bluuebunny/crossref_metadata_2025 huggingface dataset:
Climate change shifts abiotic niche of temperate skates towards deeper zones in the Southwestern Atlantic Ocean
Authors: Coelho Jéssica Fernanda Ramos , Lima Sergio Maia Queiroz , Petean Flávia de Figueiredo
Published: February 2021

Climatic changes are disrupting distribution patterns of populations through shifts in species abiotic niches and habitat loss. The abiotic niche of marine benthic taxa such as skates, however, may be more climatically stable compared to upper layers of the water column, in which aquatic organisms are more exposed to immediate impacts of warming. Here, we estimate climate change impacts in Riorajini, a tribe of four skates, as a proxy to (1) evaluate the vulnerability of a temperate coastal zone in the Atlantic Southwest, and (2) study niche dynamics in a scenario of environmental changes on this group of threatened species. We modelled each species abiotic niche under present (2000–2014) and future (2100, Representative Concentration Pathway 8.5) climatic scenarios, then measured niche overlap, stability, expansion, and unfilling. Our results reveal an expansion of suitable environment for the occurrence of the tribe in up to 20% towards deeper areas (longitudinal shift), although still within the limits of the continental shelf. We discussed the downfalls of such shift to the species and to the local biota in newly invaded areas, and suggest that even deeper layers of marine temperate zones are vulnerable to dramatic environmental changes as a consequence of global warming.
Pak1 kinase controls cell shape through ribonucleoprotein granules
Authors: Magliozzi Joseph O. , Moseley James B.
Published: February 2021

Fission yeast cells maintain a rod shape due to conserved signaling pathways that organize the cytoskeleton for polarized growth. We discovered a mechanism linking the conserved protein kinase Pak1 with cell shape through the RNA-binding protein Sts5. Pak1 (also called Shk1 and Orb2) prevents Sts5 association with P bodies by directly phosphorylating its intrinsically disordered region (IDR). Pak1 and the cell polarity kinase Orb6 both phosphorylate the Sts5 IDR but at distinct residues. Mutations preventing phosphorylation in the Sts5 IDR cause increased P body formation and defects in cell shape and polarity. Unexpectedly, when cells encounter glucose starvation, PKA signaling triggers Pak1 recruitment to stress granules with Sts5. Through retargeting experiments, we reveal that Pak1 localizes to stress granules to promote rapid dissolution of Sts5 upon glucose addition. Our work reveals a new role for Pak1 in regulating cell shape through ribonucleoprotein granules during normal and stressed growth conditions.
Association between land use and composition of amphibian species in temperate Brazilian forest remnants
Authors: dos Santos Roseli Coelho , Dalmolin Diego Anderson , Brum Diego , Veronez Mauricio Roberto , Lucas Elaine Maria , Tozetti Alexandro Marques
Published: February 2021

We evaluated the influence of landscape configuration on the diversity of anurans in Atlantic Forest remnants in southern Brazil. As natural habits provide better conditions for the survival of amphibians, we expected to find more diverse communities in areas with more forest cover. We sampled tadpoles in 28 breeding sites distributed in seven forest remnants. We recorded 22 anuran species and richness varied from 6 to 12 species between sites. Most of the recorded species were not forest specialists, except forBoana curupiandCrossodactylus schmidti. There was a significant overlap in the species composition between all remnants, and the Generalized Linear Mixed Model indicated that landscape use did not affect species richness. The PERMANOVA showed that forest and livestock farming explained the dissimilarity in the composition of the communities. One possible explanation for this is that the remnants are surrounded by a relatively well-preserved landscape, which offers favorable conditions for the maintenance of local populations and homogenizes species composition across the sampling sites. The lack of any strong association between tadpole species richness and land use suggests that anurans are primally affected by habitat characteristics that are detected only on a fine-scale analysis.
An integral genomic signature approach for tailored cancer targeted therapy using genome-wide sequencing data
Authors: Wang Xiaosong , Lee Sanghoon , Tang Gong , Wang Yue
Published: February 2021

With the advent of low-cost sequencing, transcriptome and genome sequencing is expected to become clinical routine and transform precision oncology within next decade. However, viable genome-wide modeling methods that can facilitate rational selection of patients for tailored intervention while tolerating sequencing biases are far lacking. Here we propose an integral genomic signature (iGenSig) analysis as a new class of transparent, interpretable, and resilient methods for precision oncology based on multiple types of genome-wide sequencing data. We postulate that the redundant high-dimensional genomic features, which are typically eliminated during multi-omics modeling, may help overcome the sequencing biases. We thus conceive a novel method that models the therapeutic response using the high-dimensional transcriptional and mutational features predictive of tumor response, which we termed as an integral genomic signature (iGenSig), and then algorithmically resolve the feature redundancy tailored for each patient subject. Using genomic dataset of chemical perturbations, we developed the iGenSig models for predicting targeted therapy responses, and applied selected models to independent datasets for cancer cell lines, patient-derived xenografts, and patient subjects. iGenSig models exhibit outstanding cross-dataset performance compared to artificial intelligence methods, with exceptional resilience against simulated errors in genomic features. In particular, the iGenSig model for the EGFR inhibitor Erlotinib significantly predicted the responses of patient-derived xenografts and patients from a clinical trial, biological interpretation of which led to new insights into the predictive signature pathways with clinical relevance. Together, iGenSig will provide a computational infrastructure to empower tailored cancer intervention based on genome-wide sequencing data.
Predators affect a plant virus through direct and trait-mediated indirect effects on vectors
Authors: Lee Benjamin W. , Clark Robert E. , Basu Saumik , Crowder David W.
Published: February 2021

