bluuebunny/crossref_metadata_2025 huggingface dataset:
Deep Learning in Opthalmology: Iris Melanocytic Tumors Intelligent Diagnosis
Authors: Helwan Abdulkader
Published: September 2021

Recently, Convolutional neural networks (CNN) have shown a growth due to their ability of learning different level image representations that helps in image classification in different fields. These networks have been trained on millions of images, so they gained a powerful ability of extracting the rightful features from input images, which results in accurate classification. In this research, we investigate the effects of transfer learning based convolutional neural networks for the iris tumor malignancy identification as it is notoriously hard to distinguish an iris nevus from an iris tumor. Features are transferred from a CNN trained on a source task, i.e. ImageNet, to a target task, i.e. iris tumor datasets. We transfer features learned from AlexNet and VGG-16 that are trained on ImageNet, to classify three different iris images types which are: iris nevus unaffected, iris cysts, and iris melanocytic tumors. The employed pre-trained models are modified by replacing their feedforward neural network classifier, Softmax, by a support vector machine (SVM) that is expected to slightly boost their performance (AlexNet-SVM and VGG16-SVM). All employed models are trained (fine-tuned) on a 60% of the available large dataset of iris images in order to investigate their power of generalization when trained using large amount of data. The networks are also tested on 40% of the data. The best performance was achieved by the VGG16-SVM which scored a high accuracy of 96.27% and strong features extraction capability as compared to the other models. Experimentally, it was seen that adding SVM contributed in improving the network performance compared to original models which use a feedforward neural network classifier.
Tuna-AI: tuna biomass estimation with Machine Learning models trained on oceanography and echosounder FAD data
Authors: Precioso Daniel , Navarro-García Manuel , Gavira-O’Neill Kathryn , Torres-Barrán Alberto , Gordo David , Gallego-Alcalá Víctor , Gómez-Ullate David
Published: September 2021

Echo-sounder data registered by buoys attached to drifting FADs provide a very valuable source of information on populations of tuna and their behaviour. This value increases when these data are supplemented with oceanographic data coming from CMEMS. We use these sources to develop Tuna-AI, a Machine Learning model aimed at predicting tuna biomass under a given buoy, which uses a 3-day window of echo-sounder data to capture the daily spatio-temporal patterns characteristic of tuna schools. As the supervised signal for training, we employ more than 5000 set events with their corresponding tuna catch reported by the AGAC tuna purse seine fleet.
The Physiological Landscape and Specificity of Antibody Repertoires
Authors: Csepregi Lucia , Hoehn Kenneth B. , Neumeier Daniel , Taft Joseph M. , Friedensohn Simon , Weber Cédric R. , Kummer Arkadij , Sesterhenn Fabian , Correia Bruno E. , Reddy Sai T.
Published: September 2021

Diverse antibody repertoires spanning multiple lymphoid organs (e.g., bone marrow, spleen, lymph nodes) form the foundation of protective humoral immunity. Changes in their composition across lymphoid organs are a consequence of B-cell selection and migration events leading to a highly dynamic and unique physiological landscape of antibody repertoires upon antigenic challenge (e.g., vaccination). However, to what extent B cells encoding identical or similar antibody sequences (clones) are distributed across multiple lymphoid organs and how this is shaped by the strength of a humoral response, remains largely unexplored. Here, we performed an in-depth systems analysis of antibody repertoires across multiple distinct lymphoid organs of immunized mice, and discovered that organ-specific antibody repertoire features (e.g., germline V-gene usage and clonal expansion profiles) equilibrated upon a strong humoral response (multiple immunizations and high serum titers). This resulted in a surprisingly high degree of repertoire consolidation, characterized by highly connected and overlapping B-cell clones across multiple lymphoid organs. Finally, we revealed distinct physiological axes indicating clonal migrations and showed that antibody repertoire consolidation directly correlated with antigen-specificity. Our study uncovered how a strong humoral response resulted in a more uniform but redundant physiological landscape of antibody repertoires, indicating that increases in antibody serum titers were a result of synergistic contributions from antigen-specific B-cell clones distributed across multiple lymphoid organs. Our findings provide valuable insights for the assessment and design of vaccine strategies.
Sound localization of world and head-centered space in ferrets
Authors: Town Stephen M. , Bizley Jennifer K.
Published: September 2021

The location of sounds can be described in multiple coordinate systems that are defined relative to ourselves, or the world around us. Evidence from neural recordings in animals point towards the existence of both head-centered and world-centered representations of sound location in the brain; however, it is unclear whether such neural representations have perceptual correlates in the sound localization abilities of non-human listeners. Here, we establish novel behavioral tests to determine the coordinate systems in which ferrets can localize sounds. We found that ferrets could learn to discriminate between sound locations that were fixed in either world-centered or head-centered space, across wide variations in sound location in the alternative coordinate system. Using probe sounds to assess broader generalization of spatial hearing, we demonstrated that in both head and world-centered tasks, animals used continuous maps of auditory space to guide behavior. Single trial responses of individual animals were sufficiently informative that we could then model sound localization using speaker position in specific coordinate systems and accurately predict ferrets’ actions in held-out data. Our results indicate that an animal model in which neurons are known to be tuned to sound location in egocentric and allocentric reference frames can also localize sounds in multiple head and world-centered spaces.

