bluuebunny/crossref_metadata_2025 huggingface dataset:
Pathological Functions of LRRK2 in Parkinson’s Disease
Authors: Jeong Ga Ram , Lee Byoung Dae
Published: December 2020

Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are common genetic risk factors for both familial and sporadic Parkinson’s disease (PD). Pathogenic mutations in LRRK2 have been shown to induce changes in its activity, and abnormal increase in LRRK2 kinase activity is thought to contribute to PD pathology. The precise molecular mechanisms underlying LRRK2-associated PD pathology are far from clear, however the identification of LRRK2 substrates and the elucidation of cellular pathways involved suggest a role of LRRK2 in microtubule dynamics, vesicular trafficking, and synaptic transmission. Moreover, LRRK2 is associated with pathologies of α-synuclein, a major component of Lewy bodies (LBs). Evidence from various cellular and animal models supports a role of LRRK2 in the regulation of aggregation and propagation of α-synuclein. Here, we summarize our current understanding of how pathogenic mutations dysregulate LRRK2 and discuss the possible mechanisms leading to neurodegeneration.
TCR Gene Therapy: Challenges, Opportunities, and Future Directions
Authors: Stauss Hans J. , Tran Maxine G. B.
Published: December 2020

Adoptive immunotherapy with gene-engineered T cells has provided new treatment options for cancer patients [...]
Gains or Losses in Forest Productivity under Climate Change? The Uncertainty of CO2 Fertilization and Climate Effects
Authors: Sperlich Dominik , Nadal-Sala Daniel , Gracia Carlos , Kreuzwieser Jürgen , Hanewinkel Marc , Yousefpour Rasoul
Published: December 2020

Global warming poses great challenges for forest managers regarding adaptation strategies and species choices. More frequent drought events and heat spells are expected to reduce growth and increase mortality. Extended growing seasons, warming and elevated CO2 (eCO2) can also positively affect forest productivity. We studied the growth, productivity and mortality of beech (Fagus sylvatica L.) and fir (Abies alba Mill.) in the Black Forest (Germany) under three climate change scenarios (representative concentration pathways (RCP): RCP2.6, RCP4.5, RCP8.5) using the detailed biogeochemical forest growth model GOTILWA+. Averaged over the entire simulation period, both species showed productivity losses in RCP2.6 (16–20%) and in RCP4.5 (6%), but productivity gains in RCP8.5 (11–17%). However, all three scenarios had a tipping point (between 2035–2060) when initial gains in net primary productivity (NPP) (6–29%) eventually turned into losses (1–26%). With eCO2 switched off, the losses in NPP were 26–51% in RCP2.6, 36–45% in RCP4.5 and 33–71% in RCP8.5. Improved water-use efficiency dampened drought effects on NPP between 4 and 5%. Tree mortality increased, but without notably affecting forest productivity. Concluding, cultivation of beech and fir may still be possible in the study region, although severe productivity losses can be expected in the coming decades, which will strongly depend on the dampening CO2 fertilization effect.
Assessment of Peripheral Nervous System Alterations in Patients with the Fabry Related GLA-Variant p.A143T
Authors: Godel Tim , von Cossel Katharina , Friedrich Reinhard E. , Glatzel Markus , Canaan-Kühl Sima , Duning Thomas , Kronlage Moritz , Heiland Sabine , Bendszus Martin , Muschol Nicole , Mautner Victor-Felix
Published: December 2020

The purpose of this study is to examine alterations of the peripheral nervous system (PNS) in oligo-symptomatic patients carrying the Fabry related GLA-gene variant p.A143T by Magnetic Resonance Neurography (MRN) and skin biopsy. This prospective study assessed dorsal root ganglia (DRG) volume L3 to S2, vascular permeability of the DRG L5, S1, and the spinal nerve L5 in five patients carrying p.A143T in comparison to patients with classical Fabry mutations and healthy controls. Moreover, skin punch biopsies above the lateral malleolus of the right foot were obtained in four patients and intraepidermal nerve fiber density (IENFD) was counted individually. Compared to controls, DRG volumes of p.A143T patients were enlarged by 30% (L3, p < 0.05), 35% (L4, p < 0.05), 29% (L5, p = 0.15), 36% (S1, p < 0.01), and 18% (S2, p < 0.05), but less pronounced compared to patients carrying a classical Fabry mutation. Compared to healthy controls, vascular permeability was decreased by 40% (L5 right), 49% (L5 left), 48% (S1 right), and 49% (S1) (p < 0.01–p < 0.001), but non-significant less than patients carrying a classical Fabry mutation. Compared to sex-matched 5% lower normative reference values per decade, IENFD was decreased in three of four patients. MRN and determination of IENFD is able to detect early alteration of the PNS segment in oligo-symptomatic patients with the disease-modifying GLA-variant p.A143T on an individual basis. This procedure might also help in further GLA-variants of uncertain significance for early identification of patients with single major organ manifestation.
High-PSRR Wide-Range Supply-Independent CMOS Voltage Reference for Retinal Prosthetic Systems
Authors: Zawawi Ruhaifi Bin Abdullah , Choi Hojong , Kim Jungsuk
Published: December 2020

