bluuebunny/crossref_metadata_2025 huggingface dataset:
Adaptive mechanisms facilitate robust performance in noise and in reverberation in an auditory categorization model
Authors: Parida Satyabrata , Liu Shi Tong , Sadagopan Srivatsun
Published: September 2022

For robust vocalization perception, the auditory system must generalize over variability in vocalization production as well as variability arising from the listening environment (e.g., noise and reverberation). We previously demonstrated that a hierarchical model generalized over production variability by detecting sparse intermediate-complexity features that are maximally informative about vocalization category from a dense spectrotemporal input representation. Here, we explore three biologically feasible model extensions to generalize over environmental variability: (1) training in degraded conditions, (2) adaptation to sound statistics in the spectrotemporal stage and (3) sensitivity adjustment at the feature detection stage. All mechanisms improved vocalization categorization performance, but improvement trends varied across degradation type and vocalization type. One or both adaptive mechanisms were required for model performance to approach the behavioral performance of guinea pigs on a vocalization categorization task. These results highlight the contributions of adaptive mechanisms at multiple auditory processing stages to achieve robust auditory categorization.
The Micromechanical Environment of the Impinged Achilles Tendon Insertion
Authors: Mora Keshia E. , Mlawer Samuel J. , Loiselle Alayna E. , Buckley Mark R.
Published: September 2022

Mechanical deformation applied to tendon at the tissue-scale is transferred to the microscale — including the extracellular matrix (ECM), the pericellular matrix (PCM), the cell and the nucleus — through a process known as strain transfer. Microscale strains, in turn, trigger biological activity that plays an important role in the maintenance of tendon phenotype and homeostasis. Although tendon predominantly experiences longitudinal tensile forces, transverse forces due to bony impingement have been implicated in both physiological (e.g., maintenance of the tendon insertion) and pathophysiological (e.g. insertional Achilles tendinopathy) processes. However, to our knowledge, prior studies have not characterized the micromechanical strain environment in the context of tendon impingement. Therefore, the objective of this study was to characterize the micromechanical strain environment in the impinged Achilles tendon insertion using a novel mouse hindlimb explant model in combination with finite element (FE) modeling. We hypothesized that impingement would generate large magnitudes of transverse compressive strain at the local matrix, PCM, and cell scales. Mouse hindlimb explants were imaged on a multiphoton microscope, and image stacks of the same population of tendon cells were obtained at the Achilles tendon insertion before and after dorsiflexion-induced impingement. Using an innovative multiphoton elastography approach, three-dimensional Green-Lagrange and principal strains were measured at the matrix scale, while longitudinal strain and aspect ratio were measured at the PCM and cell scales. Our results demonstrate that impingement generated substantial transverse compression at the matrix-scale, which led to longitudinal stretching of cells, an increase in cell aspect ratio, and — surprisingly — longitudinal compression of the tendon PCM. These experimental results were corroborated by an FE model developed to simulate the micromechanical environment in impinged regions of the Achilles tendon. Moreover, in both experiments and simulations, impingement-generated microscale stresses and strains were highly dependent on initial cell-cell gap spacing. Understanding the factors that influence the microscale strain environment generated by impingement could contribute to a more mechanistic understanding of impingement-induced tendinopathies and inform the development of approaches that disrupt the progression of pathology.
Gene panel design for spatial transcriptomics with prioritized gene sets
Authors: Yafi Mashrur Ahmed , Husain Hisham Md. Hasibul , Grisanti Francisco , Rahman Atif , Samee Md. Abul Hassan
Published: September 2022

A fundamental limitation of the emerging single-cell spatial transcriptomics (sc-ST) technologies is their panel size. Being based on fluorescence in situ hybridization, an sc-ST dataset can profile only a pre-determined panel of a few hundred genes. This often forces biologists to build panels from only the marker genes of different cell types and forgo other genes of interest, e.g., genes encoding ligand-receptor complexes or genes in specific pathways. We propose scGIST– a deep neural network that designs sc-ST panels through constrained feature selection. On four datasets, scGIST outperformed alternative methods in terms of cell type detection accuracy. Moreover, unlike other methods, scGIST allows genes of interest to be prioritized for inclusion in the panel while staying within the its size constraint. We demonstrate through diverse use cases that scGIST includes large fractions of prioritized genes without compromising cell type prediction efficacy making it a valuable addition to sc-ST’s algorithmic toolbox.
Hippocampo-cortical circuits for selective memory encoding, routing, and replay
Authors: Harvey Ryan E. , Robinson Heath L. , Liu Can , Oliva Azahara , Fernandez-Ruiz Antonio
Published: September 2022

Traditionally considered a homogeneous cell type, hippocampal pyramidal cells have been recently shown to be highly diverse. However, how this cellular diversity relates to the different hippocampal network computations that support memory-guided behavior is not yet known. We discovered that the anatomical identity of pyramidal cells is a major organizing principle of CA1 assembly dynamics, the emergence of memory replay, and cortical projection patterns. Segregated pyramidal cell subpopulations encoded trajectory and choice-specific information or tracked changes in reward configuration respectively, and selectively routed these representations to different cortical targets. Furthermore, distinct hippocampo-cortical assemblies coordinated the reactivation of complementary memory representations. These findings reveal the existence of specialized hippocampo-cortical subcircuits and provide a cellular mechanism that supports the computational flexibility and memory capacities of these structures.
Gut bacteria-derived serotonin promotes immune tolerance in early life
Authors: Sanidad Katherine Z. , Rager Stephanie L. , Carrow Hannah C. , Ananthanarayanan Aparna , Callaghan Ryann , Hart Lucy R. , Li Tingting , Ravisankar Purnima , Brown Julia A. , Amir Mohammed , Jin Jenny C. , Savage Alexandria Rose , Luo Ryan , Mardorsky Rowdo Florencia , Martin M. Laura , Silver Randi B. , Guo Chun-Jun , Krumsiek Jan , Inohara Naohiro , Zeng Melody Y.
Published: September 2022