Arthropods that vector plant pathogens often interact with predators within food webs. Predators affect vectors by eating them (consumptive effects) and by inducing antipredator behaviors (non-consumptive effects), and these interactions may affect transmission of vector-borne pathogens. However, it has proven difficult to experimentally tease apart the effects of predators on vector fitness and behavior as they are often correlated. We addressed this problem by assessing how both aphids and an aphid-borne pathogen were affected by variable predation risk. Specifically, we experimentally manipulated ladybeetle predators’ mouthparts to isolate consumptive, and non-consumptive, effects of predators on aphid fitness, movement, and virus transmission. We show that although lethal predators decreased aphid vector abundance, they increased pathogen transmission by increasing aphid movement among hosts. Moreover, aphids responded to risk of predation by moving to younger plant tissue that was more susceptible to the pathogen. Aphids also responded to predator risk through compensatory reproduction, which offset direct consumptive effects. Our results support predictions of disease models showing alterations of vector movement due to predators can have greater effects on transmission of pathogens than vector consumption. Broadly, our study shows isolating direct and indirect predation effects can reveal novel pathways by which predators affect vector-borne pathogens.
The Serine Protease HtrA2 mediates radiation-induced senescence in cancer cells
Authors: Hammer Liat , Levin-Salomon Vered , Yaeli-Slonim Naama , Weiss Moria , Dekel-Bird Naama P. , Olender Tsviya , Porat Ziv , Winograd-Katz Sabina , Savidor Alon , Levin Yishai , Bialik Shani , Geiger Benjamin , Kimchi Adi
Published: February 2021

Radiation therapy can induce cellular senescence in cancer cells leading to short-term tumor growth arrest, yet increased long-term recurrence. To better understand the molecular mechanisms involved, we developed a model of radiation-induced senescence in cultured cancer cells, which exhibited a typical senescent phenotype, including upregulation of p53 and its target p21, followed by sustained reduction in cellular proliferation, changes in cell size and cytoskeleton organization, and senescence-associated beta-galactosidase activity. A functional siRNA screen using a cell death-related library identified the mitochondrial Ser protease HtrA2 as necessary for senescence development. Mass spectrometry-based proteomic profiling of the senescent cells indicated downregulation of proteins involved in cell cycle progression and DNA repair, and upregulation of proteins associated with malignancy, while irradiation with HtrA2 inhibition upregulated cell proliferation components. In search of direct HtrA2 substrates following radiation, we determined that HtrA2 cleaves the intermediate filament protein vimentin, affecting its cytoplasmic organization. Ectopic expression of active cytosolic HtrA2 resulted in similar changes to vimentin filament assembly. Thus HtrA2, contributes to several hallmarks of senescence and is involved in the cytoskeletal reorganization that accompanies radiation-induced senescence.

Here the authors identify the Ser protease HtrA2 as a novel mediator of radiation-induced senescence, necessary for sustained proliferation arrest and reorganization of the vimentin filament network.
Reduced inhibition in depression impairs stimulus processing in human cortical microcircuits
Authors: Yao Heng Kang , Guet-McCreight Alexandre , Mazza Frank , Chameh Homeira Moradi , Prevot Thomas D. , Griffiths John , Tripathy Shreejoy J. , Valiante Taufik A. , Sibille Etienne , Hay Etay
Published: February 2021

Cortical processing depends on finely-tuned excitatory and inhibitory connections in neuronal microcircuits. Reduced inhibition by somatostatin-expressing interneurons is a key component of altered inhibition associated with treatment-resistant major depressive disorder (depression), which is implicated in cognitive deficits and rumination, but the link remains to be better established mechanistically in humans. Here, we tested the impact of reduced somatostatin interneuron mediated inhibition on cortical processing in human neuronal microcircuits using a data-driven computational approach. We integrated human cellular, circuit and gene-expression data to generate detailed models of human cortical microcircuits in health and depression. We simulated microcircuit baseline and response activity and found reduced signal-to-noise ratio and increased false/failed detection of stimuli due to a higher baseline activity in depression. Our results thus applied novel models of human cortical microcircuits to demonstrate mechanistically how reduced inhibition impairs cortical processing in depression, providing quantitative links between altered inhibition and cognitive deficits.
A cell atlas of chromatin accessibility across 25 adult human tissues
Authors: Zhang Kai , Hocker James D. , Miller Michael , Hou Xiaomeng , Chiou Joshua , Poirion Olivier B. , Qiu Yunjiang , Li Yang E. , Gaulton Kyle J. , Wang Allen , Preissl Sebastian , Ren Bing
Published: February 2021

