bluuebunny/crossref_metadata_2025 huggingface dataset:
Constructing Binary Matrices with Good Implementation Properties for Low-Latency Block Ciphers based on Lai-Massey Structure
Authors: Li Xiaodan , Wu Wenling
Published: October 2021

Diffusion layers are crucial components for lightweight cryptographic schemes. Optimal binary matrices are widely used diffusion layers that can be easier to achieve the best security/performance trade-off. However, most of the constructions of binary matrices are concentrated in smaller dimensions. Besides, to maximize the number of branches, the performance is often neglected. In this paper, we investigate the diffusion of the Lai-Massey (L-M) structures and propose a series of binary diffusion layers with the best possible branch number and efficient software/hardware implementations as well for feasible parameters (up to 64). Firstly, we prove the lower bound of the circuit depth of a binary matrix with a fixed branch number. Then, we construct binary matrices by L-M structure with cyclic shift as round functions because of taking account of the improvement of software performance and demonstrate that this construction can not get the diffusion layers with branch number >4. Then, we get some 4 $\times $ 4 and 6 $\times $ 6 optimal binary matrices with branch number 4 by one-round L-M structure. Note that the depth of these results is optimal, i. e. they achieve the lowest hardware costs without loss of software efficiency. Secondly, we construct diffusion layers by extended L-M structures to obtain binary matrices with large sizes. We give a list of software/hardware friendly optimal binary matrices with large dimensions, especially for dimensions 48 and 64. In particular, some of the solutions are Maximum Distance Binary Linear matrices. Finally, we also present diffusion layers constructed by the extended generalized L-M structure to improve their applicabilities on other platforms.
Clinically Recognized Varicose Veins and Physical Function in Older Individuals: The ARIC Study
Authors: Mok Yejin , Ishigami Junichi , Sang Yingying , Kucharska-Newton Anna M , Salameh Maya , Schrack Jennifer A , Palta Priya , Coresh Josef , Windham B Gwen , Lutsey Pamela L , Folsom Aaron R , Matsushita Kunihiro
Published: October 2021

Background

Although a few studies reported an association between varicose veins and physical function, this potentially bidirectional association has not been systematically evaluated in the general population.

Method

In 5 580 participants (aged 71–90 years) from the Atherosclerosis Risk in Communities study, varicose veins were identified in outpatient and inpatient administrative data prior to (prevalent cases) and after (incident cases) visit 5 (2011–2013). Physical function was evaluated by the Short Physical Performance Battery (SPPB, score ranging from 0 to 12). We evaluated (i) cross-sectional association between prevalent varicose veins and physical function, (ii) association of prevalent varicose veins with subsequent changes in physical function from visit 5 to visits 6 (2016–2017) and 7 (2018–2019), and (iii) association of physical function at visit 5 with incident varicose veins during a median follow-up of 3.6 years (105 incident varicose veins among 5 350 participants without prevalent cases at baseline).

Results

At baseline, varicose veins were recognized in 230 (4.1%) participants and cross-sectionally associated with reduced physical function. Longitudinally, prevalent varicose veins were not significantly associated with a decline in SPPB over time. In contrast, a low SPPB ≤6 was associated with a greater incidence of varicose veins compared to SPPB ≥10 (adjusted hazard ratio 2.13 [95% confidence interval = 1.19, 3.81]).

Conclusion

In community-dwelling older adults, varicose veins and low physical function were associated cross-sectionally. Longitudinally, low physical function was a risk factor for incident varicose veins, but not vice versa. Our findings suggest an etiological contribution of low physical function to incident varicose veins.
Fine-mapping of Parkinson’s disease susceptibility loci identifies putative causal variants
Authors: Schilder Brian M , Raj Towfique
Published: October 2021

Recent genome-wide association studies have identified 78 loci associated with Parkinson’s disease susceptibility but the underlying mechanisms remain largely unclear. To identify likely causal variants for disease risk, we fine-mapped these Parkinson’s-associated loci using four different fine-mapping methods. We then integrated multi-assay cell type–specific epigenomic profiles to pinpoint the likely mechanism of action of each variant, allowing us to identify Consensus single nucleotide polymorphism (SNPs) that disrupt LRRK2 and FCGR2A regulatory elements in microglia, an MBNL2 enhancer in oligodendrocytes, and a DYRK1A enhancer in neurons. This genome-wide functional fine-mapping investigation of Parkinson’s disease substantially advances our understanding of the causal mechanisms underlying this complex disease while avoiding focus on spurious, non-causal mechanisms. Together, these results provide a robust, comprehensive list of the likely causal variants, genes and cell-types underlying Parkinson’s disease risk as demonstrated by consistently greater enrichment of our fine-mapped SNPs relative to lead GWAS SNPs across independent functional impact annotations. In addition, our approach prioritized an average of 3/85 variants per locus as putatively causal, making downstream experimental studies both more tractable and more likely to yield disease-relevant, actionable results. Large-scale studies comparing individuals with Parkinson’s disease to age-matched controls have identified many regions of the genome associated with the disease. However, there is widespread correlation between different parts of the genome, making it difficult to tell which genetic variants cause Parkinson’s and which are simply co-inherited with causal variants. We therefore applied a suite of statistical models to identify the most likely causal genetic variants (i.e. fine-mapping). We then linked these genetic variants with epigenomic and gene expression signatures across a wide variety of tissues and cell types to identify how these variants cause disease. Therefore, this study provides a comprehensive and robust list of cellular and molecular mechanisms that may serve as targets in the development of more effective Parkinson’s therapeutics.
Research and application progress of transcritical CO2 refrigeration cycle system: a review
Authors: Yang Dazhang , Li Yang , Xie Jing , Wang Jinfeng
Published: October 2021