The gut microbiome promotes immune system development in early life, but the neonatal gut metabolome remains undefined. Here, we demonstrate that, distinct from adults, the neonatal mouse gut is enriched with neurotransmitters, and specific bacteria produce serotonin directly while downregulating monoamine oxidase A to limit serotonin breakdown. Serotonin inhibits mTOR activation to promote regulatory T cells and suppress T cell responses bothex vivoandin vivoin the neonatal intestine. Oral gavage of serotonin into neonatal mice leads to long-term immune tolerance toward both dietary antigens and commensal bacteria as well as alterations of the gut microbiome. Together, our study has uncovered unique microbiome-dependent mechanisms to maximize serotonin in the neonatal gut and a novel role for intestinal serotonin to promote immune tolerance in early life.
Gene inversion triggered origination of brackish archaeal heterotrophs in the aftermath of the Cryogenian Snowball Earth
Authors: Fan Lu , Xu Bu , Chen Songze , Liu Yang , Li Fuyan , Xie Wei , Prabhu Apoorva , Zou Dayu , Wan Ru , Li Hongliang , Liu Haodong , Liu Yuhang , Kao Shuh-Ji , Chen Jianfang , Zhu Yuanqing , Rinke Christian , Li Meng , Zhu Maoyan , Zhang Chuanlun
Published: September 2022

Land-ocean interactions greatly impacted the evolution of coastal life on Earth. However, the geological forces and genetic mechanisms that shaped evolutionary adaptations and allowed microorganisms to inhabit coastal brackish waters remain largely unexplored. Here, we infer the evolutionary trajectory of the ubiquitous heterotrophic archaeaPoseidoniales(Marine Group II archaea) across global aquatic habitats. Our results show that their brackish subgroups have evolved through the rearrangement of the magnesium transport genecorAthat conferred osmotic-stress tolerance dated to over 600 million years ago. The coastal family ofPoseidonialesshowed a rapid increase in the evolutionary rate during and in the aftermath of the Cryogenian Snowball Earth (~700 million years ago), possibly in response to the enhanced phosphorus supply and the rise of algae. Our study highlights the close interplay between genetic changes and ecosystem transformations that boosted microbial diversification in the Neoproterozoic continental margins.
Genetic correlations between gut microbiota genera and Alzheimer’s Disease
Authors: Cammann Davis , Lu Yimei , Cummings Melika J. , Zhang Mark L. , Cue Joan Manual , Do Jenifer , Ebersole Jeffrey , Chen Xiangning , Oh Edwin C. , Cummings Jeffrey L. , Chen Jingchun
Published: September 2022

1.

Abstract

Background

Dysbiosis of the human gut microbiota has been implicated in the development of Alzheimer’s disease (AD). However, the genetic correlation between gut microbiota and AD is not well addressed.

Methods

Using the largest genome-wide association study (GWAS) of gut microbiota genera from the MiBioGen consortium, we conducted the “best-fit” model from PRSice-2 to determine the genetic correlation between 119 genera and AD in a discovery sample (case/control: 1,278/1,293); we then replicated our findings in an independent sample (case/control: 799/778) and further performed meta-analyses to confirm the correlation. Finally, we conducted a linear regression to assess the correlation between the PRSs for the significant genera and theAPOEgenotype.

Results

In the discovery sample, 20 gut microbiota genera were initially identified genetically associated with AD. Three genera (Eubacterium fissicatenaas a protective factor,CollinsellaandVeillonellaas a risk factor) were validated in the replication sample. Meta-analysis confirmed nine genera to have a significant correlation with AD, three of which were significantly associated with theAPOErs429358 risk allele in a direction consistent with their protective/risk designation in AD association. Notably, the proinflammatory genusCollinsella, identified as a risk factor for AD, was positively correlated with theAPOErs429358 risk allele in both samples.

Conclusion

Host genetic factors influencing the abundance of nine genera are significantly associated with AD, suggesting that these genera may serve as biomarkers and targets for AD treatment and intervention. Our results highlight that proinflammatory gut microbiota might promote AD development through interaction withAPOE. Larger datasets and functional studies are required to understand their causal relationships.
Duration of viral infectiousness and correlation with symptoms and diagnostic testing in non-hospitalized adults during acute SARS-CoV-2 infection: A longitudinal cohort study
Authors: Drain Paul K. , Dalmat Ronit R. , Hao Linhui , Bemer Meagan J. , Budiawan Elvira , Morton Jennifer F. , Ireton Renee C. , Hsiang Tien-Ying , Marfatia Zarna , Prabhu Roshni , Woosley Claire , Gichamo Adanech , Rechkina Elena , Hamilton Daphne , Montaño Michalina , Cantera Jason L. , Ball Alexey S. , Golez Inah , Smith Elise , Greninger Alexander L. , McElrath M. Juliana , Thompson Matthew , Grant Benjamin D. , Meisner Allison , Gottlieb Geoffrey S. , Gale Michael J.
Published: September 2022

Background

Guidelines for SARS-CoV-2 have relied on limited data on duration of viral infectiousness and correlation with COVID-19 symptoms and diagnostic testing.

