bluuebunny/crossref_metadata_2025 huggingface dataset:
Weighted transitivity scores that account for triadic edge similarity in undirected graphs
Authors: Peron Guillaume
Published: January 2022

The graph transitivity measures the probability that adjacent vertices in a network are interconnected, thus revealing the existence of tightly connected neighborhoods playing a role in information and pathogen circulation. When the connections vary in strength, focusing on whether connections exist or not can be reductive. I score the weighted transitivity according to the similarity between the weights of the three possible links in each triad. I illustrate the biological relevance of that information with two reanalyses of animal contact networks. In the rhesus macaque Macaca mulatta, a species in which kin relationships strongly predict social relationships, the new metrics revealed striking similarities in the configuration of grooming networks in captive and free-ranging groups, but only as long as the matrilines were preserved. In the barnacle goose Branta leucopsis, in an experiment designed to test the long-term effect of the goslings’ social environment, the new metrics uncovered an excess of weak triplets closed by strong links in males compared to females, and consistent with the triadic process underlying goose dominance relationships.
Magnetic Stimulation Allows Focal Activation of the Mouse Cochlea
Authors: Lee Jae-Ik , Seist Richard , McInturff Stephen , Lee Daniel J. , Brown M. Christian , Stankovic Konstantina M. , Fried Shelley
Published: January 2022

Cochlear implants (CIs) strive to restore hearing to those with severe to profound hearing loss by artificially stimulating the auditory nerve. While most CI users can understand speech in a quiet environment, hearing that utilizes complex neural coding (e.g., appreciating music) has proved elusive, probably because of the inability of CIs to create narrow regions of spectral activation. Several novel approaches have recently shown promise for improving spatial selectivity, but substantial design differences from conventional CIs will necessitate much additional safety testing before clinical viability is established. Outside the cochlea, magnetic stimulation from small coils (micro-coils) has been shown to confine activation more narrowly than that from conventional micro-electrodes, raising the possibility that coil-based stimulation of the cochlea could improve the spectral resolution of CIs. To explore this, we delivered magnetic stimulation from micro-coils to multiple locations of the cochlea and measured the spread of activation utilizing a multi-electrode array inserted into the inferior colliculus; responses to magnetic stimulation were compared to analogous experiments with conventional micro-electrodes as well as to the responses to auditory monotones. Encouragingly, the extent of activation with micro-coils was ∼60% narrower than that from electric stimulation and largely similar to the spread arising from acoustic stimulation. The dynamic range of coils was more than three times larger than that of electrodes, further supporting a smaller spread of activation. While much additional testing is required, these results support the notion that coil-based CIs can produce a larger number of independent spectral channels and may therefore improve functional performance. Further, because coil-based devices are structurally similar to existing CIs, fewer impediments to clinical translational are likely to arise.
De novo protein structure prediction by incremental inter-residue geometries prediction and model quality assessment using deep learning
Authors: Liu Jun , He Guang-Xing , Zhao Kai-Long , Zhang Gui-Jun
Published: January 2022

Motivation

The successful application of deep learning has promoted progress in protein model quality assessment. How to use model quality assessment to further improve the accuracy of protein structure prediction, especially not reliant on the existing templates, is helpful for unraveling the folding mechanism. Here, we investigate whether model quality assessment can be introduced into structure prediction to form a closed-loop feedback, and iteratively improve the accuracy of de novo protein structure prediction.

Results

In this study, we propose a de novo protein structure prediction method called RocketX. In RocketX, a feedback mechanism is constructed through the geometric constraint prediction network GeomNet, the structural simulation module, and the model quality evaluation network EmaNet. In GeomNet, the co-evolutionary features extracted from MSA that search from the sequence databases are sent to an improved residual neural network to predict the inter-residue geometric constraints. The structure model is folded based on the predicted geometric constraints. In EmaNet, the 1D and 2D features are extracted from the folded model and sent to the deep residual neural network to estimate the inter-residue distance deviation and per-residue lDDT of the model, which will be fed back to GeomNet as dynamic features to correct the geometries prediction and progressively improve model accuracy. RocketX is tested on 483 benchmark proteins and 20 FM targets of CASP14. Experimental results show that the closed-loop feedback mechanism significantly contributes to the performance of RocketX, and the prediction accuracy of RocketX outperforms that of the state-of-the-art methods trRosetta (without templates) and RaptorX. In addition, the blind test results on CAMEO show that although no template is used, the prediction accuracy of RocketX on medium and hard targets is comparable to the advanced methods that integrate templates.

Availability

The RocketX web server are freely available athttp://zhanglab-bioinf.com/RocketX.

