bluuebunny/crossref_metadata_2025 huggingface dataset:
Triangulating evidence from longitudinal and Mendelian randomization studies of metabolomic biomarkers for type 2 diabetes
Authors: Porcu Eleonora , Gilardi Federica , Darrous Liza , Yengo Loic , Bararpour Nasim , Gasser Marie , Marques-Vidal Pedro , Froguel Philippe , Waeber Gerard , Thomas Aurelien , Kutalik Zoltán
Published: March 2021

The number of people affected by Type 2 diabetes mellitus (T2DM) is close to half a billion and is on a sharp rise, representing a major and growing public health burden. Given its mild initial symptoms, T2DM is often diagnosed several years after its onset, leaving half of diabetic individuals undiagnosed. While several classical clinical and genetic biomarkers have been identified, improving early diagnosis by exploring other kinds of omics data remains crucial. In this study, we have combined longitudinal data from two population-based cohorts CoLaus and DESIR (comprising in total 493 incident cases vs. 1360 controls) to identify new or confirm previously implicated metabolomic biomarkers predicting T2DM incidence more than 5 years ahead of clinical diagnosis. Our longitudinal data have shown robust evidence for valine, leucine, carnitine and glutamic acid being predictive of future conversion to T2DM. We confirmed the causality of such association for leucine by 2-sample Mendelian randomisation (MR) based on independent data. Our MR approach further identified new metabolites potentially playing a causal role on T2D, including betaine, lysine and mannose. Interestingly, for valine and leucine a strong reverse causal effect was detected, indicating that the genetic predisposition to T2DM may trigger early changes of these metabolites, which appear well-before any clinical symptoms. In addition, our study revealed a reverse causal effect of metabolites such as glutamic acid and alanine. Collectively, these findings indicate that molecular traits linked to the genetic basis of T2DM may be particularly promising early biomarkers.
Real time observation of the interaction between aluminium salts and sweat under microfluidic conditions
Authors: Sakhawoth Yasine , Dupire Jules , Leonforte Fabien , Chardon Marion , Monti Fabrice , Tabeling Patrick , Cabane Bernard , Botet Robert , Galey Jean-Baptiste
Published: March 2021

Aluminium salts such as aluminium chlorohydrate (ACH) are the active ingredients of antiperspirant products. Their mechanism of action involves a temporary and superficial plugging of eccrine sweat pores at the skin surface. We developed a microfluidic system that allows the real time observation of the interactions between sweat and ACH in conditions mimicking physiological sweat flow and pore dimensions. Using artificial sweat containing bovine serum albumin as a model protein, we performed experiments under flowing conditions to demonstrate that pore clogging results from the aggregation of proteins by aluminium polycations at specific location in the sweat pore. Combining microfluidic experiments, confocal microscopy and numerical models helps to better understand the physical chemistry and mechanisms involved in pore plugging. The results show that plugging starts from the walls of sweat pores before expanding into the centre of the channel. The simulations aid in explaining the influence of ACH concentration as well as the impact of flow conditions on the localization of the plug. Altogether, these results outline the potential of both microfluidic confocal observations and numerical simulations at the single sweat pore level to understand why aluminium polycations are so efficient for sweat channel plugging.
A dose-escalating toxicology study of the candidate biologic ELP-VEGF
Authors: Waller Jamarius P. , Burke Stephen P. , Engel Jason , Chade Alejandro R. , Bidwell Gene L.
Published: March 2021

Vascular Endothelial Growth Factor (VEGF), a key mediator of angiogenesis and vascular repair, is reduced in chronic ischemic renal diseases, leading to microvascular rarefaction and deterioration of renal function. We developed a chimeric fusion of human VEGF-A121 with the carrier protein Elastin-like Polypeptide (ELP-VEGF) to induce therapeutic angiogenesis via targeted renal VEGF therapy. We previously showed that ELP-VEGF improves renal vascular density, renal fibrosis, and renal function in swine models of chronic renal diseases. However, VEGF is a potent cytokine that induces angiogenesis and increases vascular permeability, which could cause undesired off-target effects or be deleterious in a patient with a solid tumor. Therefore, the current study aims to define the toxicological profile of ELP-VEGF and assess its risk for exacerbating tumor progression and vascularity using rodent models. A dose escalating toxicology assessment of ELP-VEGF was performed by administering a bolus intravenous injection at doses ranging from 0.1 to 200 mg/kg in Sprague Dawley (SD) rats. Blood pressure, body weight, and glomerular filtration rate (GFR) were quantified longitudinally, and terminal blood sampling and renal vascular density measurements were made 14 days after treatment. Additionally, the effects of a single administration of ELP-VEGF (0.1–10 mg/kg) on tumor growth rate, mass, and vascular density were examined in a mouse model of breast cancer. At doses up to 200 mg/kg, ELP-VEGF had no effect on body weight, caused no changes in plasma or urinary markers of renal injury, and did not induce renal fibrosis or other histopathological findings in SD rats. At the highest doses (100–200 mg/kg), ELP-VEGF caused an acute, transient hypotension (30 min), increased GFR, and reduced renal microvascular density 14 days after injection. In a mouse tumor model, ELP-VEGF did not affect tumor growth rate or tumor mass, but analysis of tumor vascular density by micro-computed tomography (μCT) revealed significant, dose dependent increases in tumor vascularity after ELP-VEGF administration. ELP-VEGF did not induce toxicity in the therapeutic dosing range, and doses one hundred times higher than the expected maximum therapeutic dose were needed to observe any adverse signs in rats. In breast tumor—bearing mice, ELP-VEGF therapy induced a dose-dependent increase in tumor vascularity, demanding caution for potential use in a patient suffering from kidney disease but with known or suspected malignancy.
Radon and thoron levels in the dwellings of Buddonithanda: a village in the environs of proposed uranium mining site, Nalgonda district, Telangana state, India
Authors: Suman G. , Vinay Kumar Reddy K. , Sreenath Reddy M. , Gopal Reddy Ch. , Yadagiri Reddy P.
Published: March 2021

