bluuebunny/crossref_metadata_2025_split huggingface dataset:
Detection of Chronic Wasting Disease prions in fetal tissuesoffree-ranging white-tailed deer
Authors: Nalls AV , McNulty EE , Mayfield A , Crum JM , Keel MK , Hoover EA , Ruder MG , Mathiason CK 
Published: March 2021

AbstractThe transmission of chronic wasting disease (CWD) has largely been attributed to contact with infectious prions shed in excretions (saliva, urine, feces, blood) by direct animal-to-animal exposure or indirect contact with the environment. Less-well studied has been the role mother-to-offspring transmission may play in the facile transmission of CWD. We asked whether such extensive spread may also be due to mother-to-offspring transmission, perhaps before birth. We thereby focused on a population of white-tailed deer from West Virginia, USA, in which CWD has been detected. Fetal tissues, ranging from 113 to 158 days of gestation, were harvested from the uteri of CWD+ dams in the asymptomatic phase of infection. Using serial protein misfolding amplification (sPMCA), we detected evidence of prion seeds in 6 of 14in uteroharvested fetuses, with earliest detection at 113 gestational days. This is the first report of CWD detection in free ranging white-tailed deer fetal tissues. Further investigation within cervid populations across North America will help define the role and impact of mother-to-offspring vertical transmission of CWD.
Paired feed-forward excitation with delayed inhibition allows high frequency computations across brain regions
Authors: Cao Alexandra S. , Van Hooser Stephen D. 
Published: March 2021

AbstractThe transmission of high-frequency temporal information across brain regions is critical to perception, but the mechanisms underlying such transmission remain unclear. Long-range projection patterns across brain areas are often comprised of paired feedforward excitation followed closely by delayed inhibition, including the thalamic triad synapse, thalamic projections to cortex, and projections within hippocampus. Previous studies have shown that these joint projections produce a shortened period of depolarization, sharpening the timing window over which the postsynaptic neuron can fire. Here we show that these projections can facilitate the transmission of high-frequency computations even at frequencies that are highly filtered by neuronal membranes. This temporal facilitation occurred over a range of synaptic parameter values, including variations in synaptic strength, synaptic time constants, short-term synaptic depression, and the delay between excitation and inhibition. Further, these projections can coordinate computations across multiple network levels, even amid ongoing local activity. We suggest that paired feedforward excitation and inhibition provides a hybrid signal – carrying both a value and a clock-like trigger – to allow circuits to be responsive to input whenever it arrives.
Discrete ripples reflect a spectrum of synchronous spiking activity in human association cortex
Authors: Tong Ai Phuong S. , Vaz Alex P. , Wittig John H. , Inati Sara K. , Zaghloul Kareem A. 
Published: March 2021

AbstractDirect brain recordings have provided important insights into how persistent oscillatory activity support human memory retrieval, but the extent to which transient fluctuations in intracranial EEG (iEEG) captures the dynamic coordination of underlying neurons involved in memory processing remains unclear. Here, we simultaneously record iEEG, local field potential (LFP), and single unit activity in the human temporal cortex. We demonstrate that cortical ripples contribute to broadband high frequency activity and exhibit a spectrum of amplitudes and durations related to the amount of underlying neuronal spiking. Ripples in the macro-scale iEEG are related to the number and synchrony of ripples in the micro-scale LFP, which in turn are related to the synchrony of neuronal spiking. Our data suggest that neural activity in the human cortex is organized into dynamic, discrete packets of information.
Redox Buffering Capacity of Nanomaterials as an Index of ROS-based Therapeutics and Toxicity: A Preclinical Animal Study
Authors: Adhikari Aniruddha , Mondal Susmita , Das Monojit , Ghosh Ria , Biswas Pritam , Darbar Soumendra , Singh Soumendra , Das Anjan Kumar , Bhattacharya Siddhartha Sankar , Pal Debasish , Mallick Asim Kumar , Pal Samir Kumar 
Published: March 2021