CO2 refrigerant and its transcritical cycle system have become the research focus in the refrigeration field due to their advantages of environmentally friendly, safe and low environmental temperature adaptability. This paper summarizes the research progress on the modified methods for the defects of basic transcritical CO2 refrigeration cycle system in recent years. Meanwhile, the technical status of transcritical CO2 refrigeration technology in commercial supermarket refrigeration, heat pump system, automobile air conditioning and artificial ice rink is discussed in detail. Finally, the development of transcritical CO2 refrigeration cycle system is prospected and the key problems to be solved are put forward.
Laplace–Beltrami spectrum of ellipsoids that are close to spheres and analytic perturbation theory
Authors: Eswarathasan Suresh , Kolokolnikov Theodore
Published: October 2021

We study the spectrum of the Laplace–Beltrami operator on ellipsoids. For ellipsoids that are close to the sphere, we use analytic perturbation theory to estimate the eigenvalues up to two orders. We show that for biaxial ellipsoids sufficiently close to the sphere, the first $L^2$ eigenvalues have multiplicity at most two, and characterize those that are simple. For the triaxial ellipsoids sufficiently close to the sphere that are not biaxial, we show that at least the first 16 eigenvalues are all simple. We also give the results of various numerical experiments, including comparisons to our results from the analytic perturbation theory, and approximations for the eigenvalues of ellipsoids that degenerate into infinite cylinders or two-dimensional disks. We propose a conjecture on the exact number of nodal domains of near-sphere ellipsoids.
Frequent but fragmented: use of note templates to document outpatient visits at an academic health center
Authors: Rule Adam , Hribar Michelle R
Published: October 2021

Recent changes to billing policy have reduced documentation requirements for outpatient notes, providing an opportunity to rethink documentation workflows. While many providers use templates to write notes—whether to insert short phrases or draft entire notes—we know surprisingly little about how these templates are used in practice. In this retrospective cross-sectional study, we observed the templates that primary providers and other members of the care team used to write the provider progress note for 2.5 million outpatient visits across 52 specialties at an academic health center between 2018 and 2020. Templates were used to document 89% of visits, with a median of 2 used per visit. Only 17% of the 100 230 unique templates were ever used by more than one person and most providers had their own full-note templates. These findings suggest template use is frequent but fragmented, complicating template revision and maintenance. Reframing template use as a form of computer programming suggests ways to maintain the benefits of personalization while leveraging standardization to reduce documentation burden.
Procedural Cross-Fertilization in International Commercial and Investment Arbitration: A Functional Approach
Authors: Meshel Tamar
Published: October 2021

This article examines the potential for beneficial procedural cross-fertilization between internationalcommercial and investment arbitration from a functional perspective. The article argues that botharbitration regimes share a ‘private’ dispute resolution function of resolving specific disputes, butonly investment arbitral tribunals also exercise a ‘public’ law-making function of developing the lawapplicable to the resolution of disputes. The article considers two recent procedural developmentsin international arbitration rulesjoinder of third parties and publication of arbitral awardsin thelight of these private and public functions. It argues that joinder, as an efficiency-enhancingmeasure, can lead to beneficial cross-fertilization between commercial and investment arbitrationbecause it reinforces the ‘private’ dispute resolution function shared by both regimes. In contrast,the default publication of arbitral awards, to the extent that it is intended to be systematic and createinformal precedent, is appropriate in investment but not in commercial arbitration because onlyinvestment arbitral tribunals exercise a ‘public’ law-making function that justifies and stands tobenefit from this practice. In this regard, the article rejects three rationales for default publication ofinternational commercial arbitral awards: improving consistency/predictability, enhancingtransparency and developing transnational commercial law. The article concludes that crossfertilizationbetween investment and commercial arbitration can be valuable so long as it concernstheir shared private dispute resolution function. However, attempting to develop internationalcommercial arbitral practice in the shadow of the public law-making function of investment arbitraltribunals may result in counterproductive practices and undermine the proper functioning ofinternational commercial arbitration as a whole.
A new framework for understanding systematic errors in cluster lens modelling – I. Selection and treatment of cluster member galaxies
Authors: Raney Catie A , Keeton Charles R , Zimmerman Dhruv T
Published: October 2021