Contact

zgj@zjut.edu.cn
ProtFinder: finding subcellular locations of proteins using protein interaction networks
Authors: Grover Aayush , Gatto Laurent
Published: January 2022

Abstract

Protein subcellular localization prediction plays a crucial role in improving our understanding of different diseases and consequently assists in building drug targeting and drug development pipelines. Proteins are known to co-exist at multiple subcellular locations which make the task of prediction extremely challenging. A protein interaction network is a graph that captures interactions between different proteins. It is safe to assume that if two proteins are interacting, they must share some subcellular locations. With this regard, we propose ProtFinder – the first deep learning-based model that exclusively relies on protein interaction networks to predict the multiple subcellular locations of proteins. We also integrate biological priors like the cellular component of Gene Ontology to make ProtFinder a more biology-aware intelligent system. ProtFinder is trained and tested using the STRING and BioPlex databases whereas the annotations of proteins are obtained from the Human Protein Atlas. Our model obtained an AUC-ROC score of 90.00% and an MCC score of 83.42% on a held-out set of proteins. We also apply ProtFinder to annotate proteins that currently do not have confident location annotations. We observe that ProtFinder is able to confirm some of these unreliable location annotations, while in some cases complementing the existing databases with novel location annotations. The source code for ProtFinder is available at https://github.com/UCLouvain-CBIO/ProtFinder.
Acetazolamide modulates intracranial pressure directly by its action on the cerebrospinal fluid secretion apparatus
Authors: Barbuskaite Dagne , Oernbo Eva K. , Wardman Jonathan H. , Toft-Bertelsen Trine L. , Conti Eller , Andreassen Søren N. , Gerkau Niklas J. , Rose Christine R. , MacAulay Nanna
Published: January 2022

Elevated intracranial pressure (ICP) is observed in many neurological pathologies, e.g. hydrocephalus and stroke. This condition is routinely relieved with neurosurgical approaches, since effective and targeted pharmacological tools are still lacking. The carbonic anhydrase inhibitor, acetazolamide (AZE), may be employed to treat elevated ICP. However, its effectiveness is questioned, its location of action unresolved, and its tolerability low. Here, we employed in vivo and ex vivo approaches to reveal the efficacy and mode of action of AZE in the rat brain. The drug effectively reduced the ICP, irrespective of the mode of drug administration and level of anaesthesia. The effect occurred via a direct action on the choroid plexus and an associated decrease in cerebrospinal fluid secretion, and not indirectly via the systemic action of AZE on renal and vascular processes. Upon a single administration, the reduced ICP endured for approximately 10 h post-AZE delivery with no long-term changes of brain water content or choroidal transporter expression. However, a persistent reduction of ICP was secured with repeated AZE administrations throughout the day. Future specific targeting of choroidal carbonic anhydrases may limit the systemic side effects, and therefore enhance the treatment tolerability and effectiveness in select patient groups experiencing elevated ICP.
Considering decoupled phenotypic diversification between ontogenetic phases in macroevolution: An example using Triggerfishes (Balistidae)
Authors: Dornburg Alex , Zapfe Katerina L. , Williams Rachel , Alfaro Michael E. , Morris Richard , Adachi Haruka , Flores Joseph , Santini Francesco , Near Thomas J. , Frédérich Bruno
Published: January 2022

Across the Tree of Life, most studies of phenotypic disparity and diversification have been restricted to adult organisms. However, many lineages have distinct ontogenetic phases that do not reflect the same traits as their adult forms. Non-adult disparity patterns are particularly important to consider for coastal ray-finned fishes, which often have juvenile phases with distinct phenotypes. These juvenile forms are often associated with sheltered nursery environments, with phenotypic shifts between adults and juvenile stages that are readily apparent in locomotor morphology. However, whether this ontogenetic variation in locomotor morphology reflects a decoupling of diversification dynamics between life stages remains unknown. Here we investigate the evolutionary dynamics of locomotor morphology between adult and juvenile triggerfishes. Integrating a time-calibrated phylogenetic framework with geometric morphometric approaches and measurement data of fin aspect ratio and incidence, we reveal a mismatch between morphospace occupancy, the evolution of morphological disparity, and the tempo of trait evolution between life stages. Collectively, our results illuminate how the heterogeneity of morpho-functional adaptations can decouple the mode and tempo of morphological diversification between ontogenetic stages.
Propofol anesthesia alters cortical traveling waves
Authors: Bhattacharya Sayak , Donoghue Jacob A. , Mahnke Meredith , Brincat Scott L. , Brown Emery N. , Miller Earl K.
Published: January 2022

Oscillatory dynamics in cortex seem to organize into traveling waves that serve a variety of functions. Recent studies show that propofol, a widely used anesthetic, dramatically alters cortical oscillations by increasing slow-delta oscillatory power and coherence. It is not known how this affects traveling waves. We compared traveling waves across the cortex of non-human primates (NHPs) before, during, and after propofol-induced loss-of-consciousness (LOC). After LOC, traveling waves in the slow-delta (∼ 1Hz) range increased, grew more organized, and travelled in different directions relative to the awake state. Higher frequency (8-30 Hz) traveling waves, by contrast, decreased, lost structure, and switched to directions where the slow-delta waves were less frequent. The results suggest that LOC may be due, in part, to changes in slow-delta traveling waves that, in turn, alter and disrupt traveling waves in the higher frequencies associated with cognition.
Spatial MIST Technology for Rapid, Highly Multiplexed Detection of Protein Distribution on Brain Tissue
Authors: Reddy Revanth , Yang Liwei , Liu Jesse , Liu Zhuojie , Wang Jun
Published: January 2022

