bluuebunny/crossref_metadata_2025_split huggingface dataset:
Slowing of Frontocentral Beta Oscillations in Atypical Parkinsonism
Authors: Krösche Marius , Kannenberg Silja , Butz Markus , Hartmann Christian J. , Florin Esther , Schnitzler Alfons , Hirschmann Jan 
Published: May 2022

AbstractDiagnosis of atypical parkinsonian syndromes mostly relies on clinical presentation as well as structural and molecular brain imaging. It has not been investigated whether cortical oscillatory activity exhibits features distinguishing these syndromes. Therefore, we measured resting-state magnetoencephalography in 13 patients with corticobasal syndrome, 10 patients with progressive supranuclear palsy, 23 patients with idiopathic Parkinson’s disease and 23 healthy controls. We compared spectral power as well as amplitude and frequency of power peaks between the groups.Atypical Parkinsonism was associated with spectral slowing, distinguishing both corticobasal syndrome and progressive supranuclear palsy from age-matched healthy controls and Parkinson’s disease. Patients with atypical Parkinsonism showed a shift of beta peaks (13-30 Hz) towards lower frequencies in frontal and central areas bilaterally. A concomitant increase in theta/alpha power relative to controls was observed in both atypical parkinsonian syndromes and in Parkinson’s disease.Our results demonstrate that slowing of frontocentral beta oscillations is characteristic of atypical Parkinsonism. Spectral slowing with a different topography has previously been observed in other neurodegenerative disorders, such as Alzheimer’s disease, suggesting that spectral slowing might be an electrophysiological marker of cortical neurodegeneration. As such, it might support differential diagnosis of parkinsonian syndromes in the future.HighlightsSlowing of beta oscillations distinguishes atypical parkinsonian syndromes from healthy controls and idiopathic Parkinson’s diseaseSpectral slowing is most pronounced in frontocentral areasBeta oscillations are shifted towards lower frequencies independent of their amplitude
A new in vitro checkerboard-parasite reduction ratio interaction assay for early de-risk of clinical development of antimalarial combinations
Authors: Wicha Sebastian G. , Walz Annabelle , Cherkaoui-Rbati Mohammed H. , Bundgaard Nils , Kuritz Karsten , Gumpp Christin , Gobeau Nathalie , Möhrle Jörg , Rottmann Matthias , Demarta-Gatsi Claudia 
Published: May 2022

AbstractThe development and spread of drug resistant phenotypes substantially threaten malaria control efforts. Combination therapies have the potential to minimize the risk of resistance development but require intensive preclinical studies to determine optimal combination and dosing regimens. To support the selection of new combinations, we developed a novel in vitro-in silico combination approach to help identify the pharmacodynamic interactions of the two antimalarial drugs which can be plugged into a pharmacokinetic/pharmacodynamic model built with human monotherapies parasitological data to predict the parasitological endpoints of the combination. This allows to optimally select drug combinations and doses for the clinical development of antimalarials. With this assay, we successfully predicted the endpoints of two phase 2 clinical trials in patients with the artefenomel - piperaquine and artefenomel - ferroquine drug combinations. Besides, the predictive performance of our novel in vitro model was equivalent to the humanized mouse model outcome. Lastly, our more granular in vitro combination assay provided additional insights into the pharmacodynamic drug interactions compared to the in vivo systems, e.g. a concentration-dependent change in the Emax and the EC50 values of piperaquine or artefenomel or a directional reduction of the EC50 of ferroquine by artefenomel and a directional reduction of Emax of ferroquine by artefenomel. Overall, this novel in vitro-in silico-based technology will significantly improve and streamline the economic development of new drug combinations in malaria and potentially also in other therapeutic areas.
Low-dose bivalent mRNA vaccine is highly effective against different SARS-CoV-2 variants in a transgenic mouse model
Authors: Corleis Björn , Hoffmann Donata , Rauch Susanne , Fricke Charlie , Roth Nicole , Gergen Janina , Kovacikova Kristina , Schlottau Kore , Halwe Nico Joel , Ulrich Lorenz , Schön Jacob , Wernike Kerstin , Widera Marek , Ciesek Sandra , Mueller Stefan O. , Mettenleiter Thomas C. , Petsch Benjamin , Beer Martin , Dorhoi Anca 
Published: May 2022

