bluuebunny/crossref_metadata_2025 huggingface dataset:
Online Bayesian Analysis with BEAST 2
Authors: Bouckaert Remco , Collienne Lena , Gavryushkin Alex
Published: May 2022

Abstract

There are a growing number of areas, e.g. epidemiology and within-organism cancer evolution, where re-analysing all available data from scratch every time new data becomes available or old data is refined is no longer feasible. All these and related areas can benefit from online phylogenetic inference that can booster previous data analyses.

Here, we make the case that adding/removing taxa from an analysis can have substantial non-local impact on the tree that is inferred, both in a model based setting, as well as for distance based methods. Consequently, online phylogenetic algorithms may require global updates of the trees and other parameters, a task that in general is highly non-trivial.

Motivated by this observation, we designed an online algorithm that benefits from a parallelism in a Bayesian setting that is substantially more efficient than re-running the analysis from scratch. Furthermore, our algorithm is not sensitive to the number of sequences added, allowing the sequence data to grow/be refined iteratively. We show how this approach can be used in a maximum likelihood setting, and – apart from adding/removing new sequences – demonstrate a number of practical alternative use cases of our algorithm, including how to break up a single (offline) large analysis to get results faster.

An open source implementation is available under GPL3 license as the ‘online’ package for BEAST 2 athttps://github.com/rbouckaert/onlineand a tutorial athttps://github.com/rbouckaert/online-tutorial.
Waist rotation angle as an indicator of probable human collision avoidance direction for autonomous mobile robots
Authors: Tamura Hideki , Yamauchi Tatsuto , Nakauchi Shigeki , Minami Tetsuto
Published: May 2022

Currently, the probability of pedestrians on the streets of smart cities encountering autonomous mobile robots (AMRs) is increasing. Previous studies have discussed collision avoidance between humans as they cross paths. Their avoidance behavior toward AMRs, however, remains unclear. To address this, we experimentally investigated the avoidance direction a human would choose against an AMR approaching head-on. This experiment included recording human locomotion under such a scenario. Further, an AMR was programmed to approach from various starting points, including directly through the participants (head-on collision). The participants were directed to evade it by moving rightward or leftward, and their paths were tracked. We found that the participants did not strongly prefer either direction, suggesting that the avoidance direction is not solely determined by the participants’ attributes, such as their adherence to the traffic rules of their region. The probability of rightward evasion when the AMR approached head-on indicated that humans use different avoidance strategies when encountering other humans and obstacles. Moreover, the participants’ motion analysis revealed that they involuntarily twisted their waists in the avoidance direction before they evaded the AMR. These results suggest that this twist is the most important predictor of the avoidance direction. These findings could be encoded into the programs of AMRs to adapt these vehicles to our locomotory responses more organically.
Single trial variability in neural activity during a working memory task: A window into multiple distinct information processing sequences
Authors: Nakuci Johan , Covey Thomas J. , Shucard Janet L. , Shucard David W. , Muldoon Sarah F.
Published: May 2022

Successful encoding, maintenance, and retrieval of information stored in working memory requires persistent coordination of activity among multiple brain regions. It is generally assumed that the pattern of such coordinated activity remains consistent for a given task. Thus, to separate this task-relevant signal from noise, multiple trials of the same task are completed, and the neural response is averaged across trials to generate an event-related potential (ERP). However, from trial to trial, the neuronal activity recorded with electroencephalogram (EEG) is actually spatially and temporally diverse, conflicting with the assumption of a single pattern of activity for a given task. Here, we show that variability in neuronal activity among single time-locked trials arises from the presence of multiple forms of stimulus dependent synchronized activity (i.e., distinct ERPs). We develop a data-driven classification method based on community detection to identify three discrete spatio-temporal clusters, or subtypes, of trials with different patterns of activation that are further associated with differences in decision-making processes. These results demonstrate that differences in the patterns of neural activity during working memory tasks represent fluctuations in the engagement of distinct brain networks and cognitive processes, suggesting that the brain can choose from multiple mechanisms to perform a given task.

Significance Statement

Working memory is a complex cognitive ability requiring coordinated activity among multiple brain regions to encode, maintain, and retrieve information. It is generally assumed that the pattern of coordination among brain regions remains consistent and one can average data across multiple trials of the same task. We instead show that there is significant variability in the patterns of brain activity among trials of the same task and develop a method to classify brain activity into distinct subtypes of responses, each with a different spatial and temporal pattern. The subtypes are associated with differences in decision-making processes, suggesting that the brain can use multiple mechanisms to perform a given task.
Iron homeostasis governs erythroid phenotype in Polycythemia Vera
Authors: Bennett Cavan , Jackson Victoria E , Pettikiriarachchi Anne , Hayman Thomas , Schaeper Ute , Moir-Meyer Gemma , Fielding Katherine , Ataide Ricardo , Clucas Danielle , Baldi Andrew , Garnham Alexandra L , Li-Wai-Suen Connie SN , Alexander Warren S , Bahlo Melanie , Burbury Kate , Ng Ashley P , Pasricha Sant-Rayn
Published: May 2022

