bluuebunny/crossref_metadata_2025 huggingface dataset:
Phenotypes to remember: Evolutionary developmental memory capacity and robustness
Authors: Szilágyi András , Szabó Péter , Santos Mauro , Szathmáry Eörs
Published: May 2020

There is increased awareness of the possibility of developmental memories resulting from evolutionary learning. Genetic regulatory and neural networks can be modelled by analogous formalism raising the important question of productive analogies in principles, processes and performance. We investigate the formation and persistence of various developmental memories of past phenotypes asking how the number of remembered past phenotypes scales with network size, to what extent memories stored form by Hebbian-like rules, and how robust these developmental “devo-engrams” are against networks perturbations (graceful degradation). The analogy between neural and genetic regulatory networks is not superficial in that it allows knowledge transfer between fields that used to be developed separately from each other. Known examples of spectacular phenotypic radiations could partly be accounted for in such terms.
Multimodal immersive trail making – virtual reality paradigm to study cognitive-motor interactions
Authors: Plotnik Meir , Ben-Gal Oran , Doniger Glen M. , Gottlieb Amihai , Bahat Yotam , Cohen Maya , Kimel-Naor Shani , Zeilig Gabi , Beeri Michal Schnaider
Published: May 2020

Background

Neuropsychological tests of executive function have limited real-world predictive and functional relevance. An emerging solution for this limitation is to adapt the tests for implementation in virtual reality (VR). We thus developed two VR-based versions of the classic Color-Trails Test (CTT), a well-validated pencil-and-paper executive function test assessing sustained (Trails A) and divided (Trails B) attention - one for a large-scale VR system (DOME-CTT) and the other for a portable head-mount display VR system (HMD-CTT). We then evaluated construct validity, test-retest reliability, and age-related discriminant validity of the VR-based versions and explored effects on motor function.

Methods

Healthy adults (n=147) in three age groups (young:n=50; middle-aged:n=80; older:n=17) participated. All participants were administered the original CTT, some completing the DOME-CTT (14 young, 29 middle-aged) and the rest completing the HMD-CTT. Primary outcomes were Trails A and B completion times (tA, tB). Spatiotemporal characteristics of upper-limb reaching movements during VR test performance were reconstructed from motion capture data. Statistics included correlations and repeated measures analysis of variance.

Results

Construct validity was substantiated by moderate correlations between the ‘gold standard’ pencil-and-paper CTT and the VR adaptations (DOME-CTT: tA0.58, tB0.71; HMD-CTT: tA0.62, tB0.69). VR versions showed relatively high test-retest reliability (intraclass correlation; VR: tA0.60-0.75, tB0.59-0.89; original: tA0.75-0.85, tB0.77-0.80) and discriminant validity (area under the curve; VR: tA0.70-0.92, tB0.71-0.92; original: tA0.73-0.95, tB0.77-0.95). VR completion times were longer than for the original pencil-and-paper test; completion times were longer with advanced age. Compared with Trails A, Trails B target-to-target VR hand trajectories were characterized by delayed, more erratic acceleration and deceleration, consistent with the greater executive function demands of divided vs. sustained attention; acceleration onset later for older participants.

Conclusions

The present study demonstrates the feasibility and validity of converting a neuropsychological test from two-dimensional pencil-and-paper to three-dimensional VR-based format while preserving core neuropsychological task features. Findings on the spatiotemporal morphology of motor planning/execution during the cognitive tasks may lead to multimodal analysis methods that enrich the ecological validity of VR-based neuropsychological testing, representing a novel paradigm for studying cognitive-motor interactions.
Rapid toxin sequestration modifies poison frog physiology
Authors: O’Connell Lauren A. ,   LS50: Integrated Science Laboratory Course, O’Connell Jeremy D. , Paulo Joao A. , Trauger Sunia A. , Gygi Steven P. , Murray Andrew W.
Published: May 2020

Poison frogs sequester chemical defenses from their diet of leaf litter arthropods for defense against predation. Little is known about the physiological adaptations that confer this unusual bioaccumulation ability. We conducted an alkaloid-feeding experiment with the Diablito poison frog (Oophaga sylvatica) to determine how quickly alkaloids are accumulated and how toxins modify frog physiology using quantitative proteomics. Diablito frogs rapidly accumulated the alkaloid decahydroquinoline within four days, and dietary alkaloid exposure altered protein abundance in the intestines, liver, and skin. Many proteins that increased in abundance with decahydroquinoline accumulation are plasma glycoproteins, including the complement system and the toxin-binding protein saxiphilin. Other protein classes that change in abundance with decahydroquinoline accumulation are membrane proteins involved in small molecule transport and metabolism. Overall, this work shows poison frogs can rapidly accumulate alkaloids, which alter carrier protein abundance, initiate an immune response, and alter small molecule transport and metabolism dynamics across tissues.

