bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human iPSC-based neurodevelopmental models of globoid cell leukodystrophy uncover patient- and cell type-specific disease phenotypes
Authors: Mangiameli Elisabeth , Cecchele Anna , Morena Francesco , Sanvito Francesca , Matafora Vittoria , Cattaneo Angela , Della Volpe Lucrezia , Gnani Daniela , Paulis Marianna , Susani Lucia , Martino Sabata , Di Micco Raffaella , Bachi Angela , Gritti Angela 
Published: March 2020

SummaryGloboid Cell Leukodystrophy (GLD, or Krabbe disease) is a rare lysosomal storage disease caused by inherited deficiency of β-galactocerebrosidase (GALC). The build-up of galactosylsphingosine (psychosine) and other undegraded galactosylsphingolipids in the nervous system causes severe demyelination and neurodegeneration. The molecular mechanisms of GLD are poorly elucidated in neural cells and whether murine systems recapitulate critical aspects of the human disease is still to be defined.Here, we established a collection of GLD patient-specific induced pluripotent stem cell (iPSC) lines. We differentiated iPSCs from two patients (bearing different disease-causing mutations) into neural progenitors cells (NPCs) and their neuronal/glial progeny, assessing the impact of GALC deficiency and lentiviral vector-mediated GALC rescue/overexpression by means of phenotypic, biochemical, molecular, and lipidomic analysis. We show a progressive increase of psychosine during the differentiation of GLD NPCs to neurons and glia. We report an early and persistent impairment of oligodendroglial and neuronal differentiation in GLD cultures, with peculiar differences observed in the two GLD lines. GLD cells display a global unbalance of lipid composition during the iPSC to neural differentiation and early activation of cellular senescence, depending on the disease-causing mutation. Restoration of GALC activity normalizes the primary pathological hallmarks and partially rescues the differentiation program of GLD NPCs.Our results suggest that multiple mechanisms besides psychosine toxicity concur to CNS pathology in GLD and highlight the need of a timely regulated GALC expression for proper lineage commitment and differentiation of human NPCs. These findings have important implications for establishing tailored gene therapy strategies to enhance disease correction in GLD.
Fast eco-evolutionary changes in bacterial genomes after anthropogenic perturbation
Authors: García-Ulloa Manuel , Escalante Ana Elena , Letelier Alejandra Moreno , Eguiarte Luis Enrique , Souza Valeria 
Published: March 2020

AbstractAnthropogenic perturbations such as water overexploitation introduce novel selective pressures to the natural environments, impacting on the genomic variability of organisms and thus altering the evolutionary trajectory of its populations. Bad agricultural practices and defective policies in Cuatro Cienegas, Coahuila, Mexico, have strongly impacted its water reservoir, pushing entire hydrological systems to the brink of extinction together with their native populations. Here, we studied the effects of continuous water overexploitation on an environmental aquatic lineage ofPseudomonas otitidis, inhabitant to a particularly affected lagoon of an exhaustively studied system in the middle of the desert, over a 13 year period which encompasses three desiccation events. By comparing the genomes of a population sample from 2003 (original state) and 2015 (perturbed state), we analyzed the demographic history and evolutionary response of this bacterial lineage to the perturbation. Through coalescent simulations, we obtained a demographic model of contraction-expansion-contraction which, alongside an increment in mean Tajima’sDand recombination rate, loss of genetic and nucleotidic variation and a single amino acid under positive selection, points the occurrence of an evolutionary rescue event, possibly potentiated by horizontal gene transfer, where the population nearly went extinct during the first desiccation event but sharply recovered in the second and adapted to its new environment. Furthermore, the gain of phosphorylation, DNA recombination and small-molecule metabolism and loss of biosynthetic and regulation genes on the exclusive accessory genome suggest a functional shift to a more generalist scavenger lifestyle in an environment that went from oligotrophic to nutrient-rich.
100,000 years of gene flow between Neandertals and Denisovans in the Altai mountains
Authors: Peter Benjamin M 
Published: March 2020

