bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutant SETBP1 enhances NRAS-driven MAPK pathway activation to promote aggressive leukemia
Authors: Carratt Sarah A. , Braun Theodore P. , Coblentz Cody , Schonrock Zachary , Callahan Rowan , Smith Brittany M. , Maloney Lauren , Foley Amy C. , Maxson Julia E. 
Published: February 2021

AbstractMutations in SET binding protein 1 (SETBP1) are associated with poor outcomes in myeloid leukemias. In the Ras-driven leukemia, juvenile myelomonocytic leukemia, SETBP1 mutations are enriched in relapsed disease. While some mechanisms for SETBP1-driven oncogenesis have been established, it remains unclear how SETBP1 specifically modulates the biology of Ras-driven leukemias. In this study, we found that when co-expressed with Ras pathway mutations, SETBP1 promoted oncogenic transformation of murine bone marrow in vitro and aggressive myeloid leukemia in vivo. We demonstrate that SETBP1 enhances the NRAS gene expression signature, driving upregulation of mitogen-activated protein kinase (MAPK) signaling and downregulation of differentiation pathways. SETBP1 also enhances NRAS-driven phosphorylation of MAPK proteins. Cells expressing NRAS and SETBP1 are sensitive to inhibitors of the MAPK pathway, and treatment with the MEK inhibitor trametinib conferred a survival benefit in a mouse model of NRAS/SETBP1-mutant disease. Our data demonstrate that despite driving enhanced MAPK signaling, SETBP1-mutant cells remain susceptible to trametinib in vitro and in vivo, providing encouraging pre-clinical data for the use of trametinib in SETBP1-mutant disease.
Slower prefrontal metastable dynamics during deliberation predicts error trials in a distance discrimination task
Authors: Benozzo Danilo , La Camera Giancarlo , Genovesio Aldo 
Published: February 2021

AbstractPrevious studies have established the involvement of prefrontal cortex (PFC) neurons in decision processes in many task contexts. Single neurons and populations of neurons have been found to represent stimuli, actions, and internal deliberations. However, it is much less clear which underlying computations are affected during errors. Neural activity during errors can help to disambiguate confounds and clarify which computations are essential during a specific task. Here, we used a hidden Markov model (HMM) to perform a trial-by-trial analysis of ensembles of simultaneously recorded neurons from the dorsolateral prefrontal (PFdl) cortex of two rhesus monkeys performing a distance discrimination task. The HMM segments the neural activity into sequences of metastable states, allowing to link neural ensemble dynamics with task and behavioral features in the absence of external triggers. We report a precise relationship between the modulation of the metastable dynamics and task features. Specifically, we found that errors were made more often when the metastable dynamics slowed down, while trial difficulty influenced the latency of state transitions at a pivotal point during the trial. Both these phenomena occurred during the decision interval and not following the action, with errors occurring in both easy and difficult trials. Thus, modulations of metastable dynamics reflected a state of internal deliberation rather than actions taken or, in the case of error trials, objective trial difficulty. Our results show that temporal modulations of PFdl activity are key determinants of internal deliberations, providing further support for the emerging role of metastable cortical dynamics in mediating complex cognitive functions and behavior.
Molecular mechanism of N-terminal acetylation by the ternary NatC complex
Authors: Deng Sunbin , Gottlieb Leah , Pan Buyan , Supplee Julianna , Wei Xuepeng , Petersson E James , Marmorstein Ronen 
Published: February 2021

AbstractProtein N-terminal acetylation is predominantly a ribosome-associated modification, with NatA-E serving as the major enzymes. NatC is the most unusual of these enzymes, containing one Naa30 catalytic subunit and two auxiliary subunits, Naa35 and Naa38; and substrate specificity profile that overlaps with NatE. Here, we report the Cryo-EM structure ofS. pombeNatC with a NatE/C-type bisubstrate analogue and inositol hexaphosphate (IP6), and associated biochemistry studies. We find that the presence of three subunits is a prerequisite for normal NatC acetylation activity in yeast and that IP6binds tightly to NatC to stabilize the complex. We also describe the molecular basis for IP6-mediated NatC complex stabilization and the overlapping yet distinct substrate profiles of NatC and NatE.
Working Memory Representations in Visual Cortex Mediate the Effects of Distraction
Authors: Hallenbeck Grace E. , Sprague Thomas C. , Rahmati Masih , Sreenivasan Kartik K. , Curtis Clayton E. 
Published: February 2021