ABSTRACTPrecise control of intracellular redox status, i.e., maintenance of physiological level of reactive oxygen species (ROS) for mediating normal cellular functions (oxidative eustress) while evading the excess ROS stress (distress) is central to the concept of redox medicine. In this regard, engineered nanoparticles with unique ROS generation, transition, or depletion functions have the potential to be the choice of redox therapeutics. However, it is always challenging to estimate whether ROS-induced intracellular events are beneficial or deleterious to the cell. Here, we propose the concept of redox buffering capacity as a therapeutic index of engineered nanomaterials. As a steady redox state is maintained for normal functioning cells, we hypothesize that the ability of a nanomaterial to preserve this homeostatic condition will dictate its therapeutic efficacy. Additionally, the redox buffering capacity is expected to provide information about the nanoparticle toxicity. Here, using citrate functionalized trimanganese tetroxide nanoparticles (C-Mn3O4NPs) as a model nanosystem we explored its redox buffering capacity in erythrocytes. Furthermore, we went on to study the chronic toxic effect (if any) of this nanomaterial in animal model in order to co-relate with the experimentally estimated redox buffering capacity. This study could function as a framework for assessing the capability of a nanomaterial as redox medicine (whether maintains eustress or damages by creating distress), thus orienting its application and safety for clinical use.
Redox Nanomedicine Cures Chronic Kidney Disease (CKD) by Mitochondrial Reconditioning
Authors: Adhikari Aniruddha , Mondal Susmita , Chatterjee Tanima , Das Monojit , Biswas Pritam , Darbar Soumendra , Alessa Hussain , Al-Thakafy Jalal T. , Sayqal Ali , Ahmed Saleh A. , Das Anjan Kumar , Bhattacharyya Maitree , Pal Samir Kumar 
Published: March 2021

ABSTRACTTargeting reactive oxygen species (ROS) while maintaining cellular redox signaling is crucial in the development of redox medicine for the therapeutic benefit as the origin of several prevailing diseases including chronic kidney disease (CKD) is linked to ROS imbalance and associated mitochondrial dysfunction. Here, we have shown that an indigenously developed nanomedicine comprising of Mn3O4nanoparticles duly functionalized by biocompatible ligand citrate (C-Mn3O4NPs) can maintain cellular redox balance in an animal model. We developed a cisplatin-induced CKD model in C57BL/6j mice where severe mitochondrial dysfunction resulting in oxidative distress lead to the pathogenesis. Four weeks of treatment with C-Mn3O4NPs restored renal function, preserved normal kidney architecture, ameliorated overexpression of pro-inflammatory cytokines, and arrested glomerulosclerosis and interstitial fibrosis in CKD mice. A detailed study involving human embryonic kidney (HEK 293) cells and isolated mitochondria from experimental animals revealed that the molecular mechanism behind the pharmacological action of the nanomedicine involves protection of structural and functional integrity of mitochondria from oxidative damage, the subsequent reduction in intracellular ROS, and maintenance of cellular redox homeostasis. To the best of our knowledge, such studies that efficiently treated a multifaceted disease like CKD using a biocompatible redox nanomedicine are sparse in the literature. Successful clinical translation of this nanomedicine may open a new avenue in redox-mediated therapeutics of several other diseases (e.g., diabetic nephropathy, neurodegeneration, and cardiovascular disease) where oxidative distress plays a central role in pathogenesis.
Ozone nanobubble treatments improve survivability of Nile tilapia (Oreochromis niloticus) challenged with a pathogenic multidrug-resistantAeromonas hydrophila
Authors: Dien Le Thanh , Vu Linh Nguyen , Sangpo Pattiya , Senapin Saengchan , St-Hilaire Sophie , Rodkhum Channarong , Dong Ha Thanh 
Published: March 2021