AbstractCombining optimized spike (S) protein-encoding mRNA vaccines to target multiple SARS-CoV-2 variants could improve COVID-19 control. We compared monovalent and bivalent mRNA vaccines encoding B.1.351 (Beta) and/or B.1.617.2 (Delta) SARS-CoV-2 S-protein, primarily in a transgenic mouse model and a Wistar rat model. The low-dose bivalent mRNA vaccine contained half the mRNA of each respective monovalent vaccine, but induced comparable neutralizing antibody titres, enrichment of lung-resident memory CD8+ T cells, specific CD4+ and CD8+ responses, and fully protected transgenic mice from SARS-CoV-2 lethality. The bivalent mRNA vaccine significantly reduced viral replication in both Beta- and Delta-challenged mice. Sera from bivalent mRNA vaccine immunized Wistar rats also contained neutralizing antibodies against the B.1.1.529 (Omicron BA.1) variant. These data suggest that low-dose and fit-for-purpose multivalent mRNA vaccines encoding distinct S-proteins is a feasible approach for increasing the potency of vaccines against emerging and co-circulating SARS-CoV-2 variants.
An Efficient Approach for SARS-CoV-2 Monoclonal Antibody Production via Modified mRNA-LNP Immunization
Authors: Hsu Fu-Fei , Liang Kang-Hao , Kumari Monika , Chen Wan-Yu , Lin Hsiu-Ting , Cheng Chao-Min , Tao Mi-Hua , Wu Han-Chung 
Published: May 2022

ABSTRACTThroughout the COVID-19 pandemic, many prophylactic and therapeutic drugs have been evaluated and introduced. Among these treatments, monoclonal antibodies (mAbs) that bind to and neutralize SARS-CoV-2 virus have been applied as complementary and alternative treatments to vaccines. Although different methodologies have been utilized to produce mAbs, traditional hybridoma fusion technology is still commonly used for this purpose due to its unmatched performance record. In this study, we coupled the hybridoma fusion strategy with mRNA-lipid nanoparticle (LNP) immunization. This time-saving approach can circumvent biological and technical hurdles, such as difficult to express membrane proteins, antigen instability, and the lack of posttranslational modifications on recombinant antigens. We used mRNA-LNP immunization and hybridoma fusion technology to generate mAbs against the receptor binding domain (RBD) of SARS-CoV-2 spike (S) protein. Compared with traditional protein-based immunization approaches, inoculation of mice with RBD mRNA-LNP induced higher titers of serum antibodies. In addition, the mAbs we obtained can bind to SARS-CoV-2 RBDs from several variants. Notably, RBD-mAb-3 displayed particularly high binding affinities and neutralizing potencies against both Alpha and Delta variants. In addition to introducing specific mAbs against SARS-CoV-2, our data generally demonstrate that mRNA-LNP immunization may be useful to quickly generate highly functional mAbs against emerging infectious diseases.
Rapid learning of predictive maps with STDP and theta phase precession
Authors: George Tom M , de Cothi William , Stachenfeld Kimberly , Barry Caswell 
Published: May 2022

AbstractThe predictive map hypothesis is a promising candidate principle for hippocampal function. A favoured formalisation of this hypothesis, called the successor representation, proposes that each place cell encodes the expected state occupancy of its target location in the near future. This predictive framework is supported by behavioural as well as electrophysiological evidence and has desirable consequences for both the generalisability and efficiency of reinforcement learning algorithms. However, it is unclear how the successor representation might be learnt in the brain. Error-driven temporal difference learning, commonly used to learn successor representations in artificial agents, is not known to be implemented in hippocampal networks. Instead, we demonstrate that spike-timing dependent plasticity (STDP), a form of Hebbian learning, acting on temporally compressed trajectories known as “theta sweeps”, is sufficient to rapidly learn a close approximation to the successor representation. The model is biologically plausible – it uses spiking neurons modulated by theta-band oscillations, diffuse and overlapping place cell-like state representations, and experimentally matched parameters. We show how this model maps onto known aspects of hippocampal circuitry and explains substantial variance in the temporal difference successor matrix, consequently giving rise to place cells that demonstrate experimentally observed successor representation-related phenomena including backwards expansion on a 1D track and elongation near walls in 2D. Finally, our model provides insight into the observed topographical ordering of place field sizes along the dorsal-ventral axis by showing this is necessary to prevent the detrimental mixing of larger place fields, which encode longer timescale successor representations, with more fine-grained predictions of spatial location.
Matrix stiffness regulates Notch signaling activity in endothelial cells
Authors: Kretschmer Maibritt , Mamistvalov Rose , Sprinzak David , Vollmar Angelika M. , Zahler Stefan 
Published: May 2022

