bluuebunny/crossref_metadata_2025_split huggingface dataset:
Malaria vaccine candidates displayed on novel virus-like particles are immunogenic and induce transmission-blocking activity
Authors: Chan Jo-Anne , Wetzel David , Reiling Linda , Miura Kazutoyo , Drew Damien , Gilson Paul R , Anderson David A , Richards Jack S , Long Carole A , Suckow Manfred , Jenzelewski Volker , Tsuboi Takafumi , Boyle Michelle J , Piontek Michael , Beeson James G 
Published: April 2019

ABSTRACTThe development of effective malaria vaccines remains a global health priority. Currently, the most advanced vaccine, known as RTS,S, has only shown modest efficacy in clinical trials. Thus, the development of more efficacious vaccines by improving the formulation of RTS,S for increased efficacy or to interrupt malaria transmission are urgently needed. The RTS,S vaccine is based on the presentation of a fragment of the sporozoite antigen on the surface of virus-like particles (VLPs) based on human hepatitis B virus (HBV). In this study, we have developed and evaluated a novel VLP platform based on duck HBV (known as Metavax) for malaria vaccine development. This platform can incorporate large and complex proteins into VLPs and is produced in a Hansenula cell line compatible with cGMP vaccine production. Here, we have established the expression of leading P. falciparum malaria vaccine candidates as VLPs. This includes Pfs230 and Pfs25, which are candidate transmission-blocking vaccine antigens. We demonstrated that the VLPs effectively induce antibodies to malaria vaccine candidates with minimal induction of antibodies to the duck-HBV scaffold antigen. Antibodies to Pfs230 also recognised native protein on the surface of gametocytes, and antibodies to both Pfs230 and Pfs25 demonstrated transmission-reducing activity in standard membrane feeding assays. These results establish the potential utility of this VLP platform for malaria vaccines, which may be suitable for the development of multi-component vaccines that achieve high vaccine efficacy and transmission-blocking immunity.
How the Avidity of Polymerase Binding to the -35/-10 Promoter Sites Affects Gene Expression
Authors: Einav Tal , Phillips Rob 
Published: April 2019

AbstractAlthough the key promoter elements necessary to drive transcription inEscherichia colihave long been understood, we still cannot predict the behavior of arbitrary novel promoters, hampering our ability to characterize the myriad of sequenced regulatory architectures as well as to design novel synthetic circuits. This work builds on a beautiful recent experiment by Urtechoet al.who measured the gene expression of over 10,000 promoters spanning all possible combinations of a small set of regulatory elements. Using this data, we demonstrate that a central claim in energy matrix models of gene expression – that each promoter element contributes independently and additively to gene expression – contradicts experimental measurements. We propose that a key missing ingredient from such models is the avidity between the -35 and -10 RNA polymerase binding sites and develop what we call arefined energy matrixmodel that incorporates this effect. We show that this the refined energy matrix model can characterize the full suite of gene expression data and explore several applications of this framework, namely, how multivalent binding at the -35 and -10 sites can buffer RNAP kinetics against mutations and how promoters that bind overly tightly to RNA polymerase can inhibit gene expression. The success of our approach suggests that avidity represents a key physical principle governing the interaction of RNA polymerase to its promoter.Significance StatementCellular behavior is ultimately governed by the genetic program encoded in its DNA and through the arsenal of molecular machines that actively transcribe its genes, yet we lack the ability to predict how an arbitrary DNA sequence will perform. To that end, we analyze the performance of over 10,000 regulatory sequences and develop a model that can predict the behavior of any sequence based on its composition. By considering promoters that only vary by one or two elements, we can characterize how different components interact, providing fundamental insights into the mechanisms of transcription.
Repeated phenotypic selection for cuticular blackness of armyworm larvae decreased stress resistance
Authors: Matsumura Takashi , Taya Hikaru , Matsumoto Hitoshi , Hayakawa Yoichi 
Published: April 2019