Highly multiplexed analysis of biospecimens significantly advances the understanding of biological basics of diseases, but these techniques are limited by the number of multiplexity and the speed of processing. Here, we present a rapid multiplex method for quantitative detection of protein markers on brain sections with the cellular resolution. This spatial multiplex in situ tagging (MIST) technology is built upon a MIST microarray that contains millions of small microbeads carrying barcoded oligonucleotides. Using antibodies tagged with UV cleavable oligonucleotides, the distribution of protein markers on a tissue slice could be “printed” on the MIST microarray with high fidelity. The performance of this technology in detection sensitivity, resolution and signal-to-noise level has been fully characterized by detecting brain cell markers. We showcase the codetection of 31 proteins simultaneously within 2 h which is about 10 times faster than the other immunofluorescence-based approaches of similar multiplexity. A full set of computational toolkits was developed to segment the small regions and identify the regional differences across the entire mouse brain. This technique enables us to rapidly and conveniently detect dozens of biomarkers on a tissue specimen, and it can find broad applications in clinical pathology and disease mechanistic studies.
Which lower-limb joints compensate for destabilising energy during walking in humans?
Authors: Golyski Pawel R. , Sawicki Gregory S.
Published: January 2022

Maintaining stability during perturbed locomotion requires coordinated responses across multiple levels of organization (e.g., legs, joints, muscle-tendon units). However, current approaches to investigating such responses lack a “common currency” that is both shared across scales and can be directly related to perturbation demands. We used mechanical energetics to investigate the demands imposed on a leg by a transient increase in unilateral treadmill belt speed targeted to either early or late stance. We collected full body kinematics and kinetics from 7 healthy participants during 222 total perturbations. From across-subject means, we found early stance perturbations elicited no change in net work exchanged between the perturbed leg and the treadmill but net positive work at the overall leg level, and late stance perturbations elicited positive work at the leg/treadmill interface but no change in net work at the overall leg level. Across all perturbations, changes in ankle and knee work from steady state best reflected changes in overall leg work on the perturbed and contralateral sides, respectively. Broadening this paradigm to include joint level (vs. leg level) perturbations and including muscle-tendon unit mechanical energetics may reveal neuromechanical responses used in destabilizing environments which could inform design of balance-assisting devices and interventions.

Subject Areas

biomechanics, biomedical engineering, bioengineering
Exploring the effects of prescribed fire on ticks spread and propagation in a spatial setting
Authors: Fulk Alexander , Huang Weizhang , Agusto Folashade
Published: January 2022

Lyme disease is one of the most prominent tick-borne diseases in the United States and prevalence of the disease has been steadily increasing over the past several decades due to a number of factors, including climate change. Methods for control of the disease have been considered, one of which is prescribed burning. In this paper the effects of prescribed burns on the abundance of ticks present in a spatial domain are assessed. A spatial stage-structured tick-host model with an impulsive differential equation system is developed to simulate the effect that controlled burning has on tick populations. Subsequently, a global sensitivity analysis is performed to evaluate the effect of various model parameters on the prevalence of infectious nymphs. Results indicate that while ticks can recover relatively quickly following a burn, yearly, high-intensity prescribed burns can reduce the prevalence of ticks in and around the area that is burned. The use of prescribed burns in preventing the establishment of ticks into new areas is also explored and it is observed that frequent burning can slow establishment considerably.
Lower hypothalamus subunit volumes link with long-term growth failure after preterm birth: a longitudinal case-control study
Authors: Ruzok Tobias , Schmitz-Koep Benita , Menegaux Aurore , Eves Robert , Daamen Marcel , Boecker Henning , Rieger-Fackeldey Esther , Priller Josef , Zimmer Claus , Bartmann Peter , Wolke Dieter , Sorg Christian , Hedderich Dennis M.
Published: January 2022

Background

Preterm birth is associated with an increased risk for impaired growth. While it is known that in prematurity several somatic to environmental factors such as endocrine factors or nutrition modulate short- and long-term growth failure, the contribution of potentially impaired growth control in the brain remains elusive. We hypothesized that the structure of hypothalamic nuclei involved in growth control is altered after preterm birth, with these alterations being associated with aberrant weight development into adulthood.

Methods

We assessed 101 very preterm (i.e., <32 weeks of gestational age) and/or very low birth weight (i.e., <1500g; VP/VLBW) and 110 full-term born (FT) adults of the population-based Bavarian Longitudinal Study with T1-weighted MRI, deep learning-based hypothalamus subunit segmentation, and multiple body weight assessments from birth into adulthood.

Results

Volumes of the whole hypothalamus and hypothalamus subunits relevant for growth control were reduced in VP/VLBW adults and associated with birth variables (i.e., gestational age and intensity of neonatal treatment), body weight (i.e., weight at birth and adulthood), and growth trajectories (i.e., trajectory slopes and trajectories of those small for gestational age and with long-term catch-up growth). Concerning VP/VLBW weight trajectories, relatively larger hypothalamic volumes comparable to those of FT adults, especially in subunits including the lateral hypothalamus, were associated with favorable long-term growth trajectories.

Conclusions

Results demonstrate lower volumes of growth control-related hypothalamus sub-units after preterm birth that link with long-term growth failure. Data suggest postnatal development of growth-related hypothalamic nuclei in VP/VLBW individuals that corresponds with distinct body growth trajectories into adulthood.

