bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nano-particles carried by multiple dynein motors: A Self-Regulating Nano-Machine
Authors: Fayer I. , Halbi G. , Aranovich D. , Gat S. , Bar S. , Erukhimovitch V. , Granek Rony , Bernheim-Groswasser Anne 
Published: July 2020

AbstractNative cargos demonstrate efficient intra-cellular active transport. Here we investigate the motion of spherical nano-particles (NPs) grafted with flexible polymers, each ending with a nuclear localization signal peptide, thereby allowing recruitment of mammalian cytoplasmic dynein. Bead-motility assays show several unique motility features, depending on the number of NP-bound motors. NPs perform angular motion, in which the plus-end directed and right-handed motions are correlated. To simulate the system, we formulate a theoretical model that builds on single mammalian dynein properties, generalized to include motor-motor elastic and excluded-volume interactions. We find that long time trajectories exhibit both left- and right-handed helical motion, consistent with the measured angular velocity. The number of participating motors is self-regulated, thus allowing the NP to benefit from alternations between single and multiple transporting motors. Native cargos could use a similar approach to achieve both obstacle bypassing and persistent motion in the crowded cellular environment.Significance StatementThe mechanism of active transport of native cargos, such as some viruses, is a long-standing conundrum. Their need for persistence motion towards the nucleus, while bypassing obstacles in the super-crowded intracellular milieu, requires sophisticated natural design. To fathom this machinery, we study a smartly designed nano-particle that recruitsseveraldynein motor-proteins from the cytoplasm. Motility assays and model simulations reveal long run-times, long run-lengths, and helical motion around the microtubule symmetry axis. Moreover, the nano-particles self-regulate the number of dyneins participating in the motion, which optimizes its motility properties. We suggest that alternating between single motor motility, which we believe is beneficial for obstacle bypassing, and multiple motor states, which engender persistent motion towards the nucleus, the NP achieves optimal transport efficiency.
Unravelling the developmental roadmap towards human brown adipose tissue
Authors: Carobbio Stefania , Guenantin Anne-Claire , Bahri Myriam , Samuelson Isabella , Honig Floris , Rodriguez-Fdez Sonia , Long Kathleen , Kamzolas Ioannis , Awad Sherine , Lukovic Dunja , Erceg Slaven , Bassett Andrew , Mendjan Sasha , Vallier Ludovic , Rosen Barry S. , Chiarugi Davide , Vidal-Puig Antonio 
Published: July 2020

AbstractIncreasing brown adipose tissue (BAT) mass and activation has been proposed as a potential therapeutic strategy to treat obesity and associated cardiometabolic complications. Given that obese and diabetic patients possess low amounts of BAT, an efficient way to expand their BAT mass would be necessary if BAT is to be useful. Currently, there is limited knowledge about how human BAT develops, differentiates, and is optimally activated. Moreover, to have access to human BAT is challenging, given its low volume and being anatomically dispersed. These constrain makes detailed mechanistic studies related to BAT development and function in humans virtually impossible. To overcome these limitations, we have developed a human-relevant new protocol for the differentiation of human pluripotent stem cells (hPSCs) into brown adipocytes (BAs). Unique to this protocol is that it is chemically-defined to recapitulate a physiological step-by-step developmental path of BAT that captures transient paraxial mesoderm and BAT progenitor states, on its way to reaching the adipocyte stage finally. These hPSC-derived BAs express brown adipocyte and thermogenic markers, are insulin sensitive, and respond to β-adrenergic stimuli. This new protocol is a scalable tool to study human BAs during development.
Clinical characteristics and primary management of patients diagnosed with prostate cancer between 2015 and 2019 at the Uganda Cancer Institute
Authors: Katongole Paul , Sande Obondo J. , Yusuf Mulumba , Joloba Moses , Reynolds Steven J , Niyonzima Nixon 
Published: July 2020