Summary Statement

Poison frogs rapidly accumulate toxins, which changes abundance of proteins involved in the immune system and small molecule binding and metabolism across tissues.
Wnt Signalling Orchestrates the Immune Response and Cardiac Damage DuringTrypanosoma cruziInfection
Authors: Volpini Ximena , Ambrosio Laura Fernanda , Brajín Agustina , Brugo María Belen , Aoki María Pilar , Rivarola Hector Walter , Alfonso Fernando , Fozzatti Laura , Cervi Laura , Motran Claudia Cristina
Published: May 2020

Chagas’ cardiomyopathy is the consequence of a compromised electrical and mechanical cardiac function, with parasite persistence, unbalanced inflammation and pathological tissue remodelling, being intricately related to the myocardial aggression and the impaired function. Recent studies have shown that Wnt signalling pathways, which are important for developmental processes, play a critical role in the pathogenesis of cardiac and vascular diseases. In addition, we have reported thatTrypanosoma cruziinfection activates Wnt signalling pathways in macrophages to promote their intracellular replication, with treatment of mice with IWP-L6 (an inhibitor of the O-acyl-transferase, PORCN, responsible for the post-translational modifications necessary for Wnt proteins secretion) being able to diminish parasitaemia and tissue parasitism. Therefore, Wnt signalling may contribute to the development of Chagas’ cardiomyopathy. In this work we have evaluated the effectiveness of Wnt secretion inhibition to control the parasite replication, modulate the adaptive immune response, and prevent the development of cardiac lesions in an experimental model of chronic Chagas disease. The IWP-L6 treatment, administered toT. cruziinfected BALB/c mice in a time window during the acute phase of the infection, was able to control the parasitaemia and heart parasitism together with the amelioration of the electrical, mechanical and histopathological cardiac alterations observed in chronically infected mice. Moreover, we demonstrated that during the acute phase of the infection Wnt signalling activation contributes to promote specific Th2-type immune response and to maintain the suppressive activity of Treg cells. Our data provide evidence that inhibition of Wnt signalling during the acute phase ofT. cruziinfection controls the parasite replication, inhibits the development of parasite-prone and fibrosis-prone Th2-type immune response and prevents the development of cardiac lesions characteristics of chronic Chagas disease. Our study suggests that Wnt signalling pathway might be a potential target to prevent the development ofT. cruzi-induced cardiomyopathy.
Head-to-head comparison of four antigen-based rapid detection tests for the diagnosis of SARS-CoV-2 in respiratory samples
Authors: Weitzel Thomas , Legarraga Paulette , Iruretagoyena Mirentxu , Pizarro Gabriel , Vollrath Valeska , Araos Rafael , Munita José M. , Porte Lorena
Published: May 2020

In the context of the Covid-19 pandemic, the development and validation of rapid and easy-to-perform diagnostic methods are of high priority. We compared the performance of four rapid antigen detection tests for SARS-CoV-2 in respiratory samples. Immunochromatographic SARS-CoV-2 assays from RapiGEN, Liming bio, Savant, and Bioeasy were evaluated using universal transport medium containing naso-oropharyngeal swabs from suspected Covid-19 cases. The diagnostic accuracy was determined in comparison to SARS-CoV-2 RT-PCR. A total of 111 samples were included; 80 were RT-PCR positive. Median patients’ age was 40 years, 55% were female, and 88% presented within the first week after symptom onset. The evaluation of the Liming bio assay was discontinued due to insufficient performance. The overall sensitivity values of RapiGEN, Liming bio, and Bioeasy tests were 62.0% (CI95% 51.0–71.9), 16.7% (CI95% 10.0–26.5), and 85.0% (CI95% 75.6–91.2), respectively, with specificities of 100%. Sensitivity was significantly higher in samples with high viral loads (RapiGEN, 84.9%; Bioeasy, 100%). The study highlighted the significant heterogeneity of test performance among evaluated assays, which might have been influenced by the use of a non-validated sample material. The high sensitivity of some tests demonstrated that rapid antigen detection has the potential to serve as an alternative diagnostic method, especially in patients presenting with high viral loads in early phases of infection. This is particularly important in situations with limited access to RT-PCR or prolonged turnaround time. Further comparative evaluations are necessary to select products with high performance among the growing market of diagnostic tests for SARS-CoV-2.
PRosettaC: Rosetta based modeling of PROTAC mediated ternary complexes
Authors: Zaidman Daniel , London Nir
Published: May 2020

Proteolysis-targeting chimeras (PROTACs), which induce degradation by recruitment of an E3 ligase to a target protein, are gaining much interest as a new pharmacological modality. However, designing PROTACs is challenging. Formation of a ternary complex between the protein target, the PROTAC and the recruited E3 ligase is considered paramount for successful degradation. A structural model of this ternary complex could in principle inform rational PROTAC design. Unfortunately, only a handful of structures are available for such complexes, necessitating tools for their modeling. We developed a combined protocol that alternates between sampling of the protein-protein interaction space and the PROTAC molecule conformational space. Application of this protocol - PRosettaC - to a benchmark of known PROTAC ternary complexes results in near-native predictions, with often atomic accuracy prediction of the protein chains, as well as the PROTAC binding moieties. It allowed the modeling of a CRBN/BTK complex that recapitulated experimental results for a series of PROTACs. PRosettaC generated models may be used to design PROTACs for new targets, as well as improve PROTACs for existing targets, potentially cutting down time and synthesis efforts.
The carboxyl-termini of RAN translated GGGGCC nucleotide repeat expansions modulate toxicity in models of ALS/FTD
Authors: He Fang , Flores Brittany N. , Krans Amy , Frazer Michelle , Natla Sam , Niraula Sarjina , Adefioye Olamide , Barmada Sami J. , Todd Peter K.
Published: May 2020