With high-quality data from programs like the Hubble Frontier Fields, cluster lensing has reached the point that models are dominated by systematic rather than statistical uncertainties. We introduce a Bayesian framework to quantify systematic effects by determining how different lens modelling choices affect the results. Our framework includes a new two-sample test for quantifying the difference between posterior probability distributions that are sampled by methods like Monte Carlo Markov chains. We use the framework to examine choices related to the selection and treatment of cluster member galaxies in two of the Frontier Field clusters: Abell 2744 and MACS J0416.1–2403. When selecting member galaxies, choices about depth and area affect the models; we find that model results are robust for an I-band magnitude limit of mlim ≥ 22.5 mag and a radial cut of rlim ≥ 90 arcsec (from the centre of the field), although the radial limit likely depends on the spatial extent of lensed images. Mass is typically assigned to galaxies using luminosity/mass scaling relations. We find that the slopes of the scaling relations can have significant effects on lens model parameters but only modest effects on lensing magnifications. Interestingly, scatter in the scaling relations affects the two fields differently. This analysis illustrates how our framework can be used to analyse lens modelling choices and guide future cluster lensing programs.
Bringing faint active galactic nuclei (AGNs) to light: a view from large-scale cosmological simulations
Authors: Schirra Adrian P , Habouzit Mélanie , Klessen Ralf S , Fornasini Francesca , Nelson Dylan , Pillepich Annalisa , Anglés-Alcázar Daniel , Davé Romeel , Civano Francesca
Published: October 2021

The sensitivity of X-ray facilities and our ability to detect fainter active galactic nuclei (AGNs) will increase with the upcoming Athena mission and the AXIS and Lynx concept missions, thus improving our understanding of supermassive black holes (BHs) in a luminosity regime that can be dominated by X-ray binaries. We analyse the population of faint AGNs ($L_{\rm x, 2{-}10 \, keV}\leqslant 10^{42}\, \rm erg\,s^{ -1}$) in the Illustris, TNG100, EAGLE, and SIMBA cosmological simulations, and find that the properties of their host galaxies vary from one simulation to another. In Illustris and EAGLE, faint AGNs are powered by low-mass BHs located in low-mass star-forming galaxies. In TNG100 and SIMBA, they are mostly associated with more massive BHs in quenched massive galaxies. We model the X-ray binary (XRB) populations of the simulated galaxies, and find that AGNs often dominate the galaxy AGN + XRB hard X-ray luminosity at z > 2, while XRBs dominate in some simulations at z < 2. Whether the AGN or XRB emission dominates in star-forming and quenched galaxies depends on the simulations. These differences in simulations can be used to discriminate between galaxy formation models with future high-resolution X-ray observations. We compare the luminosity of simulated faint AGN host galaxies to observations of stacked galaxies from Chandra. Our comparison indicates that the simulations post-processed with our X-ray modelling tend to overestimate the AGN + XRB X-ray luminosity; luminosity that can be strongly affected by AGN obscuration. Some simulations reveal clear AGN trends as a function of stellar mass (e.g. galaxy luminosity drop in massive galaxies), which are not apparent in the observations.
Frontiers and Opportunities in Bioenergy Crop Microbiome Research Networks
Authors: Howe The Inter-BRC Microbiome Workshop Consortium: Adina , Bonito Gregory , Chou Ming-Yi , Cregger Melissa A. , Fedders Anna , Field John L. , Martin Hector Garcia , Labbé Jesse L. , Mechan-Llontop Marco E. , Northen Trent R. , Shade Ashley , Tschaplinski Timothy J.
Published: October 2021

Researchers from across the four United States Department of Energy Bioenergy Research Centers (BRCs) engaged in a microbiome workshop that focused on identifying challenges and collaboration opportunities to better understand bioenergy-relevant plant–microbe interactions. The virtual workshop included hands-on educational sessions and a keynote address on current best practices in microbiome science and community microbiome standards, as well as breakout sessions aimed at identifying microbiome-related data and measurements that should be prioritized, opportunities for and barriers to integrating plant metabolites to microbiome research, and strategies for more effectively integrating microbiome data and processes into existing models. Based on participant discussion, key findings of the workshop were the need to prioritize scaling data sharing across BRCs and the broader research community and securing collaborative infrastructure in the areas of microbiome-ecosystem modeling and molecular plant–microbe interactions. This workshop review highlights additional main findings from this event, to encourage cross-site and more holistic metaanalyses while promoting wide scientific community engagement across plant microbiome sciences.
Ordinal regression increases statistical power to predict epilepsy surgical outcomes
Authors: Dickey Adam S. , Krafty Robert T. , Pedersen Nigel P.
Published: October 2021

Objective

Studies of epilepsy surgery outcomes are often small and thus underpowered to reach statistically valid conclusions. We hypothesized that ordinal logistic regression would have greater statistical power than binary logistic regression when analyzing epilepsy surgery outcomes.

Methods

We reviewed 10 manuscripts included in a recent meta-analysis which found that mesial temporal sclerosis (MTS) predicted better surgical outcome after a stereotactic laser amygdalohippocampectomy (SLAH). We extracted data from 239 patients from eight studies which reported four discrete Engel surgical outcomes after SLAH, stratified by the presence or absence of MTS.

Results

The rate of freedom from disabling seizures (Engel I) was 64.3% (110/171) for patients with MTS compared to 44.1% (30/68) without MTS. The statistical power to detect MTS as a predictor for better surgical outcome after a SLAH was 29% using ordinal regression, which was significantly more than the 13% power using binary logistic regression (paired t-test, p<0.001). Only 120 patients are needed to achieve 80% power to detect MTS as a predictor using ordinal regression, compared to 210 patients that are needed to achieve 80% power using binary logistic regression.

