bluuebunny/crossref_metadata_2025 huggingface dataset:
The Use of Visible-Light Hyperspectral Imaging in Evaluating Burn Wounds: A Case Report
Authors: McCarthy Melissa , Prete Victoria Irene , Oh SeungJu , Gu Garrick , Lujan-Hernandez Jorge , Stamer Danielle , Lalikos Janice
Published: April 2021

Burn depth is a critical factor in determining the healing potential of a burn as the extent of injury ultimately guides overall treatment. Visible-Light Hyperspectral Imaging is an FDA-approved, noninvasive, and noncontrast imaging technology that uses light waves within the visible spectrum to evaluate skin and superficial soft tissue perfusion. In this case report, visible-light hyperspectral imaging was used to evaluate a 37-year-old male who presented to the Emergency Department with a thermal burn of the trunk, back, and right upper extremity. Images were taken at initial evaluation, 6 hours postinjury, and again during daily dressing changes until hospital day 5 when the patient underwent surgical debridement. In this patient, operative treatment was postponed until 89.7 hours postinjury, at which point the clinical examination showed clear visual demarcation in regions of irreversible damage. Comparatively, visible-light hyperspectral imaging analysis of the permanently injured tissue demonstrated acute but varying changes in both oxygenated hemoglobin and deoxygenated hemoglobin at the time of initial evaluation. The most dramatic change in tissue oxygenation occurred between 6.5 and 39.3 hours, demonstrating visible-light hyperspectral imaging’s ability to detect significant differences in oxygenation values between areas of second-degree superficial burns and areas of second-degree deep and third-degree burns in the acute period. The data suggest that the utilization of visible-light hyperspectral imaging in this 6.5- to 39.3-hour window may help predict final burn depth before clinical assessment, potentially allowing for surgical intervention within the first 48 hours following injury.
Cost-effectiveness analysis of enzalutamide for patients with chemotherapy-naïve metastatic castration-resistant prostate cancer in Japan
Authors: Okumura Hiroyuki , Inoue Sachie , Naidoo Shevani , Holmstrom Stefan , Akaza Hideyuki
Published: April 2021

Background

We aimed to evaluate cost-effectiveness of enzalutamide in chemotherapy-naïve metastatic castration-resistant prostate cancer patients in Japan.

Methods

A Markov model was developed to capture time spent by patients in various health states: stable, progression and death. Abiraterone acetate and docetaxel were set as active comparators. Clinical outcomes were obtained from the PREVAIL, COU-AA-302 and TAX327 trials. Treatment sequence, concomitant drugs and therapies for adverse events were estimated from responses to a survey by 14 Japanese prostate cancer experts. The analytic perspective was public healthcare payer, with a 10-year time horizon. The incremental cost-effectiveness ratio was estimated from quality-adjusted life-years and Japanese public healthcare costs. Probabilistic sensitivity analysis was performed to assess the robustness of the findings.

Results

According to the survey, the most common treatment sequences were (i) enzalutamide → docetaxel → cabazitaxel (enzalutamide-first sequencing), (ii) abiraterone → enzalutamide → docetaxel (abiraterone-first sequencing) and (iii) docetaxel→ enzalutamide → cabazitaxel (docetaxel-first sequencing). In the base-case analysis, enzalutamide-first sequencing saved 1.74 million Japanese Yen versus abiraterone-first sequencing, with a 0.129 quality-adjusted life-year gain (dominant). Enzalutamide-first sequencing had a cost increase of 4.44 million Japanese Yen over docetaxel-first sequencing, with a 0.371 quality-adjusted life-years gain. The incremental cost-effectiveness ratio of enzalutamide-first sequencing versus docetaxel-first sequencing was estimated as 11.94 million Japanese Yen/quality-adjusted life-years. Probabilistic sensitivity analyses demonstrated that, compared with abiraterone-first sequencing, enzalutamide-first sequencing had an 87.4% probability of being dominant.

Conclusions

Results modeled herein suggest that the enzalutamide-first sequencing is more cost-effective than the abiraterone-first sequencing, but less cost-effective than docetaxel-first sequencing for chemotherapy-naïve patients with metastatic castration-resistant prostate cancer.
Stalking Threat and Risk Assessment
Authors: McEwan Troy E.
Published: April 2021

Stalking poses unique challenges for those seeking to characterize, assess, and manage the risks associated with this complex behavior. The victims, perpetrators, and specific behaviors involved in stalking vary dramatically, and legal definitions of stalking offenses are specific to particular jurisdictions. This chapter provides a practical, evidence-based overview of key considerations for conducting threat and risk assessments that can inform effective management of stalking cases. It is broken into four sections, with the first highlighting key concepts and issues assessors should be aware of when responding to a stalking case. The second section discusses the nature of risk and threat in stalking situations, then provides a review of research findings about risk factors for different domains of stalking risk. The third section introduces the three extant instruments designed to guide assessment of stalking risks, and reviews research evaluating their reliability and validity, before the fourth and final section of the chapter discusses stalking threat assessment and management in the context of prior intimate partner abuse or when cyberstalking is present.
ALIGNING VIDEO-AND STRUCTURED DATA FOR IMAGING OPTIMISATION
Authors: Ivarsson Jonas , Almén Anja , Falkenberg Mårten , Lundh Charlotta , Båth Magnus
Published: April 2021