Current catalogs of regulatory sequences in the human genome are still incomplete and lack cell type resolution. To profile the activity of human gene regulatory elements in diverse cell types and tissues in the human body, we applied single cell chromatin accessibility assays to 25 distinct human tissue types from multiple donors. The resulting chromatin maps comprising ∼500,000 nuclei revealed the status of open chromatin for over 750,000 candidatecis-regulatory elements (cCREs) in 54 distinct cell types. We further delineated cell type-specific and tissue-context dependent gene regulatory programs, and developmental stage specificity by comparing with a recent human fetal chromatin accessibility atlas. We finally used these chromatin maps to interpret the noncoding variants associated with complex human traits and diseases. This rich resource provides a foundation for the analysis of gene regulatory programs in human cell types across tissues and organ systems.
Surface Densities Prewet a Near-Critical Membrane
Authors: Rouches Mason , Veatch Sarah , Machta Benjamin
Published: February 2021

Recent work has highlighted roles for thermodynamic phase behavior in diverse cellular processes. Proteins and nucleic acids can phase separate into three-dimensional liquid droplets in the cytoplasm and nucleus and the plasma membrane of animal cells appears tuned close to a two-dimensional liquid-liquid critical point. In some examples, cytoplasmic proteins aggregate at plasma membrane domains, forming structures such as the post-synaptic density and diverse signaling clusters. Here we examine the physics of these surface densities, employing minimal simulations of co-acervating polymers coupled to an Ising membrane surface in conjunction with a complementary Landau theory. We argue that these surface densities are a novel phase reminiscent of pre-wetting, in which a molecularly thin three-dimensional liquid forms on a usually solid surface. However, in surface densities the solid surface is replaced by a membrane with an independent propensity to phase separate. We show that proximity to criticality in the membrane dramatically increases the parameter regime in which a pre-wetting-like transition occurs, leading to a broad region where coexisting surface phases can form even when a bulk phase is unstable. Our simulations naturally exhibit three surface phase coexistence even though both the membrane and the polymer bulk can only display two phase coexistence on their own. We argue that the physics of these surface densities enables diverse functions seen in Eukaryotic cells.
Heparan Sulfated Glypican-4 is Released from Astrocytes Predominantly by Proteolytic Shedding
Authors: Huang Kevin , Park Sungjin
Published: February 2021

Astrocytes provide neurons with diffusible factors that promote synapse formation and maturation. In particular, glypican-4/GPC4 released from astrocytes promotes the maturation of excitatory synapses. Unlike other secreted factors, GPC4 contains the C-terminal GPI-anchorage signal. However, the mechanism by which membrane-tethered GPC4 is released from astrocytes is unknown. Using primary astrocyte cultures and a quantitative luciferase-based release assay, we show that GPC4 is expressed on the astrocyte surface exclusively via a GPI-anchorage. Soluble GPC4 is robustly released from the astrocytes predominantly by proteolytic shedding and, to a lesser extent, by GPI-anchor cleavage, but not by vesicular release. Pharmacological, overexpression, and loss of function screens showed that ADAM9 in part mediates the release of GPC4 from astrocytes. The released GPC4 contains the heparan sulfate side chain, suggesting that these release mechanisms provide the active form that promotes synapse maturation and function. Overall, our studies identified the release mechanisms and the major releasing enzyme of GPC4 in astrocytes and will provide insights into understanding how astrocytes regulate synapse formation and maturation.

Significance Statement

Astrocyte-derived diffusible factors regulate synapse development and function. However, the regulatory mechanism underlying the release of astrocyte-derived factors is poorly understood. Noting that, unlike many other secreted factors, glypican-4/GPC4 is GPI-anchored, we characterized the release mechanism of GPI-anchored GPC4 from astrocytes and identified the releasing enzyme. Heparan sulfated GPC4 is robustly released from the astrocytes predominantly by proteolytic shedding. In particular, ADAM9 in part mediates the release of GPC4 from astrocytes. Our study provides an enzymatic mechanism for releasing GPC4 from astrocytes and will provide a novel opportunity to understand the regulatory mechanism of neuron-glia communication for synaptogenesis.
The temporal balance between self-renewal and differentiation of human neural stem cells requires the Amyloid Precursor Protein
Authors: Shabani Khadijeh , Pigeon Julien , Touil Zariouh Marwan Benaissa , Liu Tengyuan , Saffarian Azadeh , Komatsu Jun , Liu Elise , Danda Natasha , Limame Ridha , Bohl Delphine , Parras Carlos , Hassan Bassem A.
Published: February 2021

The approximately 16 billion neurons of the human neocortex are derived from a relatively limited number of developmental neural stem cells (NSCs). During embryogenesis, human cortical NSCs initially generate neurons at a particularly slow rate while preserving their progenitor state for a relatively long time. How this balance between the progenitor state and neurogenic state is regulated, and whether it contributes to species-specific brain patterning, is poorly understood. Here we show that the characteristic potential of human NSCs to remain in a progenitor state as they generate neurons for a prolonged amount of time requires the Amyloid Precursor Protein (APP). In contrast, APP is dispensable in mouse NSCs, which undergo neurogenesis at a much faster rate. Mechanistically, loss of APP cell-autonomously accelerates neurogenesis through activation of the AP1 transcription factor and repression of WNT signaling. We propose that the fine balance between self-renewal and differentiation is homeostatically regulated by APP, which may contribute to human-specific temporal patterns of neurogenesis.
Caffeinated soda intake in children is associated with neurobehavioral risk factors for substance misuse
Authors: Kwon Mina , Kim Hyeonjin , Yang Jaeyeong , Lee Yoseph , Hur Jihyun K. , Lee Tae-Ho , Bjork James M. , Ahn Woo-Young
Published: February 2021

Background and Objectives

Use of psychotropic substances in childhood has been associated with both impulsivity and other manifestations of poor executive function as well as escalation over time to use of progressively stronger substances. However, how this relationship may start in earlier childhood has not been well explored. Here, we investigated the neurobehavioral correlates of daily caffeinated soda consumption in preadolescent children and examined whether caffeinated soda intake is associated with a higher risk of subsequent alcohol initiation.