An intronic hexanucleotide repeat expansion inC9ORF72causes familial and sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This repeat is thought to elicit toxicity through RNA mediated protein sequestration and repeat-associated non-AUG (RAN) translation of dipeptide repeat proteins (DPRs). We generated a series of transgenicDrosophilamodels expressing GGGGCC (G4C2) repeats either inside of an artificial intron within a GFP reporter or within the 5’ UTR of GFP placed in different downstream reading frames. Expression of 484 intronic repeats elicited minimal alterations in eye morphology, viability, longevity, or larval crawling but did trigger RNA foci formation, consistent with prior reports. In contrast, insertion of repeats into the 5’ UTR elicited differential toxicity that was dependent on the reading frame of GFP relative to the repeat. Greater toxicity correlated with a short and unstructured carboxyl terminus in the glycine-arginine (GR) RAN protein reading frame. This change in C-terminal sequence triggered nuclear accumulation of all three RAN DPRs. A similar differential toxicity and dependence on the GR carboxyl terminus was observed when repeats were expressed in rodent neurons. The presence of the native carboxyl-termini across all three reading frames was partly protective. Taken together, these findings suggest that carboxyl terminal sequences outside of the repeat region may alter the behavior and toxicity of dipeptide repeat proteins derived from GGGGCC repeats.
Clarifying the role of higher-level cortices in resolving perceptual ambiguity using Ultra High Field fMRI
Authors: Dowdle Logan , Ghose Geoffrey , Ugurbil Kamil , Yacoub Essa , Vizioli Luca
Published: May 2020

The brain is organized into distinct, flexible networks. Within these networks, cognitive variables such as attention can modulate sensory representations in accordance with moment-to-moment behavioral requirements. These modulations can be studied by varying task demands; however, the tasks employed are often incongruent with the postulated functions of a sensory system, limiting the characterization of the system in relation to natural behaviors. Here we combine domain-specific task manipulations and ultra-high field fMRI to study the nature of top-down modulations. We exploited faces, a visual category underpinned by a complex cortical network, and instructed participants to perform either a stimulus-relevant/domain-specific or a stimulus-irrelevant task in the scanner. We found that 1. perceptual ambiguity (i.e. difficulty of achieving a stable percept) is encoded in top-down modulations from higher-level cortices; 2. the right inferior-temporal lobe is active under challenging conditions and uniquely encodes trial-by-trial variability in face perception.
Metabolic pathway prediction using non-negative matrix factorization with improved precision
Authors: Basher Abdur Rahman M. A. , McLaughlin Ryan J. , Hallam Steven J.
Published: May 2020

Machine learning provides a probabilistic framework for metabolic pathway inference from genomic sequence information at different levels of complexity and completion. However, several challenges including pathway features engineering, multiple mapping of enzymatic reactions and emergent or distributed metabolism within populations or communities of cells can limit prediction performance. In this paper, we present triUMPF,triple non-negative matrix factorization (NMF) with community detection formetabolicpathway inference, that combines three stages of NMF to capture myriad relationships between enzymes and pathways within a graph network. This is followed by community detection to extract higher order structure based on the clustering of vertices which share similar statistical properties. We evaluated triUMPF performance using experimental datasets manifesting diverse multi-label properties, including Tier 1 genomes from the BioCyc collection of organismal Pathway/Genome Databases and low complexity microbial communities. Resulting performance metrics equaled or exceeded other prediction methods on organismal genomes with improved precision on multi-organismal datasets.

Availability and implementation

The software package, and installation instructions are published ongithub.com/triUMPF
Survival on a semi-arid island: submersion and desiccation tolerances of fiddler crabs from the Galapagos Archipelago
Authors: Capparelli Mariana V. , Thurman Carl L. , Choueri Paloma Gusso , Abessa Denis Moledo , Fontes Mayana Karoline , Nobre Caio Rodrigues , McNamara John Campbell
Published: May 2020

During tidal cycles, semi-terrestrial fiddler crabs are subject to alternating periods of submersion and desiccation. Here, we compare physiological and biochemical adjustments to forced submersion and desiccation in two fiddler crabs from the Galapagos archipelago: the indigenousLeptuca helleri, andMinuca galapagensis. We examine ecological distributions and habitat characteristics using transect analysis; survival after 6 h forced submersion at different salinities (0, 21 and 42 ‰S), and after 6 or 12 h desiccation challenge, including alterations in hemolymph osmolality; and, oxidative stress responses in the gills and hepatopancreas, accompanying glutathione peroxidase (GPx), glutathione S-transferase (GST) and glutathione reductase (GR) activities, and lipid peroxidase (LPO). We provide an integrated biomarker response (IBR) index for each species based on oxidative stress in each tissue and condition. Our transect study revealed thatL. hellerioccupies an intertidal niche whileM. galapagensisis supralittoral,L. helleribeing less resistant to submersion and desiccation. After 6 h submersion,L. hellerisurvived only at 21 ‰S whileM. galapagensissurvived at all salinities. Hemolymph osmolality decreased at 0 ‰S inM. galapagensis. After 6 h desiccation, osmolality decreased markedly inL. helleribut increased inM. galapagensis. Enzyme assays were not performed inL. helleriowing to high mortality on submersion/desiccation challenge. After submersion inM. galapagensis, hepatopancreas GPx activities decreased in 0 and 21 ‰S while GR activity was strongly inhibited at all salinities. Gill LPO decreased in 42 ‰S. On desiccation inL. helleri, GPx activity was inhibited in the hepatopancreas but increased in the gills. GST activity increased while LPO decreased in both tissues. After desiccation inM. galapagensis, hepatopancreas GPx activity increased. Both hepatopancreas and gill GST and GR activities and LPO were strongly inhibited. The IBR indexes forL. helleriwere highest in fresh caught crabs, driven by gill and hepatopancreas LPO. ForM. galapagensis, submersion at 21 ‰S contributed most to IBR, LPO in both tissues responding markedly.Leptuca helleriappears to be a habitat specialist adapted to a narrow set of niche dimensions whileM. galapagensissurvives over a much wider range, exhibiting little oxidative stress. The species’ physiological flexibilities and limitations provide insights into how fiddler crabs might respond to global environmental change on semi-arid islands.
Direct brain recordings identify hippocampal and cortical networks that distinguish successful versus failed episodic memory retrieval
Authors: Tan Ryan Joseph , Rugg Michael D. , Lega Bradley C.
Published: May 2020

