who liked to think more about their decisions were more likely to take their medications.
Gut-derivedFlavonifractorspecies variants are differentially enriched duringin vitroincubation with quercetin
Authors: Rodriguez-Castaño Gina Paola , Rey Federico E. , Caro-Quintero Alejandro , Acosta-González Alejandro 
Published: December 2019

AbstractFlavonoids are a common component of the human diet with widely reported health-promoting properties. The gut microbiota transforms these compounds affecting the overall metabolic outcome of their consumption. Flavonoid-degrading bacteria are often studied in isolation under culture conditions that do not resemble the conditions in the colon and that eliminate the multiple interactions that take place in complex communities. In this study, a comparative metataxonomic analysis of fecal communities supplemented with the flavonoid quercetin led us to identify a potential competitive exclusion interaction between two sequence variants related to the flavonoid-degrading species,Flavonifractor plautii, that belong to the same genus but different species. During incubation of fecal slurries with quercetin, the relative abundance of these two variants was inversely correlated; one variant, ASV_65f4, increased in relative abundance in half of the libraries and the other variant, ASV_a45d, in the other half. This pattern was also observed with 6 additional fecal samples that were transplanted into germ-free mice fed two different diets. Mouse’s diet did not change the pattern of dominance of either variant, and initial relative abundances did not predict which one ended up dominating. Potential distinct metabolic capabilities of these twoFlavonifractor-related species were evidenced, as only one variant, ASV_65f4, became consistently enriched in complex communities supplemented with acetate but no quercetin. Genomic comparison analysis of the close relatives of each variant revealed that ASV_65f4 may be an efficient ethanolamine-utilizing bacterium which may increase its fitness in media with no quercetin compared to ASV_a45d. Other discordant features between ASV_65f4- and ASV_a45d-related groups may be the presence of flagellar and galactose-utilization genes, respectively. Overall, we showed that theFlavonifractorgenus harbors variants that present a pattern of negative co-occurrence and that may have different metabolic and structural traits, whether these differences affect the dynamic of quercetin degradation warrants further investigation.