Methods

We enrolled ambulatory adults with acute SARS-CoV-2 infection and performed serial measurements of COVID-19 symptoms, nasal swab viral RNA, nucleocapsid (N) and spike (S) antigens, and replication-competent SARS-CoV-2 by culture. We determined average time from symptom onset to a first negative test result and estimated risk of infectiousness, as defined by a positive viral culture.

Results

Among 95 adults, median [interquartile range] time from symptom onset to first negative test result was 9 [5] days, 13 [6] days, 11 [4] days, and >19 days for S antigen, N antigen, viral culture growth, and viral RNA by RT-PCR, respectively. Beyond two weeks, viral cultures and N antigen titers were rarely positive, while viral RNA remained detectable among half (26/51) of participants tested 21-30 days after symptom onset. Between 6-10 days from symptom onset, N antigen was strongly associated with viral culture positivity (relative risk=7.61, 95% CI: 3.01-19.2), whereas neither viral RNA nor symptoms were associated with culture positivity. During the 14 days following symptom onset, presence of N antigen (adjusted relative risk=7.66, 95% CI: 3.96-14.82), remained strongly associated with viral culture positivity, regardless of COVID-19 symptoms.

Conclusions

Most adults have replication-competent SARS-CoV-2 for 10-14 after symptom onset, and N antigen testing is a strong predictor of viral infectiousness. Within two weeks from symptom onset, N antigen testing, rather than absence of symptoms or viral RNA, should be used to safely discontinue isolation.

Funding

Bill and Melinda Gates Foundation
The Nematode Antimicrobial Peptidome: a novel opportunity for parasite control?
Authors: Irvine Allister , Huws Sharon A. , Atkinson Louise E. , Mousley Angela
Published: September 2022

Antimicrobial Peptides (AMPs) are key constituents of the invertebrate innate immune system where they provide critical protection against microbial threat. Knowledge of AMP complements within phylum Nematoda is limited however nematodes adopt diverse life strategies and frequently reside in microbe-rich environments such that they are likely possess broad AMP profiles with bioactivity against a range of microbiota. Indeed, parasitic nematode AMPs likely have roles in defence against invading pathogens and modulation of the host microbiome.

In this study the distribution and abundance of AMP-encoding genes were examined in 134 nematode genomes providing the most comprehensive profile of AMPs within phylum Nematoda. We reveal that phylum Nematoda is AMP-rich and -diverse, where 5887 genes encode AMPs. Genome and transcriptome analyses broadly reveal: (i) AMP family profiles that are influenced by nematode lifestyle where free-living nematodes appear to have an expansion of AMPs relative to parasitic species; (ii) major differences in the AMP profiles between nematode clades where Clade 9/V and 10/IV species possess expanded AMP repertoires; (iii) AMP families with highly restricted profiles (e.g. Cecropins and Diapausins) and others [e.g. Nemapores and Glycine Rich Secreted Peptides (GRSPs)] which are more widely distributed; (iv) complexity in the distribution and abundance of Defensin subfamily members; and (v) expression of AMPs in key nematode life stages.

These data indicate that phylum Nematoda has a diverse array of AMPs and underscores the need to interrogate AMP function to unravel their importance to nematode biology and host-worm-microbiome interactions. Enhanced understanding of the Nematode Antimicrobial Peptidome will inform drug discovery pipelines for pathogen control.
A monoclonal antibody targeting the Nipah virus fusion glycoprotein apex imparts protection from disease
Authors: Avanzato Victoria A. , Bushmaker Trenton , Oguntuyo Kasopefoluwa Y. , Yinda Kwe Claude , Duyvesteyn Helen M. E. , Stass Robert , Meade-White Kimberly , Rosenke Rebecca , Thomas Tina , Saturday Greg , Doores Katie J. , Lee Benhur , Bowden Thomas A. , Munster Vincent J.
Published: September 2022

Nipah virus (NiV) is a highly pathogenic paramyxovirus capable of causing severe respiratory and neurologic disease in humans. Currently, there are no licensed vaccines or therapeutics against NiV, underscoring the urgent need for the development of countermeasures. The NiV surface-displayed glycoproteins, NiV-G and NiV-F, mediate host cell attachment and fusion, respectively, and are heavily targeted by host antibodies. Here, we describe a vaccination-derived neutralizing monoclonal antibody, mAb92, that targets NiV-F. Structural characterization of the fab region bound to NiV-F (NiV-F–Fab92) by cryo-electron microscopy analysis reveals an epitope in the DIII domain at the membrane distal apex of NiV-F, an established site of vulnerability on the NiV surface. Further, prophylactic treatment of hamsters with mAb92 offered complete protection from NiV disease, demonstrating beneficial activity of mAb92 in vivo. This work provides support for targeting NiV-F in the development of vaccines and therapeutics against NiV.
Continuous transcriptome analysis reveals novel patterns of early gene expression in Drosophila embryos
Authors: Pérez-Mojica J. Eduardo , Enders Lennart , Walsh Joseph , Lau Kin H. , Lempradl Adelheid
Published: September 2022