Summary paragraphThe Siberian Altai mountains have been intermittently occupied by both Neandertals and Denisovans, two extinct hominin groups1,2. While they diverged at least 390,000 years ago3,4, later contacts lead to gene flow from Neandertals into Denisovans5,6. Using a new population genetic method that is capable of inferring signatures of admixture from highly degraded genetic data, I show that this gene flow was much more widespread than previously thought. While the two earliest Denisovans both have substantial and recent Neandertal ancestry, I find signatures of admixture in all archaic genomes from the Altai, demonstrating that gene flow also occurred from Denisovans into Neandertals. This suggests that a contact zone between Neandertals and Denisovan populations persisted in the Altai region throughout much of the Middle Paleolithic. In contrast, Western Eurasian Neandertals have little to no Denisovan ancestry. As I find no evidence of natural selection against gene flow, this suggests that neutral demographic processes and geographic isolation were likely major drivers of human differentiation.
A review of models of natural pest control: toward predictions across agricultural landscapes
Authors: Alexandridis Nikolaos , Marion Glenn , Chaplin-Kramer Rebecca , Dainese Matteo , Ekroos Johan , Grab Heather , Jonsson Mattias , Karp Daniel S. , Meyer Carsten , O’Rourke Megan E. , Pontarp Mikael , Poveda Katja , Seppelt Ralf , Smith Henrik G. , Martin Emily A. , Clough Yann 
Published: March 2020

AbstractNatural control of crop pests has the potential to complement or replace intensive agricultural practices, but its mainstream application requires reliable predictions in diverse socioecological settings. In lack of a widely accepted model of natural pest control, we review existing modelling approaches and critically examine their potential to provide understanding and predictions across agricultural landscapes. Models that explicitly represent the underlying mechanisms are better positioned to represent the diversity and context sensitivity of natural pest control than correlative models. Such mechanistic models have used diverse techniques to represent crop-pest-enemy combinations at various spatiotemporal scales. However, certain regions of the world and socioeconomic aspects of natural pest control are underrepresented, while modelling approaches are restricted by a fundamental trade-off between generality and realism. We propose that modelling natural pest control across agroecosystems requires a framework of context-specific generalizations, based on empirical evidence and theoretical expectations. Reviewed models of natural pest control indicate potential attributes of such a general predictive framework.
Precursor peptide-targeted mining of more than one hundred thousand genomes expands the lanthipeptide natural product family
Authors: Walker Mark C. , Mitchell Douglas A. , van der Donk Wilfred A. 
Published: March 2020

AbstractBackgroundLanthipeptides belong to the ribosomally synthesized and post-translationally modified peptide group of natural products and have a variety of biological activities ranging from antibiotics to antinociceptives. These peptides are cyclized through thioether crosslinks and can bear other secondary post-translational modifications. While lanthipeptide biosynthetic gene clusters can be identified by the presence of characteristic enzymes involved in the post-translational modification of these peptides, locating the precursor peptides encoded within these clusters is challenging due to their short length and high sequence variability, which limits the high-throughput exploration of lanthipeptide precursor peptides. To address this challenge, we enhanced the predictive capabilities of Rapid ORF Description & Evaluation Online (RODEO) to identify all known classes of lanthipeptides.ResultsUsing RODEO, we mined over 100,000 bacterial and archaeal genomes in the RefSeq database. We identified nearly 8,500 lanthipeptide precursor peptides. These precursor peptides were identified in a broad range of bacterial phyla as well as the Euryarchaeota phylum of archaea. Bacteroidetes were found to encode a large number of these biosynthetic gene clusters, despite making up a relatively small portion of the genomes in this dataset. While a number of these precursor peptides are similar to those of previously characterized lanthipeptides, even more were not, including potential antibiotics. Additionally, examination of the biosynthetic gene clusters revealed enzymes that install secondary post-translational modifications are more widespread than initially thought.ConclusionLanthipeptide biosynthetic gene clusters are more widely distributed and the precursor peptides encoded within these clusters are more diverse than previously appreciated, demonstrating that the lanthipeptide sequence-function space remains largely underexplored.
Functional Changes Induced by Short Term Caloric Restriction in Cardiac and Skeletal Muscle Mitochondria
Authors: Serna Julian David C. , Caldeira da Silva Camille C. , Kowaltowski Alicia J. 
Published: March 2020

