bluuebunny/crossref_metadata_2025_split huggingface dataset:
Visual Feedback Weakens the Augmentation of Perceived Stiffness by Artificial Skin Stretch
Authors: Farajian Mor , Kossowsky Hanna , Leib Raz , Nisky Ilana 
Published: July 2020

AbstractTactile stimulation devices are gaining popularity in haptic science and technology – they are lightweight, low-cost, can be easily made wearable, and do not suffer from instability during closed loop interactions with users. Applying tactile stimulation in the form of stretching the skin of the fingerpads, concurrently with kinesthetic force feedback, has been shown to augment the perceived stiffness during interactions with elastic objects. However, all of the studies to date have investigated the perceptual augmentation effects of artificial skin-stretch in the absence of visual feedback. We investigated how visual displacement feedback affects the augmentation of perceived stiffness caused by the skin-stretch. We used a forced-choice paradigm stiffness discrimination task with four different conditions: force feedback, force feedback with artificial skin-stretch, force and visual feedback, and force and visual feedback with artificial skin-stretch. We found that visual displacement feedback weakens the skin-stretch induced perceptual augmentation and improves the stiffness discrimination sensitivity.
Characterization of two novel proteins involved in mitochondrial DNA anchoring
Authors: Amodeo Simona , Hoffmann Anneliese , Fradera-Sola Albert , Bregy Irina , Baudouin Hélène , Haenni Beat , Zuber Benoît , Butter Falk , Ochsenreiter Torsten 
Published: July 2020

AbstractTrypanosoma bruceiis a single celled eukaryotic parasite in the group of the Excavates.T. bruceicells harbor a single mitochondrion with a singular mitochondrial genome, that consists of a unique network of thousands of interwoven circular DNA molecule copies and is termed the kinetoplast DNA (kDNA). To ensure proper inheritance of the kDNA to the daughter cells the genome is linked to the basal body, the master organizer of the cell cycle in trypanosomes. The structure connecting the basal body and kDNA is termed the tripartite attachment complex (TAC). Using a combination of proteomics and RNAi (depletomics) we test the current model of hierarchical TAC assembly and identify TbmtHMG44 and Tb927.11.16120 as novel candidates of a structure that connects the TAC to the kDNA. Both proteins localize in the region of the unilateral filaments between TAC102 and the kDNA and depletion of each leads to a strong kDNA loss phenotype. TbmtHMG44 and Tb927.11.16120 stably associate with extracted flagella, even after DNase treatment however they do require the kDNA for initial assembly. Furthermore we demonstrate that recombinant Tb927.11.16120 is a DNA binding protein and thus a promising candidate to link the TAC to the kDNA.
Factors of sex and age dictate the regulation of GABAergic activity by corticotropin-releasing factor receptor 1 in the medial sub-nucleus of the central amygdala
Authors: Rouzer Siara Kate , Diaz Marvin R. 
Published: July 2020

AbstractAdolescents are phenotypically characterized with hyper-sensitivity to stress and inappropriate response to stress-inducing events. Despite behavioral distinctions from adults, investigations of developmental shifts in the function of stress peptide corticotrophin-releasing factor (CRF) are generally limited. Rodent models have determined that CRF receptor 1 (CRFR1) activation within the central amygdala is associated with a stress response and induces increased GABAergic synaptic neurotransmission within adult males. To investigate age-specific function of this system, we performed whole-cell patch clamp electrophysiology in brain slices from naive adolescent (postnatal days (P) 40-49) and adult (>P70) male and female Sprague Dawley rats to assess GABAergic activity in the medial central amygdala (CeM). Our results indicate a dynamic influence of age and sex on neuronal excitability within this region, as well as basal spontaneous and miniature (m) inhibitory post-synaptic currents (IPSCs) in the CeM. In addition to replicating prior findings of CRFR1-regulated increases in mIPSC frequency in adult males, we found that the selective CRFR1 agonist, Stressin-1,attenuatedmIPSC frequency in adolescent males, at a concentration that did not affect adult males. Importantly, this age-specific distinction was absent in females, as Stressin-1 attenuated mIPSC frequency in both adolescent and adult females. Finally, only adult males exhibited an increase in mIPSC frequency in response to the CRF1R antagonist, NBI 35965, suggestive of tonic CRFR1 activation in the CeM of adult males. Together, these data emphasize the robust influence of age and sex on neurophysiological function of a brain region involved in the production of the stress response.
Detection of selection signatures in farmed coho salmon (Oncorhynchus kisutch) using dense genome-wide information
Authors: López M.E. , Cádiz M.I. , Rondeau E.B. , Koop B.F. , Yáñez J.M. 
Published: July 2020