AbstractMultidrug-resistant (MDR) bacteria has rapidly increased in aquaculture, which highlights the risk of production losses due to diseases and potential public health concerns. Previously, we reported that ozone nanobubbles (NB-O3) were effective at reducing concentrations of pathogenic bacteria in water and modulating fish immunity against pathogens; however, multiple treatments with direct NB-O3exposures caused alterations to the gills of exposed-fish. Here, we set up a modified recirculation system (MRS) assembled with an NB-O3device (MRS-NB-O3) to investigate whether MRS-NB-O3were 1) safe for tilapia (Oreochromis niloticus), 2) effective at reducing bacterial load in rearing water, and 3) improved survivability of Nile tilapia following an immersion challenge with a lethal dose of MDRAeromonas hydrophila. The results indicated no behavioral abnormalities or mortality of Nile tilapia during the 14 day study using the MRS-NB-O3system. In the immersion challenge, although high bacterial concentration (~2 × 107CFU/mL) was used, multiple NB-O3treatments in the first two days reduced the bacteria between 15.9% to 35.6% of bacterial load in water while bacterial concentration increased 13.1% to 27.9% in the untreated control. There was slight up-regulation of non-specific immune-related genes in the gills of the fish receiving NB-O3treatments. Most importantly, this treatment significantly improved survivability of Nile tilapia with relative percent survival (RPS) of 64.7 - 66.7% in treated fish and surviving fish developed specific antibody against MDRA. hydrophila. In summary, the result suggests that NB-O3is a promising alternative to antibiotics to control bacterial diseases, including MDR bacteria, and has high potential for application in recirculation aquaculture system (RAS).HighlightsMultiple treatments of NB-O3in a modified recirculation system (MRS) were relatively safe for juvenile Nile tilapiaNB-O3treatments in MRS significantly improved survivability of Nile tilapia challenged with multidrug-resistant (MDR)A. hydrophilawith RPS of 64.7 - 66.7%Concentration of MDRA. hydrophilain MRS was reduced by 15.9 to 35.6% following each NB-O3treatment, and increased by 13.1 to 27.9 % in untreated controlSurviving fish developed specific antibody IgM against MDRA. hydrophilaNB-O3is a promising non-antibiotic approach to control diseases caused by MDRA. hydrophila
BEdeepoff: anin silicotool for off-target prediction of ABE and CBE base editors
Authors: Zhang Chengdong , Wang Daqi , Qi Tao , Zhang Yuening , Hou Linghui , Lan Feng , Yang Jingcheng , Ong Sang-Ging , Wang Hongyan , Shi Leming , Wang Yongming 
Published: March 2021

AbstractBase editors, including adenine base editors (ABEs) and cytosine base editors (CBEs), are valuable tools for introducing point mutations, but they frequently induce unwanted off-target mutations. Here, we performed a high-throughput gRNA-target library screening to measure editing efficiencies at integrated genomic off-targets and obtained datasets of 48,632 and 52,429 off-targets for ABE and CBE, respectively. We used the datasets to train deep learning models, resulting in ABEdeepoff and CBEdeepoff which can predict editing efficiencies at off-targets. These tools are freely accessible via online web serverhttp://www.deephf.com/#/bedeep.
BEdeepon: an in silico tool for prediction of base editor efficiencies and outcomes
Authors: Zhang Chengdong , Yu Zimeng , Wang Daqi , Qi Tao , Zhang Yuening , Hou Linghui , Lan Feng , Yang Jingcheng , Shi Leming , Ong Sang-Ging , Wang Hongyan , Wang Yongming 
Published: March 2021

AbstractBase editors enable direct conversion of one target base into another in a programmable manner, but conversion efficiencies vary dramatically among different targets. Here, we performed a high-throughput gRNA-target library screening to measure conversion efficiencies and outcome product frequencies at integrated genomic targets and obtained datasets of 60,615 and 73,303 targets for ABE and CBE, respectively. We used the datasets to train deep learning models, resulting in ABEdeepon and CBEdeepon which can predict on-target efficiencies and outcome sequence frequencies. The software is freely accessible via online web serverhttp://www.deephf.com/#/bedeep/bedeepon.
Event-related and oscillatory signatures of response inhibition: A magnetoencephalography study with subclinical high and low impulsivity adults
Authors: Jauregi Ainara , Wang Hongfang , Hassel Stefanie , Kessler Klaus 
Published: March 2021

