bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influence of E/I balance and pruning in peri-personal space differences in schizophrenia: a computational approach
Authors: Paredes Renato , Ferri Francesca , Seriès Peggy 
Published: November 2020

AbstractThe encoding of the space close to the body, named peri-personal space (PPS), is thought to play a crucial role in the unusual experiences of the self observed in schizophrenia (SCZ). However, it is unclear why SCZ patients and high schizotypal (H-SPQ) individuals present a narrower PPS and why the boundaries of the PPS are more sharply defined in patients. We hypothesise that the unusual PPS representation observed in SCZ is caused by an imbalance of excitation and inhibition (E/I) in recurrent synapses of unisensory neurons or an impairment of bottom-up and top-down connectivity between unisensory and multisensory neurons. These hypotheses were tested computationally by manipulating the effects of E/I imbalance, feedback weights and synaptic density in the network. Using simulations we explored the effects of such impairments in the PPS representation generated by the network and fitted the model to behavioural data. We found that increased excitation of sensory neurons could account for the smaller PPS observed in SCZ and H-SPQ, whereas a decrease of synaptic density caused the sharp definition of the PPS observed in SCZ. We propose a novel conceptual model of PPS representation in the SCZ spectrum that can account for alterations in self-world demarcation, failures in tactile discrimination and symptoms observed in patients.
Selection of start codon during mRNA scanning in eukaryotic translation initiation
Authors: Basu Ipsita , Gorai Biswajit , Chandran Thyageshwar , Maiti Prabal K. , Hussain Tanweer 
Published: November 2020

AbstractDuring translational initiation in eukaryotes, the small ribosomal subunit forms a 48S preinitiation complex (PIC) with initiation factors. The 48S PIC binds to the 5’ end of mRNA and inspects long untranslated region (UTR) for the presence of the start codon (AUG). Accurate and high speed of scanning 5’ UTR and subsequent selection of the correct start codon are crucial for protein synthesis. However, the conformational state of 48S PIC required for inspecting every codon is not clearly understood. Whether the scanning or open conformation of 48S PIC can accurately select the cognate start codon over near/non-cognate codons, or this discrimination is carried out only in the scanning-arrested or closed conformation of 48S PIC. Here, using atomistic molecular dynamics (MD) simulations and free energy calculations, we show that the scanning conformation of 48S PIC can reject all but 4 of the 63 non-AUG codons. Among nine near-cognate codons with a single mismatch, only codons with a first position mismatch (GUG, CUG and UUG) or a pyrimidine mismatch at the second position (ACG) are not discriminated by scanning state of 48S PIC. In contrast, any mismatch in the third position is rejected. Simulations runs in absence of one or more eukaryotic initiation factors (eIF1, eIF1+eIF1A, eIF2ɑ or eIF2β) from the system show critical role of eIF1 and eIF2ɑ in start codon selection. The structural analysis indicates that tRNAi dynamics at the widened P site of 48S open state drives codon selection. Further, a stable codon: anticodon interaction prepares the PIC to transit to the closed state. Overall, we provide insights into the selection of start codon during scanning and how the open conformation of 48S PIC can scan long 5’ UTRs with accuracy and high speed without the requirement of sampling the closed state for every codon.
Shore crabs reveal novel evolutionary attributes of the mushroom body
Authors: Strausfeld Nicholas James , Sayre Marcel Ethan 
Published: November 2020

AbstractNeural organization of mushroom bodies is largely consistent across insects, whereas the ancestral ground pattern diverges broadly across crustacean lineages, resulting in successive loss of columns and the acquisition of domed centers retaining ancestral Hebbian-like networks and aminergic connections. We demonstrate here a major departure from this evolutionary trend in Brachyura, the most recent malacostracan lineage. Instead of occupying the rostral surface of the lateral protocerebrum, mushroom body calyces are buried deep within it, with their columns extending outwards to an expansive system of gyri on the brain’s surface. The organization amongst mushroom body neurons reaches extreme elaboration throughout its constituent neuropils. The calyces, columns, and especially the gyri show DC0 immunoreactivity, an indicator of extensive circuits involved in learning and memory.
Improved bioavailability of montelukast through a novel oral mucoadhesive film in humans and mice
Authors: Michael Johanna , de Sousa Diana Bessa , Conway Justin , Gonzales-Labrada Erick , Obeid Rodolphe , Tevini Julia , Felder Thomas , Hutter-Paier Birgit , Zerbe Horst , Paiement Nadine , Aigner Ludwig 
Published: November 2020

