bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanism of cellular production and in vivo seeding effects of hexameric β-amyloid assemblies
Authors: Vrancx Céline , Vadukul Devkee M , Contino Sabrina , Suelves Nuria , D’Auria Ludovic , Perrin Florian , Van Pesch Vincent , Hanseeuw Bernard , Quinton Loïc , Kienlen-Campard Pascal 
Published: December 2020

AbstractBackgroundThe β-amyloid peptide (Aβ) plays a key role in Alzheimer’s disease. After its production by catabolism of the amyloid precursor protein (APP) through the action of presenilin 1 (PS1)- or presenilin 2 (PS2)-dependent γ-secretases, monomeric Aβ can assemble in oligomers. In a pathological context, this eventually leads to the formation of fibrils, which deposit in senile plaques. Many studies suggest that Aβ toxicity is related to its soluble oligomeric intermediates. Among these, our interest focuses on hexameric Aβ, which acts as a nucleus for Aβ self-assembly.MethodsBiochemical analyses were used to identify hexameric Aβ in a wide range of models; cell lines, cerebrospinal fluid from cognitively impaired patients and transgenic mice exhibiting human Aβ pathology (5xFAD). We isolated this assembly and assessed both its effect on primary neuron viability in vitro, and its contribution to amyloid deposition in vivo following intracerebral injection. In both cases, we used wild-type mice (C57BL/6) to mimic an environment where hexameric Aβ is present alone and 5xFAD mice to incubate hexameric Aβ in a context where human Aβ species are pre-existing. Using CRISPR-Cas9, we produced stable knockdown human cell lines for either PS1 or PS2 to elucidate their contribution to the formation of hexameric Aβ.ResultsIn WT mice, we found that neither in vitro or in vivo exposure to hexameric Aβ was sufficient to induce cytotoxic effects or amyloid deposition. In 5xFAD mice, we observed a significant increase in neuronal death in vitro following exposure to 5μM hexameric Aβ, as well as a 1.47-fold aggravation of amyloid deposition in vivo. At the cellular level, we found hexameric Aβ in extracellular vesicles and observed a strong decrease in its excretion when PS2 was knocked down by 60%.ConclusionsOur results indicate the absence of cytotoxic effects of cell-derived hexameric Aβ by itself, but its capacity to aggravate amyloid deposition by seeding other Aβ species. We propose an important role for PS2 in the formation of this particular assembly in vesicular entities, in line with previous reports linking the restricted location of PS2 in acidic compartments to the production of more aggregation-prone Aβ.
Deciphering the mystery of influenza virus A antigenic drift and immune escape
Authors: Ma Yongping , Fang Changyin 
Published: December 2020

AbstractThe biggest challenge of influenza A virus vaccine development is the constant mutation of the virus, especially the antigenic drift. Therefore, we suggest establishing a research system for upgrading of current influenza A vaccines. The most fundamental but neglected thing is to determine the immune escape mutation (IEM) map (IEMM) of 20 amino acids in linear epitope to reveal the precise mechanism of the viral immune escape. Based on this assumption, we primarily divided IEM of HA-tag linear epitope into four types according to antibody affinity by ELISA. Our aim is to attract scholars to establish of IEMM library to deal with influenza A virus mutations in the future.
De novocoding variants in theAGO1gene cause a neurodevelopmental disorder with intellectual disability
Authors: Schalk Audrey , Cousin Margot A. , Challman Thomas D. , Wain Karen E. , Powis Zöe , Minks Kelly , Trimouille Aurélien , Lasseaux Eulalie , Lacombre Didier , Angelini Chloé , Michaud Vincent , Van-Gils Julien , Spataro Nino , Ruiz Anna , Gabau Elizabeth , Stolerman Elliot , Washington Camerun , Louie Raymond J. , Lanpher Brendan C , Kemppainen Jennifer L. , Innes A. Micheil , Kooy R. Frank , Meuwissen Marije , Goldenberg Alice , Lecoquierre François , Vera Gabriella , Diderich Karin E M , Sheidley Beth Rosen , El Achkar Christelle Moufawad , Park Meredith , Hamdan Fadi F. , Michaud Jacques L. , Lewis Ann J. , Zweier Christiane , Reis André , Wagner Matias , Weigand Heike , Journel Hubert , Keren Boris , Passemard Sandrine , Mignot Cyril , van Gassen Koen L.I. , Brilstra Eva H. , Itzikowitz Gina , O’Heir Emily , Allen Jake , Donald Kirsten A. , Korf Bruce R. , Skelton Tammi , Thompson Michelle L , Robin Nathaniel H. , Rudy Natasha , Dobyns William B. , Foss Kimberly , Zarate Yuri A , Bosanko Katherine A. , Alembik Yves , Durand Benjamin , Mau-Them Frédéric Tran , Ranza Emmanuelle , Blanc Xavier , Antonarakis Stylianos E. , McWalter Kirsty , Torti Erin , Millan Francisca , Dameron Amy , Tokita Mari J. , Zimmermann Michael T. , Dsouza Nikita R. , Klee Eric W. , Piton Amélie , Gerard Bénédicte 
Published: December 2020

