bluuebunny/crossref_metadata_2025 huggingface dataset:
Altered projection-specific synaptic remodeling and its modification by oxytocin in an idiopathic autism marmoset model
Authors: Noguchi Jun , Watanabe Satoshi , Oga Tomofumi , Isoda Risa , Nakagaki Keiko , Sakai Kazuhisa , Sumida Kayo , Hoshino Kohei , Saito Koichi , Miyawaki Izuru , Sugano Eriko , Tomita Hiroshi , Mizukami Hiroaki , Watakabe Akiya , Yamamori Tetsuo , Ichinohe Noritaka
Published: August 2022

Alterations in the experience-dependent and autonomous elaboration of neural circuits are assumed to underlie autism spectrum disorder (ASD), though it is unclear what synaptic traits are responsible. Here, we used a valproic acid-induced ASD marmoset model, which shares common molecular features with idiopathic ASD, to investigate the structural dynamics of tuft dendrites of upper-layer pyramidal neurons and adjacent axons in the dorsomedial prefrontal cortex using two-photon microscopy. In model marmosets, dendritic spine turnover was upregulated, and spines were actively generated in clusters and subsequently survived more often than in control marmosets. Presynaptic boutons in local axons but not in commissural long-range axons showed hyperdynamic turnover in model marmosets, suggesting alterations in projection-specific plasticity. Intriguingly, nasal administration of oxytocin reduced the clustered spine emergence. Enhanced clustered spine generation, possibly unique to certain presynaptic partners, may be associated with ASD and may be a potential therapeutic target.
The rubber tree kinome: genome-wide characterization and insights into coexpression patterns associated with abiotic stress responses
Authors: Santos Lucas Borges dos , Aono Alexandre Hild , Francisco Felipe Roberto , Silva Carla Cristina da , Souza Livia Moura , de Souza Anete Pereira
Published: August 2022

The protein kinase (PK) superfamily constitutes one of the largest and most conserved protein families in eukaryotic genomes, comprising core components of signaling pathways in cell regulation. Despite its remarkable relevance, only a few kinase families have been studied inHevea brasiliensis. A comprehensive characterization and global expression analysis of the PK superfamily, however, is currently lacking. In this study, with the aim of providing novel inferences about the mechanisms associated with the stress response developed by PKs and retained throughout evolution, we identified and characterized the entire set of PKs, also known as the kinome, present in the Hevea genome. A total of 1,809 PK genes were identified using the current reference genome assembly at the scaffold level, and 1,379 PK genes were identified using the latest chromosome-level assembly and combined into a single set of 2,842 PKs. These proteins were further classified into 20 different groups and 122 families, exhibiting high compositional similarities among family members and with two phylogenetically close species (Manihot esculentaandRicinus communis). Different RNA-sequencing datasets were employed to identify tissue-specific expression patterns and potential correspondences between different rubber tree genotypes. In addition, coexpression networks under several abiotic stress conditions, such as cold, drought and latex overexploitation, were employed to elucidate associations between families and tissues/stresses. Through the joint investigation of tandemly duplicated kinases, transposable elements, gene expression patterns, and coexpression events, we provided insights into the understanding of the cell regulation mechanisms in response to several conditions, which can often lead to a significant reduction in rubber yield.
Associations between regular cannabis use and brain resting-state functional connectivity in adolescents and adults
Authors: Ertl Natalie , Lawn Will , Mokrysz Claire , Freeman Tom P. , Alnagger Naji , Borissova Anna , Fernandez-Vinson Natalia , Lees Rachel , Ofori Shelan , Petrilli Kat , Trinci Katie , Viding Essi , Curran H. Valerie , Wall Matthew B.
Published: August 2022

Cannabis use is highly prevalent in adolescents however little is known about its effects on adolescent brain function. Resting-state functional Magnetic Resonance Imaging was used in matched groups of cannabis users (N=70, 35 adolescents16-17 years old, 35 adults 26-29 years old) and non-users (N=70, 35 adolescents/35 adults). Pre-registered analyses examined the connectivity of seven major cortical and sub-cortical brain networks (default mode network, executive control network, salience network, hippocampal network, and three striatal networks) using seed-based analysis methods with cross-sectional comparisons between user groups, and age groups. Cannabis users (across both age-groups), relative to controls, showed localised increases in connectivity only in the executive control network analysis. All networks showed localised connectivity differences based on age group, with the adolescents generally showing weaker connectivity than adults; consistent with developmental effects. Mean connectivity across entire network regions of interest (ROIs) was also significantly decreased in the executive control network in adolescents. However, there were no significant interactions found between age-group and user-group in any of the seed-based or ROI analyses. There were also no associations found between cannabis use frequency and any of the derived connectivity measures. Chronic cannabis use is associated with changes to connectivity of the executive control network, which may reflect allostatic or compensatory changes in response to regular cannabis intoxication. However, these associations were not significantly different in adolescents compared to adults.
Virome and nrEVEome diversity of Aedes albopictus mosquitoes from La Reunion Island and China
Authors: Palatini Umberto , Alfano Niccolò , Lejarazu Carballar Rebeca , Chen Xiaoguang , Delatte Helene , Bonizzoni Mariangela
Published: August 2022

Background

Aedes albopictus is a public health threat for its worldwide spread and ability to transmit arboviruses. Understanding mechanisms of mosquito immunity can provide new tools to control arbovirus spread. The genomes of Aedes mosquitoes contain hundreads of nonretroviral endogenous viral elements (nrEVEs), which are enriched in piRNA clusters and produce piRNAs, with the potential to target cognate viruses. Recently, one nrEVE was shown to limit cognate viral infection through nrEVE-derived piRNAs. These findings suggest that nrEVEs constitute an archive of past viral infection and that the landscape of viral integrations may be variable across populations depending on their viral exposure.