SUMMARYAlthough the contents of working memory (WM) can be decoded from activity in visual cortex, these representations may play a limited role if they are not robust to distraction. Here, we used model-based fMRI to estimate the impact that a distracting visual task had on WM representations in several visual field maps in visual and frontoparietal association cortex. Distraction caused the fidelity of WM representations in all maps to briefly dip when both the memorandum and distractor were jointly encoded by the population activities. Moreover, distraction induced small biases in memory errors which were predicted by biases in neural decoding in early visual cortex, but not other regions. Although distraction briefly disrupts WM representations, the widespread redundancy with which WM information is encoded may protect against catastrophic loss. In early visual cortex, nonetheless, the neural representation of information in WM and behavioral performance were intertwined, solidifying its importance in memory.
Bioprinting transgenic plant cells for production of a recombinant biodefense agent
Authors: Varma Anika , Gemeda Hawi B. , McNulty Matthew J. , McDonald Karen A. , Nandi Somen , Knipe Jennifer M. 
Published: February 2021

AbstractTransgenic rice cells (Oryza sativa) producing recombinant butyrylcholinesterase (BChE) as a prophylactic/therapeutic against organophosphate nerve agent poisoning, cocaine toxicity, and neurodegenerative diseases like Alzheimer’s were immobilized in a polyethylene glycol-based hydrogel. The cells were sustained for 14 days in the semi-solid matrix, undergoing a growth phase from days 0-6, a BChE production phase in sugar-free medium from days 6-12, and a growth/recovery phase from days 12-14. Throughout this period, the cells maintained similar viability to those in suspension cultures and displayed analogous sugar consumption trends. The rice cells in the bioprintable hydrogel also produced a significant amount of active BChE, comparable to the levels produced in liquid cultures. A considerable fraction of this BChE was secreted into the media, allowing for easier product separation. Overall, we demonstrate a simple, efficient, robust, modular, and potentially field-deployable bioreactor system for the manufacture of biologics.
Phenotypic and genotypic characterization of antibiotic Resistant Gram Negative Bacteria isolated in Tabuk City, Saudi Arabia
Authors: Alnour Tarig M.S. , Elssaig Elmutuz H. , Ahmed-Abakur Eltayib H. , Abuduhier Faisel M. , Alfifi Khalid A. S. , Abusuliman Mohammad S. , Albalawi Tawfiq 
Published: February 2021

AbstractAntimicrobial surveillance and identifying the genetic basis of antimicrobial resistance provide important information to optimize patient care. The present study was analytical cross sectional study aimed to determine the prevalence of MDR, XDR, PDR and extended-spectrum β-lactamases genes (SHV, CTX-M and TEM) among Gram-negative bacteria isolated in Tabuk, Saudi Arabia. A total number of 386 non-duplicate Gram-negative isolate were collected. Identification and susceptibility testing were done using automation system (BD Phoenix™). The extracted DNA were subjected to multiplex polymerase chain reaction (PCR). The results showed that only 15 (3.9%) of isolates were fully susceptible, the overall prevalence of XDR, MDR, PDR was 129 (33.4%), 113 (29.3%) and 48(12.4%) respectively. High resistant rate was observed against the antibiotic agents of cephalosporins class 79.3% followed by the agents of penicillins class 69.4%. The most dominant gene was bla SHV which detected in 106/386 (27.5%) isolates followed by bla CTX-M 90/386 (23.3%). Bla CTX-M showed significant relation with all used antibiotic except ampicillin/clavulanic acid, aztreonam, cefoxtin, and meropene. The isolates which showed most frequent resistant genes wereKlebsiella pneumoniae 90/124 (72.6%), A. baumanni37/67 (55.2%),and P.mirabilis24/44 (54.5%). These findings underscores the need for optimization of current therapies and prevention of the spread of these organisms.
Outer membrane vesicles derived fromSalmonellaTyphimurium can deliverShigella flexneri2a O-polysaccharide antigen to prevent lethal pulmonary infection in mice
Authors: Tian Huizhen , Li Biaoxian , Chen Yuxuan , Jie Kaiwen , Xu Tian , Song Zifan , Huang Xiaotian , Liu Qiong 
Published: February 2021

