Single-cell RNA sequencing uncovers the nuclear decoy lincRNA PIRAT as a regulator of systemic monocyte immunity during COVID-19.

The systemic immune response to viral infection is shaped by master transcription factors, such as NF-κB, STAT1, or PU.1. Although long noncoding RNAs (lncRNAs) have been suggested as important regulators of transcription factor activity, their contributions to the systemic immunopathologies observed during SARS-CoV-2 infection have remained unknown. Here, we employed a targeted single-cell RNA sequencing approach to reveal lncRNAs differentially expressed in blood leukocytes during severe COVID-19. Our results uncover the lncRNA PIRAT (PU.1-induced regulator of alarmin transcription) as a major PU.1 feedback-regulator in monocytes, governing the production of the alarmins S100A8/A9, key drivers of COVID-19 pathogenesis. Knockout and transgene expression, combined with chromatin-occupancy profiling, characterized PIRAT as a nuclear decoy RNA, keeping PU.1 from binding to alarmin promoters and promoting its binding to pseudogenes in naïve monocytes. NF-κB-dependent PIRAT down-regulation during COVID-19 consequently releases a transcriptional brake, fueling alarmin production. Alarmin expression is additionally enhanced by the up-regulation of the lncRNA LUCAT1, which promotes NF-κB-dependent gene expression at the expense of targets of the JAK-STAT pathway. Our results suggest a major role of nuclear noncoding RNA networks in systemic antiviral responses to SARS-CoV-2 in humans.

Life Cycle Economic and Environmental Assessment of Producing Synthetic Jet Fuel Using CO2/Biomass Feedstocks.

The aviation industry is responsible for over 2% of global CO2 emissions. Synthetic jet fuels generated from biogenic feedstocks could help reduce life cycle greenhouse gas (GHG) emissions compared to petroleum-based fuels. This study assesses three processes for producing synthetic jet fuel via the synthesis of methanol using water and atmospheric CO2 or biomass. A life cycle assessment and cost analysis are conducted to determine GHG emissions, energy demand, land occupation, water depletion, and the cost of producing synthetic jet fuel in Switzerland. The results reveal that the pathway that directly hydrogenates CO2 to methanol exhibits the largest reductions in terms of GHG emission (almost 50%) compared to conventional jet fuel and the lowest production cost (7.86 EUR kgJF-1); however, its production cost is currently around 7 times higher than the petroleum-based counterpart. Electrical energy was found to be crucial in capturing CO2 and converting water into hydrogen, with the sourcing and processing of the feedstocks contributing to 79% of the electric energy demand. Furthermore, significant variations in synthetic jet fuel cost and GHG emissions were shown when the electricity source varies, such as utilizing grid electricity pertaining to different countries with distinct electricity mixes. Thus, upscaling synthetic jet fuels requires energy-efficient supply chains, sufficient feedstock, large amounts of additional (very) low-carbon energy capacity, suitable climate policy, and comprehensive environmental analyses.

Cerebral baylisascariosis in a rainbow lorikeet (Trichoglossus moluccanus) in a German Zoo.

BACKGROUND: The raccoon roundworm, Baylisascaris procyonis, can cause a meningoencephalitis as neural larva migrans which is known in avian species, including rainbow lorikeets in North America, but has not been described in Old World parrots in Germany yet. CASE PRESENTATION: A 2-month-old, male rainbow lorikeet from a zoo in Germany was submitted for necropsy. Prior to death the animal had progressive neurological signs like apathy and torticollis. In the cerebrum a focally extensive severe granulomatous to necrotizing encephalitis with an intralesional larval nematode was diagnosed. Based on the clinical and pathological findings, the larval morphology and the epidemiological background, the larva was identified as Baylisascaris procyonis. CONCLUSIONS: Cerebral baylisascariosis should be considered as a differential diagnosis in zoo and pet birds with neurological signs having contact to racoons or rather racoon faeces in Germany due to the high prevalence of Baylisascaris procyonis in the German raccoon population.