Conclusion

Ordinal regression should be considered when analyzing ordinal outcomes (such as Engel surgical outcome), especially for datasets with small sample sizes.
Redefining snakebite envenoming as a zoonosis: disease incidence is driven by snake ecology, socioeconomics and anthropogenic impacts
Authors: Martin Gerardo , Erinjery Joseph , Ediriweera Dileepa , de Silva H. Janaka , Lalloo David G. , Iwamura Takuya , Murray Kris A.
Published: October 2021

Snakebite is the only WHO-listed, not infectious neglected tropical disease (NTD), although its eco-epidemiology is similar to that of zoonotic infections: envenoming occurs after a vertebrate host contacts a human. Accordingly, snakebite risk represents the interaction between snake and human factors, but their quantification has been limited by data availability. Models of infectious disease transmission are instrumental for the mitigation of NTDs and zoonoses. Here, we represented snake-human interactions with disease transmission models to approximate geospatial estimates of snakebite incidence in Sri Lanka, a global hotspot. Snakebites and envenomings are described by the product of snake and human abundance, mirroring directly transmitted zoonoses. We found that human-snake contact rates vary according to land cover (surrogate of occupation and socioeconomic status), the impacts of humans and climate on snake abundance, and by snake species. Our findings show that redefining snakebite as zoonosis provides a mechanistic eco-epidemiological basis to understand snakebites, and the possible implications of global environmental and demographic change for the burden of snakebite.
Detection of the 40-Hz Auditory Steady-state Response with Optically Pumped Magnetometers
Authors: An Kyung-min , Shim Jung Hyun , Kwon Hyukchan , Lee Young-Ho , Yu Kwon-Kyu , Kwon Moonyoung , Chun Woo Young , Hirosawa Tetsu , Hasegawa Chiaki , Iwasaki Sumie , Kikuchi Mitsuru , Kim Kiwoong
Published: October 2021

Magnetoencephalography (MEG) is a functional neuroimaging technique that noninvasively detects the brain magnetic field from neuronal activations. Conventional MEG measures brain signals using superconducting quantum interference devices (SQUIDs). SQUID-MEG requires a cryogenic environment involving a bulky non-magnetic dewar and the consumption of liquid helium, which restricts the variability of the sensor array and the gap between the cortical sources and sensors. Recently, miniature optically pumped magnetometers (OPMs) have been developed and commercialized. OPMs do not require cryogenic cooling and can be placed within millimeters from the scalp. In the present study, we arranged six OPM sensors on the temporal area to detect auditory-related brain responses in a two-layer magnetically shielded room. We presented the auditory stimuli of 1-kHz pure-tone bursts with 200-ms duration and obtained the M50 and M100 components of auditory evoked fields. We delivered the periodic stimuli with a 40-Hz repetition rate and observed the gamma-band power changes and inter-trial phase coherence of auditory steady-state responses at 40 Hz. We found that the OPM sensors have a performance comparable to that of conventional SQUID-MEG sensors, and our results suggest the feasibility of using OPM sensors for functional neuroimaging and brain–computer interface applications.
Episodic timing: how spontaneous alpha clocks, retrospectively
Authors: Azizi Leila , Polti Ignacio , van Wassenhove Virginie
Published: October 2021

We seldom time life events intently yet recalling the duration of events is lifelike. Is episodic time the outcome of a rational after-thought or of physiological clocks keeping track of time without our conscious awareness of it? To answer this, we recorded human brain activity with magnetoencephalography (MEG) during quiet wakefulness. Unbeknownst to participants, we asked them after the MEG recording to guess its duration. In the absence of overt attention to time, the relative amount of time participants’ alpha brain rhythms (α ~10 Hz) were in bursting mode predicted participants’ retrospective duration estimate. This relation was absent when participants prospectively measured elapsed time during the MEG recording. We conclude that α bursts embody discrete states of awareness for episodic timing.

One-Sentence Summary

In the human brain, the relative number of alpha oscillatory bursts at ~10 Hz can tell time when the observer does not attend to it.
Macroscopic dynamics of gene regulatory networks revealed by individual entropy
Authors: Liu Cong , Hao Lijie , Lei Jinzhi
Published: October 2021

Complex systems are usually high-dimensional with intricate interactions among internal components, and may display complicated dynamics under different conditions. While it is difficult to measure detail dynamics of each component, proper macroscopic description of a complex system is crucial for quantitative studies. In biological systems, each cell is a complex system containing a huge number of molecular components that are interconnected with each other through intricate molecular interaction networks. Here, we consider gene regulatory networks in a cell, and introduce individual entropy as a macroscopic variable to quantify the transcriptional dynamics in response to changes in random perturbations and/or network structures. The proposed individual entropy measures the information entropy of a system at each instant with respect to a basal reference state, and may provide temporal dynamics to characterize switches of system states. Individual entropy provides a method to quantify the stationary macroscopic dynamics of a gene set that is dependent on the gene regulation connections, and can be served as an indicator for the evolution of network structure variation. Moreover, the individual entropy with reference to a preceding state enable us to characterize different dynamic patterns generated from varying network structures. Our results show that the proposed individual entropy can be a valuable macroscopic variable of complex systems in characterizing the transition processes from order to disorder dynamics, and to identify the critical events during the transition process.
Functional alterations of two salience-related systems jointly and independently contribute to psychosis
Authors: Miyata Jun , Winton-Brown Toby , Sedlak Thomas , Aso Toshihiko , Cascella Nicola , Coughlin Jennifer , Crossley Nicolas A. , Duezel Emrah , Ezaki Takahiro , Fukunaga Masaki , Howell Carolyn , Isobe Masanori , Kamiya Kouhei , Kasai Kiyoto , Kochiyama Takanori , Koike Shinsuke , Kunimatsu Akira , Masuda Naoki , Mori Susumu , Mori Yasuo , Murai Toshiya , Nemoto Kiyotaka , Nucifora Frederick , Ohi Kazutaka , Okada Naohiro , Sakai Yuki , Sawamoto Nobukatsu , Takahashi Tsutomu , Urayama Shinichi , Watanabe Yoshiyuki , Watkins Crystal C. , Yamamori Hidenaga , Yasuda Yuka , Hashimoto Ryota , Takahashi Hidehiko , Sawa Akira , McGuire Philip
Published: October 2021

