bluuebunny/crossref_metadata_2025 huggingface dataset:
Synthetic multiantigen MVA vaccine COH04S1 protects against SARS-CoV-2 in Syrian hamsters and non-human primates
Authors: Chiuppesi Flavia , Nguyen Vu H. , Park Yoonsuh , Contreras Heidi , Karpinski Veronica , Faircloth Katelyn , Nguyen Jenny , Kha Mindy , Johnson Daisy , Martinez Joy , Iniguez Angelina , Zhou Qiao , Kaltcheva Teodora , Frankel Paul , Kar Swagata , Sharma Ankur , Andersen Hanne , Lewis Mark G. , Shostak Yuriy , Wussow Felix , Diamond Don J.
Published: January 2022

Second-generation COVID-19 vaccines could contribute to establish protective immunity against SARS-CoV-2 and its emerging variants. We developed COH04S1, a synthetic multiantigen modified vaccinia Ankara-based SARS-CoV-2 vaccine that co-expresses spike and nucleocapsid antigens. Here, we report COH04S1 vaccine efficacy in animal models. We demonstrate that intramuscular or intranasal vaccination of Syrian hamsters with COH04S1 induces robust Th1-biased antigen-specific humoral immunity and cross-neutralizing antibodies (NAb) and protects against weight loss, lower respiratory tract infection, and lung injury following intranasal SARS-CoV-2 challenge. Moreover, we demonstrate that single-dose or two-dose vaccination of non-human primates with COH04S1 induces robust antigen-specific binding antibodies, NAb, and Th1-biased T cells, protects against both upper and lower respiratory tract infection following intranasal/intratracheal SARS-CoV-2 challenge, and triggers potent post-challenge anamnestic antiviral responses. These results demonstrate COH04S1-mediated vaccine protection in animal models through different vaccination routes and dose regimens, complementing ongoing investigation of this multiantigen SARS-CoV-2 vaccine in clinical trials.
AI-based atomic force microscopy image analysis allows to predict electrochemical impedance spectra of defects in tethered bilayer membranes
Authors: Raila Tomas , Penkauskas Tadas , Ambrulevičius Filipas , Jankunec Marija , Meškauskas Tadas , Valinčius Gintaras
Published: January 2022

Atomic force microscopy (AFM) image analysis of supported bilayers, such as tethered bilayer membranes (tBLMs) can reveal the nature of the membrane damage by pore-forming proteins and predict the electrochemical impedance spectroscopy (EIS) response of such objects. However, automated analysis involving pore detection in such images is often non-trivial and can require AI-based object detection techniques. The specific object-detection algorithm we used to determine the defect coordinates in real AFM images was a convolutional neural network (CNN). Defect coordinates allow to predict the EIS response of tBLMs populated by the pore-forming toxins using finite element analysis (FEA) modeling. We tested if the accuracy of the CNN algorithm affected the EIS spectral features sensitive to defect densities and other physical parameters of tBLMs. We found that the EIS spectra can be predicted sufficiently well, however, systematic errors of characteristic spectral points were observed and need to be taken into account. Importantly, the comparison of predicted EIS curves with experimental ones allowed to estimate important physical parameters of tBLMs such as the specific resistance of submembrane reservoir. This reservoir separates phospholipid bilayer from the solid support. We found that the specific resistance of the reservoir amounts to $$10^{4.25 \pm 0.10}$$

10

4.25
±
0.10

$$\Omega \cdot cm$$

Ω
·
c
m

which is approximately two orders of a magnitude higher compared to the specific resistance of the buffer bathing tBLMs studied in this work. We hypothesize that such effect may be related in part due to decreased concentration of ionic carriers in the submembrane due to decreased relative dielectric permittivity in this region.
Metabolic adjustments of blood-stage Plasmodium falciparum in response to sublethal pyrazoleamide exposure
Authors: Tewari Shivendra G. , Kwan Bobby , Elahi Rubayet , Rajaram Krithika , Reifman Jaques , Prigge Sean T. , Vaidya Akhil B. , Wallqvist Anders
Published: January 2022

Due to the recurring loss of antimalarial drugs to resistance, there is a need for novel targets, drugs, and combination therapies to ensure the availability of current and future countermeasures. Pyrazoleamides belong to a novel class of antimalarial drugs that disrupt sodium ion homeostasis, although the exact consequences of this disruption in Plasmodium falciparum remain under investigation. In vitro experiments demonstrated that parasites carrying mutations in the metabolic enzyme PfATP4 develop resistance to pyrazoleamide compounds. However, the underlying mechanisms that allow mutant parasites to evade pyrazoleamide treatment are unclear. Here, we first performed experiments to identify the sublethal dose of a pyrazoleamide compound (PA21A092) that caused a significant reduction in growth over one intraerythrocytic developmental cycle (IDC). At this drug concentration, we collected transcriptomic and metabolomic data at multiple time points during the IDC to quantify gene- and metabolite-level alterations in the treated parasites. To probe the effects of pyrazoleamide treatment on parasite metabolism, we coupled the time-resolved omics data with a metabolic network model of P. falciparum. We found that the drug-treated parasites adjusted carbohydrate metabolism to enhance synthesis of myoinositol—a precursor for phosphatidylinositol biosynthesis. This metabolic adaptation caused a decrease in metabolite flux through the pentose phosphate pathway, causing a decreased rate of RNA synthesis and an increase in oxidative stress. Our model analyses suggest that downstream consequences of enhanced myoinositol synthesis may underlie adjustments that could lead to resistance emergence in P. falciparum exposed to a sublethal dose of a pyrazoleamide drug.
Grass-roots entrepreneurship complements traditional top-down innovation in lung and breast cancer
Authors: Ramadi Khalil B. , Mehta Rhea , He David , Chao Sichen , Chu Zen , Atun Rifat , Nguyen Freddy T.
Published: January 2022