Polycythemia Vera (PV) is a myeloproliferative neoplasm driven by activating mutations in JAK2 that result in unrestrained erythrocyte production, increasing patients’ hematocrit and hemoglobin concentration, placing them at risk of life-threatening thrombotic events. Our GWAS of 440 PV cases and 403,351 controls utilising UK Biobank data found that SNPs in HFE known to cause hemochromatosis are highly associated with PV diagnosis, linking iron regulation to PV. Analysis of the FinnGen dataset independently confirmed over-representation of homozygous HFE mutations in PV patients. HFE influences expression of hepcidin, the master regulator of systemic iron homeostasis. Through genetic dissection of PV mouse models, we show that the PV erythroid phenotype is directly linked to hepcidin expression: endogenous hepcidin upregulation alleviates erythroid disease whereas hepcidin ablation worsens it. Further, we demonstrate that in PV, hepcidin is not regulated by expanded erythropoiesis but is likely governed by inflammatory cytokines signalling via GP130 coupled receptors. These findings have important implications for understanding the pathophysiology of PV and offer new therapeutic strategies for this disease.
A pro-oxidant combination of resveratrol and copper down-regulates multiple biological hallmarks of ageing and neurodegeneration
Authors: Pal Kavita , Raghuram Gorantla V , Dsouza Jenevieve , Shinde Sushma , Jadhav Vishalkumar , Shaikh Alfina , Rane Bhagyeshri , Tandel Harshali , Kondhalkar Dipali , Chaudhary Shahid , Mittra Indraneel
Published: May 2022

Several hundred billion to a trillion cells die in the body every day, and cell-free chromatin particles (cfChPs) that are released from them enter into the extracellular compartments of the body, including into the circulation. We have earlier reported that cfChPs can readily enter into healthy cells to damage their DNA, activate apoptotic pathways and induce inflammatory cytokines. We hypothesized that repeated lifelong assault on healthy cells by cfChPs is the underlying cause of ageing, and that the ageing process could be retarded by deactivating cfChPs. The latter can be effected by oxygen radicals that are generated upon admixing the nutraceuticals resveratrol (R) and copper (Cu). Using confocal microscopy and antibodies against DNA and histone we detected copious presence of extra-cellular cfChPs in brain of ageing mice, and observed that these were deactivated / eradicated following prolong oral administration of small quantities of R-Cu. Deactivation / eradication of cfChPs was associated with down-regulation of several biological hallmarks of ageing in brain cells which included reduction in: 1) telomere attrition, 2) amyloid deposition, 3) DNA damage, 4) apoptosis, 5) inflammation, 6) senescence, 7) aneuploidy and 8) mitochondrial dysfunction. At a systemic level, R- Cu treatment led to significant reduction in blood levels of glucose, cholesterol and C-reactive protein. These results suggest that cfChPs may be global instigators of ageing and neurodegeneration, and that therapeutic use of R-Cu may help to retard the process of ageing.
Neural correlates for neonicotinoid-induced impairment of olfactory long-term memory
Authors: Cabirol Amélie , Calliari Nicola , Fayolle Marie , Bariselli Sara , Schloetel Jan-Gero , Haase Albrecht
Published: May 2022

Reports of olfactory learning and memory deficits in honey bees exposed to neonicotinoid pesticides have been accumulating over the past decades. As agonists of the nicotinic receptors to acetylcholine, neonicotinoids target most of the projection neurons conveying olfactory information to the memory brain centres, the mushroom bodies (MBs). However, the neural mechanisms by which neonicotinoids interfere with memory formation are poorly understood. Here, we investigated the consequences of chronic exposure to the neonicotinoid imidacloprid on the number of projection neuron terminal boutons and on their plasticity in the context of long-term memory formation. Using super-resolution STED microscopy, we also measured the density of synapsin-positive units (SPUs) within boutons, as synapsin is known to be enriched in new boutons following neuronal activation. We show that imidacloprid suppresses the synaptic pruning of projection neurons naturally occurring with age and experience. The resulting excessive number of boutons in the MBs of treated bees was associated with long-term memory deficits. The subset of treated bees that showed successful memory formation had a similar number of boutons as untreated bees, suggesting that synaptic pruning might have been involved in the memorization process. As the SPU density was not affected by the imidacloprid treatment, the high bouton number in the lip of treated bees was not due to synaptogenesis. Altogether, our experiments show that, by altering synaptic pruning, imidacloprid interferes with long-term memory formation.
AptaMat: a matrix-based algorithm to compare single-stranded oligonucleotides secondary structures
Authors: Binet Thomas , Avalle Bérangère , Felipe Miraine Dávila , Maffucci Irene
Published: May 2022

Comparing single-stranded nucleic acids (ssNAs) secondary structures is fundamental when investigating their function and evolution and predicting the effect of mutations on the ssNAs structures. Many comparison metrics exist, although they are either too elaborate or not enough sensitive to distinguish close ssNAs structures.