ABSTRACTArmywormMythimna separatalarvae show changes in cuticle darkening depending on population densities and are roughly categorized into two phenotypes, a pale brown solitary type and black-colored gregarious type. Although the color difference in both larval types is apparent, it remains ambiguous whether any change in physiological traits accompanies the cuticle darkening. To answer this query, we repeated genetic selection of the blackness phenotype over one hundred generations in our laboratory colony and produced a black-colored (BL) strain. Comparison between non-selected control (CTL) and BL strains revealed an increased fecundity and adult life span in the BL strain compared with the CTL strain. In contrast, BL strain larvae were found to be significantly more sensitive to heat stress than CTL strain larvae. Hemolymph reactive oxygen species (ROS) levels were higher in the BL strain than in the CTL strain irrespective of stress. Antioxidant activities of the hemolymph were not significantly different between the two strains under non-stress condition, but the activities increased to higher levels in the CTL strain than those in the BL strain after heat stress. Activities and gene expression levels of antioxidant enzymes such as catalase and superoxide dismutase (SOD) in the fat body were significantly higher in CTL strain larvae than in BL strain larvae after heat treatment. Analysis of heat stress tolerance of F1 hybrids of CTL and BL strain adults showed that phenotype of stress tolerance was inherited maternally. These results indicate a trade-off between reproductive activity and stress resistance during repeated genetic selection.Summary statementDiscrete cuticle color change from whitish to blackish, which was created by repeating the reciprocal crossing of selected dark-colored individuals, increased fecundity but lowered stress tolerance in the armyworm.
A meiosis-specific AAA+ assembly reveals repurposing of ORC during budding yeast gametogenesis
Authors: Villar-Fernández María Ascensión , da Silva Richard Cardoso , Pan Dongqing , Weir Elisabeth , Sarembe Annika , Raina Vivek B. , Weir John R. , Vader Gerben 
Published: April 2019

ABSTRACTORC (Orc1-6) is an AAA+ complex that loads the AAA+ MCM helicase to replication origins. Orc1, a subunit of ORC, functionally interacts with budding yeast Pch2, a meiosis-specific AAA+ protein. Pch2 regulates several chromosomal events of gametogenesis, but mechanisms that dictate Pch2 function remain poorly understood. We demonstrate that ORC directly interacts with an AAA+ Pch2 hexamer. The ORC-Pch2 assembly is established without Cdc6, a factor crucial for ORC-MCM binding. Biochemical analysis suggests that Pch2 utilizes ORC’s Cdc6-binding interface and employs its non-enzymatic NH2-terminal domain and AAA+ core to engage ORC. In contrast to phenotypes observed upon Orc1 impairment, nuclear depletion of other subunits of ORC does not lead to Pch2-like phenotypes, indicating that ORC integrity per se is not required to support Pch2 function. We thus reveal functional interplay between Pch2 and ORC, and uncover the repurposing of ORC to establish a non-canonical and meiosis-specific AAA+ assembly.
Initial neural representation of individual rules after first-time instruction
Authors: Ruge Hannes , Schäfer Theo A. J. , Zwosta Katharina , Mohr Holger , Wolfensteller Uta 
Published: April 2019

AbstractBy following explicit instructions humans can instantaneously get the hang of tasks they have never performed before. Here, we used a specially calibrated multivariate analysis technique to uncover the elusive representational states following newly instructed arbitrary behavioural rules such as ‘for coffee, press red button’, while transitioning from ‘knowing what to do’ to ‘actually doing it’. Subtle variation in distributed neural activity patterns reflected rule-specific representations within the ventrolateral prefrontal cortex (VLPFC), confined to instructed stimulus-response learning in contrast to incidental learning involving the same stimuli and responses. VLPFC representations were established right after first-time instruction and remained stable across early implementation trials. More and more fluent application of novel rule representations was channelled through increasing cooperation between VLPFC and anterior striatum. These findings inform representational theories on how the prefrontal cortex supports behavioural flexibility by enabling ad-hoc coding of novel task rules without recourse to familiar sub-routines
Increased expression of schizophrenia-associated gene C4 leads to hypoconnectivity of prefrontal cortex and reduced social interaction
Authors: Comer Ashley L. , Jinadasa Tushare , Kretsge Lisa N. , Nguyen Thanh P.H. , Lee Jungjoon , Newmark Elena R. , Hausmann Frances S. , Rosenthal SaraAnn , Kot Kevin Liu , Yen William W. , Cruz-Martín Alberto 
Published: April 2019