The majority of biomedical research is funded by public, governmental, and philanthropic grants. These initiatives often shape the avenues and scope of research across disease areas. However, the prioritization of disease-specific funding is not always reflective of the health and social burden of each disease. We identify a prioritization disparity between lung and breast cancers, whereby lung cancer contributes to a substantially higher socioeconomic cost on society yet receives significantly less funding than breast cancer. Using search engine results and natural language processing (NLP) of Twitter tweets, we show that this disparity correlates with enhanced public awareness and positive sentiment for breast cancer. Interestingly, disease-specific venture activity does not correlate with funding or public opinion. We use outcomes from recent early-stage innovation events focused on lung cancer to highlight the complementary mechanism by which bottom-up “grass-roots” initiatives can identify and tackle under-prioritized conditions.
Ex vivo anticoagulants affect human blood platelet biomechanics with implications for high-throughput functional mechanophenotyping
Authors: Sachs Laura , Wesche Jan , Lenkeit Lea , Greinacher Andreas , Bender Markus , Otto Oliver , Palankar Raghavendra
Published: January 2022

Inherited platelet disorders affecting the human platelet cytoskeleton result in increased bleeding risk. However, deciphering their impact on cytoskeleton-dependent intrinsic biomechanics of platelets remains challenging and represents an unmet need from a diagnostic and prognostic perspective. It is currently unclear whether ex vivo anticoagulants used during collection of peripheral blood impact the mechanophenotype of cellular components of blood. Using unbiased, high-throughput functional mechanophenotyping of single human platelets by real-time deformability cytometry, we found that ex vivo anticoagulants are a critical pre-analytical variable that differentially influences platelet deformation, their size, and functional response to agonists by altering the cytoskeleton. We applied our findings to characterize the functional mechanophenotype of platelets from a patient with Myosin Heavy Chain 9 (MYH9) related macrothrombocytopenia. Our data suggest that platelets from MYH9 p.E1841K mutation in humans affecting platelet non-muscle myosin heavy chain IIa (NMMHC-IIA) are biomechanically less deformable in comparison to platelets from healthy individuals.
Two distinct Notch signals, Delta-like 4/Notch1 and Jagged-1/Notch2, antagonistically regulate chemical hepatocarcinogenesis in mice
Authors: Nakano Yasuhiro , Nakao Sachie , Sueoka Minako , Kasahara Daigo , Tanno Yuri , Sumiyoshi Hideaki , Itoh Tohru , Miyajima Atsushi , Hozumi Katsuto , Inagaki Yutaka
Published: January 2022

Notch signaling is one of the most common drivers of carcinogenesis in many types of cancers, including hepatocellular carcinoma (HCC); however, it occasionally suppresses tumor progression. Moreover, it is virtually unknown how different sets of Notch ligands and receptors regulate the HCC development. In this study, we demonstrate that the expression of the Notch ligands, Delta-like 4 (Dll4) and Jagged-1 (Jag1), is upregulated during diethylnitrosamine-induced hepatocarcinogenesis. Dll4 is detected in the preneoplastic hepatocytes and HCC cells, but not in the normal hepatocytes, while Jag1 is expressed in the desmin-positive mesenchymal cells. Hepatocyte-specific Dll4 knockout abolishes the Notch1 signaling and suppresses the tumor progression. In contrast, Jag1 deletion induces the ectopic expression of Dll4 in hepatocytes along with the loss of Notch2 signaling, leading to the tumor progression. These results indicate that the two distinct Notch signals, Dll4/Notch1 and Jag1/Notch2, are antagonistic to each other, exerting opposite effects on HCC progression.
Cryofouling avoidance in the Antarctic scallop Adamussium colbecki
Authors: Wong William S. Y. , Hauer Lukas , Cziko Paul A. , Meister Konrad
Published: January 2022

The presence of supercooled water in polar regions causes anchor ice to grow on submerged objects, generating costly problems for engineered materials and life-endangering risks for benthic communities. The factors driving underwater ice accretion are poorly understood, and passive prevention mechanisms remain unknown. Here we report that the Antarctic scallop Adamussium colbecki appears to remain ice-free in shallow Antarctic marine environments where underwater ice growth is prevalent. In contrast, scallops colonized by bush sponges in the same microhabitat grow ice and are removed from the population. Characterization of the Antarctic scallop shells revealed a hierarchical micro-ridge structure with sub-micron nano-ridges which promotes directed icing. This concentrates the formation of ice on the growth rings while leaving the regions in between free of ice, and appears to reduce ice-to-shell adhesion when compared to temperate species that do not possess highly ordered surface structures. The ability to control the formation of ice may enable passive underwater anti-icing protection, with the removal of ice possibly facilitated by ocean currents or scallop movements. We term this behavior cryofouling avoidance. We posit that the evolution of natural anti-icing structures is a key trait for the survival of Antarctic scallops in anchor ice zones.
NapB Restores cytochrome c biosynthesis in bacterial dsbD-deficient mutants
Authors: Guo Kailun , Feng Xue , Sun Weining , Han Sirui , Wu Shihua , Gao Haichun
Published: January 2022