Significance Statement

Humans can describe the location of sounds either relative to themselves, or in the world, independent of their momentary position. These different spaces are also represented in the activity of neurons in animals, but it’s not clear whether non-human listeners also perceive both head and world-centered sound location. Here, we designed two behavioral tasks in which ferrets had to discriminate between two sounds using their position in the world, or relative to the head. Subjects learnt to solve both problems and showed the ability to generalize sound location in each space when presented with infrequent probe sounds. These findings reveal a perceptual correlate of neural sensitivity previously observed in the ferret brain and establish that, like humans, ferrets can access an auditory map of their local environment.
OmicsView: omics data analysis through interactive visual analytics
Authors: Casey Fergal , Negi Soumya , Zhu Jing , Zavodszky Maria , Cheng Derrick , Lin Dongdong , John Sally , Penny Michelle A. , Sexton David , Zhang Baohong
Published: September 2021

With advances in NGS technologies, transcriptional profiling of human tissue across many diseases is becoming more routine, leading to the generation of petabytes of data deposited in public repositories. There is a need for bench scientists with little computational expertise to be able to access and mine this data to understand disease pathology, identify robust biomarkers of disease and the effect of interventions (in vivo or in vitro). To this end we release an open source analytics and visualization platform for expression data called OmicsView, http://omicsview.org.

This platform comes preloaded with 1000s of samples across many disease areas and normal tissue, including the GTEx database, all processed with a harmonized pipeline. We demonstrate the power and ease-of-use of the platform by means of a Crohn’s disease data mining exercise where we can quickly uncover disease pathology and identify strong biomarkers of disease and response to treatment.
The rt-TEP tool: real-time visualization of TMS-Evoked Potential to maximize cortical activation and minimize artifacts
Authors: Casarotto S , Fecchio M , Rosanova M , Varone G , D’Ambrosio S , Sarasso S , Pigorini A , Russo S , Comanducci A , Ilmoniemi RJ , Massimini M
Published: September 2021

Background

The impact of transcranial magnetic stimulation (TMS) on cortical neurons is currently hard to predict based on a priori biophysical and anatomical knowledge alone. This problem can hamper the reliability and reproducibility of protocols aimed at measuring electroencephalographic (EEG) responses to TMS.

New Method

We introduce and release a novel software tool to facilitate and standardize the acquisition of TMS-evoked potentials (TEPs). The tool, rt-TEP (real-time TEP), interfaces with different EEG amplifiers and offers a series of informative visualization modes to assess in real time the immediate impact of TMS on the underlying neuronal circuits.

Results

We show that rt-TEP can be used to abolish or minimize magnetic and muscle artifacts contaminating the post-stimulus period thus affording a clear visualization and quantification of the amplitude of the early (<50 ms) EEG response after averaging a limited number of trials. This real-time readout can then be used to adjust TMS parameters (e.g. site, orientation, intensity) and experimental settings (e.g. loudness and/or spectral features of the noise masking) to ultimately maximize direct cortical effects over the undesired sensory effects of the coil’s discharge.

Comparison with Existing Methods

The ensemble of real-time visualization modes of rt-TEP are not implemented in any current commercial software and provide a key readout to titrate TMS parameters beyond the a priori information provided by anatomical models.

Conclusions

Real-time optimization of stimulation parameters with rt-TEP can facilitate the acquisition of reliable TEPs with a high signal-to-noise ratio and improve the standardization and reproducibility of data collection across laboratories.

Highlights

rt-TEP provides an immediate EEG readout to assess the quality of TEPs in real time

rt-TEP interfaces with most commercial EEG systems

Informative, real time visualization allows maximising the cortical impact of TMS while minimizing artifacts

rt-TEP facilitates the acquisition of reliable TEPs with a high signal-to-noise ratio
White Matter Signals Reflect Information Transmission Between Brain Regions During Seizures
Authors: Revell Andrew Y. , Silva Alexander B. , Mahesh Dhanya , Armstrong Lena , Arnold T. Campbell , Bernabei John M. , Gleichgerrcht Ezequiel , Bonilha Leonardo , Stein Joel M. , Das Sandhitsu R. , Shinohara Russell T. , Bassett Dani S. , Litt Brian , Davis Kathryn A.
Published: September 2021

White matter supports critical brain functions such as learning and memory, modulates the distribution of action potentials, and transmits neural information between brain regions. Notably, neuronal cell bodies exist in deeper white matter tissue, neurotransmitter vesicles are released directly in white matter, and white matter blood-oxygenation level dependent (BOLD) signals are detectable across a range of different tasks—all appearing to reflect a dynamic, active tissue from which recorded signals can reveal meaningful information about the brain. Yet, the signals within white matter have largely been ignored. Here, we elucidate the properties of white matter signals using intracranial EEG in a bipolar montage. We show that such signals capture the communication between brain regions and differentiate pathophysiologies of epilepsy. In direct contradiction to past assumptions that white matter functional signals provide little value, we show that white matter recordings can elucidate brain function and pathophysiology. Broadly, white matter functional recordings acquired through implantable devices may provide a wealth of currently untapped knowledge about the neurobiology of disease.
Computational capability of ecological dynamics
Authors: Ushio Masayuki , Watanabe Kazufumi , Fukuda Yasuhiro , Tokudome Yuji , Nakajima Kohei
Published: September 2021