Methods

Using Adolescent Brain Cognitive Development study data, we first investigated cross-sectional relationships between frequent caffeinated soda intake and well-known risk factors of substance misuse: impaired working memory, high impulsivity, and aberrant reward processing. We then examined whether caffeinated soda intake at baseline predicts more alcohol sipping at 12 months follow-up using a machine learning algorithm.

Results

Daily consumption of caffeinated soda was cross-sectionally associated with neurobehavioral risk factors for substance misuse such as higher impulsivity scores and lower working memory performance. Furthermore, caffeinated soda intake predicted greater alcohol sipping after 12 months even after controlling for rates of baseline alcohol sipping; children who drink caffeinated soda daily are twice as likely to start sipping alcohol after one year compared to those who do not drink caffeinated soda at all.

Conclusions

These findings suggest that previous linkages between caffeine and substance use in adolescence also extend to younger initiation, and may stem from core neurocognitive features thought conducive to substance initiation.
A Programmable Toolkit to Dynamically Signal Cells using Peptide Strand Displacement
Authors: Riker Kyle D. , Daly Margaret L. , Papanikolas Micah J. , Jian Tengyue , Klawa Stephen J. , Sahin Jacqueline (Yalin) S. , Liu Dingyuan , Singh Anamika , Miller A. Griffin , Freeman Ronit
Published: February 2021

The native extracellular matrix communicates and interacts with cells by dynamically displaying signals to control their behavior. Mimicking this dynamic environmentin vitrois essential in order to unravel how cell-matrix interactions guide cell fate. Here, we present a synthetic platform for the temporal display of cell adhesive signals using coiled-coil peptides. By designing an integrin-engaging coiled-coil pair to have a toehold (unpaired domain), we were able to use a peptide strand displacement reaction to remove the cell cue from the surface. This allowed us to test how the on-demand display of RGDS ligands at variable duration and periodicity of ligand exposure influence cell spreading degree and kinetics. Transient display of αVβ3selective ligands instructed fibroblast cells to reversibly spread and contract in response to changes in ligand exposure over multiple cycles, exhibiting a universal kinetic response. Also, cells that were triggered to spread and contract repeatedly exhibited greater enrichment of integrins in focal adhesions versus cells cultured on persistent RGDS-displaying surfaces. This dynamic platform will allow us to uncover the molecular code by which cells sense and respond to changes in their environment and will provide insights into ways to program cellular behavior.
Quantifying Viscous Damping and Stiffness in Parkinsonism Using Data-Driven Model Estimation
Authors: Werning Alec , Umbarila Daniel , Fite Maxwell , Fergus Sinta , Zhang Jianyu , Molnar Gregory F. , Johnson Luke A. , Wang Jing , Vitek Jerrold L. , Sanabria David Escobar
Published: February 2021

Rigidity of upper and lower limbs in Parkinson’s disease (PD) is typically assessed via a clinical rating scale that is subject to biases inherent to human perception. Methodologies and systems to systematically quantify changes in rigidity associated with angular position (stiffness) or velocity (viscous damping) are needed to enhance our understanding of PD pathophysiology and objectively assess therapies. We developed a robotic system and a model-based approach to estimate viscous damping and stiffness of the elbow. Our methodology enables the subject to freely rotate the elbow, while torque perturbations tailored to identify the arm dynamics are delivered. The viscosity and stiffness are calculated based on the experimental data using least-squares optimization. We validated our technique using computer simulations of the arm dynamics and experiments with a nonhuman animal model of PD in the presence and absence of deep brain stimulation (DBS) therapy. Computer simulations of the arm demonstrate that the proposed approach can accurately estimate viscous damping and stiffness. The experimental data show that both viscosity and stiffness significantly decreased when DBS was delivered. Computer simulations and experiments showed that stiffness and viscosity measurements obtained with the proposed methodology could better differentiate changes in rigidity than scores previously used for research, including the work score, impulse score, and modified Unified Parkinson’s Disease Rating Scale (mUPDRS). The proposed estimation method is suitable to quantify the effect of therapies on viscous damping and stiffness and study the pathophysiological mechanisms underlying rigidity in PD.
Singlet oxygen-dependent chloroplast degradation is independent of macroautophagy in theArabidopsis ferrochelatasetwo mutant
Authors: Lemke Matthew D. , Fisher Karen E. , Kozlowska Marta A. , Tano David , Woodson Jesse D.
Published: February 2021

Background

Chloroplasts respond to stress and changes in the environment by producing reactive oxygen species (ROS) that have specific signaling abilities. The ROS singlet oxygen (1O2) is unique in that it can signal to initiate selective degradation of damaged chloroplasts and then cell death. This chloroplast quality control pathway can be monitored in theArabidopsismutantplastid ferrochelatase two(fc2) that conditionally accumulates chloroplast1O2under diurnal light cycling conditions leading to rapid chloroplast degradation and eventual cell death. The cellular machinery involved in such degradation, however, remains unknown. Recently it has been demonstrated that whole damaged chloroplasts can be transported to the central vacuole via a process requiring autophagosomes and core components of the autophagy machinery. The relationship between this process, referred to as chlorophagy, and the degradation of1O2-stressed chloroplasts and cells has remained unexplored.

