bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biofilm matrix proteome of clinical strain of P. aeruginosa
Authors: Egorova Daria A. , Solovyev Andrey I. , Polyakov Nikita B. , Danilova Ksenya V. , Scherbakova Anastasya A. , Kravtsov Ivan N. , Dmitrieva Maria A. , Rykova Valentina S. , Tutykhina Irina L. , Romanova Yulia M. , Gintsburg Alexander L. 
Published: December 2021

AbstractExtracellular matrix plays a pivotal role in biofilm biology and proposed as a potential target for therapeutics development. As matrix is responsible for some extracellular functions and influence bacterial cytotoxicity against eukaryotic cells, it must have unique protein composition. P. aeruginosa is one of the most important pathogens with emerging antibiotic resistance, but only a few studies were devoted to matrix proteomes and there are no studies describing matrix proteome for any clinical isolates. Here we report the first biofilm matrix proteome of P. aeruginosa isolated from bronchoalveolar lavage of patient in intensive care unit. We have identified the largest number of proteins in the matrix among all published studies devoted to P. aeruginosa biofilms. Comparison of matrix proteome with proteome from embedded cells let us to identify several enriched bioprocess groups. Bioprocess groups with the largest number of overrepresented in matrix proteins were oxidation-reduction processes, proteolysis, and transmembrane transport. The top three represented in matrix bioprocesses concerning the size of the GO annotated database were cell redox homeostasis, nucleoside metabolism, and fatty acid synthesis. Finally, we discuss the obtained data in a prism of antibiofilm therapeutics development.
L-type calcium channel blocker increases VEGF concentrations in retinal cells and human serum
Authors: Kumar Anmol , Mutter Stefan , Parente Erika B. , Harjutsalo Valma , Lithovius Raija , Mathavan Sinnakaruppan , Forsblom Carol , Lehto Markku , Hiltunen Timo P. , Kontula Kimmo K. , Groop Per-Henrik 
Published: December 2021

AbstractObjectiveVascular endothelial growth factor (VEGF) plays a key role in diabetic retinopathy (DR). L-type calcium channel blockers (LTCCBs) have been widely used as antihypertensive medication (AHM), but their association with VEGF and DR is still unclear. Therefore, we explored the effect of LTCCBs compared to other AHMs on VEGF concentrations in retinal cells and human serum. Furthermore, we evaluated the association between the use of LTCCBs and the risk of severe diabetic eye disease (SDED).Research design and methodsMüller cells (MIO-M1) were cultured as per recommended protocol and treated with LTCCBs and other AHMs. VEGF secreted from cells were collected at 24 hours intervals. In an interventional study, 39 individuals received LTCCBs or other AHM for four weeks with a four-week wash-out placebo period between treatments. VEGF was measured during the medication and placebo periods. Finally, we evaluated the risk of SDED associated with LTCCB usage in 192 individuals from the FinnDiane Study in an oberservational setting.ResultsIn the cell cultures, medium VEGF concentration increased time-dependently after amlodipine (p<0.01) treatment, but not after losartan (p>0.01), or lisinopril (p>0.01). Amlodipine, but no other AHM, increased serum VEGF concentration (p<0.05) during the interventional clinical study. The usage of LTCCB was not associated with the risk of SDED in the observational study.ConclusionsLTCCB increases VEGF concentrations in retinal cells and human serum. However, the usage of LTCCBs does not appear to be associated with SDED in adults with type 1 diabetes.
Engineered High-Affinity ACE2 Peptide Mitigates ARDS and Death Induced by Multiple SARS-CoV-2 Variants
Authors: Zhang Lianghui , Dutta Soumajit , Xiong Shiqin , Chan Matthew , Chan Kui K. , Fan Timothy M. , Bailey Keith L. , Lindeblad Matthew , Cooper Laura M. , Rong Lijun , Gugliuzza Anthony F. , Shukla Diwakar , Procko Erik , Rehman Jalees , Malik Asrar B. 
Published: December 2021