AbstractBackgroundProstate cancer is the second most common cancer among men in Uganda, with over 2086 incident cases in 2018. This study’s objective was to report the clinical characteristics and primary management of men diagnosed with prostate cancer at the Uganda Cancer Institute from 1stJanuary 2015 to 31stDecember 2019.MethodsRecords from all men diagnosed with Prostate cancer at the Uganda Cancer Institute from 1stJanuary 2015 to 31stDecember 2019 were reviewed. Clinical characteristics and primary treatment were recorded. Risk categorization was done using the European Society for Medical Oncology prostate cancer risk group classification.Resultstotal of 874 medical records for men diagnosed with prostate cancer was retrieved. The median age was 70 years (interquartile range 64–77). In this study, 501 (57.32%) patients had localized disease. Among patients with localized disease, 2 (0.23%) were classified as low-risk, 5 (0.53%) as intermediate-risk, and 494 (56.52%) as high-risk. Three hundred seventy-three (373) patients had metastatic disease at diagnosis. Among patients with distant metastases, the most common site of metastases was bone 143 (16.36%), followed by spinal cord 54 (6.18%), abdomen 22 (2.52%), and lungs 14 (1.60%). Regarding the primary treatment options majority of the patients were on chemotherapy 384(43.94%) followed by hormonal therapy 336 (38.44%) and radiotherapy 127 (14.53%).ConclusionThe majority of the patients diagnosed with prostate cancer at the Uganda Cancer Institute presented with advanced disease. The primary treatments were mostly chemotherapy, hormonal therapy, and radiotherapy. There is a need to improve prostate cancer screening in regional health care facilities and the communities to enhance early detection and management of prostate cancer.
Overlaid positive and negative feedback loops shape dynamical properties of PhoPQ two-component system
Authors: Rao Satyajit D , Igoshin Oleg A 
Published: July 2020

AbstractBacteria use two-component systems (TCSs) to sense environmental conditions and change gene expression to adapt to those conditions. To amplify cellular responses, many bacterial TCSs are under positive feedback control, i.e. increase their own expression when activated. InE. coli, Mg2+-sensing TCS, PhoPQ, in addition to the positive feedback includes a negative feedback via upregulation of MgrB protein that inhibits PhoQ. How interplay of these feedback loops shapes steady state and dynamical responses of PhoPQ TCS to change in Mg2+remains poorly understood. In particular, how the presence of MgrB feedback affects the robustness of PhoPQ response to overexpression of TCS is unclear. It is also unclear why the steady state response to decreasing Mg2+is biphasic, i.e. plateaus over a range of Mg2+concentrations and then increases again at growth-limiting Mg2+. In this study, we use mathematical modeling to identify potential mechanisms behind these experimentally observed dynamical properties. The results make experimentally testable predictions for the regime with response robustness and propose novel explanation of biphasic response constraining the mechanisms for modulation of PhoQ activity by Mg2+and MgrB. Finally, we show how interplay of positive and negative feedback loops affect networks steady-state sensitivity and response dynamics. In the absence of MgrB feedback, the model predicts oscillations thereby suggesting a general mechanism of oscillatory or pulsatile dynamics in autoregulated TCSs. These results help better understanding of TCS signaling and other networks with overlaid positive and negative feedback.Author summaryFeedback loops are commonly observed in bacterial gene-regulatory networks to enable proper dynamical responses to stimuli. Positive feedback loops often amplify the response to stimulus, whereas negative feedback loops are known to speed-up the response and increase robustness. Here we demonstrate how combination of positive and negative feedback in network sensing extracellular ion concentrations affects its steady state and dynamic responses. We utilize published experimental data to calibrate mathematical models of the gene regulatory network. The resulting model quantitatively matches experimentally observed behavior and can make predictions on the mechanism of negative feedback control. Our results show the advantages of such a combination feedback loops and predict the effect of their perturbation on the steady state and dynamic responses. This study improves our understanding of how feedback loops shape dynamical properties of signaling networks.
Transmission delays and frequency detuning can regulate information flow between brain regions
Authors: Pariz Aref , Fischer Ingo , Valizadeh Alireza , Mirasso Claudio 
Published: July 2020