Funding

This study was supported by the Deutsche Forschungsgemeinschaft (BA 6370/2-1 to C.S.), the German Federal Ministry of Education and Science (BMBF 01ER0801 to P.B. and D.W., BMBF 01ER0803 to C.S.) and the Kommission für Klinische Forschung, Technische Universität München (KKF 8700000474 to D.M.H.).
Imprinted SARS-CoV-2-specific memory lymphocytes define hybrid immunity
Authors: Rodda Lauren B. , Morawski Peter A. , Pruner Kurt B. , Fahning Mitchell L , Howard Christian A. , Franko Nicholas , Logue Jennifer , Eggenberger Julie , Stokes Caleb , Golez Inah , Hale Malika , Gale Michael , Chu Helen Y. , Campbell Daniel J. , Pepper Marion
Published: January 2022

Immune memory is tailored by cues that lymphocytes perceive during priming. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic created a situation in which nascent memory could be tracked through additional antigen exposures. Both SARS-CoV-2 infection and vaccination induce multifaceted, functional immune memory, but together they engender improved protection from disease, termed “hybrid immunity”. We therefore investigated how vaccine-induced memory is shaped by previous infection. We found that following vaccination, previously infected individuals generated more SARS-CoV-2 RBD-specific memory B cells and variant-neutralizing antibodies and a distinct population of IFN-γ and IL-10-expressing memory SARS-CoV-2 spike-specific CD4+ T cells than previously naive individuals. While additional vaccination could increase humoral memory, it did not recapitulate the distinct CD4+ T cell cytokine profile in previously naive individuals. Thus, imprinted features of SARS-CoV-2-specific memory lymphocytes define hybrid immunity.
Phenotypic and transcriptomic analysis reveals early stress responses in transgenic rice expressing Arabidopsis DREB1a
Authors: Berchembrock Yasmin Vasques , Pathak Bhuvan , Maurya Chandan , Barbosa Silva Botelho Flávia , Srivastava Vibha
Published: January 2022

Overexpression of Arabidopsis Dehydration Response Element Binding 1a (DREB1a) is a well-known approach for developing salinity, cold and/or drought stress tolerance. However, understanding of the genetic mechanisms associated with DREB1a expression in rice is generally limited. In this study, DREB1a associated early responses were investigated in a transgenic rice line harboring cold-inducible DREB1a at a gene stacked locus. While the function of other genes in the stacked locus was not relevant to stress tolerance, this study demonstrates DREB1a can be colocalized with other genes for multigenic trait enhancement. As expected, the transgenic lines displayed improved tolerance to salinity stress and water withholding when compared to non-transgenic controls. RNA sequencing and transcriptome analysis showed upregulation of complex transcriptional networks and metabolic reprogramming as DREB1a expression led to the upregulation of multiple transcription factor gene families, suppression of photosynthesis and induction of secondary metabolism. In addition to the detection of previously described mechanisms such as production of protective molecules, potentially novel pathways were also revealed. These include jasmonate, auxin, and ethylene signaling, induction of JAZ and WRKY regulons, trehalose synthesis and polyamine catabolism. These genes regulate various stress responses and ensure timely attenuation of the stress signal. Furthermore, genes associated with heat stress response were downregulated in DREB1a overexpressing lines, suggesting antagonism between heat and dehydration stress pathways. In summary, through a complex transcriptional network, multiple stress signaling pathways are induced by DREB1a that presumably lead to early perception and rapid response towards stress tolerance as well as attenuation of the signal to prevent deleterious effects of the runoff response.
Cross-linking of the Endolysosomal System Reveals Flotillin Structures and Putative Cargo
Authors: Singh Jasjot , Elhabashy Hadeer , Muthukottiappan Pathma , Stepath Markus , Eisenacher Martin , Kohlbacher Oliver , Gieselmann Volkmar , Winter Dominic
Published: January 2022

Lysosomes are well-established as the main cellular organelles for the degradation of macromolecules and emerging as regulatory centers of metabolism. They are of crucial importance for cellular homeostasis, which is exemplified by a plethora of disorders related to alterations in lysosomal function. In this context, protein complexes play a decisive role, regulating not only metabolic lysosomal processes, but also lysosome biogenesis, transport, and interaction with other organelles. Using cross-linking mass spectrometry, we analyzed lysosomes and early endosomes. Based on the identification of 5,376 cross-links, we investigated protein-protein interactions and structures of lysosome- and endosome-related proteins. In particular, we present evidence for a tetrameric assembly of the lysosomal hydrolase PPT1 and heterodimeric/- multimeric structures of FLOT1/FLOT2 at lysosomes and early endosomes. For FLOT1-/FLOT2- positive early endosomes, we identified >300 proteins presenting putative cargo, and confirm the latrophilin family of adhesion G protein-coupled receptors as substrates for flotillin-dependent endocytosis.
An ancestral genomic sequence that serves as a nucleation site for de novo gene birth
Authors: Delihas Nicholas
Published: January 2022