Results

To further understand1O2-induced cellular degradation and determine what role autophagy may play, the expression of autophagy-related genes were monitored in1O2-stressedfc2seedlings and found to be induced. Although autophagosomes were present infc2cells, they did not associate with chloroplasts during1O2stress. Mutations blocking the core autophagy machinery (atg5, atg7, andatg10) were unable to suppress1O2-induced chloroplast degradation or cell death in thefc2mutant, suggesting autophagosome formation and macroautophagy are dispensable for1O2–mediated cellular degradation. However, bothatg5andatg7led to specific defects in chloroplast ultrastructure and photosynthetic efficiencies, suggesting macroautophagy may be involved in protecting chloroplasts from photo-oxidative damage. Finally, genes predicted to be involved in microautophagy were shown to be induced in stressedfc2seedlings, indicating a possible role for an alternate form of autophagy in the dismantling of1O2-damaged chloroplasts.

Conclusions

Our results support the hypothesis that1O2-dependent chloroplast degradation is independent from autophagosome formation, canonical macroautophagy, and chlorophagy. Instead, ATG-independent microautophagy may be involved in such degradation. However, canonical macroautophagy may still play a role in protecting chloroplasts from1O2-induced photo-oxidative stress. Together, this suggests chloroplast function and degradation is a complex process that utilizes multiple autophagy and degradation machineries, possibly depending on the type of stress or damage incurred.
Functional cooperativity mediated by rationally selected combinations of human monoclonal antibodies targeting the henipavirus receptor binding protein
Authors: Doyle Michael P. , Kose Nurgun , Borisevich Viktoriya , Binshtein Elad , Amaya Moushimi , Nagel Marcus , Annand Edward J. , Armstrong Erica , Bombardi Robin , Dong Jinhui , Schey Kevin L. , Broder Christopher C. , Zeitlin Larry , Kuang Erin A. , Bornholdt Zachary A. , West Brandyn R. , Geisbert Thomas W. , Cross Robert W. , Crowe James E.
Published: February 2021

Hendra virus (HeV) and Nipah virus (NiV), the prototypic members of theHenipavirus(HNV) genus, are emerging, zoonotic paramyxoviruses known to cause severe disease across six mammalian orders, including humans (Eaton et al., 2006). While several research groups have made strides in developing candidate vaccines and therapeutics against henipaviruses, such countermeasures have not been licensed for human use, and significant gaps in knowledge about the human immune response to these viruses exist. To address these gaps, we isolated a large panel of human monoclonal antibodies (mAbs) from the B cells of an individual with prior occupation-related exposure to the equine HeV vaccine (Equivac® HeV). Competition-binding and hydrogen-deuterium exchange mass spectrometry (HDX-MS) studies identified at least six distinct antigenic sites on the HeV/NiV receptor binding protein (RBP) that are recognized by human mAbs. Antibodies recognizing multiple antigenic sites potently neutralized NiV and/or HeV isolatesin vitro.The most potent class of cross-reactive antibodies achieved neutralization by blocking viral attachment to the host cell receptors ephrin-B2 and ephrin-B3. Antibodies from this class mimic receptor binding by inducing a receptor-bound conformation to the HeV-RBP protein tetramer, exposing an epitope that appears to lie hidden in the interface between protomers within the HeV-RBP tetramer. Antibodies that recognize this cryptic epitope potently neutralized HeV and NiV. Flow cytometric studies using cell-surface-displayed HeV-RBP protein showed that cross-reactive, neutralizing mAbs from each of these classes cooperate for binding. In a highly stringent hamster model of NiVBinfection, antibodies from both classes reduced morbidity and mortality and achieved synergistic protection in combination and provided therapeutic benefit when combined into two bispecific platforms. These studies identified multiple candidate mAbs that might be suitable for use in a cocktail therapeutic approach to achieve synergistic antiviral potency and reduce the risk of virus escape during treatment.
Competence-associated peptide BriC alters fatty acid biosynthesis inStreptococcus pneumoniae
Authors: Aggarwal Surya D. , Gullett Jessica M. , Fedder Tara , Safi J. Pedro F. , Rock Charles O. , Hiller N. Luisa
Published: February 2021

Membrane lipid homeostasis is required for bacteria to survive in a spectrum of host environments. This homeostasis is achieved by regulation of fatty acid chain length and of the ratio of saturated to unsaturated fatty acids. In the pathogenStreptococcus pneumoniae, fatty acid biosynthesis is encoded by a cluster of fatty acid biosynthesis (fab) genes (FASII locus) whose expression is controlled by the FabT repressor. Encoded immediately downstream of the FASII locus is BriC, a competence-induced, cell-cell communication peptide that promotes biofilm development as well as nasopharyngeal colonization in a murine model of pneumococcal carriage. Here, we demonstrate thatbriCis co-transcribed with genes of thefabgene cluster and that a reduction ofbriClevels, caused by decoupling its transcription fromfabgene cluster, negatively impacts biofilm development. BriC elevatesfabTtranscription, which is predicted to alter the balance of saturated and unsaturated fatty acids produced by the pathway. We find thatbriCinactivation results in a decreased production of unsaturated fatty acids that impact the membrane properties by decreasing the abundance of di-unsaturated phosphatidylglycerol molecular species. We propose that the link between BriC, FabT and phospholipid composition contributes to the ability ofS. pneumoniaeto alter membrane homeostasis in response to the production of a quorum-sensing peptide.