Imaging optimisation can benefit from combining structured data with qualitative data in the form of audio and video recordings. Since video is complex to work with, there is a need to find a workable solution that minimises the additional time investment. The purpose of the paper is to outline a general workflow that can begin to address this issue. What is described is a data management process comprising the three steps of collection, mining and contextualisation. This process offers a way to work systematically and at a large scale without succumbing to the context loss of statistical methods. The proposed workflow effectively combines the video and structured data to enable a new level of insights in the optimisation process.
Electrophysiological Correlates of Rodent Default-Mode Network Suppression Revealed by Large-Scale Local Field Potential Recordings
Authors: Fakhraei Leila , Francoeur Miranda , Balasubramani Pragathi P , Tang Tianzhi , Hulyalkar Sidharth , Buscher Nathalie , Mishra Jyoti , Ramanathan Dhakshin S
Published: April 2021

The default-mode network (DMN) in humans consists of a set of brain regions that, as measured with functional magnetic resonance imaging (fMRI), show both intrinsic correlations with each other and suppression during externally oriented tasks. Resting-state fMRI studies have previously identified similar patterns of intrinsic correlations in overlapping brain regions in rodents (A29C/posterior cingulate cortex, parietal cortex, and medial temporal lobe structures). However, due to challenges with performing rodent behavior in an MRI machine, it is still unclear whether activity in rodent DMN regions are suppressed during externally oriented visual tasks. Using distributed local field potential measurements in rats, we have discovered that activity in DMN brain regions noted above show task-related suppression during an externally oriented visual task at alpha and low beta-frequencies. Interestingly, this suppression (particularly in posterior cingulate cortex) was linked with improved performance on the task. Using electroencephalography recordings from a similar task in humans, we identified a similar suppression of activity in posterior cingulate cortex at alpha/low beta-frequencies. Thus, we have identified a common electrophysiological marker of DMN suppression in both rodents and humans. This observation paves the way for future studies using rodents to probe circuit-level functioning of DMN function.

Significance

Here we show that alpha/beta frequency oscillations in rats show key features of DMN activity, including intrinsic correlations between DMN brain regions, task-related suppression, and interference with attention/decision-making. We found similar task-related suppression at alpha/low beta-frequencies of DMN activity in humans.
The Association of American Medical Colleges’ Local Area Physician Workforce Modeling Project
Authors: Dill Michael J. , Hirsch Gary B.
Published: April 2021

Physician workforce planning must address multiple concerns such as having sufficient numbers and adequate geographic distribution of physicians and pressures for physicians to adapt to new models of care and payment. Though there are national workforce planning tools, planning tools for local areas have been scarce. This article describes a dynamic simulation model developed as a pilot project to support physician workforce planning in 2 metropolitan areas, Cleveland and Albuquerque (February 2014–June 2016). This model serves as a prototype for planning tools that could be used by medical educators and local health systems to project the effect of different policies on physician supply and demand.

System dynamics and group model building approaches were used to develop the model with the participation of local stakeholders to create the model’s causal structure. The model included determinants of the demand for primary and specialty care for the local population and projected the effects of births and deaths, aging, level of chronic illness present, and migration on demand. Physician supply was disaggregated by primary versus specialty care, age, sex, and work setting and projected based on completions of local residency programs, physician migration in and out of the area, and retirements. Feedback relationships between supply and demand (e.g., adequacy of care affecting the distribution of chronic illnesses, demand for care influencing in- and out-migration of physicians) were also included and had important effects on the results produced by the model.

Scenarios were simulated that projected increased demand for care (e.g., through expanded insurance coverage) and increased supply (e.g., through practice incentives to encourage in-migration) and a combination of these. An expanded advanced practice registered nurse and physician assistant capacity scenario was also simulated. In Albuquerque, the combination scenario yielded the greatest increases in local physician supply.
Pathophysiology and Treatment of Malignant Hyperthermia
Authors: Gregory Haili , Weant Kyle A.
Published: April 2021

Malignant hyperthermia (MH) is caused by a genetic disorder of the skeletal muscle that induces a hypermetabolic response when patients are exposed to a triggering agent such as volatile inhaled anesthetics or depolarizing neuromuscular blockers. Symptoms of MH include increased carbon dioxide production, hyperthermia, muscle rigidity, tachypnea, tachycardia, acidosis, hyperkalemia, and rhabdomyolysis. Common scenarios for triggering agents are those used are during surgery and rapid sequence intubation. Hypermetabolic symptoms have a rapid onset; hence, prompt recognition and treatment are vital to prevent morbidity and mortality. The first-line treatment agent for an MH response is dantrolene. Further treatment includes managing complications related to a hypermetabolic response such as hyperkalemia and arrhythmias. This review is focused on the recognition and treatment considerations of MH in the emergency department to optimize therapy and improve patient morbidity and mortality.
The effect of resource limitation on the temperature dependence of mosquito population fitness
Authors: Huxley Paul J. , Murray Kris A. , Pawar Samraat , Cator Lauren J.
Published: April 2021