IL-17A-producing CD8+ T cells promote PDAC via induction of inflammatory cancer-associated fibroblasts.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is characterised by an abundant desmoplastic stroma composed of cancer-associated fibroblasts (CAF) and interspersed immune cells. A non-canonical CD8+ T-cell subpopulation producing IL-17A (Tc17) promotes autoimmunity and has been identified in tumours. Here, we evaluated the Tc17 role in PDAC. DESIGN: Infiltration of Tc17 cells in PDAC tissue was correlated with patient overall survival and tumour stage. Wild-type (WT) or Il17ra-/- quiescent pancreatic stellate cells (qPSC) were exposed to conditional media obtained from Tc17 cells (Tc17-CM); moreover, co-culture of Tc17-CM-induced inflammatory (i)CAF (Tc17-iCAF) with tumour cells was performed. IL-17A/F-, IL-17RA-, RAG1-deficient and Foxn1nu/nu mice were used to study the Tc17 role in subcutaneous and orthotopic PDAC mouse models. RESULTS: Increased abundance of Tc17 cells highly correlated with reduced survival and advanced tumour stage in PDAC. Tc17-CM induced iCAF differentiation as assessed by the expression of iCAF-associated genes via synergism of IL-17A and TNF. Accordingly, IL-17RA controlled the responsiveness of qPSC to Tc17-CM. Pancreatic tumour cells co-cultured with Tc17-iCAF displayed enhanced proliferation and increased expression of genes implicated in proliferation, metabolism and protection from apoptosis. Tc17-iCAF accelerated growth of mouse and human tumours in Rag1-/- and Foxn1nu/nu mice, respectively. Finally, Il17ra-expressed by fibroblasts was required for Tc17-driven tumour growth in vivo. CONCLUSIONS: We identified Tc17 as a novel protumourigenic CD8+ T-cell subtype in PDAC, which accelerated tumour growth via IL-17RA-dependent stroma modification. We described a crosstalk between three cell types, Tc17, fibroblasts and tumour cells, promoting PDAC progression, which resulted in poor prognosis for patients.

Impaired systemic nucleocapsid antigen clearance in severe COVID-19.

The circulating nucleocapsid (NCP) antigen of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is detectable in coronavirus disease-2019 (COVID-19) patients. To better understand the biology of disease severity, we investigated NCP clearance kinetics in hospitalized COVID-19 patients. Serum NCP was quantified using a commercial NCP-specific enzyme-linked immunoassay in hospitalized COVID-19 patients (n = 63) during their hospital stay. Results were correlated to COVID-19 disease severity, inflammation parameters, antibody response, and results of SARS-CoV-2 PCR from nasopharyngeal swabs. We demonstrate that NCP antigen levels in serum remained elevated in 21/45 (46.7%) samples from patients in intensive care units (ICU) after >8 days postdiagnosis. The proportion of ICU patients with detectable antigenemia declined only gradually from 84.6% to 25.0% over several weeks. This was in contrast to complete NCP clearance in all non-ICU patients after 8 days, and also in contrast to mucosal clearance of the virus as measured by PCR. Antigen clearance was associated with higher IgG against S1 but not NCP. Clearance of NCP antigenemia is delayed in >40% of severely ill COVID-19 patients. Thus, NCP antigenemia detected after 8 days post COVID-19 diagnosis is a characteristic of patients requiring intensive care. Prospective trials should further investigate NCP antigen clearance kinetics as a mechanistic biomarker.

Effect of intravenous lidocaine on pain after head and neck cancer surgery (ELICO trial): A randomised controlled trial.