AbstractCaloric restriction (CR) is widely known to increase life span and resistance against different types of injuries in several organisms. We have previously shown that mitochondria from livers or brains of CR animals exhibit higher calcium uptake rates and lower sensitivity to calcium-induced mitochondrial permeability transition (mPT), an event related to the resilient phenotype exhibited by these organs. Given the importance of calcium in metabolic control and cell homeostasis, we aimed here to uncover possible changes in mitochondrial calcium handling, redox balance and bioenergetics in cardiac and skeletal muscle mitochondria. Unexpectedly, we found that CR does not alter the susceptibility to mPT in muscle (cardiac or skeletal), nor calcium uptake rates. Despite the lack in changes in calcium transport properties, CR consistently decreased respiration in the presence of ATP synthesis in heart and soleus muscle. In heart, such changes were accompanied by a decrease in respiration in the absence of ATP synthesis, lower maximal respiratory rates and a reduced rate of hydrogen peroxide release. Hydrogen peroxide release was unaltered by CR in skeletal muscle. No changes were observed in inner membrane potentials and respiratory control ratios. Together, these results highlight the tissue-specific bioenergetic and ion transport effects induced by CR, demonstrating that resilience against calcium-induced mPT is not present in all tissues.
AuthentiCT: a model of ancient DNA damage to estimate the proportion of present-day DNA contamination
Authors: Peyrégne Stéphane , Peter Benjamin M. 
Published: March 2020

ABSTRACTSummaryContamination from present-day DNA is a fundamental issue when studying ancient DNA from historical or archaeological material, and quantifying the amount of contamination is essential for downstream analyses. We present AuthentiCT, a command-line tool to estimate the proportion of present-day DNA contamination in ancient DNA datasets generated from single-stranded DNA libraries. The prediction is based solely on the patterns of post-mortem damage observed on ancient DNA sequences. The method has the power to quantify contamination from as few as 10,000 mapped sequences, making it particularly useful for analysing specimens that are poorly preserved or for which little data is available.Contactstephane.peyregne@gmail.com
Identifying priority connectivity in a tropical forest hotspot severely affected by land use changes
Authors: de Oliveira-Junior Neil Damas , Heringer Gustavo , Bueno Marcelo Leandro , Pontara Vanessa , Meira-Neto João Augusto Alves 
Published: March 2020

AbstractThe probability that a propagule reaches a certain location where it can establish and persist is affected by the distance from the source. Fragmented landscapes often promote the isolation of habitats that hinder or impede the movement of species that affect their range distribution, even when environmental conditions are adequate. Studies that assess the connectivity of the landscape are essential to ensure that ecological conservation planning covers all vital processes that occur on a landscape scale. Based on the classification of land cover in the Rio Doce Basin - RDB, we used a habitat / non-habitat approach to assess RDB connectivity for tree species. Based on circuit theory, we built 6 surface models of resistance based on habitat and non-habitat areas. We performed the analysis using the GIS plug-in and Linkage Mapper to generate lest cost path maps. The RDB is very fragmented, but still has functionally connected regions. The west to nothwestern and southeastern portions of the basin are well-connected and demand conservation practices, while the center-north of the basin and the far southwest are regions with greater resistance to connectivity as a result of strong anthropic pressures that reduce forests, requiring intervention through restoration projects avoiding loss due to lack of connectivity. In addition, land reclamation projects in degraded areas must also be organized in the Linhares region, as it is inserted in a region of very high biodiversity with a high level of endemism and a high number of threatened species.
A novel HER2-targeted antibody-drug conjugate offers the possibility of clinical dosing at trastuzumab-equivalent exposure levels
Authors: Barfield Robyn M. , Kim Yun Cheol , Chuprakov Stepan , Zhang Fangjiu , Bauzon Maxine , Ogunkoya Ayodele O. , Yeo Dominick , Hickle Colin , Pegram Mark D. , Rabuka David , Drake Penelope M. 
Published: March 2020