Elevated levels of radon and thoron in the indoor atmosphere may cause the deleterious effects on the mankind. Mining sites and their environs attract a special interest in radon studies as higher levels are frequently reported in the habitats. In the present study, radon and thoron levels were measured in the dwellings of Buddonithanda, a village in the environs of proposed uranium mining site, with pin-hole (SSNTDs) dosimeters for the period of a year. The measured radon and thoron levels were found to vary widely from 14 to 675 Bq m−3 (geometric mean = 94 Bq m−3) and from 21 to 704 Bq m−3 (geometric mean = 121 Bq m−3), respectively. An attempt was made to understand the large spatial variation of these levels. The seasonal and diurnal variation studies were used in unraveling the behavior of the radioactive isotopes in indoor environment and the same was explained with the help of a simplified mathematical model. Quantification of inhalation dose due to radon and thoron was done with suitable occupancy factors.
Significance of lactate clearance in septic shock patients with high bilirubin levels
Authors: Takahashi Nozomi , Nakada Taka-aki , Walley Keith R. , Russell James A.
Published: March 2021

Lactate clearance is affected by hepatic function. However, it is unclear whether the association between hepatic dysfunction and lactate clearance can act as a prognostic marker of clinical outcomes in patients with septic shock. We aimed to evaluate the association between lactate clearance and mortality in two cohorts of septic shock patient who had hepatic dysfunction based on their total serum bilirubin levels (TBIL). Lactate clearance at 24 h after the onset of septic shock was analyzed using two cohorts, sub-categorized into two groups based on TBIL: < 2 mg/dL and ≥ 2 mg/dL. In the derivation cohort, lactate clearance was lower in non-survivors than in survivors with TBIL ≥ 2 mg/dL, while there was no significant difference in lactate clearance between non-survivors and survivors with TBIL < 2 mg/dL. Multivariate logistic regression analysis revealed that increased lactate clearance was significantly associated with decreased 28-day mortality in the TBIL ≥ 2 mg/dL group (10% lactate clearance, adjusted odds ratio [OR]: 0.88, 95% confidence interval (CI): 0.80–0.97, P = 0.0075), Creatinine level ≥ 2 mg/dL group (adjusted OR: 0.88, 95% CI: 0.81–0.95, P = 0.00069) and APACHE II score ≥ 35 group (adjusted OR: 0.93, 95% CI: 0.87–0.98, P = 0.013). In the validation cohort, lactate clearance was lower in non-survivors than in survivors with TBIL ≥ 2 mg/dL, while no significant difference in lactate clearance was observed between non-survivors and survivors with TBIL < 2 mg/dL. Increased lactate clearance was significantly associated with decreased 28-day mortality in the TBIL ≥ 2 mg/dL group (10% lactate clearance, adjusted OR: 0.89, 95% CI: 0.83–0.96, P = 0.0038) and the association was just about significant in APACHE II score ≥ 35 group (adjusted OR: 0.86, 95% CI: 0.74–1.00, P = 0.051). In conclusion, increased lactate clearance in septic shock patients with hepatic dysfunction (TBIL ≥ 2 mg/dL) or high severity (APACHE II score ≥ 35) was associated with decreased 28-day mortality.
Destruction of Staphylococcus aureus biofilms by combining an antibiotic with subtilisin A or calcium gluconate
Authors: Liu JingJing , Madec Jean-Yves , Bousquet-Mélou Alain , Haenni Marisa , Ferran Aude A.
Published: March 2021

In S. aureus biofilms, bacteria are embedded in a matrix of extracellular polymeric substances (EPS) and are highly tolerant to antimicrobial drugs. We thus sought to identify non-antibiotic substances with broad-spectrum activity able to destroy the EPS matrix and enhance the effect of antibiotics on embedded biofilm bacteria. Among eight substances tested, subtilisin A (0.01 U/mL) and calcium gluconate (CaG, Ca2+ 1.25 mmol/L) significantly reduced the biomass of biofilms formed by at least 21/24 S. aureus isolates. Confocal laser scanning microscopy confirmed that they both eliminated nearly all the proteins and PNAG from the matrix. By contrast, antibiotics alone had nearly no effect on biofilm biomass and the selected one (oxytetracycline-OTC) could only slightly reduce biofilm bacteria. The combination of OTC with CaG or subtilisin A led to an additive reduction (average of 2 log10 CFU/mL) of embedded biofilm bacteria on the isolates susceptible to OTC (MBC < 10 μg/mL, 11/24). Moreover, these two combinations led to a reduction of the embedded biofilm bacteria higher than 3 log10 CFU/mL for 20–25% of the isolates. Further studies are now required to better understand the factors that cause the biofilm produced by specific isolates (20–25%) to be susceptible to the combinations.
Anti-mucin 1 chimeric antigen receptor T cells for adoptive T cell therapy of cholangiocarcinoma
Authors: Supimon Kamonlapat , Sangsuwannukul Thanich , Sujjitjoon Jatuporn , Phanthaphol Nattaporn , Chieochansin Thaweesak , Poungvarin Naravat , Wongkham Sopit , Junking Mutita , Yenchitsomanus Pa-thai
Published: March 2021