Early organismal development consists of transformative events that lay the foundation for body formation and long-term phenotype. Despite this understanding, the rapid progression of events and the limited material available are major barriers to studying the earliest stages. The size and accessibility of Drosophila embryos overcome some of these limitations, and several studies characterizing early transcriptional events have been reported. Unfortunately, manual embryo staging, and elaborate protocols make the techniques employed in these studies prone to human and technical errors and incompatible with routine laboratory use. Herein, we present a straight-forward and operationally simple methodology for studying the early transcription (≤3 hours) in Drosophila. This method relies on single-embryo RNA-sequencing and transcriptome ordering along a developmental trajectory (pseudo-time), thereby avoiding the need for the staging of the embryos. The obtained high-resolution and time-sensitive mRNA expression profiles uncovered the exact onset of transcription and degradation of transcripts and revealed an earlier transcription start for several zygotic genes. In addition, degradation patterns suggest that maternal mRNA decay is independent of mRNA levels. By classifying each embryo as male or female, we were also able to study sex-biased transcription between the beginning of zygotic transcription to gastrulation and identified 120 differentially expressed mRNAs. Using sex-specific transcription signatures, embryos can be sexed directly, eliminating the need for Y-chromosome genotyping. Herein, we report an accessible, single-embryo sequencing approach for high-resolution, time-sensitive transcriptome analysis. Our data provide an unparalleled resolution of gene expression during early development and enhance the current understanding of early transcriptional processes.
Prototyping of a lateral flow assay based on monoclonal antibodies for detection of Bothrops venoms
Authors: Knudsen Cecilie , Jürgensen Jonas A. , Knudsen Pelle D. , Oganesyan Irina , Harrison Julian A. , Dam Søren H. , Haack Aleksander M. , Friis Rasmus U. W. , Belfakir Selma B. , Ross Georgina M. S. , Zenobi Renato , Laustsen Andreas H.
Published: September 2022

Background

Brazil is home to a multitude of venomous snakes, perhaps the most medically relevant of which belong to the Bothrops genus. Bothrops spp. are responsible for roughly 70% of all snakebites in Brazil, and envenomings caused by their bites can be treated with three types of antivenom: bothropic antivenom, bothro-lachetic antivenom, and bothro-crotalic antivenom. The choice in antivenom that is administered depends not only on its availability and how certain the treating physician is that the patient was bitten by a bothropic snake. The diagnosis of a bothropic envenoming can be made based on expert identification of a photo of the snake or based on a syndromic approach wherein the clinician examines the patient for characteristic manifestations of envenoming. This approach can be very effective but requires staff that has been trained in clinical snakebite management, which, unfortunately, far from all relevant staff has.

Results

In this paper, we describe a prototype of the first lateral flow assay (LFA) capable of detecting venoms from Brazilian Bothrops spp. The monoclonal antibodies for the assay were generated using hybridoma technology and screened in sandwich enzyme-linked immunosorbent assays (ELISAs) to identify Bothrops spp. specific antibody sandwich pairs. The sandwich pairs were used to develop a prototype LFA that was able to detect venom from several different Bothrops spp. The limit of detection (LoD) of the prototype was evaluated using Brazilian B. atrox whole venom and was determined to be 8.0 ng/mL in spiked serum samples and 9.5 ng/mL in spiked urine samples, when using a portable reader, and < 25 ng/mL in spiked buffer when reading by eye.

Significance

The work presented here serves as a proof of concept of a genus-specific venom detection kit, which could support physicians in diagnosing Bothrops envenomings. Although further optimization and testing is needed before the LFA can find clinical use, such a device could aid in decentralizing antivenoms in the Brazilian Amazon and help ensure optimal snakebite management for even more victims of this highly neglected disease.
Residual Complex I activity supports glutamate catabolism and mtSLP via canonical Krebs cycle activity during acute anoxia without OXPHOS
Authors: Ravasz Dora , Bui David , Nazarian Sara , Pallag Gergely , Karnok Noemi , Roberts Jennie , Tennant Daniel A , Greenwood Bennett , Kitayev Alex , Hill Collin , Komlódi Timea , Doerrier Carolina , Gnaiger Erich , Kiebish Michael A , Raska Alexandra , Kolev Krasimir , Czumbel Bence , Narain Niven R , Seyfried Thomas N , Chinopoulos Christos
Published: September 2022

Anoxia halts oxidative phosphorylation (OXPHOS) causing an accumulation of reduced compounds in mitochondrial matrix which impedes dehydrogenases. By simultaneously measuring oxygen concentration, NADH autofluorescence, mitochondrial membrane potential and ubiquinone reduction extentin organelloin real-time, we show that Complex I utilized endogenous quinones to oxidize NADH under acute anoxia. Untargeted or [U-13C]glutamate-targeted metabolomic analysis of matrix and effluxed metabolites extracted during anoxia in the presence or absence of site-specific inhibitors of the electron transfer system inferred that NAD+regenerated by Complex I is reduced by the 2-oxoglutarate dehydrogenase complex yielding succinyl-CoA supporting mitochondrial substrate-level phosphorylation (mtSLP), releasing succinate. Yet, targeted metabolomic analysis using [U-13C]malate also revealed concomitant succinate dehydrogenase reversal during anoxia yielding succinate by reducing fumarate, albeit to a small extent. Our results highlight the importance of quinone availability to Complex I oxidizing NADH, thus maintaining glutamate catabolism and mtSLP in the absence of OXPHOS.
EEG-neurofeedback for promoting neuromodulation in the elderly: evidence from a double-blind study
Authors: Andrade Katia , Guieysse Thomas , Razafimahatratra Solofo , Houmani Nesma , Klarsfeld André , Dreyfus Gérard , Dubois Bruno , Medani Takfarinas , Vialatte François
Published: September 2022