Laboratory-derived temperature dependencies of life-history traits are increasingly being used to make mechanistic predictions for how climatic warming will affect vector-borne disease dynamics, partially by affecting abundance dynamics of the vector population. These temperature–trait relationships are typically estimated from juvenile populations reared on optimal resource supply, even though natural populations of vectors are expected to experience variation in resource supply, including intermittent resource limitation. Using laboratory experiments on the mosquito
Aedes aegypti
, a principal arbovirus vector, combined with stage-structured population modelling, we show that low-resource supply in the juvenile life stages significantly depresses the vector's maximal population growth rate across the entire temperature range (22–32°C) and causes it to peak at a lower temperature than at high-resource supply. This effect is primarily driven by an increase in juvenile mortality and development time, combined with a decrease in adult size with temperature at low-resource supply. Our study suggests that most projections of temperature-dependent vector abundance and disease transmission are likely to be biased because they are based on traits measured under optimal resource supply. Our results provide compelling evidence for future studies to consider resource supply when predicting the effects of climate and habitat change on vector-borne disease transmission, disease vectors and other arthropods.
Single-cell multi-omics analysis reveals IFN-driven alterations in T lymphocytes and natural killer cells in systemic lupus erythematosus
Authors: Trzupek Dominik , Lee Mercede , Hamey Fiona , Wicker Linda S. , Todd John A. , Ferreira Ricardo C.
Published: April 2021

Background

The characterisation of the peripheral immune system in the autoimmune disease systemic lupus erythematosus (SLE) at the single-cell level has been limited by the reduced sensitivity of current whole-transcriptomic technologies. Here we employ a targeted single-cell multi-omics approach, combining protein and mRNA quantification, to generate a high-resolution map of the T lymphocyte and natural killer (NK) cell populations in blood from SLE patients.

Methods

We designed a custom panel to quantify the transcription of 534 genes in parallel with the expression of 51 surface protein targets using the BD Rhapsody AbSeq single-cell system. We applied this technology to profile 20,656 T and NK cells isolated from peripheral blood from an SLE patient with a type I interferon (IFN)-induced gene expression signature (IFNhi), and an age- and sex- matched IFNlow SLE patient and healthy donor.

Results

We confirmed the presence of a rare cytotoxic CD4+ T cell (CTL) subset, which was exclusively present in the IFNhi patient. Furthermore, we identified additional alterations consistent with increased immune activation in this patient, most notably a shift towards terminally differentiated CD57+ CD8+ T cell and CD16+ NKdim phenotypes, and the presence of a subset of recently-activated naïve CD4+ T cells.

Conclusions

Our results identify IFN-driven changes in the composition and phenotype of T and NK cells that are consistent with a systemic immune activation within the IFNhi patient, and underscore the added resolving power of this multi-omics approach to identify rare immune subsets. Consequently, we were able to find evidence for novel cellular peripheral biomarkers of SLE disease activity, including a subpopulation of CD57+ CD4+ CTLs.
A feasibility trial of a digital mindfulness-based intervention to improve asthma-related quality of life for primary care patients with asthma
Authors: Ainsworth Ben , Stanescu Sabina , Stuart Beth , Russell Daniel , Liddiard Megan , Djukanovic Ratko , Thomas Mike
Published: April 2021

Objective

Asthma outcomes remain suboptimal, despite effective pharmacotherapy. Psychological dysfunction (such as anxiety) is common, and associated with poorer outcomes. We evaluated a digital mindfulness programme as an intervention to improve asthma-related quality of life for primary care patients, in a prospectively registered randomized-controlled feasibility study.

Methods

We offered ‘Headspace’, a widely-used digital mindfulness intervention, to adults with asthma through 16 UK GP practices. Participants were randomised on a 2:1 basis to the mindfulness intervention, or waitlist control. Participants completed questionnaires (including asthma symptom control, asthma-related quality of life, anxiety, depression) at baseline, 6-week and 3-month follow-up.

Results

114 participants completed primary outcomes at 3-month follow-up (intervention 73 (71.6%), control 41 (70.7%)). Compared to baseline, the intervention group but not the control group reported significantly improved asthma-related quality of life, with a non-significant between-group difference favouring the intervention group (Mean difference = 0.16, 95%CI: - 0.11 – 0.44). Intervention use varied but was generally high.

Conclusions

Digital mindfulness interventions are feasible and acceptable adjunct treatments for mild and moderate asthma to target quality of life. Further research should adapt ‘generic’ mindfulness-based stress-reduction to maximize effectiveness for asthma, and validate our findings in a fully-powered randomized controlled trial.

Trial registration

Prospectively registered: ISRCTN52212323
PodoCount: A robust, fully automated whole-slide podocyte quantification tool
Authors: Santo Briana A. , Govind Darshana , Daneshpajouhnejad Parnaz , Yang Xiaoping , Wang Xiaoxin X. , Myakala Komuraiah , Jones Bryce A. , Levi Moshe , Kopp Jeffrey B. , Niedernhofer Laura J. , Manthey David , Moon Kyung Chul , Han Seung Seok , Rosenberg Avi Z. , Sarder Pinaki
Published: April 2021

Background

Podocyte depletion is an established indicator of glomerular injury and predicts clinical outcomes. The semi-quantitative nature of existing podocyte estimation methods or podometrics hinders incorporation of such analysis into experimental and clinical pathologic workflows. Computational image analysis offers a robust approach to automate podometrics through objective quantification of cell and tissue structure. Toward this goal, we developed PodoCount, a computational tool for quantitative analysis of podocytes, and validated the generalizability of the tool across a diverse dataset.