Ecological dynamics is driven by an ecological network consisting of complex interactions. Information processing capability of artificial networks has been exploited as a computational resource, yet whether an ecological network possesses a computational capability and how we can exploit it remain unclear. Here, we show that ecological dynamics can be exploited as a computational resource. We call this approach “Ecological Reservoir Computing” (ERC) and developed two types of ERC.In silicoERC reconstructs ecological dynamics from empirical time series and uses simulated system responses as reservoir states, which predicts near future of chaotic dynamics and emulates nonlinear dynamics. The real-time ERC uses population dynamics of a unicellular organism,Tetrahymena thermophila. Medium temperature is an input signal and changes in population abundance are reservoir states. Intriguingly, the real-time ERC has necessary conditions for reservoir computing and is able to make near future predictions of model and empirical time series.
The MultimorbiditY COllaborative Medication Review And DEcision Making (MyComrade) study: A protocol for a cross-border pilot cluster randomised controlled trial
Authors: Hynes Lisa , Murphy Andrew W , Hart Nigel , Kirwan Collette , Mulligan Sarah , Leathem Claire , McQuillan Laura , Maxwell Marina , Carr Emma , Walkin Scott , McCarthy Caroline , Bradley Colin , Byrne Molly , Smith Susan M , Hughes Carmel , Corry Maura , Kearney Patricia M , McCarthy Geraldine , Cupples Margaret , Gillespie Paddy , Newell John , Glynn Liam , Alvarez-Iglesias Alberto , Sinnott Carol
Published: September 2021

Background

While international guidelines recommend medication reviews as part of the management of multimorbidity, evidence on how to implement reviews in practice in primary care is lacking. The MyComrade (MultimorbiditY Collaborative Medication Review And Decision Making) intervention is an evidence-based, theoretically-informed novel intervention which aims to support the conduct of medication reviews for patients with multimorbidity in primary care. Our aim in this pilot study is to evaluate the feasibility of a trial of the intervention with unique modifications accounting for contextual variations in two neighbouring health systems (Republic of Ireland (ROI) and Northern Ireland (NI)).

Methods

A pilot cluster randomised controlled trial will be conducted, using a mixed methods process evaluation to investigate the feasibility of a trial of the MyComrade intervention. A total of 16 practices will be recruited (eight in ROI; eight in NI) and four practices in each jurisdiction will be randomly allocated to intervention or control. Twenty people living with multimorbidity and prescribed ≥10 repeat medications will be recruited from each practice prior to practice randomisation. In intervention practices, the MyComrade intervention will be delivered by pairs of GPs in ROI, and a GP and Practice Based Pharmacist (PBP) in NI. The GPs/GP and PBP will schedule time to review medications together using a checklist. Usual care will proceed in practices in the control arm. Data will be collected via electronic health records and postal questionnaires at recruitment, and 4- and 8-months after randomisation. Qualitative interviews to assess the feasibility and acceptability of the intervention, and explore experiences related to multimorbidity management will be conducted with a purposive sample of GPs, PBPs, practice administration staff and patients in intervention and control practices. The feasibility of conducting a health economic evaluation as part of a future definitive trial will be assessed.

Discussion

The findings of this pilot study will assess the feasibility of a trial of the MyComrade intervention in two different health systems. Evaluation of the progression criteria will guide the decision to progress to a definitive trial and inform trial design. The findings will also contribute to the growing evidence-base related to intervention development and feasibility studies.

Trial registration

Registry: ISRCTN,ISRCTN80017020; Date of confirmation 4/11/2019; Retrospectively registered;http://www.isrctn.com/ISRCTN80017020.
Reduction of exposure to simulated respiratory aerosols using ventilation, physical distancing, and universal masking
Authors: Coyle Jayme P. , Derk Raymond C. , Lindsley William G. , Boots Theresa , Blachere Francoise M. , Reynolds Jeffrey S. , McKinney Walter G. , Sinsel Erik W. , Lemons Angela R. , Beezhold Donald H. , Noti John D.
Published: September 2021

To limit community spread of SARS-CoV-2, CDC recommends universal masking indoors, maintaining 1.8 m of physical distancing, adequate ventilation, and avoiding crowded indoor spaces. Several studies have examined the independent influence of each control strategy in mitigating transmission in isolation, yet controls are often implemented concomitantly within an indoor environment. To address the influence of physical distancing, universal masking, and ventilation on very fine respiratory droplets and aerosol particle exposure, a simulator that coughed and exhaled aerosols (the source) and a second breathing simulator (the recipient) were placed in an exposure chamber. When controlling for the other two mitigation strategies, universal masking with 3-ply cotton masks reduced exposure to 0.3–3 µm coughed and exhaled aerosol particles by > 77% compared to unmasked tests, whereas physical distancing (0.9 or 1.8 m) significantly changed exposure to cough but not exhaled aerosols. The effectiveness of ventilation depended upon the respiratory activity, i.e., coughing or breathing, as well as the duration of exposure time. Our results demonstrate that a combination of administrative and engineering controls can reduce personal inhalation exposure to potentially infectious very fine respiratory droplets and aerosol particles within an indoor environment.

PRACTICAL IMPLICATIONS

Universal masking provided the most effective strategy in reducing inhalational exposure to simulated aerosols.