ABSTRACTSchizophrenia is a severe mental disorder with an unclear pathophysiology. Increased expression of the immune gene C4 has been linked to a greater risk of developing schizophrenia; however, it is unknown whether C4 plays a causative role in this brain disorder. Using confocal imaging and whole-cell electrophysiology, we demonstrate that overexpression of C4 in mouse prefrontal cortex neurons leads to perturbations in dendritic spine development and hypoconnectivity, which mirror neuropathologies found in schizophrenia. We find evidence that microglia-neuron interactions and microglia-mediated synaptic engulfment are enhanced with increased expression of C4. We also show that C4-dependent circuit dysfunction in the frontal cortex leads to decreased social interactions in juvenile mice. These results demonstrate that increased expression of the schizophrenia-associated gene C4 causes aberrant circuit wiring in the developing prefrontal cortex and leads to deficits in early social behavior, suggesting that altered C4 expression contributes directly to schizophrenia pathogenesis.
Behavioural and neural interactions between objective and subjective performance in a Matching Pennies game
Authors: Dyson Benjamin James , Musgrave Cecile , Rowe Cameron , Sandhur Rayman 
Published: April 2019

AbstractTo examine the behavioural and neural interactions between objective and subjective performance during competitive decision-making, participants completed a Matching Pennies game where win-rates were fixed within three conditions (win > lose, win = lose, win < lose) and outcomes were predicted at each trial. Using random behaviour as the hallmark of optimal performance, we observed item (heads), contingency (win-stay, lose-shift) and combinatorial (HH, HT, TH, TT) biases across all conditions. Higher-quality behaviour represented by a reduction in combinatorial bias was observed during high win-rate exposure. In contrast, over-optimism biases were observed only in conditions where win rates were equal to, or less than, loss rates. At a group level, a neural measure of outcome evaluation (feedback-related negativity; FRN) indexed the binary distinction between positive and negative outcome. At an individual level, increased belief in successful performance accentuated FRN amplitude differences between wins and losses. Taken together, the data suggest that objective experiences of, or, subjective beliefs in, the predominance of positive outcomes are mutual attempts to self-regulate performance during competition. In this way, increased exposure to positive outcomes (real or imagined) help to weight the output of the more diligent and analytic System 2, relative to the impulsive and intuitive System 1.
Auditory and semantic cues facilitate decoding of visual object category in MEG
Authors: Brandman Talia , Avancini Chiara , Leticevscaia Olga , Peelen Marius V. 
Published: April 2019

AbstractSounds (e.g., barking) help us to visually identify objects (e.g., a dog) that are distant or ambiguous. While neuroimaging studies have revealed neuroanatomical sites of audiovisual interactions, little is known about the time-course by which sounds facilitate visual object processing. Here we used magnetoencephalography (MEG) to reveal the time-course of the facilitatory influence of natural sounds (e.g., barking) on visual object processing, and compared this to the facilitatory influence of spoken words (e.g., “dog”). Participants viewed images of blurred objects preceded by a task-irrelevant natural sound, a spoken word, or uninformative noise. A classifier was trained to discriminate multivariate sensor patterns evoked by animate and inanimate intact objects with no sounds, presented in a separate experiment, and tested on sensor patterns evoked by the blurred objects in the three auditory conditions. Results revealed that both sounds and words, relative to uninformative noise, significantly facilitated visual object category decoding between 300-500 ms after visual onset. We found no evidence for earlier facilitation by sounds than by words. These findings provide evidence for a semantic route of facilitation by both natural sounds and spoken words, whereby the auditory input first activates semantic object representations, which then modulate the visual processing of objects.
Pathological and non-pathological aging, SAMP8 and SAMR1. What do hippocampal neuronal populations tell us?
Authors: Lagartos-Donate MJ , Gonzáles-Fuentes J , Marcos-Rabal P , Insausti R , Arroyo-Jiménez MM 
Published: April 2019