Cytochromes c (cyts c), essential for respiration and photosynthesis in eukaryotes, confer bacteria respiratory versatility for survival and growth in natural environments. In bacteria having a cyt c maturation (CCM) system, DsbD is required to mediate electron transport from the cytoplasm to CcmG of the Ccm apparatus. Here with cyt c-rich Shewanella oneidensis as the research model, we identify NapB, a cyt c per se, that suppresses the CCM defect of a dsbD mutant during anaerobiosis, when NapB is produced at elevated levels, a result of activation by cAMP-Crp. Data are then presented to suggest that NapB reduces CcmG, leading to the suppression. We further show that NapB proteins capable of rescuing CCM in the dsbD mutant form a small distinct clade. The study sheds light on multifunctionality of cyts c, and more importantly, unravels a self-salvation strategy through which bacteria have evolved to better adjust to the natural world.
Evaluation of plant-derived semi-synthetic molecules against BRD3-BD2 protein: a computational strategy to combat breast cancer
Authors: Kumar Sachin , Bhardwaj Vijay Kumar , Singh Rahul , Das Pralay , Purohit Rituraj
Published: January 2022

BRD3-BD2 protein belongs to the bromodomain and extra-terminal domain (BET) protein family.
A novel l-histidine based ionic liquid (LHIL) as an efficient corrosion inhibitor for mild steel
Authors: Wang Jing , Liu Chengbao , Qian Bei
Published: January 2022

A novel l-histidine based ionic liquid (LHIL) was developed and successfully synthesized.
Spontaneous self-healing ionogels for efficient and reliable carbon dioxide separation
Authors: Fu Yonghao , Chen Liyuan , Xu Fuchang , Li Xiang , Li Yang , Sun Junqi
Published: January 2022

Spontaneous self-healing ionogels with imine bond cross-linked supramolecular polymer networks were fabricated for efficient and reliable CO2 separation.
Investigating the detectability of hydrocarbons in exoplanet atmospheres with JWST
Authors: Gasman Danny , Min Michiel , Chubb Katy L.
Published: January 2022

Aims.We investigate at what abundances various hydrocarbon molecules (e.g. acetylene (C2H2), ethylene (C2H4), and methane (CH4)) become detectable when observing the atmospheres of various planets using theJames WebbSpace Telescope (JWST).

Methods.We focused on atmospheric models based on the parameters of a small sample of planets: HD 189733b, HD 209458b (hot Jupiters orbiting bright stars); HD 97658b (a sub-Neptune/super-Earth orbiting a bright star); and Kepler-30c (a warm Jupiter orbiting a faint star). We computed model transmission spectra, assuming equilibrium chemistry and clear atmospheres for all planets apart from HD 189733b, where we also computed spectra with a moderate cloud layer included. We used the Bayesian retrieval package ARCiS for the model atmospheres, and simulated observed spectra from different instruments that will be on board JWST using the PandExo package. We subsequently ran retrievals on these spectra to determine whether the parameters input into the forward models, with a focus on molecular abundances, can be accurately retrieved from these simulated spectra.

Results.We find that generally we can detect and retrieve abundances of the hydrocarbon species as long as they have a volume mixing ratio above approximately 1  × 10−7–1  × 10−6, at least for the brighter targets. There are variations based on planet type and instrument(s) used, and these limits will likely change depending on the abundance of other strong absorbers. We also find scenarios where the presence of one hydrocarbon is confused with another, particularly when a small wavelength region is covered; this is often improved when two instruments are combined.

Conclusions.The molecules C2H2, CH4, and C2H4will all be detectable with JWST, provided they are present in high enough abundances, and that the optimal instruments are chosen for the exoplanet system being observed. Our results indicate that generally a combination of two instruments, either NIRSpec G395M and MIRI LRS, or NIRCam F322W2 and MIRI LRS, are best for observing these hydrocarbons in bright exoplanet systems with planets of various sizes, with NIRSpec G395M and MIRI LRS the best option for the HD 189733b-like atmosphere with clouds included. The use of NIRSpec Prism is tentatively found to be best for fainter targets, potentially in combination with the MIRI LRS slit mode, although the target we test is too faint to draw any strong conclusions. Instrument sensitivity, noise, and wavelength range are all thought to play a role in being able to distinguish spectral features.
Upstream solar wind speed at comet 67P
Authors: Nilsson H. , Moeslinger A. , Williamson H. N. , Bergman S. , Gunell H. , Stenberg Wieser G. , Futaana Y. , Karlsson T. , Behar E. , Holmström M.
Published: January 2022

Context.Rosetta followed comet 67P at heliocentric distances from 1.25 to 3.6 au. The solar wind was observed for much of this time, but was significantly deflected and to some extent slowed down by the interaction with the coma.

Aims.We use the different changes in the speed of H+and He2+when they interact with the coma to estimate the upstream speed of the solar wind. The different changes in the speed are due to the different mass per charge of the particles, while the electric force per charge due to the interaction is the same. A major assumption is that the speeds of H+and He2+were the same in the upstream region. This is investigated.

Methods.We derived a method for reconstructing the upstream solar wind from H+and He2+observations. The method is based on the assumption that the interaction of the comet with the solar wind can be described by an electric potential that is the same for both H+and He2+. This is compared to estimates from the Tao model and to OMNI and Mars Express data that we propagated to the observation point.