BACKGROUND: Treatment of postoperative pain after ear, nose and throat (ENT) cancer surgery is mainly morphine administration. Additional systemic lidocaine has shown promising results in some surgical procedures. OBJECTIVE: The main objective was to evaluate morphine consumption in the first 48 postoperative hours after intra-operative lidocaine infusion during major ENT cancer surgery. DESIGN: A randomised, double-blind, placebo-controlled trial. SETTING: Bicentric study including a university hospital and a major cancer centre, conducted from December 2016 to December 2019. PATIENTS: A total of 144 patients undergoing major ENT cancer surgery were included. INTERVENTION: The patients were randomly assigned to receive intravenous lidocaine or placebo during surgery and in the recovery room. MAIN OUTCOME MEASURES: Endpoints were postoperative morphine consumption in the first 24 and 48 h postoperatively, intra-operative remifentanil consumption, adverse events occurrence and assessment 3 to 6 months after surgery with the McGill pain questionnaire. RESULTS: A total of 118 patients were included (lidocaine n  = 57; placebo n  = 61, 26 patients were excluded). There was no significant difference in morphine consumption during the first 48 postoperative hours in the lidocaine group compared with the placebo group with a median [IQR] of 0.60 [0.30 to 1.03] mg kg -1 vs. 0.57 [0.37 to 0.96] mg kg -1 , total dose 44 [21 to 73.3] mg vs. 38 [23.3 to 56.5] mg, P  = 0.92.There was no significant difference between the two groups in any of the other endpoints, including at follow up 3 to 6 months after surgery. CONCLUSION: Intravenous lidocaine in ENT cancer surgery did not show any additional analgesic or morphine-sparing effect 48 h after surgery. Three to six months after surgery, there was no significant difference in pain scores or consumption of analgesics. Patients treated pre-operatively with opioids were not evaluated in the study. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02894710 and EUDRACT number 2015-005799-90.

Simulating Collider Physics on Quantum Computers Using Effective Field Theories.

Simulating the full dynamics of a quantum field theory over a wide range of energies requires exceptionally large quantum computing resources. Yet for many observables in particle physics, perturbative techniques are sufficient to accurately model all but a constrained range of energies within the validity of the theory. We demonstrate that effective field theories (EFTs) provide an efficient mechanism to separate the high energy dynamics that is easily calculated by traditional perturbation theory from the dynamics at low energy and show how quantum algorithms can be used to simulate the dynamics of the low energy EFT from first principles. As an explicit example we calculate the expectation values of vacuum-to-vacuum and vacuum-to-one-particle transitions in the presence of a time-ordered product of two Wilson lines in scalar field theory, an object closely related to those arising in EFTs of the standard model of particle physics. Calculations are performed using simulations of a quantum computer as well as measurements using the IBMQ Manhattan machine.

Quantum Algorithm for High Energy Physics Simulations.

Simulating quantum field theories is a flagship application of quantum computing. However, calculating experimentally relevant high energy scattering amplitudes entirely on a quantum computer is prohibitively difficult. It is well known that such high energy scattering processes can be factored into pieces that can be computed using well established perturbative techniques, and pieces which currently have to be simulated using classical Markov chain algorithms. These classical Markov chain simulation approaches work well to capture many of the salient features, but cannot capture all quantum effects. To exploit quantum resources in the most efficient way, we introduce a new paradigm for quantum algorithms in field theories. This approach uses quantum computers only for those parts of the problem which are not computable using existing techniques. In particular, we develop a polynomial time quantum final state shower that accurately models the effects of intermediate spin states similar to those present in high energy electroweak showers with a global evolution variable. The algorithm is explicitly demonstrated for a simplified quantum field theory on a quantum computer.

Mitigating Depolarizing Noise on Quantum Computers with Noise-Estimation Circuits.

A significant problem for current quantum computers is noise. While there are many distinct noise channels, the depolarizing noise model often appropriately describes average noise for large circuits involving many qubits and gates. We present a method to mitigate the depolarizing noise by first estimating its rate with a noise-estimation circuit and then correcting the output of the target circuit using the estimated rate. The method is experimentally validated on a simulation of the Heisenberg model. We find that our approach in combination with readout-error correction, randomized compiling, and zero-noise extrapolation produces close to exact results even for circuits containing hundreds of CNOT gates. We also show analytically that zero-noise extrapolation is improved when it is applied to the output of our method.

Life Cycle Assessment of Direct Air Carbon Capture and Storage with Low-Carbon Energy Sources.

Direct air carbon capture and storage (DACCS) is an emerging carbon dioxide removal technology, which has the potential to remove large amounts of CO2 from the atmosphere. We present a comprehensive life cycle assessment of different DACCS systems with low-carbon electricity and heat sources required for the CO2 capture process, both stand-alone and grid-connected system configurations. The results demonstrate negative greenhouse gas (GHG) emissions for all eight selected locations and five system layouts, with the highest GHG removal potential in countries with low-carbon electricity supply and waste heat usage (up to 97%). Autonomous system layouts prove to be a promising alternative, with a GHG removal efficiency of 79-91%, at locations with high solar irradiation to avoid the consumption of fossil fuel-based grid electricity and heat. The analysis of environmental burdens other than GHG emissions shows some trade-offs associated with CO2 removal, especially land transformation for system layouts with photovoltaics (PV) electricity supply. The sensitivity analysis reveals the importance of selecting appropriate locations for grid-coupled system layouts since the deployment of DACCS at geographic locations with CO2-intensive grid electricity mixes leads to net GHG emissions instead of GHG removal today.