Current treatments for cholangiocarcinoma (CCA) are largely unsuccessful due to late diagnosis at advanced stage, leading to high mortality rate. Consequently, improved therapeutic approaches are urgently needed. Chimeric antigen receptor (CAR) T cell therapy is a newly potential therapy that can recognize specific surface antigen without major histocompatibility complex (MHC) restriction. Mucin 1 (MUC1) is an attractive candidate antigen as it is highly expressed and associated with poor prognosis and survival in CCA. We, therefore, set forth to create the fourth-generation CAR (CAR4) construct containing anti-MUC1-single-chain variable fragment (scFv) and three co-stimulatory domains (CD28, CD137, and CD27) linked to CD3ζ and evaluate anti-MUC1-CAR4 T cells in CCA models. Compared to untransduced T cells, anti-MUC1-CAR4 T cells produced increased levels of TNF-α, IFN-γ and granzyme B when exposed to MUC1-expressing KKU-100 and KKU-213A CCA cells (all p < 0.05). Anti-MUC1-CAR4 T cells demonstrated specific killing activity against KKU-100 (45.88 ± 7.45%, p < 0.05) and KKU-213A cells (66.03 ± 3.14%, p < 0.001) at an effector to target ratio of 5:1, but demonstrated negligible cytolytic activity against immortal cholangiocytes. Furthermore, the anti-MUC1-CAR4 T cells could effectively disrupt KKU-213A spheroids. These activities of anti-MUC1-CAR4 T cells supports the development of this approach as an adoptive T cell therapeutic strategy for CCA.
A global association between Covid-19 cases and airborne particulate matter at regional level
Authors: Solimini Angelo , Filipponi F. , Fegatelli D. Alunni , Caputo B. , De Marco C. M. , Spagnoli A. , Vestri A. R.
Published: March 2021

Evidences of an association between air pollution and Covid-19 infections are mixed and inconclusive. We conducted an ecological analysis at regional scale of long-term exposure to air-borne particle matter and spread of Covid-19 cases during the first wave of epidemics. Global air pollution and climate data were calculated from satellite earth observation data assimilated into numerical models at 10 km resolution. Main outcome was defined as the cumulative number of cases of Covid-19 in the 14 days following the date when > 10 cumulative cases were reported. Negative binomial mixed effect models were applied to estimate the associations between the outcome and long-term exposure to air pollution at the regional level (PM10, PM2.5), after adjusting for relevant regional and country level covariates and spatial correlation. In total we collected 237,749 Covid-19 cases from 730 regions, 63 countries and 5 continents at May 30, 2020. A 10 μg/m3increase of pollution level was associated with 8.1% (95% CI 5.4%, 10.5%) and 11.5% (95% CI 7.8%, 14.9%) increases in the number of cases in a 14 days window, for PM2.5and PM10respectively. We found an association between Covid-19 cases and air pollution suggestive of a possible causal link among particulate matter levels and incidence of COVID-19.
Long-term treated HIV infection is associated with platelet mitochondrial dysfunction
Authors: van der Heijden Wouter A. , van de Wijer Lisa , Jaeger Martin , Grintjes Karin , Netea Mihai G. , Urbanus Rolf T. , van Crevel Reinout , van den Heuvel Lambertus P. , Brink Maaike , Rodenburg Richard J. , de Groot Philip G. , van der Ven Andre J. , de Mast Quirijn
Published: March 2021

HIV infection and antiretroviral therapy have been linked to mitochondrial dysfunction. The role of platelet mitochondrial dysfunction in thrombosis, immunoregulation and age-related diseases is increasingly appreciated. Here, we studied platelet mitochondrial DNA content (mtDNApl) and mitochondrial function in people living with HIV (PLHIV) and related this to platelet function. In a cohort of 208 treated PLHIV and 56 uninfected controls, mtDNApl was quantified, as well as platelet activation, platelet agonist-induced reactivity and inflammation by circulating factors and flow cytometry. In a subgroup of participants, the metabolic activity of platelets was further studied by mitochondrial function tests and the Seahorse Flux Analyzer. PLHIV had significantly lower mtDNApl compared to controls (8.5 copies/platelet (IQR: 7.0–10.7) vs. 12.2 copies/platelet (IQR: 9.5–16.6); p < 0.001), also after correction for age, sex and BMI. Prior zidovudine-use (n = 46) was associated with a trend for lower mtDNApl. PLHIV also had reduced ex vivo platelet reactivity and mean platelet volume compared to controls. MtDNApl correlated positively with both platelet parameters and correlated negatively with inflammatory marker sCD163. Mitochondrial function tests in a subgroup of participants confirmed the presence of platelet mitochondrial respiration defects. Platelet mitochondrial function is disturbed in PLHIV, which may contribute to platelet dysfunction and subsequent complications. Interventions targeting the preservation of normal platelet mitochondrial function may ultimately prove beneficial for PLHIV.
Low CETP activity and unique composition of large VLDL and small HDL in women giving birth to small-for-gestational age infants
Authors: Roland Marie Cecilie Paasche , Godang Kristin , Aukrust Pål , Henriksen Tore , Lekva Tove
Published: March 2021