This paper presents a fully integrated voltage-reference circuit for implantable devices such as retinal implants. The recently developed retinal prostheses require a stable supply voltage to drive a high-density stimulator array. Accordingly, a voltage-reference circuit plays a critical role in generating a constant reference voltage, which is provided to a low-voltage-drop regulator (LDO), and filtering out the AC ripples in a power-supply rail after rectification. For this purpose, we use a beta-multiplier voltage-reference architecture to which a nonlinear current sink circuit is added, to improve the supply-independent performance drastically. The proposed reference circuit is fabricated using the standard 0.35 µm technology, along with an LDO that adopts an output ringing compensation circuit. The novel reference circuit generates a reference voltage of 1.37 V with a line regulation of 3.45 mV/V and maximum power-supply rejection ratio (PSRR) of −93 dB.
Acetylation Treatment for the Batch Processing of Natural Fibers: Effects on Constituents, Tensile Properties and Surface Morphology of Selected Plant Stem Fibers
Authors: Oladele Isiaka Oluwole , Michael Omokafe Seun , Adediran Adeolu Adesoji , Balogun Oluwayomi Peter , Ajagbe Folorunso Ojo
Published: December 2020

This work was on the comparative evaluation of the property effects obtainable when acetylation is applied to parts of selected agro fibers that are obtainable within common localities. The fibers were subjected to different concentrations of acetylation treatment at ambient temperature for 3 h. The physico-chemical, morphological, and tensile properties of the fibers were examined after the treatment. It was discovered from the results that the procedures variedly influenced the constituents of the fibers, their resulting tensile properties as well as their post-acetylation treatment surface morphology. The proportion of crystalline cellulose in the starting fibers greatly influenced their post treatment composition, behaviour and properties. The results show that plantain fibers had the highest aspect ratios, followed by banana fibers with values of about 1000 and 417, respectively. These fibers exhibited the least density and are thus potential plant fibers for composite development. Banana fiber had the least density of about 1.38 g/cm3 while that of DombeyaBuettneri fiber possessed the highest value of 1.5 g/cm3. There was significant enhancement in the hemicellulose content of Combretum Racemosum, while the lignin content of the plantain fibers was highly reduced. The treatment favoured the enhancement of the tensile properties in Combretum Racemosum fibers, which had enhanced tensile strength and strain at all compositions of the treatment. Optimum tensile strength and strain values of 155 MPa and 0.046, respectively, are achieved at 4% composition. Dombeya Buettneri fibers showed the highest ultimate tensile strength among the plant fibers in the untreated condition, which was gradually decreased as the concentration of the reagents was increased. Overall, 4% acetylation treatment is optimum for tensile properties’ enhancement for most of the natural fibers evaluated.
Rapid Profiling of the Volatilome of Cooked Meat by PTR-ToF-MS: Characterization of Chicken, Turkey, Pork, Veal and Beef Meat
Authors: Ni Qianlin , Khomenko Iuliia , Gallo Luigi , Biasioli Franco , Bittante Giovanni
Published: December 2020

This study aimed to compare the volatile organic compound (VOC) profiles of cooked meat from different species. Four burgers were prepared and cooked from each of 100 meat samples obtained from 100 animals of five species/categories (chicken, turkey, pork, veal and beef) sourced from five supermarkets and five local butchers. Two burgers were cooked in a water bath and two were grilled. Direct proton-transfer-reaction time-of-flight mass-spectrometry (PTR-ToF-MS) analysis of the sample headspace yielded 129 mass peaks, 64 of which were tentatively identified. The results showed that turkey and chicken had the largest and the smallest total concentrations of all VOCs, respectively. Of the mammalian meats, veal and beef had greater total VOC concentrations than pork. The proportions of the amounts of all the individual VOCs differed significantly according to species. Additionally, 14 of 17 independent latent explanatory factors (LEFs) identified by multivariate analysis exhibited significant differences between meat species/categories, and therefore helped to characterize them. PTR-ToF-MS has been used for the first time for the rapid and non-invasive profiling of cooked meat of different species/categories. Knowledge of specific VOC profiles paves new avenues for research aimed at characterizing species through sensory description, at authenticating species or at identifying abnormalities or fraud.
Analysis of SF-6D Health State Utility Scores: Is Beta Regression Appropriate?
Authors: Kharroubi Samer A
Published: December 2020