AbstractBrain networks exhibit very variable and dynamical functional connectivity and flexible configurations of information exchange despite their overall fixed structure (connectome). Brain oscillations are hypothesized to underlie time-dependent functional connectivity by periodically changing the excitability of neural populations. In this paper, we investigate the role that the connection delay and the frequency detuning between different neural populations play in the transmission of signals. Based on numerical simulations and analytical arguments, we show that the amount of information transfer between two oscillating neural populations can be determined solely by their connection delay and the mismatch in their oscillation frequencies. Our results highlight the role of the collective phase response curve of the oscillating neural populations for the efficacy of signal transmission and the quality of the information transfer in brain networks.Author summaryCollective dynamics in brain networks is characterized by a coordinated activity of their constituent neurons that lead to brain oscillations. Many evidences highlight the role that brain oscillations play in signal transmission, the control of the effective communication between brain areas and the integration of information processed by different specialized regions. Oscillations periodically modulate the excitability of neurons and determine the response those areas receiving the signals. Based on the communication trough coherence (CTC) theory, the adjustment of the phase difference between local oscillations of connected areas can specify the timing of exchanged signals and therefore, the efficacy of the communication channels. An important factor is the delay in the transmission of signals from one region to another that affects the phase difference and timing, and consequently the impact of the signals. Despite this delay plays an essential role in CTC theory, its role has been mostly overlooked in previous studies. In this manuscript, we concentrate on the role that the connection delay and the oscillation frequency of the populations play in the signal transmission, and consequently in the effective connectivity, between two brain areas. Through extensive numerical simulations, as well as analytical results with reduced models, we show that these parameters have two essential impacts on the effective connectivity of the neural networks: First, that the populations advancing in phase to others do not necessarily play the role of the information source; and second, that the amount and direction of information transfer dependents on the oscillation frequency of the populations.
Comparison of target enrichment strategies for ancient pathogen DNA
Authors: Furtwängler Anja , Neukamm Judith , Böhme Lisa , Reiter Ella , Vollstedt Melanie , Arora Natasha , Singh Pushpendra , Cole Stewart T. , Knauf Sascha , Calvignac-Spencer Sébastien , Krause-Kyora Ben , Krause Johannes , Schuenemann Verena J. , Herbig Alexander 
Published: July 2020

AbstractIn ancient DNA research, the degraded nature of the samples generally results in poor yields of highly fragmented DNA, and targeted DNA enrichment is thus required to maximize research outcomes. The three commonly used methods – (1) array-based hybridization capture and in-solution capture using either (2) RNA or (3) DNA baits – have different characteristics that may influence the capture efficiency, specificity, and reproducibility. Here, we compared their performance in enriching pathogen DNA ofMycobacterium lepraeandTreponema pallidumof 11 ancient and 19 modern samples. We find that in-solution approaches are the most effective method in ancient and modern samples of both pathogens, and RNA baits usually perform better than DNA baits.Method summaryWe compared three targeted DNA enrichment strategies used in ancient DNA research for the specific enrichment of pathogen DNA regarding their efficiency, specificity, and reproducibility for ancient and modernMycobacterium lepraeandTreponema pallidumsamples. Array-based capture and in-solution capture with RNA and DNA baits were all tested in three independent replicates.
Structures of potent and convergent neutralizing antibodies bound to the SARS-CoV-2 spike unveil a unique epitope responsible for exceptional potency
Authors: Du Shuo , Cao Yunlong , Zhu Qinyu , Wang Guopeng , Du Xiaoxia , He Runsheng , Xu Hua , Zheng Yinghui , Wang Bo , Bai Yali , Ji Chenggong , Yisimayi Ayijiang , Wang Qisheng , Gao Ning , Xie X. Sunney , Su Xiao-dong , Xiao Junyu 
Published: July 2020

SummaryUnderstanding the mechanism of neutralizing antibodies (NAbs) against SARS-CoV-2 is critical for effective vaccines and therapeutics development. We recently reported an exceptionally potent NAb, BD-368-2, and revealed the existence ofVH3-53/VH3-66convergent NAbs in COVID-19. Here we report the 3.5-Å cryo-EM structure of BD-368-2’s Fabs in complex with a mutation-induced prefusion-state-stabilized spike trimer. UnlikeVH3-53/VH3-66NAbs, BD-368-2 fully blocks ACE2 binding by occupying all three receptor-binding domains (RBDs) simultaneously, regardless of their “up” and “down” positions. BD-368-2 also triggers fusogenic-like structural rearrangements of the spike trimer, which could impede viral entry. Moreover, BD-368-2 completely avoids the common epitope ofVH3-53/VH3-66NAbs, evidenced by multiple crystal structures of their Fabs in tripartite complexes with RBD, suggesting a new way of pairing potent NAbs to prevent neutralization escape. Together, these results rationalize a unique epitope that leads to exceptional neutralization potency, and provide guidance for NAb therapeutics and vaccine designs against SARS-CoV-2.
The effects of environmental complexity on microbial community yield and structure
Authors: Pacheco Alan R. , Segrè Daniel 
Published: July 2020