AbstractAnimal domestication and artificial selection give rise to gradual changes at the genomic level in populations. Subsequent footprints of selection known as selection signatures or selective sweeps have been traced in the genomes of many animal livestock species by exploiting variations in linkage disequilibrium patterns and/or reduction of genetic diversity.Domestication of most aquatic species is recent in comparison with land animals, and salmonids are one of the most important fish species in aquaculture. Coho salmon (Oncorhynchus kisutch), cultivated primarily in Chile, has been subject to breeding programs to improve growth, disease resistance traits, and flesh color. This study aimed to identify selection signatures that may be involved in adaptation to culture conditions and traits of productive interest. To do so, individuals of two domestic populations cultured in Chile were genotyped with 200 thousand SNPs, and analyses were conducted using iHS, XP-EHH and CLR. Several signatures of selection on different chromosomal regions were detected across both populations. Some of the identified regions under selection contained genes suchanapc2,alad,chp2andmynthat have been previously associated with body weight in Atlantic salmon orsec24dandrobo1that have been associated with disease resistance toPiscirickettsia salmonisin coho salmon. Findings in our study can contribute to an integrated genome-wide map of selection signatures, to help identify the genetic mechanisms of phenotypic diversity in coho salmon.
Computational investigation of protein photoinactivation by molecular hyperthermia
Authors: Kang Peiyuan , Xie Chen , Fall Oumar , Randrianalisoa Jaona , Qin Zhenpeng 
Published: July 2020

AbstractTo precisely control protein activity in a living system is a challenging yet long-pursued objective in biomedical sciences. Recently we have developed a new approach named molecular hyperthermia (MH) to photoinactivate protein activity of interest without genetic modification. MH utilizes nanosecond laser pulse to create nanoscale heating around plasmonic nanoparticles to inactivate adjacent protein in live cells. Here we use a numerical model to study important parameters and conditions for MH to efficiently inactivate proteins in nanoscale. To quantify the protein inactivation process, the impact zone is defined as the range where proteins will be inactivated by nanoparticle localized heating. Factors that reduce the MH impact zone include stretching the laser pulse duration, temperature-dependent thermal conductivity (versus constant properties), and non-spherical nanoparticle geometry. In contrast, the impact zone is insensitive to temperature-dependent material density and specific heat, as well as thermal interface resistance based on reported data. The low thermal conductivity of cytoplasm increases the impact zone. Different proteins with various Arrhenius kinetic parameters have significantly different impact zones. This study provides guidelines to design the protein inactivation process in MH.
Efficiency of a Randomized Confirmatory Basket Trial Design Constrained to Control the False Positive Rate by Indication
Authors: He Linchen , Ren Yuru , Chen Han , Guinn Daphne , Parashar Deepak , Chen Cong , Yuan Shuai Sammy , Korostyshevskiy Valeriy , Beckman Robert A. 
Published: July 2020