IMPORTANCE

Adaptation of bacteria to their host environment is a key component of colonization and pathogenesis. As an essential component of bacterial membranes, fatty acid composition contributes to host adaptation. Similarly, so does cell-cell communication, which serves as a mechanism for population levels responses. While much is known about the pathways that control the biosynthesis of fatty acids, many questions remain regarding regulation of these pathways and consequently the factors that impacts the balance between saturated and unsaturated fatty acids. We find that BriC, a cell-cell communication peptide implicated in biofilm regulation and colonization, is both influenced by a fatty acid biosynthesis pathway and impacts this same pathway. This study identified a link between cell-cell communication, fatty acid composition, and biofilms and, in doing so, suggests that these pathways are integrated into the networks that control pneumococcal colonization and host adaptation.
Accelerated vaccine induction of IgM neutralising antibody enables vaccine protection against same day lethal influenza virus challenge
Authors: Honda-Okubo Yoshikazu , Li Lei , Baldwin Jeremy , Petrovsky Nikolai
Published: February 2021

Novel influenza strains to which humans have no pre-existing immunity can trigger global pandemics without warning. Current pandemic vaccines typically require two doses and up to 6 weeks to induce protective immunity. In addition, to their role in increasing vaccine-induced immune response, adjuvants may also play a part in reducing the time between immunization and vaccine protection, although this role has seldom been previously explored in literature. This study assessed the speed of protection achievable with a standard inactivated influenza vaccine when formulated with or without a novel delta-inulin adjuvant (Advax). When formulated with Advax adjuvant mice were protected even when the vaccine was administered intramuscularly contemporaneously with a lethal intranasal virus challenge. The protection was found to be B-cell dependent and transfer of day 6 immune serum from mice immunised with Advax-adjuvanted influenza vaccine conferred protection to naïve animals. This protection was shown to be mediated by vaccine induced IgM rather than IgG neutralising antibodies. The results show that influenza vaccine can be formulated to provide immediate protection following immunization with this novel concept warranting testing in human trials.

IMPORTANCE

In the past 100 years there have been several major influenza pandemics that resulted in significant loss of life. The time taken for individuals to develop vaccine protection is an important factor in curbing the spread of infection and reducing pandemic mortality rates. Current influenza vaccines can take up to 5-6 weeks to generate full protection leaving front-line heath care workers and others, at risk for an extended period of time. Our novel accelerated vaccine protection approach provides effectively immediate vaccine protection against lethal virus challenge. This would assist front-line workers to continue to provide essential services and maintain critical infrastructure during pandemic. The study also highlights the often-overlooked role that antigen-specific IgM plays in virus protection and provides a novel adjuvanted strategy for enlisting IgM to provide accelerated vaccine protection.
Aspergillus fumigatusIn-Host HOG pathway mutation for Cystic Fibrosis Lung Microenvironment Persistence
Authors: Ross Brandon S. , Lofgren Lotus A. , Ashare Alix , Stajich Jason E. , Cramer Robert A.
Published: February 2021

The prevalence ofAspergillus fumigatuscolonization in individuals with Cystic Fibrosis (CF) and subsequent fungal persistence in the lung is increasingly recognized. However, there is no consensus for clinical management ofA. fumigatusin CF individuals, due largely to uncertainty surroundingA. fumigatusCF pathogenesis and virulence mechanisms. To address this gap in knowledge, a longitudinal series ofA. fumigatusisolates from an individual with CF were collected over 4.5 years. Isolate genotypes were defined with whole genome sequencing that revealed both transitory and persistentA. fumigatusin the lung. Persistent lineage isolates grew most readily in a low oxygen culture environment and conidia were more sensitive to oxidative stress inducing conditions compared to non-persistent isolates. Closely related persistent isolates harbor a unique allele of the high osmolarity glycerol (HOG) pathway mitogen activated protein kinase kinase, Pbs2 (pbs2C2). Data suggest this novelpbs2C2allele arosein vivoand is necessary for the fungal response to osmotic stress in a low oxygen environment through hyperactivation of the HOG (SakA) signaling pathway. Hyperactivation of the HOG pathway throughpbs2C2comes at the cost of decreased conidia stress resistance in the presence of atmospheric oxygen levels. These novel findings shed light on pathoadaptive mechanisms ofA. fumigatusin CF, lay the foundation for identifying persistentA. fumigatusisolates that may require antifungal therapy, and highlight considerations for successful culture of persistent fungal CF isolates.