Methods

We used bioinformatics and molecular approaches to identify known and novel (i.e. absent in the reference genome) viral integrations in the genome of wild collected Aedes albopictus mosquitoes and characterize their virome.

Results

We showed that the landscape of viral integrations is dynamic with seven novel viral integrations being characterised, but does not correlate with the virome, which includes both viral species known and unknown to infect mosquitoes. However, the small RNA coverage profile of nrEVEs and the viral genomic contigs we identified confimed an interaction among these elements and the piRNA and siRNA pathways in mosquitoes.

Conclusions

Mosquitoes nrEVEs have been recently descrived as a new form of heritable, sequence-specific mechanism of antiviral immunity. Our results contribute to understanding the dynamic distribution of nrEVEs in the genomes of wild Ae. albopictus and their interaction with mosquito viruses.
Virtual Environments for Research into Social Evolution (VERSE): A novel experimental environment for the study of human social learning
Authors: Easter C.
Published: August 2022

1.

Social learning (learning from others) can be a cost-effective way of gaining information compared to asocial (independent) learning. However, learning from others indiscriminately can lead to the acquisition of maladaptive behaviours or outdated information. Evolutionary theory therefore predicts that individuals will use social information adaptively through the use of ‘social learning strategies’. Restrictive laboratory conditions, however, make studying human learning strategies problematic. Abstract tasks, unrealistic sources of social information and methodologies that do not take into account the influence of physical location over large spaces make it difficult to ascertain if previous findings are representative of the way we would use social information in reality. Here I describe a novel platform for studying human social behaviour within immersive virtual environments: “Virtual Environments for Research into Social Evolution” (VERSE). Through the use of gaming technology, VERSE allows researchers to build realistic, three-dimensional, open world environments where participants can complete ecologically relevant tasks while actively observing computer-controlled artificial intelligence agents (AIs) that act as realistic yet controllable sources of social information. This methodological article begins by exploring what social learning strategies are and the problems with studying social learning behaviour in humans (compared to animal populations, for example). I then discuss how gaming technology can be used in behavioural research and follow on with a detailed account of the specific functionalities available in VERSE. I conclude with a worked example of how VERSE can be used to construct a novel behavioural experiment. Altogether, VERSE has great potential to give us insight into how human individuals learn within novel environments in a way that has never before been possible.
Unsupervised, frequent and remote: a novel platform for personalised digital phenotyping of spatial working memory and image recognition in humans
Authors: Bauza Marius , Krstulovic Marino , Krupic Julija
Published: August 2022

Spatial working memory and image recognition tests are commonly used to facilitate the diagnosis of hippocampal-related neurological disorders such as Alzheimer’s disease due to their relatively high specificity and sensitivity to damage to the medial temporal lobes compared to standard commonly used clinical tests. Pathological changes in Alzheimer’s disease start years before the formal diagnosis is made, partially due to testing too late. To address this challenge, we developed a novel digital platform, hAge (‘healthy Age’), which integrates double spatial alternation, image recognition and visuospatial tasks for frequent remote unsupervised assessment of spatial and non-spatial working memory. 191 healthy adults (67% females, 18-81 years old) participated in the study. In line with findings using standard laboratory tests, we showed that performance on the spatial alternation task negatively correlated with inter-trial periods and performance levels on image recognition and visuospatial tasks can be controlled by varying image similarity. Importantly, we demonstrated that frequent engagement with the double spatial alternation task leads to a strong practice effect, previously identified as a potential measure of cognitive decline in MCI patients. Finally, we discuss how lifestyle and motivation confounds may present a serious challenge for cognitive assessment in real-world uncontrolled environments.
Cotranscriptional RNA strand displacement underlies the regulatory function of the E. coli thiB TPP translational riboswitch
Authors: Berman Katherine E. , Steans Russell , Hertz Laura M. , Lucks Julius B.
Published: August 2022