Results.The reconstruction agrees well with the Tao model for most of the observations, in particular for the statistical distribution of the solar wind speed. The electrostatic potential relative to the upstream solar wind is derived and shows values from a few dozen volts at large heliocentric distances to about 1 kV during solar events and close to perihelion. The reconstructed values of the solar wind for periods of high electrostatic potential also agree well with propagated observations and model results.

Conclusions.The reconstructed upstream solar wind speed during the Rosetta mission agrees well with the Tao model. The Tao model captures some slowing down of high-speed streams as compared to observations at Earth or Mars. At low solar wind speeds, below 400 km s−1, the agreement is better between our reconstruction and Mars observations than with the Tao model. The magnitude of the reconstructed electrostatic potential is a good measure of the slowing-down of the solar wind at the observation point.
Maladie de Parkinson
Authors: Bezard Erwan , Dehay Benjamin
Published: January 2022

La vaste majorité des maladies neurodégénératives sont associées à une accumulation de protéines non dégradées et agrégées. On appelle ainsi ces maladies, protéinopathies. Les synucléinopathies en sont une des composantes, en particulier la maladie de Parkinson. Les caractéristiques neuropathologiques de la maladie de Parkinson comprennent la perte progressive de neurones dopaminergiques du mésencéphale et la formation d’agrégats protéiques, constitués notamment de la protéine a-synucléine. Des preuves expérimentales suggèrent que dans des conditions pathologiques, cette protéine, normalement soluble, adopte un repliement anormal et s’agrège, avec une propension à se propager dans tout le système nerveux central. Dans cette Synthèse, nous discuterons des spécificités de l’agrégation de l’a-synucléine et de ses mécanismes, qui permettent désormais de comprendre sa propagation et fournissent une explication moléculaire à la progression de la maladie chez l’homme.
L’actualité scientifique de ce début 2022 vue par les étudiants du Master Biologie Santé de l’université de Montpellier
Authors: Prothon Juliette , Machu Margot , Baud Bastien , Berthon Émilie , Desoutter Alban , Soula Antoine , Le Gallic Soline , Nowicki Nathan , Bari Imen , Hien Tizaanuo , Sow Marliatou , Idrici Mélissa , Rouquier Nicolas , Farnole Fréderic , Hervé Florian , Raimundo Nicolas
Published: January 2022

L’unité d’enseignement « Immunopathologie » qui propose les brèves présentées dans ce numéro est suivie par des étudiants de divers parcours du Master Biologie Santé de l’Université de Montpellier. Ce Master rassemble des étudiants issus du domaine des sciences et technologies et de celui de la santé. On y étudie les bases physiopathologiques des maladies immunologiques, les cibles thérapeutiques et les mécanismes d’échappement des microorganismes et des tumeurs. Les articles présentés ont été choisis par les étudiants selon leur domaine de prédilection.
Plasma Ascorbic Acid Levels in Critically Ill Pediatric Patients
Authors: Choi Daniel Horim , Basu Sonali , Levine Mark , Steinhorn David
Published: January 2022

Ascorbic acid, or vitamin C, is a physiological antioxidant that has been found to be deficient in critically ill adults with sepsis and acute respiratory distress system. In adults, ascorbic acid supplementation has been shown to reduce the need for vasopressors and mechanical ventilation. This study aimed to describe the prevalence of ascorbic acid deficiency in critically ill pediatric patients. This prospective, single-centered study analyzed 34 patients aged 1 month to 18 years old with septic shock and/or acute respiratory failure requiring mechanical ventilation in a quaternary, urban, pediatric intensive care unit. Plasma ascorbic acid levels were measured by high-performance liquid chromatography within 24 hours of meeting eligibility criteria. The median level was 23.34 µM (IQR [11.45, 39.14]). Twenty-three patients had repeat samples that were collected 3 to 5 days later. The median for repeat samples was higher at 42.41 µM (IQR [13.08, 62.43]). Patients who were enterally fed had significantly higher levels than those who were not (62.4 ± 7.7 µM vs. 32.4 ± 7.1 µM; p = 0.03). Ascorbic acid levels vary widely among critically ill children with septic shock and/or respiratory failure requiring mechanical ventilation, but one-half of our patients had deficient levels that are typically seen in scurvy. Further studies are warranted to investigate the significance of low levels as well as the impact of normalizing levels through nutritional support.
The Decision to Extubate: The Association between Clinician Impressions and Objective Extubation Readiness Criteria in a Pediatric Intensive Care Unit
Authors: Marupudi Neelima K. , Steurer-Muller Martina , Franzon Deborah
Published: January 2022

Objective Objective tools such as spontaneous breathing trials (SBT) aim to identify patients ready for extubation and shorten the length of mechanical ventilation (MV). Despite passing an SBT, patients sometimes are not extubated based on clinicians' subjective impressions. In this article, we explored the factors that influence the decision to extubate among pediatric intensivists and their association with objective criteria.

Design This is a single-center prospective observational study.

Setting This study was conducted in an academic, multidisciplinary 20-bed pediatric intensive care unit (PICU).

Patients The study group involves mechanically ventilated, orally intubated patients admitted to the PICU from January 1 to June 30, 2019.

Measurements and Main Results Objective clinical data were collected for 650 MV days. Attending surveys about extubation readiness were completed for 419 (64.5%) MV days and 63 extubation events. Extubation occurred on 42% of days after passing an SBT. The primary reasons patients who passed an SBT were not extubated on days were unresolved lung pathology (66.6%) and fluid overload (37.6%). On days without extubation, there was no association between a specific reason for not extubating and SBT result (p > 0.05).