AbstractThe threat to health from shigellosis has become quite serious in many developing countries, causing severe diarrhea.Shigella flexneri2a (S. flexneri2a) is the principal species responsible for this endemic disease. Although there have been multiple attempts to design a vaccine against Shigellosis, one that is effective has not yet been developed. Lipopolysaccharide (LPS) is both an essential virulence factor and a protective antigen againstShigella, due to its outer domain, termed O-polysaccharide antigen. In the present study,S. flexneri2a O-polysaccharide antigen was innovatively bio-synthesized inSalmonellaand attached to core-lipid A by the ligase WaaL, and thus purified outer membrane vesicles (OMVs) were used as a vaccine for subsequent research. Here, we identified the expression of the heterologous polysaccharide antigen and described the isolation, characterization, and immune protection efficiency of the OMV vaccine. The expression ofS. flexneri2a did not affect the formation ofSalmonellaOMVs or their cytotoxicity. Furthermore, the results of the animal experiments indicated that immunization of the mice both intranasally and intraperitoneally with the OMV vaccine induced significant specific anti-Shigella LPS antibodies in both vaginal secretions and fluid from bronchopulmonary lavage, in addition to within sera. The OMV vaccine immunized by both routes of administration provided significant protection against virulentS. flexneri2a infection, as judged by a serum bactericidal assay (SBA), opsonization assay, challenge experiment, and pathological analysis. The present study firstly indicates that the proposed vaccination strategy represents a novel and improved approach to control Shigellosis by the combination of bioconjugation ofSalmonellaglycosyl carrier lipid and OMV. In addition, the strategy of genetic manipulation described here is ideally suited for designs based on otherShigellaserotypes, allowing the development of aShigellavaccine with broad-protection.
Mosaic Ends Tagmentation (METa) assembly for extremely efficient construction of functional metagenomic libraries
Authors: Crofts Terence S. , McFarland Alexander G. , Hartmann Erica M. 
Published: February 2021

ABSTRACTFunctional metagenomic libraries, physical bacterial libraries which allow the high-throughput capture and expression of microbiome genes, have been instrumental in the sequence-naïve and cultivation-independent discovery of novel genes from microbial communities. Preparation of these libraries is limited by their high DNA input requirement and their low cloning efficiency. Here, we describe a new method, METa assembly, for extremely efficient functional metagenomic library preparation. We apply tagmentation to metagenomic DNA from soil and gut microbiomes to prepare DNA inserts for high-throughput cloning into functional metagenomic libraries. The presence of mosaic end sequences in the resulting DNA fragments synergizes with homology-based assembly cloning to result in a 300-fold increase in library size compared to traditional blunt cloning based protocols. Compared to published libraries prepared by state-of-the-art protocols we show that METa assembly is on average 23- to 270-fold more efficient and can be effectively used to prepare gigabase-sized libraries with as little as 200 ng of input DNA. We demonstrate the utility of METa assembly to capture novel genes based on their function by discovering novel aminoglycoside (26% amino acid identity) and colistin (36% amino acid identity) resistance genes in soil and goose gut microbiomes. METa assembly provides a streamlined, flexible, and efficient method for preparing functional metagenomic libraries, enabling new avenues of genetic and biochemical research into low biomass or scarce microbiomes.IMPORTANCEMedically and industrially important genes can be recovered from microbial communities by high-throughput sequencing but are limited to previously sequenced genes and their relatives. Cloning a metagenomeen masseinto an expression host to produce a functional metagenomic library is a sequence-naïve and cultivation-independent method to discover novel genes. This directly connects genes to functions, but the process of preparing these libraries is DNA greedy and inefficient. Here we describe a library preparation method that is an order of magnitude more efficient and less DNA greedy. This method is consistently efficient across libraries prepared from cultures, a soil microbiome, and from a goose fecal microbiome and allowed us to discover novel antibiotic resistance genes. This new library preparation method will potentially allow for the functional metagenomic exploration of microbiomes that were previously off limits due to their rarity or low microbial biomass, such biomedical swabs or exotic samples.
DEFINING THE DIVERSITY OF HNRNPA1 MUTATIONS IN CLINICAL PHENOTYPE AND PATHOMECHANISM
Authors: Beijer D , Kim HJ , Guo L , O’Donovan K , Mademan I , Deconinck T , Van Schil K , Fare CM , Drake LE , Ford AF , Kochański A , Kabzińska D , Dubuisson N , Van den Bergh P , Voermans NC , Lemmers RJLF , van der Maarel SM , Bonner D , Sampson JB , Wheeler MT , Mehrabyan A , Palmer S , De Jonghe P , Shorter J , Taylor JP , Baets J 
Published: February 2021