Background: Typically, modeling of health-related quality of life data is often troublesome since its distribution is positively or negatively skewed, spikes at zero or one, bounded and heteroscedasticity. Objectives: In the present paper, we aim to investigate whether Bayesian beta regression is appropriate for analyzing the SF-6D health state utility scores and respondent characteristics. Methods: A sample of 126 Lebanese members from the American University of Beirut valued 49 health states defined by the SF-6D using the standard gamble technique. Three different models were fitted for SF-6D via Bayesian Markov chain Monte Carlo (MCMC) simulation methods. These comprised a beta regression, random effects and random effects with covariates. Results from applying the three Bayesian beta regression models were reported and compared based on their predictive ability to previously used linear regression models, using mean prediction error (MPE), root mean squared error (RMSE) and deviance information criterion (DIC). Results: For the three different approaches, the beta regression model was found to perform better than the normal regression model under all criteria used. The beta regression with random effects model performs best, with MPE (0.084), RMSE (0.058) and DIC (−1621). Compared to the traditionally linear regression model, the beta regression provided better predictions of observed values in the entire learning sample and in an out-of-sample validation. Conclusions: Beta regression provides a flexible approach to modeling health state values. It also accounted for the boundedness and heteroscedasticity of the SF-6D index scores. Further research is encouraged.
Prosthetic Joint Infection: Updates on Prevention, Diagnosis and Therapy
Authors: Gallo Jiri
Published: December 2020

Total joint arthroplasty (TJA) delivers highly valuable outcomes to patients with end-stage joint diseases [...]
NO Synthesis Markers Are Not Significantly Associated with Blood Pressure and Endothelial Dysfunction in Patients with Arterial Hypertension: A Cross-Sectional Study
Authors: Malle Oliver , Trummer Christian , Theiler-Schwetz Verena , Meinitzer Andreas , Keppel Martin H. , Grübler Martin R. , Tomaschitz Andreas , Voelkl Jakob , März Winfried , Pilz Stefan
Published: December 2020

Nitric oxide (NO) synthesis markers, comprising L-homoarginine, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), are significantly associated with cardiovascular events and mortality. Being involved in NO pathways, they may be of high importance regulating vascular tone and arterial hypertension, but data on this topic are sparse and controversial. In this study, we evaluated whether these NO synthesis markers are associated with blood pressure values and pulse wave velocity (PWV). This analysis was based on the data of the Styrian Vitamin D Hypertension Trial, which included adults with arterial hypertension. We analyzed correlations of NO synthesis markers with 24 h ambulatory blood pressure values and PWV (primary outcomes), as well as with anthropometric and laboratory data. A total of 509 patients were included in the present analysis. The mean age was 61.2 ± 10.5 years, mean PWV was 8.6 ± 2.4 m/s, mean 24 h systolic blood pressure was 127.5 ± 13.8 mmHg and mean 24 h diastolic blood pressure was 76.4 ± 9.5 mmHg. In bivariate analyses, there was a significant positive correlation between homoarginine and 24 h diastolic blood pressure (r = 0.1; p = 0.02), which was revealed to be no longer significant after adjustment for age, gender and glomerular filtration rate (GFR) in multivariate regression analysis. No other significant correlations of any NO synthesis markers with blood pressure or PWV were observed. In line with previous studies, there were inverse associations between homoarginine and age and between ADMA or SDMA and GFR (p < 0.05 for all). This study did not reveal a significant association between homoarginine, ADMA or SDMA and blood pressure or PWV in hypertensive adults. These results suggested that the associations of these parameters with adverse outcome may not be mediated by hypertension and/or endothelial dysfunction.
Metabolomic Profiles Predict Diabetes Remission after Bariatric Surgery
Authors: Ha Jane , Jang Mi , Kwon Yeongkeun , Park Young Suk , Park Do Joong , Lee Joo-Ho , Lee Hyuk-Joon , Ha Tae Kyung , Kim Yong-Jin , Han Sang-Moon , Han Sang-Uk , Heo Yoonseok , Park Sungsoo
Published: December 2020

Background: Amino acid metabolites (AAMs) have been linked to glucose homeostasis and type 2 diabetes (T2D). We investigated whether (1) baseline AAMs predict T2D remission 12 months after bariatric surgery and (2) whether AAMs are superior for predicting T2D remission postoperatively compared with existing prediction models. Methods: Among 24 participants undergoing bariatric surgery, 16 diabetes-related AAMs were quantified at baseline and postoperative 3 and 12 months. Existing prediction models included the ABCD, DiaRem, and IMS models. Results: Baseline L-dihydroxyphenylalanine (L-DOPA) (areas under receiver operating characteristic curves (AUROC), 0.92; 95% confidence interval (CI), 0.75 to 1.00) and 3-hydroxyanthranilic acid (3-HAA) (AUROC, 0.85; 95% CI, 0.67 to 1.00) better predicted T2D remission 12 months postoperatively than the ABCD model (AUROC, 0.81; 95% CI, 0.54 to 1.00), which presented the highest AUROC value among the three models. The superior prognostic performance of L-DOPA (AUROC at 3 months, 0.97; 95% CI, 0.91 to 1.00) and 3-HAA (AUROC at 3 months, 0.86; 95% CI, 0.63 to 1.00) continued until 3 months postoperatively. Conclusions: The AAM profile predicts T2D remission after bariatric surgery more effectively than the existing prediction models.
Sequence Variation in the DDAH1 Gene Predisposes for Delayed Cerebral Ischemia in Subarachnoidal Hemorrhage
Authors: Hannemann Juliane , Appel Daniel , Seeberger-Steinmeister Miriam , Brüning Tabea , Zummack Julia , Böger Rainer
Published: December 2020