PURPOSEMolecular oncology determines biomarker-defined niche indications. Basket trials pool histologic indications sharing molecular pathophysiology, potentially improving development efficiency. Currently basket trials have been confirmatory only for exceptional therapies. Our previous randomized basket design may be generally suitable in the resource-intensive confirmatory phase, maintains high power, and provides nearlyk-fold increased efficiency forkindications, but controls false positives for the pooled result only. Since false positive control by indications (FWER) may sometimes be required, we now simulate a variant of this basket design controlling FWER at 0.025k, the total FWER ofkseparate randomized trials.METHODSThe previous design eliminated indications at an interim analysis, conducting a final pooled analysis of remaining indications. To control FWER, we rechecked individual indications at a prospectively defined level of statistical significance after any positive pooled result. We simulated this modified design under numerous scenarios varying design parameters. Only designs controlling FWER and minimizing estimation bias were allowable.RESULTSSequential analyses (interim, pooled, and post-individual tests)) result in cumulative power losses. Optimal performance results whenk= 3,4. We report efficiency (expected # true positives/expected sample size) relative tokparallel studies, at 90% power (“uncorrected”) or at the power achieved in the basket trial (“corrected”, because conventional designs could also increase efficiency by sacrificing power). Efficiency and power (percentage active indications identified) improve with higher percentage of initial indications active. Up to 92% uncorrected and 38% corrected efficiency improvement is possible, with power ≈ 60%.CONCLUSIONSEven under FWER control, randomized confirmatory basket trials substantially improve development efficiency. Initial indication selection is critical. The design is particularly attractive when enrollment challenges preclude full powering of individual indications.
Post-mitotic Prox1 expression controls the final specification of cortical VIP interneuron subtypes
Authors: Stachniak Tevye Jason , Kastli Rahel , Hanley Olivia , Argunsah Ali Özgür , Karayannis Theofanis 
Published: July 2020

SummaryNeuronal identity is controlled in multiple developmental steps by key transcription factors that determine the unique properties of a cell. During embryogenesis, the transcription factor Prox1 has been shown to regulate VIP interneuron migration, survival, and as a result, circuit integration. Here, we explore the role of Prox1 as a regulator of genetic programs that guide the final specification of VIP interneuron subtypes in early post-natal life. Using in-vitro electrophysiology we find that post-natal removal of Prox1 differentially affects the synaptic integration of VIP bipolar and multipolar subtypes.RNA sequencing reveals that one of the downstream targets of Prox1 is the postsynaptic protein Elfn1, a constitutive regulator of presynaptic release probability. Genetic, pharmacological and electrophysiological experiments demonstrate that knocking out Prox1 reduces Elfn1 function in VIP multipolar but not in bipolar cells. Thus, in addition to the activity-dependent and contextual processes that finalize developmental trajectories, genetic programs engaged by Prox1 control the differentiation and connectivity of VIP interneuron subtypes.
Hydroxychloroquine-mediated inhibition of SARS-CoV-2 entry is attenuated by TMPRSS2
Authors: Ou Tianling , Mou Huihui , Zhang Lizhou , Ojha Amrita , Choe Hyeryun , Farzan Michael 
Published: July 2020