Cholesteryl ester transfer protein (CETP) regulates high density lipoproteins (HDL)-cholesterol (C) and HDL-C is essential for fetal development. We hypothesized that women giving birth to large-for-gestational-age (LGA) and small-for-gestational age (SGA) infants differed in longitudinal changes in lipoproteins, CETP activity and HDL-C and that placentas from women with higher or lower circulating HDL-C displayed differential expression of mRNAs involved in cholesterol/nutrient transport, insulin signaling, inflammation/ extracellular matrix (ECM) remodeling. Circulating lipids and CETP activity was measured during pregnancy, NMR lipidomics in late pregnancy, and associations with LGA and SGA infants investigated. RNA sequencing was performed in 28 placentas according to higher and lower maternal HDL-C levels. Lipidomics revealed high triglycerides in large VLDL and lipids/cholesterol/cholesteryl esters in small HDL in women giving birth to SGA infants. Placentas from women with higher HDL-C had decreased levels ofCETPexpression which was associated with mRNAs involved in cholesterol/nutrient transport, insulin signaling and inflammation/ECM remodeling. Both placental and circulating CETP levels were associated with growth of the fetus. Low circulating CETP activity at 36–38 weeks was associated with giving birth to SGA infants. Our findings suggest a link between increased maternal HDL-C levels, low CETP levels both in circulation and placenta, and SGA infants.
Influential factors and spatial–temporal distribution of tuberculosis in mainland China
Authors: Bie Siyu , Hu Xijian , Zhang Huiguo , Wang Kai , Dou Zhihui
Published: March 2021

Tuberculosis (TB) is an infectious disease that threatens human safety. Mainland China is an area with a high incidence of tuberculosis, and the task of tuberculosis prevention and treatment is arduous. This paper aims to study the impact of seven influencing factors and spatial–temporal distribution of the relative risk (RR) of tuberculosis in mainland China using the spatial–temporal distribution model and INLA algorithm. The relative risks and confidence intervals (CI) corresponding to average relative humidity, monthly average precipitation, monthly average sunshine duration and monthly per capita GDP were 1.018 (95% CI 1.001–1.034), 1.014 (95% CI 1.006–1.023), 1.026 (95% CI 1.014–1.039) and 1.025 (95% CI 1.011–1.040). The relative risk for average temperature and pressure were 0.956 (95% CI 0.942–0.969) and 0.767 (95% CI 0.664–0.875). Spatially, the two provinces with the highest relative risks are Xinjiang and Guizhou, and the remaining provinces with higher relative risks were mostly concentrated in the Northwest and South China regions. Temporally, the relative risk decreased year by year from 2013 to 2015. It was higher from February to May each year and was most significant in March. It decreased from June to December. Average relative humidity, monthly average precipitation, monthly average sunshine duration and monthly per capita GDP had positive effects on the relative risk of tuberculosis. The average temperature and pressure had negative effects. The average wind speed had no significant effect. Mainland China should adapt measures to local conditions and develop tuberculosis prevention and control strategies based on the characteristics of different regions and time.
Metabolomics analysis reveals a modified amino acid metabolism that correlates with altered oxygen homeostasis in COVID-19 patients
Authors: Páez-Franco José C. , Torres-Ruiz Jiram , Sosa-Hernández Víctor A. , Cervantes-Díaz Rodrigo , Romero-Ramírez Sandra , Pérez-Fragoso Alfredo , Meza-Sánchez David E. , Germán-Acacio Juan Manuel , Maravillas-Montero José L. , Mejía-Domínguez Nancy R. , Ponce-de-León Alfredo , Ulloa-Aguirre Alfredo , Gómez-Martín Diana , Llorente Luis
Published: March 2021

We identified the main changes in serum metabolites associated with severe (n = 46) and mild (n = 19) COVID-19 patients by gas chromatography coupled to mass spectrometry. The modified metabolic profiles were associated to an altered amino acid catabolism in hypoxic conditions. Noteworthy, three α-hydroxyl acids of amino acid origin increased with disease severity and correlated with altered oxygen saturation levels and clinical markers of lung damage. We hypothesize that the enzymatic conversion of α-keto-acids to α- hydroxyl-acids helps to maintain NAD recycling in patients with altered oxygen levels, highlighting the potential relevance of amino acid supplementation during SARS-CoV-2 infection.
Simulations with Australian dragon lizards suggest movement-based signal effectiveness is dependent on display structure and environmental conditions
Authors: Bian Xue , Pinilla Angela , Chandler Tom , Peters Richard
Published: March 2021

Habitat-specific characteristics can affect signal transmission such that different habitats dictate the optimal signal. One way to examine how the environment influences signals is by comparing changes in signal effectiveness in different habitats. Examinations of signal effectiveness between different habitats has helped to explain signal divergence/convergence between populations and species using acoustic and colour signals. Although previous research has provided evidence for local adaptations and signal divergence in many species of lizards, comparative studies in movement-based signals are rare due to technical difficulties in quantifying movements in nature and ethical restrictions in translocating animals between habitats. We demonstrate herein that these issues can be addressed using 3D animations, and compared the relative performance of the displays of four Australian lizard species in the habitats of each species under varying environmental conditions. Our simulations show that habitats differentially affect signal performance, and an interaction between display and habitat structure. Interestingly, our results are consistent with the hypothesis that the signal adapted to the noisier environment does not show an advantage in signal effectiveness, but the noisy habitat was detrimental to the performance of all displays. Our study is one of the first studies for movement-based signals that directly compares signal performance in multiple habitats, and our approach has laid the foundation for future investigations in motion ecology that have been intractable to conventional research methods.
Estimating included animal species in mixed crude drugs derived from animals using massively parallel sequencing
Authors: Nakanishi Hiroaki , Yoneyama Katsumi , Hara Masaaki , Takada Aya , Saito Kazuyuki
Published: March 2021