ABSTRACTHigh-impact pathogenic variants in more than 1,000 protein-coding genes cause Mendelian forms of neurodevelopmental disorders (NDD), including the newly reportedAGO2gene. This study describes the molecular and clinical characterization of 28 probands with NDD harboring heterozygousAGO1coding variants.De novostatus was always confirmed when parents were available (26/28). A total of 15 unique variants leading to amino acid changes or deletions were identified: 12 missense variants, two in-frame deletions of one codon, and one canonical splice variant leading to a deletion of two amino acid residues. Some variants were recurrently identified in several unrelated individuals: p.(Phe180del), p.(Leu190Pro), p.(Leu190Arg), p.(Gly199Ser), p.(Val254Ile) and p.(Glu376del).AGO1encodes the Argonaute 1 protein, which functions in gene-silencing pathways mediated by small non-coding RNAs. Three-dimensional protein structure predictions suggest that these variants might alter the flexibility of the AGO1 linkers domains, which likely would impair its function in mRNA processing. Affected individuals present with intellectual disability of varying severity, as well as speech and motor delay, autistic behavior and additional behavioral manifestations. Our study establishes thatde novocoding variants inAGO1are involved in a novel monogenic form of NDD, highly similar toAGO2phenotype.
RNA polymerase II assembly and mRNA decay regulation are mediated and interconnectedviaCTD Ser5P phosphatase Rtr1 inSaccharomyces cerevisiae
Authors: Garrido-Godino A.I. , Cuevas-Bermúdez A. , Gutiérrez-Santiago F. , Mota-Trujillo M.C. , Navarro F. 
Published: December 2020

ABSTRACTRtr1 is an RNA pol II CTD-phosphatase that influences gene expression by acting during the transition from transcription initiation to elongation, and during transcription termination. Rtr1 has been proposed as an RNA pol II import factor in RNA pol II biogenesis, and participating in mRNA decay by autoregulating the turnover of its own mRNA. In addition, the interaction of Rtr1 with RNA pol II depends on the phosphorylation state of CTD, which also influences Rpb4/7 dissociation during transcription. In this work, we demonstrate that Rtr1 acts in RNA pol II assembly, likely in a final cytoplasmic RNA pol II biogenesis step, and mediates the Rpb4 association with the rest of the enzyme, However, we do not rule out discard a role in the Rpb4 association with RNA pol II in the nucleus. This role of Rtr1 interplays RNA pol II biogenesis and mRNA decay regulation. In fact,RTR1deletion alters RNA pol II assembly and leads to the chromatin association of RNA pol II lacking Rpb4, in addition to whole RNA pol II, decreasing mRNA-Rpb4 imprinting and, consequently, increasing mRNA stability. Notably, theRPB5overexpression that overcomes RNA pol II assembly and the defect in Rpb4 binding to chromatin-associated RNA pol II partially suppresses the mRNA stability defect ofrtr1Δcells. Our data also indicate that Rtr1 mediates mRNA decay regulation more broadly than previously proposed in cooperation with Rpb4 and Dhh1. Interestingly, these data include new layers in the crosstalk between mRNA synthesis and decay.
C53 interacting with UFM1-protein ligase 1 regulates microtubule nucleation in response to ER stress
Authors: Klebanovych Anastasiya , Vinopal Stanislav , Dráberová Eduarda , Sládková Vladimíra , Sulimenko Tetyana , Sulimenko Vadym , Vosecká Věra , Macůrek Libor , Legido Agustin , Dráber Pavel 
Published: December 2020