ABSTRACTVaccine hesitancy and continuing emergence of SARS-CoV-2 variants of concern that may escape vaccine-induced immune responses highlight the urgent need for effective COVID-19 therapeutics. Monoclonal antibodies used in the clinic have varying efficacies against distinct SARS-CoV-2 variants; thus, there is considerable interest in engineered ACE2 peptides with augmented binding affinities for SARS-CoV-2 Spike protein. These could have therapeutic benefit against multiple viral variants. Using molecular dynamics simulations, we show how three amino acid substitutions in an engineered soluble ACE2 peptide (sACE22.v2.4-IgG1) markedly increase affinity for the SARS-CoV-2 Spike (S) protein. We demonstrate high binding affinity to S protein of the early SARS-CoV-2 WA-1/2020 isolate and also to multiple variants of concern: B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), and B.1.617.2 (Delta) SARS-CoV-2 variants. In humanized K18-hACE2 mice, prophylactic and therapeutic administration of sACE22.v2.4-IgG1 peptide prevented acute lung vascular endothelial injury and lung edema (essential features of ARDS) and significantly improved survival after infection by SARS-CoV-2 WA-1/2020 as well as P.1 variant of concern. These studies demonstrate for the first time broad efficacy in vivo of an ACE2 decoy peptide against multiple SARS-CoV-2 variants and point to its therapeutic potential.
Induction of flight via midbrain projections to the cuneiform nucleus
Authors: Tsang Emmy , Orlandini Camilla , Sureka Rahul , Crevenna Alvaro H. , Perlas Emerald , Prankerd Izzie , Masferrer Maria E. , Gross Cornelius T. 
Published: December 2021

AbstractThe dorsal periaqueductal gray is a midbrain structure implicated in the control of defensive behaviors and the processing of painful stimuli. Electrical stimulation or optogenetic activation of excitatory neurons in dorsal periaqueductal gray results in freezing or flight behavior at low or high intensity, respectively. However, the output structures that mediate these defensive behaviors remain unconfirmed. Here we carried out a targeted classification of neuron types in dorsal periaqueductal gray using multiplex in situ sequencing and then applied cell-type and projection-specific optogenetic stimulation to identify projections from dorsal periaqueductal grey to the cuneiform nucleus that promoted goal-directed flight behavior. These data confirmed that descending outputs from dorsal periaqueductal gray serve as a trigger for directed escape behavior.
PAR recognition by PARP1 regulates DNA-dependent activities and independently stimulates catalytic activity of PARP1
Authors: Deeksha Waghela , Abhishek Suman , Rajakumara Eerappa 
Published: December 2021

AbstractPoly(ADP-ribosyl)ation is predominantly catalyzed by Poly(ADP-ribose) polymerase 1 (PARP1) in response to DNA damage, mediating the DNA repair process to maintain genomic integrity. Single strand (SSB) and double strand (DSB) DNA breaks are bonafide stimulators of PARP1 activity. However, PAR mediated PARP1 regulation remains unexplored. Here, we report ZnF3, BRCT and WGR, hitherto uncharacterized, as PAR reader domains of PARP1. Surprisingly, these domains recognize PARylated protein with a higher affinity compared to PAR but bind with weak or no affinity to DNA breaks as standalone domains. Conversely, ZnF1 and ZnF2 of PARP1 recognize DNA breaks but weakly to PAR. In addition, PAR reader domains, together, exhibit a synergy to recognize PAR or PARylated protein. Further competition binding studies suggest that PAR binding releases DNA from PARP1, and WGR domain facilitates the DNA release. Unexpectedly, PAR showed catalytic stimulation of PARP1 but hampers the DNA-dependent stimulation. Altogether, our work discovers dedicated high-affinity PAR reader domains of PARP1 and uncovers a novel mechanism of allosteric stimulation, but retardation of DNA-dependent activities of PARP1 by its catalytic product PAR. Therefore, our studies can be used as a model to understand the effect of one or more allosteric activators on the regulation of receptors or modular enzyme activities by another allosteric activator.
Targeting BRPF3 moderately reverses olaparib resistance in high grade serous ovarian carcinoma
Authors: Bitler Benjamin G. , Yamamoto Tomomi M. , McMellen Alexandra , Kim Hyunmin , Watson Zachary L. 
Published: December 2021