In this context, we developed AptaMat, a simple and sensitive algorithm for ssNAs secondary structures comparison based on matrices representing the ssNAs secondary structures and a metric built upon the Manhattan distance in the plane. We applied AptaMat to several examples and compared the results to those obtained by the most frequently used metrics, namely the Hamming distance and the RNAdistance, and by a recently developed image-based approach. We showed that AptaMat is able to discriminate between similar sequences, outperforming all the other here considered metrics.
Efficient and accurate prime editing strategy to correct genetic alterations in hiPSC using single EF-1alpha driven all-in-one plasmids
Authors: Weuring Wout J. , Dirkx N , Vriendt E De , Smal N , Vondervoort J van de , Slot van ’t Ruben , Koetsier M , Weckhuysen S , Koeleman Bobby PC
Published: May 2022

Prime editing (PE) is currently the most effective and versatile technology to make targeted alterations in the genome. Several improvements to the PE machinery have recently been made, and have been tested in a range of model systems, including immortalized cell lines, stem-cells and animal models. While nick RNA (ncRNA)-dependent PE systems like PE3 and PE5 are currently considered to be the most effective, they come with undesired indels or SNVs at the edit locus. Here, we aimed to improve ncRNA-independent systems PE2 and PE4max by generating novel all-in-one (pAIO) plasmids, driven by a tissue-broad EF-1alpha promoter, that is especially suitable for human iPSC models, and linked to a GFP tag for fluorescent based sorting. These novel pAIO systems effectively corrected mutations observed in patients suffering from epileptic encephalopathy, including a truncating SCN1A R612* variant in HEK293T cells and a gain-of-function KCNQ2 R201C variant in patient-derived hiPSC, with edit efficiency up to 50%. We also show that introducing additional silent PAM-removing mutations can negatively influence edit efficiency. Finally, we observed an absence of genome-wide PE off-target effects at pegRNA homology sites. Taken together, our study shows an improved efficacy and accuracy of EF-1alpha driven ncRNA-independent pAIO PE plasmids in hiPSC.
A marked enhancement of a BLOC-1 gene, pallidin, associated with somnolent mouse models deficient in histamine transmission
Authors: Seugnet Laurent , Anaclet Christelle , Perier Magali , Ghersi-Egea Jean-François , Lin Jian-Sheng
Published: May 2022

Histamine (HA) and orexin (Ox, or hypocretin) neurons act distinctly and synergistically in wake control. A double knock out mouse genotype lacking both HA and Ox shows all sleep disorders of human narcolepsy. We identified in this mouse brain a sharp upregulation of a BLOC-1 gene, pallidin that is associated with dramatic changes in the balance of cholinergic and aminergic systems in mice and an enhanced sleep in drosophila. This study demonstrates potential sleep disorders-associated compensatory mechanisms with pallid as a novel biomarker.
Hypereosinophilia causes progressive cardiac pathologies in mice
Authors: Diny Nicola Laura , Wood Megan Kay , Won Taejoon , Talor Monica Vladut , Lukban Clarisse , Bedja Djahida , Wang Nadan , Talbot C. Conover , Lin Brian Leei , Čiháková Daniela
Published: May 2022

Hypereosinophilic syndrome is a progressive disease with extensive eosinophilia that results in organ damage. Cardiac pathologies are the main reason for its high mortality rate. A better understanding of the mechanisms of eosinophil-mediated tissue damage would benefit therapeutic development. Here, we describe the cardiac pathologies that developed in a mouse model of hypereosinophilic syndrome. These IL-5 transgenic mice exhibited decreased left ventricular function at a young age which worsened with age. Mechanistically, we demonstrated infiltration of activated eosinophils into the heart tissue that led to an inflammatory environment. Gene expression signatures showed tissue damage as well as repair and remodeling processes. Cardiomyocytes from IL-5Tg mice exhibited significantly reduced contractility relative to WT controls. This impairment may result from the inflammatory stress experienced by the cardiomyocytes and suggest that dysregulation of contractility and Ca2+reuptake in cardiomyocytes contributes to cardiac dysfunction at the whole organ level in hypereosinophilic mice.

Teaser

Too many eosinophils cause inflammation in the heart and change cardiomyocyte contraction leading to poor heart function.
Combination therapy targeting inflammasome and fibrogenesis alleviates inflammation and fibrosis in a zebrafish model of silicosis
Authors: Tyrkalska Sylwia D. , Pedoto Annamaria , Martínez-López Alicia , Candel Sergio , Ros-Lucas José A. , Mesa-del-Castillo Pablo , Mulero Victoriano
Published: May 2022

Silicosis is a long-term lung disease caused by the inhalation of large amounts of crystalline silica dust. As there is no effective treatment available, patients are provided with supportive care, and some may be considered for lung transplantation. There is therefore an evident need for a better understanding of the disease’s biology and for identifying new therapeutic targets and therapies. In this context, our group has developed a larval zebrafish model of silicosis by injecting silica crystals into the hindbrain ventricle, a cavity into which immune cells can be recruited and that mimics the alveolar environment of the human lung. The injection of silica crystals into this cavity led to the initiation of local and systemic immune responses driven through both TLR- and inflammasome-dependent signaling pathways, followed by fibrosis, as happens in human patients. The combination of the inflammasome inhibitor VX-765 and the antifibrotic agent pirfenidone was found to be the best therapy to alleviate both inflammation and fibrosis. The zebrafish model of silicosis developed here is a unique tool that will shed light onto the molecular mechanisms involved in the progression of this devastating disease and for identifying novel drugs that improve the quality of life of silicosis patients.
Effects of microplastics mixed with natural particles onDaphnia magnapopulations
Authors: Schür Christoph , Beck Joana , Lambert Scott , Scherer Christian , Oehlmann Jörg , Wagner Martin
Published: May 2022