AbstractER distribution depends on microtubules, and ER homeostasis disturbance activates the unfolded protein response resulting in ER remodeling. CDK5RAP3 (C53) implicated in various signaling pathways interacts with UFM1-protein ligase 1 (UFL1), which mediates the ufmylation of proteins in response to ER stress. Here we find that UFL1 and C53 associate with γ-tubulin ring complex proteins. Knockout ofUFL1orC53in human osteosarcoma cells induces ER stress, centrosomal microtubule nucleation accompanied by γ-tubulin accumulation and ER expansion. C53, whose protein level is modulated by UFL1, associates with the centrosome and rescues microtubule nucleation in cells lacking UFL1. Pharmacological induction of ER stress by tunicamycin also leads to increased microtubule nucleation and ER expansion. Furthermore, tunicamycin suppresses the association of C53 with the centrosome. These findings point to a novel mechanism for the relief of ER stress by stimulation of centrosomal microtubule nucleation.
Infrared spectral markers for the nephroprotective effects ofFicus deltoideain streptozotocin-induced diabetic rats
Authors: Samsulrizal Nurdiana , Yong-Meng Goh , Ahmad Hafandi , Syimal’ain Azmi Nur , Mohamad Zin Noor Syaffinaz Noor , Mahdi Ebrahimi 
Published: December 2020

AbstractFourier Transform Infrared (FTIR) is an established analytical technique to elucidate new discriminatory biomarkers. Our previous study showed thatFicus deltoidea(Ficus: Moraceae) is capable of increasing insulin secretion and improving tissue regeneration by reducing oxidative stress in diabetic rats. However, the assessment of treatment response is limited by the paucity of biomarkers. We aimed to evaluate the potential use of FTIR for assessing the nephroprotective effects ofFicus deltoidea(Ficus: Moraceae) in diabetic rats. A rat model of diabetes was induced using a single intraperitoneal injection of streptozotocin (STZ) (60 mg/kg body weight). Methanolic extract ofF. deltoideawas administered orally at a dose of 1000 mg/kg body weight for eight weeks. Fasting blood glucose, serum insulin and kidney function parameters were examined. The kidneys were subsequently subjected to FTIR and histological analyses. Enzyme-linked immunosorbent assays (ELISA) assessed the levels of oxidative stress, antioxidant, and apoptosis-related proteins in the kidney tissue. The results show, for the first time, that there is a good agreement between changes in kidney and FTIR peaks. The IR peaks (1545 cm−1and 1511 cm-1) corresponding to amide II were restored by treatment withF. deltoidea. Multivariate analysis demonstrated that the diabetic rats treated withF. deltoideahad similar clustering pattern that of the normal animals. Biochemical and histological examination further confirmed the nephroprotective effect ofF. deltoidea. Thus, demonstrating how FTIR spectroscopy could be used for the diagnosis of diabetes kidney disease.
KATK: fast genotyping of rare variants directly from unmapped sequencing reads
Authors: Kaplinski Lauris , Möls Märt , Puurand Tarmo , Pajuste Fanny-Dhelia , Remm Maido 
Published: December 2020

AbstractMotivationKATK is a fast and accurate software tool for calling variants directly from raw NGS reads. It uses predefined k-mers to retrieve only the reads of interest from the FASTQ file and calls genotypes by aligning retrieved reads locally. KATK does not use data about known polymorphisms and has NC (No Call) as default genotype. The reference or variant allele is called only if there is sufficient evidence for their presence in data. Thus it is not biased against rare variants orde novomutations.ResultsWith simulated datasets, we achieved a false negative rate of 0.23% (sensitivity 99.77%) and a false discovery rate of 0.19%. Calling all human exonic regions with KATK requires 1-2 h, depending on sequencing coverage.AvailabilityKATK is distributed under the terms of GNU GPL v3. The k-mer databases are distributed under the Creative Commons CC BY-NC-SA license. The source code is available at GitHub as part of Genometester4 package (https://github.com/bioinfo-ut/GenomeTester4/). The binaries of KATK package and k-mer databases described in the current paper are available onhttp://bioinfo.ut.ee/KATK/.
Are indigenous territories effective natural climate solutions? A neotropical analysis using matching methods and geographic discontinuity designs
Authors: Alejo Camilo , Meyer Chris , Walker Wayne S. , Gorelik Seth R. , Josse Carmen , Aragon-Osejo Jose Luis , Rios Sandra , Augusto Cicero , Llanos Andres , Coomes Oliver T. , Potvin Catherine 
Published: December 2020