Background

Electroencephalography (EEG) is a non-invasive method that records the brain signals with time resolution in the millisecond range, thereby allowing the monitoring of subjects’ mental states in real time. Using appropriate biomarkers extracted from these EEG signals and presenting them back in a neurofeedback loop can foster neural compensation mechanisms by teaching subjects to modulate their brain activity. Over the last decades, several neural biomarkers of aging have been described, with growing evidence suggesting that neuromodulation may have an important role in regulating brain activity in the elderly.

Methods and objectives

We used three neural biomarkers of aging, namely the Peak Alpha Frequency, the Gamma-band synchronization, and the Theta/Beta ratio, in the framework of an EEG-based brain-computer interface, with two main objectives: 1) to test whether healthy elderly people with subjective memory complaints may learn to modulate their brain activity through EEG-neurofeedback training in a double-blind, placebo-controlled study; and 2) whether that neuromodulation may have a positive impact on subjects’ cognition.

Results

A significant self-modulation of two neural biomarkers that usually decline with age was observed exclusively in the group of subjects who underwent the EEG-neurofeedback training, in clear contrast with the subjects who received the sham feedback. This neuromodulation did not have a direct effect on subjects’ cognitive abilities, as measured by neuropsychological tests pre-versus post-training, probably because all the subjects accurately performed these tests already at study entry (i.e., pre-training).

Conclusion

The results of this double-blind study are in line with one of the main criteria for successful neuromodulation, thus encouraging research on EEG-neurofeedback as a promising non-pharmacological intervention for promoting self-regulation of brain activity with a view to improve cognitive aging.
CRISPR/Cas9 mediated gene editing in non-model nematodePanagrolaimussp. PS1159
Authors: Hellekes Viktoria , Claus Denise , Seiler Johanna , Illner Felix , Schiffer Philipp H. , Kroiher Michael
Published: September 2022

The phylum Nematoda harbors a huge diversity of species in a broad range of ecosystems and habitats. Nematodes share a largely conserved Bauplan but major differences have been found in early developmental processes. The development of the nematode model organismCaenorhabditis eleganshas been studied in great detail for decades. These efforts have provided the community with a large number of protocols and methods. Unfortunately, many of these tools are not easily applicable in non-Caenorhabditisnematodes. In recent years it has become clear that many crucial genes in theC. elegansdevelopmental toolkit are absent in other nematode species. It is thus necessary to study the developmental program of other nematode species in detail to understand evolutionary conservation and novelty in the phylum.

Panagrolaimussp. PS1159 is a non-parasitic nematode exhibiting parthenogenetic reproduction and we are establishing the species to comparatively study evolution, biodiversity and alternative reproduction and survival strategies. Here, we demonstrate the first successful application of the CRISPR/Cas9 system for genome editing inPanagrolaimussp. PS1159 and its closely related hermaphroditic speciesPropanagrolaimussp. JU765 with both the non-homologous end joining and the homology-directed repair mechanism. Using microinjections and modifying published protocols fromC. elegans and P. pacificuswe induced mutations in the orthologue ofunc-22, which resulted in a visible uncoordinated twitching phenotype. We also compared the HDR efficiency following the delivery of different repair templates. This work will expand the applicability for a wide range of non-model nematodes from across the tree and facilitate functional analysis into the evolution of parthenogenesis, changes in the developmental program of Nematoda, and cryptobiosis.
Genetic Variation in Chromatin State Across Multiple Tissues inDrosophila melanogaster
Authors: Huynh Khoi , Smith Brittny R. , Macdonald Stuart J. , Long Anthony D.
Published: September 2022

We use ATAC-seq to examine chromatin accessibility for four different tissues inDrosophila melanogaster: adult female brain, ovaries, and both wing and eye-antennal imaginal discs from males. Each tissue is assayed in eight different inbred strain genetic backgrounds, seven associated with a reference quality genome assembly. We develop a method for the quantile normalization of ATAC-seq fragments and test for differences in coverage among genotypes, tissues, and their interaction at 44099 peaks throughout the euchromatic genome. For the strains with reference quality genome assemblies, we correct ATAC-seq profiles for read mis-mapping due to nearby polymorphic structural variants (SVs). Comparing coverage among genotypes without accounting for SVs results in a highly elevated rate (55%) of identifying false positive differences in chromatin state between genotypes. After SV correction, we identify 1050, 30383, and 4508 regions whose peak heights are polymorphic among genotypes, among tissues, or exhibit genotype-by-tissue interactions, respectively. Finally, we identify 3988 candidate causative variants that explain at least 80% of the variance in chromatin state at nearby ATAC-seq peaks.