Riboswitches are cis-regulatory RNA elements that regulate gene expression in response to ligand through the coordinated action of a ligand-binding aptamer domain (AD) and a downstream expression platform (EP). Previous studies of transcriptional riboswitches have uncovered diverse examples that utilize cotranscriptional strand displacement to mediate the switching mechanism. The coupling of transcription and translation in bacteria motivates the intriguing question as to whether translational riboswitches can utilize the same mechanistic features. Here we investigate this question by studying the Escherichia coli thiB thiamine pyrophosphate (TPP) riboswitch. Using cellular gene expression assays, we first confirmed that the riboswitch acts at the level of translational regulation. Deletion mutagenesis showed the importance of the AD-EP linker sequence for riboswitch function, which based on sequence complementarity with the AD P1 stem suggested the possibility of an intermediate structure reminiscent of transcriptional riboswitches that exploit strand displacement. Point mutation analysis of this intermediate structure, followed by designed changes to P1, supported a strand displacement mechanism for E. coli thiB. This work provides an important new example of diverse riboswitch AD-EP combinations that exploit this switching mechanism.
Age, experience, social goals, and engagement with research scientists may promote innovation in ecological restoration
Authors: Mohr Jakki J. , Cummins Tina M. , Floyd Theresa M. , Metcalf Elizabeth Covelli , Callaway Ragan M. , Nelson Cara R.
Published: August 2022

Innovation in ecological restoration is necessary in order to achieve the ambitious targets established in United Nations conventions and other global restoration initiatives. Innovation is also crucial for navigating uncertainties in repairing and restoring ecosystems, and thus practitioners often develop innovations at project design and implementation stages. However, innovation in ecological restoration can be hindered by many factors (e.g., time and budget constraints, project complexity, and others). Theory and research on innovation has been formally applied in many fields, yet explicit study of innovation in ecological restoration remains nascent. In order to assess the use of innovation in restoration projects, including its drivers and inhibitors, we conducted a social survey of restoration practitioners in the United States. Specifically, we assessed relationships between project-based innovation and traits of: theindividual practitioner(including, for example, age, gender, experience);company(including, for example, company size and company’s inclusion of social goals);project(including, for example, complexity and uncertainty); andproject outcomes(such as completing the project on time/on budget and personal satisfaction with the work). We found positive relationships between project-based innovation and practitioner traits (age, gender, experience, engagement with research scientists), one company trait (company’s inclusion of social goals in their portfolio), and project traits (project complexity and length). In contrast, two practitioner traits, risk aversion and the use of industry-specific information, were negatively related to project-based innovation. Satisfaction with work outcomes was positively correlated with project-based innovation. Collectively, the results provide insights into the drivers and inhibitors of innovation in restoration and suggest opportunities for research and application.
Progenitor derived glia are required for spinal cord regeneration in zebrafish
Authors: Zhou Lili , McAdow Ryan , Yamada Hunter , Burris Brooke , Shaw Dana Klatt , Oonk Kelsey , Poss Kenneth D. , Mokalled Mayssa H.
Published: August 2022

Unlike mammals, adult zebrafish undergo spontaneous recovery after major spinal cord injury. Whereas reactive gliosis presents a roadblock for mammalian spinal cord repair, glial cells in zebrafish elicit pro-regenerative bridging functions after injury. Here, we perform genetic lineage tracing, assessment of regulatory sequences, and inducible cell ablation to define mechanisms that direct the molecular and cellular responses of glial cells after spinal cord injury in adult zebrafish. Using a newly generated CreERT2 transgenic line, we show that cells that direct expression of the bridging glial marker ctgfa give rise to regenerating glia after injury, with negligible contribution to either neuronal or oligodendrocyte lineages. A 1 kb sequence upstream of the ctgfa gene was sufficient to direct expression in early bridging glia after injury. Finally, ablation of ctgfa-expressing cells using a transgenic nitroreductase strategy impaired glial bridging and recovery of swim behavior after injury. This study identifies key regulatory features, cellular progeny, and requirements of glial cells during innate spinal cord regeneration.
SHIFTS IN THE CONFLICT-COEXISTENCE CONTINUUM: EXPLORING SOCIAL-ECOLOGICAL DETERMINANTS OF HUMAN-ELEPHANT INTERACTIONS
Authors: Malley Grace S. , Gorenflo L.J.
Published: August 2022

In Morogoro Region of south-central Tanzania, loss of crops and safety concerns due to elephants compromises livelihoods in many rural communities relying on subsistence agriculture. Using a social-ecological system framework to examine conflict-coexistence between people and elephants, this paper explores drivers that influence human-elephant interaction and subsistence farmer attitudes towards elephants in 10 villages from three different districts. Surveys and interviews document experiences interacting with elephants along with direct and indirect costs incurred in sharing the landscape, revealing different tolerance levels by residents of subject communities towards elephants that have important implications for elephant conservation. Rather than uniformly negative beliefs about elephants, analyses reveal that over the past decade a shift has occurred from largely favorable to unfavorable. The variables influencing attitudes included amounts of crops lost to elephants, perceived benefits from elephants, amounts of crops lost to other causes, perceived trend of human-elephant conflict (HEC) in the past three decades and level of education. Villager tolerance varied by level of income, perception on how the community coexists with elephants, amounts of crops lost to elephants and compensation. The study contributes to understanding how HEC is affecting the relationship between people and elephants, revealing a shift in the conflict-coexistence continuum from positive to broadly negative and identifying characteristics underlying varying tolerance towards elephants in different communities. Rather than a static condition, HEC emerges under specific conditions at particular times and places through varying, uneven interactions between rural villagers and elephants. In communities vulnerable to food insecurity, such conflict exacerbates existing problems of poverty, social inequality, and feelings of oppression. Addressing the causes of HEC, when possible, will be essential to elephant conservation as well as to improving the wellbeing of rural villagers.
A phased, chromosome-scale genome of ‘Honeycrisp’ apple (Malus domestica)
Authors: Khan Awais , Carey Sarah B. , Serrano Alicia , Zhang Huiting , Hargarten Heidi , Hale Haley , Harkess Alex , Honaas Loren
Published: August 2022