A short non-coding sequence present between the gamma-glutamyltransferase 1 (GGT1) and gamma-glutamyltransferase 5 (GGT5) genes, termed a spacer sequence has been detected in the genomes of Mus musculus, the house mouse and in Philippine tarsier, a primitive ancestral primate. It is highly conserved during primate evolution with certain sequences being totally invariant from mouse to humans. Evidence is presented to show this intergenic sequence serves as a nucleation site for the initiation of diverse genes. We also outline the birth of the human lincRNA gene BCRP3 (BCR activator of RhoGEF and GTPase 3 pseudogene) during primate evolution. The gene developmental process involves sequence initiation, addition of a complex of tandem transposable elements and addition of a segment of another gene. The sequence, initially formed in the Old World Monkeys such as the Rhesus monkey (Macaca mulatta) and the baboon (Papio anubis), develops into different primate genes before evolving into the human BCRP3 gene; it appears to also include trial and error during sequence/gene formation. The protein gene, GGT5 may have also formed by spacer sequence initiation in an ancient ancestor such as zebrafish, but spacer and GGT5 gene sequence drift during evolution produced a divergence that precludes further assessment.

Author summary

For a number of decades researchers have been interested in how genes evolve and a number of mechanisms of gene formation have been defined. This manuscript describes a different process of gene formation, that of a small DNA sequence that does not code for a gene but serves as a nucleation site for the initiation of de novo gene formation. This non-coding DNA sequence appears to have been in existence for about hundred million years or more and has formed the basis for the birth of diverse genes during evolution of the primates. The questions of how and why new genes are born are important in terms of revealing how organisms, especially primates, progress to greater complexity during evolution; the question of “how” is particularly relevant to the creation of biological information ab initio during prebiotic and early cellular evolution.
Comparison of dsDNA and ssDNA-based NGS library construction methods for targeted genome and methylation profiling of cfDNA
Authors: Zheng Jianchao , Li Zhilong , Zhang Xiuqing , Zhang Hongyun , Zhu Shida , Sun Jianlong , Wang Yuying
Published: January 2022

Cell-free DNA (cfDNA) profiling by next generation sequencing (NGS) has wide applications in cancer diagnosis, prognosis, and therapy response monitoring. One key step of cfDNA deep sequencing workflow is NGS library construction, whose efficiency determines effective sequencing depth, sequencing quality, and accuracy. In this study, we compared two different cfDNA library construction methods for the applications of mutation detection and methylation profiling: the conventional method which captures double-stranded DNA (dsDNA) molecules, namely the dsLib workflow, and an alternative method which captures single-stranded DNA (ssDNA), namely the ssLib workflow. Our results suggest that the dsLib method was preferrable for mutation detection while the ssLib method proved more efficient for methylation analysis. Our findings could help researchers choose more appropriate library construction method for corresponding downstream sequencing applications.
GNN-SubNet: disease subnetwork detection with explainable Graph Neural Networks
Authors: Pfeifer Bastian , Secic Afan , Saranti Anna , Holzinger Andreas
Published: January 2022

The tremendous success of graphical neural networks (GNNs) has already had a major impact on systems biology research. For example, GNNs are currently used for drug target recognition in protein-drug interaction networks as well as cancer gene discovery and more. Important aspects whose practical relevance is often underestimated are comprehensibility, interpretability, and explainability. In this work, we present a graph-based deep learning framework for disease subnetwork detection via explainable GNNs. In our framework, each patient is represented by the topology of a protein-protein network (PPI), and the nodes are enriched by molecular multimodal data, such as gene expression and DNA methylation. Therefore, our novel modification of the GNNexplainer for model-wide explanations can detect potential disease subnetworks, which is of high practical relevance. The proposed methods are implemented in the GNN-SubNet Python program, which we have made freely available on our GitHub for the international research community (https://github.com/pievos101/GNN-SubNet).
Localized Cardiolipin Synthesis is Required for the Assembly of MreB During the Polarized Cell Division ofChlamydia trachomatis
Authors: Ouellette Scot P. , Fisher-Marvin Laura A. , Harpring McKenna , Lee Junghoon , Rucks Elizabeth A. , Cox John V.
Published: January 2022

PathogenicChlamydiaspecies are coccoid bacteria that use the rod-shape determining protein MreB to direct septal peptidoglycan synthesis during their polarized cell division process. How the site of polarized budding is determined in this bacterium, where contextual features like membrane curvature are seemingly identical, is unclear. We hypothesized that the accumulation of the phospholipid, cardiolipin (CL), in specific regions of the cell membrane induces localized membrane changes that trigger the recruitment of MreB to the site where the bud will arise. To test this, we ectopically expressed cardiolipin synthase (Cls) and observed a polar distribution for this enzyme inChlamydia trachomatis. In early division intermediates, Cls was restricted to the bud site where MreB is localized and peptidoglycan synthesis is initiated. The localization profile of Cls throughout division mimicked the distribution of lipids that stain with NAO, a dye that labels CL. Treatment ofChlamydiawith 3’,6-dinonylneamine (diNN), an antibiotic targeting CL-containing membrane domains, resulted in redistribution of Cls and NAO-staining phospholipids. In addition, MreB localization was altered by diNN treatment, suggesting an upstream regulatory role for CL-containing membranes in directing the assembly of MreB. This hypothesis is consistent with the observation that the clustered localization of Cls is not dependent upon MreB function or peptidoglycan synthesis. Furthermore, expression of a CL-binding protein at the inner membrane ofC. trachomatisdramatically inhibited bacterial growth supporting the importance of CL in the division process. Our findings implicate a critical role for localized CL synthesis in driving MreB assembly at the bud site during the polarized cell division ofChlamydia.
Individual variation in dispersal, and its sources, shape the fate of pushed vs. pulled range expansions
Authors: Dahirel Maxime , Guicharnaud Chloé , Vercken Elodie
Published: January 2022