Methods

Podocyte nuclei and glomerular boundaries were labeled in murine whole kidney sections,n= 135, from six disease models and human kidney biopsies,n= 45, from diabetic nephropathy (DN) patients. Digital whole slide images (WSIs) of tissues were then acquired. Classical image analysis was applied to obtain podocyte nuclear and glomerular morphometrics. Statistically significant morphometric features, which correlated with each murine disease, were identified. Engineered features were also assessed for their ability to predict outcomes in human DN.PodoCounthas been disbursed for other researchers as an open-source, cloud-based computational tool.

Results

PodoCountoffers highly accurate quantification of podocytes. Engineered podometric features were benchmarked against routine glomerular histopathology and were found to be significant predictors of disease diagnosis, proteinuria level, and clinical outcomes.

Conclusions

PodoCountoffers high quantification performance in diverse murine disease models as well as in human DN. Resultant podometric features offers significant correlation with associated metadata as well as outcome. Our cloud-based end-user tool will provide a standardized approach for podometric analysis from gigapixel size WSIs in basic research and clinical practice.
Transcriptomic encoding of sensorimotor transformation in the midbrain
Authors: Xie Zhiyong , Wang Mengdi , Liu Zeyuan , Shang Congping , Zhang Changjiang , Sun Le , Gu Huating , Ran Gengxin , Pei Qing , Ma Qiang , Huang Meizhu , Zhang Junjing , Zhang Jiyao , Zhao Miao , Wu Qian , Cao Peng , Wang Xiaoqun
Published: April 2021

Sensorimotor transformation, a process that converts sensory stimuli into motor actions, is critical for the brain to initiate behaviors. Although the circuitry involved in sensorimotor transformation has been well delineated, the molecular logic behind this process remains poorly understood. Here, we performed high-throughput and circuit-specific single-cell transcriptomic analyses of neurons in the superior colliculus (SC), a midbrain structure implicated in early sensorimotor transformation. We found that SC neurons in distinct laminae express discrete marker genes. Of particular interest, Cbln2 and Pitx2 are key markers that define glutamatergic projection neurons in the optic nerve (Op) and intermediate gray (InG) layers, respectively. The Cbln2+ neurons responded to visual stimuli mimicking cruising predators, while the Pitx2+ neurons encoded prey-derived vibrissal tactile cues. By forming distinct input and output connections with other brain areas, these neuronal subtypes independently mediate behaviors of predator avoidance and prey capture. Our results reveal that, in the midbrain, sensorimotor transformation for different behaviors may be performed by separate circuit modules that are molecularly defined by distinct transcriptomic codes.
The inhibition of Macrophage Migration Inhibitory Factor by ISO-1 attenuates trauma-induced multi organ dysfunction in rats
Authors: Martin Lukas , Patel Nikita Mayur , Yamada Noriaki , Borges Oliveira Filipe Rodolfo Moreira , Stiehler Lara , Zechendorf Elisabeth , Hinkelmann Daniel , Kraemer Sandra , Stoppe Christian , Collino Massimo , Collotta Debora , Alves Gustavo Ferreira , Ramos Hanna Pillmann , Sordi Regina , Marzi Ingo , Relja Borna , Marx Gernot , Thiemermann Christoph
Published: April 2021

Background

Multi organ dysfunction syndrome caused by systemic inflammation after trauma is responsible for a high number of deaths worldwide. The cytokine Migration Inhibitory Factor (MIF) is recognized as a modulator of inflammatory response, however, its role in trauma is unknown. The aim of this study was to investigate (a) the levels of MIF in serum of trauma patients and of rats after hemorrhagic shock, (b) the potential of the MIF tautomerase activity inhibitor ISO-1 to reduce multi organ dysfunction syndrome in an acute and chronic hemorrhagic shock rat model and (c) whether treatment with ISO-1 attenuates NF-κB and NLRP3 activation in hemorrhagic shock.

Methods

The serum MIF-levels in trauma patients and rats with hemorrhagic shock were measured by Enzyme-Linked Immunosorbent Assays. Acute and chronic hemorrhagic shock rat models were performed to determine the influence of ISO-1 on multi organ dysfunction syndrome. The activation of NF-κB and NLRP3 pathways were analyzed by western blot.

Results

We demonstrated that (a) MIF levels are increased in serum of trauma patients on arrival in the emergency room and in serum of rats after hemorrhagic shock, (b) hemorrhagic shock caused organ damage and low blood pressure (after resuscitation) in rats, while (c) treatment of hemorrhagic shock rats with ISO-1 attenuated organ injury and dysfunction in acute and chronic hemorrhagic shock rat models and (d) decreased the activation of NF-κB and NLRP3 pathways.