ABSTRACTMutations in HNRNPA1 encoding heterogeneous nuclear ribonucleoprotein (hnRNP) A1 are a rare cause of amyotrophic lateral sclerosis (ALS) and multisystem proteinopathy (MSP). hnRNPA1 is part of the group of RNA-binding proteins (RBPs) that assemble with RNA to form ribonucleoproteins. hnRNPs are a major subclass of evolutionarily conserved RBPs that are primarily concentrated in the nucleus and are heavily involved in pre-mRNA splicing, mRNA stability and transcriptional/translational regulation. During times of stress, standard translational programming is interrupted, and hnRNPs, mRNA, and other RBPs condense in the cytoplasm, forming liquid-liquid phase separated (LLPS) membraneless organelles termed stress granules (SGs). SGs are central to the pathogenesis of (neuro-)degenerative diseases, including ALS and inclusion body myopathy (IBM). hnRNPs and other RBPs are critical components of SGs. Indeed, the link between SGs, hnRNPs, and neurodegenerative diseases has been established by the identification of additional mutations in RBPs that affect SG biology, including FUS, TDP-43, hnRNPA1, hnRNPA2B1, and TIA1, each of which can directly lead to ALS, IBM and other related neurodegenerative diseases. Here, we report and characterize four novel HNRNPA1 mutations and two known HNRNPA1 mutations, previously reported as being causal for ALS, in a broad spectrum of patients with hereditary motor neuropathy (HMN), ALS, and myopathy. Our results show the different effects of mutations on hnRNPA1 fibrillization, liquid-liquid phase separation, and SG dynamics, indicating the possibility of different underlying pathomechanisms for HNRNPA1 mutations with a possible link to the clinical phenotypes.
First indication of the effect of COVID-19 vaccinations on the course of the outbreak in Israel
Authors: De-Leon H. , Calderon-Margalit R. , Pederiva F. , Ashkenazy Y. , Gazit D. 
Published: February 2021

AbstractConcomitantly with rolling out its rapid COVID-19 vaccine program, Israel is experiencing its third, and so far largest, surge in morbidity. We aimed to estimate whether the high vaccine coverage among individuals aged over 60 years old creates an observable change in disease dynamics. Using observed and simulated data, we suggest that the shape of the outbreak as measured by daily new moderate and severe cases, and in particular of patients aged over 60, has changed because of vaccination, bringing the decline in new moderate and severe cases earlier than expected, by about a week. Our analyses is consistent with the assumption that vaccination lead to higher than 50% protection in preventing clinical disease and with at least some effectiveness in blocking transmission of elderly population, and supports the importance of prioritizing vulnerable population. This is the first indication of the effectivity of COVID-19 vaccine in changing the course of an ongoing pandemic outbreak.One Sentence SummaryWe show, by data analysis and modelling of the dynamics of COVID-19 pandemic in Israel, that the current nationwide outbreak, that had up to 0.1% of the population confirmed daily, is clearly affected by the vaccination program, that reached a coverage of more than 80% among people ≥ 60 years old.
Timing of convalescent plasma administration and 28-day mortality for COVID-19 pneumonia
Authors: González Soledad E. , Regairaz Lorena , R. Salazar Martín , Ferrando Noelia S. , González Martínez Verónica V. , Carrera Ramos Patricia M. , Pesci Santiago A. , Vidal Juan M. , Kreplak Nicolas , Estenssoro Elisa 
Published: February 2021