Human data collected using noninvasive imaging techniques have established the importance of parietal regions towards episodic memory retrieval, including the angular gyrus and posterior cingulate cortex. Such regions comprise part of a putative core episodic retrieval network. In free recall, comparisons between contextually appropriate and inappropriate recall events (i.e. prior list intrusions) provide the opportunity to study memory retrieval networks supporting veridical recall, and existing findings predict that differences in electrical activity in these brain regions should be identified according to the accuracy of recall. However, prior iEEG studies, utilizing principally subdural grid electrodes, have not fully characterized brain activity in parietal regions during memory retrieval and have not examined connectivity between core recollection areas and the hippocampus or prefrontal cortex. Here, we employed a data set obtained from 100 human patients implanted with stereo EEG electrodes for seizure mapping purposes as they performed a free recall task. This data set allowed us to separately analyze activity in midline versus lateral parietal brain regions, and in anterior versus posterior hippocampus, to identify areas in which retrieval–related activity predicted the recollection of a correct versus an incorrect memory. With the wide coverage afforded by the stereo EEG approach, we were also able to examine interregional connectivity. Our key findings were that differences in gamma band activity in the angular gyrus, precuneus, posterior temporal cortex, and posterior (more than anterior) hippocampus discriminated accurate versus inaccurate recall as well as active retrieval versus memory search. The left angular gyrus exhibited a significant power decrease preceding list intrusions as well as unique phase-amplitude coupling properties, whereas the prefrontal cortex was unique in exhibiting a power increase during list intrusions. Analysis of connectivity revealed significant hemispheric asymmetry, with relatively sparse left– sided functional connections compared to the right hemisphere. One exception to this finding was elevated connectivity between the prefrontal cortex and left angular gyrus. This finding is interpreted as evidence for the engagement of prefrontal cortex in memory monitoring and mnemonic decision–making.
Were ancestral proteins less specific?
Authors: Wheeler Lucas C. , Harms Michael J.
Published: May 2020

Some have hypothesized that ancestral proteins were, on average, less specific than their descendants. If true, this would provide a universal axis along which to organize protein evolution and suggests that reconstructed ancestral proteins may be uniquely powerful tools for protein engineering. Ancestral sequence reconstruction studies are one line of evidence used to support this hypothesis. Previously, we performed such a study, investigating the evolution of peptide binding specificity for the paralogs S100A5 and S100A6. The modern proteins appeared more specific than their last common ancestor (ancA5/A6), as each paralog bound a subset of the peptides bound by ancA5/A6. In the current study, we revisit this transition, using quantitative phage display to measure the interactions of 19,194 random peptides with human S100A5, S100A6, and ancA5/A6. This unbiased screen reveals a different picture. While S100A5 and S100A6 do indeed bind to a subset of the peptides recognized by ancA5/A6, they also acquired new peptide partners outside of the set recognized by ancA5/A6. Our previous work showed that ancA5/A6 had lower specificity than its descendants when measured against biological targets; our new work shows that ancA5/A6 has similar specificity to the modern proteins when measured against a random set of peptide targets. This demonstrates that altered biological specificity does not necessarily indicate altered intrinsic specificity, and sounds a cautionary note for using ancestral reconstruction studies with biological targets as a means to infer global evolutionary trends in specificity.
Common properties of visually-guided saccadic behavior and bottom-up attention in marmoset, macaque, and human
Authors: Chen Chih-Yang , Matrov Denis , Veale Richard , Onoe Hirotaka , Yoshida Masatoshi , Miura Kenichiro , Isa Tadashi
Published: May 2020

The saccade is a stereotypic behavior whose investigation improves our understanding of how primate brains implement precise motor control. Furthermore, saccades offer an important window into the cognitive and attentional state of the brain. Historically, saccade studies have largely relied on macaque. However, the cortical network giving rise to the saccadic command is difficult to study in macaque because relevant cortical areas lie in sulci and are difficult to access. Recently, a New World monkey – the marmoset – has garnered attention as an attractive alternative to macaque because of its smooth cortical surface, its smaller body, and its amenability to transgenic technology. However, adoption of marmoset for oculomotor research has been limited due to a lack of in-depth descriptions of marmoset saccade kinematics and their ability to perform psychophysical and cognitive tasks. Here, we directly compare free-viewing and visually-guided behavior of marmoset, macaque, and human engaged in identical tasks under similar conditions. In video free-viewing task, all species exhibited qualitatively similar saccade kinematics including saccade main sequence up to 25° in amplitude. Furthermore, the conventional bottom-up saliency model predicted gaze targets at similar rates for all species. We further verified their visually-guided behavior by training them with step and gap saccade tasks. All species showed similar gap effect and express saccades in the gap paradigm. Our results suggest that the three species have similar natural and task-guided visuomotor behavior. The marmoset can be trained on saccadic tasks and thus can serve as a model for oculomotor, attention, and cognitive research.