‘Honeycrisp’ is one of the most valuable apple cultivars grown in the United States and a popular breeding parent due to its superior fruit quality traits, high levels of cold hardiness, and disease resistance. However, it suffers from a number of physiological disorders and is susceptible to production and postharvest issues. Although several apple genomes have been sequenced in the last decade, there is still a substantial knowledge gap in understanding the genetic mechanisms underlying cultivar-specific traits. Here we present a fully phased, chromosome-level genome of ‘Honeycrisp’ apples, using PacBio HiFi, Omni-C, and Illumina sequencing platforms. Our genome assembly is by far the most contiguous among all the apple genomes. The sizes of the two assembled haplomes are 674 Mb and 660 Mb, with contig N50s of 32.8 Mb and 31.6 Mb, respectively. In total, 47,563 and 48,655 protein coding genes were annotated from each haplome, capturing 96.8-97.4% complete BUSCOs in the eudicot database, the most complete among all Malus annotations. A gene family analysis using seven Malus genomes shows that a vast majority of ‘Honeycrisp’ genes are assigned into orthogroups shared with other genomes, but it also reveals 121 ‘Honeycrisp’-specific orthogroups. We provide a valuable resource for understanding the genetic basis of horticulturally important traits in apples and other related tree fruit species, including at-harvest and postharvest fruit quality, abiotic stress tolerance, and disease resistance, all of which can enhance breeding efforts in Rosaceae.
An abstract categorical decision code in dorsal premotor cortex
Authors: Diaz-deLeon Gabriel , Alvarez Manuel , Bayones Lucas , Zainos Antonio , Zizumbo Jerónimo , Parra Sergio , Pujalte Sebastián , Romo Ranulfo , Rossi-Pool Román , De Lafuente Victor
Published: August 2022

The dorsal premotor cortex (DPC) has classically been associated with a role in preparing and executing the physical motor variables during cognitive tasks. While recent work has provided nuanced insights into this role, here we propose that DPC also participates more actively in decision-making. We recorded neuronal activity in DPC while two trained monkeys performed a vibrotactile categorization task, utilizing two distinct ranges of stimuli values that varied on two physical attributes: vibrotactile frequency and amplitude. We observed a broad heterogeneity across DPC neurons, the majority of which maintained the same response patterns across attributes and ranges, coding in the same periods, mixing temporal and categorical dynamics. The predominant categorical signal was maintained throughout the delay, movement periods and notably during the inter-trial period. Putting the entire population’s data through two dimensionality reduction techniques, we found that imposing the sensory structure yielded pure categorical and temporal representations. Furthermore, projecting the activity of one population over the population axes of the other yielded identical categorical and temporal responses. Finally, we sought to identify functional subpopulations based on the combined activity of all stimuli, neurons, and time points, however we found a continuum of single-unit responses mixing temporal and categorical dynamics. All this points to DPC playing a more decision-related role than previously anticipated.

SIGNIFICANCE STATEMENT

The DPC’s role in the somatosensory processing network has been generally limited to movement, but our current results suggest a more abstract function. We recorded DPC’s activity in two monkeys trained in a vibrotactile categorization task of two distinct physical attributes, and found a strong decision signal throughout the population, underpinned by purely temporal signals. Importantly, this abstract decision signal remains during the inter-trial period suggesting a consolidation role. Neurons maintained consistent and significant responses for both attributes, and the entire population activity converged to identical categorical representations, even when cross-projected between two contexts. These results suggest that DPC plays a larger role during decision-making and consolidation, regardless of the stimulus attributes that triggered the decision report.
C4Grasses Employ Distinct Strategies to Acclimate Rubisco Activase to Heat Stress
Authors: Stainbrook Sarah C , Aubuchon Lindsey N , Chen Amanda , Johnson Emily , Si Audrey , Walton Laila , Ahrendt Angela , Strenkert Daniela , Jez Joseph
Published: August 2022