SummaryConvalescent plasma administration (CPA) is widely used to treat Covid-19, but its effectiveness remains controversial. Here we report the results of an Expanded Access Program of CPA in the province of Buenos Aires, Argentina. We evaluated the relationship between the timing of CPA and 28-day mortality in 4719 hospitalized patients with COVID-19 pneumonia. Early (≤3 days from admission) CPA was associated to decreased mortality in patients in the general ward and in the Intensive Care Unit not requiring mechanical ventilation. This suggests that the favorable effect of CPA might be related both to disease acuity and to the therapeutic window.
Scientists’ opinion, attitudes, and consensus towards immunity passports
Authors: Aranzales Iván , Chan Ho Fai , Eichenberger Reiner , Hegselmann Rainer , Stadelmann David , Torgler Benno 
Published: February 2021

AbstractObjectivesWe measured attitudes towards “immunity passports” in the context of COVID-19 of a large sample of scientists. Consensus of scientists’ opinions on a different aspect of immunity passports was assessed.MethodsWe designed and implemented a survey to capture what scientists from around the world and different scientific background think about immunity certification. The survey was sent to the corresponding authors of scholarly articles published in the last five years in the top 20-ranked journals in each of the 27 subject areas between May and June 2020. Responses from 12,738 scientists were captured, and their distribution was tabulated by participants in health science and other fields. Consensus of responses was calculated using a variant of Shannon Entropy, made suitable for the ordinal response variables.ResultsHalf of the scientists surveyed, regardless of academic background agree that a potential immunity passport program will be good for public health (50.2%) and the economy (54.4%), with 19.1% and 15.4% of participants disagree, respectively. A significant proportion of scientists raised concerns about immunity certification over fairness to others (36.5%) and social inequality (45.5%). There is little consensus in the different aspects of immunity passport among scientists. Overall, scientists with health background hold a more conservative view towards immunity certification.ConclusionsOur findings suggest a lack of general agreement regarding the potential health and economic benefits, societal costs, and ethical issues of an immunity certification program within the scientific community. Given the relevant and important implications of immunity passport due to the increasing vaccine availability and efficacy, more attention should be given to the discussion of the design and implementation of immunity certification program.Strengths and limitations of this studyFirst cross-disciplinary survey with a large and international sample size that enables mapping of scientists’ opinions and attitudes towards COVID-19 immunity certificates.From the survey responses, we measured, reported, and compared the levels of consensus of scientists between health-related and non-health-related discipline.Response rate and sample representativeness are moderate.
Effective subthalamic and pallidal deep brain stimulation – are we modulating the same network?
Authors: Sobesky Leon , Goede Lukas , Odekerken Vincent J.J. , Wang Qiang , Li Ningfei , Al-Fatly Bassam , Reich Martin , Volkmann Jens , de Bie Rob M.A. , Kühn Andrea A. , Horn Andreas 
Published: February 2021

AbstractThe subthalamic nucleus and internal pallidum are main target sites for deep brain stimulation in Parkinson’s disease. Multiple trials that investigated subthalamic versus pallidal stimulation were unable to settle on a definitive optimal target between the two. One reason could be that the effect is mediated via a common network. To test this hypothesis, we calculated connectivity profiles seeding from deep brain stimulation electrodes in 94 patients that underwent subthalamic treatment and 28 patients with pallidal treatment based on a normative connectome atlas calculated from 1,000 healthy subjects. In each cohort, we calculated connectivity profiles that were associated with optimal clinical improvements. The two maps showed striking similarity and were able to cross-predict outcomes in the respective other cohort (R = 0.38 at p < 0.001 & R = 0.35 at p = 0.027). Next, we calculated an agreement map which retained regions common of both target sites. Crucially, this map was able to explain an additional amount of variance in clinical improvements of either cohort when compared to the maps calculated on the two cohorts alone. Finally, we tested profiles and predictive utility of connectivity maps calculated from different motor symptom subscores with a specific focus on bradykinesia and rigidity. While our study is based on retrospective data and indirect connectivity metrics, it delivers empirical data to support the hypothesis of a largely overlapping network associated with effective deep brain stimulation in Parkinson’s disease irrespective of the specific target.