AbstractThe Notch signaling pathway plays a critical role in many developmental and disease related processes. It is widely accepted that Notch has a mechano-transduction module that regulates cleavage of the receptor. However, the role of biomechanical properties of the cellular environment on this module and on Notch signaling in general is still poorly understood. During angiogenesis, differentiation into tip and stalk cells is regulated by Notch. The endothelial cells in this process respond to biochemical and mechanical cues triggered by local stiffening of the ECM. Here, we investigated the influence of substrate stiffness on the Notch signaling pathway in endothelial cells. Using stiffness tuned PDMS substrates we show that Notch signaling pathway activity inversely correlates with the physiologically relevant substrate stiffness, with increased Notch activity on softer substrates. We show that trans-endocytosis of the Notch extracellular domain, but not the overall endocytosis, is regulated by substrate stiffness. Furthermore, we could show that integrin cell-matrix connections are both stiffness-dependent and influenced by Notch. Cadherin mediated cell-cell adhesion and Notch, however, influence each other in that basal Notch signaling is cell-cell contact dependent, but inhibition of the Notch signaling pathway also results in a reduction of VE-cadherin levels. We conclude that mechano-transduction of Notch activation depends on substrate stiffness highlighting the role of substrate rigidity as a modulator of Notch signaling. This may have important implications in pathological situations, such as tumor growth, associated with stiffening of the extracellular matrix.
Multistage and transmission-blocking tubulin targeting potent antimalarial discovered from the open access MMV Pathogen Box
Authors: Kumari Geeta , Jain Ravi , Sah Raj Kumar , Kalia Inderjeet , Vashistha Manu , Singh Pooja , Singh Agam Prasad , Samby Kirandeep , Burrows Jeremy , Singh Shailja 
Published: May 2022

ABSTRACTDevelopment of resistance to current antimalarial therapies remains a significant source of concern. To address this risk, new drugs with novel targets in distinct developmental stages of Plasmodium parasites are required. In our current work, we have targeted P. falciparum Tubulin (PfTubulin) proteins which represent some of the potential drug targets for malaria chemotherapy. Plasmodial Microtubules play a crucial role during parasite proliferation, growth, and transmission, which render them highly desirable targets for the development of next-generation chemotherapeutics. Towards this, we have evaluated the antimalarial activity of Tubulin targeting compounds received from the Medicines for Malaria Venture (MMV) “Pathogen Box” against the human malaria parasite, P. falciparum (including 3D7, RKL-9 (Chloroquine resistant) and R539T (Artemisinin resistant) strains). At nanomolar concentrations, filtered out compounds exhibited pronounced multistage antimalarial effects across the parasite life cycle, including intra-erythrocytic blood stages, liver stage parasites, gametocytes and ookinetes. Concomitantly, these compounds were found to impede male gamete ex-flagellation, thus showing transmission-blocking potential of these compounds. Target mining of these potent compounds, by combining in silico, biochemical and biophysical assays, implicated PfTubulin as their molecular target, which may possibly act by disrupting microtubule assembly dynamics by binding at the interface of α-βTubulin-dimer. Further, promising ADME profile of the parent scaffold supported its consideration as a lead compound for further development. Thus, our work highlights the potential of targeting PfTubulin proteins in discovering and developing next-generation, multistage antimalarial agents for treating Multi-Drug Resistant (MDR) malaria parasites.GRAPHICAL ABSTRACT
G6PD Inhibition Sensitizes Ovarian Cancer Cells to Oxidative Stress in the Metastatic Omental Microenvironment
Authors: Bose Shree , Huang Qiang , Ma Yunhan , Wang Lihua , Rivera Grecia O. , Ouyang Yunxin , Whitaker Regina , Gibson Rebecca A. , Kontos Christopher D. , Berchuck Andrew , Previs Rebecca , Shen Xiling 
Published: May 2022