AbstractThe leukotriene receptor antagonist Montelukast (MTK) is an approved medication for the treatment of asthma and allergic rhinitis. The existing marketed tablet forms of MTK exhibit inconsistent uptake and bioavailability, which partially explains the presence of a significant proportion of MTK low- and non-responders in the population. Besides that, tablets are suboptimal formulations for patients suffering of dysphagia, for example seen in COVID-19 patients or in patients with neurodegenerative diseases such as Alzheimer’s Disease. The increasing interest in repurposing of MTK for the treatment of such patients and the need for an improved bioavailability triggered us to reformulate MTK. The aim was to develop a mucoadhesive MTK film with a good safety and improved pharmacological, i.e. improved bioavailability, profile in humans as well as in a mouse model of Alzheimer’s Disease.We tested dissolution of the mucoadhesive film containing MTK in saliva buffer and assessed pharmacoexposure and −kinetics after acute and chronic oral application in mice. Furthermore, we performed a Phase I safety / bioavailability / pharmacokinetic analysis in healthy volunteers. The latter included a comparison with the marketed tablet form as well as a quantitative analysis of the MTK levels in the cerebrospinal fluid.The novel MTK film demonstrated significantly improved bioavailability compared to the marketed tablet in the clinical phase 1a study in healthy humans. Furthermore, there were measurable amounts of MTK present in the cerebrospinal fluid (CSF) at the 3.0 and 7.0 hour time points post drug administration in humans. In mice, MTK was detected in serum and CSF after acute and chronic exposure in a dose-dependent manner.The developed mucoadhesive film of MTK represents a promising alternative for the tablet delivery. The oral film might lower the non-responder rate in patients with asthma and might be an interesting product for repurposing of MTK in other diseases. As we demonstrate BBB penetrance in a preclinical model as well as in a clinical study, the oral film of MTK might find its use as a therapeutic for acute and chronic neurodegenerative diseases such as dementias and stroke.
Molecular Elucidation of Pancreatic Elastase Inhibition by Baicalein
Authors: Ghosh Debajeet , Bansode Sneha , Joshi Rakesh , Kolte Baban , Gacche Rajesh 
Published: November 2020

ABSTRACTThe serine protease, elastase exists in various forms and plays diverse roles in the human body. Pharmacological inhibition of elastase has been investigated for its therapeutic role in managing conditions such as diabetes, pneumonia and arthritis. Sivelestat, a synthetic molecule, is the only elastase inhibitor to have been approved by any major drug regulatory authority (PMDA, in this case) – but still has failed to attain widespread clinical usage owing to its high price, cumbersome administration and obscure long-term safety profile. In order to find a relatively better-suited alternative, screening was conducted using plant flavonoids, which yielded Baicalein – a molecule that showed robust inhibition against Pancreatic Elastase inhibition (IC50: 3.53 μM). Other than having an IC50almost 1/5thof that of sivelestat’s, baicalein is also cheaper, safer and easier to administer. While Microscale thermophoresis validated baicalein-elastase interaction, enzyme-kinetic studies, molecular docking and molecular dynamic simulation revealed the mode of inhibition to be non-competitive. Baicalein exhibited binding to a distinct allosteric site on the enzyme. The current study demonstrates the elastase inhibition properties of baicalein in anin-vitroandin-silicoenvironment.
“Tracking the Rain Bird”: Modeling the monthly distribution of Pied cuckoo in India
Authors: Sarkar Debanjan , Tomar Bharti , Kumar R. Suresh , Saran Sameer , Talukdar Gautam 
Published: November 2020