The toxicity of microplastics onDaphnia magnaas a key model for freshwater zooplankton is well described. While several studies predict population-level effects based on short-term, individual-level responses, only very few have validated these predictions experimentally. Thus, we exposedD. magnapopulations to irregular polystyrene microplastics and diatomite as natural particle (both ≤ 63 μm) over 50 days. We used mixtures of both particle types at fixed particle concentrations (50,000 particles mL-1) and recorded the effects on overall population size and structure, the size of the individual animals, and resting egg production. Particle exposure adversely affected the population size and structure and induced resting egg production. The terminal population size was 28–42% lower in exposed compared to control populations. Interestingly, mixtures containing diatomite induced stronger effects than microplastics alone, highlighting that natural particles are notper seless toxic than microplastics. Our results demonstrate that an exposure to synthetic and natural particles has negative population-level effects on zooplankton. Understanding the mixture toxicity of microplastics and natural particles is important given that aquatic organisms will experience exposure to both. Just as for chemical pollutants, better knowledge of such joint effects is essential to fully understand the environmental impacts of complex particle mixtures.

Environmental Implications

While microplastics are commonly considered hazardous based on individual-level effects, there is a dearth of information on how they affect populations. Since the latter is key for understanding the environmental impacts of microplastics, we investigated how particle exposures affect the population size and structure ofDaphnia magna. In addition, we used mixtures of microplastics and natural particles because neither occurs alone in nature and joint effects can be expected in an environmentally realistic scenario. We show that such mixtures adversely affect daphnid populations and highlight that population-level and mixture-toxicity designs are one important step towards more environmental realism in microplastics research.

Graphical Abstract

Highlights

Daphniapopulations exposed to mixtures of microplastics and diatomite

Effects on population size, structure, and resting egg production

Diatomite as natural particle more toxic than microplastics

Particle mixtures induce negative population-level effects

Particle mixtures represent more realistic exposure scenario
FAIRsoft - A practical implementation of FAIR principles for research software
Authors: del Pico Eva Martín , Gelpi Josep Lluis , Capella-Gutiérrez Salvador
Published: May 2022

Software plays a crucial and growing role in research. Unfortunately, the computational component in Life Sciences research is challenging to reproduce and verify most of the time. It could be undocumented, opaque, may even contain unknown errors that affect the outcome, or be directly unavailable, and impossible to use by others. These issues are detrimental to the overall quality of scientific research. One step to address this problem is the formulation of principles that research software in the domain should meet to ensure its quality and sustainability, resembling the FAIR (Findable, Accessible, Interoperable and Reusable) Data Principles. Within the ELIXIR infrastructure, OpenEBench aims to be an open platform providing both support for scientific benchmarking and an active observatory of software quality for the universe of Life Sciences research software. We present our initial proposal to instantiate a FAIR-like framework for assessing software quality as the first step toward the implementation of such an observatory in OpenEBench.

Supplementary Material:FAIRsoft - Supplementary materials FAIRsoft.SupplementaryTables FAIRsoft.SupplementaryTables-Landscape

Other Figures:figures draft

Repository:https://gitlab.bsc.es/inb/elixir/software-observatory/FAIRsoft_ETL
KIF21B binds Myosin Va for Spine Entry and regulates Actin Dynamics to control Homeostatic Synaptic Downscaling
Authors: Gromova Kira V. , Thies Edda , Dürst Céline D. , Stajano Daniele , Schweizer Michaela , Mikhaylova Marina , Gee Christine E. , Kneussel Matthias
Published: May 2022

Homeostatic synaptic plasticity adjusts the strength of synapses to restrain neuronal activity within a physiological range. Postsynaptic GKAP controls the bidirectional synaptic scaling of AMPA receptors (AMPARs) however how chronic activity triggers postsynaptic protein remodeling to downscale synaptic transmission is barely understood. Here we report that the microtubule-dependent kinesin motor KIF21B interacts with GKAP and likewise enters dendritic spines in a myosin Va- and activity-dependent manner. We observed that under conditions of chronic activity KIF21B regulates actin dynamics in spines, triggers spine removal of GluA2-containing AMPA receptors, and mediates homeostatic synaptic downscaling of AMPA receptor-mediated mEPSC amplitudes. Our data highlight a myosin-kinesin interaction that enables the entry of the microtubule-dependent motor KIF21B into actin-rich spine compartments. A slow actin turnover rate might be beneficial for efficient protein removal from excitatory synapses, suggesting a functional role of KIF21B in a GKAP- and AMPA receptor-dependent mechanism, underlying homeostatic downscaling of neuronal firing.
A dynamical low-rank approach to solve the chemical master equation for biological reaction networks
Authors: Prugger Martina , Einkemmer Lukas , Lopez Carlos F.
Published: May 2022

