bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional Context Affects Scene Processing
Authors: Aminoff Elissa M. , Tarr Michael J.
Published: October 2020

Rapid visual perception is often viewed as a bottom-up process. Category-preferred neural regions are often characterized as automatic, default processing mechanisms for visual inputs of their categorical preference. To explore the sensitivity of such regions to top-down information, we examined three scene-preferring brain regions, the occipital place area (OPA), the parahippocampal place area (PPA), and the retrosplenial complex (RSC), and tested whether the processing of outdoor scenes is influenced by the functional contexts in which they are seen. Context was manipulated by presenting real-world landscape images as if being viewed through a window or within a picture frame; manipulations that do not affect scene content but do affect one’s functional knowledge regarding the scene. This manipulation influences neural scene processing (as measured by fMRI): the OPA and PPA exhibited greater neural activity when participants viewed images as if through a window as compared to within a picture frame, while the RSC did not show this difference. In a separate behavioral experiment, functional context affected scene memory in predictable directions (boundary extension). Our interpretation is that the window context denotes three-dimensionality, therefore rendering the perceptual experience of viewing landscapes as more realistic. Conversely, the frame context denotes a two-dimensional image. As such, more spatially-biased scene representations in the OPA and the PPA are influenced by differences in top-down, perceptual expectations generated from context. In contrast, more semantically-biased scene representations in the RSC are likely to be less affected by top-down signals that carry information about the physical layout of a scene.
A novel density-based neural mass model for simulating neuronal network dynamics with conductance-based synapses and membrane current adaptation
Authors: Huang Chih-Hsu , Lin Chou-Ching K.
Published: October 2020

Nowadays, building low-dimensional mean-field models of neuronal populations is still a critical issue in the computational neuroscience community, because their derivation is difficult for realistic networks of neurons with conductance-based interactions and spike-frequency adaptation that generate nonlinear properties of neurons. Here, based on a colored-noise population density method, we derived a novel neural mass model, termed density-based neural mass model (dNMM), as the mean-field description of network dynamics of adaptive exponential integrate-and-fire neurons. Our results showed that the dNMM was capable of correctly estimating firing rate responses under both steady- and dynamic-input conditions. Finally, it was also able to quantitatively describe the effect of spike-frequency adaptation on the generation of asynchronous irregular activity of excitatory-inhibitory cortical networks. We conclude that in terms of its biological reality and calculation efficiency, the dNMM is a suitable candidate to build very large-scale network models involving multiple brain areas.
SARS-CoV-2 infections in Italian schools: preliminary findings after one month of school opening during the second wave of the pandemic
Authors: Buonsenso Danilo , De Rose Cristina , Moroni Rossana , Valentini Piero
Published: October 2020

Introduction

The impact of school opening on the SARS-CoV-2 pandemic is still unknown. This study aims to provide preliminary information about the number of SARS-CoV-2 cases among students attending Italian schools.

Methods

Data are extracted and analysed from an open access, online dataset that monitor, on a daily basis, media news about SARS-CoV-2 infections of students attending Italian schools

Results

As of 5 October 2020, a total of 1350 cases of SARS-CoV-2 infections have been registered in the Italian territory schools (involving 1059 students, 145 teachers and 146 other school members), for a total of 1212 out of 65104 (1.8%) Italian schools involved. National schools reported only 1 case of SARS-CoV-2 infection in more than 90% of cases, and only in one high school a cluster of more than 10 cases have been described (P 0.015). The detection of one or more SARS-CoV-2 infections leaded to the closure of 192 (14.2%) entire schools, more frequently nursery/kindergartens (P<0.0005).

Discussion

Our preliminary data support low transmission of SARS-CoV-2 within schools, at least among younger students. However, entire schools are frequently closed in the fear of larger outbreaks. Continuous monitoring of school settings, hopefully through daily updated open access datasets, are needed to better understand the impact of schools on the pandemic, and provide guidelines that better consider different risks within different age groups.
Development of wastewater pooled surveillance of SARS-CoV-2 from congregate living settings
Authors: Colosi Lisa M. , Barry Katie E. , Kotay Shireen M. , Porter Michael D. , Poulter Melinda D. , Ratliff Cameron , Simmons William , Steinberg Limor I. , Wilson D. Derek , Morse Rena , Zmick Paul , Mathers Amy J.
Published: October 2020

Wastewater-based monitoring for SARS-CoV-2 holds promise as tool to inform public health-decision making. Testing at individual building-level could be an efficient, passive means of preventing early detection of new cases in congregate living settings, but this approach has not been validated. Sample collection protocols were developed and refined during preliminary sampling from a hospital and a local municipal wastewater treatment plant. Molecular diagnostic methods were compared side-by-side to assess feasibility, performance and sensitivity. Optimized sample collection and processing protocols were then used to monitor two occupied dormitory complexes (n=105 and 66) over eight weeks. Wastewater results were validated using known case counts from external clinical testing of building occupants. Results confirm that ultracentrifugation from a 24 hour composite collection had a sensitivity of 95% and a specificity of 100%. However, if the detection of convalescent shedding is considered a false positive then the sensitivity would be 95.2% but the specificity would drop to 52%. We determined a highly sensitive method for detecting SARS-CoV-2 shedding in building wastewater however our methods could not distinguish new infectious cases from persistent convalescent shedding of SARS-CoV-2 RNA. Future work must focus on methods to distinguish new infections from convalescent shedding to widely deploy this promising wastewater surveillance tool.
Quality assessment of studies included in Cochrane oral health systematic reviews
Authors: Sofi-Mahmudi Ahmad , Iranparvar Pouria , Shakiba Maryam , Shamsoddin Erfan , Mohammad-Rahimi Hossein , Naseri Sadaf , Motie Parisa , Mesgarpour Bita
Published: October 2020

Objectives

The Risk of Bias (RoB) and other characteristics of randomized clinical trials included in Cochrane oral health systematic reviews were assessed.