New & noteworthy

We directly compared the results of video free-viewing task and visually-guided saccade tasks (step and gap) among three different species: the marmoset, macaque and human. We found that all species exhibit qualitatively similar saccadic behavior and bottom-up saliency albeit with small differences. Our results suggest that the marmoset possesses similar neural mechanisms to macaque and human for saccadic control, and it is an appropriate model animal to study neural mechanisms for active vision and attention.
Living apart together: modelling the consequences of the dikaryotic life cycle of mushroom-forming fungi for genomic conflict
Authors: Auxier Ben , Czaran Tamás , Aanen Duur K.
Published: May 2020

Generally, sexual organisms contain two haploid genomes, one from each parent, united in a single diploid nucleus of the zygote which links their fate during growth. A fascinating exception to this are Basidiomycete fungi, where the two haploid genomes remain separate in a dikaryon, retaining the option to fertilize subsequent monokaryons encountered. How the ensuing nuclear competition influences the balance of selection within and between individuals is largely unexplored. We test the consequences of the dikaryotic lifecycle for mating success and mycelium-level fitness components. We assume a tradeoff between mating fitness at the level of the haploid nucleus and fitness of the fungal mycelium. We show that the maintenance of fertilization potential by dikaryons leads to a higher proportion of fertilized monokaryons, but that the ensuing intra-dikaryon selection for increased nuclear mating fitness leads to reduced mycelium fitness relative to a diploid life cycle. However, this fitness reduction is lower compared to a hypothetical life cycle where dikaryons can also exchange nuclei. Prohibition of fusion between dikaryons therefore reduces the level of nuclear parasitism. The number of loci influencing fitness is an important determinant of the degree to which average mycelium-level fitness is reduced. The results of this study crucially hinge upon a tradeoff between nucleus and mycelium-level fitness. We discuss the evidence for this assumption and the implications of an alternative that there is a positive relationship between nucleus and mycelium-level fitness.
N-acetylaspartate improves cell survival when glucose is limiting
Authors: Alkan H. Furkan , Walter Katharina E. , Hackl Hubert , Vander Heiden Matthew G. , Madl Tobias , Bogner-Strauss Juliane G.
Published: May 2020

N-acetylasparate (NAA), previously considered a brain-specific metabolite, is found in several cancers. However, whether it plays a role in tumor growth or survival is not fully understood. We provide evidence that NAA prevents cell death in low-glucose conditions via sustaining intracellular UDP-N-acetylglucosamine (UDP-GlcNac) levels, suppressing endoplasmic reticulum (ER) stress, and enabling continued protein synthesis. NAA production is critical forin vivotumor growth where lower glucose levels are present than those in cell culture. Furthermore, the breakdown of NAA leads to ER stress and cell death, suggesting that the role of NAA in low-glucose is independent of its catabolism to produce aspartate or acetate. Together, these data suggest NAA can support the growth of some tumors by helping them cope with glucose limitationsin vivo.

Highlights

Endogenous N-acetylaspartate (NAA) production boosts tumor growth

NAA supports cell survival in low glucose via suppressing ER stress

Breaking down NAA limits tumor growth and induces ER stressin vivo

The role of NAA to rescue low glucose is independent of donating acetate or aspartate

In brief

Cancer cells need N-acetylaspartate to avoid ER stress and cell death when glucose availability is low.
Chronic Perinatal Hypoxia Delays Cardiac Maturation in a Mouse Model for Cyanotic Congenital Heart Disease
Authors: Romanowicz Jennifer , Dhari Zaenab , Guerrelli Devon , Mulvany Colm , Reilly Marissa , Swift Luther , Vasandani Nimisha , Ramadan Manelle , Ishibashi Nobuyuki , Posnack Nikki Gillum
Published: May 2020

Background

Compared to acyanotic congenital heart disease (CHD), cyanotic CHD has an increased risk of lifelong mortality and morbidity. These adverse outcomes may be attributed to delayed cardiomyocyte maturation, since the transition from a hypoxic fetal milieu to oxygen rich postnatal environment is disrupted. We established a rodent model to replicate hypoxic myocardial conditions spanning perinatal development, and tested the hypothesis that chronic hypoxia impairs cardiac development.

Methods

Mouse dams were housed in hypoxia beginning at embryonic day 16. Pups stayed in hypoxia until postnatal day (P)8 when cardiac development is nearly complete. Global gene expression was quantified at P8 and at P30, after recovering in normoxia. Phenotypic testing included electrocardiogram, echocardiogram, andex-vivoelectrophysiology study.

Results

Hypoxic animals were 48% smaller than controls. Gene expression was grossly altered by hypoxia at P8 (1427 genes affected), but normalized after recovery (P30). Electrocardiograms revealed bradycardia and slowed conduction velocity in hypoxic animals at P8, which resolved after recovery (P30). Notable differences that persisted after recovery (P30) included a 65% prolongation in ventricular effective refractory period, sinus node dysfunction, and a 24% reduction in contractile function in animals exposed to hypoxia.