1

Rising temperatures due to the current climate crisis will have devastating impacts on crop performance and resilience in the near future. One key step that limits plant photosynthetic performance under higher temperatures is the activity of the thermolabile enzyme rubisco activase (RCA). RCA is highly conserved in photosynthetic organisms, including C4crops such asZea mays(maize) andSorghum bicolor(sorghum) which are crucial components of global food supply and the bioenergy sector. While rubisco is the most abundant protein on earth and responsible for carbon fixation, RCA is an essential chaperone required to remove inhibitory sugar phosphates from the active site of rubisco to allow for continued CO2fixation. We set out to understand temperature-dependent RCA regulation in four different C4plants, with a focus on the crop plants maize (two cultivars) and sorghum, as well as the model grassSetaria viridis(setaria). Gas exchange measurements confirm that CO2assimilation is indeed limited by Ribulose 1,5-bisphosphate (RuBP) carboxylation in these organisms and at high temperatures. All three species express distinct sets of RCA isoforms and each species alters the isoform and proteoform abundances in response to heat; however, the changes are species-specific. In order to understand how even subtle changes in the molecular environment of the chloroplast stroma affect RCA function during heat acclimation, we examined the regulation of RCA activity directly with respect thermostability, the ratio of ADP to ATP and the concentration of Mg2+ions. As shown previously, the activity of RCA is modulated by a combination of these variables, but surprisingly, how these biochemical environment factors affect RCA function differs vastly between the different C4species, and differences are even apparent between different cultivars within a single species, both with respect to proteoform abundance and regulation. Our results suggest that each grass evolved different parts of the RCA regulation portfolio and we conclude that a successful engineering approach aimed at improving carbon capture in C4 grasses will need to accommodate these individual regulatory mechanisms.
Screening cell-cell communication in spatial transcriptomics via collective optimal transport
Authors: Cang Zixuan , Zhao Yanxiang , Almet Axel A. , Stabell Adam , Ramos Raul , Plikus Maksim , Atwood Scott X. , Nie Qing
Published: August 2022

Spatial transcriptomic technologies and spatially annotated single cell RNA-sequencing (scRNA-seq) datasets provide unprecedented opportunities to dissect cell-cell communication (CCC). How to incorporate the spatial information and complex biochemical processes in reconstructing CCC remains a major challenge. Here we present COMMOT to infer CCC in spatial transcriptomics, which accounts for the competition among different ligand and receptor species as well as spatial distances between cells. A novel collective optimal transport method is developed to handle complex molecular interactions and spatial constraints. We introduce downstream analysis tools on spatial directionality of signalings and genes regulated by such signalings using machine learning models. We apply COMMOT to simulation data and eight spatial datasets acquired with five different technologies, showing its effectiveness and robustness in identifying spatial CCC in data with varying spatial resolutions and gene coverages. Finally, COMMOT reveals new CCCs during skin morphogenesis in a case study of human epidermal development. Both the method and the computational package have broad applications in inferring cell-cell interactions within spatial genomics datasets.
Integrity of membrane fluidity and fatty acid environment are necessary for Ebola virus VP40 assembly and release of viral particles
Authors: Amiar Souad , Johnson Kristen A. , Husby Monica L. , Marzi Andrea , Stahelin Robert V.
Published: August 2022

Plasma membrane (PM) domains and order phases have been shown to play a key role in the assembly, release, and entry of several lipid-enveloped viruses. In the present study, we provide a mechanistic understanding of the Ebola virus (EBOV) matrix protein VP40 interaction with PM lipids and their effect on VP40 oligomerization, a crucial step for viral assembly and budding. VP40 matrix formation is sufficient to induce changes in the PM fluidity. We demonstrate that the distance between the lipid headgroups, the fatty acid tail saturation and the order between the two leaflets are important factors for the stability of VP40 binding and oligomerization at the PM. Use of FDA-approved drugs (dibucaine, propranolol and trifluoperazine) to fluidize the plasma membrane, destabilizes the viral matrix assembly leading to a reduction in budding efficiency. Lastly, we show that VP40 can tether and cluster lipid vesicles upon protein enrichment at the membrane. This is a new characteristic of the protein, and it opens the door to new avenues of exploration to deepen our understanding of VP40 host interactions and EBOV assembly. Indeed, our findings support a complex assembly mechanism of the EBOV viral matrix that reaches beyond lipid headgroup specificity using ordered PM lipid regions independent of cholesterol.
Neural Decoding of Inferior Colliculus Multiunit Activity for Sound Category identification with temporal correlation and deep learning
Authors: Özcan F. , Alkan A.
Published: August 2022

Natural sounds are easily perceived and identified by humans and animals. Despite this, the neural transformations that enable sound perception remain largely unknown. Neuroscientists are drawing important conclusions about neural decoding that may eventually aid research into the design of brain-machine interfaces (BCIs). It is thought that the time-frequency correlation characteristics of sounds may be reflected in auditory assembly responses in the midbrain and that this may play an important role in identification of natural sounds. In our study, natural sounds will be predicted from multi-unit activity (MUA) signals collected in the inferior colliculus. The temporal correlation values of the MUA signals are converted into images. We used two different segment sizes and thus generated four subsets for the classification. Using pre-trained convolutional neural networks (CNNs), features of the images were extracted and the type of sound heard was classified. For this, we applied transfer learning from Alexnet, GoogleNet and Squeezenet CNNs. The classifiers support vector machines (SVM), k-nearest neighbour (KNN), Naive Bayes and Ensemble were used. The accuracy, sensitivity, specificity, precision and F1 score were measured as evaluation parameters. Considering the trials one by one in each, we obtained an accuracy of 85.69% with temporal correlation images over 1000 ms windows. Using all trials and removing noise, the accuracy increased to 100%.
Bacteroides thetaiotaomicron outer membrane vesicles modulate virulence of Shigella flexneri
Authors: Xerri Nicholas L. , Payne Shelley M.
Published: August 2022