Physical distancing provided limited reductions in exposure to small aerosol particles.

Ventilation promotes air mixing in addition to aerosol removal, thus altering the exposure profile to individuals.

A combination of mitigation strategies can effectively reduce exposure to potentially infectious aerosols.
Influence of Rule and Reward-based Strategies on Inferences of Serial Order by Monkeys
Authors: Ferhat Allain-Thibeault , Jensen Greg , Terrace Herbert S. , Ferrera Vincent P.
Published: September 2021

Knowledge of transitive relationships between items can contribute to learning the order of a set of stimuli from pairwise comparisons. However, cognitive mechanisms of transitive inferences based on rank order remain unclear, as are contributions of reward magnitude and rule-based inference. To explore these issues, we created a conflict between rule- and reward-based learning during a serial ordering task. Rhesus macaques learned two lists, each containing five stimuli, that were trained exclusively with adjacent pairs. Selection of the higher-ranked item resulted in rewards. “Small reward” lists yielded 2 drops of fluid reward, while “large reward” lists yielded 5 drops. Following training of adjacent pairs, monkeys were tested on novels pairs. One item was selected from each list, such that a ranking rule could conflict with preferences for large rewards. Differences in associated reward magnitude had a strong influence on accuracy, but we also observed a symbolic distance effect. That provided evidence of a rule-based influence on decisions. Reaction time comparisons suggested a conflict between rule and reward-based processes. We conclude that performance reflects the contributions of two strategies, and that a model-based strategy is employed in the face of a strong countervailing reward incentive.
Water stress-associated isolation barriers between two sympatric oak species
Authors: Le Provost Grégoire , Brachi Benjamin , Lesur Isabelle , Lalanne Céline , Labadie Karine , Aury Jean-Marc , Da Silva Corinne , Postolache Dragos , Leroy Thibault , Plomion Christophe
Published: September 2021

Drought and waterlogging impede tree growth and may even lead to tree death. With climate change, these environmental factors are a growing source of concern, particularly for temperate forests. Oaks, an emblematic group of tree species, have evolved a range of adaptations to cope with these constraints. The two most widely distributed European species — pedunculate oak (PO) and sessile oaks (SO) — have overlapping ranges, but are highly constrained locally by soil water content variation. These differences in local ecological requirements provide a powerful biological model for studying the role of ecological barriers in speciation. We used an experimental set-up mimicking the ecological preferences of these species, in which seedlings were subjected to waterlogging and drought. We studied gene expression in roots by RNA-seq and identified genes differentially expressed between treatments with different outcomes depending on species. These “species x environment”-responsive genes revealed adaptive molecular strategies involving adventitious and lateral root formation, aerenchyma formation in PO, and osmoregulation and ABA regulation in SO. With this experimental design, we also identified genes with expression profiles presenting a “species” effect regardless of imposed constraints with important roles in intrinsic reproductive barriers. Finally, we compared our findings with those for a genome scan of species divergence and found that the candidate genes were enriched in highly differentiated SNPs. This suggests that many of the genes involved in the contrasting transcriptomic responses are subject to natural selection and that gene regulation helps to maintain these two different oak species in sympatry.
Task-Level Value Affects Trial-Level Reward Processing
Authors: Hassall Cameron D. , Hunt Laurence T. , Holroyd Clay B.
Published: September 2021

Despite disagreement about how anterior cingulate cortex (ACC) supports decision making, a recent hypothesis suggests that activity in this region is best understood in the context of a task or series of tasks. One important task-level variable is average reward because it is both a known driver of effortful behaviour and an important determiner of the tasks in which we choose to engage. Here we asked how average task value affects reward-related ACC activity. To answer this question, we measured a reward-related signal said to be generated in ACC called the reward positivity (RewP) while participants gambled in three tasks of differing average value. The RewP was reduced in the high-value task, an effect that was not explainable by either reward magnitude or outcome expectancy. This result suggests that ACC does not evaluate outcomes and cues in isolation, but in the context of the value of the current task.
Named Entity Recognition and Linking: a Portuguese and Spanish Oncological Parallel Corpus
Authors: Andrade Vitor D.T , Ruas Pedro , Couto Francisco M.
Published: September 2021

Biomedical literature is the main mean of communication for researchers to share their findings. Since biomedical literature is composed of a large collection of text expressed in natural language, the usage of text mining tools to extract information from those texts automatically is of utmost importance. The problem is that the majority of the state-of-the-art tools were not developed to deal with other languages besides English, which in biomedical literature is even more critical since a significant part of health-related texts is written in the author’s native language. To address this issue, this work presents a deep learning NERL (Named Entity Recognition and Linking) system and a parallel corpus for the Spanish and Portuguese languages focused on the oncological domain. Both the system and the corpus are available at https://github.com/lasigeBioTM/ICERL_system-ICR_Corpus.
Molecular plasticity to soil water deficit differs between sessile oak (Quercus Petraea (Matt.) Liebl.) high- and low-water use efficiency genotypes
Authors: Provost Gregoire Le , Gerardin Theo , Plomion Christophe , Brendel Oliver
Published: September 2021

Background

Water use efficiency (WUE) is an important adaptive trait for soil water deficit. The molecular and physiological bases of WUE regulation in crops have been studied in detail in the context of plant breeding. Knowledge for most forest tree species lags behind, despite the need to identify populations or genotypes able to cope with the longer, more intense drought periods likely to result from climate warming.