AUTHOR SUMMARY

Chromatin states are well described inDrosophila melanogasterembryos, but adult and pre-adult tissues are poorly studied, as are differences among genotypes. We carried out ATAC-seq on four different tissues in eight different inbred genotypes with biological replicates within tissue and genotype. We discover that apparent differences in coverage, and by inference chromatin openness, are often due to segregating structural variants (SVs) that can only be corrected for if strains are associated with high-quality genome assemblies. After correction for false positives associated with SVs, we identify thousands of regions that appear to vary in chromatin state between genotypes or vary between genotypes in a tissue-dependent manner. It has been widely speculated thatcis-regulatory variants contribute to standing variation in complex traits. If this is true, chromatin states that vary between individuals, perhaps in a tissue-dependent manner, are likely to be enriched for quantitative trait loci.
Impact of non-proteinogenic amino acid norvaline and proteinogenic valine misincorporation on a secondary structure of a model peptide
Authors: Škibola Zara , Sovulj Ita Gruić , Maršavelski Aleksandra
Published: September 2022

Norvaline is a straight-chain, hydrophobic, non-proteinogenic amino acid, isomeric with valine. Both amino acids can be misincorporated into proteins at isoleucine positions by isoleucyl-tRNA synthetase when the mechanisms of translation fidelity are impaired. Our previous study showed that proteome-wide substitution of isoleucine with norvaline resulted in higher toxicity in comparison to the proteome-wide substitution of isoleucine with valine. Although mistranslated proteins/peptides are considered to have non-native structures responsible for their toxicity, the observed difference in protein stability between norvaline and valine misincorporation has not yet been fully understood. To examine the observed effect, we choose the model peptide with three isoleucines in the native structure, introduced selected amino acids at isoleucine positions and applied molecular-dynamics simulations at different temperatures. The obtained results showed that norvaline has the highest destructive effect on the β-sheet structure and suggest that the higher toxicity of norvaline over valine is predominantly due to the misincorporation within the β-sheet secondary elements.
Prospective and retrospective representations of saccadic movements in primate prefrontal cortex
Authors: Calangiu Ioana , Kollmorgen Sepp , Reppas John , Mante Valerio
Published: September 2022

Dorso-lateral prefrontal cortex (dlPFC) in primates plays a key role in the acquisition and execution of flexible, goal-directed behaviors. Recordings in monkey dlPFC have revealed possible neural correlates of the underlying cognitive processes like attention, planning, or decision-making, both at the single-neuron and population levels. Integrating these observations into a coherent picture of dlPFC function is challenging, as these studies typically focused on neural activity in relation to a few, specific events within a single, fully learned behavioral task. Here we obtain a more comprehensive description of dlPFC activity from a large dataset of population recordings in monkeys across a variety of behavioral contexts. We characterized neural activity in relation to saccades that monkeys made freely, or at different stages of training in multiple tasks involving instructed saccades, perceptual discriminations, and reward-based decisions. Across all contexts, we observed reliable and strong modulations of neural activity in relation to a retrospective representation of the most recent saccadic movement. Prospective, planning-like activity was instead limited to task-related, delayed saccades that were directly eligible for a reward. The link between prospective and retrospective representations was highly structured, potentially reflecting a hard-wired feature of saccade responses in these areas. Only prospective representations were modulated by the recent behavioral history, but neither representations were modulated by learning occurring over days, despite obvious concurrent behavioral changes. Dorso-lateral PFC thus combines tightly linked flexible and rigid representations, with a dominant contribution from retrospective signals maintaining the memory of past actions.
3D Bioelectronics with a Remodellable Matrix for Long-term Tissue Integration and Recording
Authors: Boys Alexander J. , Lombarte Alejandro Carnicer , Gonzalez Amparo Güemes , van Niekerk Douglas C. , Hilton Sam , Barone Damiano G. , Proctor Christopher M. , Owens Róisín M. , Malliaras George G.
Published: September 2022

Bioelectronics hold the key for understanding and treating disease. However, achieving stable, long-term interfaces between electronics and the body remains a challenge. Implantation of a bioelectronic device typically initiates a foreign body response, which can limit long-term recording and stimulation efficacy. Techniques from regenerative medicine have shown a high propensity for promoting integration of implants with surrounding tissue, but these implants lack the capabilities for the sophisticated recording and actuation afforded by electronics. Combining these two fields can achieve the best of both worlds. Here, we show the construction of a hybrid implant system for creating long-term interfaces with tissue. We create implants by combining a microelectrode array with a bioresorbable and remodellable gel. These implants are shown to produce a minimal foreign body response when placed into musculature, allowing us to record long-term electromyographic signals with high spatial resolution. This device platform drives the possibility for a new generation of implantable electronics for long-term interfacing.
In vitro to in vivo pharmacokinetic translation guidance
Authors: Fagerholm Urban
Published: September 2022

Background

Pharmacokinetics (PK), exposure profiles and doses of candidate drugs in man are commonly predicted using data produced using various in vitro methods, such as hepatocytes (for intrinsic metabolic clearance (CLint)), plasma (for unbound fraction (fu)), Caco-2 (measuring apparent permeability (Papp) for prediction of in vivo fraction absorbed (fa)) and plasma water and buffers (measuring solubility (S) for prediction of in vivo fraction dissolved (fdiss)). For best possible predictions it is required that the clinical relevance of in vitro data is understood (in vitro-in vivo relationships) and that uncertainties have been investigated and considered.