Conclusions

We investigated the impact of chronic hypoxia on the developing heart. Perinatal hypoxia was associated with changes in gene expression and cardiac function. Persistent changes to the electrophysiologic substrate and contractile function warrant further investigation, and may contribute to adverse outcomes observed in the cyanotic CHD population.
Insulin-like growth factor 2 (IGF2) protects against Huntington’s disease through the extracellular disposal of protein aggregates
Authors: García-Huerta Paula , Troncoso-Escudero Paulina , Wu Di , Thiruvalluvan Arun , Cisternas Marisol , Henríquez Daniel R. , Plate Lars , Chana-Cuevas Pedro , Saquel Cristian , Thielen Peter , Longo Kenneth A. , Geddes Brad J. , Lederkremer Gerardo L. , Sharma Neeraj , Shenkman Marina , Naphade Swati , Ellerby Lisa M. , Sardi Pablo , Spichiger Carlos , Richter Hans G. , Court Felipe A. , Wiseman R. Luke , Gonzalez-Billault Christian , Bergink Steven , Vidal Rene L. , Hetz Claudio
Published: May 2020

Impaired neuronal proteostasis is a salient feature of many neurodegenerative diseases, highlighting alterations in the function of the endoplasmic reticulum (ER). We previously reported that targeting the transcription factor XBP1, a key mediator of the ER stress response, delays disease progression and reduces protein aggregation in various models of neurodegeneration. To identify disease-modifier genes that may explain the neuroprotective effects of XBP1 deficiency, we performed gene expression profiling of brain cortex and striatum of these animals and uncovered insulin-like growth factor 2 (Igf2) as the major upregulated gene. Here we studied the impact of IGF2 signaling on protein aggregation in models of Huntington’s disease (HD) as proof-of-concept. Cell culture studies revealed that IGF2 treatment decreases the load of intracellular aggregates of mutant huntingtin and a polyglutamine peptide. These results were validated using induced pluripotent stem cells (iPSC)-derived medium spiny neurons from HD patients. The reduction in the levels of mutant huntingtin was associated with a decrease in the half-life of the intracellular protein. The decrease in the levels of abnormal protein aggregation triggered by IGF2 were independent of the activity of autophagy and the proteasome pathways, the two main routes for mutant huntingtin clearance. Conversely, IGF2 signaling enhanced the secretion of soluble mutant huntingtin species through exosomes and microvesicles involving changes in actin dynamics. Administration of IGF2 into the brain of HD mice using gene therapy led to a significant decrease in the levels of mutant huntingtin in three different animal models. Moreover, analysis of human post-mortem brain tissue, and blood samples from HD patients showed a reduction of IGF2 level. This study identifies IGF2 as a relevant factor deregulated in HD, operating as a disease modifier that buffers the accumulation of abnormal protein aggregates.

One sentence summary

IGF2 reduces the load of intracellular protein aggregates through the extracellular disposal of the mutant protein.
Taxallnomy: Closing gaps in the NCBI Taxonomy
Authors: Sakamoto Tetsu , Ortega J. Miguel
Published: May 2020

NCBI Taxonomy is the main taxonomic source for several bioinformatics tools and databases since all organisms with sequence accessions deposited on INSDC are organized in its hierarchical structure. Despite the extensive use and application of this data source, taking advantage of its taxonomic tree could be challenging because (1) some taxonomic ranks are missing in some lineages and (2) some nodes in the tree do not have a taxonomic rank assigned (referred to as “no rank”). To address this issue, we developed an algorithm that takes the tree structure from NCBI Taxonomy and generates a hierarchically complete taxonomic tree. The procedures performed by the algorithm consist of attempting to assign a taxonomic rank to “no rank” nodes and of creating/deleting nodes throughout the tree. The algorithm also creates a name for the new nodes by borrowing the names from its ranked child or, if there is no child, from its ranked parent node. The new hierarchical structure was named taxallnomy and it contains 33 hierarchical levels corresponding to the 33 taxonomic ranks currently used in the NCBI Taxonomy database. From taxallnomy, users can obtain the complete taxonomic lineage with 33 nodes of all taxa available in the NCBI Taxonomy database. Taxallnomy is applicable to several bioinformatics analyses that depend on NCBI Taxonomy data. In this work, we demonstrate its applicability by embedding taxonomic information of a specified rank into a phylogenetic tree; and by making metagenomics profiles. Taxallnomy algorithm was written in PERL and all its resources are available atbioinfo.icb.ufmg.br/taxallnomy.

Database URL:http://bioinfo.icb.ufmg.br/taxallnomy
The clonal and molecular aetiology of emergency dendritic cell development
Authors: Lin Dawn S. , Tian Luyi , Tomei Sara , Amann-Zalcenstein Daniela , Baldwin Tracey M. , Weber Tom S. , Schreuder Jaring , Stonehouse Olivia , Rautela Jai , Huntington Nicholas D. , Ng Ashley P. , Nutt Stephen L. , Taoudi Samir , Ritchie Matthew E. , Hodgkin Philip D. , Naik Shalin H.
Published: May 2020