Conclusions In this single-center study, the decision to extubate was not strongly associated with passing an SBT, indicating that clinician impressions, namely unresolved lung pathology and fluid overload, outweighed objective measures for determining extubation readiness. To mitigate morbidities and costs associated with unnecessarily prolonged intubations, a better-defined extubation readiness process is needed to guide the decision to extubate in the pediatric population.
Primary Diffuse Leptomeningeal Atypical Teratoid/Rhabdoid Tumor Initially Masquerading as Guillain–Barré Syndrome: A Case Report and Literature Review
Authors: Kobayashi Kenichiro , Tanaka Kuniaki , Iwai Atsushi , Taki Junya , Kitagawa Masashi , Hayashi Tomoko , Tsuzuki Sadatoshi , Yamamoto Tetsuro , Yoshioka Takako , Hirato Junko , Maihara Toshiro , Yamada Keisuke , Usami Ikuya , Heike Toshio
Published: January 2022

A 10-year-old male child patient was admitted with a chief complaint of progression of lower limb weakness lasting for 5 weeks. An initial clinical picture was reminiscent of Guillain–Barré syndrome. Repeated cerebrospinal fluid (CSF) cytological examinations were negative for neoplastic cells, but leptomeningeal biopsy targeting positron emission tomography (PET) avid lesion confirmed the invasion of tumor cells which were negatively stained with Brahma-related gene 1. An extensive literature review identified five cases of primary diffuse leptomeningeal atypical teratoid/rhabdoid tumors, and the clinical characteristics, including ours, were characterized as follows: (1) there was a bimodal age distribution in young children and adolescents with a male predominance, (2) roughly half of the patients fulfilled the diagnostic criteria of albuminocytologic dissociation and CSF cytology was neither sensitive nor specific to establish a definitive diagnosis, and (3) cerebrospinal magnetic resonance imaging findings were mostly indistinguishable from those of infectious or inflammatory diseases. We would like to suggest that primary leptomeningeal tumor should be included in the differential diagnosis of progressive polyneuropathy even in the absence of CSF cytological findings and implementation of preoperative PET may enhance the diagnostic accuracy of such a miscellaneous central nervous system tumor.
Different oxygen migration behaviors at CoFe/MgO and CoFe/HfO2 interfaces and their effects on the magnetic anisotropy
Authors: Feng Guonan , Zhang Jinyan , Liu Jintao , Yang Xinyan , Chen Xi , Yu Guanghua
Published: January 2022

We have studied annealing-induced oxygen migration at CoFe/MgO and CoFe/HfO2 interfaces and its effect on the magnetic anisotropy of Ta/CoFe/MgO (HfO2) films. Through x-ray photoelectron spectroscopy, we found that the Fe–O bonds exist at both CoFe/MgO and CoFe/HfO2 interfaces at the as-deposited state due to the oxidation of interfacial Fe atoms during the deposition of the MgO and HfO2 layers. After annealing, the amount of the Fe–O bonds at the CoFe/MgO interface decreases, whereas at the CoFe/HfO2 interface, it increases, indicating that the oxygen atoms migrate from Fe–O bonds to MgO layers at the CoFe/MgO interface, whereas they migrate from the HfO2 layer to Fe–O bonds at the CoFe/HfO2 interface. Correspondingly, the magnetic anisotropy energy decreases in the Ta/CoFe/MgO film but increases in the Ta/CoFe/HfO2 film after annealing. We attributed these results to interfacial Fe 3d–O 2p orbital hybridization modulated by different oxygen migration behaviors. Our results may improve the understanding of the oxygen migration effect on magnetic anisotropy and anomalous Hall sensitivity in ferromagnet/oxide heterostructures.
Seed priming with nitric oxide and/or spermine mitigate the chromium toxicity in rice (
Authors: Basit Farwa , Ulhassan Zaid , Mou Qingshan , Nazir Muhammad Mudassar , Hu Jin , Hu Weimin , Song Wenjian , Sheteiwy Mohamed Salah , Zhou Weijun , Bhat Javaid Akhter , Jeddi Kaouthar , Hessini Kamel , Guan Yajing
Published: January 2022

Chromium (Cr) is a serious environmental contaminant that drastically limited the crop yields. Nitric oxide (NO) and spermine (Spm) portrayal significance in improving the plant tolerance against abiotic stresses. Therefore, we investigate the protective efficacy of seed priming with NO (100 μM) and/or Spm (0.01 mM) in minimising the Cr-induced toxic effects in rice (Oryza sativa L.) plants. Our outcomes revealed that Cr alone treatments (100 μM) notably reduced the seed germination rate, plant growth, photosynthetic apparatus, nutrients uptake and antioxidant defence system, but extra generation of reactive oxygen species (ROS). Interestingly, the combine applications of NO and Spm significantly reversed the Cr-induced toxic effects by reducing the Cr-accumulation, maintaining the nutrient balance, improving the germination indices, levels of photosynthetic pigments (chl a by 24.6%, chl b by 36.3%, chl (a + b) by 57.2% and carotenoids by 79.4%), PSII, photosynthesis gas exchange parameters and total soluble sugar (74.9%) by improving antioxidative enzyme activities. As a result, NO + Spm lowered the accumulation of oxidative markers (H2O2 by 93.9/70.4%, O2˙− by 86.3/69.9% and MDA by 97.2/73.7% in leaves/roots), electrolyte leakage (71.4% in leaves) and improved the plant growth traits. Based on these findings, it can be concluded that NO triggers Spm to minimise the Cr-accumulation and its adverse effects on rice plants. Additionally, combined treatments (NO + Spm) were more effective in minimising the Cr-induced toxic effects in comparison to NO and Spm alone treatments. Thus, co-exposure of NO and Spm may be utilised to boost rice tolerance under Cr stress conditions.
Probabilistic Pareto plan generation for semiautomated multicriteria radiation therapy treatment planning
Authors: Zhang Tianfang , Bokrantz Rasmus , Olsson Jimmy
Published: January 2022