AbstractBackgroundPARP inhibitors (PARPi) kill cancer cells by stalling DNA replication and preventing DNA repair, resulting in a critical accumulation of DNA damage. Resistance to PARPi is a growing clinical problem in the treatment of high grade serous ovarian carcinoma (HGSOC). Acetylation of histone H3 lysine 14 (H3K14ac) and associated histone acetyltransferases (HATs) and epigenetic readers have known functions in DNA repair and replication. Our objectives are to examine their expression and activities in the context of PARPi-resistant HGSOC, and to determine if targeting H3K14ac or associated proteins has therapeutic potential.ResultsUsing mass spectrometry profiling of histone modifications, we observed increased H3K14ac enrichment in PARPi-resistant HGSOC cells relative to isogenic PARPi-sensitive lines. By RT-qPCR and RNA-Seq, we also observed altered expression of numerous HATs in PARPi-resistant HGSOC cells and a PARPi-resistant PDX model. Knockdown of HATs only modestly altered PARPi response, although knockdown and inhibition of PCAF significantly increased resistance. Pharmacologic inhibition of HBO1 severely depleted H3K14ac but did not affect PARPi response. However, knockdown and inhibition of BRPF3, which is known to interact in a complex with HBO1, did reduce PARPi resistance.ConclusionsThis study demonstrates that severe depletion of H3K14ac does not affect PARPi response in HGSOC. Our data suggest that bromodomain functions of HAT proteins, such as PCAF, or accessory proteins, such as BRPF3, may play a more direct role compared to direct histone acetyltransferase functions in PARPi response.
Young APPKINL-G-F/NL-G-Fmice display high-fat diet-induced metabolic disturbances and specific disorders associated with brain energy homeostasis
Authors: Wang Wei , Tanokashira Daisuke , Maruyama Megumi , Kuroiwa Chiemi , Saito Takashi , Saido Takaomi C. , Taguchi Akiko 
Published: December 2021

ABSTRACTAimType 2 diabetes mellitus (T2DM) is an increased risk factor for Alzheimer’s disease (AD); however, the relationship between the two conditions is controversial. High-fat diet (HFD) causes cognitive impairment with/without Aβ accumulation in middle-aged or aged transgenic (Tg) and knock-in (KI) AD mouse models, except for metabolic disorders, which commonly occur in all mice types. Alternatively, whether HFD in early life impacts energy metabolism and neurological phenotypes in young AD mouse models remains unknown. In the present study, we examined the effects of HFD on young APPKINL-G-F/NL-G-Fmice, one of the novel knock-in (KI)-AD mouse models.MethodsThe mice were categorized by diet into two experimental groups, normal diet (ND) and HFD. Four-week-old WT and APPKINL-G-F/NL-G-Fmice were fed ND or HFD for nine weeks. Both types of mice on ND and HFD were examined during young adulthood.ResultsHFD causes T2DM-related metabolic disturbances in young WT and APPKINL-G-F/NL-G-Fmice and specific impairment of brain energy homeostasis only in young APPKINL-G-F/NL-G-Fmice. However, HFD-induced metabolic dysfunctions had no impact on behaviors, Aβ levels, and specific IRS1 modifications in both young APPKINL-G-F/NL-G-Fmice and young WT mice.ConclusionHFD in early life is effective in causing metabolic disturbances in young WT and APPKINL-G-F/NL-G-Fmice but is ineffective in inducing neurological disorders in young mice, which suggests that the aging effects along with long-term HFD cause neurological alterations.
Goal-directed motor actions drive acetylcholine dynamics in sensory cortex
Authors: Zou Jing , Willem de Gee Jan , Mridha Zakir , Trinh Simon , Erskine Andrew , Jing Miao , Yao Jennifer , Walker Stefanie , Li Yulong , McGinley Matthew , Hires Samuel Andrew 
Published: December 2021

SummaryNumerous cognitive functions including attention and learning are influenced by the dynamic patterns of acetylcholine release across the brain. How acetylcholine mediates these functions in cortex remains unclear, as the relationship between cortical acetylcholine and behavioral events has not been precisely measured across task learning. To dissect this relationship, we quantified motor behavior and sub-second acetylcholine dynamics in primary somatosensory and auditory cortex during rewarded sensory detection and discrimination tasks. We found that acetylcholine dynamics were directly attributable to goal-directed actions (whisker motion and licking), rather than delivery of sensory cues or rewards. As task performance improved across training, acetylcholine release associated with the first lick in a trial was strongly and specifically potentiated. These results show that acetylcholine dynamics in sensory cortex are driven by directed motor actions to gather information and act upon it.
Meta analysis of variant predictions in congenital adrenal hyperplasia caused by mutations in CYP21A2
Authors: Prado Mayara J. , Ligabue-Braun Rodrigo , Zaha Arnaldo , Rosa Rossetti Maria Lucia , Pandey Amit V. 
Published: December 2021