AbstractPied cuckooClamator jacobinus(Boddart, 1783) is a migratory, brood-parasitic bird found in the African and Indian Subcontinent. Although the southern Indian population is presumably resident, the North Indian Population migrates from Africa to India during the summer. The arrival of the bird is linked to the onset of monsoon in India from scientific literature to folklore. It is known to make its appearance in central and northern India in the last week of May or early June, indicating the imminent arrival of the monsoon with its unmistakably loud metallic calls. There have been few attempts to compile relevant information on the species migration in the early 1900s and citizen science approach by Bird-count India; little information is available on how environmental factors might be affecting its migration. Here, we have used Maximum Entropy modeling to identify the monthly and seasonal distribution patterns and major bioclimatic factors that might be influencing the distribution of the species in India. We have used E-Bird citizen science platform data, seven bioclimatic variables, and monthly NDVI of respective months for building the models. The predicted output shows the species presence throughout the year in southern India. In contrast, in northern India, the distribution is dynamic, peaking in summers in the Month of May-June and no presence in winter. The influence of bioclimatic variables used in SDM varied monthly; Water vapor pressure was the primary contributing variable in the months prior to species arrival. In July, it was NDVI (Higher NDVI suggests abundance of food resources for the species). In August-September, Windspeed and water vapor pressure (Factors might be responsible for the departure of the species) have contributed highest. Our approach provides a more concise understanding of Pied cuckoo’s monthly distributions throughout India, which helps understand the complex seasonal shifts in the distribution of such migratory birds.
Liver environment-imposed constraints diversify movement strategies of liver-localized CD8 T cells
Authors: Rajakaruna Harshana , O’Connor James , Cockburn Ian A. , Ganusov Vitaly V. 
Published: November 2020

AbstractPathogen-specific CD8 T cells face the problem of finding rare cells that present their cognate antigen either in the lymph node or infected tissue. While quantitative details of T cell movement strategies in some tissues such lymph nodes or skin have been relatively well characterized, we still lack quantitative understanding of T cell movement in many other important tissues such as the spleen, lung, liver, and gut. Furthermore, how environmental constraints influence movement patterns of T cells in tissues remains incompletely characterized. Liver is one of the major organs in mice and humans and is the target site for many pathogens such as hepatitis B and C viruses in humans andPlasmodiumparasites in multiple mammalian species. We developed a protocol to generate stable numbers of liver-located CD8 T cells, used intravital microscopy to record movement patterns of CD8 T cells in livers of live mice, and analyzed these and previously published data using well-established statistical and computational methods. We show that in most of our experimentsPlasmodium-specific liver-localized CD8 T cells perform correlated random walks characterized by transiently superdiffusive displacement with persistence times of 10-15 min that exceed those observed for T cells in lymph nodes. Liver-localized CD8 T cells typically crawl on the lumenal side of liver sinusoids (i.e., are in the blood); simulating T cell movement in digital structures derived from the liver sinusoids illustrates that liver structure alone is sufficient to explain the relatively long superdiffusive displacement of T cells. In experiments when CD8 T cells in the liver poorly attach to the sinusoids (e.g., one week post immunization with radiation-attenuatedPlasmodiumsporozoites) T cells also undergo Levy flights – large displacements occurring due to cell deattaching from the endothelium, floating with the blood flow, and re-attaching at another location. Our analysis, thus, provides quantitative details of movement patterns of liver-localized CD8 T cells and illustrates how structural and physiological details of the tissue may impact T cell movement patterns.
Landscape analysis of escape variants identifies SARS-CoV-2 spike mutations that attenuate monoclonal and serum antibody neutralization
Authors: Liu Zhuoming , VanBlargan Laura A. , Bloyet Louis-Marie , Rothlauf Paul W. , Chen Rita E. , Stumpf Spencer , Zhao Haiyan , Errico John M. , Theel Elitza S. , Liebeskind Mariel J. , Alford Brynn , Buchser William J. , Ellebedy Ali H. , Fremont Daved H. , Diamond Michael S. , Whelan Sean P. J. 
Published: November 2020