AbstractHydroxychloroquine, used to treat malaria and some autoimmune disorders, potently inhibits viral infection of SARS coronavirus (SARS-CoV-1) and SARS-CoV-2 in cell-culture studies. However, human clinical trials of hydroxychloroquine failed to establish its usefulness as treatment for COVID-19. This compound is known to interfere with endosomal acidification necessary to the proteolytic activity of cathepsins. Following receptor binding and endocytosis, cathepsin L can cleave the SARS-CoV-1 and SARS-CoV-2 spike (S) proteins, thereby activating membrane fusion for cell entry. The plasma membrane-associated protease TMPRSS2 can similarly cleave these S proteins and activate viral entry at the cell surface. Here we show that the SARS-CoV-2 entry process is more dependent than that of SARS-CoV-1 on TMPRSS2 expression. This difference can be reversed when the furin-cleavage site of the SARS-CoV-2 S protein is ablated. We also show that hydroxychloroquine efficiently blocks viral entry mediated by cathepsin L, but not by TMPRSS2, and that a combination of hydroxychloroquine and a clinically-tested TMPRSS2 inhibitor prevents SARS-CoV-2 infection more potently than either drug alone. These studies identify functional differences between SARS-CoV-1 and -2 entry processes, and provide a mechanistic explanation for the limitedin vivoutility of hydroxychloroquine as a treatment for COVID-19.Author SummaryThe novel pathogenic coronavirus SARS-CoV-2 causes COVID-19 and remains a threat to global public health. Chloroquine and hydroxychloroquine have been shown to prevent viral infection in cell-culture systems, but human clinical trials did not observe a significant improvement in COVID-19 patients treated with these compounds. Here we show that hydroxychloroquine interferes with only one of two somewhat redundant pathways by which the SARS-CoV-2 spike (S) protein is activated to mediate infection. The first pathway is dependent on the endosomal protease cathepsin L and sensitive to hydroxychloroquine, whereas the second pathway is dependent on TMPRSS2, which is unaffected by this compound. We further show that SARS-CoV-2 is more reliant than SARS coronavirus (SARS-CoV-1) on the TMPRSS2 pathway, and that this difference is due to a furin cleavage site present in the SARS-CoV-2 S protein. Finally, we show that combinations of hydroxychloroquine and a clinically tested TMPRSS2 inhibitor work together to effectively inhibit SARS-CoV-2 entry. Thus TMPRSS2 expression on physiologically relevant SARS-CoV-2 target cells may bypass the antiviral activities of hydroxychloroquine, and explain its lack ofin vivoefficacy.
Chemotherapeutic Nanoparticles Accumulate in the Female Reproductive System during Ovulation Affecting Fertility and Anticancer Activity
Authors: Poley Maria , Shammai Yael , Kaduri Maya , Koren Lilach , Adir Omer , Shklover Jeny , Shainsky Janna , Ben-Aharon Irit , Zinger Assaf , Schroeder Avi 
Published: July 2020

AbstractThroughout the female menstrual cycle, physiological changes occur that affect the biodistribution of nanoparticles within the reproductive system. This can have positive or negative effects. We demonstrate a 2-fold increase in nanoparticle accumulation in the ovaries during female mouse ovulation compared to the non-ovulatory stage following intravenous administration. Accumulation in the reproductive system is favored by nanoparticles smaller than 100 nm. Chemotherapeutic nanoparticles administered during ovulation increased ovarian toxicity and decreased short-term and long-term fertility when compared to the free drug. Breast cancer treated with nanomedicines during ovulation results in higher drug accumulation in the reproductive system rather than at the site of the tumor, reducing treatment efficacy. Conversely, ovarian cancer treatment was improved by enhanced nanoparticle accumulation in the ovaries during ovulation. Our findings suggest that the menstrual cycle should be considered when designing and implementing nanotherapeutics for females.
Sparsification of AP firing in adult-born hippocampal granule cells via voltage-dependent α5-GABAAreceptors
Authors: Lodge Meredith , Hernandez Maria-Clemencia , Schulz Jan M. , Bischofberger Josef 
Published: July 2020

AbstractGABA can depolarize immature neurons close to the action potential (AP) threshold in development and adult neurogenesis. Nevertheless, GABAergic synapses effectively inhibit AP firing in newborn granule cells of the adult hippocampus as early as 2 weeks post mitosis. The underlying mechanisms are largely unclear. Here we analyzed GABAergic inputs in newborn 2- to 4-week-old hippocampal granule cells mediated by soma-targeting parvalbumin (PV) and dendrite-targeting somatostatin (SOM) interneurons. Surprisingly, both interneuron subtypes activate α5-subunit containing GABAAreceptors (α5-GABAARs) in young neurons, showing a nonlinear voltage dependence with increasing conductance around the AP threshold. By contrast, in mature cells, PV interneurons mediate linear GABAergic synaptic currents lacking α5-subunits, while SOM-interneurons continue to target nonlinear α5-GABAARs. Computational modelling shows that the voltage-dependent amplification of α5-GABAAR opening in young neurons is crucial for inhibition of AP firing to generate balanced and sparse firing activity, even with depolarized GABA reversal potentials.
A normative account of choice history effects in mice and humans
Authors: Lopez-Yepez Junior Samuel , Martin Juliane , Hulme Oliver , Kvitsiani Duda 
Published: July 2020