AbstractTrastuzumab and the related antibody-drug conjugate (ADC), ado-trastuzumab emtansine (T-DM1), both target HER2-overexpressing cells. Together, these drugs have treatment indications in both early-stage and metastatic settings for HER2+ breast cancer. T-DM1 retains the antibody functionalities of trastuzumab and adds the potency of a cytotoxic maytansine payload. Interestingly, in the clinic, T-DM1 cannot always replace the use of trastuzumab plus chemotherapy administered together as single agents. We hypothesize that this failure may be due in part to the limited systemic exposure achieved by T-DM1 relative to trastuzumab because of toxicity-related dosing constraints on the ADC. We have developed a trastuzumab-based ADC site-specifically conjugated to maytansine through a noncleavable linker. This construct, termed CAT-01-106, has a drug-to-antibody ratio (DAR) of 1.8, approximately half the average DAR of T-DM1, which comprises a mixture of antibodies variously conjugated with DARs ranging from 0-8. The high DAR species present in T-DM1 contribute to its toxicity and limit its clinical dose. CAT-01-106 showed superior in vivo efficacy compared to T-DM1 at equal payload dosing and was equally or better tolerated compared to T-DM1 at equal payload dosing up to 120 mg/kg in Sprague-Dawley rats and 60 mg/kg in cynomolgus monkeys. CAT-01-106 also showed improved pharmacokinetics in rats relative to T-DM1, with 40% higher ADC exposure levels. Together, the data suggest that CAT-01-106 may be sufficiently tolerable to enable clinical dosing at trastuzumab-equivalent exposure levels, combining the functions of both the antibody and the payload in one drug and potentially improving patient outcomes.
Menthol in Electronic Cigarettes: A Contributor to Respiratory Disease?
Authors: Nair Vijayalekshmi , Tran Malcolm , Behar Rachel Z. , Zhai Song , Cui Xinping , Phandthong Rattapol , Wang Yuhuan , Pan Songqin , Luo Wentai , Pankow James F. , Volz David C. , Talbot Prue 
Published: March 2020

SUMMARYMenthol is widely used in tobacco products. This study compared the effects of menthol on human bronchial epithelium using submerged cultures, a VITROCELL® cloud chamber that provides air liquid interface (ALI) exposure without solvents or heating, and a Cultex ALI system that delivers aerosol equivalent to that inhaled during vaping. In submerged culture, menthol significantly increased calcium influx and mitochondrial reactive oxygen species (ROS) via the TRPM8 receptor, responses that were inhibited by a TRPM8 antagonist. VITROCELL® cloud chamber exposure of BEAS-2B monolayers increased mitochondrial protein oxidation, expression of the antioxidant enzyme SOD2, activation of NF-κB, and secretion of inflammatory cytokines (IL-6 and IL-8). Proteomics data collected following ALI exposure of 3D EpiAirway tissue in the Cultex showed upregulation of NRF-2-mediated oxidative stress, oxidative phosphorylation, and IL-8 signaling. Across the three platforms, menthol adversely effected human bronchial epithelium in a manner that could lead to respiratory disease.Graphical Abstract. Mechanism of action of menthol on human bronchial epithelium.Threein vitroplatforms were used to study the effect of menthol on bronchial epithelium. In submerged culture (using BEAS-2B cells), menthol produced rapid calcium influx followed by an increase in oxidative stress and inflammatory cytokines. ALI exposure of BEAS-2B cells to unheated menthol in a cloud chamber caused activation of an inflammatory transcription factor (NF-κB) and oxidative stress. Proteomics analysis of human EpiAirway tissues exposed at the ALI to heated menthol EC aerosols identified changes in the expression of proteins involved in oxidative stress and in an inflammatory response.
JNK signaling regulates oviposition in the malaria vectorAnopheles gambiae
Authors: Peirce Matthew J. , Mitchell Sara N. , Kakani Evdoxia G. , Scarpelli Paolo , South Adam , Shaw W. Robert , Werling Kristine L. , Gabrieli Paolo , Marcenac Perrine , Bordoni Martina , Talesa Vincenzo , Catteruccia Flaminia 
Published: March 2020