Background and hypothesis

Salience is a critical mechanism for animal survival. Aberrant salience is essentially implicated in psychosis, involving the midbrain–striatum–hippocampus and the anterior cingulate cortex (ACC)–insula salience network (SN) systems. However, whether these two systems jointly or independently contribute to psychosis traits, staging, and state remains unknown.

Study design

Eight scanners at seven institutions recruited 209 subjects with psychosis at the ultra-high-risk (UHR), first-episode (FEP), and chronic (ChrP) stages and 279 matched healthy controls (HC). Resting-state functional MRI data, which were intensively denoised and scanner effect-removed, revealed the two systems comprising five networks: midbrain-thalamic and striatal parts of the basal ganglia network (BGN-MbThal and BGN-Str), the medial temporal lobe network (MTLN), and the ACC and insular parts of the SN (SN-ACC and SN-Ins). Group differences, correlations with positive symptoms, and effects of medication/psychosis type of the networks were investigated in each psychosis stage.

Study results

Connectivity within the SN-ACC was reduced in UHR compared to HC (p<0.05, family-wise-error [FWE] corrected) and in the FEP and ChrP stages at liberal thresholds, with effect sizes of UHR>FEP>ChrP. FEP showed reduced connectivity within the BGN-MbThal, increased brain-state instability among the five networks, and positive correlations between positive symptoms and connectivity within and between the MTLN (all p<0.05, FWE). The correlation was stronger in unmedicated than in medicated, and in affective than in non-affective psychosis patients (p<0.05, FWE).

Conclusions

The results provide a novel concept that the two salience mechanisms work in an integrated and separate manner in psychosis.
Characterization of Heat Responsive microRNAs and Phased Small Interfering RNAs in Reproductive Development of Flax
Authors: Pokhrel Suresh , Meyers Blake C.
Published: October 2021

Plants will face increased heat stress due to rising global temperatures. Heat stress affects plant reproductive development and decreases productivity; however, the underlying molecular mechanisms of these processes are poorly characterized. Plant small RNAs (sRNAs) have important regulatory roles in plant reproductive development following abiotic stress responses. We generated sRNA transcriptomes of three reproductive bud stages at three different time points to identify sRNA-mediated pathways responsive to heat stress in flax. With added sRNA transcriptomes of vegetative tissues, we comprehensively annotated miRNA and phasiRNA-encoding genes (PHAS) in flax. We identified 173 miRNA genes, of which 42 are novel. Our analysis revealed that 141 miRNA genes were differentially expressed between tissue types while 18 miRNA genes were differentially expressed in reproductive tissues following heat stress, including members of miR2118/482 and miR2275 families, known triggers of reproductive phasiRNAs. Furthermore, we identified 68 21-PHAS flax loci from protein coding and non-coding regions, four 24-PHAS loci triggered by miR2275, and 658 24-PHAS-like loci with unknown triggers, derived mostly from non-coding regions. The reproductive phasiRNAs are mostly downregulated in response to heat stress. Overall, we found that several previously unreported miRNAs and phasiRNAs are responsive to heat stress in flax reproductive tissues.
De Novo Whole Genome Assembly of the Roborovski Dwarf Hamster (Phodopus roborovskii) Genome, an Animal Model for Severe/Critical COVID-19
Authors: Andreotti Sandro , Altmüller Janine , Quedenau Claudia , Borodina Tatiana , Nouailles Geraldine , Alves Luiz Gustavo Teixeira , Landthaler Markus , Bieniara Maximilian , Trimpert Jakob , Wyler Emanuel
Published: October 2021

The Roborovski dwarf hamster Phodopus roborovskii belongs to the Phodopus genus, one of seven within Cricetinae subfamily. Like other rodents such as mice, rats or ferrets, hamsters can be important animal models for a range of diseases. Whereas the Syrian hamster from the genus Mesocricetus is now widely used as a model for mild to moderate COVID-19, Roborovski dwarf hamster show a severe to lethal course of disease upon infection with the novel human coronavirus SARS-CoV-2.
OMA1 High-throughput Screen Reveals Protease Activation by Kinase Inhibitors
Authors: Alavi Marcel V.
Published: October 2021