Extrinsic regulation of single haematopoietic stem and progenitor cell (HSPC) fate is crucial for immune cell development. Here, we examine the aetiology of Flt3 ligand (Flt3L)-mediated emergency development of type 1 conventional dendritic cells (cDC1s), which results in enhanced immunity against infections and cancer. Using cellular barcoding, we demonstrate a predominant role of enhanced clonal expansion and moderate contribution via recruitment of additional cDC1-generating HSPCs. The selective cDC1 expansion occurs primarily via multi-/oligo-potent clones, without compromising output to other lineages. To understand the molecular hallmarks early during a Flt3L response, we developDivi-Seqto simultaneously profile cell division history, surface phenotype and transcriptional state of single HSPCs. We discover that Flt3L-responsive HSPCs maintain a proliferative ‘early progenitor’-like state, which leads to selective emergence of CD11c+cKit+transitional precursors with high cellular output to cDC1s. These findings inform the mechanistic action of Flt3L in natural immunity and immunotherapy at a clonal level.
Transcriptomic response ofCaenorhabditis elegansexpressing human Aβ42gene treated with Salvianolic acid A
Authors: Yuen Chee Wah , Halim Mardani Abdul , Najimudin Nazalan , Azzam Ghows
Published: May 2020

Alzheimer’s disease (AD) is a brain disease attributed to the accumulation of extracellular senile plaques comprising β-amyloid peptide (Aβ). In this study, a global transcriptomic analysis of the response of transgenicCaenorhabditis elegansworms expressing full length human Aβ42gene towards Salvianolic acid A (Sal A) was analysed. Antioxidant response genes, namelygst-4,gst-10,spr-1andtrxr-2, were upregulated. The production of Aβ42caused oxidative stress and the antioxidant response genes possibly provide defence to the strain. The gene product oftrxr-2also functionally interacts with the defence system and has a role in life span. Genes involved in replication, reproduction, immune response to microbes and antimicrobial activities were also upregulated. Exposure to Sal A also increased the rate of reproduction of nematodes, and heightened its immunological protection system towards microorganisms. In contrast, genes responsible for locomotion, ligand-gated cation channel, embryonic and postembryonic development, and neuromodulation of chemosensory neurons were significantly down-regulated. As an effector, Sal A might conceivably reduce the movement of the worm by interfering with neuronal transmission and embryonic and post-embryonic development.
Habitat fragmentation and food security in crop pollination systems
Authors: Montoya Daniel , Haegeman Bart , Gaba Sabrina , De Mazancourt Claire , Loreau Michel
Published: May 2020

Ensuring stable food supplies is recognized as a major challenge for the 21stcentury, and one of the UN Sustainable Development Goals. Biodiversity-based approaches to food security are increasingly being supported based on the fact that biodiversity can increase and stabilize crop yields. But agricultural systems are often highly fragmented and it is unclear how such fragmentation affects biodiversity and food production, limiting our capacity to manage agricultural landscapes for food security. Here, we develop a model of crop yield dynamics to investigate how fragmentation of natural habitats for agricultural conversion impacts food production, with a focus on crop pollination. Our results show that fragmentation produces spatial and biodiversity-mediated effects that affect the mean and stability of pollination-dependent crops, with strong consequences for food security. The net effects of fragmentation depend on the strength of the spillover of pollinators to crop land and the degree to which crops depend on animal pollination. Our study sheds new light in the food security debate by showing that high and stable yields depend on biodiversity and the spatial structure of agricultural landscapes, and by revealing the ecological mechanisms of food security in crop pollination systems.
Minimum conductance in leaves—cuticle, leaky stomata, or water vapor saturation?
Authors: Tominaga Jun , Stinziano Joseph R. , Hanson David T.
Published: May 2020

Minimum conductance (gw,min) in leaves is important for water relations in land plants. Yet, its regulation is unclear due to measurement constraints.

Cuticle conductance to water vapor (gcw) was estimated from the difference between calculated and direct measurement of CO2concentration in the leaf airspace (Ci) of amphi-stomatous tobacco and sunflower. We estimatedgcwin a series of light and dark experiments, and partitionedgw,mininto cuticle and stomatal components. Some leaves were detached to simulate severe drought through desiccation conditions wheregw,minis generally determined.

Between light and dark experiments eachgcwwas in close agreement, and successfully corrected the discrepancies of calculations from direct measurements. In the dark, either stomatal or cuticle conductance dominated thegw,min, suggesting either of them can control the minimum water loss. In the detached leaves,gcwcould not be estimated likely due to unsaturation in the leaf airspace, andgw,minwas progressively underestimated.

Besides cuticle, leaf water status is a potential pitfall of the standard gas exchange model. Our technique is useful to study the minimal gas exchange as well as to refine the model.
Molecules inhibit the enzyme activity of 3-chymotrypsin-like cysteine protease of SARS-CoV-2 virus: the experimental and theory studies
Authors: He Zhesheng , Zhao Wencong , Niu Wenchao , Gao Xuejiao , Gao Xingfa , Gong Yong , Gao Xueyun
Published: May 2020

SARS-CoV-2 has emerged as a world public health threat. Herein, we report that the clinical approved auranofin could perfectly inhibit the activity of 3-chymotrypsin-like cysteine protease (Mpro or 3CLpro) of SARS-CoV-2. Gold cluster could significantly inhibit 3CLpro of SARS-COV-2. Phenyl isothiocyanate and Vitamin K3 could well suppress the activity of 3CLpro. For Mpro inhibition, IC50 of auranofin, Vitamin K3, phenyl isothiocyanate, gold cluster are about 0.51μM, 7.96μM, 10.13μM, 1.61μM, respectively. These compounds may be with potentials for treatment SARS-CoV-2 virus replication. Especially for FDA approved auranofin, it is an anti-inflammation drug in clinic, thus it may with strong potential to inhibit virus replication and suppress the inflammation damage in COVID-19 patients. Gold cluster is with better safety index and well anti-inflammation in vitro/vivo, therefore it is with potential to inhibit virus replication and suppress the inflammation damage caused by COVID-19 virus. As Au(I) ion is active metabolism specie derived from gold compounds or gold clusters in vivo, further computational studies revealed Au ion could tightly bind thiol group of Cys145 residue of 3CLpro thus inhibit enzyme activity. Also, phenyl isothiocyanate and Vitamin K3 may interact with thiol group of Cys145 via Michael addition reaction, molecular dynamic (MD) theory studied are applied to confirmed these small molecules are stable in the pocket and inhibit Mpro activity.
Tumor-free elongation of mammalian nephrogenesis by excess fetal GDNF
Authors: Li Hao , Kupari Jussi , Gui Yujuan , Siefker Edward , Lu Benson , Mätlik Kärt , Olfat Soophie , Montaño-Rodríguez Ana R , Huh Sung-Ho , Costantini Franklin , Andressoo Jaan-Olle , Kuure Satu
Published: May 2020