Conclusion

Our results point to a role of MIF in the pathophysiology of the organ injury and dysfunction caused by trauma/hemorrhage and indicate that MIF tautomerase activity inhibitors may have potential in the therapy of the multi organ dysfunction syndrome after trauma and/or hemorrhage.
Pyridostigmine in the treatment of adults with severe SARS-CoV-2 infection (PISCO): a randomised, double-blinded, phase 2/3, placebo-controlled trial
Authors: Fragoso-Saavedra Sergio , Núñez Isaac , Audelo-Cruz Belem M. , Arias-Martínez Sarahi , Manzur-Sandoval Daniel , Quintero-Villegas Alejandro , Benjamín García-González H. , Carbajal-Morelos Sergio L. , de León-Rosales Sergio Ponce , Gotés-Palazuelos José , Maza-Larrea José A. , Caro-Vega Yanink , Batina Isabella , Islas-Weinstein León , Iruegas-Nunez David A. , Calva Juan J. , Belaunzarán-Zamudio Pablo F. , Sierra-Madero Juan , Crispín José C. , Valdés-Ferrer Sergio I.
Published: April 2021

Background

Hospitalised patients with severe COVID-19 have an increased risk of developing acute respiratory distress syndrome (ARDS) and death from severe systemic inflammatory response. Acetylcholine modulates the acute inflammatory response through a neuro-immune mechanism known as the inflammatory reflex. Pyridostigmine, an acetylcholine-esterase inhibitor, increases the half-life of endogenous ACh, reducing lung and systemic inflammation in murine sepsis. This trial aimed to evaluate whether pyridostigmine could decrease invasive mechanical ventilation (IMV) and death in patients with severe COVID-19.

Methods

We performed a parallel-group, multicentre, double-blinded, placebo-controlled, randomised clinical trial in two COVID-19-designated hospitals in Mexico City, Mexico. Adult (≥ 18-year-old), hospitalised patients with confirmed SARS-CoV-2 infection based on a positive RT-PCR test in a respiratory specimen, a computed tomography compatible with pneumonia, as well as requiring supplementary oxygen were included. Patients were randomly assigned (1:1) to receive oral pyridostigmine (60 mg per day) or placebo for a maximum of 14 days. The intention-to-treat analysis included all the patients who underwent randomisation. The primary endpoint was the composite outcome of initiation of IMV and 28-day all-cause mortality. The trial is registered in ClinicalTrials.gov, NCT04343963.

Findings

Between May 5, 2020, and Jan 29, 2021,188 participants were randomly assigned to placebo (n=94) or pyridostigmine (n=94). The composite outcome occurred in 22 (23·4%) vs. 11 (11·7%) participants, respectively (hazard ratio 0·46, 95% CI 0·22-0·96, p=0·03). The most frequent adverse event was diarrhoea (5 [5·3%] in the pyridostigmine group vs 3 [3·2%] in the placebo group). Most of the adverse events were mild to moderate, with no serious adverse events related to pyridostigmine.

Interpretation

Our data indicates that the addition of pyridostigmine to standard treatment reduces significantly the fatality rate among patients hospitalized for severe COVID-19.

Funding

Consejo Nacional de Ciencia y Tecnología, México.
Capturing site-to-site variability through Hierarchical Bayesian calibration of a process-based dynamic vegetation model
Authors: Fer Istem , Shiklomanov Alexey , Novick Kimberly A. , Gough Christopher M. , Altaf Arain M. , Chen Jiquan , Murphy Bailey , Desai Ankur R. , Dietze Michael C.
Published: April 2021

Process-based ecosystem models help us understand and predict ecosystem processes, but using them has long involved a difficult choice between performing data- and labor-intensive site-level calibrations or relying on general parameters that may not reflect local conditions. Hierarchical Bayesian (HB) calibration provides a third option that frees modelers from assuming model parameters to be completely generic or completely site-specific and allows a formal distinction between prediction at known calibration sites and “out-of-sample” prediction to new sites. Here, we compare calibrations of a process-based dynamic vegetation model to eddy-covariance data across 12 temperate deciduous Ameriflux sites fit using either site-specific, joint cross-site, or HB approaches. To be able to apply HB to computationally demanding process-based models we introduce a novel emulator-based HB calibration tool, which we make available through the PEcAn community cyberinfrastructure. Using these calibrations to make predictions at held-out tower sites, we show that the joint cross-site calibration is falsely over-confident because it neglects parameter variability across sites and therefore underestimates variance in parameter distributions. By showing which parameters show high site-to-site variability, HB calibration also formally gives us a structure that can detect which process representations are missing from the models and prioritize errors based on the magnitude of the associated uncertainty. For example, in our case-study, we were able to identify large site-to-site variability in the parameters related to the temperature responses of respiration and photosynthesis, associated with a lack of thermal acclimation and adaptation in the model. Moving forward, HB approaches present important new opportunities for statistical modeling of the spatiotemporal variability in modeled parameters and processes that yields both new insights and improved predictions.
LPMO-oxidized cellulose oligosaccharides evoke immunity in Arabidopsis conferring resistance towards necrotrophic fungusB. cinerea
Authors: Zarattini Marco , Corso Massimiliano , Kadowaki Marco Antonio , Monclaro Antonielle , Magri Silvia , Milanese Irma , Jolivet Sylvie , de Godoy Mariana Ortiz , Hermans Christian , Fagard Mathilde , Cannella David
Published: April 2021