Study Design and Settings

All the trials included in Cochrane oral health systematic reviews were examined. The RoB was evaluated for all the included clinical trials according to the Cochrane review standards. The Overall Risk of Bias (ORoB) was defined in this study based on the criteria for determining the overall bias in Cochrane’s RoB tool-v2. Descriptive analyses were carried out to determine the frequency of each intended variable.

Results

A total of 2565 studies were included in our analysis. The majority of the studies (n=1600) had sample sizes of 50 or higher. As for blinding, 907 studies were labelled as double-blind. Performance bias showed the highest rate of high risk (31.4%). Almost half of the studies had a high ORoB compared to 11.1% with low ORoB. The studies that used placebos had higher low ORoB (14.8% vs. 10.7%). The double-blind studies had the highest low ORoB (23.6%). The studies with a cross-over design had the highest low ORoB (28.8%).

Conclusion

Overall, the RoB for the studies on dentistry and oral health in Cochrane reviews was deemed high.
Micro topographical instruction of bacterial attachment, biofilm formation andin vivohost response
Authors: Romero Manuel , Luckett Jeni , Figueredo Grazziela P. , Carabelli Alessandro M. , Scurr David , Hook Andrew L. , Dubern Jean-Frédéric , Ison Elizabeth , Kammerling Lisa , da Silva Ana C. , Xue Xuan , Blackburn Chester , Carlier Aurélie , Vasilevich Aliaksei , Sudarsanam Phani , Vermeulen Steven , Winkler David , Ghaemmaghami Amir M , de Boer Jan , Williams Paul , Alexander Morgan R
Published: October 2020

Bio-instructive materials that prevent bacterial biofilm formation and drive an appropriate host immune response have the potential to significantly reduce the burden of medical device-associated infections. Since bacterial surface attachment is known to be sensitive to surface topography, we experimentally survey 2,176 combinatorially generated shapes using an unbiased high-throughput micro topographical screen on polystyrene. This identifies topographies that reduce colonizationin vitroby up to 15-fold compared with a flat surface for both motile and non-motile bacterial pathogens. Equivalent reductions are achieved on polyurethane, a polymer commonly used in medical devices. Using machine learning methods, a set of design rules based on generalisable descriptors is established for predicting bacteria-resistant micro topographies. In a murine foreign body infection model, anti-attachment topographies are shown to be refractory toP. aeruginosaand to recruit a productive host response, highlighting the potential of simple topographical patterning of non-eluting implants for preventing medical device associated infections.
Comprehensive identification of somatic nucleotide variants in human brain tissue
Authors: Wang Yifan , Bae Taejeong , Thorpe Jeremy , Sherman Maxwell A. , Jones Attila G. , Cho Sean , Daily Kenneth , Dou Yanmei , Ganz Javier , Galor Alon , Lobon Irene , Pattni Reenal , Rosenbluh Chaggai , Tomasi Simone , Tomasini Livia , Yang Xiaoxu , Zhou Bo , Akbarian Schahram , Ball Laurel L. , Bizzotto Sara , Emery Sarah B. , Doan Ryan , Fasching Liana , Jang Yeongjun , Juan David , Lizano Esther , Moldovan John B. , Narurkar Rujuta , Oetjens Matthew T. , Sekar Shobana , Shin Joo Heon , Soriano Eduardo , Straub Richard E. , Zhou Weichen , Chess Andrew , Gleeson Joseph G. , Marquès-Bonet Tomas , Park Peter J. , Peters Mette A. , Pevsner Jonathan , Walsh Christopher A. , Weinberger Daniel R. ,   Brain Somatic Mosaicism Network, Vaccarino Flora M. , Moran John V. , Urban Alexander E. , Kidd Jeffrey M. , Mills Ryan E. , Abyzov Alexej
Published: October 2020

Post-zygotic mutations incurred during DNA replication, DNA repair, and other cellular processes lead to somatic mosaicism. Somatic mosaicism is an established cause of various diseases, including cancers. However, detecting mosaic variants in DNA from non-cancerous somatic tissues poses significant challenges, particularly if the variants only are present in a small fraction of cells. Here, the Brain Somatic Mosaicism Network conducted a coordinated, multi-institutional study to: (i) examine the ability of existing methods to detect simulated somatic single nucleotide variants (SNVs) in DNA mixing experiments; (ii) generate multiple replicates of whole genome sequencing data from the dorsolateral prefrontal cortex, other brain regions, dura mater, and dural fibroblasts of a single neurotypical individual; (iii) devise strategies to discover somatic SNVs; and (iv) apply various approaches to validate somatic SNVs. These efforts led to the identification of 43bona fidesomatic SNVs that ranged in variant allele fractions from ~0.005 to ~0.28. Guided by these results, we devised best practices for calling mosaic SNVs from 250X whole genome sequencing data in the accessible portion of the human genome that achieve 90% specificity and sensitivity. Finally, we demonstrated that analysis of multiple bulk DNA samples from a single individual allows the reconstruction of early developmental cell lineage trees. Thus, this study provides a unified set of best practices to detect somatic SNVs in non-cancerous tissues. The data and methods are freely available to the scientific community and should serve as a guide to assess the contributions of somatic SNVs to neuropsychiatric diseases.
Culture influences audiovisual emotion perception in early sensory areas
Authors: Tanaka Akihiro , Takagi Sachiko , Harada Tokiko , Huis In ’t Veld Elisabeth , de Gelder Beatrice , Hamano Yuki , Tabei Ken-ichi , Sadato Norihiro
Published: October 2020