Mitochondrial proteases are interesting but challenging drug targets for multifactorial diseases, such as neurodegeneration and cancer. The mitochondrial inner membrane protease OMA1 is a bona fide drug target for heart failure supported by data from human linkage analysis and animal disease models, but presumably relevant for more indications. OMA1 acts at the intersection of energy metabolism and stress signaling. The protease cleaves the structural protein OPA1, which organizes the cristae, as well as the signaling peptide DELE1, which can stimulate the integrated stress response. OMA1 shows little activity under physiological conditions but hydrolyzes OPA1 in mitochondria destined for mitophagy and during apoptosis. Little is known about OMA1, its structure has not been solved, let alone its context-dependent regulation. Autocatalytic processing and the lack of OMA1 inhibitors are thereby creating the biggest roadblocks. This study introduces a scalable, cellular OMA1 protease assay suitable for high-throughput drug screening. The assay utilizes an engineered luciferase targeted to the inner membrane as artificial OMA1 substrate, whereby the reporter signal inversely correlates to OMA1 activity. Testing different screening protocols and sampling different compound collections validated the reporter and demonstrated that both OMA1 activators as well as OMA1 inhibitors can be identified with the assay. Ten kinase-targeted cancer drugs triggered OMA1 in the assays, which suggests—considering cardiotoxicity as a rather common side-effect of this class of drugs—cross-reactivity with the OMA1 pathway.
Genetic basis of body shape variation along the benthic-pelagic axis in cichlid fishes
Authors: DeLorenzo Leah , Mathews Destiny , Brandon A. Allyson , Joglekar Mansi , Baez Aldo Carmona , Moore Emily C. , Ciccotto Patrick J. , Roberts Natalie B. , Roberts Reade B. , Powder Kara E.
Published: October 2021

Divergence along the benthic-pelagic axis is one of the most widespread and repeated patterns of morphological variation in fishes, producing body shape diversity associated with ecology and swimming mechanics. This ecological shift is also the first stage of the explosive adaptive radiation of cichlid fishes in the East African Rift Lakes. We use two hybrid crosses of cichlids (Metriaclimasp. xAulonocarasp. andLabidochromissp. xLabeotropheussp., >975 animals total) along the benthic-pelagic ecomorphological axis to determine the genetic basis of body shape diversification. Using a series of both linear and geometric shape measurements, we identify 55 quantitative trait loci (QTL) that underlie various aspects of body shape variation associated with benthic-pelagic divergence. These QTL are spread throughout the genome, each explain 3.0-7.2% of phenotypic variation, and are largely modular. Further, QTL are distinct both between these two crosses of Lake Malawi cichlids and compared to previously identified QTL for body shape in fishes such as sticklebacks. We find that body shape is controlled by many genes of small effects. In all, we find that convergent benthic and pelagic body phenotypes commonly observed across fish clades are most likely due to distinct genetic and molecular mechanisms.
Cell wall synthesis and remodeling dynamics determine bacterial division site architecture and cell shape
Authors: Navarro Paula P. , Vettiger Andrea , Ananda Virly Y. , Llopis Paula Montero , Allolio Christoph , Bernhardt Thomas G. , Chao Luke H.
Published: October 2021

The bacterial division apparatus builds daughter cell poles by catalyzing the synthesis and remodeling of the septal peptidoglycan (sPG) cell wall. Understanding of this essential process has been limited by the lack of native three-dimensional visualization of developing septa. Here, we used state-of-the-art cryogenic electron tomography (cryo-ET) and fluorescence microscopy to understand the division site architecture and sPG biogenesis dynamics of the Gram-negative bacterium Escherichia coli. Our results with mutant cells altered in the regulation of sPG biogenesis revealed a striking and unexpected similarity between the architecture of E. coli septa with those from Gram-positive bacteria, suggesting a conserved morphogenic mechanism. Furthermore, we found that the cell elongation and division machineries are in competition and that their relative activities determine the shape of cell constrictions and the poles they form. Overall, our results highlight how the activity of the division system can be modulated to generate the diverse array of morphologies observed in the bacterial domain.

Highlights

The division site architecture of E. coli can be modulated to resemble that of diverse bacteria.

Cell wall degradation at the division site activates septal cell wall synthesis.

Assembly of the cytoskeletal ring at the division site is modulated by cell wall remodeling.

Balance between the activities of the elongation and division systems modulates cell shape.
Ultrastructural analysis of neuroimplant-parenchyma interfaces uncover remarkable neuroregeneration along-with barriers that limit the implant electrophysiological functions
Authors: Sharon Aviv , Shmoel Nava , Erez Hadas , Jankowski Maciej M. , Friedmann Yael , Spira Micha E.
Published: October 2021

Despite increasing use of in-vivo multielectrode array (MEA) implants for basic research and medical applications, the critical structural interfaces formed between the implants and the brain parenchyma, remain elusive. Prevailing view assumes that formation of multicellular inflammatory encapsulating-scar around the implants (the foreign body response) degrades the implant electrophysiological functions. Using gold mushroom shaped microelectrodes (gMμEs) based perforated polyimide MEA platforms (PPMPs) that in contrast to standard probes can be thin sectioned along with the interfacing parenchyma; we examined here for the first time the interfaces formed between brains parenchyma and implanted 3D vertical microelectrode platforms at the ultrastructural level. Our study demonstrates remarkable regenerative processes including neuritogenesis, axon myelination, synapse formation and capillaries regrowth in contact and around the implant. In parallel, we document that individual microglia adhere tightly and engulf the gMμEs. Modeling of the formed microglia-electrode junctions suggest that this configuration suffice to account for the low and deteriorating recording qualities of in vivo MEA implants. These observations help define the anticipated hurdles to adapting the advantageous 3D in-vitro vertical-electrode technologies to in-vivo settings, and suggest that improving the recording qualities and durability of planar or 3D in-vivo electrode implants will require developing approaches to eliminate the insulating microglia junctions.
Enzymes degraded under high light maintain proteostasis by transcriptional regulation in Arabidopsis
Authors: Li Lei , Duncan Owen , Ganguly Diep R , Lee Chun Pong , Crisp Peter A. , Wijerathna-Yapa Akila , Salih Karzan , Trösch Josua , Pogson Barry J , Millar A. Harvey
Published: October 2021