Lytic Polysaccharide Monooxygenases (LPMOs) are powerful redox enzymes able to oxidatively cleave cellulose polymers. Widely conserved across biological kingdoms, LPMOs of the AA9 family are deployed by phytopathogens during necrotrophic attack of plant cell wall. In response, plants have evolved sophisticated mechanisms to sense cell wall damage and thus self-triggering Damage Triggered Immunity (DTI) responses. Here, we show that Arabidopsis plants exposed to LPMO products responds by activating the innate immunity ultimately leading to increased resistance to pathogenic fungus Botrytis cinerea. We demonstrated with microarray hybridization that plants undergo a deep transcriptional reprogramming upon elicitation with AA9 derived cellulose- or cello-oligosaccharides (AA9_COS). To decipher the specific effects of native and oxidized LPMO-generated cello-oligosaccharides, a pairwise comparison with cellobiose, the smallest non-oxidized unit constituting cellulose, is presented. Moreover, we identified two leucine-rich repeat receptor-like kinases, namely STRESS INDUCED FACTOR 2 and 4, playing a crucial role in signaling the AA9_COS-dependent responses such as camalexin production. We observed an increased production of ethylene, jasmonic and salicylic acid hormones, and finally deposition of callose in cell wall. Collectively, our data reveal that LPMOs might play a crucial role in plant-pathogen interactions.
Loss of SORCS2 is associated with neuronal DNA double-strand breaks
Authors: Gospodinova Katerina O. , Olsen Ditte , Kaas Mathias , Anderson Susan M. , Phillips Jonathan , Walker Rosie M. , Bermingham Mairead L. , Payne Abigail L. , Giannopoulos Panagiotis , Pandya Divya , Spires-Jones Tara L. , Abbott Catherine M. , Porteous David J. , Glerup Simon , Evans Kathryn L.
Published: April 2021

SORCS2 is one of five proteins that constitute the Vps10p-domain receptor family. Members of this family play important roles in cellular processes linked to neuronal survival, differentiation and function. Genetic and functional studies implicate SORCS2 in cognitive function, as well as in neurodegenerative and psychiatric disorders. DNA damage and DNA repair deficits are linked to ageing and neurodegeneration, and transient neuronal DNA double-strand breaks (DSBs) also occur as a result of neuronal activity. Here, we report a novel role for SORCS2 in DSB formation. We show that SorCS2 loss is associated with elevated DSB levels in the mouse dentate gyrus and that knocking outSORCS2in a human neuronal cell line increased Topoisomerase IIβ-dependent DSB formation and reduced neuronal viability. Neuronal stimulation had no impact on levels of DNA breaksin vitro, suggesting that the observed differences may not be the result of aberrant neuronal activity in these cells. Our findings are consistent with studies linking the VPS10 receptors and DNA damage to neurodegenerative conditions.
Differential tracking of linguistic vs. mental state content in naturalistic stimuli by language and Theory of Mind (ToM) brain networks
Authors: Paunov Alexander M. , Blank Idan A. , Jouravlev Olessia , Mineroff Zachary , Gallée Jeanne , Fedorenko Evelina
Published: April 2021

Language and social cognition, especially the ability to reason about mental states, known as Theory of Mind (ToM), are deeply related in development and everyday use. However, whether these cognitive faculties rely on distinct, overlapping, or the same mechanisms remains debated. Some evidence suggests that, by adulthood, language and ToM draw on largely distinct—though plausibly interacting—cortical networks. However, the broad topography of these networks is similar, and some have emphasized the importance of social content / communicative intent in the linguistic signal for eliciting responses in the language areas. Here, we combine the power of individual-subjects functional localization with the naturalistic-cognition inter-subject correlation approach to illuminate the language-ToM relationship. Using fMRI, we recorded neural activity as participants (n=43) listened to stories and dialogs with mental state content (+linguistic, +ToM), viewed silent animations and live action films with mental state content but no language (-linguistic, +ToM), or listened to an expository text (+linguistic, -ToM). The ToM network robustly tracked stimuli rich in mental state information regardless of whether mental states were conveyed linguistically or non-linguistically, while tracking a +linguistic/-ToM stimulus only weakly. In contrast, the language network tracked linguistic stimuli more strongly than a) non-linguistic stimuli, and than b) the ToM network, and showed reliable tracking even for the linguistic condition devoid of mental state content. These findings suggest that in spite of their indisputably close links, language and ToM dissociate robustly in their neural substrates—and thus plausibly cognitive mechanisms—including during the processing of rich naturalistic materials.
Bioremediation of industrial pollutants by insects expressing a fungal laccase
Authors: Clark Michael , Tepper Kate , Petroll Kerstin , Kumar Sheemal , Sunna Anwar , Maselko Maciej
Published: April 2021