Ecological and evolutionary dynamics of range expansions are shaped by both dispersal and population growth. Accordingly, density-dependence in either dispersal or growth can determine whether expansions are pulled or pushed, i.e. whether expansion velocities and genetic diversity are mainly driven by recent, low-density edge populations, or by older populations closer to the core. Despite this and despite abundant evidence of dispersal evolution during expansions, the impact of density-dependent dispersal and its evolution on expansion dynamics remains understudied. Here, we used simulation models to examine the influence of individual trait variation in both dispersal capacity and dispersal density- dependence on expansions, and how it impacts the position of expansions on the pulled-pushed continuum. First, we found that knowing about the evolution of density-dependent dispersal at the range edge can greatly improve our ability to predict whether an expansion is (more) pushed or (more) pulled. Second, we found that both dispersal costs and the sources of variation in dispersal (genetic or non-genetic, in dispersal capacity versus in density- dependence) greatly influence how expansion dynamics evolve. Among other scenarios, pushed expansions tended to become more pulled with time only when density-dependence was highly heritable, dispersal costs were low and dispersal capacity could not evolve. When, on the other hand, variation in density-dependence had no genetic basis, but dispersal capacity could evolve, then pushed expansions tended to become more pushed with time, and pulled expansions more pulled. More generally, our results show that trying to predict expansion velocities and dynamics using trait information from non-expanding regions only may be problematic, that both dispersal variation and its sources play a key role in determining whether an expansion is and stays pushed, and that environmental context (here dispersal costs) cannot be neglected. Those simulations suggest new avenues of research to explore, both in terms of theoretical studies and regarding ways to empirically study pushed vs. pulled range expansions.
A bacterial secretosome for regulated envelope biogenesis and quality control
Authors: Watkins Daniel W. , Collinson Ian
Published: January 2022

As the first line of defence against antibiotics, the Gram-negative bacterial envelope and its biogenesis are of considerable interest to the microbiological and biomedical communities. All bacterial proteins are synthesised in the cytosol, so inner- and outer-membrane proteins, and periplasmic residents have to be transported to their final destinationsviaspecialised protein machinery. The Sec translocon, a ubiquitous integral inner-membrane (IM) complex, is key to this process as the major gateway for protein transit from the cytosol to the cell envelope; this can be achieved during their translation, or afterwards. Proteins need to be directed to the inner-membrane (usually co-translational), otherwise SecA utilises ATP and the proton-motive-force (PMF) to drive proteins across the membrane post-translationally. These proteins are then picked up by chaperones for folding in the periplasm or delivered to the β-barrel assembly machinery (BAM) for incorporation into the outer-membrane. The core heterotrimeric SecYEG-complex forms the hub for an extensive network of interactions that regulate protein delivery and quality control. Here, we conduct a biochemical exploration of this ‘secretosome’ – a very large, versatile and inter-changeable assembly with the Sec-translocon at its core; featuring interactions that facilitate secretion (SecDF), inner- and outer-membrane protein insertion (respectively, YidC and BAM), protein folding and quality control (e.g. PpiD, YfgM and FtsH). We propose the dynamic interplay amongst these and other factors act to ensure efficient whole envelope biogenesis, regulated to accommodate the requirements of cell elongation and division. This organisation would be essential for cell wall biogenesis and remodelling and thus its perturbation would be a good strategy for the development of anti-microbials.
Histone H3K4 methyltransferase DcATX1 promotes ethylene induced petal senescence in carnation
Authors: Feng Shan , Wang Ruiming , Tan Hualiang , Zhong Linlin , Cheng Yunjiang , Bao Manzhu , Qiao Hong , Zhang Fan
Published: January 2022

Petal senescence is controlled by a complex regulatory network. Epigenetic regulation like histone modification influences chromatin state and gene expression. However, involvement of histone methylation in regulating petal senescence is still largely unknown. Here, we found that the trimethylation of histone H3 at Lysine 4 (H3K4me3) is increased during the ethylene induced petal senescence in carnation (Dianthus caryophyllus L.). The H3K4me3 levels are positively associated with the expression of transcription factor DcWRKY75, ethylene biosynthetic genes DcACS1 and DcACO1, and senescence associated genes (SAGs) DcSAG12 and DcSAG29. Further, we identified that carnation DcATX1 (ARABIDOPSIS HOMOLOG OF TRITHORAX1) encodes a histone lysine methyltransferase which can methylate H3K4. Knockdown of DcATX1 delays ethylene induced petal senescence in carnation, which is associated with the downregulated expression of DcWRKY75, DcACO1 and DcSAG12. While overexpression of DcATX1 exhibits the opposite effects. DcATX1 promotes the transcription of DcWRKY75, DcACO1 and DcSAG12 by targeting to their promoters to elevate the H3K4me3 levels. Overall, our results demonstrate that DcATX1 is a H3K4 methyltransferase that promotes the expression of DcWRKY75, DcACO1 and DcSAG12 by regulating H3K4me3 levels, thereby accelerating ethylene induced petal senescence in carnation. This study further indicates that epigenetic regulation is important for plant senescence process.