ABSTRACTAlthough neutralizing antibodies against the SARS-CoV-2 spike (S) protein are a goal of COVID-19 vaccines and have received emergency use authorization as therapeutics, viral escape mutants could compromise their efficacy. To define the immune-selected mutational landscape in S protein, we used a VSV-eGFP-SARS-CoV-2-S chimeric virus and 19 neutralizing monoclonal antibodies (mAbs) against the receptor-binding domain (RBD) to generate 50 different escape mutants. The variants were mapped onto the RBD structure and evaluated for cross-resistance to mAbs and convalescent human sera. Each mAb had a unique resistance profile, although many shared residues within an epitope. Some variants (e.g., S477N) were resistant to neutralization by multiple mAbs, whereas others (e.g., E484K) escaped neutralization by convalescent sera, suggesting some humans induce a narrow repertoire of neutralizing antibodies. Comparing the antibody-mediated mutational landscape in S with sequence variation in circulating SARS-CoV-2, we define substitutions that may attenuate neutralizing immune responses in some humans.
Knockdown of LC3 increases mitochondria-to-micronucleus transition
Authors: Hou Bolin , Li Erwei , Huang Haiwen , Yang Huaiyi , Xi Zhijun , Jiang Xuejun 
Published: November 2020

AbstractNuclear-localized mitochondria were discovered over sixty years ago1; however, the function of these organelles in the initiation of nuclear formation and development remains unknown. Here, we showed that mitochondria fragmented into dense particles to initiate and develop a nucleus, and multiple nuclei were separately and simultaneously formed by fragmented mitochondria in a single cell. The combination of nuclei individually constructed by the mitochondrial assembly of dense particles for nuclear transition partitioned the cytoplasm to form an intranuclear inclusion (INC), whose formation was not related to herniation or invagination of the cytoplasm. During nuclear conversion of itself and neighbouring organelles, the mitochondrion was incorporated into the nucleus to become a nuclear mitochondrion. Knockdown of microtubule-associated protein light chain 3 (LC3), a key autophagic protein, increased free micronuclei by delaying nuclear fusion and enhancing the mitochondria-to-micronuclei transition.
Variability of Accessory Proteins Rules the SARS-CoV-2 Pathogenicity
Authors: Hassan Sk. Sarif , Choudhury Pabitra Pal , Uversky Vladimir N. , Dayhoff Guy W. , Aljabali Alaa A. A. , Uhal Bruce D. , Lundstrom Kenneth , Rezaei Nima , Seyran Murat , Pizzol Damiano , Adadi Parise , Lal Amos , Soares Antonio , Abd El-Aziz Tarek Mohamed , Kandimalla Ramesh , Tambuwala Murtaza , Azad Gajendra Kumar , Sherchan Samendra P. , Baetas-da-Cruz Wagner , Takayama Kazuo , Serrano-Aroca Ángel , Chauhan Gaurav , Palu Giorgio , Brufsky Adam M. 
Published: November 2020

AbstractThe coronavirus disease 2019 (COVID-19) is caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) which is pandemic with an estimated fatality rate less than 1% is ongoing. SARS-CoV-2 accessory proteins ORF3a, ORF6, ORF7a, ORF7b, ORF8, and ORF10 with putative functions to manipulate host immune mechanisms such as interferons, immune signaling receptor NLRP3 (NOD-, LRR-, and pyrin domain-containing 3) inflammasome, inflammatory cytokines such as interleukin 1β(IL-1β) are critical in COVID-19 pathology. Outspread variations of each of the six accessory proteins of all complete proteomes (available as of October 26, 2020, in the National Center for Biotechnology Information depository) of SARS-CoV-2, were observed across six continents. Across all continents, the decreasing order of percentage of unique variations in the accessory proteins was found to be ORF3a>ORF8>ORF7a>ORF6>ORF10>ORF7b. The highest and lowest unique variations of ORF3a were observed in South America and Oceania, respectively. This finding suggests that the wide variations of accessory proteins seem to govern the pathogenicity of SARS-CoV-2, and consequently, certain propositions and recommendations can be made in the public interest.
βPix sequesters IDOL and prevents LDL receptor degradation through a β2AR-regulated signaling pathway in Alport Syndrome
Authors: Chahdi Ahmed , Yousefi Keyvan , Capcha Jose Manuel Condor , Irion Camila Iansen , Lambert Guerline , Shehadeh Serene A. , Dunkley Julian C. , Lee Yee-Shuan , Khan Aisha , Ramic Melina , Andrade Nadja S. , Zeier Zane , Dykxhoorn Derek M. , Katsoufis Chryso Pefkaros , Freundlich Michael , Hare Joshua M. , Nabity Mary , Rivera Carolina , Lymperopoulos Anastasios , Shehadeh Lina A. 
Published: November 2020