Inadequate management of household and industrial wastes pose major challenges to human and environmental health. Advances in synthetic biology may help address these challenges by engineering biological systems to perform new functions such as biomanufacturing of high-value compounds from low-value waste streams and bioremediation of industrial pollutants. The current emphasis on microbial systems for biomanufacturing, which often require highly pre-processed inputs and sophisticated infrastructure, is not feasible for many waste streams. Concerns about transgene biocontainment have limited the release of engineered microbes or plants for bioremediation. Engineering animals may provide opportunities for utilizing various waste streams that are not suitable for microbial biomanufacturing while effective transgene biocontainment options should enablein situbioremediation. Here, we engineer the model insectDrosophila melanogasterto express a functional laccase from the fungusTrametes trogii. Laccase expressing flies reduced concentrations of the endocrine disruptor bisphenol A by more than 50% when present in their growth media. A lyophilized powder made from engineered adult flies retained substantial enzymatic activity, degrading more than 90% of bisphenol A and the textile dye indigo carmine in aqueous solutions. Our results demonstrate that transgenic animals may be used to bioremediate environmental contaminantsin vivoand serve as novel production platforms for industrial enzymes. These results support further development of insects, and possibly other animals, as bioproduction platforms and their potential use in bioremediation.
Will Current Protected Areas Harbour Refugia for Threatened Arctic Vegetation Types until 2050?
Authors: Chacko Merin Reji , Goerens Ariane K.A. , Oehri Jacqueline , Plekhanova Elena , Schaepman-Strub Gabriela
Published: April 2021

Arctic vegetation is crucial for fauna and the livelihoods of Northern peoples, and tightly linked to climate, permafrost soils, and water. Yet, a comprehensive understanding of climate change effects on Arctic vegetation is lacking. Protected areas cannot halt climate change, but could reduce future pressure from additional drivers, such as land use change and local industrial pollution. Therefore, it is crucial to understand the contribution of protected areas in safeguarding threatened Arctic vegetation types. We compare the 2003 baseline with existing 2050 predictions of circumpolar Arctic vegetation type distributions and demonstrate an overrepresentation of dominant and underrepresentation of declining vegetation types within protected areas. According to IUCN criteria, five of eight assessed vegetation types were classified as threatened by 2050. Potential climate change refugia, areas with the highest potential for safeguarding threatened vegetation types, were also identified. This study provides an essential first step to assessing vegetation type vulnerability based on predictions covering 46% of Arctic landscapes. The co-development of new protective measures by policymakers and indigenous peoples at a pan-Arctic scale requires more robust and spatially complete vegetation prediction, as increasing pressures from resource exploration and infrastructure development threaten the sustainable development of the rapidly thawing and greening Arctic.
Testing the adaptive walk model of gene evolution
Authors: Moutinho Ana Filipa , Eyre-Walker Adam , Dutheil Julien Y.
Published: April 2021

Understanding the dynamics of species adaptation to their environments has long been a central focus of the study of evolution. Theories of adaptation propose that populations evolve by “walking” in a fitness landscape. This “adaptive walk” is characterised by a pattern of diminishing returns, where populations further away from their fitness optimum take larger steps than those closer to their optimal conditions. Hence, we expect young genes to evolve faster and experience mutations with stronger fitness effects than older genes because they are further away from their fitness optimum. Testing this hypothesis, however, constitutes an arduous task. Young genes are small, encode proteins with a higher degree of intrinsic disorder, are expressed at lower levels, and are involved in species-specific adaptations. Since all these factors lead to increased protein evolutionary rates, they could be masking the effect of gene age. While controlling for these factors, we used population genomic datasets ofArabidopsisandDrosophilaand estimated the rate of adaptive substitutions across genes from different phylostrata. We found that a gene’s evolutionary age significantly impacts the molecular rate of adaptation. Moreover, we observed that substitutions in young genes tend to have larger physicochemical effects. Our study, therefore, provides strong evidence that molecular evolution follows an adaptive walk model across a large evolutionary timescale.
Five years of GenoTyphi: updates to the globalSalmonellaTyphi genotyping framework
Authors: Dyson Zoe A. , Holt Kathryn E.
Published: April 2021

In 2016 a whole genome sequence (WGS) based genotyping framework (GenoTyphi) was developed providing a phylogenetically informative nomenclature for lineages ofSalmonellaTyphi, the aetiological agent of typhoid fever. Subsequent surveillance studies have revealed additional epidemiologically important subpopulations, necessitating the definition of new genotypes and extension of associated software to facilitate the detection of antimicrobial resistance (AMR) mutations. Analysis of 4,632 WGS provide an updated overview of the globalS.Typhi population structure and genotyping framework, revealing the widespread nature of H58 (4.3.1) genotypes and the diverse range of genotypes carrying AMR mutations.
Selective neural coding of object, feature, and geometry spatial cues in humans
Authors: Ramanoël Stephen , Durteste Marion , Bizeul Alice , Ozier-Lafontaine Anthony , Bécu Marcia , Sahel José-Alain , Habas Christophe , Arleo Angelo
Published: April 2021