SummaryOvarian cancer (OC) is the most lethal gynecological malignancy, with aggressive metastatic disease responsible for the majority of ovarian cancer related deaths. In particular, OC tumors preferentially metastasize to and proliferate rapidly in the omentum. Here, we show metastatic OC cells experience increased oxidative stress in the omental microenvironment. Metabolic reprogramming, including upregulation of the pentose phosphate pathway (PPP), a key cellular redox homeostasis mechanism, allows OC cells to compensate for this challenge. Inhibition of G6PD, the rate-limiting enzyme of the PPP, reduces tumor burden in pre-clinical models of OC, suggesting this adaptive metabolic dependency is important for OC omental metastasis.HighlightsThe omental microenvironment poses a high oxidative stress metastatic niche for ovarian cancer cells.G6PD, a key enzyme involved in redox homeostasis and the rate-limiting enzyme of the pentose phosphate pathway (PPP) is upregulated in omental metastasis.Inhibition of G6PD increases oxidative stress and cytotoxicity in the omental microenvironment.Pharmacological G6PD inhibition reduces omental metastases in vivo.
Persistent Memory as an Effective Alternative to Random Access Memory in Metagenome Assembly
Authors: Sun Jingchao , Egan Rob , Ho Harrison , Li Yue , Wang Zhong 
Published: May 2022

ABSTRACTThe assembly of metagenomes decomposes members of complex microbe communities and allows the characterization of these genomes without laborious cultivation or single-cell metagenomics. Metagenome assembly is a process that is memory intensive and time consuming. Multi-terabyte sequences can become too large to be assembled on a single computer node, and there is no reliable method to predict the memory requirement due to data-specific memory consumption pattern. Currently, out-ofmemory (OOM) is one of the most prevalent factors that accounts for metagenome assembly failures. In this study, we explored the possibility of using Persistent Memory (PMem) as a less expensive substitute for dynamic random access memory (DRAM) to reduce OOM and increase the scalability of metagenome assemblers. We evaluated the execution time and memory usage of three popular metagenome assemblers (MetaSPAdes, MEGAHIT, and MetaHipMer2) in datasets up to one terabase. We found that PMem can enable metagenome assemblers on terabyte-sized datasets by partially or fully substituting DRAM at a cost of longer running times. In addition, different assemblers displayed distinct memory/speed trade-offs in the same hardware/software environment. Because PMem was provided directly without any application-specific code modification, these findings are likely to be generalized to other memory-intensive bioinformatics applications.
Strategies for enriching and characterizing proteins with inhibitory properties on the yeast surface
Authors: Rezhdo Arlinda , Lessard Catherine T. , Islam Mariha , Van Deventer James A. 
Published: May 2022

AbstractDisplay technologies are powerful tools for discovering antibodies and other binding proteins against a broad range of biological targets. However, it remains challenging to adapt display technologies for the discovery of proteins that inhibit the enzymatic activities of such targets because the phenotypic readout during display screens is binding. The goal of this work is to investigate approaches for discovering inhibitory antibodies in yeast display format using a well-defined series of constructs and the target matrix metalloproteinase-9 (MMP-9). Three previously reported antibodies (DX-2802, M0076 and FAPB2.3.6) were used to create model libraries that are representative of protein libraries consisting of inhibitory binders, non-inhibitory binders, and non-binding constructs. Conditions that preferentially enrich for inhibitory clones were identified for both magnetic bead-based enrichments and fluorescence-activated cell sorting (FACS). Finally, we used direct titration of yeast to estimate inhibitor IC50 values with yeast-displayed and soluble constructs and found that the IC50 obtained for DX-2802 in yeast display format (20.01 ± 9.01 nM) falls within the confidence interval of IC50 the soluble scFv-Fc form of DX-2802 (17.56 ± 6.16 nM). Thus, it is possible to obtain IC50 values on the yeast surface, which greatly streamlines initial characterizations of inhibitory properties. Overall, we used these well-defined constructs to identify strategies for the discovery and characterization of inhibitory clones directly in surface display format.
Genome-wide identification and expression analysis of bHLH transcription factors reveal their putative regulatory effects on petal nectar spur development in Aquilegia
Authors: Li Xueyan , Huang Hui , Zhang Zhi-Qiang 
Published: May 2022