ABSTRACTAlport syndrome (AS) is a rare disease of the glomerular basement membrane type IV collagen causing progressive renal failure. We reported increased accumulation of low-density lipoprotein (LDL) receptor (LDLR) and subsequent LDL cholesterol (LDL-C) uptake in renal tubular epithelial cells (TEC) in Alport mice, but the mechanisms regulating LDLR stability and function remain unknown. Here, we show that a selective β2-Adrenoceptor (β2AR) agonist, salbutamol, decreased LDLR levels and LDL-C uptake in Alport kidneys accompanied with reduced albuminuria and improved cardiac systolic and diastolic function. Similarly, salbutamol decreased LDL-C uptake in HK2 and HEK293 human renal epithelial cell lines, in smooth muscle cells from an X-linked hereditary nephropathy dog model (a large animal model of AS), and in TECs differentiated from AS patient-derived iPSCs. We show that the Rac1/Cdc42 guanine nucleotide exchange factor β1Pix blocked β2AR-induced LDLR degradation and, hence, increased LDL-C uptake. β1Pix also abrogated ubiquitination and degradation of LDLR induced by the inducible degrader of the LDLR (IDOL), an E3 ubiquitin ligase that promotes lysosomal LDLR ubiquitination and degradation. We identify a multimolecular complex comprised of βPix, IDOL, and LDLR and demonstrate that βPix counteracts β2AR-mediated LDLR degradation by sequestering IDOL. Our findings show βPix acts as a significant post-transcriptional regulator of IDOL-mediated LDLR degradation and identify β2AR activation as a potential treatment for Alport pathology.
Phosphorylation of the canonical histone H2A marks foci of damaged DNA in malaria parasites
Authors: Goyal Manish , Heinberg Adina , Mitesser Vera , Kandelis-Shalev Sofia , Singh Brajesh Kumar , Dzikowski Ron 
Published: November 2020

AbstractPlasmodium falciparumparasites proliferate within circulating red blood cells and are responsible for the deadliest form of human malaria. These parasites are exposed to numerous intrinsic and external sources that could cause DNA damage, therefore, they have evolved efficient mechanisms to protect their genome integrity and allow them to proliferate in such conditions. In higher eukaryotes, double strand breaks rapidly lead to phosphorylation of the core histone variant H2A.X which marks the site of damaged DNA. We show that inP. falciparumthat lacks the H2A.X variant, the canonical PfH2A is phosphorylated on serine 121 upon exposure to sources of DNA damage in a dose dependent manner. We further demonstrate that phosphorylated PfH2A is recruited to foci of damaged chromatin shortly after exposure to sources of damage, while the non-phosphorylated PfH2A remains spread throughout the nucleoplasm. In addition, we found that PfH2A phosphorylation is dynamic and as the parasite repairs its DNA over time, this phosphorylation is removed. We also demonstrate that these phosphorylation dynamics could be used to establish a novel and direct DNA repair assay inP. falciparum.ImportancePlasmodium falciparumis the deadliest human parasite that causes malaria when it reaches the blood stream and begins proliferating inside red blood cells where the parasites are particularly prone to DNA damage. The molecular mechanisms that allow these pathogens to maintain their genome integrity under such condition are also the driving force for acquiring genome plasticity that enable them to create antigenic variation and become resistant to essentially all available drugs. However, mechanisms of DNA damage response and repair have not been extensively studied in these parasites. The paper addresses our recent discovery, thatP. falciparumthat lacks the histone variant H2A.X, phosphorylates its canonical core histone PfH2A in response to exposure to DNA damage. The process of DNA repair in Plasmodium was mostly studied indirectly. Our findings enabled us to establish a direct DNA repair assay forP. falciparumsimilar to assays that are widely used in model organisms.