The role of the gut microbiota in the pathogenesis of Shigella flexneri remains largely unknown. To understand the impact of the gut microbiota on S. flexneri virulence, we examined the effect of interspecies interactions with Bacteroides thetaiotaomicron (Bt), a prominent member of the gut microbiota, on S. flexneri invasion. When grown in Bt conditioned medium, S. flexneri showed reduced invasion of human epithelial cells. This decrease in invasiveness of S. flexneri resulted from a reduction in the level of S. flexneri’s master virulence regulator VirF. Reduction of VirF corresponded with a decrease in expression of a secondary virulence regulator virB, as well as expression of S. flexneri virulence genes required for invasion, intracellular motility, and spread. Repression of S. flexneri virulence factors by Bt conditioned medium was not caused by either a secreted metabolite or protein, but rather, was due to the presence of Bt outer membrane vesicles (OMVs) in the conditioned medium. The addition of purified Bt OMVs to S. flexneri growth medium recapitulated the inhibitory effects of Bt conditioned medium on invasion, virulence gene expression, and virulence protein levels. Total lipids extracted from either Bt cells or Bt OMVs also recapitulated the effects of Bt condition medium on expression of the S. flexneri virulence factor IpaC, indicating that Bt OMV lipids, rather than a cargo contained in the vesicles, are the active factor responsible for the inhibition of S. flexneri virulence.

Importance

Shigella flexneri is the causative agent of bacillary dysentery in humans. Shigella spp. are one of the leading causes of diarrheal morbidity and mortality, especially among children in low and middle-income countries. The rise of antimicrobial resistance combined with the lack of an effective vaccine for Shigella heightens the importance of studies aimed at better understanding previously uncharacterized aspects of Shigella pathogenesis. Here, we show that conditioned growth medium from the commensal bacteria Bacteroides thetaiotaomicron represses the invasion of S. flexneri. This repression is due to the presence of B. thetaiotaomicron outer membrane vesicles. These findings establish a role for interspecies interactions with a prominent member of the gut microbiota in modulating the virulence of S. flexneri and identify a novel function of outer membrane vesicles in interbacterial signaling between members of the gut microbiota and an enteric pathogen.
Effects of diacutaneous fibrolysis in patients with tension-type headache: A randomized controlled trial
Authors: Cabanillas-Barea Sara , Pérez-Guillén Silvia , López-de-Celis Carlos , Rodríguez-Sanz Jacobo , Fanlo-Mazas Pablo , Carrasco-Uribarren Andoni
Published: August 2022

Background

Manual therapy appears to be effective for the relief of tension-type headache (TTH), just as diacutaneous fibrolysis (DF) has shown to be a beneficial technique for the relief of symptoms in other dysfunctions. However, no studies have evaluated the potential beneficial effect of DF in TTH. The aim of this study is to analyze the effect of three sessions of DF in patients with TTH.

Methods

Randomized controlled trial in 86 subjects (43 intervention/ 43 control group). The headache frequency, the headache intensity, the pressure pain thresholds (PPTs) at trapeziometacarpal joint, upper trapezius, suboccipital, frontal and temporal muscles, parietal sutures and the cervical mobility were measured at baseline, at the end of the third intervention and one-month after the last intervention.

Results

Statistically significant differences with p values <0.05 were observed between groups in favor of the intervention group in the one-month follow-up in the following variables: headache frequency, headache intensity, flexion, extension, right and left side-bending, right and left rotation, PPTs in left trapeziometacarpal joint, right suboccipital muscle, right and left temporal muscle, left frontal muscle and right and left parietal.

Conclusions

DF provides a beneficial effect in reducing headache frequency, relieving pain, and improving cervical mobility in patients with TTH.
Hypotension During Vasopressor Infusion Occurs in Predictable Clusters: A Multicenter Analysis
Authors: Horiguchi Daisuke , Shin Sungtae , Pepino Jeremy , Peterson Jeffrey , Kehoe Iain , Goldstein Joshua , McAuley Mary , Lee Jarone , Lux Laura , Kwon Brian , Hahn Jin-Oh , Reisner Andrew
Published: August 2022

The authors have withdrawn their manuscript owing to significantly revising their methodology. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Model Evaluation of Secondary Chemistry due to Disinfection of Indoor Air with Germicidal Ultraviolet Lamps
Authors: Peng Zhe , Miller Shelly L. , Jimenez Jose L.
Published: August 2022

Air disinfection using Germicidal Ultraviolet light (GUV) has received increasing attention during the COVID-19 pandemic. GUV uses UVC lamps to inactivate microorganisms, but it also initiates photochemistry in air. However, GUV’s indoor-air-quality impact has not been investigated in detail. Here, we model the chemistry initiated by GUV at 254 (“GUV254”) or 222 nm (“GUV222”) in a typical indoor setting for different ventilation levels. Our analysis showed that GUV254, usually installed in the upper room, can significantly photolyze O3, generating OH radicals that oxidize indoor volatile organic compounds (VOCs) into more oxidized VOCs. Secondary organic aerosol (SOA) is also formed as a VOC-oxidation product. GUV254-induced SOA formation is of the order of 0.1-1 μg/m3for the cases studied here. GUV222 (described by some as harmless to humans and thus applicable for the whole room) with the same effective virus-removal rate makes a smaller indoor-air-quality impact at mid-to-high ventilation rates. This is mainly because of the lower UV irradiance needed and also less efficient OH-generating O3photolysis than GUV254. GUV222 has a higher impact than GUV254 under poor ventilation due to a small but significant photochemical production of O3at 222 nm, which does not occur with GUV254.