Objective. We propose a semiautomatic pipeline for radiation therapy treatment planning, combining ideas from machine learning–automated planning and multicriteria optimization (MCO). Approach. Using knowledge extracted from historically delivered plans, prediction models for spatial dose and dose statistics are trained and furthermore systematically modified to simulate changes in tradeoff priorities, creating a set of differently biased predictions. Based on the predictions, an MCO problem is subsequently constructed using previously developed dose mimicking functions, designed in such a way that its Pareto surface spans the range of clinically acceptable yet realistically achievable plans as exactly as possible. The result is an algorithm outputting a set of Pareto optimal plans, either fluence-based or machine parameter–based, which the user can navigate between in real time to make adjustments before a final deliverable plan is created. Main results. Numerical experiments performed on a dataset of prostate cancer patients show that one may often navigate to a better plan than one produced by a single-plan-output algorithm. Significance. We demonstrate the potential of merging MCO and a data-driven workflow to automate labor-intensive parts of the treatment planning process while maintaining a certain extent of manual control for the user.
Experimental validation of a linac head Geant4 model under a grid computing environment
Authors: Didi Samir , Bahhous Karim , Zerfaoui Mustapha , Aboulbanine Zakaria , Ouhadda Hassan , Halimi Abdellah
Published: January 2022

Background and purpose

. This work aims to present the strategy to simulate a clinical linear accelerator based on the geometry provided by the manufacturer and summarize the corresponding experimental validation. Simulations were performed with the Geant4 Monte Carlo code under a grid computing environment. The objective of this contribution is reproducing therapeutic dose distributions in a water phantom with an accuracy less than 2%.
Materials and methods.
A Geant4 Monte Carlo model of an Elekta Synergy linear accelerator has been established, the simulations were launched in a large grid computing platform. Dose distributions are calculated for a 6 MV photon beam with treatment fields ranging from 5 × 5 cm2 to 20 × 20 cm2 at a source—surface distance of 100 cm.
Results.
A high degree of agreement is achieved between the simulation results and the measured data, with dose differences of about 1.03% and 1.96% for the percentage depth dose curves and lateral dose profiles, respectively. This agreement is evaluated by the gamma index comparisons. Over 98% of the points for all simulations meet the restrictive acceptability criteria of 2%/2 mm.
Conclusion.
We have demonstrated the possibility to establish an accurate linac head Monte Carlo model for dose distribution simulations and quality assurance. Percentage depth dose curves and beam quality indices are in perfect agreement with the measured data with an accuracy of better than 2%.
OP34 Efficacy and safety of advanced induction and maintenance therapies in patients with moderately to severely active Ulcerative Colitis: An indirect treatment comparison using Bayesian network meta-analysis
Authors: Panaccione R , Collins E B , Melmed G Y , Vermeire S , Danese S , Higgins P D R , Zhou W , Ilo D , Sharma D , Sanchez Gonzalez Y , Wang S T
Published: January 2022

Background

The therapeutic armamentarium to treat adult patients with moderately to severely active ulcerative colitis (UC) continues to evolve. With this rapid innovation, the comparative efficacy and safety of more recent advanced therapies remain unknown.

Methods

Bayesian network meta-analysis was used to indirectly compare the efficacy and safety of advanced therapies for induction (6–10 weeks) and maintenance (44–54 weeks post-induction response) in adults with moderately-to-severely active UC. Efficacy was assessed separately in bio-naïve and bio-exposed populations by clinical remission (Full Mayo score [FM] of ≤2 with no subscore >1), clinical response (decrease from baseline in FM ≥3 points and ≥30% with decrease in rectal bleeding score [RBS] of ≥1 or absolute RBS ≤1) and endoscopic improvement (endoscopic score ≤1); ad hoc analyses were conducted on upadacitinib (UPA) RCT data to produce FM outcomes. Safety was assessed by discontinuation due to adverse events (AEs), serious AEs, and serious infections. Induction therapies included UPA 45 mg, adalimumab 160/80 mg, filgotinib 100 and 200 mg, golimumab 200/100 mg, infliximab 10 and 5 mg/kg, ozanimod 0.92 mg, tofacitinib 10 mg, ustekinumab (UST) 6 mg/kg, and vedolizumab (VED) 300 mg. The maintenance analysis included low and high maintenance doses of these therapies. Phase 3 randomized controlled trials (RCTs) were identified via systematic literature review. Random effects models were used to account for expected heterogeneity in endpoints and study design. Guidelines from the National Institute for Health and Care Excellence were followed.

Results

Out of 31 RCTs identified, 23 were included (18 for induction and 14 for maintenance). Odds ratios vs. placebo (PBO), numbers needed to treat/harm, and surface under the cumulative ranking curve estimates are presented for efficacy in bio-naïve (Table 1) and bio-exposed (Table 2) populations and for safety in overall populations (Table 4). Intent-to-treat rates of maintenance efficacy outcomes adjusted by the likelihood of induction response show UPA to be consistently the most efficacious therapy (Table 3). There were no significant differences in serious AEs or serious infections for any advanced therapy vs PBO. For discontinuation due to AEs, only UPA had significantly lower odds vs PBO after induction, while UST and VED had significantly lower odds vs PBO after maintenance (Table 4).