Photo-inhibitory high light stress in Arabidopsis leads to increases in markers of protein degradation and transcriptional upregulation of proteases and proteolytic machinery, but proteostasis is largely maintained. We find significant increases in the in vivo degradation rate for specific molecular chaperones, nitrate reductase, glyceraldehyde-3 phosphate dehydrogenase, and phosphoglycerate kinase and other plastid, mitochondrial, peroxisomal, and cytosolic enzymes involved in redox shuttles. Coupled analysis of protein degradation rates, mRNA levels, and protein abundance reveal that 57% of the nuclear-encoded enzymes with higher degradation rates also had high light-induced transcriptional responses to maintain proteostasis. In contrast, plastid-encoded proteins with enhanced degradation rates showed decreased transcript abundances and must maintain protein abundance by other processes. This analysis reveals a light-induced transcriptional program for nuclear-encoded genes, beyond the regulation of PSII D1 subunit and the function of PSII, to replace key protein degradation targets in plants and ensure proteostasis under high light stress.
Microglia mediate synaptic plasticity induced by 10 Hz repetitive transcranial magnetic stimulation
Authors: Eichler Amelie , Kleidonas Dimitrios , Turi Zsolt , Fliegauf Maximilian , Kirsch Matthias , Pfeifer Dietmar , Masuda Takahiro , Prinz Marco , Lenz Maximilian , Vlachos Andreas
Published: October 2021

Microglia—the resident immune cells of the central nervous system—sense the activity of neurons and regulate physiological brain functions. They have been implicated in the pathology of brain diseases associated with alterations in neural excitability and plasticity. However, experimental and therapeutic approaches that modulate microglia function in a brain-region-specific manner have not been established. In this study, we tested for the effects of repetitive transcranial magnetic stimulation (rTMS), a clinically employed non-invasive brain stimulation technique, on microglia-mediated synaptic plasticity. 10 Hz electromagnetic stimulation triggered a release of plasticity-promoting cytokines from the microglia in organotypic brain tissue cultures, while no changes in microglial morphology or microglia dynamics were observed. Indeed, substitution of tumor necrosis factor alpha (TNFα) and interleukin 6 (IL6) preserved synaptic plasticity induced by 10 Hz stimulation in the absence of microglia. Consistent with these findings, in vivo depletion of microglia abolished rTMS-induced changes in neurotransmission in the medial prefrontal cortex (mPFC) of anesthetized mice. We conclude that rTMS affects neural excitability and plasticity by modulating the release of cytokines from microglia.
Unique Peptide Signatures Of SARS-CoV-2 Against Human Proteome Reveal Variants’ Immune Escape And Infectiveness
Authors: Pierros Vasileios , Kontopodis Evangelos , Stravopodis Dimitrios J. , Tsangaris George Th.
Published: October 2021

SARS-CoV-2 pandemic has emerged the necessity of the identification of sequences sites in viral proteome appropriate as antigenic sites and treatment targets. In the present study, we apply a novel approach for deciphering the virus-host organism interaction, by analyzing the Unique Peptides of the virus with a minimum amino acid sequence length defined as Core Unique Peptides (CrUPs) not of the virus per se, but against the entire proteome of the host organism. The result of this approach is the identification of the CrUPs of the virus itself, which do not appear in the host organism proteome. Thereby, we analyzed the SARS-CoV-2 proteome for identification of CrUPs against the Human Proteome and they are defined as C/H-CrUPs. We found that SARS-CoV-2 include 7.503 C/H-CrUPs, with the SPIKE_SARS2 being the protein with the highest density of C/H-CrUPs. Extensive analysis indicated that the P681R mutation produces new C/H-CrUPs around the R685 cleavage site, while the L452R mutation induces the loss of antigenicity of the NF9 peptide and the strong(er) binding of the virus to ACE2 receptor protein. The simultaneous existence of these mutations in variants like Delta results in the immune escape of the virus, its massive entrance into the host cell, a notable increase in virus formation, and its massive release and thus elevated infectivity.
Severe distortion in the representation of foveal visual image locations in short term memory
Authors: Willeke Konstantin F. , Cardenas Araceli R. , Bellet Joachim , Hafed Ziad M.
Published: October 2021

The foveal visual image region provides the human visual system with the highest acuity. However, it is unclear whether such a high fidelity representational advantage is maintained when foveal image locations are committed to short term memory. Here we describe a paradoxically large distortion in foveal target location recall by humans. We briefly presented small, but high contrast, points of light at eccentricities ranging from 0.1 to 12 deg, while subjects maintained their line of sight on a stable target. After a brief memory period, the subjects indicated the remembered target locations via computer controlled cursors. The biggest localization errors, in terms of both directional deviations and amplitude percentage overshoots or undershoots, occurred for the most foveal targets, and such distortions were still present, albeit with qualitatively different patterns, when subjects shifted their gaze to indicate the remembered target locations. Foveal visual images are severely distorted in short term memory.
iLoci: Robust evaluation of genome content and organization for provisional and mature genome assemblies
Authors: Standage Daniel S , Lai Tim , Brendel Volker P
Published: October 2021