Results

We aimed to bridge this gap in knowledge for sessile oak (Quercus Petraeae Matt. L.), one of the most ecologically and economically important tree species in Europe, using a factorial design including two genotypes (low and high WUE) and two watering regimes (control and drought). By monitoring the ecophysiological response, we were able to identify groups of genotypes with high and low WUE. We then performed RNA-seq to quantify gene expression for the most extreme genotypes exposed to two watering regimes. By analyzing the interaction term, we were able to capture the molecular strategy of each group of plants for coping with drought. Regardless of water availability, the high WUE genotypes overexpressed genes associated with drought responses, and the control of stomatal density and distribution, and displayed a downregulation of genes associated with early stomatal closure and high transpiration rate. High-WUE genotypes, thus, coped with drought by fine-tuning the expression of genes with known functions in the regulation of stomatal size, density, movement or aperture and transpiration rate.

Conclusion

Fine physiological screening of sessile oaks with contrasting WUE, and their molecular characterization i) highlighted subtle differences in transcription between low and high WUE genotypes, identifying key molecular players in the genetic control of this trait, and ii) revealed the genes underlying the molecular strategy that had evolved in each group to cope with water deficit, providing new insight into the value of WUE for adaptation to drought.
A distinctive ligand recognition mechanism by the human vasoactive intestinal polypeptide receptor 2
Authors: Xu Yingna , Feng Wenbo , Zhou Qingtong , Liang Anyi , Li Jie , Dai Antao , Zhao Fenghui , Zhao Lihua , Xia Tian , Jiang Yi , Xu H. Eric , Yang Dehua , Wang Ming-Wei
Published: September 2021

Activated by physiologically important peptide hormones, class B1 G protein-coupled receptors (GPCRs) modulate key physiological functions and serve as valuable drug targets for many diseases. Among them, vasoactive intestinal polypeptide receptor 2 (VIP2R) is the last member whose full-length 3-dimensional structure has yet to be determined. VIP2R, expressed in the central and peripheral nervous systems and involved in a number of pathophysiological conditions, is implicated in pulmonary arterial hypertension, autoimmune and psychiatric disorders. Here, we report the cryo-electron microscopy structure of the human VIP2R bound to its endogenous ligand PACAP27 and the stimulatory G protein. Different from all reported peptide-bound class B1 GPCR structures, the N-terminal α-helix of VIP2R adopts a unique conformation that deeply inserts into a cleft between PACAP27 and the extracellular loop 1, thereby stabilizing the peptide-receptor interface. Its truncation or extension significantly decreased VIP2R-mediated cAMP accumulation. Our results provide additional information on peptide recognition and receptor activation among class B1 GPCRs and may facilitate the design of better therapeutics.
Enterococcus faecalis persists and replicates within epithelial cells in vitro and in vivo during wound infection
Authors: Tay Wei Hong , da Silva Ronni A.G. , Ho Foo Kiong , Chong Kelvin K.L. , Ludwig Alexander , Kline Kimberly A.
Published: September 2021

Enterococcus faecalis is a frequent opportunistic pathogen of wounds, whose infections are associated with biofilm formation, persistence, and recalcitrance toward treatment. We have previously shown that E. faecalis wound infection persists for at least 7 days. Here we report that viable E. faecalis are present within both immune and non-immune cells at the wound site up to 5 days after infection, raising the prospect that intracellular persistence contributes to chronic E. faecalis infection. Using an in vitro keratinocyte infection model, we show that a subpopulation of E. faecalis becomes internalized via macropinocytosis into single membrane-bound compartments, where they can survive and replicate. These intracellular E. faecalis can persist in late endosomes up to 72 hours after infection in the absence of colocalization with the lysosomal protease cathepsin D or apparent fusion with the lysosome, suggesting that E. faecalis blocks endosomal maturation. Indeed, intracellular E. faecalis infection results in a marked reduction in Rab7 expression, a small GTPase required for endosome-lysosome fusion. Finally, we demonstrate that intracellular E. faecalis derived from infected keratinocytes are significantly more efficient in reinfecting new keratinocytes. Together, these data suggest that intracellular proliferation of E. faecalis may contribute to its persistence in the face of a robust immune response, providing a primed reservoir of bacteria for subsequent reinfection.