Delayed cerebral ischemia (DCI) often causes poor long-term neurological outcome after subarachnoidal hemorrhage (SAH). Asymmetric dimethylarginine (ADMA) inhibits nitric oxide synthase (NOS) and is associated with DCI after SAH. We studied single nucleotide polymorphisms (SNPs) in the NOS3, DDAH1, DDAH2, PRMT1, and AGXT2 genes that are part of the L-arginine–ADMA–NO pathway, and their association with DCI. We measured L-arginine, ADMA and symmetric dimethylarginine (SDMA) in plasma and cerebrospinal fluid (CSF) of 51 SAH patients at admission; follow-up was until 30 days post-discharge. The primary outcome was the incidence of DCI, defined as new infarctions on cranial computed tomography, which occurred in 18 of 51 patients. Clinical scores did not significantly differ in patients with or without DCI. However, DCI patients had higher plasma ADMA and SDMA levels and higher CSF SDMA levels at admission. DDAH1 SNPs were associated with plasma ADMA, whilst AGXT2 SNPs were associated with plasma SDMA. Carriers of the minor allele of DDAH1 rs233112 had a significantly increased relative risk of DCI (Relative Risk = 2.61 (1.25–5.43), p = 0.002). We conclude that the DDAH1 gene is associated with ADMA concentration and the incidence of DCI in SAH patients, suggesting a pathophysiological link between gene, biomarker, and clinical outcome in patients with SAH.
New OPTN Simultaneous Liver-Kidney Transplant (SLKT) Policy Improves Racial and Ethnic Disparities
Authors: Goyes Daniela , Nsubuga John Paul , Medina-Morales Esli , Patwardhan Vilas , Bonder Alan
Published: December 2020

(1) Background: On 10 August 2017, the Organ Procurement and Transplantation Network (OPTN) adopted standardized eligibility criteria to properly determine which transplant candidates should undergo Simultaneous Liver-Kidney Transplant (SLKT). Racial and ethnic disparities have not been examined after 2017. Therefore, using the United Network for Organ Sharing (UNOS), we aim to evaluate post-graft survival outcomes among Caucasians, African Americans, and Hispanics. (2) Methods: Kaplan–Meier curves and Cox regression models are used to compare post-transplant graft survival for Caucasians, African Americans (AAs), and Hispanics. Competing risk analysis is used to evaluate the cumulative incidence of death or re-transplantation with re-transplantation and death as competing risks. (3) Results: On multivariate Cox regression analysis, no differences in graft survival are found in AA (hazard ratio (HR): 1.30; 95% CI: 0.74–2.29 p = 0.354) or Hispanics (HR: 1.18; 95% CI: 0.70–2 p = 0.520) compared to Caucasians after 2017. On competing risk analysis of the risk of death with re-transplantation as a competing risk, no difference is found between ethnic minorities after 2017. There is a similar finding from competing risk analysis of the risk of re-transplantation with death as a competing risk. (4) Conclusion: After introducing standardized eligibility criteria for SLKT allocation, the post-graft survival outcomes remain similar between the different racial and ethnic groups, displaying the benefits of adopting such policy in 2017.
Analyses of AUC(0–12) and C0 Compliances within Therapeutic Ranges in Kidney Recipients Receiving Cyclosporine or Tacrolimus
Authors: Radzevičienė Aurelija , Marquet Pierre , Maslauskienė Rima , Vaičiūnienė Rūta , Kaduševičius Edmundas , Stankevičius Edgaras
Published: December 2020

The AUC (area under the concentration time curve) is considered the pharmacokinetic exposure parameter best associated with clinical effects. Unfortunately, no prospective studies of clinical outcomes have been conducted in adult transplant recipients to investigate properly the potential benefits of AUC(0–12) monitoring compared to the C0-guided therapy. The aim of the present study was to compare two methods, C0 (through level) and AUC(0–12) (area under the concentration time curve), for assessing cyclosporine and tacrolimus concentrations. The study included 340 kidney recipients. The AUC(0–12) was estimated using a Bayesian estimator and a three-point limited sampling strategy. Therapeutic drug monitoring of tacrolimus performed by using AUC(0–12) and C0 showed that tacrolimus in most cases is overdosed when considering C0, while determination of the AUC(0–12) showed that tacrolimus is effectively dosed for 27.8–40.0% of patients receiving only tacrolimus and for 25.0–31.9% of patients receiving tacrolimus with MMF (mycophenolate mofetil). In the 1–5 years post-transplantation group, 10% higher CsA (cyclosporine) dose was observed, which was proportionate with a 10% higher AUC(0–12) exposure value. This indicates good compatibility of the dosage and the AUC(0–12) method. The Bland–Altman plot demonstrated that C0 and AUC(0–12) might be interchangeable methods, while the ROC (receiver operating characteristic) curve analysis of the C0/AUC(0–12) ratio in the tacrolimus-receiving patient group demonstrated reliable performance to predict IFTA (interstitial fibrosis and tubular atrophy) after kidney transplantation, with an ROC curve of 0.660 (95% confidence interval (CI): 0.576–0.736), p < 0.01. Moreover, AUC(0–12) and C0 of tacrolimus depend on concomitant medication and adjustment of the therapeutic range for AUC(0–12) might influence the results.
Numerical and Experimental Study of Flow Field between the Main Hull and Demi-Hull of a Trimaran
Authors: Sun Cong , Guo Chunyu , Wang Chao , Wang Lianzhou , Lin Jianfeng
Published: December 2020