Synopsis

Germicidal ultraviolet light initiates indoor oxidation chemistry, potentially forming indoor air pollutants. The amount is not negligible and depends on both the wavelength of light and the ventilation level.
Jagged1 overexpression on T cells induces thymic regulatory T cells leading to thymic involution
Authors: Kritikou Joanna S. , Sánchez-Pascual Irene , Muñoz-Miranda Juan Pedro , Vashist Neha , Wagner Arnika K. , Zhang Xing-Mei , Assarsson Erika , Dominguez-Villar Margarita , Yagita Hideo , Garcia-Cozar Francisco , Riese Peggy , Harris Robert A. , Ljunggren Hans-Gustaf , Chambers Benedict J.
Published: August 2022

We previously described a mouse model, tg66, with a severe defect resulting in diminished thymic size and complete involution by early adulthood. In the current study, we identified overexpression of Jagged1 as a mechanism for the alterations in thymic development in tg66 mice. T cells in the tg66 thymus were skewed towards CD8+T cells, and within the CD4+T cell compartment there was an over-representation of Foxp3+cells. Regulatory Foxp3+T cells (Tregs) isolated from tg66 mice had increased ST2 and CD103 expression. These Tregs could suppress proliferation to the same extent as conventional Tregs. Corroborating these results, tg66 mice were resistant to experimental induction of neuroinflammation in a common animal model for multiple sclerosis (EAE). Using bone marrow chimeras, we recorded a stark reduction in the number of thymocytes and a corresponding increase in Tregs in the thymus of mice receiving tg66 bone marrow. Conversely, through blocking Jagged1, the number of thymocytes was significantly increased, being concomitantly associated with a drop in the frequency of Tregs. We conclude that Tregs may play a role in thymic involution and could explain early thymic involution or loss as it is observed in diseases of thymic atrophy such as Down syndrome.
GATK-gCNV: A Rare Copy Number Variant Discovery Algorithm and Its Application to Exome Sequencing in the UK Biobank
Authors: Babadi Mehrtash , Fu Jack M. , Lee Samuel K. , Smirnov Andrey N. , Gauthier Laura D. , Walker Mark , Benjamin David I. , Karczewski Konrad J. , Wong Isaac , Collins Ryan L. , Sanchis-Juan Alba , Brand Harrison , Banks Eric , Talkowski Michael E.
Published: August 2022

Copy number variants (CNVs) are major contributors to genetic diversity and disease. To date, exome sequencing (ES) has been generated for millions of individuals in international biobanks, human disease studies, and clinical diagnostic screening. While standardized methods exist for detecting short variants (single nucleotide and insertion/deletion variants) using tools such as the Genome Analysis ToolKit (GATK), technical challenges have confounded similarly uniform large-scale CNV analyses from ES data. Given the profound impact of rare and de novo coding CNVs on genome organization and human disease, the lack of widely-adopted and robustly benchmarked rare CNV discovery tools has presented a barrier to routine exome-wide assessment of this critical class of variation. Here, we introduce GATK-gCNV, a flexible algorithm to discover rare CNVs from genome sequencing read-depth information, which we distribute as an open-source tool packaged in GATK. GATK-gCNV uses a probabilistic model and inference framework that accounts for technical biases while simultaneously predicting CNVs, which enables self-consistency between technical read-depth normalization and variant calling. We benchmarked GATK-gCNV in 7,962 exomes from individuals in quartet families with matched genome sequencing and microarray data. These analyses demonstrated 97% recall of rare (≤1% site frequency) coding CNVs detected by microarrays and 95% recall of rare coding CNVs discovered by genome sequencing at a resolution of more than two exons. We applied GATK-gCNV to generate a reference catalog of rare coding CNVs in 197,306 individuals with ES from the UK Biobank. We observed strong correlations between CNV rates per gene and measures of mutational constraint, as well as rare CNV associations with multiple traits. In summary, GATK-gCNV is a tunable approach for sensitive and specific CNV discovery in ES, which can easily be applied across trait association and clinical screening.
STAT3 restricts prostate cancer metastasis and antiandrogen resistance by controlling LKB1/CREB signaling pathway
Authors: Pencik Jan , Philippe Cecile , Schlederer Michaela , Pecoraro Matteo , Grund-Gröschke Sandra , Li Wen Jess , Tracz Amanda , Heidegger Isabel , Lagger Sabine , Trachtová Karolína , Oberhuber Monika , Heitzer Ellen , Aksoy Osman , Neubauer Heidi A. , Wingelhofer Bettina , Orlova Anna , Witzeneder Nadine , Dillinger Thomas , Redl Elisa , Greiner Georg , D’Andrea David , Östman Johnny R. , Tangermann Simone , Hermanova Ivana , Schäfer Georg , Varady Adam , Horvath Jaqueline , Stoiber Dagmar , Malcolm Timothy I. , Turner Suzanne D. , Parkes Eileen , Hantusch Brigitte , Egger Gerda , Rose-John Stefan , Poli Valeria , Jain Suneil , Armstrong Chris W.D. , Hoermann Gregor , Goffin Vincent , Aberger Fritz , Moriggl Richard , Carracedo Arkaitz , McKinney Cathal , Kennedy Richard D , Klocker Helmut , Speicher Michael R. , Tang Dean G. , Mann Matthias , Moazzami Ali A. , Heery David M. , Hacker Marcus , Kenner Lukas
Published: August 2022