Solving the chemical master equation is an indispensable tool in understanding the behavior of biological and chemical systems. In particular, it is increasingly recognized that commonly used ODE models are not able to capture the stochastic nature of many cellular processes. Solving the chemical master equation directly, however, suffers from the curse of dimensionality. That is, both memory and computational effort scale exponentially in the number of species. In this paper we propose a dynamical low-rank approach that enables the simulation of large biological networks. The approach is guided by partitioning the network into biological relevant subsets and thus avoids the use of single species basis functions that are known to give inaccurate results for biological systems. We use the proposed method to gain insight into the nature of asynchronous vs. synchronous updating in Boolean models and successfully simulate a 41 species apoptosis model on a standard desktop workstation.
Group A streptococci induce high-affinity M protein-fibronectin interaction when specific human antibodies are bound
Authors: Wrighton Sebastian , Ahnlide Vibha Kumra , André Oscar , Bahnan Wael , Nordenfelt Pontus
Published: May 2022

Group A streptococcus (GAS) is a highly adapted, humanspecific pathogen that is known to manipulate the immune system through various mechanisms. GAS’ M protein constitutes a primary target of the immune system due to its spatial configuration and dominance on the bacterial surface. Antibody responses targeting the M protein have been shown to favor the conserved C region. Such antibodies circumvent antigenic escape and efficiently bind to various M types. The ability of GAS to bind to fibronectin (Fn), a high molecular weight glycoprotein of the extracellular matrix, has long been known to be essential for the pathogen’s evolutionary success and fitness. However, some strains lack the ability to efficiently bind Fn. Instead, they have been found to inefficiently bind Fn via the M protein A-B domains. Here, we show that human antibodies can induce a high-affinity Fn-binding state in M proteins, likely by enhancing the weak A-B domain binding. The antibodies bind to a conserved region of M proteins, and the high-affinity binding only occurs on the individual M proteins with bound specific antibodies. By allowing the binding of antibodies to a certain region in M, and thereby enhancing Fn-binding, GAS exploits the human humoral immune response to efficiently bind Fn without needing to waste energy on the production of additional proteins – potentially giving such strains an evolutionary advantage.
In search of the universal method: a comparative survey of bottom-up proteomics sample preparation methods
Authors: Varnavides Gina , Madern Moritz , Anrather Dorothea , Hartl Natascha , Reiter Wolfgang , Hartl Markus
Published: May 2022

Robust, efficient and reproducible protein extraction and sample processing is a key step for bottom-up proteomics analyses. While many sample preparation protocols for mass spectrometry have been described, selecting an appropriate method remains challenging, since some protein classes may require specialized solubilization, precipitation, and digestion procedures. Here we present a comprehensive comparison of 16 most widely used sample preparation methods, covering in-solution digests, device-based methods, as well as commercially available kits. We find a remarkably good performance of the majority of the protocols with high reproducibility, little method dependencies and low levels of artifact formation. However, we revealed method-dependent differences in the recovery of specific protein features, which we summarized in a descriptive guide-matrix. Our work thereby provides a solid basis for the selection of MS sample preparation strategies for a given proteomics project.
Morphological evolution and diversity of pectoral fin skeletons in teleosts
Authors: Tanaka Yoshitaka , Miura Hiroki , Tamura Koji , Abe Gembu
Published: May 2022

The Teleostei class has the most species of the fishes. Members of this group have paired rostral appendages and pectoral fins, enabling refined movements in the water. Although teleosts live in a diverse set of environments, the skeletal pattern of pectoral fins in teleosts is considered to show little morphological variability. Here, in order to elucidate variations in pectoral fin skeletons and to identify their evolutionary processes, we compared the pectoral fin skeletons from 27 species of teleosts. We identified several variations and a diversity of pectoral fin skeletal patterns within some teleost groups. Taken together with previous reports on teleost skeletons, our findings reveal that in the course of teleost evolution, there are a mixture of conserved and non- conserved components in the pectoral fin skeletons of teleosts, and that teleosts may have experienced the variation and conservation of the number and shape of the proximal radials, the loss of the mesocoracoid, and the change in the distal radial-fin ray relationship.
Role of High Mobility Group B protein HmbA, orthologue of yeast Nhp6p in Aspergillus nidulans
Authors: Ámon J. , Varga G. , Pfeiffer I. , Karácsony Z. , Hegedűs Z. , Vágvölgyi C. , Hamari Z.
Published: May 2022

The mammalian HMGB1 protein belongs to the high-mobility-group B (HMG-B) family, which is not only architectural but also functional element of the chromatin. The fungal counterpart of HMGB1 was identified in Saccharomyces cerevisiae as Nhp6p and the pleiotropic physiological functions of this protein were thoroughly studied during the last decades. Although filamentous Ascomycete fungi also possess the orthologues of Nhp6p, their physiological functions, apart from their role in the sexual development, have not been investigated, yet. Here we study the physiological functions of the Nhp6p orthologue HmbA from Aspergillus nidulans in the primary and secondary metabolism, stress tolerance, hypha elongation and maintenance of polarized growth through the analysis of hmbA deletion mutant. We also revealed that the endochitinase ChiA acts in the cell wall remodelling and contributes to polar growth. Additionally, by conducting heterologous expression studies, we further demonstrated that HmbA and Nhp6p is interchangeable for several functions. We hypothesized that the fully complemented functions might predominantly depend on the DNA binding ability of the HmbA and Nhp6p proteins rather than on the interaction of these HMG-B proteins with other functional protein components of the chromatin.
Katanin is involved in Microtubule Polymerization into Dendritic Spines and regulates Synaptic Plasticity
Authors: Lombino Franco L. , Schwarz Jürgen R. , Pechmann Yvonne , Schweizer Michaela , Glatzel Markus , Gee Christine E. , Gromova Kira V. , Kneussel Matthias
Published: May 2022