The interactions between the main hull and demi-hull of trimarans have been arousing increasing attention, and detailed circumferential flow fields greatly influence trimaran research. In this research, the unsteady wake flow field of a trimaran was obtained by Reynolds-Averaged Navier-Stokes (RANS) equations on the basis of the viscous flow principles with consideration of the heaving and pitching of the trimaran. Then, we designed an experimental method based on particle-image velocimetry (PIV) and obtained a detailed flow field between the main hull and demi-hull of the trimaran. A trimaran model with one demi-hull made of polycarbonate material with 90% light transmission rate and a refractive index 1.58 (close to that of water 1.33) was manufactured as the experiment sample. Using polycarbonate material, the laser-sheet light-source transmission and high-speed camera recording problems were effectively rectified. Moreover, a nonstandard calibration was added into the PIV flow field measurement system. Then, we established an inverse three-dimensional (3D) distortion coordinate system and obtained the corresponding coordinates by using optics calculations. Further, the PIV system spatial mapping was corrected, and the real flow field was obtained. The simulation results were highly consistent with the experimental data, which showed the methods established in this study provided a strong reference for obtaining the detailed flow field information between the main hull and demi-hull of trimarans.
The Relationship between Autism and Ehlers-Danlos Syndromes/Hypermobility Spectrum Disorders
Authors: Casanova Emily L. , Baeza-Velasco Carolina , Buchanan Caroline B. , Casanova Manuel F.
Published: December 2020

Considerable interest has arisen concerning the relationship between hereditary connective tissue disorders such as the Ehlers-Danlos syndromes (EDS)/hypermobility spectrum disorders (HSD) and autism, both in terms of their comorbidity as well as co-occurrence within the same families. This paper reviews our current state of knowledge, as well as highlighting unanswered questions concerning this remarkable patient group, which we hope will attract further scientific interest in coming years. In particular, patients themselves are demanding more research into this growing area of interest, although science has been slow to answer that call. Here, we address the overlap between these two spectrum conditions, including neurobehavioral, psychiatric, and neurological commonalities, shared peripheral neuropathies and neuropathologies, and similar autonomic and immune dysregulation. Together, these data highlight the potential relatedness of these two conditions and suggest that EDS/HSD may represent a subtype of autism.
Geochemical Characteristics and Uranium Neutral Leaching through a CO2 + O2 System—An Example from Uranium Ore of the ELZPA Ore Deposit in Pakistan
Authors: Asghar Fiaz , Sun Zhanxue , Chen Gongxin , Zhou Yipeng , Li Guangrong , Liu Haiyan , Zhao Kai
Published: December 2020

Geochemical characterization studies and batch leaching experiments were conducted to explore the effects of a CO2 + O2 leaching system on uranium (U) recovery from ores obtained from an eastern limb of Zinda Pir Anticline ore deposit in Pakistan. The mineralogy of the ore was identified by Electron Probe Micro-analyzer (EPMA) and Scanning Electron Microscope-Energy Dispersive Spectrometer (SEM-EDS), showing that pitchblende is the main ore mineral. XRD was also used along with EPMA and SEM characterization data. Experimental results indicate that U mobility was readily facilitated in the CO2 + O2 system with Eh 284 mV and pH 6.24, and an 86% recovery rate of U3O8 was obtained. U speciation analysis implied the formation of UO2 (CO3)22− in the pregnant solution. The plausible mechanism may be attributed to the dissolved CO2 gas that forms carbonate/bicarbonate ion releasing oxidized U from the ore mineral. However, U recovery in the liquid phase was shown to decrease by higher U(VI) initial concentration, which may be due to the saturation of Fe adsorption capacity, as suggested by an increase in Fe concentration with increasing initial U(VI) concentration in the solid phase. However, further studies are needed to reveal the influencing mechanism of U(VI) initial concentration on U recovery in the solid phase. This study provides new insights on the feasibility and validity of the site application of U neutral in situ leaching.
Integrative Metabolomics to Identify Molecular Signatures of Responses to Vaccines and Infections
Authors: Diray-Arce Joann , Conti Maria Giulia , Petrova Boryana , Kanarek Naama , Angelidou Asimenia , Levy Ofer
Published: December 2020