Author Summary

Enterococcus faecalis is often isolated from chronic wounds. Prior to this study, E. faecalis has been observed within different cell types, suggesting that it can successfully colonize intracellular spaces. However, to date, little is known about the mechanisms E. faecalis use to survive intracellularly. Here, we describe key features of the intracellular lifestyle of E. faecalis. We show that E. faecalis exists in an intracellular state within immune cells and non-immune cells during mammalian wound infection. We show that E. faecalis can survive and replicate inside keratinocytes, and intracellularly replicating E. faecalis are primed to more efficiently cause reinfection, potentially contributing to chronic or persistent infections. In order to establish this intracellular lifestyle, E. faecalis is taken up by keratinocytes via macropinocytosis, whereupon it manipulates the endosomal pathway and expression of trafficking molecules required for endo-lysosomal fusion, enabling E. faecalis to avoid lysosomal degradation and consequent death. These results advance our understanding of E. faecalis pathogenesis, demonstrating mechanistically how this classic extracellular pathogen can co-opt host cells for intracellular persistence, and highlight the heterogeneity of mechanisms bacteria can use to avoid host-mediated killing in order to cause disease.
Strong humoral immune responses against SARS-CoV-2 Spike after BNT162b2 mRNA vaccination with a 16-week interval between doses
Authors: Tauzin Alexandra , Gong Shang Yu , Beaudoin-Bussières Guillaume , Vézina Dani , Gasser Romain , Nault Lauriane , Marchitto Lorie , Benlarbi Mehdi , Chatterjee Debashree , Nayrac Manon , Laumaea Annemarie , Prévost Jérémie , Boutin Marianne , Sannier Gérémy , Nicolas Alexandre , Bourassa Catherine , Gendron-Lepage Gabrielle , Medjahed Halima , Goyette Guillaume , Bo Yuxia , Perreault Josée , Gokool Laurie , Morrisseau Chantal , Arlotto Pascale , Bazin Renée , Dubé Mathieu , De Serres Gaston , Brousseau Nicholas , Richard Jonathan , Rovito Roberta , Côté Marceline , Tremblay Cécile , Marchetti Giulia C. , Duerr Ralf , Martel-Laferrière Valérie , Kaufmann Daniel E. , Finzi Andrés
Published: September 2021

While the standard regimen of the BNT162b2 mRNA vaccine includes two doses administered three weeks apart, some public health authorities decided to space them, raising concerns about vaccine efficacy. Here, we analyzed longitudinal humoral responses including antibody binding, Fc-mediated effector functions and neutralizing activity against the D614G strain but also variants of concern and SARS-CoV-1 in a cohort of SARS-CoV-2 naïve and previously infected individuals, with an interval of sixteen weeks between the two doses. While the administration of a second dose to previously infected individuals did not significantly improve humoral responses, we observed a significant increase of humoral responses in naïve individuals after the 16-weeks delayed second shot, achieving similar levels as in previously infected individuals. We compared these responses to those elicited in individuals receiving a short (4-weeks) dose interval. For the naïve donors, these responses were superior to those elicited by the short dose interval.
Estimates of presumed population immunity to SARS-CoV-2 by state in the United States, August 2021
Authors: Stoner Marie C.D. , Angulo Frederick J. , Rhea Sarah , Brown Linda Morris , Atwell Jessica E. , Nguyen Jennifer L. , McLaughlin John , Swerdlow David L. , MacDonald Pia D.M.
Published: September 2021

Background

Information is needed to monitor progress toward a level of population immunity to SARS-CoV-2 sufficient to disrupt viral transmission. We estimated the percentage of the United States (US) population with presumed immunity to SARS-CoV-2 due to vaccination, natural infection, or both as of August 26, 2021.

Methods

Publicly available data as of August 26, 2021, from the Centers for Disease Control and Prevention (CDC) were used to calculate presumed population immunity by state. Seroprevalence data were used to estimate the percentage of the population previously infected with SARS-CoV-2, with adjustments for underreporting. Vaccination coverage data for both fully and partially vaccinated persons were used to calculate presumed immunity from vaccination. Finally, we estimated the percentage of the total population in each state with presumed immunity to SARS-CoV-2, with a sensitivity analysis to account for waning immunity, and compared these estimates to a range of population immunity thresholds.

Results

Presumed population immunity varied among states (43.1% to 70.6%), with 19 states with 60% or less of their population having been infected or vaccinated. Four states have presumed immunity greater than thresholds estimated to be sufficient to disrupt transmission of less infectious variants (67%), and none were greater than the threshold estimated for more infectious variants (78% or higher).

Conclusions

The US remains a distance below the threshold sufficient to disrupt viral transmission, with some states remarkably low. As more infectious variants emerge, it is critical that vaccination efforts intensify across all states and ages for which the vaccines are approved.

As of August 26, 2021, no state has reached a population level of immunity thought to be sufficient to disrupt transmission. (78% or higher), with some states having remarkably low presumed immunity.
Nitrogen partitioning between branched-chain amino acids and urea cycle enzymes sustains renal cancer progression
Authors: Sciacovelli Marco , Dugourd Aurelien , Jimenez Lorea Valcarcel , Yang Ming , Nikitopoulou Efterpi , Costa Ana S.H. , Tronci Laura , Caraffini Veronica , Rodrigues Paulo , Schmidt Christina , Ryan Dylan , Young Tim , Zecchini Vincent R. , Rossi Sabrina Helena , Massie Charlie , Lohoff Caroline , Barcon Maria Masid , Hatzimanikatis Vassily , Kuppe Christoph , Von Kriegsheim Alex , Kramann Rafael , Gnanapragasam Vincent , Warren Anne Y. , Stewart Grant D. , Erez Ayelet , Vanharanta Sakari , Saez-Rodriguez Julio , Frezza Christian
Published: September 2021

Metabolic reprogramming is critical for tumor initiation and progression. However, the exact impact of specific metabolic changes on cancer progression is poorly understood. Here, we combined multi-omics datasets of primary and metastatic clonally related clear cell renal cancer cells (ccRCC) and generated a computational tool to explore the metabolic landscape during cancer progression. We show that aVHLloss-dependent reprogramming of branched-chain amino acid catabolism is required to maintain the aspartate pool in cancer cells across all tumor stages. We also provide evidence that metastatic renal cancer cells reactivate argininosuccinate synthase (ASS1), a urea cycle enzyme suppressed in primary ccRCC, to enable invasionin vitroand metastasisin vivo. Overall, our study provides the first comprehensive elucidation of the molecular mechanisms responsible for metabolic flexibility in ccRCC, paving the way to the development of therapeutic strategies based on the specific metabolism that characterizes each tumor stage.