ABSTRACTAlterations of cognitive processes and memory are one of the most important manifestations related to aging. However, not all memory types are affected in the same way. Learning and spatial memory are susceptible to these changes. The hippocampus represents the anatomical substrate of this type of memory, affected by structural and functional alterations along the normal aging and neurological diseases such as Alzheimer’s disease, Parkinson’s, schizophrenia and epilepsy. Some of the alterations related to aging are associated with alterations in the hippocampal interneuron populations and with an increase in excitability in the hippocampal circuit.In order to understand better the underlying processes in normal and pathological aging mechanisms, a murine model (Senescence-Accelerated Mouse Prone, SAMP8) and its respective controls (Senescence-Accelerated Mouse Resistant, SAMR1) have been used. While SAMP8 is a naturally occurring mouse line that displays a phenotype of accelerated aging with learning and memory impairment and these changes of learning and memory might be linked to some alterations in neuronal populations of the hippocampus. Thus, we analyzed the distribution and density of PV, CR and STT interneurons in the hippocampus of young and old mice as well as possible morphological and cholinergic changes in hippocampal formation. Comparing SAMR1 and SAMP8 we did not find any neural population that was specifically affected by aging in both groups. Interestingly, CR immunoreactivity and STT immunoreactivity showed changes in SAMP8 mice when they were compared to their controls. In SAMP8 CR+ and STT+ neurons decreased significantly along aging which suggests that CR and STT interneurons play a more important role than PV neurons in the pathological aging of the brain. In the case of SAMP8 mice the neural changes might be related to changes of the cholinergic system that might be affecting the wiring into the hippocampus formation through the perforant pathway. Further studies of this local circuitry will help to comprehend better how different inputs into these neural populations of the hippocampus could be affecting the development of neurodegerative diseases.
Time resolved quantitative phosphoproteomics reveals distinct patterns of SHP2 dependence in EGFR signaling
Authors: Vemulapalli Vidyasiri , Chylek Lily , Erickson Alison , LaRochelle Jonathan , Subramanian Kartik , Mohseni Morvarid , LaMarche Matthew , Acker Michael G. , Sorger Peter K. , Gygi Steven P. , Blacklow Stephen C. 
Published: April 2019

AbstractSHP2 is a protein tyrosine phosphatase that normally potentiates intracellular signaling by growth factors, antigen receptors, and some cytokines; it is frequently mutated in childhood leukemias and other cancers. Here, we examine the role of SHP2 in the responses of breast cancer cells to EGF by monitoring phosphoproteome dynamics when SHP2 is allosterically inhibited by the small molecule SHP099. Data on phosphotyrosine abundance at more than 400 tyrosine residues reveals six distinct response signatures following SHP099 treatment and washout. These include putative substrate sites with increased phosphotyrosine abundance at early or late timepoints, and another class of sites that shows reduced phosphotyrosine abundance when SHP099 is present. Sites of decreased phospho-abundance are enriched on proteins with two nearby phosphotyrosine residues, which can be directly protected from dephosphorylation by the paired SH2 domains of SHP2 itself. These findings highlight how analysis of phosphoproteomic dynamics can provide insight into transmembrane signaling responses.
Disease-related single-point mutations alter the global dynamics of a tetratricopeptide (TPR) a-solenoid domain
Authors: Llabrés Salomé , Zachariae Ulrich 
Published: April 2019

ABSTRACTTetratricopeptide repeat (TPR) proteins belong to the class of α-solenoid proteins, in which repetitive units of α-helical hairpin motifs stack to form superhelical, often highly flexible structures. TPR domains occur in a wide variety of proteins, and perform key functional roles including protein folding, protein trafficking, cell cycle control and post-translational modification. Here, we look at the TPR domain of the enzyme O-linked GlcNAc-transferase (OGT), which catalyses O-GlcNAcylation of a broad range of substrate proteins. A number of single-point mutations in the TPR domain of human OGT have been associated with the disease Intellectual Disability (ID). By extended steered and equilibrium atomistic simulations, we show that the OGT-TPR domain acts as a reversibly elastic nanospring, and that each of the ID-related local mutations substantially affect the global dynamics of the TPR domain. Since the nanospring character of the OGT-TPR domain is key to its function in binding and releasing OGT substrates, these changes of its biomechanics likely lead to defective substrate interaction. Our findings may not only help to explain the ID phenotype of the mutants, but also aid the design of TPR proteins with tailored biomechanical properties.
Scopolamine and medial frontal stimulus-processing during interval timing
Authors: Zhang Qiang , Jung Dennis , Larson Travis , Kim Youngcho , Narayanan Nandakumar S. 
Published: April 2019