Approaches to the identification of metabolites have progressed from early biochemical pathway evaluation to modern high-dimensional metabolomics, a powerful tool to identify and characterize biomarkers of health and disease. In addition to its relevance to classic metabolic diseases, metabolomics has been key to the emergence of immunometabolism, an important area of study, as leukocytes generate and are impacted by key metabolites important to innate and adaptive immunity. Herein, we discuss the metabolomic signatures and pathways perturbed by the activation of the human immune system during infection and vaccination. For example, infection induces changes in lipid (e.g., free fatty acids, sphingolipids, and lysophosphatidylcholines) and amino acid pathways (e.g., tryptophan, serine, and threonine), while vaccination can trigger changes in carbohydrate and bile acid pathways. Amino acid, carbohydrate, lipid, and nucleotide metabolism is relevant to immunity and is perturbed by both infections and vaccinations. Metabolomics holds substantial promise to provide fresh insight into the molecular mechanisms underlying the host immune response. Its integration with other systems biology platforms will enhance studies of human health and disease.
Metabolic Drug Response Phenotyping in Colorectal Cancer Organoids by LC-QTOF-MS
Authors: Neef Sylvia K. , Janssen Nicole , Winter Stefan , Wallisch Svenja K. , Hofmann Ute , Dahlke Marc H. , Schwab Matthias , Mürdter Thomas E. , Haag Mathias
Published: December 2020

As metabolic rewiring is crucial for cancer cell proliferation, metabolic phenotyping of patient-derived organoids is desirable to identify drug-induced changes and trace metabolic vulnerabilities of tumor subtypes. We established a novel protocol for metabolomic and lipidomic profiling of colorectal cancer organoids by liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) facing the challenge of capturing metabolic information from a minimal sample amount (<500 cells/injection) in the presence of an extracellular matrix (ECM). The best procedure of the tested protocols included ultrasonic metabolite extraction with acetonitrile/methanol/water (2:2:1, v/v/v) without ECM removal. To eliminate ECM-derived background signals, we implemented a data filtering procedure based on the p-value and fold change cut-offs, which retained features with signal intensities >120% compared to matrix-derived signals present in blank samples. As a proof-of-concept, the method was applied to examine the early metabolic response of colorectal cancer organoids to 5-fluorouracil treatment. Statistical analysis revealed dose-dependent changes in the metabolic profiles of treated organoids including elevated levels of 2′-deoxyuridine, 2′-O-methylcytidine, inosine and 1-methyladenosine and depletion of 2′-deoxyadenosine and specific phospholipids. In accordance with the mechanism of action of 5-fluorouracil, changed metabolites are mainly involved in purine and pyrimidine metabolism. The novel protocol provides a first basis for the assessment of metabolic drug response phenotypes in 3D organoid models.
Hedgehogs, Squirrels, and Blackbirds as Sentinel Hosts for Active Surveillance of Borrelia miyamotoi and Borrelia burgdorferi Complex in Urban and Rural Environments
Authors: Majerová Karolina , Hönig Václav , Houda Michal , Papežík Petr , Fonville Manoj , Sprong Hein , Rudenko Natalie , Golovchenko Maryna , Černá Bolfíková Barbora , Hulva Pavel , Růžek Daniel , Hofmannová Lada , Votýpka Jan , Modrý David
Published: December 2020

Lyme borreliosis (LB), caused by spirochetes of the Borrelia burgdorferi sensu lato (s.l.) complex, is one of the most common vector-borne zoonotic diseases in Europe. Knowledge about the enzootic circulation of Borrelia pathogens between ticks and their vertebrate hosts is epidemiologically important and enables assessment of the health risk for the human population. In our project, we focused on the following vertebrate species: European hedgehog (Erinaceus europaeus), Northern white-breasted hedgehog (E. roumanicus), Eurasian red squirrel (Sciurus vulgaris), and Common blackbird (Turdus merula). The cadavers of accidentally killed animals used in this study constitute an available source of biological material, and we have confirmed its potential for wide monitoring of B. burgdorferi s.l. presence and genospecies diversity in the urban environment. High infection rates (90% for E. erinaceus, 73% for E. roumanicus, 91% for S. vulgaris, and 68% for T. merula) were observed in all four target host species; mixed infections by several genospecies were detected on the level of individuals, as well as in particular tissue samples. These findings show the usefulness of multiple tissue sampling as tool for revealing the occurrence of several genospecies within one animal and the risk of missing particular B. burgdorferi s.l. genospecies when looking in one organ alone.
Reduction of Hg(II) by Fe(II)-Bearing Smectite Clay Minerals
Authors: O’Loughlin Edward J. , Boyanov Maxim I. , Kemner Kenneth M. , Thalhammer Korbinian O.
Published: December 2020