AbstractIndigenous Territories (ITs) with less centralized forest governance than Protected Areas (PAs) may represent cost-effective natural climate solutions to meet the Paris agreement. However, the literature has been limited to examining the effect of ITs on deforestation, despite the influence of anthropogenic degradation. Thus, little is known about the temporal and spatial effect of allocating ITs on carbon stocks dynamics that account for losses from deforestation and degradation. Using Amazon Basin countries and Panama, this study aims to estimate the temporal and spatial effects of ITs and PAs on carbon stocks. To estimate the temporal effects, we use annual carbon density maps, matching analysis, and linear mixed models. Furthermore, we explore the spatial heterogeneity of these estimates through geographic discontinuity designs, allowing us to assess the spatial effect of ITs and PAs boundaries on carbon stocks. The temporal effects highlight that allocating ITs preserves carbon stocks and buffer losses as PAs in Panama and Amazon Basin countries. The geographic discontinuity designs reveal that ITs’ boundaries secure more extensive carbon stocks than their surroundings, and this difference tends to increase towards the least accessible areas, suggesting that indigenous land use in neotropical forests may have a temporarily and spatially stable impact on carbon stocks. Our findings imply that ITs in neotropical forests support Nationally Determined Contributions (NDCs) under the Paris Agreement. Thus, Indigenous peoples must become recipients of countries’ results-based payments.
DeterminingAspergillus fumigatustranscription factor expression and function during invasion of the mammalian lung
Authors: Liu Hong , Xu Wenjie , Bruno Vincent M. , Phan Quynh T. , Solis Norma V. , Woolford Carol A. , Ehrlich Rachel , Shetty Amol C. , McCraken Carie , Lin Jianfeng , Mitchell Aaron P. , Filler Scott G. 
Published: December 2020

AbstractTo gain a better understanding of the transcriptional response ofAspergillus fumigatusduring invasive pulmonary infection, we used a NanoString nCounter to assess the transcript levels of 467A. fumigatusgenes during growth in the lungs of immunosuppressed mice. These genes included ones known to respond to diverse environmental conditions and those encoding most transcription factors in theA. fumigatusgenome. We found that invasive growthin vivoinduces a unique transcriptional profile as the organism responds to nutrient limitation and attack by host phagocytes. Thisin vivotranscriptional response is largely mimicked byin vitrogrowth inAspergillusminimal medium that is deficient in nitrogen, iron, and/or zinc. From the transcriptional profiling data, we selected 9 transcription factor genes that were either highly expressed or strongly up-regulated duringin vivogrowth. Deletion mutants were constructed for each of these genes and assessed for virulence in mice. Two transcription factor genes were found to be required for maximal virulence. One wasrlmA,which governs the ability of the organism to proliferate in the lung. The other wasace1, which regulates of the expression of multiple secondary metabolite gene clusters and mycotoxin genes independently oflaeA. Using deletion and overexpression mutants, we determined that the attenuated virulence of the Δace1mutant is due to decreased expressionaspf1,which specifies a ribotoxin, but is not mediated by reduced expression of the fumigaclavine gene cluster or the fumagillin-pseruotin supercluster. Thus,in vivotranscriptional profiling focused on transcription factors genes provides a facile approach to identifying novel virulence regulators.Author summaryAlthoughA. fumigatuscauses the majority of cases of invasive aspergillosis, the function of most of the genes in its genome remains unknown. To identify genes encoding transcription factors that may be important for virulence, we used a NanoString nCounter to measure the mRNA levels ofA. fumigatustranscription factor genes in the lungs of mice with invasive aspergillosis. The transcriptional profiling data indicate that the organism is exposed to nutrient limitation and stress during growth in the lungs, and that it responds by up-regulating genes that encode mycotoxins and secondary metabolites.In vitro,this response was most closely mimicked by growth in medium that was deficient in nitrogen, iron and/or zinc. Using the transcriptional profiling data, we identified two transcription factors that governA. fumigatusvirulence. These were RlmA, which is governs proliferation in the lung and Ace1, which controls the production of mycotoxins and secondary metabolites.
Shared population-level dynamics in monkey premotor cortex during solo action, joint action and action observation
Authors: Pezzulo Giovanni , Donnarumma Francesco , Ferrari-Toniolo Simone , Cisek Paul , Battaglia-Mayer Alexandra 
Published: December 2020