Methods

The aim was to investigate in vitro-in vivo relationships for CLint, Pappvs fa and S vs fdiss and interlaboratory variability for fu, describe the clinical significance and uncertainties at certain levels of in vitro CLint, fu, Papp and S, and (based on the findings) develop a general in vitro-in vivo translation guide.

Results and Conclusion

It was possible to finf data for describing how in vivo CLint, fa and fdiss distribute and varies at different levels of in vitro CLint, Papp and S and how fu varies between laboratories and methods at different fu-levels. It is apparent that there are considerable interlaboratory variabilities for CLint, fu and Papp: corresponding to up to 2500-, 700- and 35-fold variability for CLint, fu and fa, respectively. Apparently, S is a poor predictor of fdiss. Proposed S-thresholds do not seem clinically useful (overestimated). It does not seem appropriate to define in vitro CLint of 0.5-2 µL/min/106 cells as good metabolic stability (rather moderate to moderately high). Results shown for CLint, Papp and fu are applicable as general guidelines when internal standard values for reference compounds are unavailable.
Quantitative proteomic analysis of skeletal muscles from wild type and transgenic mice carrying recessive Ryr1 mutations linked to congenital myopathies
Authors: Eckhardt Jan , Ruiz Alexis , Koenig Stéphane , Frieden Maud , Schmidt Alexander , Treves Susan , Zorzato Francesco
Published: September 2022

Skeletal muscle is a highly structured and differentiated tissue responsible for voluntary movement and metabolic regulation. Muscles however, are heterogeneous and depending on their location, speed of contraction, fatiguability and function, can be broadly subdivided into fast and slow twitch as well as subspecialized muscles, with each group expressing common as well as specific proteins. Congenital myopathies are a group of non-inflammatory non-dystrophic muscle diseases caused by mutations in a number of genes, leading to a weak muscle phenotype. In most cases specific muscles types are affected, with preferential involvement of fast twitch muscles as well as extraocular and facial muscles. Here we performed relative and absolute quantitative proteomic analysis of EDL, soleus and extraocular muscles from wild type and transgenic mice carrying compound heterozygous mutations in Ryr1 identified in a patient with a severe congenital myopathy. Our quantitative proteomic study shows that recessive Ryr1 mutations not only decrease the content of RyR1 protein in muscle, but also impact the content of many other proteins; in addition, we provide important insight into the pathological mechanism of congenital myopathies linked to mutations in other genes encoding components of the excitation contraction coupling molecular complex.
Complex plumages spur rapid color diversification in island kingfishers (Aves: Alcedinidae)
Authors: Eliason Chad M. , McCullough Jenna M. , Hackett Shannon J. , Andersen Michael J.
Published: September 2022

Oceanic islands are cradles for diversity. Differences in predation pressures and lack of competition on islands are thought to drive both phenotypic and species diversification. While most work exploring these patterns has focused on life history, behavioral and morphological traits, many island species are uniquely colorful. Yet, a recent study of island bird coloration found that insular species are duller than continental species. Whether such shifts in color are associated with increased rates of color evolution on islands remains unknown. Here, we incorporate geometric morphometric techniques to study plumage color diversity in a speciose clade of colorful birds that inhabit nearly all areas of the globe—kingfishers (Aves: Alcedinidae). In particular, we test two hypotheses: (i) that plumage complexity enhances interspecific rates of color evolution and (ii) that plumage color diversity is elevated on islands. Our results show that more complex plumages result in more diverse colors among species and plumage color evolves faster on islands. Importantly, we found that insular species did not have more complex plumages than their continental relatives. Thus, complexity may be a key innovation that facilitates response to divergent (or relaxed) selection pressures on islands. Lack of support for competition driving rates of evolution along different color axes hints at an allopatric model of color evolution in which species adapt to local conditions on different islands. This work demonstrates how a truly multivariate treatment of color data can reveal evolutionary patterns that might otherwise go unnoticed.
Population Structure and Migration in the Eastern Highlands of Papua New Guinea; a Region Impacted by the kuru Epidemic
Authors: Quinn Liam , Moltke Ida , Whitfield Jerome , Alpers Michael , Campbell Tracy , Hummerich Holger , Pomat William , Siba Peter , Koki George , Collinge John , Hellenthal Garrett , Mead Simon
Published: September 2022

Populations of the Eastern Highlands of Papua New Guinea (EHPNG, area 11,157 km2) lived in relative isolation from the rest of the world until the mid-20th century, and the region contains a wealth of linguistic and cultural diversity. Notably, several populations of EHPNG were devastated by an epidemic prion disease, kuru, which at its peak in the mid-twentieth century led to some villages being almost depleted of adult women. Until now, population genetic analyses to learn about genetic diversity, migration, admixture and the impact of the kuru epidemic have been restricted to a small number of variants or samples. Here, we present a population genetic analysis of the region based on genome-wide genotype data of 943 individuals from 21 linguistic groups and 68 villages in EHPNG, including 34 villages in the South Fore linguistic group, which the group most affected by kuru. We find a striking degree of genetic population structure in the relatively small region (average FST between linguistic groups 0.024; area similar to Jamaica). The genetic population structure correlates well with linguistic grouping, with some noticeable exceptions. Also, we find evidence of a series of discrete admixture events that appear to coincide with previously expected introduction dates and movement of the sweet potato in the region. Finally, we find signatures of more recent migration within the EHPNG region and observe a substantial excess of female migration into the heavily kuru-affected South Fore linguistic group (p=0.0017, Chi Squared Test), likely reflecting the sex-bias in incidence of kuru. These data provide an in-depth look at the population genetics of a region devastated by a prion disease epidemic and which was until recently relatively isolated from the rest of the world.
GutMeta: online microbiome analysis and interactive visualization with build-in curated human gut microbiome database
Authors: Jiang Yiqi , Wang Yanfei , Che Lijia , Zhou Qian , Li Shuaicheng
Published: September 2022