Highlights

Branched-chain amino acids catabolism is reprogrammed in ccRCC tumors

BCAT-dependent transamination supplies nitrogen forde novobiosynthesis of amino acids including aspartate and asparagine in ccRCC

Aspartate produced downstream of BCAT is used specifically by metastatic cells through argininosuccinate synthase (ASS1) and argininosuccinate lyase (ASL) to generate arginine, providing a survival advantage in the presence of microenvironments with rate limiting levels of arginine

ASS1 is re-expressed in metastatic 786-M1A through epigenetic remodeling and it is sensitive to arginine levels

Silencing of ASS1 impairs the metastatic potentialin vitroandin vivoof ccRCC cells
Transformation of Primary Sensory Cortical Representations from Layer 4 to Layer 2
Authors: Voelcker Bettina , Peron Simon
Published: September 2021

Sensory input arrives from thalamus in cortical layer (L) 4, from which it flows predominantly to superficial layers, so that L4 to L2 constitutes one of the earliest cortical feedforward networks. Despite extensive study, the transformation performed by this network remains poorly understood. We use two-photon calcium imaging in L2-4 of primary vibrissal somatosensory cortex (vS1) to record neural activity as mice perform an object localization task with two whiskers. We find that touch responses sparsen but become more reliable from L4 to L2, with superficial neurons responding to a broader range of touches. Decoding of sensory features either improves from L4 to L2 or remains unchanged. Pairwise correlations increase superficially, with L2/3 containing ensembles of mostly broadly tuned neurons responding robustly to touch. Thus, from L4 to L2, cortex transitions from a dense probabilistic code to a sparse and robust ensemble-based code that improves stimulus decoding, facilitating perception.
Proximity proteome mapping reveals PD-L1-dependent pathways disrupted by anti-PD-L1 antibody specifically in EGFR-mutant lung cancer cells
Authors: Letian Anudari , Lemma Eyoel Yemanaberhan , Cavaliere Paola , Dephoure Noah , Altorki Nasser K. , McGraw Timothy E.
Published: September 2021

PD-L1, a transmembrane ligand for immune checkpoint receptor PD1, has been successfully targeted to activate an anti-tumor immune response in a variety of solid tumors, including non-small cell lung cancer (NSCLC). Despite the success of targeting PD-L1, only about 20% of patients achieve a durable response. The reasons for the heterogeneity in response are not understood, although some molecular subtypes (e.g., mutant EGF receptor tumors) are generally poor responders. Although PD-L1 is best characterized as a transmembrane PD1 ligand, the emerging view is that PD-L1 has functions independent of activating PD1 signaling. It is not known whether these cell-intrinsic functions of PD-L1 are shared among non-transformed and transformed cells, if they vary among cancer molecular subtypes, or if they are impacted by anti-PD-L1 therapy. Here we use quantitative microscopy techniques and APEX2 proximity mapping to describe the behavior of PD-L1 and to identify PD-L1’s proximal proteome in human lung epithelial cells. Our data reveal growth factor control of PD-L1 recycling as a mechanism for acute and reversible regulation of PD-L1 density on the plasma membrane. In addition, we describe novel PD-L1 biology restricted to mutant EGFR cells. Anti-PD-L1 antibody treatment of mutant EGFR cells perturbs cell intrinsic PD-L1 functions, leading to reduced cell migration, increased half-life of EGFR and increased extracellular vesicle biogenesis, whereas anti-PD-L1 antibody does not induce these changes in wild type EGFR cells. These specific effects in mutant EGFR cells might contribute to the poor anti-PD-L1 response of mutant EGFR tumors.
Structural and functional characterization of Rv0792c from Mycobacterium tuberculosis: identifying small molecule inhibitors against GntR protein
Authors: Chauhan Neeraj Kumar , Anand Anjali , Sharma Arun , Dhiman Kanika , Gosain Tannu Priya , Singh Prashant , Khan Eshan , Kumar Amit , Sharma Deepak , Ashish  , Sharma Tarun Kumar , Singh Ramandeep
Published: September 2021

In order to adapt in host tissues, microbial pathogens regulate their gene expression through an array of transcription factors. Here, we have functionally characterized Rv0792c, a GntR homolog from M. tuberculosis. In comparison to the parental strain, ΔRv0792c mutant strain of M. tuberculosis was compromised for survival upon exposure to oxidative stress, cell wall agents and infection in guinea pigs. RNA-seq analysis revealed that Rv0792c regulates the expression of genes that are involved in stress adaptation and virulence of M. tuberculosis. Solution small angle X-ray scattering (SAXS) data steered model building confirmed that the C-terminal region plays a pivotal role in dimer formation. Systematic evolution of ligands by exponential enrichment resulted in identification of ssDNA aptamers that can be used as a tool to identify small molecule inhibitors targeting Rv0792c. Using SELEX and SAXS data based modelling, we identified residues essential for the DNA binding activity of Rv0792c and I-OMe-Tyrphostin as an inhibitor of Rv0792c aptamer binding activity. Taken together, we provide a detailed shape-function characterization of GntR family of transcription factors from M. tuberculosis. To the best of our knowledge, this is the first study that has resulted in the identification of small molecule inhibitors against GntR family of transcription factors from bacterial pathogens.
A Novel Mistranslating tRNA Model in Drosophila melanogaster has Diverse, Sexually Dimorphic Effects
Authors: Isaacson Joshua R. , Berg Matthew D. , Jagiello Jessica , Villén Judit , Brandl Christopher J. , Moehring Amanda J.
Published: September 2021