AbstractContextCYP21A2 deficiency represents 95% of congenital adrenal hyperplasia cases (CAH), a group of genetic disorders that affect steroid biosynthesis. The genetic and functional analysis provides critical tools to elucidate complex CAH cases. One of the most accessible tools to infer the pathogenicity of new variants is in silico prediction.ObjectiveAnalyze the performance of in silico prediction tools to categorize missense single nucleotide variants (SNVs) of the CYP21A2.MethodsSNVs of the CYP21A2 characterized in vitro by functional assays were selected to assess the performance of online single and meta predictors. SNVs were tested separately or in combination with the related phenotype (severe or mild CAH form). In total, 103 SNVs of the CYP21A2 (90 pathogenic and 13 neutral) were used to test the performance of 13 single-predictors and four meta-predictors.ResultsSNVs associated with the severe phenotypes were well categorized by all tools, with an accuracy between 0.69 (PredictSNP2) and 0.97 (CADD), and Matthews’ correlation coefficient (MCC) between 0.49 (PoredicSNP2) and 0.90 (CADD). However, SNVs related to the mild phenotype had more variation, with the accuracy between 0.47 (S3Ds&GO and MAPP) and 0.88 (CADD), and MCC between 0.18 (MAPP) and 0.71 (CADD).ConclusionFrom our analysis, we identified four predictors of CYP21A2 pathogenicity with good performance. These results can be used for future analysis to infer the impact of uncharacterized SNVs’ in CYP21A2.
Deep Learning-powered Bessel-beam Multi-parametric Photoacoustic Microscopy
Authors: Zhou Yifeng , Sun Naidi , Hu Song 
Published: December 2021

AbstractEnabling simultaneous and high-resolution quantification of the total concentration of hemoglobin (CHb), oxygen saturation of hemoglobin (sO2), and cerebral blood flow (CBF), multi-parametric photoacoustic microscopy (PAM) has emerged as a promising tool for functional and metabolic imaging of the live mouse brain. However, due to the limited depth of focus imposed by the Gaussian-beam excitation, the quantitative measurements become inaccurate when the imaging object is out of focus. To address this problem, we have developed a hardware-software combined approach by integrating Bessel-beam excitation and conditional generative adversarial network (cGAN)-based deep learning. Side-by-side comparison of the new cGAN-powered Bessel-beam multi-parametric PAM against the conventional Gaussian-beam multi-parametric PAM shows that the new system enables high-resolution, quantitative imaging of CHb, sO2, and CBF over a depth range of ∼600 μm in the live mouse brain, with errors 13–58 times lower than those of the conventional system. Better fulfilling the rigid requirement of light focusing for accurate hemodynamic measurements, the deep learning-powered Bessel-beam multi-parametric PAM may find applications in large-field functional recording across the uneven brain surface and beyond (e.g., tumor imaging).
How synaptic strength, short-term plasticity, and input synchrony contribute to neuronal spike output
Authors: Guilabert Alexandra Gastone , Buchholz Moritz O. , Ehret Benjamin , Schuhknecht Gregor F.P. 
Published: December 2021

AbstractNeurons integrate from thousands of synapses whose strengths span an order of magnitude. Intriguingly, in mouse neocortex, the few ‘strong’ synapses are formed between similarly tuned cells, suggesting they determine neuronal spiking output. This raises the question of how other computational primitives, including ‘background’ activity from the many ‘weak’ synapses, short-term plasticity, and temporal factors contribute to spiking. We combined extracellular stimulation and whole-cell recordings in mouse barrel cortex to map excitatory postsynaptic potential (EPSP) amplitudes and paired-pulse ratios of excitatory synaptic connections converging onto individual layer 2/3 (L2/3) neurons. While net short-term plasticity was weak, connections with EPSPs > 2 mV were exclusively depressing. There was no evidence for clustering of synaptic properties on individual neurons. Instead, EPSPs and paired-pulse ratios of connections converging onto the same cells spanned the full range observed across L2/3, which critically constrains theoretical models of cortical filtering. To investigate how different computational primitives of synaptic information processing interact to shape spiking, we developed a computational model of a pyramidal neuron in the rodent L2/3 circuitry, which was constrained by our own experiments and published in vivo data. We found that the ability of strong inputs to evoke spiking depended on their high temporal synchrony and high firing rates observed in vivo and on synaptic background activity – and not primarily on synaptic strength, which further amplified information transfer. Our results provide a framework of how cortical neurons exploit complex synergies between temporal coding, synaptic properties, and noise to transform synaptic inputs into output firing.
Using synthetic activity to design ultra-potent antibody cocktails
Authors: Zhao Hui , Dodds Michael , Tasch Michael , Gewe Mesfin , Martinez Anissa , Hutton Melanie , Keeney Kristie , Pollock Alex , Jester Benjamin W. , Khuong Nhi , Zhang Mia , Ertel Stacey , Brady Colin , Heinnickel Mark , Tabakh Hannah , Sanjaya Nathan , Cruickshank Kendra , Paddock Troy , Struyvenberg Sarah , Dang Jason , Saveria Tracy , Shanitta Chelsea , Fletcher David , Sigmar Kristjan , Goetsch Lauren , Gamble Caitlin , Mileto Steven J. , Heselpoth Ryan , Lyras Dena , Behnke Craig A. , Fischetti Vincent , Finrow Brian , Roberts James M. 
Published: December 2021