One sentence summary

A histone methyltransferase promotes ethylene induced petal senescence in cut flower
Antisense oligonucleotides targeting the miR-29b binding site in the GRN mRNA increase progranulin translation
Authors: Aggarwal Geetika , Banerjee Subhashis , Jones Spencer A. , Benchaar Yousri , Bélanger Jasmine , Sévigny Myriam , Smith Denise M. , Niehoff Michael L. , Pavlack Monica , de Vera Ian Mitchelle S. , Petkau Terri L. , Leavitt Blair R. , Ling Karen , Jafar-Nejad Paymaan , Rigo Frank , Morley John E. , Farr Susan A. , Dutchak Paul A. , Sephton Chantelle F. , Nguyen Andrew D.
Published: January 2022

Heterozygous GRN (progranulin) mutations cause frontotemporal dementia (FTD) due to haploinsufficiency, and increasing progranulin levels is a major therapeutic goal. Several microRNAs, including miR-29b, negatively regulate progranulin protein levels. Antisense oligonucleotides (ASOs) are emerging as a promising therapeutic modality for neurological diseases, but strategies for increasing target protein levels are limited. Here, we tested the efficacy of ASOs as enhancers of progranulin expression by sterically blocking the miR-29b binding site in the 3’ UTR of the human GRN mRNA. We found 16 ASOs that increase progranulin protein in a dose-dependent manner in neuroglioma cells. A subset of these ASOs also increased progranulin protein in iPSC-derived neurons and in a humanized GRN mouse model. In FRET-based assays, the ASOs effectively competed miR-29b from binding to the GRN 3’ UTR RNA. The ASOs increased levels of newly synthesized progranulin protein by increasing its translation, as revealed by ribosomal profiling. Together, our results demonstrate that ASOs can be used to effectively increase target protein levels by partially blocking miR binding sites. This ASO strategy may be therapeutically feasible for progranulin-deficient FTD as well as other conditions of haploinsufficiency.
A survey on antimicrobial resistance genes of frequently used bacteria in kefir and yoghurt
Authors: Judge Maura Fiona , Tóth Adrienn Gréta , Nagy Sára Ágnes , Papp Márton , Solymosi Norbert
Published: January 2022

Antimicrobial resistance (AMR) is one of the foremost threats facing the treatment of infectious diseases worldwide. Recent studies have highlighted the potential for antimicrobial resistance genes (ARGs) in fermented foods to contribute to AMR via horizontal gene transfer (HGT). The focus of our study was investigating the ARG content (resistome) and mobility potential of the ARGs (mobilome) of bacterial strains commonly used in probiotic products, namely yoghurt and kefir. We performed metagenomic analyses on freely available data sets (n=584) originating from various kefir and yoghurt strains using next generation sequencing (NGS) in order to gain an insight into the ARG diversity, frequency and mobility. Our study shows that kefir and yoghurt products carry diverse and significant amounts of ARGs and that these genes may often be associated with iMGEs or plasmids, conferring mobility. Certain bacteria species such as Bifidobacterium animalis and Streptococcus thermophilus were found to have higher ARG content. Overall, our results support the hypothesis that ARGs are present in fermented foods, namely yoghurt and kefir, and have the potential to contribute to AMR.
Dynamical Latent State Computation in the Posterior Parietal Cortex
Authors: Lakshminarasimhan Kaushik J , Avila Eric , Pitkow Xaq , Angelaki Dora E
Published: January 2022

Success in many real-world tasks depends on our ability to dynamically track hidden states of the world. To understand the underlying neural computations, we recorded brain activity in posterior parietal cortex (PPC) of monkeys navigating by optic flow to a hidden target location within a virtual environment, without explicit position cues. In addition to sequential neural dynamics and strong interneuronal interactions, we found that the hidden state – monkey’s displacement from the goal – was encoded in single neurons, and could be dynamically decoded from population activity. The decoded estimates predicted navigation performance on individual trials. Task manipulations that perturbed the world model induced substantial changes in neural interactions, and modified the neural representation of the hidden state, while representations of sensory and motor variables remained stable. The findings were recapitulated by a task-optimized recurrent neural network model, suggesting that neural interactions in PPC embody the world model to consolidate information and track task-relevant hidden states.
Bulk and Single-nucleus Transcriptomics Highlight Intra-telencephalic and Somatostatin Neurons in Alzheimer’s Disease
Authors: Consens Micaela E , Chen Yuxiao , Menon Vilas , Wang Yanling , Schneider Julie A , De Jager Philip L , Bennett David A , Tripathy Shreejoy J , Felsky Daniel
Published: January 2022

Background

Cortical neuron loss is a pathological hallmark of late-onset Alzheimer’s disease (AD). However, it remains unclear which neuronal subtypes are most vulnerable to degeneration and contribute most to cognitive decline.