Emotion perception from facial and vocal expressions is a multisensory process critical for human social interaction. When asked to judge emotions by attending to either face or voice, the accuracy was higher when facial expressions are congruent with vocal expressions than when they are incongruent. This congruency effect was shown to be affected by cultural background. Here we conducted functional MRI alongside a multisensory emotion perception task involving Japanese and Dutch participants. They were presented with movies in which congruent or incongruent emotions were expressed through faces and voices. The participants were asked to judge the emotion of either the face or the voice. Consistent with previous studies, behavioral results showed an interaction between group and task. fMRI results revealed that during voice-based judgement, congruency effects of the primary visual cortex, by means of the task related activity of congruent stimuli subtracted by that of incongruent stimuli, were more prominent in the Dutch group than in Japanese group. Finally, behavioral and neural congruency effects of the primary visual cortex were positively correlated only in the Dutch group. Taken together, our results show that culture affects the activities of early sensory areas in multisensory perception from facial and vocal expressions.
BAli-Phy version 3: Model-based co-estimation of Alignment and Phylogeny
Authors: Redelings Benjamin D.
Published: October 2020

We describe improvements to BAli-Phy, a Markov chain Monte Carlo (MCMC) program that jointly estimates phylogeny, alignment, and other parameters from unaligned sequence data. Version 3 is substantially faster for large trees, and implements covarion models, RNA stem models, and other new models. It implements ancestral state reconstruction, allows prior selection for all model parameters, and can also analyze multiple genes simultaneously.

Availability

Software is available for download athttp://www.bali-phy.org. C++source code is freely available on Github under the GPL2 License.

Contact

benjamin.redelings@gmail.com
Features of Functional Human Genes
Authors: Cooper Helena B. , Gardner Paul P.
Published: October 2020

Proteins and non-coding RNAs are functional products of the genome that carry out the bulk of crucial cellular processes. With recent technological advances, researchers can sequence genomes in the thousands as well as probe for specific genomic activities of multiple species and conditions. These studies have identified thousands of potential proteins, RNAs and associated activities, however there are conflicting conclusions on the functional implications depending upon the burden of evidence researchers use, leading to diverse interpretations of which regions of the genome are “functional”. Here we investigate the association between gene functionality and genomic features, by comparing established functional protein-coding and non-coding genes to non-genic regions of the genome. We find that the strongest and most consistent association between functional genes and any genomic feature is evolutionary conservation and transcriptional activity. Other strongly associated features include sequence alignment statistics, such as maximum between-site covariation. We have also identified some concerns with 1,000 Genomes Project and Genome Aggregation Database SNP densities, as short non-coding RNAs tend to have greater than expected SNP densities. Our results demonstrate the importance of evolutionary conservation and transcription for sequence functionality, which should both be taken into consideration when differentiating between functional sequences and noise.
Dynamic binning peak detection and assessment of various lipidomics liquid chromatography-mass spectrometry pre-processing platforms
Authors: Feng Xiaodong , Zhang Wenxuan , Kuipers Folkert , Kema Ido , Barcaru Andrei , Horvatovich Péter
Published: October 2020

Liquid chromatography-mass spectrometry (LC-MS) based lipidomics generate a large dataset, which requires high-performance data pre-processing tools for their interpretation such as XCMS, mzMine and Progenesis. These pre-processing tools rely heavily on accurate peak detection, which depends on setting the peak detection mass tolerance (PDMT) properly. The PDMT is usually set with a fixed value in either ppm or Da units. However, this fixed value may result in duplicates or missed peak detection. Therefore, we developed the dynamic binning method for accurate peak detection, which takes into account the peak broadening described by well-known physics laws of ion separation and set dynamically the value of PDMT as a function of m/z. Namely, in our method, the PDMT is proportional tofor FTICR, tofor Orbitrap, tom/zfor Q-TOF and is a constant for Quadrupole mass analyzer, respectively. The dynamic binning method was implemented in XCMS [1,2] and the adopted source code is available in the Appendix. Our further goal was to compare the performance of different lipidomics pre-processing tools to find differential compounds. We have generated set samples with 43 lipids internal standards differentially spiked to aliquots of one human plasma lipid sample using Orbitrap LC-MS/MS. The performance of the various pipelines using aligned parameter sets was quantified by a quality score system which reflects the ability of a pre-processing pipeline to detect differential peaks spiked at various concentration levels. The quality score indicates that the dynamic binning method improves the performance of XCMS (maximum p-value 9.8·10−3of two-sample Wilcoxon test). The modified XCMS software was further compared with mzMine and Progenesis. The results showed that modified XCMS and Progenesis had a similarly good performance in the aspect of finding differential compounds. In addition, Progenesis shows lower variability as indicated by lower CVs, followed by XCMS and mzMine. The lower variability of Progenesis improve the quantification, however, provide an incorrect quantification abundance order of spiked-in internal standards.
A 180 My-old female-specific genome region in sturgeon reveals the oldest known vertebrate sex determining system with undifferentiated sex chromosomes
Authors: Kuhl Heiner , Guiguen Yann , Höhne Christin , Kreuz Eva , Du Kang , Klopp Christophe , Lopez-Roques Céline , Yebra-Pimentel Elena Santidrian , Ciorpac Mitica , Gessner Jörn , Holostenco Daniela , Kleiner Wibke , Kohlmann Klaus , Lamatsch Dunja K. , Prokopov Dmitry , Bestin Anastasia , Bonpunt Emmanuel , Debeuf Bastien , Haffray Pierrick , Morvezen Romain , Patrice Pierre , Suciu Radu , Dirks Ron , Wuertz Sven , Kloas Werner , Schartl Manfred , Stöck Matthias
Published: October 2020