Does Size Matter? The Influence of Size, Load Factor, Range Autonomy, and Application Type on the Life Cycle Assessment of Current and Future Medium- and Heavy-Duty Vehicles.

The transparent, flexible, and open-source Python library carculator_truck is introduced to perform the life cycle assessment of a series of medium- and heavy-duty trucks across different powertrain types, size classes, fuel pathways, and years in a European context. Unsurprisingly, greenhouse gas emissions per ton-km reduce as size and load factor increase. By 2040, battery and fuel cell electric trucks appear to be promising options to reduce greenhouse gas emissions per ton-km on long distance segments, even where the required range autonomy is high. This requires that various conditions are met, such as improvements at the energy storage level and a drastic reduction of the greenhouse gas intensity of the electricity used for battery charging and hydrogen production. Meanwhile, these options may be considered for urban and regional applications, where they have a competitive advantage thanks to their superior engine efficiency. Finally, these alternative options will have to compete against more mature combustion-based technologies which, despite lower drivetrain efficiencies, are expected to reduce their exhaust emissions via engine improvements, hybridization of their powertrain, as well as the use of biomass-based and synthetic fuels.

Pterygodermatites nycticebi infections in golden lion tamarins (Leontopithecus rosalia rosalia) and aye-ayes (Daubentonia madagascariensis) from a German zoo.

In a golden lion tamarin (Leontopithecus rosalia rosalia) colony kept indoors in a German zoo, two animals presented a sudden onset of reduced general condition, lethargy, and diarrhea. At animal capture for clinical examination, adult nematode stages were observed after stress-induced defecation. Despite treatment, two golden lion tamarins died in the following 2 days. At necropsy, spirurid stages were found in the lungs and intestine. Additionally, adult Pterygodermatites spp. were identified in histopathological samples of intestine and pancreas, confirming the previous diagnosis. Upon diagnosis, all animals were treated with ivermectin (0.2 mg/kg; SC). Thereafter, the general condition of the golden lion tamarins improved, whereby some of them excreted spirurid nematodes over 3 days. Four weeks after treatment, 20 fecal samples from the colony were examined and proved negative for parasitic stages. Given that common German cockroaches (Blattella germanica) are suitable intermediate hosts of Pterygodermatites nycticebi, 30 specimens were collected from seven different locations around the golden lion tamarins housing. Third-stage larvae of Pterygodermatites spp. were recovered from those cockroaches. Regular anthelmintic treatments, coprological screenings, and controls for intermediate hosts were recommended. More than 2 years later, P. nycticebi infection was diagnosed again histopathologically in an aye-aye (Daubentonia madagascariensis) which suddenly died. Coprological analysis confirmed the presence of spirurid eggs. Due to prosimian primates' cockroach-eating habits and given that total cockroach eradication proved impossible, continuous cockroach control strategies and regular treatments of primates are currently performed to prevent further P. nycticebi infections.

Energy System Pathways with Low Environmental Impacts and Limited Costs: Minimizing Climate Change Impacts Produces Environmental Cobenefits and Challenges in Toxicity and Metal Depletion Categories.

Environmental indicators based on the life cycle assessment method are integrated into an energy system model. This integration allows for the generation of comprehensive environmental assessments of future energy systems and for determining energy scenarios with less environmental impacts and moderate cost increases. In Switzerland, which is used as a case study to demonstrate the feasibility of our approach, it is possible to generate pathways with a 5% cost increase on the cost-optimal situation, causing an impact score for climate change that is 2% higher than the minimum feasible solution. The minimization of life-cycle impacts on climate change generates substantial environmental cobenefits with regard to human health, air pollution, ozone depletion, acidification, and land transformation. However, this minimization also creates trade-offs that exacerbate the effects of metal depletion and human toxicity caused by upstream extraction and manufacturing linked to technologies such as solar panels and electric vehicles. Finally, ambitious reduction targets of 95% direct (i.e., within the country) CO2 emissions for the year 2050 might still result in substantial climate change impacts should emissions embodied in the infrastructure and upstream supply chain not be jointly mitigated jointly.