ABSTRACTThe reproductive fitness of theAnopheles gambiaemosquito represents a promising target to prevent malaria transmission. The ecdysteroid hormone 20-hydroxyecdysone (20E), transferred from male to female during copulation, is key toAn. gambiaereproductive success as it licenses females to oviposit eggs developed after blood feeding. Here we show that 20E-triggered oviposition in these mosquitoes is regulated by the stress- and immune-responsive c-Jun N-terminal kinase (JNK). The heads of mated females exhibit a transcriptional signature reminiscent of a JNK-dependent wounding response while mating — or injection of virgins with exogenous 20E — selectively activates JNK in the same tissue. RNAi-mediated depletion of JNK pathway components inhibits oviposition in mated females, whereas JNK activation by silencing the JNK phosphatasepuckeredinduces egg laying in virgins. Together, these data identify JNK as a potential conduit linking stress responses and reproductive success in the most important vector of malaria.
Sex determining gene transposition as an evolutionary platform for chromosome turnover
Authors: Ayllon Fernando , Favnebøe Solberg Monica , Besnier François , Fjelldal Per Gunnar , Hansen Tom Johnny , Wargelius Anna , Edvardsen Rolf Brudvik , Glover Kevin Alan 
Published: March 2020

SummaryDespite the key role that sex-determination plays in evolutionary processes, it is still poorly understood in many species. In salmonids, which are the best studied family of fishes, the master sex-determining gene sexually dimorphic on the Y-chromosome (sdY) has been identified. However,sdYdisplays unexplained discordance to the phenotypic sex, with a variable frequency of phenotypic females being reported as genetic males. Multiple sex determining loci in Atlantic salmon have also been reported, possibly as a result of transposition, suggesting a recent and non-random sex chromosome turnover in this species. We hypothesized the existence of an autosomic pseudocopy ofsdYthat is transmitted in accordance with Mendelian inheritance. To test this we developed a qPCR methodology to detect the number ofsdYcopies present in the genome. Based on the observed phenotype/genotype frequencies and linkage analysis among 2025 offspring from 64 pedigree-controlled families of accurately phenotyped Atlantic salmon, we identified both males and females carrying one or two autosomic copies in addition to the Y-specific copy present in males. Copy number frequencies were consistent with Mendelian inheritance. Pseudocopy loci were mapped to different chromosomes evidencing non-random transitions of the sex determining gene in Atlantic salmon and the existence of functional constraints for chromosome turnover.
Effect of egg cannibalism on mating preferences and reproductive fitness ofMenochilus sexmaculatusFabricius (Coleoptera: Coccinellidae)
Authors: Yadav Tripti , Omkar  , Mishra Geetanjali 
Published: March 2020

AbstractCannibalism has been reported in a large proportion of coccinellids in fields as well as in laboratories but studies involving mate preferences and potential benefits of cannibalism on reproduction inMenochilus sexmaculatusFabricius (Coleoptera: Coccinellidae)have yet not been done. Thus, we assessed the effect of conspecific egg cannibalism on mate preferences and reproductive outputs including offspring development. Higher mate preferences were recorded for non-cannibal mates (fed onA. craccivora) than cannibal ones (fed on conspecific eggs). Mating parameters significantly influenced by cannibalism. Time to commence mating lasted less for homogeneous diet pairs than heterogeneous diet pairs. Longer copulation duration and higher fecundity were recorded when one of the individuals in mating pair or both was a non-cannibal. Egg viability did not differed significantly in all reciprocal crosses. Total developmental durations of offspring were similar for all mating pairs.
Cellular-resolution mapping uncovers spatial adaptive filtering at the cerebellum input stage
Authors: Stefano Casali , Marialuisa Tognolina , Egidio D’Angelo 
Published: March 2020

AbstractLong-term synaptic plasticity, in the form of either potentiation or depression (LTP or LTD), is thought to provide the substrate for adaptive computations in brain circuits. Although molecular and cellular processes of plasticity have been clarified to a considerable extent at individual synapses, very little is known about the spatiotemporal organization of LTP and LTD in local microcircuits. Here, we have combined multi-spot two-photon laser microscopy and realistic modeling to map the distribution of plasticity in multi-neuronal units of the cerebellar granular layer activated by stimulating an afferent mossy fiber bundle. The units, composed by ~300 active neurons connected to ~50 glomeruli, showed potentiation concentrated in the core and depression in the periphery. This plasticity was effectively accounted for by an NMDA receptor and calcium-dependent induction rule and was regulated by local microcircuit mechanisms in the inhibitory Golgi cell loops. The organization of LTP and LTD created effective spatial filters tuning the time-delay and gain of spike retransmission at the cerebellum input stage and provided a plausible basis for the spatiotemporal recoding of input spike patterns anticipated by the motor learning theory.