Background

The rate at which new draft genome assemblies and corresponding annotation versions are being produced has long outpaced the scientific community’s capacity to refine these drafts into “finished,” reference-quality data resources to a standard typically expected from dedicated efforts of model organism research communities. Nonetheless, scientists must be able to evaluate newly sequenced genomes in the context of previously published data, requiring summaries of genome content and organization that can be quickly computed, updated, and meaningfully compared. As annotation quality will necessarily vary within and across data sets, the ability to select subsets of only those data that are well supported is critical for distinguishing technical artifacts from biological effects in genome-wide analyses.

Results

We introduce a new framework for genome analyses based on parsing an annotated genome assembly into distinct interval loci (iLoci), available as open source software as part of the AEGeAn Toolkit (https://github.com/BrendelGroup/AEGeAn). We demonstrate that iLoci provide an alternative coordinate system that is robust to changes in assembly and annotation versions and facilitates granular quality control of genome data. We discuss how statistics computed on iLoci reflect various characteristics of genome content and organization and illustrate how these statistics can be used to establish a baseline for assessment of the completeness and accuracy of the data. We also introduce a well-defined measure of relative genome compactness and compute other iLocus statistics that reveal genome-wide characteristics of gene arrangements in the whole genome context.

Conclusions

We present a coherent computational framework that calculates informative statistics from genome assembly/annotation data input. Given the fast pace of assembly/annotation updates, our AEGeAn Toolkit fills a niche in computational genomics based on deriving persistent and species-specific genome statistics. Gene structure model centric iLoci provide a precisely defined coordinate system that can be used to store assembly/annotation updates that reflect either stable or changed assessments. Large-scale application of the approach revealed species and clade specific genome organization in precisely defined computational terms, promising intriguing forays into the forces of shaping genome structure as more and more genome assemblies are being deposited.
Prefrontal signals precede striatal signals for biased credit assignment to (in)actions
Authors: Algermissen Johannes , Swart Jennifer C. , Scheeringa René , Cools Roshan , den Ouden Hanneke E.M.
Published: October 2021

Actions are biased by the outcomes they can produce: Humans are more likely to show action under reward prospect, but hold back under punishment prospect. Such motivational biases derive not only from biased response selection, but also from biased learning: humans tend to attribute rewards to their own actions, but are reluctant to attribute punishments to having held back. The neural origin of these biases is unclear; in particular, it remains open whether motivational biases arise primarily from the architecture of subcortical regions or also reflect cortical influences, the latter being typically associated with increased behavioral flexibility and emancipation from stereotyped behaviors. Simultaneous EEG-fMRI allowed us to track which regions encoded biased prediction errors in which order. Biased prediction errors occurred in cortical regions (dACC, PCC) before subcortical regions (striatum). These results highlight that biased learning is not a mere feature of the basal ganglia, but arises through prefrontal cortical contributions, revealing motivational biases to be a potentially flexible, sophisticated mechanism.
Discovery of Aminoglycosides as first in class, nanomolar inhibitors of Heptosyltransferase I
Authors: Milicaj Jozafina , Hassan Bakar A. , Cote Joy M. , Ramirez-Mondragon Carlos A. , Jaunbocus Nadiya , Rafalowski Angelika , Patel Kaelan R. , Muthyala Ramaiah , Sham Yuk Y. , Taylor Erika A.
Published: October 2021

A clinically relevant inhibitor for Heptosyltransferase I (HepI) has been sought after for many years and while many have designed novel small-molecule inhibitors, these compounds lack the bioavailability and potency necessary for therapeutic use. Extensive characterization of the HepI protein has provided valuable insight into the dynamic motions necessary for catalysis that could be targeted for inhibition. With the help of molecular dynamic simulations, aminoglycoside antibiotics were shown to be putative inhibitors for HepI and in this study, they were experimentally determined to be the first in-class nanomolar inhibitors of HepI with the best inhibitor demonstrating a Ki of 600 +/- 90 nM. Detailed kinetic analyses were performed to determine the mechanism of inhibition while circular dichroism spectroscopy, intrinsic tryptophan fluorescence, docking, and MD simulations were used to corroborate kinetic experimental findings. Kinetic analysis methods include Lineweaver-Burk, Dixon, Cornish-Bowden and Mixed-Model of Inhibition which allowed for unambiguous assignment of inhibition mechanism for each inhibitor. In this study, we show that neomycin and kanamycin b are competitive inhibitors against the sugar acceptor substrate while tobramycin exhibits a mixed inhibitory effect and streptomycin is non-competitive. MD simulations also allowed us to suggest that the inhibitors bind tightly and inhibit catalytic dynamics due to a major desolvation penalty of the enzyme active site. While aminoglycosides have long been known as a class of potent antibiotics, they also have been scientifically shown to impact cell membrane stability, and we propose that inhibition of HepI contributes to this effect by disrupting lipopolysaccharide biosynthesis.