AbstractChoice history effects describe how future choices depend on the history of past choices. Choice history effects are typically framed as a bias rather than an adaptive phenomenon because the phenomenon generally degrades reward rates in experimental tasks. How-ever, in natural habitats, choices made in the past constrain choices that can be made in the future. For foraging animals, the probability of obtaining a reward in a given patch depends on the degree to which the animals have exploited the patch in the past. One problem with many experimental tasks that show choice history effects is that such tasks artificially decouple choice history from its consequences in regard to reward availability over time. To circumvent this, we used a variable interval (VI) reward schedule that reinstates a more natural contingency between past choices and future reward availability. By manipulating first- and second-order statistics of the environment, we dissociated choice history, reward history, and reaction times. We found that choice history effects reflect the growth rate of the reward probability of the unchosen option, reward history effects reflect environmental volatility, and reaction time reflects overall reward rate. By testing in mice and humans, we show that the same choice history effects can be generalized across species and that these effects are similar to those observed in optimal agents. Furthermore, we develop a new reinforcement learning model that explicitly incorporates choice history over multiple timescales into the decision process, and we examine its predictive adequacy in accounting for the associated behavioral data. We show that this new variant, known as the double trace model, has a higher predictive adequacy of choice data, in addition to better reward harvesting efficiency in simulated environments. Finally, we show that the choice history effects emerge in optimal models of foraging in habitats with diminishing returns, thus linking this phenomenon to a wider class of optimality models in behavioral ecology. These results suggests that choice history effects may be adaptive for natural contingencies between consumption and reward availability. This concept lends credence to a normative account of choice history effects that extends beyond its description as a bias.
Fast Whole-Genome Phylogeny of the COVID-19 Virus SARS-CoV-2 by Compression
Authors: Cilibrasi Rudi L. , Vitányi Paul M.B. 
Published: July 2020

AbstractWe analyze the whole genome phylogeny and taxonomy of the SARS-CoV-2 virus using compression. This is a new fast alignment-free method called the “normalized compression distance” (NCD) method. It discovers all effective similarities based on Kolmogorov complexity. The latter being incomputable we approximate it by a good compressor such as the modern zpaq. The results comprise that the SARS-CoV-2 virus is closest to the RaTG13 virus and similar to two bat SARS-like coronaviruses bat-SL-CoVZXC21 and bat-SL-CoVZC4. The similarity is quantified and compared with the same quantified similarities among the mtDNA of certain species. We treat the question whether Pangolins are involved in the SARS-CoV-2 virus. The compression method is simpler and possibly faster than any other whole genome method, which makes it the ideal tool to explore phylogeny.
Beclin-1-mediated activation of autophagy improves proximal and distal urea cycle disorders
Authors: Soria Leandro R. , Perocheau Dany P. , De Sabbata Giulia , De Angelis Angela , Bruno Gemma , Polishchuk Elena , Gurung Sonam , Paris Debora , Cuomo Paola , Motta Andrea , Orford Michael , Eaton Simon , Waddington Simon , Settembre Carmine , Muro Andrés F. , Baruteau Julien , Brunetti-Pierri Nicola 
Published: July 2020

ABSTRACTUrea cycle disorders (UCD) are inherited defects in clearance of waste nitrogen with high morbidity and mortality. Novel and more effective therapies for UCD are needed. Studies in mice with constitutive activation of autophagy unraveled Beclin-1 asdruggablecandidate for therapy of hyperammonemia. Next, we investigated efficacy of cell penetrating autophagy inducing Tat-Beclin-1 (TB-1) peptide for therapy of the two most common UCD, namely ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL) deficiencies. TB-1 reduced urinary orotic acid and hyperammonemia, and improved survival under protein-rich diet inspf-ashmice, a model of OTC deficiency (proximal UCD). InAslNeo/Neomice, a model of ASL deficiency (distal UCD), TB-1 increased ureagenesis, reduced argininosuccinate, and improved survival. Moreover, it alleviated hepatocellular injury and decreased both cytoplasmic and nuclear glycogen accumulation inAslNeo/Neomice. In conclusion, Beclin-1-dependent activation of autophagy improved biochemical and clinical phenotypes of proximal and distal defects of the urea cycle.