Bovine Babesiosis Diagnosed in Formalin-Fixed, Paraffin-Embedded Tissues by Using In Situ Hybridization.

Bovine babesiosis, caused by Babesia divergens, is in general a rare disease in Europe. Nonetheless, local outbreaks can cause severe economic damage, and postmortem identification represents a diagnostic challenge. During a recent outbreak in May 2018 in northern Germany, 21 animals of a herd of 150 cattle died within 40 days having had clinical signs of fever and hemoglobinuria. Gross examination of 4 of the 21 deceased animals revealed a tick infestation, jaundice, and dark brown staining of urine and kidneys. Histologically, there were iron-positive deposits, hyperplasia of the red pulp of the spleen, and centrilobular necrosis of hepatocytes. In several locations, small basophilic granules suggestive of intraerythrocytic parasites were visible in hematoxylin-eosin- and Giemsa-stained sections. Peripheral blood smears from a living cow from the herd and polymerase chain reaction (PCR) of feeding ticks revealed B. divergens infection. In situ hybridization (ISH) was applied on formalin-fixed, paraffin-embedded (FFPE) tissue of the necropsied cattle to confirm babesiosis in these animals postmortem. Digoxigenin-labeled DNA probes were generated based on a specific nucleotide sequence for B. divergens, obtained by PCR and sequencing of DNA isolates from infected Ixodes ricinus ticks from deceased cattle. ISH using these probes allowed postmortem diagnosis of B. divergens infection in routinely fixed FFPE tissues.

Sensor Positioning Influences the Accuracy of Knee Rom Data of an E-Rehabilitation System: A Preliminary Study with Healthy Subjects.

E-rehabilitation is the term used to define medical rehabilitation programs that are implemented at home with the use of information and communication technologies. The aim was to test whether sensor position and the sitting position of the patient influence the accuracy of knee range of movement (ROM) data displayed by the BPMpathway e-rehabilitation system. A preliminary study was conducted in a laboratory setting with healthy adults. Knee ROM data was measured with the BPMpathway e-rehabilitation system and simultaneously with a BIOPAC twin-axis digital goniometer. The main outcome was the root mean squared error (RMSE). A 20% increase or reduction in sitting height led to a RMSE increase. A ventral shift of the BPMpathway sensor by 45° and 90° caused significant measurement errors. A vertical shift was associated with a diminution of the measurement errors. The lowest RMSE (2.4°) was achieved when the sensor was placed below the knee. The knee ROM data measured by the BPMpathway system is comparable to the data of the concurrent system, provided the instructions of the manufacturer are respected concerning the sitting position of the subject for knee exercises, and disregarding the same instructions for sensor positioning, by placing the sensor directly below the knee.

The Immune Microenvironment in Pancreatic Cancer.

The biology of solid tumors is strongly determined by the interactions of cancer cells with their surrounding microenvironment. In this regard, pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) represents a paradigmatic example for the multitude of possible tumor-stroma interactions. PDAC has proven particularly refractory to novel immunotherapies, which is a fact that is mediated by a unique assemblage of various immune cells creating a strongly immunosuppressive environment in which this cancer type thrives. In this review, we outline currently available knowledge on the cross-talk between tumor cells and the cellular immune microenvironment, highlighting the physiological and pathological cellular interactions, as well as the resulting therapeutic approaches derived thereof. Hopefully a better understanding of the complex tumor-stroma interactions will one day lead to a significant advancement in patient care.