AbstractEnvironmental composition is a major, though poorly understood determinant of microbiome dynamics. Here we ask whether general principles govern how key microbial community properties, i.e. yield and diversity, scale with the number of environmental molecules. By assembling hundreds of synthetic consortia, we found that community yield remains constant as a function of environmental complexity, in agreement with additive expectations of an idealized model. However, taxonomic diversity is much lower than expected. By quantifying this deviation with a metric for epistatic interactions between environments, we uncovered simple ecological rules that govern how communities respond nonlinearly to the coupling of different nutrient sets. Our results demonstrate that environmental complexity alone is not sufficient for maintaining microbiome diversity, and provide practical guidance for designing and controlling microbial communities.
Limited genetic diversity ofblaCMY-2-containing IncI1-pST12 plasmids from Enterobacteriaceae of human and broiler chicken origin in the Netherlands
Authors: den Drijver Evert , Stohr Joep J.J.M. , Verweij Jaco J. , Verhulst Carlo , Velkers Francisca C. , Stegeman Arjan , Kluytmans-van den Bergh Marjolein F.Q. , Kluytmans Jan A.J.W. ,   i-4-1-Health Study Group
Published: July 2020

AbstractDistinguishing epidemiologically related and unrelated plasmids is essential to confirm plasmid transmission. We compared IncI1-pST12 plasmids from both human and livestock origin and explored the degree of sequence similarity between plasmids from Enterobacteriaceae with different epidemiological links. Short-read sequence data of Enterobacteriaceae cultured from humans and broilers were screened for the presence of both ablaCMY-2gene and an IncI1-pST12 replicon. Isolates were long-read sequenced on a MinION sequencer (OxfordNanopore Technologies). After plasmid reconstruction using hybrid assembly, pairwise single nucleotide polymorphisms (SNP) were determined. The plasmids were annotated, and a pan-genome was constructed to compare genes variably present between the different plasmids. NineEscherichia colisequences of broiler origin, fourEscherichia colisequences and oneSalmonella entericasequence of human origin were selected for the current analysis. A circular contig with the IncI1-pST12 replicon andblaCMY-2gene was extracted from the assembly graph of all fourteen isolates. Analysis of the IncI1-pST12 plasmids revealed a low number of SNP differences (range of 0-9 SNPs). The range of SNP differences overlapped in isolates with different epidemiological links. One-hundred and twelve from a total of 113 genes of the pan-genome were present in all plasmid constructs. NGS-analysis ofblaCMY--2-containing IncI1-pST12 plasmids isolated from Enterobacteriaceae with different epidemiological links show a high degree of sequence similarity in terms of SNP differences and the number of shared genes. Therefore, statements on the horizontal transfer of these plasmids based on genetic identity should be made with caution.
The genetic paradigms of dietary restriction fail to extend life span incep-1(gk138)mutant ofC. elegansp53 due to possible background mutations
Authors: Goyala Anita , Baruah Aiswarya , Mukhopadhyay Arnab 
Published: July 2020

AbstractDietary restriction (DR) increases life span and improves health in most model systems tested, including non-human primates. InC. elegans, as in other models, DR leads to reprogramming of metabolism, improvements in mitochondrial health, large changes in gene expression, including increase in expression of cytoprotective genes, better proteostasis etc. Understandably, multiple global transcriptional regulators like transcription factors FOXO/DAF-16, FOXA/PHA-4, HSF1/HSF-1 and NRF2/SKN-1 are important for DR longevity. Considering the wide-ranging effects of p53 on organismal biology, we asked whether theC. elegansortholog, CEP-1 is required for DR-mediated longevity assurance. We employed the widely-used TJ1 strain ofcep-1(gk138). We show thatcep-1(gk138)suppresses the life span extension of two genetic paradigms of DR, but two non-genetic modes of DR remain unaffected in this strain. We find that incep-1(gk138), two aspects of DR, increased autophagy and the up-regulation of expression of cytoprotective xenobiotic detoxification program (cXDP) genes are dampened. Importantly, we find that background mutation(s) in the strain may be the actual cause for the phenotypic differences that we observed andcep-1may not be directly involved in genetic DR-mediated longevity assurance in worms. Identifying these mutation(s) may reveal a novel regulator of longevity required specifically by genetic modes of DR.
Error propagation in constraint-based modeling of Chinese hamster ovary cells
Authors: Széliová Diana , Iurashev Dmytro , Ruckerbauer David E , Koellensperger Gunda , Borth Nicole , Melcher Michael , Zanghellini Jürgen 
Published: July 2020