ABSTRACTStudies of neural population dynamics of cell activity from monkey motor areas during reaching show that it mostly represents the generation and timing of motor behavior. We compared neural dynamics in dorsal premotor cortex (PMd) during the performance of a visuomotor task executed individually or cooperatively and during an observation task. In the visuomotor conditions, monkeys applied isometric forces on a joystick to guide a visual cursor in different directions, either alone or jointly with a conspecific. In the observation condition, they observed the cursor’s motion guided by the partner. We found that in PMd neural dynamics were widely shared across action execution and observation, with cursor motion directions more accurately discriminated than task types. This suggests that PMd encodes spatial aspects irrespective of specific behavioral demands. Furthermore, our results suggest that largest components of premotor population dynamics, which have previously been suggested to reflect a transformation from planning to movement execution, may rather reflect higher cognitive-motor processes, such as the covert representation of actions and goals shared across tasks that require movement and those that do not.HIGHLIGHTSIn PMd neural dynamics is shared across action execution and mere observationTask directional features are more accurately discriminated than action typesSpatial aspects are encoded in PMd independently from specific behavioral demandsPMd dynamics largely reflect higher cognitive-motor processes rather than strictly motor-related functions
Optogenetic Amplification Circuits for Light-Induced Metabolic Control
Authors: Zhao Evan M. , Lalwani Makoto A. , Chen Jhong-Min , Orillac Paulina , Toettcher Jared E. , Avalos José L. 
Published: December 2020

AbstractDynamic control of microbial metabolism is an effective strategy to improve chemical production in fermentations. While dynamic control is most often implemented using chemical inducers, optogenetics offers an attractive alternative due to the high tunability and reversibility afforded by light. However, a major concern of applying optogenetics in metabolic engineering is the risk of insufficient light penetration at high cell densities, especially in large bioreactors. Here, we present a new series of optogenetic circuits we call OptoAMP, which amplify the transcriptional response to blue light by as much as 21.8-fold compared to the basal circuit (OptoEXP). These circuits show as much as a 41-fold induction between dark and light conditions, efficient activation at light doses as low as ~1%, and strong homogeneous light-induction in bioreactors of at least 5L, with limited illumination at cell densities above 40 OD600. We demonstrate the ability of OptoAMP circuits to control engineered metabolic pathways in novel three-phase fermentations using different light schedules to control enzyme expression and improve production of lactic acid, isobutanol, and naringenin. These circuits expand the applicability of optogenetics to metabolic engineering.
Prenatal THC does not affect female mesolimbic dopaminergic system in preadolescent rats
Authors: Traccis Francesco , Serra Valeria , Sagheddu Claudia , Congiu Mauro , Saba Pierluigi , Giua Gabriele , Devoto Paola , Frau Roberto , Cheer Joseph Francois , Melis Miriam 
Published: December 2020

AbstractCannabis use among pregnant women is increasing worldwide along with permissive sociocultural attitudes towards it. Prenatal cannabis exposure (PCE), however, is associated with adverse outcome among offspring ranging from reduced birth weight to child psychopathology. We have previously shown that male rat offspring prenatally exposed to Δ9-tetrahydrocannabinol (THC), a rat model of PCE, exhibit extensive molecular, cellular and synaptic changes in dopamine neurons of the ventral tegmental area (VTA), resulting in a susceptible mesolimbic dopamine system associated with a psychotic-like endophenotype. This phenotype only reveals itself upon a single exposure to THC in males but not females. Here, we characterized the impact of PCE on female behaviors and mesolimbic dopamine system function by combining in vivo single-unit extracellular recordings in anesthetized animals and ex vivo patch clamp recordings, along with neurochemical and behavioral analyses. We find that PCE female offspring do not show any spontaneous or THC-induced behavioral disease-relevant phenotypes. The THC-induced increase of dopamine levels in nucleus accumbens was reduced in PCE female offspring, even when VTA dopamine activity in vivo and ex vivo did not differ compared to control. These findings indicate that PCE impacts mesolimbic dopamine function and its related-behavioral domains in a sex-dependent manner and warrant further investigations to decipher the mechanisms determining this sex-related protective effect from intrauterine THC exposure.HighlightsPCE female offspring do not manifest a disease-relevant phenotypePrenatal THC does not affect female dopaminergic neuronsPCE female mesolimbic dopamine function is less responsive to acute THC