Transfer RNAs (tRNAs) are the adaptor molecules required for reading of the genetic code and the accurate production of proteins. tRNA variants can lead to genome-wide mistranslation, the misincorporation of amino acids not specified by the standard genetic code into nascent proteins. While genome sequencing has identified putative mistranslating tRNA variants in human populations, little is known regarding how mistranslation affects multicellular organisms. Here, we create a Drosophila melanogaster model for mistranslation by integrating a serine tRNA variant that mistranslates serine for proline (tRNASerUGG, G26A) into the fly genome. Using mass spectrometry, we find that tRNASerUGG, G26A misincorporates serine for proline at a frequency of ∼ 0.6% per codon. We find that mistranslation extends development time and decreases the number of flies that reach adulthood. Adult flies containing tRNASerUGG, G26A present with more morphological deformities and worse climbing performance than flies expressing only wild type tRNA. Female flies with the serine tRNA variant have more deformities and experience a faster decline in climbing performance than males, suggesting sex-specific effects. This model will enable studies into the synergistic effects of mistranslating tRNA variants and disease-causing alleles.
Impact of zoonotic disease outbreaks on international wildlife trade dynamics in Ghana
Authors: Bempah Godfred , Nartey Moses A. , Dakwa Kwaku B. , Messenger Kevin
Published: September 2021

Wildlife is under intense pressure from trade, which most likely contributes to zoonotic diseases. The study explores the impact of zoonotic disease outbreaks on the wildlife trade of Ghana. This study provides an in-depth analysis of the trends of taxa trade and factors that influence trade from 1975–2018 by combining zoonotic disease data with data from the CITES database. Trade flow showed that reptiles were the most traded group, followed by birds, mammals, and amphibians. Species of the families Pythonidae, Dendrobatidae, Cercopithecidae, and Psittacidae were the most traded. The decade mean number of trade for 1997–2007 was the highest (n = 62) followed by 2008–2018 (n = 54.4). Most exporter countries that traded with Ghana are from Africa and importers from the United States of America, Europe and Asia. Continuous trade in reptiles and birds, especially the endangered pythons and psittacus species, could lead to their extinction in the wild. The outbreak of zoonotic diseases influenced the dynamics of the wildlife trade in Ghana as traders shifted their activities among taxa over a period of time. Because those taxa were observed to harbour zoonotic diseases and constitute high health risks when traded. Mammals’ trade flow decreased with disease outbreaks over time, while reptiles increased. Early detection of zoonotic diseases and the adoption of an expanded education module on avoiding species capable of harbouring pathogens will most likely help reduce trade in wildlife.
Potential COVID-19 vaccination opportunities in primary care practices in the United States
Authors: Basu Sanjay , Weintraub Rebecca , Ganguli Ishani , Phillips Russell , Phillips Robert , Bitton Asaf
Published: September 2021

Rapid, widespread COVID-19 vaccination is critical to pandemic mitigation and recovery. To help policymakers interested in further enhancing primary care delivery of COVID-19 vaccines, it is important to estimate the absolute number of vaccination opportunities, and identify how these opportunities may fall disproportionately among different communities given the unequal way that COVID-19 falls upon communities of color, low-income, and rural communities. To quantify the potential benefits of greater primary care engagement in vaccination efforts, we estimated the number of potential vaccination opportunities (PVOs) in primary care in the remaining calendar months of year 2021, and the possible uptake if we supplied enough vaccine to primary care practices to fulfill their opportunities. To estimate how many potential vaccination opportunities (PVOs) may occur in primary care, we used three sets of data, analyzing the latest available waves of the following: (i) the National Ambulatory Medical Care Survey (NAMCS, 2016, N = 677 providers); (ii) the National Health Interview Survey (NHIS, 2018, N = 29,839 individuals in 29,839 households); and (iii) the Medical Expenditure Panel Survey (MEPS, 2018, N = 40,025 individuals in 14,500 households). Per the NAMCS data, which provide a nationally-representative sample of ambulatory care visits, primary care physicians normally provide 40.2 million primary care visits per month. The majority of the primary care utilization is absorbed by those aged 16 to 64 years old who are not otherwise priority groups (i.e., not having chronic diseases as defined by ACIP) but the second large group of visits are those with a chronic disease (27.2% of all visits). As compared to the NAMCS data providing an estimate of care from the perspective of providers, the overall sample in NHIS provides a view of primary care access and utilization from a population perspective. Per NHIS, 34% of the civilian US population saw a generalist physician in the prior calendar year, or 109.8 million people. Overall, we would estimate that over the latter half of calendar year 2021, approximately 15 million potential vaccine opportunities per month would be available through US primary care practices.