AbstractNeurodegenerative diseases such as Parkinson’s disease (PD), dementia with Lewy Bodies (DLB), and Alzheimer’s disease (AD) involve loss of cholinergic neurons in the basal forebrain. Here, we investigate how cholinergic dysfunction impacts the frontal cortex during interval timing, a process that can be impaired in PD and AD patients. Interval timing requires participants to estimate an interval of several seconds by making a motor response, and depends on the medial frontal cortex (MFC), which is richly innervated by basal forebrain cholinergic projections. Past work has shown that scopolamine, a muscarinic cholinergic receptor antagonist, reliably impairs interval timing. We tested the hypothesis that scopolamine would attenuate time-related ramping, a key form of temporal processing in the MFC. We recorded neuronal ensembles from 8 mice during performance of a 12-s fixed-interval timing task, which was impaired by the administration of scopolamine. Consistent with past work, scopolamine impaired timing. To our surprise, we found that time-related ramping was unchanged, but stimulus-related activity was enhanced in the MFC. Principal component analyses revealed no consistent changes in time-related ramping components, but did reveal changes in higher components. Taken together, these data indicate that scopolamine changes stimulus-processing rather than temporal processing in the MFC. These data could help understand how cholinergic dysfunction affects cortical circuits in diseases such as PD, DLB, and AD.HighlightsThe cholinergic muscarinic inhibitor scopolamine impairs interval timing behavior.Scopolamine does not change time-related ramping activity in the medial frontal cortex.Medial prefrontal stimulus-related modulation increased
Restoration of susceptibility to amikacin by 8-hydroxyquinoline analogs complexed to zinc
Authors: Magallón Jesus , Chiem Kevin , Tran Tung , Ramirez María S. , Jimenez Verónica , Tolmasky Marcelo E. 
Published: April 2019

AbstractGram-negative pathogens resistant to amikacin and other aminoglycosides of clinical relevance usually harbor the 6’-N-acetyltransferase type Ib [AAC(6’)-Ib], an enzyme that catalyzes inactivation of the antibiotic by acetylation using acetyl-CoA as donor substrate. Inhibition of the acetylating reaction could be a way to induce phenotypic conversion to susceptibility in these bacteria. We have previously observed that Zn+2 acts as an inhibitor of the enzymatic acetylation of aminoglycosides by AAC(6’)-Ib, and in complex with ionophores it effectively reduced the levels of resistance in cellulo. We compared the activity of 8-hydroxyquinoline, three halogenated derivatives, and 5-[N-Methyl-N-Propargylaminomethyl]-8-Hydroxyquinoline in complex with Zn+2 to inhibit growth of amikacin-resistant Acinetobacter baumannii in the presence of the antibiotic. Two of the compounds, clioquinol (5-chloro-7-iodo-8-hydroxyquinoline) and 5,7-diiodo-8-hydroxyquinoline, showed robust inhibition of growth of the two A. baumannii clinical isolates that produce AAC(6’)-Ib. However, none of the combinations had any activity on another amikacin-resistant A. baumannii strain that possesses a different, still unknown mechanism of resistance. Time-kill assays showed that the combination of clioquinol or 5,7-diiodo-8-hydroxyquinoline with Zn+2 and amikacin was bactericidal. Addition of 8-hydroxyquinoline, clioquinol, or 5,7-diiodo-8-hydroxyquinoline, alone or in combination with Zn+2, and amikacin to HEK293 cells did not result in significant toxicity. These results indicate that ionophores in complex with Zn+2 could be developed into potent adjuvants to be used in combination with aminoglycosides to treat Gram-negative pathogens in which resistance is mediated by AAC(6’)-Ib and most probably other related aminoglycoside modifying enzymes.