We developed a method that can detect each animal species of origin for crude drugs derived from multiple animal species based on massively parallel sequencing analysis of mitochondrial genes. The crude drugs derived from animals investigated in this study were Cervi Parvum Cornu and Trogopterorum feces, which are derived from a mix of different animal species, two chopped cicada sloughs, and two commercial Kampo drugs. The mitochondrial 12S rRNA, 16S rRNA, and cytochrome oxidase subunit I gene regions were amplified and sequenced using MiSeq. The ratios of haplotype to total number of sequences reads were calculated after sequence extraction and trimming. Haplotypes that exceeded the threshold were defined as positive haplotypes, which were compared with all available sequences using BLAST. In the Cervi Parvum Cornu and Trogopterorum feces samples, the haplotype ratios corresponded roughly to the mixture ratios, although there was a slight difference from mixture ratios depending on the gene examined. This method could also roughly estimate the compositions of chopped cicada sloughs and Kampo drugs. This analysis, whereby the sequences of several genes are elucidated, is better for identifying the included animal species. This method should be useful for quality control of crude drugs and Kampo drugs.
Impact of comorbidity burden on mortality in patients with COVID-19 using the Korean health insurance database
Authors: Cho Soo Ick , Yoon Susie , Lee Ho-Jin
Published: March 2021

We aimed to investigate the impact of comorbidity burden on mortality in patients with coronavirus disease (COVID-19). We analyzed the COVID-19 data from the nationwide health insurance claims of South Korea. Data on demographic characteristics, comorbidities, and mortality records of patients with COVID-19 were extracted from the database. The odds ratios of mortality according to comorbidities in these patients with and without adjustment for age and sex were calculated. The predictive value of the original Charlson comorbidity index (CCI) and the age-adjusted CCI (ACCI) for mortality in these patients were investigated using the receiver operating characteristic (ROC) curve analysis. Among 7590 patients, 227 (3.0%) had died. After age and sex adjustment, hypertension, diabetes mellitus, congestive heart failure, dementia, chronic pulmonary disease, liver disease, renal disease, and cancer were significant risk factors for mortality. The ROC curve analysis showed that an ACCI threshold > 3.5 yielded the best cut-off point for predicting mortality (area under the ROC 0.92; 95% confidence interval 0.91–0.94). Our study revealed multiple risk factors for mortality in patients with COVID-19. The high predictive power of the ACCI for mortality in our results can support the importance of old age and comorbidities in the severity of COVID-19.
Algal magnetic nickel oxide nanocatalyst in accelerated synthesis of pyridopyrimidine derivatives
Authors: Moavi Javad , Buazar Foad , Sayahi Mohammad Hosein
Published: March 2021

This research presents a novel biological route for the biosynthesis of nickel oxide nanoparticles (NiO NPs) using marine macroalgae extract as a reducing and coating agent under optimized synthesis conditions. XRD and TEM analyses revealed that phytosynthesized NiO NPs are crystalline in nature with a spherical shape having a mean particle size of 32.64 nm. TGA results indicated the presence of marine-derived organic constituents on the surface of NiO NPs. It is found that biogenic NiO NPs with BET surface area of 45.59 m2g−1 is a highly efficient catalyst for benign one-pot preparation of pyridopyrimidine derivatives using aqueous reaction conditions. This environmentally friendly procedure takes considerable advantages of shorter reaction times, excellent product yields (up to 96%), magnetically viable nanocatalyst (7 runs), low catalyst loadings, and free toxic chemical reagents.
Quercetin can reduce viral RNA level of O’nyong-nyong virus and resulting innate immune cytokine responses in cultured human synovial fibroblasts
Authors: Septembre-Malaterre Axelle , Bedoui Yosra , Giry Claude , Gasque Philippe , Guiraud Pascale , Sélambarom Jimmy
Published: March 2021

O’nyong-nyong virus is an alphavirus closely related to chikungunya virus, causing arthralgia, rash and fever. Alphaviruses mainly target synovial fibroblasts and persists in the joints of patients, possibly leading to chronic arthritis. To date, no specific antiviral treatment is available for ONNV infection and induced-inflammation. Primary human synovial fibroblasts cells were used to assess infection by ONNV and the resulting cytokine responses. Phenolics (gallic acid, caffeic acid and chlorogenic acid, curcumin and quercetin) and a curcuminoids-rich extract from turmeric were tested for their antiviral and anti-inflammatory capacities. We showed that infection occurred in HSF cells and increased gene expression and protein secretion of two major proinflammatory CCL-2 and IL-1β markers. In ONNV-infected HSF cells (MOI 1), we found that non-cytotoxic concentrations of phenolics (10 µM) reduced the level of viral RNA (E1, E2, nsP1, nsP2) and downregulated CCL-2 and IL-1β expression and secretion. These results highlighted the high value of the flavonol quercetin to reduce viral RNA levels and inflammatory status induced by ONNV in HSF cells.
Oculomotor anticipation reveals a multitude of learning processes underlying the serial reaction time task
Authors: Tal Amir , Bloch Ayala , Cohen-Dallal Haggar , Aviv Or , Schwizer Ashkenazi Simone , Bar Moshe , Vakil Eli
Published: March 2021