Several hypotheses explain the prevalence of undifferentiated sex chromosomes in poikilothermic vertebrates. Turnovers change the master sex determination gene, the sex chromosome or the sex determination system (e.g. XY to WZ). Jumping master genes stay main triggers but translocate to other chromosomes. Occasional recombination (e.g. in sex-reversed females) prevents sex chromosome degeneration. Recent research has uncovered conserved heteromorphic or even homomorphic sex chromosomes in several clades of non-avian and non-mammalian vertebrates. Sex determination in sturgeons (Acipenseridae) has been a long-standing basic biological question, linked to economical demands by the caviar-producing aquaculture. Here, we report the discovery of a sex-specific sequence from sterlet (Acipenser ruthenus). Using chromosome-scale assemblies and pool-sequencing, we first identified a ~16 kb female-specific region. We developed a PCR-genotyping test, yielding female-specific products in six species, spanning the entire phylogeny with the most divergent extant lineages (A. sturio, A. oxyrinchusvs.A. ruthenus, Huso huso), stemming from an ancient tetraploidization. Similar results were obtained in two octoploid species (A. gueldenstaedtii, A. baerii). Conservation of a female-specific sequence for a long period, representing 180 My of sturgeon evolution, and across at least one polyploidization event, raises many interesting biological questions. We discuss a conserved undifferentiated sex chromosome system with a ZZ/ZW-mode of sex determination and potential alternatives.
A General Birth-Death-Sampling Model for Epidemiology and Macroevolution
Authors: MacPherson Ailene , Louca Stilianos , McLaughlin Angela , Joy Jeffrey B. , Pennell Matthew W.
Published: October 2020

Birth-death stochastic processes are the foundation of many phylogenetic models and are widely used to make inferences about epidemiological and macroevolutionary dynamics. There are a large number of birth-death model variants that have been developed; these impose different assumptions about the temporal dynamics of the parameters and about the sampling process. As each of these variants was individually derived, it has been difficult to understand the relationships between them as well as their precise biological and mathematical assumptions. Without a common mathematical foundation, deriving new models is non-trivial. Here we unify these models into a single framework, prove that many previously developed epidemiological and macroevolutionary models are all special cases of a more general model, and illustrate the connections between these variants. This framework centers around a technique for deriving likelihood functions for arbitrarily complex birth-death(-sampling) models that will allow researchers to explore a wider array of scenarios than was previously possible. We then use this frame-work to derive general model likelihoods for both the “single-type” case in which all lineages diversify according to the same process and the “multi-type” case, where there is variation in the process among lineages. By re-deriving existing single-type birth-death sampling models we clarify and synthesize the range of explicit and implicit assumptions made by these models.
GlycoPathDB: A database of monosaccharide biosynthesis pathways
Authors: Srivastava Jaya , Sunthar P. , Balaji Petety V.
Published: October 2020

A distinctive feature of glycans vis-à-vis proteins and nucleic acids is its structural complexity which arises from the huge repertoire of monosaccharides, isomeric linkages and branching. Around 70 monosaccharides have so far been discovered in natural glycans and the pathway for the biosynthesis of 57 of these have been experimentally characterized. However, there is no common platform with a comprehensive information of monosaccharide pathways and enzymes. We have gathered 542 experimentally characterized enzymes of these pathways from literature and set up a first of its kind database called GlycoPathDB (http://www.bio.iitb.ac.in/glycopathdb/). Annotations such as the reaction catalysed, substrate specificity, biosynthesis pathway and PubMed IDs are provided for all the enzymes in the database. Sequence homologs of the experimentally characterized enzymes found in nearly 13,000 completely sequenced genomes from Bacteria and Archaea have also been included in the database. This platform will help in deduction of evolutionary relationships among enzymes such as aminotransferases, nucleotidyltransferases, acetyltransferases and SDR family enzymes. It can also facilitate experimental studies such as direct enzyme assays to validate putative annotations, establish structure-function relationship, expression profiling to determine the function, determine the phenotypic consequences of gene knock-out/knock-in and complementation studies.
VOLTAGE-GATED POTASSIUM CHANNELS CONTROL THE GAIN OF ROD-DRIVEN LIGHT RESPONSES IN MIXED-INPUT ON BIPOLAR CELLS
Authors: Joselevitch Christina , Klooster Jan , Kamermans Maarten
Published: October 2020