Background

The human gut microbiome is associated with numerous human diseases. The whole-genome shotgun metagenomics sequencing helps accumulate a massive amount of gut microbiome data. However, few curated integrated platforms are available to explore the vast dataset. Advances in data generation pose new challenges to researchers attempting to analyze, visualize, and reuse published data.

Result

GutMeta (human GUT whole-genome shotgun METAgenomics data analysis platform) is a one-stop online human gut metagenomic research platform that integrates a curated database, analyses, and visualizations.

First, we built the Human Gut Metagenomics Database (HGMD), which contained taxonomy profiling and metadata of the metagenomics. HGMD collected the published human gut microbiome samples with whole metagenome shotgun (WMGS) sequencing data and consistently performed taxonomy classification using MetaPhlan3 for each sample. The various related metadata information was curated, and phenotypes were according to the MeSH ID. At this moment, HGMD contains 20,898 samples from 91 projects related to 65 diseases. Embedded tools could help users to explore the samples by keywords. Second, GutMeta provides researchers with user-friendly metagenomics analysis modules, including community diversity calculation, differential testing, dimension reduction, disease classifier construction, etc. Then, GutMeta provides corresponding interactive visualizations which can download as Scalable Vector Graphics (SVG), providing high-quality images. Further, GutMeta supplies two additional visualizations for the multi-level taxonomy overview for advanced investigations. GutMeta also supports online editing, including attribute adjustment, recoloring, reordering, and drag-and-drop. Third, GutMeta supports users in building their metagenomics analysis workspaces, including standard profiles uploading and built-in HGMD data import for online customized analyses and visualization.

Conclusion

GutMeta offers a solution to improve reproducibility in metagenomic research, with the standardized procedure from input data to downstream analysis and visualization. GutMeta is a free access analysis platform that integrates human gut WMGS sequencing data, nine online bioinformatics analysis and data visualization modules/pipelines, and a customized workspace. GutMeta is avaiable at https://GutMeta.deepomics.org.
Allosteric regulation and crystallographic fragment screening of SARS-CoV-2 NSP15 endoribonuclease
Authors: Godoy Andre Schutzer , Nakamura Aline Minalli , Douangamath Alice , Song Yun , Noske Gabriela Dias , Gawriljuk Victor Oliveira , Fernandes Rafaela Sachetto , Muniz Pereira Humberto D. , Zagato Oliveira Ketllyn Irene , Fearon Daren , Dias Alexandre , Krojer Tobias , Fairhead Michael , Powell Alisa , Dunnet Louise , Brandao-Neto Jose , Skyner Rachael , Chalk Rod , von Delft Frank , Bajusz Dávid , Bege Miklós , Borbás Anikó , Miklós Keserű György , Oliva Glaucius
Published: September 2022

SARS-CoV-2 is the causative agent of COVID-19. The highly conserved viral NSP15 endoribonuclease, NendoU, is a key enzyme involved in viral immune evasion, and a promising target for the development of new classes of antivirals. Yet, the broad variety of recognition sequences, complex assembly and kinetics, and lack of structural complexes hampers the development of new competitive or allosteric inhibitors for this target. Here, we performed enzymatic characterization of NendoU in its monomeric and hexameric form, showing that hexamers are allosteric enzymes with a positive cooperative index of 2. By using cryo-EM at distinct pH’s combined with X-ray crystallography and structural analysis, we demonstrate the potential for NendoU to shift between open and closed states, and assembly in larger supramolecular entities, which might serve as a mechanism of self-regulation. Further, we report results from a large fragment screening campaign against NendoU, revealing multiple new allosteric sites for the development of inhibitors.
An ABM of biting midge dynamics to understand Bluetongue outbreaks
Authors: Gladson Shane L. , Stepien Tracy L.
Published: September 2022

Abstract

Bluetongue (BT) is a well-known vector-borne disease that infects ruminants such as sheep, cattle, and deer with high mortality rates. Recent outbreaks in Europe highlight the importance of understanding vector-host dynamics and potential courses of action to mitigate the damage that can be done by BT. We present an agent-based model (ABM), entitled MidgePy, that focuses on the movement of individualCulicoidesspp. biting midges and their interactions with ruminants to understand their role as vectors in BT outbreaks, especially in regions that do not regularly experience outbreaks. Sensitivity analysis is performed and results indicate that midge survival rate has a significant impact on the probability of a BTV outbreak as well as its severity. Parameter regions where outbreaks are more likely to occur are determined, with an increase in environmental temperature corresponding with an increased probability of outbreak, where midge flight activity is used as a proxy for temperature. This suggests that future methods to control BT spread could combine large-scale vaccination programs with biting midge population control measures such as the use of pesticides. Spatial heterogeneity in the environment is also explored to give insight on optimal farm layouts to reduce the potential for BT outbreaks.