Due to poor regenerative capacity of adult kidneys, nephron endowment defined by the nephrogenic program during the fetal period dictates renal and related cardiovascular health throughout life. We show that the neurotropic factor GDNF, which is in clinical trials for Parkinson’s disease, is capable of prolonging the nephrogenic program beyond its normal cessation without increasing the risk of kidney tumors. Our data demonstrates that excess GDNF expands the nephrogenic program by maintaining nephron progenitors and nephrogenesis in postnatal mouse kidneys. GDNF, through its transcriptional targets excreted from the adjacent epithelium, has a major effect on nephron progenitor self-renewal and maintenance; abnormally high GDNF inhibits nephron progenitor proliferation, but lowering its level normalizes the nephrogenic program to that permissive for nephron progenitor self-renewal and differentiation. Based on our results, we propose that the lifespan of nephron progenitors is determined by mechanisms related to perception of GDNF and other signaling levels.
Pathogenesis, transmission and response to re-exposure of SARS-CoV-2 in domestic cats
Authors: Bosco-Lauth Angela M. , Hartwig Airn E. , Porter Stephanie M. , Gordy Paul W. , Nehring Mary , Byas Alex D. , VandeWoude Sue , Ragan Izabela K. , Maison Rachel M. , Bowen Richard A.
Published: May 2020

The pandemic caused by SARS-CoV-2 has reached nearly every country in the world with extraordinary person-to-person transmission. The most likely original source of the virus was spillover from an animal reservoir and subsequent adaptation to humans sometime during the winter of 2019 in Wuhan Province, China. Because of its genetic similarity to SARS-CoV-1, it is likely that this novel virus has a similar host range and receptor specificity. Due to concern for human-pet transmission, we investigated the susceptibility of domestic cats and dogs to infection and potential for infected cats to transmit to naïve cats. We report that cats are highly susceptible to subclinical infection, with a prolonged period of oral and nasal viral shedding that is not accompanied by clinical signs, and are capable of direct contact transmission to other cats. These studies confirm that cats are susceptible to productive SARS-CoV-2 infection, but are unlikely to develop clinical disease. Further, we document that cats develop a robust neutralizing antibody response that prevented re-infection to a second viral challenge. Conversely, we found that dogs do not shed virus following infection, but do mount an anti-viral neutralizing antibody response. There is currently no evidence that cats or dogs play a significant role in human exposure; however, reverse zoonosis is possible if infected owners expose their domestic pets during acute infection. Resistance to re-exposure holds promise that a vaccine strategy may protect cats, and by extension humans, to disease susceptibility.
The evolution of non-motif selectivity determinants inMonosiga brevicollisPDZ domains
Authors: Gao Melody , Mackley Iain G. P. , Mesbahi-Vasey Samaneh , Bamonte Haley A. , Struyvenberg Sarah A. , Landolt Louisa , Pederson Nick J. , Williams Lucy I. , Bahl Christopher D. , Brooks Lionel , Amacher Jeanine F.
Published: May 2020

The evolution of signaling pathways is complex and well-studied. In particular, the emergence of animal multicellularity had a major impact on protein-protein interactions and signaling systems in eukaryotic cells. However, choanoflagellates, our closest non-metazoan ancestor, contain a number of closely related signaling and trafficking proteins and domains. In addition, because choanoflagellates can adopt a rosette-/multicellular-like state, a lot can be gained by comparing proteins involved in choanoflagellate and human signaling pathways. Here, we look at how selectivity determinants evolved in the PDZ domain. There are over 250 PDZ domains in the human proteome, which are involved in critical protein-protein interactions that result in large multimolecular complexes, e.g., in the postsynaptic density of neuronal synapses. Binding of C-terminal sequences by PDZ domains is often transient and recognition typically involves 6 residues or less, with only 2 residues specifying the binding motif. We solved high resolution crystal structures ofMonosiga brevicollisPDZ domains homologous to human Dlg1 PDZ2, Dlg1 PDZ3, GIPC, and SHANK1 PDZ domains to investigate if the non-motif preferences are conserved, despite hundreds of millions of years of evolution. We also calculated binding affinities for GIPC, SHANK1, and SNX27 PDZ domains fromM. brevicollis. Overall, we found that peptide selectivity is conserved between these two disparate organisms, with one exception, mbDLG-3. In addition, we identify 178 PDZ domains in theM. brevicollisproteome, including 11 new sequences, which we verified using Rosetta and homology modeling. Overall, our results provide novel insight into signaling pathways in the choanoflagellate organism.