Orienting in space requires the processing and encoding of visual spatial cues. The dominant hypothesis about the brain structures mediating the coding of spatial cues stipulates the existence of a hippocampal-dependent system for the representation of geometry and a striatal-dependent system for the representation of landmarks. However, this dual-system hypothesis is based on paradigms that presented spatial cues conveying either conflicting or ambiguous spatial information and that amalgamated the concept of landmark into both discrete 3D objects and wall features. These confounded designs introduce difficulties in interpreting the spatial learning process. Here, we test the hypothesis of a complex interaction between the hippocampus and the striatum during landmark and geometry visual coding in humans. We also postulate that object-based and feature-based navigation are not equivalent instances of landmark-based navigation as currently considered in human spatial cognition. We examined the neural networks associated with geometry-, object-, and feature-based spatial navigation in an unbiased, two-choice behavioral paradigm using fMRI. We showed evidence of a synergistic interaction between hippocampal and striatal coding underlying flexible navigation behavior. The hippocampus was involved in all three types of cue-based navigation, whereas the striatum was more strongly recruited in the presence of geometric cues than object or feature cues. We also found that unique, specific neural signatures were associated with each spatial cue. Critically, object-based navigation elicited a widespread pattern of activity in temporal and occipital regions relative to feature-based navigation. These findings challenge and extend the current view of a dual, juxtaposed hippocampal-striatal system for visual spatial coding in humans. They also provide novel insights into the neural networks mediating object vs. feature spatial coding, suggesting a need to distinguish these two types of landmarks in the context of human navigation.

Highlights

Complex hippocampal-striatal interaction during visual spatial coding for flexible human navigation behavior.

Distinct neural signatures associated with object-, feature-, and geometry-based navigation.

Object- and feature-based navigation are not equivalent instances of landmark-based navigation.
Met-signaling Controls Dendritic Cell Migration by Regulating Podosome Formation and Function
Authors: Hamouda Ahmed E.I. , Schalla Carmen , Sechi Antonio , Zenke Martin , Hieronymus Thomas
Published: April 2021

Signaling by the HGF receptor/Met in skin-resident Langerhans cells (LC) and dermal dendritic cells (dDC) is essential for their emigration toward draining lymph nodes upon inflammation-induced activation. Here we addressed the role of Met-signaling in distinct steps of LC/dDC emigration from skin by employing a conditional Met-deficient mouse model (Metflox/flox). We found that Met deficiency severely impaired podosome formation in DC and concomitantly decreased proteolytic degradation of gelatin. Accordingly, Met-deficient LC failed to efficiently cross the extracellular matrix (ECM) rich basement membrane between epidermis and dermis. We further observed that Met-signaling by HGF reduced adhesion of bone marrow-derived LC to various ECM factors and enhanced the motility of Met-signaling competent DC in a 3D collagen matrix, which was not the case for Met-deficient LC/DC. We found no impact of Met-signaling on the integrin-independent amoeboid migration of DC in response to the CCR7 chemokine CCL19. Collectively, our data show that the Met-signaling pathway regulates the migratory properties of DC in HGF-dependent and HGF-independent manners.
Structural basis of the P4B ATPase lipid flippase activity
Authors: Bai Lin , Jain Bhawik K. , You Qinglong , Duan H. Diessel , Graham Todd R. , Li Huilin
Published: April 2021

P4 ATPases are lipid flippases that are phylogenetically grouped into P4A, P4B and P4C clades. The P4A ATPases are heterodimers composed of a catalytic α-subunit and accessory β-subunit, and the structures of several heterodimeric flippases have been reported. TheS. cerevisiaeNeo1 and its orthologs represent the P4B ATPases, which function as monomeric flippases without a β-subunit. It has been unclear whether monomeric flippases retain the architecture and transport mechanism of the dimeric flippases. Here we report the first structure of a P4B ATPase, Neo1, in its E1-ATP, E2P-transition, and E2P states. The structure reveals a conserved architecture as well as highly similar functional intermediate states relative to dimeric flippases. Consistently, structure-guided mutagenesis of residues in the proposed substrate translocation path disrupted Neo1’s ability to establish membrane asymmetry. These observations indicate that evolutionarily distant P4 ATPases use a structurally conserved mechanism for substrate transport.
Validation of predicted anonymous proteins simply using Fisher’s exact test
Authors: Claverie Jean-Michel , Santini Sébastien
Published: April 2021

Motivation

Genomes sequencing has become the primary (and often the sole) experimental method to characterize newly discovered organisms, in particular from the microbial world (bacteria, archaea, viruses). This generates an ever increasing number of predicted proteins the existence of which is unwarranted, in particular among those without homolog in model organisms. As a last resort, the computation of the selection pressure from pairwise alignments of the corresponding “Open Reading Frames” (ORFs) can be used to validate their existences. However, this approach is error-prone, as not usually associated with a significance test.

Results

We introduce the use of the straightforward Fisher’s exact test as a post processing of the results provided by the popular CODEML sequence comparison software. The respective rates of nucleotide changes at the non-synonymous vs. synonymous position (as determined by CODEML), are turned into entries into a 2×2 contingency table, the probability of which is computed under the Null hypothesis that they should not behave differently if the ORFs do not encode actual proteins. Using the genome sequences of two recently isolated giant viruses, we show that strong negative selection pressures do not always provide a solid argument in favor of the existence of proteins.

Contact

Jean-Michel.Claverie@univ-amu.fr