AbstractInhibition, the ability to withhold a response or to stop an initiated response, is a necessary cognitive function that can be vulnerable to an impairment. High levels of impulsivity have been shown to impact response inhibition and/or cognitive task performance. The present study investigated the spectral and spatio-temporal dynamics of response inhibition, during a combined go/no-go/stop-signal task, using magnetoencephalography (MEG) in a healthy undergraduate student population. Participants were divided by their level of impulsivity, as assessed by self-report measures, to explore potential differences between high (n=17) and low (n=17) impulsivity groups. Results showed that individuals scoring high on impulsivity failed significantly more NOGO and STOP trials than those scoring low, but no significant differences were found between stop-signal reaction times. During NOGO and STOP conditions, high impulsivity individuals showed significantly smaller M1 components in posterior regions, which could suggest an attentional processing deficit. During NOGO trials, the M2 component was found to be reduced in individuals scoring high, possibly reflecting less pre-motor inhibition efficiency, whereas in STOP trials, the network involved in the stopping process was engaged later in high impulsivity individuals. The high impulsivity group also engaged frontal networks more during the STOP-M3 component only, possibly as a late compensatory process. The lack of response time differences on STOP trials could indicate that compensation was effective to some degree (at the expense of higher error rates). Decreased frontal delta and theta band power was observed in high impulsivity individuals, suggesting a possible deficit in frontal pathways involved in motor suppression, however, unexpectedly, increased delta and theta band power in central and posterior sensors was also observed, which could be indicative of an increased effort to compensate for frontal deficits. Individuals scoring highly also showed decreased alpha power in frontal sensors, suggesting decreased inhibitory processing, along with reduced alpha suppression in posterior regions, reflecting reduced cue processing. These results provide evidence for how personality traits, such as impulsivity, relate to differences in the neural correlates of response inhibition.
AKAP79 enables calcineurin to directly suppress protein kinase A activity
Authors: Church Timothy W. , Tewatia Parul , Hannan Saad , Antunes João , Eriksson Olivia , Smart Trevor G. , Kotaleski Jeanette Hellgren , Gold Matthew G. 
Published: March 2021

AbstractInterplay between the second messengers cAMP and Ca2+is a hallmark of dynamic cellular processes. A common motif is the opposition of the Ca2+-sensitive phosphatase calcineurin and the major cAMP receptor, protein kinase A (PKA). Calcineurin dephosphorylates sites primed by PKA to bring about changes including synaptic long-term depression (LTD). AKAP79 supports signaling of this type by anchoring PKA and calcineurin in tandem. In this study, we discovered that AKAP79 increases the rate of calcineurin dephosphorylation of type II PKA regulatory subunits by an order of magnitude. Fluorescent PKA activity reporter assays, supported by kinetic modeling, show how AKAP79-enhanced calcineurin activity enables suppression of PKA without altering cAMP levels by increasing PKA catalytic subunit capture rate. Experiments with hippocampal neurons indicate that this mechanism contributes towards LTD. This non- canonical mode of PKA regulation may underlie many other cellular processes.
Primordial capsid and spooled ssDNA genome structures penetrate ancestral events of eukaryotic viruses
Authors: Munke Anna , Kimura Kei , Tomaru Yuji , Wang Han , Yoshida Kazuhiro , Mito Seiya , Hongo Yuki , Okamoto Kenta 
Published: March 2021

AbstractMarine algae viruses are important for controlling microorganism communities in the marine ecosystem and played fundamental roles during the early events of viral evolution. Here, we have focused on one major group of marine algae viruses, the ssDNA viruses from theBacilladnaviridaefamily. We present the capsid structure of the bacilladnavirus,Chaetoceros tenuissimusDNA virus type II (CtenDNAV-II), determined at 2.3 Å resolution. A structure-based phylogenetic analysis supported the previous theory that bacilladnaviruses have acquired their capsid protein via horizontal gene transfer from a ssRNA virus. The capsid protein contains the widespread virus jelly-roll fold, but has additional unique features; a third β-sheet and a long C-terminal tail. Further, low-resolution reconstructions of the CtenDNAV-II genome revealed a partially spooled structure, an arrangement previously only described for dsRNA and dsDNA viruses. Together, these results exemplify the importance of genetic recombination for the emergence and evolution of ssDNA viruses and provide important insights into the underlying mechanisms that dictate genome organisation.
Rational engineering of low temperature activity in thermoalkalophilicGeobacillus thermocatenulatuslipase
Authors: Wang Weigao , Dasetty Siva , Sarupria Sapna , Blenner Mark 
Published: March 2021