Importance

Aspergillus fumigatusinfection causes a spectrum of clinical manifestations. For individuals with Cystic Fibrosis (CF), Allergic Bronchopulmonary Aspergillosis (ABPA) is an established complication, but there is a growing appreciation forA. fumigatusairway persistence in CF disease progression. There currently is little consensus for clinical management ofA. fumigatuslong-term culture positivity in CF. A better understanding ofA. fumigatuspathogenesis mechanisms in CF is expected to yield insights into when antifungal therapies are warranted. Here, a 4.5-year longitudinal collection ofA. fumigatusisolates identified a persistent lineage that harbors a unique allele of the Pbs2 MAPKK necessary for unique CF-relevant stress phenotypes. Importantly forA. fumigatusCF patient diagnostics, this allele provides increased CF lung fitness at a cost of reducedin vitrogrowth in standard laboratory conditions. These data illustrate a molecular mechanism forA. fumigatusCF lung persistence with implications for diagnostics and antifungal therapy.
Indoleamine 2,3-dioxygenase upregulates PD-1 expression on ovarian tumor infiltrating CD8+ T cells via kynurenine activation of the aryl hydrocarbon receptor
Authors: Amobi-McCloud Adaobi , Muthuswamy Ravikumar , Battaglia Sebastiano , Yu Han , Liu Tao , Wang Jianmin , Putluri Vasanta , Singh Prashant K , Qian Feng , Huang Ruea-Yea , Putluri Nagireddy , Tsuji Takemasa , Lugade Amit A , Liu Song , Odunsi Kunle
Published: February 2021

The immunoregulatory enzyme, indoleamine 2,3-dioxygenase (IDO1) and the PD-1/PD-L1 axis are potent mechanisms that impede effective anti-tumor immunity in ovarian cancer. However, whether the IDO pathway regulates PD-1 expression in T cells is currently unknown. Here we show that tumoral IDO1 expression led to profound changes in tryptophan, nicotinate/nicotinamide, and purine metabolic pathways in the ovarian tumor microenvironment, and to an increased frequency of PD-1+CD8+ tumor infiltrating T cells. We determined that activation of the aryl hydrocarbon receptor (AHR) by kynurenine induced PD-1 expression, and this effect was significantly abrogated by the AHR antagonist CH223191. Mechanistically, kynurenine alters chromatin accessibility in regulatory regions of T cell inhibitory receptors, allowing AHR to bind to consensus XRE motifs in the promoter region of PD-1. These results enable the design of strategies to target the IDO1 and AHR pathways for enhancing anti-tumor immunity in ovarian cancer.
Genome-wide insights into population structure and host specificity ofCampylobacter jejuni
Authors: Epping Lennard , Walther Birgit , Piro Rosario M. , Knüver Marie-Theres , Huber Charlotte , Thürmer Andrea , Flieger Antje , Fruth Angelika , Janecko Nicol , Wieler Lothar H. , Stingl Kerstin , Semmler Torsten
Published: February 2021

The zoonotic pathogenCampylobacter jejuniis among the leading causes of foodborne diseases worldwide. WhileC. jejunicolonises many wild animals and livestock, persistence mechanisms enabling the bacterium to adapt to host species’ guts are not fully understood. In order to identify putative determinants influencing host preferences of distinct lineages, bootstrapping based on stratified random sampling combined with ak-mer-based genome-wide association was conducted on 490 genomes from diverse origins in Germany and Canada.

We show a strong association of both the core and the accessory genome characteristics with distinct host animal species, indicating multiple adaptive trajectories defining the evolution ofC. jejunilifestyle preferences in different ecosystems. Here, we demonstrate that adaptation towards a specific host niche ecology is most likely a long evolutionary and multifactorial process, expressed by gene absence or presence and allele variations of core genes. Several host-specific allelic variants from different phylogenetic backgrounds, includingdnaE,rpoB,ftsX or pycB play important roles for genome maintenance and metabolic pathways. Thus, variants of genes important forC. jejunito cope with specific ecological niches or hosts may be useful markers for both surveillance and future pathogen intervention strategies.
Replication-related control over cell division inEscherichia coliis growth-rate dependent
Authors: Tiruvadi-Krishnan Sriram , Männik Jaana , Kar Prathitha , Lin Jie , Amir Ariel , Männik Jaan
Published: February 2021

How replication and division processes are coordinated in the cell cycle is a fundamental yet poorly understood question in cell biology. InEscherichia colidifferent data sets and models have supported a range of conclusions from one extreme where these two processes are tightly linked to another extreme where these processes are completely independent of each other. Using high throughput optical microscopy and cell cycle modeling, we show that in slow growth conditions replication and division processes are strongly correlated, indicating a significant coupling between replication and division. This coupling weakens as the growth rate of cells increases. Our data suggest that the underlying control mechanism in slow growth conditions is related to unreplicated chromosome blocking the onset of constriction at the midcell. We show that the nucleoid occlusion protein SlmA does not play a role in this process and neither do other known factors involved in positioning bacterial Z-ring relative to the chromosome. Altogether this work reconciles different ideas from the past and brings out a more nuanced role of replication in controlling the division process in a growth-rate dependent manner.
Revisiting the early evolution of Cyanobacteria with a new thylakoid-less and deeply diverged isolate from a hornwort
Authors: Rahmatpour Nasim , Hauser Duncan A. , Nelson Jessica M. , Chen Pa Yu , Villarreal A. Juan Carlos , Ho Ming-Yang , Li Fay-Wei
Published: February 2021