Prostate cancer (PCa) lethality is driven by its progression to a metastatic castration-resistant state, yet the signaling mechanisms underlying metastatic spread remain unknown. Here we show that STAT3 converges with the LKB1/mTORC1 and CREB to control metastatic disease in PCa mouse models. Unexpectedly, STAT3 was found to be upregulated in diabetic PCa patients undergoing metformin therapy with a concomitant reduction in mTORC1 expression. In preclinical mouse models of PCa, genetic ablation or activation of STAT3 had opposing effects on LKB1/AMPK/mTORC1- dependent tumorigenesis. Using genetic and pharmacological approaches, we identified LKB1 as a direct STAT3 target while repressing CREB. Furthermore, PCa patients with high CREB expression had inferior clinical outcome with significantly increased risk of disease and metastatic recurrence. We observe that castration state lowers STAT3 abundance and increases AR and CREB levels, leading to castration-resistant PCa (CRPC). Our findings revealed that STAT3 controls mTORC1 and CREB in metastatic disease, suggesting CREB as a promising target for lethal CRPC.
RNA origami scaffolds as a cryo-EM tool for investigating aptamer-ligand binding of a Broccoli-Pepper FRET pair
Authors: Vallina Néstor Sampedro , McRae Ewan K.S. , Hansen Bente Kring , Boussebayle Adrien , Andersen Ebbe Sloth
Published: August 2022

RNA nanotechnology uses motifs from nature as well as aptamers from in vitro selection to construct nanostructures and devices for applications in RNA medicine and synthetic biology. The RNA origami method allows cotranscriptional folding of large RNA scaffolds that can position functional motifs in a precise manner, which has been verified by Förster Resonance Energy Transfer (FRET) between fluorescent aptamers. Cryogenic electron microscopy (cryo-EM) is a promising method for characterizing the structure of larger RNA nanostructures. However, the structure of individual aptamers is difficult to solve by cryo-EM due to their low molecular weight. Here, we place aptamers on the RNA origami scaffolds to increase the contrast for cryo-EM and solve the structure of a new Broccoli-Pepper FRET pair. We identify different modes of ligand binding of the two aptamers and verify by selective probing. 3D variability analysis of the cryo-EM data show that the relative position between the two bound fluorophores on the origami fluctuate by only 3.5 Angstrom. Our results demonstrate the use of RNA origami scaffolds for characterizing small RNA motifs by cryo-EM and for positioning functional RNA motifs with high spatial precision. The Broccoli-Pepper apta-FRET pair has potential use for developing advanced sensors that are sensitive to small conformational changes.
Relating local connectivity and global dynamics in recurrent excitatory-inhibitory networks
Authors: Shao Yuxiu , Ostojic Srdjan
Published: August 2022

How the connectivity of cortical networks determines the neural dynamics and the resulting computations is one of the key questions in neuroscience. Previous works have pursued two complementary strategies to quantify the structure in connectivity, by specifying either the local statistics of connectivity motifs between small groups of neurons, or by defining network-wide low-rank patterns of connectivity that determine the resulting low-dimensional dynamics. A direct relationship between these two approaches is however currently missing, and in particular it remains to be clarified how local connectivity statistics are related to the global connectivity structure and shape the low-dimensional activity. To bridge this gap, here we develop a method for mapping local connectivity statistics onto an approximate global low-rank structure. Our method rests on approximating the global connectivity matrix using dominant eigenvectors, which we compute using perturbation theory for random matrices. This approach demonstrates that multi-population networks defined from local connectivity properties can in general be approximated by low-rank connectivity with Gaussian-mixture statistics. We specifically apply this method to excitatory-inhibitory networks, and show that it leads to accurate predictions for both the low-dimensional dynamics, and for the activity of individual neurons. Altogether, our approach allows us to disentangle the effects of mean connectivity and reciprocal motifs on the global recurrent feedback, and provides an intuitive picture of how local connectivity shapes global network dynamics.

Author summary

The structure of connections between neurons is believed to determine how cortical networks control behaviour. Current experimental methods typically measure connections between small numbers of simultaneously recorded neurons, and thereby provide information on statistics of local connectivity motifs. Collective network dynamics are however determined by network-wide patterns of connections. How these global patterns are related to local connectivity statistics and shape the dynamics is an open question that we address in this study. Starting from networks defined in terms of local statistics, we develop a method for approximating the resulting connectivity by global low-rank patterns. We apply this method to classical excitatory-inhibitory networks and show that it allows us to predict both collective and single-neuron activity. More generally, our approach provides a link between local connectivity statistics and global network dynamics.