AbstractWhile thermophilic enzymes have thermostability desired for broad industrial applications, they can lose activity at ambient temperatures far from their optimal. Engineering cold activity into thermophilic enzymes has the potential to broaden the range of temperatures resulting in significant activity (i.e., decreasing the temperature dependence of kcat). Even though it has been widely suggested that cold temperature enzyme activity results from active flexibility that is at odds with the rigidity necessary for thermostable enzymes; however, directed evolution experiments have shown us these properties are not mutually exclusive. In this study, rational protein engineering was used to introduce flexibility inducing mutations around the active sites ofGeobacillus thermocatenulatuslipase (GTL). Two mutants were found to have enhanced specific activity compared to wild-type at temperatures between 283 K to 363 K with p-nitrophenol butyrate but not with larger substrates. Kinetics assay revealed both mutations resulted in psychrophilic traits, such as lower activation enthalpy and more negative entropy values compared to wild type in all substrates. Furthermore, the mutants had significantly improved thermostability compared to wild type enzyme, which proves that it is feasible to improve the cold activity without trade-off. Our study provides insight into the enzyme cold adaptation mechanism and design principles for engineering cold activity into thermostable enzymes.
A mechanistic model captures the emergence and implications of non-genetic heterogeneity and reversible drug resistance in ER+ breast cancer cells
Authors: Sahoo Sarthak , Mishra Ashutosh , Kaur Harsimran , Hari Kishore , Muralidharan Srinath , Mandal Susmita , Jolly Mohit Kumar 
Published: March 2021

AbstractResistance to anti-estrogen therapy is an unsolved clinical challenge in successfully treating ER+ breast cancer patients. Acquisition of mutations can confer heritable resistance to cancer cells, enabling their clonal selection to establish a drug-resistant population. Recent studies have demonstrated that cells can tolerate drug treatment without any genetic alterations too; however, the mechanisms and dynamics of such non-genetic adaptation remain elusive. Here, we investigate coupled dynamics of epithelial-mesenchymal transition (EMT) in breast cancer cells and emergence of reversible drug resistance. Our mechanism-based model for the underlying regulatory network reveals that these two axes can drive one another, thus conferring bidirectional plasticity. This network can also enable non-genetic heterogeneity in a population of cells by allowing for six co-existing phenotypes: epithelial-sensitive, mesenchymal-resistant, hybrid E/M-sensitive, hybrid E/M-resistant, mesenchymal-sensitive and epithelial-resistant, with the first two ones being most dominant. Next, in a population dynamics framework, we exemplify the implications of phenotypic plasticity (both drug-induced and intrinsic stochastic switching) and/or non-genetic heterogeneity in promoting population survival in a mixture of sensitive and resistant cells, even in the absence of any cell-cell cooperation. Finally, we propose the potential therapeutic use of MET (mesenchymal-epithelial transition) inducers besides canonical anti-estrogen therapy to limit the emergence of reversible drug resistance. Our results offer mechanistic insights into empirical observations on EMT and drug resistance and illustrate how such dynamical insights can be exploited for better therapeutic designs.
Evaluation of the OsTIR1 and AtAFB2 AID systems for chromatin protein degradation in mammalian cells
Authors: Yunusova Anastasia , Smirnov Alexander , Shnaider Tatiana , Afonnikova Svetlana , Battulin Nariman 
Published: March 2021

ABSTRACTAuxin-inducible degron (AID) system is a promising tool for dynamic protein degradation. In mammalian cells, this approach has become indispensable to study fundamental molecular functions, such as replication, chromatin dynamics or transcription, that are otherwise difficult to dissect. We present evaluation of the two prominent AID systems based on OsTIR1 and AtAFB2 auxin receptor F-box proteins (AFBs). We analyzed degradation dynamics of cohesin/condensin complexes subunits in mouse embryonic stem cells (mRad21, mSMC2, mCapH, mCapH2) and human haploid HAP1 line (hRad21, hSMC2). Double antibiotic selection helped to achieve high homozygous AID targeting efficiency for all genes, ranging from 11 to 77%. We found that the main challenge for successful protein degradation is obtaining cell clones with high and stable AFB expression levels due to mosaic expression of AFBs, which also tends to decline with passages in the absence of constant puromycin selection, even at the AAVS1 safe-harbor locus. Comparing two AFBs, we found that OsTIR1 system showed weak dynamics of protein degradation. At the same time, AtAFB2 approach was very efficient even in random integration. Other factors such as degradation dynamics and low basal depletion were also in favor of AtAFB2 system. Our main conclusion is that repeated addition of puromycin to culture medium prevents AtAFB2 silencing and restores auxin sensitivity, facilitating robust protein degradation. We hope that our report will be useful for researchers that plan to establish AID method in their lab.