To achieve high sensitivity at scotopic levels, vision sacrifices spatial and temporal resolution. The detection of dim light, however, depends crucially on the ability of the visual system to speed up rod signals as they advance towards the brain. At higher light levels, gain control mechanisms are necessary to prevent premature saturation of second-order neurons. We investigated how goldfish mixed-input ON bipolar cells (ON mBCs) manage to partially compensate for the intrinsically slow kinetics of rod signals in the dark-adapted state, and at the same time control the gain of rod signals. Rod-driven responses of axotomized ON mBCs become faster and more transient than those of rod horizontal cells as stimulus intensity increases. This transientness has a voltage-dependency consistent with the activation of a voltage-gated K+conductance. Simulations with NEURON indicate that the voltage-gated K+channels responsible for speeding up responses are concentrated at the distal tips of the bipolar cell dendrites, close to the glutamate receptors. These channels act as a gain control mechanism, by shunting the effect of tonically hyperpolarized rods onto the ON mBC. Further activation of K+channels accelerates the ON mBC response by decreasing the membrane time constant as light levels increase. Therefore, the presence of voltage-gated K+channels at the dendritic tips of ON mBCs extends the dynamic range of these neurons, and at the same time generates a transient signal already at the first visual synapse.

Key Points Summary

Here we show that voltage-gated potassium channels can adjust the gain of the rod input to mixed-input ON bipolar cells and generate a transient signal already at the first visual synapse.

These channels are activated during the light-induced depolarization, making bipolar cell light responses smaller, faster, and more transient, effects that can be abolished by the K+channel blocker TEA.

Mathematical simulations suggest that these channels are concentrated at the bipolar cell dendritic tips, close to the site of rod input.

This kind of gain control happens at all levels in the retina and is especially important for cells that receive mixed input from rods and cones, in order to prevent premature saturation with increasing light levels and remove the temporal redundancy of the photoreceptor signal.
Simulation of FUS protein condensates with an adapted coarse-grained model
Authors: Benayad Zakarya , von Bülow Sören , Stelzl Lukas S. , Hummer Gerhard
Published: October 2020

Disordered proteins and nucleic acids can condense into droplets that resemble the membraneless organelles observed in living cells. MD simulations offer a unique tool to characterize the molecular interactions governing the formation of these biomolecular condensates, their physico-chemical properties, and the factors controlling their composition and size. However, biopolymer condensation depends sensitively on the balance between different energetic and entropic contributions. Here, we develop a general strategy to fine-tune the potential energy function for molecular dynamics simulations of biopolymer phase separation. We rebalance protein-protein interactions against solvation and entropic contributions to match the excess free energy of transferring proteins between dilute solution and condensate. We illustrate this formalism by simulating liquid droplet formation of the FUS low complexity domain (LCD) with a rebalanced MARTINI model. By scaling the strength of the nonbonded interactions in the coarse-grained MARTINI potential energy function, we map out a phase diagram in the plane of protein concentration and interaction strength. Above a critical scaling factor ofαc≈ 0.6, FUS LCD condensation is observed, whereα= 1 and 0 correspond to full and repulsive interactions in the MARTINI model, respectively. For a scaling factorα= 0.65, we recover the experimental densities of the dilute and dense phases, and thus the excess protein transfer free energy into the droplet and the saturation concentration where FUS LCD condenses. In the region of phase separation, we simulate FUS LCD droplets of four different sizes in stable equilibrium with the dilute phase and slabs of condensed FUS LCD for tens of microseconds, and over one millisecond in aggregate. We determine surface tensions in the range of 0.01 to 0.4mN/m from the fluctuations of the droplet shape and from the capillary-wave-like broadening of the interface between the two phases. From the dynamics of the protein end-to-end distance, we estimate shear viscosities from 0.001 to 0.02Pas for the FUS LCD droplets with scaling factorsαin the range of 0.625 to 0.75, where we observe liquid droplets. Significant hydration of the interior of the droplets keeps the proteins mobile and the droplets fluid.
Extended and dynamic linker histone-DNA interactions control chromatosome compaction
Authors: Rudnizky Sergei , Khamis Hadeel , Ginosar Yuval , Goren Efrat , Melamed Philippa , Kaplan Ariel
Published: October 2020

Chromatosomes play a fundamental role in chromatin regulation, but a detailed understanding of their structure is lacking, partially due to their complex dynamics. Using single-molecule DNA unzipping with optical tweezers, we reveal that linker histone interactions with DNA are remarkably extended, with the C-terminal domain binding both DNA linkers as far as ~ ±140 bp from the dyad. In addition to a symmetrical compaction of the nucleosome core governed by globular domain contacts at the dyad, the C-terminal domain compacts the nucleosome’s entry and exit. These interactions are dynamic, exhibiting rapid binding and dissociation, sensitive to phosphorylation of a specific residue, and crucial to determining the symmetry of the chromatosome’s core. Extensive unzipping of the linker DNA, which mimics its invasion by motor proteins, shifts H1 into an asymmetric, off-dyad configuration and triggers nucleosome decompaction, highlighting the plasticity of the chromatosome structure and its potential regulatory role.
Lis1 mutation prevents basal radial glia-like cell production in the mouse
Authors: Penisson Maxime , Hirotsune Shinji , Francis Fiona , Belvindrah Richard
Published: October 2020