Sequence learning is the cognitive faculty enabling everyday skill acquisition. In the lab, it is typically measured in speed of response to sequential stimuli, whereby faster responses are taken to indicate improved anticipation. However, response speed is an indirect measure of anticipation, that can provide only limited information on underlying processes. As a result, little is known about what is learned during sequence learning, and how that unfolds over time. In this work, eye movements that occurred before targets appeared on screen in an ocular serial reaction time (O-SRT) task provided an online indication of where participants anticipated upcoming targets. When analyzed in the context of the stimuli preceding them, oculomotor anticipations revealed several simultaneous learning processes. These processes influenced each other, as learning the task grammar facilitated acquisition of the target sequence. However, they were dissociable, as the grammar was similarly learned whether a repeating sequence inhabited the task or not. Individual differences were found in how the different learning processes progressed, allowing for similar performance to be produced for different latent reasons. This study provides new insights into the processes subserving sequence learning, and a new method for high-resolution study of it.
Prognostic impacts of glucocorticoid treatment in patients with polymyalgia rheumatica and giant cell arteritis
Authors: Emamifar Amir , Ellingsen Torkell , Hermann Anne Pernille , Hess Søren , Gerke Oke , Ahangarani Farahani Ziba , Syrak Hansen Per , Jensen Hansen Inger Marie , Thye-Rønn Peter
Published: March 2021

Identifying comorbidities in polymyalgia rheumatica/giant cell arteritis (PMR/GCA) is crucial for patients’ outcomes. The present study aimed to evaluate the impact of the inflammatory process and glucocorticoid treatment on aortic arterial stiffness and body composition in PMR/GCA. 77 patients with newly diagnosed PMR/GCA were treated with oral glucocorticoids and followed for 40 weeks. Aortic pulse wave velocity (PWV) was measured at baseline and during the follow-up period and compared to the results of temporal artery biopsy (TAB) and 18F-FDG PET/CT. Body composition was assessed by total body DXA at baseline and the end of the study. Of 77 patients (49 (63.6%) female, mean of age: (71.8 ± 8.0)), 64 (83.1%) had pure PMR, 10 (13.0%) concomitant PMR and GCA, and 3 (3.9%) pure GCA. Compared to baseline values, aortic PWV was initially decreased at week 16 (p = 0.010) and remained lower than baseline at week 28 (p = 0.002) and week 40 (p < 0.001), with no association with results of TAB and 18F-FDG PET/CT. Aortic PWV was significantly associated with age, male gender, left systolic and diastolic blood pressure, right diastolic blood pressure, and CRP. Total bone mineral content (BMC) was decreased in both genders (p < 0.001), while fat mass (FM) was significantly increased (p < 0.001). However, lean body mass did not significantly change during the study. Changes in FM were correlated with cumulative prednisolone dose (rho: 0.26, p = 0.031). Glucocorticoid treatment of patients with PMR/GCA had several prognostic impacts. Arterial stiffness was decreased due either to the treatment or a reduction in the inflammatory load. Additionally, treatment led to changes in body composition, including a decrease in BMC and FM excess.
Curvature sensing amphipathic helix in the C-terminus of RTNLB13 is conserved in all endoplasmic reticulum shaping reticulons in Arabidopsis thaliana
Authors: Brooks Rhiannon L. , Mistry Chandni S. , Dixon Ann M.
Published: March 2021

The reticulon family of integral membrane proteins are conserved across all eukaryotes and typically localize to the endoplasmic reticulum (ER), where they are involved in generating highly-curved tubules. We recently demonstrated that Reticulon-like protein B13 (RTNLB13) from Arabidopsis thaliana contains a curvature-responsive amphipathic helix (APH) important for the proteins’ ability to induce curvature in the ER membrane, but incapable of generating curvature by itself. We suggested it acts as a feedback element, only folding/binding once a sufficient degree of curvature has been achieved, and stabilizes curvature without disrupting the bilayer. However, it remains unclear whether this is unique to RTNLB13 or is conserved across all reticulons—to date, experimental evidence has only been reported for two reticulons. Here we used biophysical methods to characterize a minimal library of putative APH peptides from across the 21 A. thaliana isoforms. We found that reticulons with the closest evolutionary relationship to RTNLB13 contain curvature-sensing APHs in the same location with sequence conservation. Our data reveal that a more distantly-related branch of reticulons developed a ~ 20-residue linker between the transmembrane domain and APH. This may facilitate functional flexibility as previous studies have linked these isoforms not only to ER remodeling but other cellular activities.
Proteomic blood profiling in mild, severe and critical COVID-19 patients
Authors: Patel Hamel , Ashton Nicholas J. , Dobson Richard J. B. , Andersson Lars-Magnus , Yilmaz Aylin , Blennow Kaj , Gisslen Magnus , Zetterberg Henrik
Published: March 2021

The recent SARS-CoV-2 pandemic manifests itself as a mild respiratory tract infection in most individuals, leading to COVID-19 disease. However, in some infected individuals, this can progress to severe pneumonia and acute respiratory distress syndrome (ARDS), leading to multi-organ failure and death. This study explores the proteomic differences between mild, severe, and critical COVID-19 positive patients to further understand the disease progression, identify proteins associated with disease severity, and identify potential therapeutic targets. Blood protein profiling was performed on 59 COVID-19 mild (n = 26), severe (n = 9) or critical (n = 24) cases and 28 controls using the OLINK inflammation, autoimmune, cardiovascular and neurology panels. Differential expression analysis was performed within and between disease groups to generate nine different analyses. From the 368 proteins measured per individual, more than 75% were observed to be significantly perturbed in COVID-19 cases. Six proteins (IL6, CKAP4, Gal-9, IL-1ra, LILRB4 and PD-L1) were identified to be associated with disease severity. The results have been made readily available through an interactive web-based application for instant data exploration and visualization, and can be accessed at https://phidatalab-shiny.rosalind.kcl.ac.uk/COVID19/. Our results demonstrate that dynamic changes in blood proteins associated with disease severity can potentially be used as early biomarkers to monitor disease severity in COVID-19 and serve as potential therapeutic targets.
Comparative transcriptome analysis during developmental stages of direct somatic embryogenesis in Tilia amurensis Rupr
Authors: Kang Hye-In , Lee Chae-Bin , Kwon Soon-Ho , Park Ji-Min , Kang Kyu-Suk , Shim Donghwan
Published: March 2021