Dynamic microtubules transiently polymerize into dendritic spines, however intracellular factors that regulate this process and their functional role at synapses are hardly understood. Using live imaging, electrophysiology, and glutamate uncaging, we show that the microtubule-severing complex katanin is located at individual spine synapses, participates in the activity-dependent process of microtubule polymerization into dendritic spines, and regulates synaptic plasticity. Overexpression of a dominant-negative ATPase-deficient katanin subunit, did not alter microtubule growth velocities or comet density in dendrites, but significantly reduced the activity-dependent invasion of microtubules into dendritic spines. Notably, functional inhibition of katanin significantly affected the potentiation of AMPA-receptor-mediated excitatory currents after chemical induction of long-term potentiation (cLTP). Furthermore, interference with katanin function prevented structural spine remodeling following single spine glutamate uncaging. Our data identify katanin at individual spine synapses in association with PSD-95. Thus, katanin regulates postsynaptic microtubules and modulates synaptic structure and function.
Early structural connectivity within the sensorimotor network: deviations related to prematurity and association to neurodevelopmental outcome
Authors: Sara Neumane , Andrea Gondova , Yann Leprince , Lucie Hertz-Pannier , Tomoki Arichi , Jessica Dubois
Published: May 2022

The sensorimotor (SM) network is crucial for optimal neurodevelopment. However, undergoing rapid maturation during the perinatal period, it is particularly vulnerable to preterm birth.

Our work explores the prematurity impact on the microstructure and maturation of primary SM white matter (WM) tracts at term-equivalent age (TEA) and evaluates the relationships between these alterations and neurodevelopmental outcome.

We analyzed diffusion MRI data from the developing Human Connectome Project (dHCP) database: 59 preterm (PT) low-risk infants scanned near TEA, compared to a control group of full-term (FT) neonates paired for age at MRI and sex. We dissected pairwise connections between primary SM cortices and subcortical structures using probabilistic tractography and evaluated their microstructure with diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) models. In addition to tract- specific univariate analyses of diffusion metrics, we computed a maturational distance related to prematurity based on a multi-parametric Mahalanobis distance of each PT infant relative to the FT group. Finally, we evaluated the relationships between this distance and Bayley Scales of Infant and Toddler Development (BSID-III) scaled scores at 18 months corrected age.

Our results confirm important microstructural differences in SM tracts between PT and FT infants, with effects increasing with lower gestational age at birth. Additionally, comparisons of maturational distances highlight that prematurity has a differential effect on SM tracts which follows the established WM caudo-rostral developmental pattern. Our results suggest a particular vulnerability of projections involving the primary sensorimotor cortices (S1) and of the most rostral tracts, with cortico-cortical and S1-Lenticular tracts presenting the highest alterations at TEA. Finally, NODDI-derived maturational distances of specific tracts seem related to fine motor and cognitive scores.

This study expands the understanding of the impact of early WM alterations in the emerging SM network on long-term neurodevelopment. In the future, related approaches have potential to lead to the development of neuroimaging markers for neurodevelopmental disorders, with special interest for subtle neuromotor impairments frequently observed in preterm-born children.
Microbial population dynamics decouple growth response from environmental nutrient concentration
Authors: Fink Justus Wilhelm , Held Noelle A. , Manhart Michael
Published: May 2022

How the growth rate of a microbial population responds to the environmental availability of chemical nutrients and other resources is a fundamental question in microbiology. Models of this response, such as the widely-used Monod model, are generally characterized by a maximum growth rate and a half-saturation concentration of the resource. What values should we expect for these half-saturation concentrations, and how should they depend on the environmental concentration of the resource? We survey growth response data across a wide range of organisms and resources. We find that the half-saturation concentrations vary across orders of magnitude, even for the same organism and resource. To explain this variation, we develop an evolutionary model to show that demographic fluctuations (genetic drift) can constrain the adaptation of half-saturation concentrations. We find that this effect fundamentally differs depending on the type of population dynamics: populations undergoing periodic bottlenecks of fixed size will adapt their half-saturation concentration in proportion to the environmental resource concentration, but populations undergoing periodic dilutions of fixed size will evolve half-saturation concentrations that are largely decoupled from the environmental concentration. Our model not only provides testable predictions for laboratory evolution experiments, but it also reveals how an evolved half-saturation concentration may not reflect the organism’s environment. In particular, this explains how organisms in resource-rich environments can still evolve fast growth at low resource concentrations. Altogether our results demonstrate the critical role of population dynamics in shaping fundamental ecological traits.
Effects of Body Mass on Leg and Vertical Stiffness in Running Humans
Authors: Fox Maria C. , Hsiao-Wecksler Elizabeth T. , Polk John D.
Published: May 2022