AbstractThe basic helix-loop-helix (bHLH) transcription factors (TFs) control a diversity of organ morphogenesis involved in cell division and cell expansion processes. The development of petal nectar spur, which plays important roles in plant-pollinator interaction and adaptive radiation, comprised cell division and cell expansion phases in Aquilegia. Here, we conducted a genome-wide identification of the bHLH gene family in Aquilegia to determine the characteristics and the expression profiles of this gene family during the development of petal nectar spur. A total of 120 AqbHLH proteins were identified from the Aquilegia coerulea genome. The phylogenetic tree showed that AqbHLH members were divided into 15 subfamilies, among which S7 and S8 subfamilies occurred marked expansion. Nineteen residues with conservation of more than 50% were found in the four conserved regions. The publicly RNA-Seq data and qRT-PCR results showed that AqbHLH027, AqbHLH083, AqbHLH046, and AqbHLH092 would be associated with the development of petal nectar spur by regulating cell division and cell cycle in phase I. While AqbHLH036 might participate the spur cell elongation and cell expansion in phase Ⅱ. This study provides useful insights for further probing on the function of AqbHLH TFs in the regulation of petal nectar spur development.
The AraC/XylS protein MxiE and its co-regulator IpgC control a negative feedback loop in the transcription cascade that regulates type III secretion in Shigella flexneri
Authors: McKenna Joy A. , Karney Monika MA. , Chan Daniel K. , Weatherspoon-Griffin Natasha , Larios Brianda Becerra , Pilonieta Maria Carolina , Munson George P. , Wing Helen J. 
Published: May 2022

ABSTRACTMembers of the AraC Family of Transcriptional Regulators (AFTRs) control the expression of many genes important to cellular processes, including virulence. In Shigella species, the type III secretion system (T3SS), a key determinant for host cell invasion, is regulated by the three-tiered VirF/VirB/MxiE transcription cascade. Both VirF and MxiE belong to the AFTRs and are characterized as positive transcriptional regulators. Here, we identify a novel regulatory activity for MxiE and its co-regulator IpgC, which manifests as a negative feedback loop in the VirF/VirB/MxiE transcription cascade. Our findings show that MxiE and IpgC down-regulate the virB promoter and hence VirB protein production, thus, decreasing VirB-dependent promoter activity at ospD1, one of the nearly 50 VirB-dependent genes. At the virB promoter, regions required for negative MxiE- and IpgC-dependent regulation were mapped and found to be coincident with regions required for positive VirF-dependent regulation. In tandem, negative MxiE- and IpgC-dependent regulation of the virB promoter only occurred in the presence of VirF suggesting that MxiE and IpgC can function to counter VirF activation of the virB promoter. Lastly, MxiE and IpgC do not down-regulate another VirF-activated promoter, icsA, demonstrating that this negative feedback loop targets the virB promoter. Our study provides insight into a mechanism that may reprogram Shigella virulence gene expression following type III secretion and provides the impetus to examine if MxiE and IpgC homologs in other important bacterial pathogens such as Burkholderia pseudomallei and Salmonella enterica serovars Typhimurium and Typhi coordinate similar negative feedback loops.IMPORTANCEThe large AraC Family of Transcriptional Regulators (AFTRs) control virulence gene expression in many bacterial pathogens. In Shigella species, the AraC/XylS protein MxiE and its co-regulator IpgC positively regulate the expression of type III secretion system genes within the three-tiered VirF/VirB/MxiE transcription cascade. Our findings suggest a negative feedback loop in the VirF/VirB/MxiE cascade in which MxiE and IpgC counter VirF-dependent activation of the virB promoter, thus, making this the first characterization of negative MxiE- and IpgC-dependent regulation. Our study provides insight into a mechanism that likely reprograms Shigella virulence gene expression following type III secretion, which has implications for other important bacterial pathogens with functional homologs of MxiE and IpgC.
McaA and McaB control the dynamic positioning of a bacterial magnetic organelle
Authors: Wan Juan , Monteil Caroline L , Taoka Azuma , Ernie Gabriel , Park Kieop , Amor Matthieu , Taylor-Cornejo Elias , Lefevre Christopher T , Komeili Arash 
Published: May 2022

AbstractMagnetotactic bacteria (MTB) are a diverse group of microorganisms that use intracellular chains of ferrimagnetic nanocrystals, produced within their magnetosome organelles, to align and navigate along the geomagnetic field. The cell biological and biochemical properties of magnetosomes make them a powerful model for studying the molecular mechanisms of biomineralization and compartmentalization in bacteria. While several conserved magnetosome formation genes have been described, the evolutionary strategies for their species-specific diversification remain unknown. Here, we demonstrate that the fragmented nature of magnetosome chains in Magnetospirillum magneticum AMB-1 is controlled by two genes named mcaA and mcaB. McaA recognizes the positive curvature of the inner cell membrane while McaB localises to magnetosomes. Along with the MamK actin-like cytoskeleton, they create space for addition of new magnetosomes in between pre-existing magnetosomes. Phylogenetic analyses suggest that McaAB homologs are widespread and may represent an ancient strategy for organelle positioning in MTB.