Conclusion

In patients with moderately-to-severely active UC, UPA 45 mg induction and 30 mg maintenance appear more efficacious than other advanced therapies/PBO at inducing and maintaining clinical response, clinical remission, and endoscopic response, with no greater safety assessments vs PBO, over 1-year.
OP37 Bacterial suppression of intestinal fungi via activation of human gut Vδ2+ T-cells
Authors: Mathew L , Savage M , Pardieu C , O’Brien M , Sze S K , Eberl M , Stagg A , Gasparetto M , Kok K , Lindsay J , McCarthy N
Published: January 2022

Background

The human gut is colonized by diverse microbes including fungi such as Candida albicans, which has been implicated in the pathogenesis of Crohn’s disease (CD). Intestinal C. albicans typically exists as commensal yeast, but can also form tissue-invasive filaments that secrete Candidalysin toxin to disrupt epithelial barriers. Commensal gut bacteria produce molecules that induce host immunity, including phosphoantigen HMB-PP which stimulates Vδ2+ T-cell homing to intestine and mucosal expression of IL-22 to promote barrier integrity. We aimed to identify mechanisms of gut barrier defence against fungal invasion in health and CD.

Methods

Colonic biopsies / resected tissue were stimulated or not with HMB-PP in the presence or absence of anti-IL-22 blocking antibody and analysed by flow-cytometry / microscopy to determine extent of fungal outgrowth. Fungal isolates were identified using standard morphological and biochemical criteria before assessment of filamentation, cell wall composition, and NETosis induction.

Results

Mucosal Vδ2+ T-cell activation with bacterial phosphoantigen HMB-PP, in the presence of epithelial damage-associated cytokine IL-15, potently suppressed growth of endogenous fungi in human colonic organ cultures. Vδ2-mediated fungal suppression required IL-22 and was sufficient to restrict the growth of multiple fungal species, including a range of emerging pathogenic moulds as well as archetypal pathobiont C. albicans. In Vδ2-deficient CD patients, mucosal biopsy stimulation with HMB-PP failed to control fungal growth. CD-derived C. albicans strains also displayed rapid filamentation ex vivo and higher levels of NOD2 ligand chitin than were observed in isolates from healthy controls. Comparing hypoxic with oxygenated cultures that mimic inflamed intestine, pSILAC proteomic analysis of a representative CD-derived C. albicans strain confirmed features of invasive growth (e.g. DAO1, IHD1), whereas a healthy control isolate exhibited metabolic hallmarks of symbiosis (Jen1p, SCH9). These divergent characteristics directly impacted on host anti-fungal immune responses, since the CD-derived strain rapidly induced neutrophil extracellular traps in vitro, whereas the healthy control isolate did not.

Conclusion

These data suggest that commensal bacteria can activate host Vδ2 T-cells to suppress fungal invasion of the gut epithelium via an IL22-dependent mechanism that is deficient in CD patients.
DOP01 A multi-centre study to explore the prevalence of Inflammatory Bowel Disease indicators in patients with moderate- to- severe psoriasis: Baseline results from the EPIC study
Authors: Hayee B , Ghosh S , Carter B , Bartlett S , Powles E , Millward R , Watcham S , Blanthorn-Hazell S , Crooks J , Hansell C , Millar J , Williams C , Migas S , Hajne J , Warren R
Published: January 2022

Background

Evidence suggests there is an increased incidence of inflammatory bowel disease (IBD) in the psoriasis (PsO) population. However prior studies may have underestimated the degree of this association, by not considering (pre-)clinical markers or symptoms of IBD (e.g. elevated faecal calprotectin [FCal] and/or IBD red flags). Furthermore, patients with PsO are not typically screened for IBD. Here we describe the prevalence of IBD indicators in patients with moderate-to-severe PsO.

Methods

This was a multi-centre UK study of adults (≥18 years) with moderate-to-severe PsO. Patients were recruited from 12 primary care practices in Greater Manchester between November 2019 – April 2021 (in total, 983 eligible patients from an original cohort of 3485 were invited to participate). Retrospective review of primary care medical records was used to confirm a prior IBD diagnosis at baseline. For patients without a confirmed diagnosis, FCal monitoring and a bespoke questionnaire derived from validated measures of gastrointestinal (GI) symptoms and IBD red flags (CalproQuest IBD and Red Flag Index) were used to screen for IBD risk. Baseline interim data are presented as observed proportions, descriptive statistics, and counts along with 95% confidence intervals (CI).

Results

252 patients were included: mean age was 57 (±15 SD) years and 54% were female (Table 1).

Use of non-steroidal anti-inflammatory drug therapy was reported by 15.5% of patients. In total, 64.7% (CI: 53.4−70.6%) of patients had ≥1 indicator of IBD risk at baseline (i.e., ≥1 of: IBD diagnosis, FCal ≥50 ɥg/g or ≥1 IBD red flag) and 3.6% (CI: 1.7−6.7%) of patients had a confirmed diagnosis of IBD. At baseline, 38.1% (CI: 33.5–46.1%) of patients had elevated (≥50μg/g) FCal (Table 2), and 34.9% (CI: 30.2−42.6%) of patients reported ≥1 IBD red flag. Both elevated FCal and GI symptoms were observed in 26.2% (CI: 21.8−33.5%) of patients.