IL-18 but Not IL-1 Signaling Is Pivotal for the Initiation of Liver Injury in Murine Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is rising in prevalence, and a better pathophysiologic understanding of the transition to its inflammatory phenotype (NASH) is key to the development of effective therapies. To evaluate the contribution of the NLRP3 inflammasome and its downstream effectors IL-1 and IL-18 in this process, we applied the true-to-life "American lifestyle-induced obesity syndrome" (ALiOS) diet mouse model. Development of obesity, fatty liver and liver damage was investigated in mice fed for 24 weeks according to the ALiOS protocol. Lipidomic changes in mouse livers were compared to human NAFLD samples. Receptor knockout mice for IL-1 and IL-18 were used to dissect the impact of downstream signals of inflammasome activity on the development of NAFLD. The ALiOS diet induced obesity and liver steatosis. The lipidomic changes closely mimicked changes in human NAFLD. A pro-inflammatory gene expression pattern in liver tissue and increased serum liver transaminases indicated early liver damage in the absence of histological evidence of NASH. Mechanistically, Il-18r-/-- but not Il-1r-/- mice were protected from early liver damage, possibly due to silencing of the pro-inflammatory gene expression pattern. Our study identified NLRP3 activation and IL-18R-dependent signaling as potential modulators of early liver damage in NAFLD, preceding development of histologic NASH.

How to Save a Life From Macroscopic Fat Embolism: A Narrative Review of Treatment Options.

Macroscopic fat embolism (MAFE) has grabbed the attention of the plastic surgery community in recent years because of its high mortality rate. Many articles on preventing MAFE during gluteal fat grafting are available in the literature. However, total prevention is difficult: a number of factors, both technical and human, mean that MAFE remains a potential complication. This review was written with the main goal of providing a treatment plan. MAFE shares many similar pathophysiologic and hemodynamic features with massive thrombotic pulmonary embolism (PE), especially the associated cardiopulmonary decompensation. Lessons learned from PE management were used to devise a management algorithm for MAFE. The use of extracorporeal membrane oxygenation and its potential application as a main modality of treatment for MAFE was explored. The lack of evidence in the literature for the treatment of MAFE, and its high mortality, lent urgency to the need to write an article on the management aspect in the form of a narrative review, to ensure that every plastic surgeon practicing gluteal fat grafting is knowledgeable about the treatment aspect of this deadly complication.

Stromal biology and therapy in pancreatic cancer: ready for clinical translation?

Pancreatic ductal adenocarcinoma (PDA) is notoriously aggressive and hard to treat. The tumour microenvironment (TME) in PDA is highly dynamic and has been found to promote tumour progression, metastasis niche formation and therapeutic resistance. Intensive research of recent years has revealed an incredible heterogeneity and complexity of the different components of the TME, including cancer-associated fibroblasts, immune cells, extracellular matrix components, tumour vessels and nerves. It has been hypothesised that paracrine interactions between neoplastic epithelial cells and TME compartments may result in either tumour-promoting or tumour-restraining consequences. A better preclinical understanding of such complex and dynamic network systems is required to develop more powerful treatment strategies for patients. Scientific activity and the number of compelling findings has virtually exploded during recent years. Here, we provide an update of the most recent findings in this area and discuss their translational and clinical implications for basic scientists and clinicians alike.

Interdisciplinary approach towards a systems medicine toolbox using the example of inflammatory diseases.

Electronic access to multiple data types, from generic information on biological systems at different functional and cellular levels to high-throughput molecular data from human patients, is a prerequisite of successful systems medicine research. However, scientists often encounter technical and conceptual difficulties that forestall the efficient and effective use of these resources. We summarize and discuss some of these obstacles, and suggest ways to avoid or evade them.The methodological gap between data capturing and data analysis is huge in human medical research. Primary data producers often do not fully apprehend the scientific value of their data, whereas data analysts maybe ignorant of the circumstances under which the data were collected. Therefore, the provision of easy-to-use data access tools not only helps to improve data quality on the part of the data producers but also is likely to foster an informed dialogue with the data analysts.We propose a means to integrate phenotypic data, questionnaire data and microbiome data with a user-friendly Systems Medicine toolbox embedded into i2b2/tranSMART. Our approach is exemplified by the integration of a basic outlier detection tool and a more advanced microbiome analysis (alpha diversity) script. Continuous discussion with clinicians, data managers, biostatisticians and systems medicine experts should serve to enrich even further the functionality of toolboxes like ours, being geared to be used by 'informed non-experts' but at the same time attuned to existing, more sophisticated analysis tools.