AbstractDrugs which independently inhibit a shared target or pathway can have synthetic activities that result in multiplicative instead of merely additive potencies. This characteristic of drug combinations can be quantified by expressing the potency of the combination as if it were a single agent. We show that by optimizing this quantity we can prospectively design drug cocktails with apparent potencies that far exceed any of its individual components. We illustrate the power of this approach, which is based on statistical design of experiments to select optimal drug combinations, and response surface methodology to determine optimal drug ratios, by building a drug cocktail comprised of three antibodies for treating C. difficile infection that is almost 1000-fold more potent than the current, clinically approved antibody monotherapy. High synthetic activities do not require unusual drug interactions, and therefore may be achievable much more readily than generally appreciated.One-Sentence SummaryA development pathway is described for designing antibody cocktails with potencies that far exceed what is achievable with single antibodies
Stabilized COre gene and Pathway Election uncovers pan-cancer shared pathways and a cancer specific driver
Authors: Kossinna Pathum , Cai Weijia , Lu Xuewen , Shemanko Carrie S , Zhang Qingrun 
Published: December 2021

SummaryApproaches systematically characterizing interactions via transcriptomic data usually follow two systems: (1) co-expression network analyses focusing on correlations between genes; (2) linear regressions (usually regularized) to select multiple genes jointly. Both suffer from the problem of stability: a slight change of parameterization or dataset could lead to dramatic alternations of outcomes. Here, we proposeStabilizedCore gene andPathwayElection, orSCOPE, a tool integrating bootstrapped LASSO and co-expression analysis, leading to robust outcomes insensitive to variations in data. By applying SCOPE to six cancer expression datasets (BRCA, COAD, KIRC, LUAD, PRAD and THCA) in The Cancer Genome Atlas, we identified core genes capturing interaction effects in crucial pan-cancer pathways related to genome instability and DNA damage response. Moreover, we highlighted the pivotal role of CD63 as an oncogenic driver and a potential therapeutic target in kidney cancer. SCOPE enables stabilized investigations towards complex interactions using transcriptome data.Availabilityhttps://github.com/QingrunZhangLab/SCOPE
Understanding implicit sensorimotor adaptation as a process of proprioceptive re-alignment
Authors: Tsay Jonathan S. , Kim Hyosub E. , Haith Adrian M. , Ivry Richard B. 
Published: December 2021

AbstractMultiple learning processes contribute to successful goal-directed actions in the face of changing physiological states, biomechanical constraints, and environmental contexts. Amongst these processes, implicit sensorimotor adaptation is of primary importance, ensuring that movements remain well-calibrated and accurate. A large body of work on reaching movements has emphasized how adaptation centers on an iterative process designed to minimize visual errors. The role of proprioception has been largely neglected, thought to play a passive role in which proprioception is affected by the visual error but does not directly contribute to adaptation. Here we present an alternative to this visuo-centric framework, arguing that that implicit adaptation can be understood as minimizing a proprioceptive error, the distance between the perceived hand position and its intended goal. We use this proprioceptive re-alignment model (PReMo) to re-examine many phenomena that have previously been interpreted in terms of learning from visual errors, as well as offer novel accounts for unexplained phenomena. We discuss potential challenges for this new perspective on implicit adaptation and outline a set of predictions for future experimentation.