Figure 1 depicts the overlap between different IBD markers in this cohort.

Conclusion

The risk of IBD in patients with PsO may be higher than previously reported. While 3.6% of patients in this cohort of patients with moderate-to-severe PsO had a confirmed IBD diagnosis, approximately two-thirds of patients exhibited at least one indicator of IBD risk (FCal ≥50μg/g and/or IBD red flag[s]). This study therefore highlights a population for whom further investigation to confirm IBD may be warranted. Prospective follow-up over the next two years will report on the outcomes of investigations, the final diagnoses and treatments in the identified ‘at risk’ cohort.
DOP26 COVID-19 vaccine effectiveness in Inflammatory Bowel Disease patients on tumor-necrosis factor inhibitors: Real world data from a mass-vaccination campaign
Authors: Lev Zion R , Focht G , Lujan R , Mendelovici A , Friss C , Greenfeld S , Kariv R , Ben-Tov A , Matz E , Nevo D , Barak-Corren Y , Dotan I , Turner D
Published: January 2022

Background

Some studies have shown decreased serological response to vaccination in patients on anti-tumor necrosis factor (TNF) medications. While the large majority of these patients do seroconvert after vaccination, titers have generally been lower and one study showed reduced neutralizing and inhibitory functions. One real-world population-based study compared found no increased infection rate in anti-TNF treated patients, but infection rates were low. The low event rate mandates exploration in longer-term population-based data. We used the epi-Israeli IBD Research Nucleus (IIRN) database to explore the effectiveness of COVID-19 vaccination in IBD patients in Israel.

Methods

We included all IBD patients insured in two of the four Israeli HMOs, covering 35% of the population, by validated algorithms, and selected those who received two doses of Pfizer BNT162b2 vaccine. These were matched by date of vaccination ±3 days and demographic variables to non-IBD controls. The primary outcome was incidence of positive COVID-19 PCR following vaccination between December, 2020 to June, 2021.

Results

12,640 IBD patients received two vaccine doses; the matched cohort included 4,946 matched pairs (total 9,892 subjects). Mean age was 50.5±16.1 years and median follow-up was 22 weeks (range 4.1–24.4). Fifteen (0.3%) vaccinated IBD patients tested positive compared with 15 (0.3%) vaccinated non-IBD controls (OR=1 [95%CI 0.49–2.05], p=1.0). Patients on anti-TNF and/or corticosteroids did not have a higher incidence of positivity – neither compared to the entire group nor to IBD patients treated with vedolizumab/ustekinumab, even after precise matching for demographics, underlying diseases and IBD severity.

Conclusion

In a large population-based cohort of IBD patients in Israel, vaccine effectiveness was equivalent to non-IBD controls and was not influenced by treatment with anti-TNF or corticosteroids. Notwithstanding previous findings of impaired serological response in anti-TNF treated IBD patients, this real-world large-scale study shows that vaccine protection is robust in IBD patients, including those on immunosuppressive medications.
DOP52 Development of a host-microbe interaction workflow to reveal the cell- and condition-specific effects of a commensal bacteria upon IBD
Authors: Potari-gul L , Modos D , Fonseca S , Madgwick M , Thomas J P , Sudhakar P , Booth C , Stentz R , Carding S R , Korcsmaros T
Published: January 2022

Background

Humans are colonized by complex microbial communities which contribute to physiological processes in the host. The communication between microbes and host is crucial to maintain the homeostasis and gut health. Disruption in the microbiome composition leads to increased inflammation and appearance of diseases, such as inflammatory bowel disease (IBD). Interspecies interaction prediction combined with gene expression patterns on individual cell level by single-cell omics data reveals a new insight into the molecular background of cell-type specific host-microbe interactions.

Methods

Previously we developed the MicrobioLink pipeline (Andrighetti et al, Cells, 2020), an in silico microbe-host protein-protein interaction prediction algorithm. Here, we implemented a computational workflow based on MicrobioLink to predict and compare the cell-specific effects of a commensal bacteria in healthy and diseased conditions using a publicly available single-cell RNAseq dataset (Smilie et al, Cell, 2019) from colon biopsies describing 51 cell types - including fibroblasts, epithelial and immune cells - in healthy, non-inflamed and inflamed ulcerative colitis (UC). With functional analysis, microbe-affected processes have been discovered, while reliable network biology resources, such as OmniPath and Reactome, were used to identify the direct mechanism of action of the bacterial molecules.

Results

Demonstrating the applicability of the new computational workflow, we analysed the effect of a common gut commensal bacteria - Bacteroides thetaiotaomicron (Bt) - on human immune cells focusing on the Toll-like receptor (TLR) signalling. We found that extracellular vesicles (EVs) secreted by Bt may be able to modulate the TLR pathway intracellularly. The analysis highlighted that Bt targets differ among cells and between the same cells in healthy versus UC conditions. The in silico findings were validated in EV-monocyte co-cultures demonstrating the requirement for TLR4 and Toll-interleukin-1 receptor domain-containing adaptor protein (TIRAP) in EV-elicited NF-kB activation.

Conclusion

The current pipeline offers potentially interesting connection points and detailed mechanistic insight containing mechanistic information about microbe-host interactions. This information can be tested and harnessed to understand better how microbial proteins may be of therapeutic value in inflammatory diseases, such as IBD.