Human cortical malformations are associated with progenitor proliferation and neuronal migration abnormalities. Progenitor cells include apical radial glia, intermediate progenitors and basal (or outer) radial glia (bRGs or oRGs). bRGs are few in number in lissencephalic species (e.g. the mouse) but abundant in gyrencephalic brains. TheLIS1gene coding for a dynein regulator, is mutated in human lissencephaly, associated also in some cases with microcephaly. LIS1 was shown to be important during cell division and neuronal migration. Here, we generated bRG-like cells in the mouse embryonic brain, investigating the role of Lis1 in their formation. This was achieved byin uteroelectroporation of a hominoid-specific geneTBC1D3(coding for a RAB-GAP protein) at mouse embryonic day (E) 14.5. We first confirmed thatTBC1D3expression in wild-type (WT) brain generates numerous Pax6+bRG-like cells that are basally localized. Second, using the same approach, we assessed the formation of these cells in heterozygoteLis1 mutant brains. Our novel results show thatLis1 depletion in the forebrain from E9.5 prevented subsequentTBC1D3-induced bRG-like cell amplification. Indeed, we observe disruption of the ventricular zone (VZ) in the mutant.Lis1 depletion altered adhesion proteins and mitotic spindle orientations at the ventricular surface and increased the proportion of abventricular mitoses. Progenitor outcome could not be further altered by TBC1D3. We conclude that perturbation ofLis1/LIS1 dosage is likely to be detrimental for appropriate progenitor number and position, contributing to lissencephaly pathogenesis.
Aberrant replication licensing drives Copy Number Gains across species
Authors: Nathanailidou Patroula , Petropoulos Michalis , Maxouri Styliani , Kasselimi Eirini , Symeonidou Ioanna Eleni , Preza Ourania , Spiliopoulou-Sdougkou Iris , Beneš Vladimir , Taraviras Stavros , Lygerou Zoi
Published: October 2020

Copy Number Gains (CNGs) lead to genetic heterogeneity, driving evolution and carcinogenesis. The mechanisms promoting CNG formation however remain poorly characterized. We show that abnormal expression of the replication licensing factor Cdc18 in fission yeast, which leads to genome-wide re-replication, drives the formation of CNGs at different genomic loci, promoting the acquisition of new selectable traits. Whole genome sequencing reveals Mb long, primarily extrachromosomal amplicons. Genetic analysis shows that homology-mediated repair is required to resolve re-replication intermediates into heritable CNGs. Consistently, we show that in mammalian cells overexpression of CDC6 and/or CDT1 leads to CNGs and promotes drug resistance. In human cells, multiple repair pathways are activated upon rereplication and act antagonistically, with RAD52 promoting and 53BP1 inhibiting CNG formation. In tumours, CDT1 and/or CDC6 overexpression correlates with copy number gains genome-wide. We propose re-replication as an evolutionary-conserved driver of CNGs, highlighting a link between aberrant licensing, CNGs and cancer.
Innate Behavior Sequence Progression by Peptide-Mediated Interorgan Crosstalk
Authors: Heredia Fabiana , Volonté Yanel , Pereirinha Joana , Fernandez-Acosta Magdalena , Casimiro Andreia P. , Belém Cláudia G. , Viegas Filipe , Tanaka Kohtaro , Menezes Juliane , Arana Maite , Cardoso Gisele A. , Macedo André , Kotowicz Malwina , Prado Spalm Facundo H. , Dibo Marcos J. , Monfardini Raquel D. , Torres Tatiana T. , Mendes César S. , Garelli Andres , Gontijo Alisson M.
Published: October 2020

Innate behaviors consist of a succession of genetically-hardwired motor and physiological subprograms that can be coupled to drastic morphogenetic changes. How these integrative responses are orchestrated is not completely understood. Here, we provide insight into these mechanisms by studying pupariation, a multi-step innate behavior of fly larvae that is critical for survival during metamorphosis. We find that the steroid-hormone ecdysone triggers parallel pupariation neuromotor and morphogenetic subprograms, which include the induction of the relaxin-peptide hormone, Dilp8, in the epidermis. Dilp8 acts on six Lgr3-positive thoracic interneurons to couple both subprograms in time and to instruct neuromotor subprogram switching during behavior. Our work reveals that interorgan feedback gates progression between subunits of an innate behavior and points to an ancestral neuromodulatory function of relaxin signaling.
sc-REnF:An entropy guided robust feature selection for clustering of single-cell rna-seq data
Authors: Lall Snehalika , Ghosh Abhik , Ray Sumanta , Bandyopadhyay Sanghamitra
Published: October 2020

Many single-cell typing methods require pure clustering of cells, which is susceptible towards the technical noise, and heavily dependent on high quality informative genes selected in the preliminary steps of downstream analysis. Techniques for gene selection in single-cell RNA sequencing (scRNA-seq) data are seemingly simple which casts problems with respect to the resolution of (sub-)types detection, marker selection and ultimately impacts towards cell annotation. We introducesc-REnF, a novel androbustentropy basedfeature (gene) selection method, which leverages the landmark advantage of ‘Renyi’ and ‘Tsallis’ entropy achieved in their original application, in single cell clustering. Thereby, gene selection is robust and less sensitive towards the technical noise present in the data, producing a pure clustering of cells, beyond classifying independent and unknown sample with utmost accuracy. The corresponding software is available at:https://github.com/Snehalikalall/sc-REnF
Introducing and benchmarking the accuracy of cayenne: a Python package for stochastic simulations
Authors: Kishore Dileep , Chandrasekaran Srikiran
Published: October 2020

Biological systems are intrinsically noisy and this noise may determine the qualitative outcome of the system. In the absence of analytical solutions to mathematical models incorporating noise, stochastic simulation algorithms are useful to explore the possible trajectories of these systems. Algorithms used for such stochastic simulations include the Gillespie algorithm and its approximations. In this study we introduce cayenne, an easy to use Python package containing accurate and fast implementations of the Gillespie algorithm (direct method), the tau-leaping algorithm and a tau-adaptive algorithm. We compare the accuracy of cayenne with other stochastic simulation libraries (BioSimulator.jl, GillespieSSA and Tellurium) and find that cayenne offers the best trade-off between accuracy and speed. Additionally, we highlight the importance of performing accuracy tests for stochastic simulation libraries, and hope that it becomes standard practice when developing the same.