Numerous cross-species comparisons have examined the scaling of gait parameters with respect to body mass (i.e., allometry), but few have done so within humans. This study examined how leg and vertical stiffness, force, displacement, and leg spring angle scaled in 64 healthy adults of varying body masses during slow and fast leg-length-adjusted running speeds. We calculated scaling patterns for stiffness and its components via kinematic and kinetic data using log-log regressions with 95% confidence/highest density intervals. To determine if the chosen statistical method influenced conclusions about scaling patterns, we compared regression results across three statistical methods, ordinary least squares (OLS) regression, linear mixed models (LMM), and Bayesian linear mixed models (BLMM). We also performed sex-specific analyses to determine if each sex revealed similar scaling patterns as the pooled sample. In the pooled sample, all variables scaled according to the isometric expectations, suggesting that different-sized humans move in a similar manner. Sex-specific analyses revealed similar patterns of isometry in all variables, except for vertical stiffness, which displayed slight negative allometry (i.e., lower than expected stiffness) in both sexes at the slow speed and negative allometry in females during fast running. Model choice did not significantly affect results, and scaling patterns were the same regardless of the statistical method employed.
The Tryptophan Metabolizing Enzyme Indoleamine 2,3-Dioxygenase 1 Regulates Polycystic Kidney Disease Progression
Authors: Nguyen Dustin T. , Kleczko Emily K. , Dwivedi Nidhi , Gitomer Berenice Y. , Chonchol Michel B. , Clambey Eric T. , Nemenoff Raphael A. , Klawitter Jelena , Hopp Katharina
Published: May 2022

Autosomal dominant polycystic kidney disease (ADPKD), the most common monogenic nephropathy, is characterized by phenotypic variability exceeding genic effects. Dysregulated metabolism and immune cell function are key disease modulators. The tryptophan metabolites, kynurenines, produced through IDO1, are known immunomodulators. Here, we study the role of tryptophan metabolism in PKD using an orthologous disease model (C57Bl/6J Pkd1RC/RC). We found elevated kynurenine and IDO1 levels in Pkd1RC/RC kidneys versus wildtype. Further, IDO1 levels were increased in ADPKD cell lines and patient cyst cells. Genetic Ido1 loss in Pkd1RC/RC animals resulted in reduced PKD severity as measured by %kidney weight/body weight and cystic index. Consistent with a immunomodulatory role of kynurenines, Pkd1RC/RC;Ido1-/- mice presented with significant changes in the cystic immune microenvironment (CME) versus controls. Of note, kidney macrophage numbers decreased and CD8+ T cell numbers increased, both known PKD modulators. Also, pharmacological IDO1 inhibition using a tryptophan analog in Pkd1RC/RC animals resulted in less severe PKD versus controls with similar changes in the CME as in the genetic model. Together, our data suggest that tryptophan metabolism is dysregulated in ADPKD and that its inhibition results in changes to the CME and slows disease progression, making IDO1 a novel therapeutic target for ADPKD.
Physics of Self-Assembly and Morpho-Topological Changes of Klebsiella Pneumoniae in Desiccating Sessile Droplets
Authors: Rasheed Abdur , Hegde Omkar , Chaterjee Ritika , Sampathirao Srinivas Rao , Chakravortty Dipshikha , Basu Saptarshi
Published: May 2022

We have investigated the flow and desiccation-driven self-assembly of Klebsiella Pneumoniae in the naturally evaporating sessile droplets. Klebsiella Pneumoniae exhibits extensive changes in its morphology and forms unique patterns as the droplet dries, revealing hitherto unexplored rich physics governing its survival and infection strategies. Self-assembly of bacteria at the droplet contact line is characterized by order-to-disorder packing transitions with high packing densities and excessive deformations (bacteria deforms nearly twice its original length scales). In contrast, thin-film instability-led hole formation at the center of the droplet engenders spatial packing of bacteria analogous to honeycomb weathering. The varying physical forces acting on bacteria based on their respective spatial location inside the droplet cause an assorted magnitude of physical stress. Self-assembly favors the bacteria at the rim of the droplet, leading to enhanced viability and pathogenesis on the famously known “coffee ring” of the droplet compared to the bacteria present at the center of the droplet residue. Mechanistic insights gained via our study can have far-reaching implications for bacterial infection through droplets, e.g., through open wounds.
Spt6 directly interacts with Cdc73 and is required for Paf1C recruitment to active genes
Authors: Ellison Mitchell A. , Blacksmith Matthew S. , Namjilsuren Sanchirmaa , Shirra Margaret K. , Schusteff Rachel A. , Kerr Eleanor M. , Fang Fei , Xiang Yufei , Shi Yi , Arndt Karen M.
Published: May 2022