Tilia species are valuable woody species due to their beautiful shape and role as honey trees. Somatic embryogenesis can be an alternative method for mass propagation of T. amurensis. However, the molecular mechanisms of T. amurensis somatic embryogenesis are yet to be known. Here, we conducted comparative transcriptional analysis during somatic embryogenesis of T. amurensis. RNA-Seq identified 1505 differentially expressed genes, including developmental regulatory genes. Auxin related genes such as YUC, AUX/IAA and ARF and signal transduction pathway related genes including LEA and SERK were differentially regulated during somatic embryogenesis. Also, B3 domain family (LEC2, FUS3), VAL and PKL, the regulatory transcription factors, were differentially expressed by somatic embryo developmental stages. Our results could provide plausible pathway of signaling somatic embryogenesis of T. amurensis, and serve an important resource for further studies in direct somatic embryogenesis in woody plants.
Systemic immunity markers associated with lymphocytes predict the survival benefit from paclitaxel plus bevacizumab in HER2 negative advanced breast cancer
Authors: Nakamoto Shogo , Ikeda Masahiko , Kubo Shinichiro , Yamamoto Mari , Yamashita Tetsumasa , Notsu Akifumi
Published: March 2021

Although paclitaxel plus bevacizumab (PB) therapy is an effective chemotherapeutic regimen for HER2-negative advanced breast cancer (ABC), predictive markers for its effectiveness remain undefined. We investigated the usefulness of systemic immunity markers associated with lymphocytes as predictive markers for PB therapy in patients with HER2-negative ABC. We retrospectively reviewed data from 114 patients with HER2-negative ABC who underwent PB therapy from November 2011 to December 2019. We calculated the absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) as representative systemic immunity markers. The time to treatment failure (TTF) and overall survival (OS) of the patients with high ALC, low NLR, and high LMR were significantly longer compared with those of the patients with low ALC, high NLR, and low LMR. A multivariable analysis revealed that high ALC, low NLR, and low PLR were independent predictors for TTF and high ALC, low NLR, and high LMR were independent predictors for OS. Systemic immunity markers were significantly associated with longer TTF and OS in patients who underwent PB therapy and may represent predictive markers for PB therapy in patients with HER2-negative ABC.
Enhancing flotation separation of chalcopyrite and magnesium silicate minerals by surface synergism between PAAS and GA
Authors: Chen Zhiqiang , Wang Yanhong , Luo Liqun , Peng Tiefeng , Guo Feng , Zheng Mingyu
Published: March 2021

Separation effects of sodium polyacrylate (PAAS) and gum Arabic (GA) on flotation of chalcopyrite and magnesium silicate minerals using potassium butyl xanthate (PBX) as collector were investigated by micro-flotation experiments, zeta potential, Infrared spectral (IR), SEM–EDS, XPS analysis and copper sulphide ore beneficiation test. The micro-flotation experiments and zeta potential measurements showed that combined depressant consisting of PAAS and GA could efficiently reduce the recoveries of mixed minerals of serpentine and talc more than 25%, while that of chalcopyrite remained above 70% at pH 9.2. Infrared spectral (IR), SEM–EDS and XPS analysis showed that PAAS chemically reacted with Mg on the surface of serpentine, while GA adsorbed on talc surface mainly via physical interaction and hydrogen bond may also play a role. Surface synergism between PAAS and GA was investigated by turbidity test and its depression mechanism was proposed. The technology feasibility of using PAAS and GA to improve the copper sulphide ore flotation performance was verified through artificial mixed ore flotation and laboratory closed-flotation operation.
A ceRNA-associated risk model predicts the poor prognosis for head and neck squamous cell carcinoma patients
Authors: Xu Yuzi , Xu Fengqin , Lv Yiming , Wang Siyuan , Li Jia , Zhou Chuan , Jiang Jimin , Xie Binbin , He Fuming
Published: March 2021

Head and neck squamous cell carcinoma (HNSCC) is one of the most malignant cancers with poor prognosis worldwide. Emerging evidence indicates that competing endogenous RNAs (ceRNAs) are involved in various diseases, however, the regulatory mechanisms of ceRNAs underlying HNSCC remain unclear. In this study, we retrieved differentially expressed long non-coding RNAs (DElncRNAs), messenger RNAs (DEmRNAs) and microRANs (DEmiRNAs) from The Cancer Genome Atlas database and constructed a ceRNA-based risk model in HNSCC by integrated bioinformatics approaches. Functional enrichment analyses showed that DEmRNAs might be involved in extracellular matrix related biological processes, and protein–protein interaction network further selected out prognostic genes, including MYL1 and ACTN2. Importantly, co-expressed RNAs identified by weighted co-expression gene network analysis constructed the ceRNA networks. Moreover, AC114730.3, AC136375.3, LAT and RYR3 were highly correlated to overall survival of HNSCC by Kaplan–Meier method and univariate Cox regression analysis, which were subsequently implemented multivariate Cox regression analysis to build the risk model. Our study provides a deeper understanding of ceRNAs on the regulatory mechanisms, which will facilitate the expansion of the roles on the ceRNAs in the tumorigenesis, development and treatment of HNSCC.
Immunomodulatory effect of Noni fruit and its isolates: insights into cell-mediated immune response and inhibition of LPS-induced THP-1 macrophage inflammation
Authors: Ezzat Marwa I. , Hassan Mariam , Abdelhalim Mai A. , EL-Desoky Ahmed M. , Mohamed Shanaz O. , Ezzat Shahira M.
Published: March 2021