Aluminosilicate clay minerals are often a major component of soils and sediments and many of these clays contain structural Fe (e.g., smectites and illites). Structural Fe(III) in smectite clays is redox active and can be reduced to Fe(II) by biotic and abiotic processes. Fe(II)-bearing minerals such as magnetite and green rust can reduce Hg(II) to Hg(0); however, the ability of other environmentally relevant Fe(II) phases, such as structural Fe(II) in smectite clays, to reduce Hg(II) is largely undetermined. We conducted experiments examining the potential for reduction of Hg(II) by smectite clay minerals containing 0–25 wt% Fe. Fe(III) in the clays (SYn-1 synthetic mica-montmorillonite, SWy-2 montmorillonite, NAu-1 and NAu-2 nontronite, and a nontronite from Cheney, Washington (CWN)) was reduced to Fe(II) using the citrate-bicarbonate-dithionite method. Experiments were initiated by adding 500 µM Hg(II) to reduced clay suspensions (4 g clay L−1) buffered at pH 7.2 in 20 mM 3-morpholinopropane-1-sulfonic acid (MOPS). The potential for Hg(II) reduction in the presence of chloride (0–10 mM) and at pH 5–9 was examined in the presence of reduced NAu-1. Analysis of the samples by Hg LIII-edge X-ray absorption fine structure (XAFS) spectroscopy indicated little to no reduction of Hg(II) by SYn-1 (0% Fe), while reduction of Hg(II) to Hg(0) was observed in the presence of reduced SWy-2, NAu-1, NAu-2, and CWN (2.8–24.8% Fe). Hg(II) was reduced to Hg(0) by NAu-1 at all pH and chloride concentrations examined. These results suggest that Fe(II)-bearing smectite clays may contribute to Hg(II) reduction in suboxic/anoxic soils and sediments.
Minerals in Pregnancy and Their Impact on Child Growth and Development
Authors: Farias Patricia Miranda , Marcelino Gabriela , Santana Lidiani Figueiredo , de Almeida Eliane Borges , Guimarães Rita de Cássia Avellaneda , Pott Arnildo , Hiane Priscila Aiko , Freitas Karine de Cássia
Published: December 2020

During pregnancy, women undergo metabolic and physiological changes, and their needs are higher, to maintain growth and development of the fetus. If the nutritional status of the expectant mother is not satisfactory, some maternal and neonatal complications can occur. In the second and third trimester of pregnancy, there is a reserve of nutrients in the fetus that can be utilized after birth; thereby, children present an accelerated growth in the first years of life, which is a proven response to the available nutrition pattern. However, if such a pattern is insufficient, there will be deficits during development, including brain function. Therefore, despite many recent published works about gestational nutrition, uncertainties still remain on the mechanisms of absorption, distribution, and excretion of micronutrients. Further elucidation is needed to better understand the impacts caused either by deficiency or excess of some micronutrients. Thus, to illustrate the contributions of minerals during prenatal development and in children, iodine, selenium, iron, zinc, calcium, and magnesium were selected. Our study sought to review the consequences related to gestational deficiency of the referred minerals and their impact on growth and development in children born from mothers with such deficiencies
Shock Processing of Amino Acids Leading to Complex Structures—Implications to the Origin of Life
Authors: Singh Surendra V. , Vishakantaiah Jayaram , Meka Jaya K. , Sivaprahasam Vijayan , Chandrasekaran Vijayanand , Thombre Rebecca , Thiruvenkatam Vijay , Mallya Ambresh , Rajasekhar Balabhadrapatruni N. , Muruganantham Mariyappan , Datey Akshay , Hill Hugh , Bhardwaj Anil , Jagadeesh Gopalan , Reddy Kalidevapura P. J. , Mason Nigel J. , Sivaraman Bhalamurugan
Published: December 2020

The building blocks of life, amino acids, are believed to have been synthesized in the extreme conditions that prevail in space, starting from simple molecules containing hydrogen, carbon, oxygen and nitrogen. However, the fate and role of amino acids when they are subjected to similar processes largely remain unexplored. Here we report, for the first time, that shock processed amino acids tend to form complex agglomerate structures. Such structures are formed on timescales of about 2 ms due to impact induced shock heating and subsequent cooling. This discovery suggests that the building blocks of life could have self-assembled not just on Earth but on other planetary bodies as a result of impact events. Our study also provides further experimental evidence for the ‘threads’ observed in meteorites being due to assemblages of (bio)molecules arising from impact-induced shocks.
New Freeze-Dried Andean Blueberry Juice Powders for Potential Application as Functional Food Ingredients: Effect of Maltodextrin on Bioactive and Morphological Features
Authors: Estupiñan-Amaya Mauren , Fuenmayor Carlos Alberto , López-Córdoba Alex
Published: December 2020