Methods

We analyzed postmortem bulk brain RNA-sequencing (RNAseq) data collected from three studies of aging and AD comprising six neocortical regions (704 individuals; 1037 samples). We estimated relative cell type proportions from each brain sample using neuronal subclass-specific marker genes derived from ultra-high depth single-nucleus RNAseq data (snRNAseq). We associated cell type proportions with AD across all samples using mixed-effects mega-analyses. Bulk tissue analyses were complemented by analyses of three AD snRNAseq datasets using the same cell type definitions and diagnostic criteria (51 individuals). Lastly, we identified cell subtype associations with specific neuropathologies, cognitive decline, and residual cognition.

Results

In our mega-analyses, we identified the strongest associations of AD with fewer somatostatin (SST) inhibitory neurons (β=−0.48, pbonf=8.98×10−9) and intra-telencephalic (IT) excitatory neurons (β=−0.45, pbonf =4.32×10−7). snRNAseq-based cell type proportion analyses especially supported the association of SST neurons. Analyses of cell type proportions with specific AD-related phenotypes in ROS/MAP consistently implicated fewer SST neurons with greater brain-wide postmortem tau and beta amyloid (β=−0.155, pFDR=3.1×10−4) deposition, as well as more severe cognitive decline prior to death (β=0.309, pFDR=3.9×10−6). Greater IT neuron proportions were associated strongly with improved cognition (β=0.173, pFDR=8.3×10−5) and residual cognition (β=0.175, pFDR=1.2×10−5), but not canonical AD neuropathology.

Conclusions

Proportionally fewer SST and IT neurons were significantly associated with AD diagnosis across multiple studies and cortical regions. These findings support seminal work implicating somatostatin and pyramidal neurons in the pathogenesis of AD and improves our current understanding of neuronal vulnerability in AD.
Autophagy is impaired in fetal hypoplastic lungs and rescued by administration of amniotic fluid stem cell extracellular vesicles
Authors: Khalaj Kasra , Antounians Lina , Figueira Rebeca Lopes , Post Martin , Zani Augusto
Published: January 2022

Rationale

Pulmonary hypoplasia secondary to congenital diaphragmatic hernia (CDH) is characterized by reduced branching morphogenesis, which is responsible for poor clinical outcomes. Administration of amniotic fluid stem cell extracellular vesicles (AFSC-EVs) rescues branching morphogenesis in rodent fetal models of pulmonary hypoplasia. Herein, we hypothesized that AFSC-EVs exert their regenerative potential by affecting autophagy, a process required for normal lung development.

Objectives

To evaluate autophagy in hypoplastic lungs throughout gestation and establish whether AFSC-EV administration improves branching morphogenesis through autophagy-mediated mechanisms.

Methods

EVs were isolated from c-kit+ AFSC conditioned medium by ultracentrifugation and characterized for size, morphology, and EV markers. Branching morphogenesis was inhibited in rat fetuses by nitrofen administration to dams and in human fetal lung explants by blocking RAC1 activity with NSC23766. Expression of autophagy activators (BECN1 and ATG5) and adaptor (SQSTM1/p62) was analyzed in vitro (rat and human fetal lung explants) and in vivo (rat fetal lungs). Mechanistic studies on rat fetal primary lung epithelial cells were conducted using inhibitors for microRNA-17 and -20a contained in the AFSC-EV cargo and known to regulate autophagy.

Measurements and Main Results

Rat and human models of fetal pulmonary hypoplasia showed reduced autophagy mainly at pseudoglandular and canalicular stages. AFSC-EV administration restored autophagy in both pulmonary hypoplasia models by transferring miR-17∼92 cluster members contained in the EV cargo.

Conclusions

AFSC-EV treatment rescues branching morphogenesis partly by restoring autophagy through miRNA cargo transfer. This study enhances our understanding of pulmonary hypoplasia pathogenesis and creates new opportunities for fetal therapeutic intervention in CDH babies.
A split ribozyme that links detection of a native RNA to orthogonal protein outputs
Authors: Gambill Lauren , Staubus August , Ameruoso Andrea , Chappell James
Published: January 2022

Individual RNA remains a challenging signal to synthetically transduce into different types of cellular information. Here, we describe Ribozyme-ENabled Detection of RNA (RENDR), a plug-and-play strategy that uses cellular transcripts to template the assembly of split ribozymes, triggering splicing reactions that generate orthogonal protein outputs. To identify split ribozymes that require templating for splicing, we used laboratory evolution to evaluate the activities of different split variants of the Tetrahymena thermophila ribozyme. The best design delivered a 93-fold dynamic range of splicing with RENDR controlling fluorescent protein production in response to an RNA input. We resolved a thermodynamic model to guide RENDR design, showed how input signals can be transduced into diverse visual, chemical, and regulatory outputs, and used RENDR to detect an antibiotic resistance phenotype in bacteria. This work shows how transcriptional signals can be monitored in situ using RNA synthetic biology and converted into different types of biochemical information.