Immunomodulatory activity of Morinda citrifolia and its isolated compounds.
Effects of applied voltage on water at a gold electrode interface from ab initio molecular dynamics
Authors: Goldsmith Zachary K. , Calegari Andrade Marcos F. , Selloni Annabella
Published: March 2021

Ab initio molecular dynamics of an aqueous electrode interface reveal the electrostatic, structural, and dynamic effects of quantifiable voltage biases on water.
A Conceptual Framework for Understanding Speaking Dyspnea
Authors: Lansing Robert W. , Hoit Jeannette D.
Published: March 2021

Purpose

A conceptual framework is proposed to better understand the experience of people who have dyspnea (breathing discomfort) when speaking: its nature, its physiological mechanisms, and its impacts on their lives.

Method

The components of the framework are presented in their natural order. They are a Speaking Domain (Speaking Activities and Speaking Variables), a Physiological Domain (Speech Breathing Variables and Physiological Mechanisms), a Perceptual Domain (Dyspnea), a Symptom Impact Domain (Emotional Responses, Immediate Behavioral Responses, and Long-Term Behavioral Response), and a Life Impact Domain (Short-Term Impacts and Long-Term Impacts).

Results

We discuss literature that most directly supports these components and includes findings from healthy people and those with disorders in whom speaking dyspnea was either evoked or measured. Caveats are noted where information is limited and further study is needed. A case example is provided to illustrate how to apply the framework.

Conclusions

This framework provides a broader view of the elements that contribute to the experience of speaking dyspnea. It is meant to guide researchers, clinicians, instructors, caregivers, and those for whom speaking dyspnea is a daily or even a life-long challenge.
An algorithm for fitting passive equivalent circuits for lumped parameter frequency dependent transmission line models
Authors: Challa Kiran Kumar , Gurrala Gurunath , Mukherjee Pritam
Published: March 2021

Accurately fitting rational functions to the frequency response of modal impedances is crucial for including frequency dependency in lumped parameter models of transmission lines. Vector fitting is widely used for fitting rational functions to the frequency response of modal impedances and then an R‐L equivalent circuit is obtained from the rational functions. A single‐step method based on the properties of Foster equivalent circuit is proposed to directly fit an R‐L equivalent circuit to the frequency response of modal impedances. The positive peaks, negative peaks and the positive zero crossings of the slope change plot of the frequency response are found to provide a good approximation of zeros, poles and the flat region locations of the frequency response. An enhanced fitting algorithm is proposed based on these observations. A close enough fitting is achieved using the proposed method with less number of passive elements. Using the proposed model in EMTP‐RV, 400, 765, 1200 kV transmission lines and a 11‐bus 500 kV network are simulated for switching transients. The results are compared with the constant parameter cascaded ‐model and the Frequency‐dependent line model in EMTP‐RV. The switching transient results of the proposed model are found to be comparable to the Marti's model in EMTP‐RV.
An image encryption algorithm with a plaintext‐related quantisation scheme
Authors: Oravec Jakub , Ovseník Ľuboš , Papaj Ján
Published: March 2021

This paper describes an image encryption algorithm that utilises a plaintext‐related quantisation scheme. Various plaintext‐related approaches from other algorithms are presented and their properties are briefly discussed. Main advantage of the proposed solution is the achievement of a similar behaviour like that of more complex approaches with a plaintext‐related technique used in a rather simple step such as quantisation. This design should result in a favourable computational complexity of the whole algorithm. The properties of the proposal are evaluated by a number of commonly used numerical parameters. Also, the statistical properties of a pseudo‐random sequence that is quantised according to the plain image pixel intensities are investigated by tests from NIST 800‐22 suite. Obtained results are compared to values reported in related works and they imply that the proposed solution produces encrypted images with comparable statistical properties but authors' design is faster and more efficient.
MSR‐FAN: Multi‐scale residual feature‐aware network for crowd counting
Authors: Zhao Haoyu , Min Weidong , Wei Xin , Wang Qi , Fu Qiyan , Wei Zitai
Published: March 2021

Crowd counting aims to count the number of people in crowded scenes, which is important to the security systems, traffic control and so on. The existing methods typically using local features cannot properly handle the perspective distortion and the varying scales in congested scene images, and henceforth perform wrong people counting. To alleviate this issue, this study proposes a multi‐scale residual feature‐aware network (MSR‐FAN) that combines multi‐scale features using multiple receptive field sizes and learns the feature‐aware information on each image. The MSR‐FAN is trained end‐to‐end to generate high‐quality density map and evaluate the crowd number. The method consists of three parts. To handle the perspective changes problem, the first part, the direction‐based feature‐enhanced network, is designed to encode the perspective information in four directions based on the initial image feature. The second part, the proposed multi‐scale residual block module, gets the global information to handle the represent the regional feature better. This module explores features of different scales as well as reinforce the global feature. The third part, the feature‐aware block, is designed to extract the feature hidden in the different channels. Experiment results based on benchmark datasets show that the proposed approach outperforms the existing state‐of‐the‐art methods.