Paf1C is a conserved transcription elongation factor that regulates transcription elongation efficiency, facilitates co-transcriptional histone modifications, and impacts molecular processes linked to RNA synthesis, such as polyA site selection. Coupling of the activities of Paf1C to transcription elongation requires its association with RNA polymerase II (Pol II). Mutational studies in yeast identified Paf1C subunits Cdc73 and Rtf1 as important mediators of Paf1C recruitment to Pol II on active genes. While the interaction between Rtf1 and the general elongation factor Spt5 is relatively well-understood, the interactions involving Cdc73 remain to be elucidated. Using an in vivo site-specific protein cross-linking strategy, we identified direct interactions between Cdc73 and two components of the elongation complex, the elongation factor Spt6 and the largest subunit of Pol II. Through in vitro protein binding assays and crosslinking/mass spectrometry, we show that Cdc73 and Spt6 can interact in the absence of additional factors and propose a binding interface. Rapid depletion of Spt6 dissociated Paf1 from chromatin and altered patterns of Paf1C-dependent histone modifications genome-wide. These results reveal previously unrecognized interactions between Cdc73 and the Pol II elongation complex and identify Spt6 as a key factor contributing to Paf1C recruitment to active genes in Saccharomyces cerevisiae.
The effects of physical and temporal certainty on locomotion with discrete underfoot perturbations
Authors: Kreter Nicholas , Lybbert Carter , Gordon Keith E. , Fino Peter C.
Published: May 2022

Background

Ambulation over complex terrain requires active control of foot placement to maintain a normal kinematic relationship between the center of mass and base of support. Recent investigations have suggested that foot placement location may be selected to anticipate shifts to the underfoot center of pressure. However, it is unclear whether temporal affordance and physical certainty contribute to the selection of a perturbation-specific anticipatory strategy. This study investigates anticipatory and reactive locomotor strategies for repeated underfoot perturbations with varying levels of temporal certainty, temporal affordance, and physical certainty.

Methods

Thirteen healthy adults walked with random underfoot perturbations from a mechanized shoe. Temporal certainty was challenged by presenting the perturbations with or without warning. Temporal affordance was challenged by adjusting the timing of a warning tone before the perturbation. Physical certainty was challenged with conditions that included only eversion perturbations, only inversion perturbations, or both eversion and inversion perturbations. Linear-mixed effects models assessed the effect of each condition on the percent change of margin of stability and step width, respectively.

Results

For temporally uncertain perturbations and perturbations with one stride or less of affordance, we observed few changes to step width or margin of stability. As affordance increased to two strides, participants adopted a wider step width in anticipation of the perturbation (p = 0.001). Physical certainty had little effect on gait for the step of the perturbation, but participants recovered normal gait sooner when the physical nature of the perturbation was predictable (p < 0.001).

Discussion

Despite having information about the timing and magnitude of upcoming perturbations, individuals do not develop perturbation specific feedforward strategies but instead rely on feedback control to recover normal gait after a perturbation. However, physical certainty appears to improve the efficiency of the feedback controller and allows individuals to recover normal gait sooner.
Actin nano-architecture of phagocytic podosomes
Authors: Herron J. Cody , Hu Shiqiong , Watanabe Takashi , Nogueira Ana T. , Liu Bei , Kern Megan , Aaron Jesse , Taylor Aaron , Pablo Michael , Chew Teng-Leong , Elston Timothy C. , Hahn Klaus M.
Published: May 2022

Podosomes are actin-enriched adhesion structures important for multiple cellular processes, including migration, bone remodeling, and phagocytosis. Here, we characterized the structure and organization of phagocytic podosomes using interferometric photoactivated localization microscopy (iPALM), a super-resolution microscopy technique capable of 15-20 nm resolution, together with structured illumination microscopy (SIM) and localization-based superresolution microscopy. Phagocytic podosomes were observed during frustrated phagocytosis, a model in which cells attempt to engulf micro-patterned IgG antibodies. For circular patterns, this resulted in regular arrays of podosomes with well-defined geometry. Using persistent homology, we developed a pipeline for semi-automatic identification and measurement of podosome features. These studies revealed an “hourglass” shape of the podosome actin core, a protruding “knob” at the bottom of the core, and two actin networks extending from the core. Additionally, the distributions of paxillin, talin, myosin II, α-actinin, cortactin, and microtubules relative to actin were characterized.
Contributions and synaptic basis of diverse cortical neuron responses to task performance
Authors: Insanally Michele N. , Albanna Badr F. , Toth Jack , DePasquale Brian , Fadaei Saba , Gupta Trisha , Kuchibhotla Kishore , Rajan Kanaka , Froemke Robert C.
Published: May 2022

Neuronal responses during behavior are diverse, ranging from highly reliable ‘classical’ responses to irregular or seemingly-random ‘non-classically responsive’ firing. While a continuum of response properties is frequently observed across neural systems, little is known about the synaptic origins and contributions of diverse response profiles to network function, perception, and behavior. Here we use a task-performing, spiking recurrent neural network model incorporating spike-timing-dependent plasticity that captures heterogeneous responses measured from auditory cortex of behaving rodents. Classically responsive and non-classically responsive model units contributed to task performance via output and recurrent connections, respectively. Excitatory and inhibitory plasticity independently shaped spiking responses and task performance. Local patterns of synaptic inputs predicted spiking response properties of network units as well as the responses of auditory cortical neurons from in vivo whole-cell recordings during behavior. Thus a diversity of neural response profiles emerges from synaptic plasticity rules with distinctly important functions for network performance.