The cayenne package can be found athttps://github.com/Heuro-labs/cayennewhile the bench-marks can be found athttps://github.com/Heuro-labs/cayenne-benchmarks
The Synergism Between DHODH Inhibitors and Dipyridamole Leads to Metabolic Lethality in Acute Myeloid Leukemia
Authors: Gaidano Valentina , Houshmand Mohammad , Vitale Nicoletta , Carrà Giovanna , Morotti Alessandro , Tenace Valerio , Rapelli Stefania , Sainas Stefano , Pippione Agnese Chiara , Giorgis Marta , Boschi Donatella , Lolli Marco Lucio , Cignetti Alessandro , Saglio Giuseppe , Circosta Paola
Published: October 2020

Background

Dihydroorotate Dehydrogenase (DHODH) is a key enzyme of thede novopyrimidine biosynthesis, whose inhibition was recently found to induce differentiation and apoptosis in acute myeloid leukemia (AML). DHODH inhibitors were previously investigated in solid tumors, where they showed promising antiproliferative activity, bothin vitroandin vivo. However, their effectiveness was not confirmed in clinical trials, probably due to the pyrimidine salvage pathway that cancer cells could exploit to survive. In this study we investigated the pro-apoptotic activity of MEDS433, the DHODH inhibitor developed by our group, against AML. Learning from previous failures, we challenged our model mimickingin vivoconditions, and looked for synergic combination to boost apoptosis.

Methods

We evaluated the apoptotic rate of multiple AML cell lines and AML primary cells treated with MEDS433 or other DHODH inhibitors, alone and in combination with classical antileukemic drugs or with dipyridamole, a blocker of the pyrimidine salvage pathway. Experiments were also performed mimickingin vivoconditions, i.e., in the presence of physiological uridine plasma levels (5μM).

Results

MEDS433 showed a strong apoptotic effect against multiple AML cell lines, which was at least partially independent from the differentiation process. Its combination with classical antileukemic agents resulted in a further increase of the apoptotic rate. However, when MEDS433 was tested in the presence of 5μM uridine and/or in primary AML cells, results were less impressive. On the contrary, the combination of MEDS433 with dipyridamole resulted in an outstanding synergistic effect, with a dramatic increase of the apoptotic rate both in AML cell lines and AML primary cells, which was unaffected by physiological uridine concentrations. Preliminary analyses show that the toxicity of this treatment should be limited to proliferating cells.

Conclusions

The combination of a DHODH inhibitor and dipyridamole is characterized by differentiating and pro-apoptotic features and induces metabolic lethality on a wide variety of AMLs with different genetic backgrounds.
Animal chromosome counts reveal similar range of chromosome numbers but with less polyploidy in animals compared to flowering plants
Authors: Román-Palacios Cristian , Medina Cesar A. , Zhan Shing H. , Barker Michael S.
Published: October 2020

Understanding the mechanisms that underlie chromosome evolution may provide insights into the processes underpinning the origin, persistence, and evolutionary tempo of lineages. Here we present the first database of chromosome counts for animals (the Animal Chromosome Count database, ACC) summarizing chromosome numbers for ∼18,000 species. We found remarkable similarity in the distribution of chromosome counts between animals and flowering plants. At larger timescales, selection towards a specific range might explain the similar distribution of chromosome counts between these two groups. Nevertheless, changes in chromosome number are still potential drivers of divergence among species at shorter timescales. We also found that while animals and plants exhibit similar frequencies of speciation-related changes in chromosome number, plant speciation is more often related to changes in ploidy. Based on the ACC, our analyses suggest that changes in chromosome number alone could help explain patterns of diversity within animal clades.
Brain aging-dependent glioma traits reversible by NAD+/BDNF-mediated neuronal reactivation
Authors: Yamashita Daisuke , Flanary Victoria L , Munk Rachel B , Sonomura Kazuhiro , Ozaki Saya , Kawaguchi Riki , Suehiro Satoshi , Bastola Soniya , Pavlyukov Marat S , Yamaguchi Shinobu , Nakano Mayu A , Kunieda Takeharu , Hambardzumyan Dolores , Kondo Toru , Kornblum Harley I , Crossman David K , Hackney James R , Sato Taka-aki , Gorospe Myriam , Nakano Ichiro
Published: October 2020