AbstractBackgroundChinese hamster ovary (CHO) cells are the most popular mammalian cell factories for the production of glycosylated biopharmaceuticals. To further increase titer and productivity and ensure product quality, rational systems-level engineering strategies based on constraint-based metabolic modeling, such as flux balance analysis (FBA), have gained strong interest. However, the quality of FBA predictions depends on the accuracy of the experimental input data, especially on the exchange rates of extracellular metabolites. Yet it is not standard practice to devote sufficient attention to the accurate determination of these rates.ResultsIn this work we investigated to what degree the sampling frequency during a batch culture and the measurement errors of metabolite concentrations influence the accuracy of the calculated exchange rates and further, how this error then propagates into FBA predictions of growth rates. We determined that accurate measurements of essential amino acids with low uptake rates are crucial for the accuracy of FBA predictions, followed by a sufficient number of analysed time points.ConclusionsWe observed that the measured difference in growth rates of two cell lines can only be reliably predicted when both high measurement accuracy and sampling frequency are ensured.
Multiplexed End-point Microfluidic Chemotaxis Assay using Centrifugal Alignment
Authors: Satti Sampath , Deng Pan , Matthews Kerryn , Duffy Simon P. , Ma Hongshen 
Published: July 2020

AbstractA fundamental challenge to multiplexing microfluidic chemotaxis assays at scale is the requirement for time-lapse imaging to continuously track migrating cells. Drug testing and drug screening applications require the ability to perform hundreds of experiments in parallel, which is not feasible for assays that require continuous imaging. To address this limitation, end-point chemotaxis assays have been developed using fluid flow to align cells in traps or sieves prior to cell migration. However, these methods require precisely controlled fluid flow to transport cells to the correct location without undesirable mechanical stress, which introduce significant set up time and design complexity. Here, we describe a microfluidic device that eliminates the need for precise flow control by using centrifugation to align cells at a common starting point. A chemoattractant gradient is then formed using passive diffusion prior to chemotaxis in an incubated environment. This approach provides a simple and scalable approach to multiplexed chemotaxis assays. Centrifugal alignment is also insensitive to cell geometry, enabling this approach to be compatible with primary cell samples that are often heterogeneous. We demonstrate the capability of this approach by assessing chemotaxis of primary neutrophils in response to an fMLP (N-formyl-met-leu-phe) gradient. Our results show that cell alignment by centrifugation offers a potential avenue to develop scalable end-point multiplexed microfluidic chemotaxis assays.
Lilikoi V2.0: a deep-learning enabled, personalized pathway-based R package for diagnosis and prognosis predictions using metabolomics data
Authors: Fang Xinying , Liu Yu , Ren Zhijie , Du Yuheng , Huang Qianhui , Garmire Lana X. 
Published: July 2020

ABSTRACTPreviously we developedLilikoi, a personalized pathway-based method to classify diseases using metabolomics data. Given the new trends of computation in the metabolomics field, here we report the next version ofLilikoias a significant upgrade. The newLilikoiv2.0 R package has implemented a deep-learning method for classification, in addition to popular machine learning methods. It also has several new modules, including the most significant addition of prognosis prediction, implemented by Cox-PH model and the deep-learning based Cox-nnet model. Additionally,Lilikoiv2.0 supports data preprocessing, exploratory analysis, pathway visualization and metabolite-pathway regression. In summary,Lilikoiv2.0 is a modern, comprehensive package to enable metabolomics analysis in R programming environment.