Cyanobacteria have played pivotal roles in Earth’s geological history especially during the rise of atmospheric oxygen. However, our ability to infer the early transitions in Cyanobacteria evolution has been limited by their extremely lopsided tree of life—the vast majority of extant diversity belongs to Phycobacteria (or “crown Cyanobacteria”), while its sister lineage, Gloeobacteria, is depauperate and contains only two closely related species ofGloeobacterand a metagenome-assembled genome. Here we describe a new culturable member of Gloeobacteria,Anthocerobacter panamensis, isolated from a tropical hornwort.Anthocerobacterdiverged fromGloeobacterover 1.4 billion years ago and has low 16S identities with environmental samples. Our ultrastructural, physiological, and genomic analyses revealed that this species possesses a unique combination of traits that are exclusively shared with either Gloeobacteria or Phycobacteria. For example, similar toGloeobacter, it lacks thylakoids and circadian clock genes, but the carotenoid biosynthesis pathway is typical of Phycobacteria. Furthermore,Anthocerobacterhas one of the most reduced gene sets for photosystems and phycobilisomes among Cyanobacteria. Despite this,Anthocerobacteris capable of oxygenic photosynthesis under a wide range of light intensities, albeit with much less efficiency. Given its key phylogenetic position, distinct trait combination, and availability as a culture,Anthocerobacteropens a new window to further illuminate the dawn of oxygenic photosynthesis.
Dynamics and nanoscale organization of the postsynaptic endocytic zone at excitatory synapses
Authors: Catsburg Lisa A.E. , Westra Manon , van Schaik Annemarie M. L. , MacGillavry Harold D.
Published: February 2021

At postsynaptic sites of neurons, a prominent clathrin-coated structure, the endocytic zone (EZ), controls the trafficking of glutamate receptors and is essential for synaptic plasticity. Despite its importance, little is known about how this clathrin structure is organized to mediate endocytosis. We used live-cell and super-resolution microscopy techniques to reveal the dynamic organization of this poorly understood clathrin structure. We found that a subset of endocytic proteins only transiently appeared at postsynaptic sites. In contrast, other proteins, including Eps15, intersectin1L, and β2-adaptin, were persistently enriched and partitioned at the edge of the EZ. We found that uncoupling the EZ from the synapse led to the loss of most of these components, while disrupting the actin cytoskeleton or AP2-membrane interactions did not alter EZ positioning. We conclude that the EZ is a stable, highly organized molecular platform where components are differentially recruited and positioned to orchestrate the endocytosis of synaptic receptors.
MITOCHONDRIAL GENOME REVEALS CONTRASTING PATTERN OF ADAPTIVE SELECTION IN TURTLES AND TORTOISES
Authors: Sahoo Subhashree , Kumar Ajit , Rai Jagdish , Gupta Sandeep Kumar
Published: February 2021

Testudinoidea represents an evolutionarily unique taxon comprising both turtles and tortoises. The contrasting habitats that turtles and tortoises inhabit are associated with unique physio-ecological challenges hence enable distinct adaptive evolutionary strategies. To comparatively understand the pattern and strength of Darwinian selection and physicochemical evolution in turtle and tortoise mitogenomes, we employed adaptive divergence and selection analyses. We evaluated changes in structural and biochemical properties, and codon models on the mitochondrial protein-coding genes (PCGs) among three turtles and a tortoise lineage. We used mitochondrial PCGs that constitute the crucial oxidative phosphorylation (OXPHOS) respiratory system, a critical metabolic regulator which assumes key significance in energy regulation of ectotherms.

We detected strong evidence of positive selection along the turtle lineages: Geoemydidae, Emydidae, and Platysternidae, but relatively weak signals in tortoises. The Platysternidae turtles revealed the highest gene and site-wise positive selection. In turtles, positively selected sites were prevalent in NAD2 and NAD4 genes in OXPHOS Complex I, and COB gene of Complex III, indicating convergent adaptive evolution. Besides, NAD3 was the only subunit that showed adaptive selection in both turtles and tortoises, expressing its relevance for all Testudinoidea. Structural and functional analysis revealed many sites and physiochemical changes in important conserved as well as biomedically significant regions, suggesting the influence of adaptive pressure on mitogenome functions. Hence, our study furnished novel evidence of contrasting evolutionary selective pressure acting on closely related groups such as turtles and tortoises with unique habitat preferences and associated eco-physiological challenges.
Substrate dynamics contribute to enzymatic specificity in human and bacterial methionine adenosyltransferases
Authors: Gade Madhuri , Tan Li Lynn , Damry Adam M. , Sandhu Mahakaran , Brock Jospeh S. , Delaney Andie , Villar-Briones Alejandro , Jackson Colin J. , Laurino Paola
Published: February 2021

Protein conformational change can facilitate the binding of non-cognate substrates and underlie promiscuous activities. However, the contribution of substrate conformational dynamics to this process is comparatively poorly understood. Here we analyse human (hMAT2A) andEscherichia coli(eMAT) methionine adenosyltransferases that have identical active sites but different substrate specificity. In the promiscuous hMAT2A, non-cognate substrates bind in a stable conformation to allow catalysis. In contrast, non-cognate substrates rarely sample stable productive binding modes in eMAT owing to altered mobility in the enzyme active site. Different cellular concentrations of substrate likely drove the evolutionary divergence of substrate specificity in these orthologs. The observation of catalytic promiscuity in hMAT2A led to the detection of a new human metabolite, methyl thioguanosine, that is produced at elevated level in a cancer cell line. This work establishes that identical active sites can result in different substrate specificity owing to the effects of substrate and enzyme dynamics.