The rise in aging population worldwide is increasing death from cancer, including glioblastoma. Here, we explore the impact of brain aging on glioma tumorigenesis. We find that glioblastoma in older patients and older mice displayed reduced neuronal signaling, including a decline of NTRK-like family member 6 (SLITRK6), a receptor for neurotrophic factor BDNF. This reduction was linked to the systemic decline of nicotinamide adenine dinucleotide (NAD+) with aging, as old mice exposed to young bloodviaparabiosis or supplemented with the NAD+precursor NMN (nicotinamide mononucleotide) reverted phenotypically to young-brain responses to glioma, with reactivated neuronal signaling and reduced death from tumor burden. Interestingly, the phenotypic reversal by NMN was largely absent in old mice undergoing parabiosis with BDNF+/-young mice and in BDNF+/-mice undergoing tumor challenge, supporting the notion that the lower NAD+-BDNF signaling in the aging brain aggravated glioma tumorigenesis. We propose that the aging-associated decline in brain NAD+worsens glioma outcomes at least in part by decreasing neuronal/synaptic activity and increasing neuroinflammation.
Flexible and transparent silver nanowire structures for multifunctional electrical and optical biointerfacing
Authors: Chen Zhiyuan , Boyajian Nicolas , Lin Zexu , Yin Rose T. , Obaid Sofian N. , Tian Jinbi , Brennan Jaclyn A. , Chen Sheena W. , Miniovich Alana N. , Lin Leqi , Qi Yarong , Liu Xitong , Efimov Igor R. , Lu Luyao
Published: October 2020

Transparent microelectrodes have recently emerged as a promising approach to combine electrophysiology with optophysiology for multifunctional biointerfacing. High-performance flexible platforms that allow seamless integration with soft tissue systems for such applications are urgently needed. Here, silver nanowires (Ag NWs)-based transparent microelectrodes and interconnects are designed to meet this demand. The Ag NWs percolating networks are patterned on flexible polymer substrates using an innovative photolithography-based solution-processing technique. The resulting nanowire networks exhibit a high average optical transparency of 76.1-90.0% over the visible spectrum, low normalized electrochemical impedance of 3.4-15 Ω cm2at 1 kHz which is even better than those of opaque solid Ag films, superior sheet resistance of 11-25 Ω sq−1, excellent mechanical stability up to 10,000 bending cycles, good biocompatibility and chemical stability. Studies on Langendorff-perfused mouse and rat hearts demonstrate that the Ag NWs microelectrodes enable high-fidelity real-time monitoring of heart rhythm during co-localized optogenetic pacing and optical mapping with negligible light-induced electrical artifacts. This proof-of-concept work illustrates that the solution-processed, transparent, and flexible Ag NWs networks are a promising candidate for the next-generation of large-area multifunctional biointerfaces for interrogating complex biological systems in basic and translational research.
Structural Perturbations of Exon Skipping Edits within the Dystrophin D20:24 Region
Authors: Niu Xin , Menhart Nick
Published: October 2020

Exon skipping is a disease modifying therapy that operates at the RNA level. In this strategy, oligonucleotide analog drugs are used to specifically mask specific exons and prevent them from inclusion in the mature mRNA. Of course, this also results in loss of the corresponding region from the cognate protein, which is one possible therapeutic aim. Exon skipping can also be used to restore protein expression in cases where a genetic frameshift mutation has occurred, and this how it is applied to Duchenne muscular dystrophy, DMD. DMD most commonly arises as a result of large exonic deletions that juxtapose flanking exons of incompatible reading frame in the dystrophin gene, creating a frameshift and abolishing protein expression. Loss of dystrophin protein leads to the pathology of the disease, which is severe, causing death generally in the second or third decade of life. Here, the primary aim of exon skipping is the restoration of the reading frame by skipping an exon adjacent to the patient’s original defect. However, the therapeutically expressed protein is of course edited, and missing both the region of the underlying genetic defect, as well as the therapeutically skipped exon. While restoring some protein expression is good, how removing some region from the middle of a protein effects its structure and function is unclear. Complicating this in the case of DMD is the fact that the dystrophin gene is very large, containing 79 exons. Many different underlying deletions are known, and exon skipping can be applied in many ways. It has previously been shown that many exon-skip edits result in structural perturbations of varying degrees. What has been unclear is whether and how exon editing can be done to minimize these perturbations. In this study we examine a systematic and comprehensive panel of possible exon edits in a region of the dystrophin protein, and identify for the first time, exon edits that appear to maintain structural stability similar to wildtype protein. We also identify factors that appear to be correlated with the degree of structural perturbation, such as the number of cooperative protein domains, as well as how the underlying exon structure interacts with the protein domain structure.
Colitis is associated with loss of LHPP and up-regulation of histidine phosphorylation in intestinal epithelial cells
Authors: Linder Markus , Liko Dritan , Kancherla Venkatesh , Piscuoglio Salvatore , Hall Michael N.
Published: October 2020

Protein histidine phosphorylation (pHis) is a posttranslational modification involved in cell cycle regulation, ion channel activity and phagocytosis (1). Using novel monoclonal antibodies to detect pHis (2), we recently reported that loss of the histidine phosphatase LHPP results in elevated pHis levels in hepatocellular carcinoma (3). Here, we show that intestinal inflammation correlates with loss of LHPP, in DSS-treated mice and in inflammatory bowel disease (IBD) patients. Increased histidine phosphorylation was observed in intestinal epithelial cells (IECs), as determined by pHis immunofluorescence staining of colon samples from a colitis mouse model. However, ablation ofLhppdid not cause increased pHis or promote intestinal inflammation in physiological conditions or after DSS treatment. Our observations suggest that increased histidine phosphorylation plays a role in colitis, but loss of LHPP is not sufficient to increase pHis or to cause inflammation in the intestine.