Andean blueberry (Vaccinium meridionale Swartz) fruits are an underutilized source of anthocyanins and other valuable bioactive phytochemicals. The purpose of this work was to obtain Andean blueberry juice powders via freeze-drying processing and evaluate the effect of maltodextrin as a drying aid on their physicochemical, technological, microstructural, and bioactive characteristics. Andean blueberry juices were mixed with variable proportions of maltodextrin (20–50%); freeze-dried; and characterized in terms of their tristimulus color, Fourier transform infrared spectra (FTIR), moisture content, water activity, morphology, water solubility, flow properties, total polyphenols and anthocyanins content, and DPPH•-scavenging capacity. The powders obtained presented suitable characteristics in terms of their water activity (<0.5), solubility (>90%), and bioactive compound recovery (>70% for total phenolics, and >60% for total monomeric anthocyanins), with antioxidant activities up to 4 mg equivalent of gallic acid/g of dry matter. Although an increased content of maltodextrin resulted in lower concentrations of phytochemicals, as expected, it also favored an increased % recovery (over 90% of total phenolics at the highest maltodextrin proportion) and improved their flow properties. Freeze-dried juice powders are a potential alternative for the stabilization and value addition of this fruit as a new source of functionality for processed foods.
Pogostemon cablin Triggered ROS-Induced DNA Damage to Arrest Cell Cycle Progression and Induce Apoptosis on Human Hepatocellular Carcinoma In Vitro and In Vivo
Authors: Huang Xiao-Fan , Sheu Gwo-Tarng , Chang Kai-Fu , Huang Ya-Chih , Hung Pei-Hsiu , Tsai Nu-Man
Published: December 2020

The purpose of the study was to elucidate the anti-hepatoma effects and mechanisms of Pogostemon cablin essential oils (PPa extract) in vitro and in vivo. PPa extract exhibited an inhibitory effect on hepatocellular carcinoma (HCC) cells and was less cytotoxic to normal cells, especially normal liver cells, than it was to HCC cells, exerting a good selective index. Additionally, PPa extract inhibited HCC cell growth by blocking the cell cycle at the G0/G1 phase via p53 dependent or independent pathway to down regulated cell cycle regulators. Moreover, PPa extract induced the FAS-FASL-caspase-8 system to activate the extrinsic apoptosis pathway, and it increased the bax/bcl-2 ratio and reduced ΔΨm to activate the intrinsic apoptosis pathway that might be due to lots of reactive oxygen species (ROS) production which was induced by PPa extract. In addition, PPa extract presented to the potential to act synergistically with sorafenib to effectively inhibit HCC cell proliferation through the Akt/mTOR pathway and reduce regrowth of HCC cells. In an animal model, PPa extract suppressed HCC tumor growth and prolonged lifespan by reducing the VEGF/VEGFR axis and inducing tumor cell apoptosis in vivo. Ultimately, PPa extract demonstrated nearly no or low system-wide, physiological, or pathological toxicity in vivo. In conclusion, PPa extract effectively inhibited HCC cell growth through inducing cell cycle arrest and activating apoptosis in vitro and in vivo. Furthermore, PPa extract exhibits less toxicity toward normal cells and organs than it does toward HCC cells, which might lead to fewer side effects in clinical applications. PPa extract may be developed into a clinical drug to suppress tumor growth or functional food to prevent HCC initiation or chemoprotection of HCC recurrence.
Synergistic Effect of Propidium Iodide and Small Molecule Antibiotics with the Antimicrobial Peptide Dendrimer G3KL against Gram-Negative Bacteria
Authors: Gan Bee-Ha , Cai Xingguang , Javor Sacha , Köhler Thilo , Reymond Jean-Louis
Published: December 2020

There is an urgent need to develop new antibiotics against multidrug-resistant bacteria. Many antimicrobial peptides (AMPs) are active against such bacteria and often act by destabilizing membranes, a mechanism that can also be used to permeabilize bacteria to other antibiotics, resulting in synergistic effects. We recently showed that G3KL, an AMP with a multibranched dendritic topology of the peptide chain, permeabilizes the inner and outer membranes of Gram-negative bacteria including multidrug-resistant strains, leading to efficient bacterial killing. Here, we show that permeabilization of the outer and inner membranes of Pseudomonas aeruginosa by G3KL, initially detected using the DNA-binding fluorogenic dye propidium iodide (PI), also leads to a synergistic effect between G3KL and PI in this bacterium. We also identify a synergistic effect between G3KL and six different antibiotics against the Gram-negative Klebsiella pneumoniae, against which G3KL is inactive.
Design of Nanosystems for the Delivery of Quorum Sensing Inhibitors: A Preliminary Study
Authors: Hallan Supandeep Singh , Marchetti Paolo , Bortolotti Daria , Sguizzato Maddalena , Esposito Elisabetta , Mariani Paolo , Trapella Claudio , Rizzo Roberta , Cortesi Rita
Published: December 2020

Biofilm production is regulated by the Quorum Sensing system. Nowadays, Quorum Sensing represents an appealing target to design new compounds to increase antibiotics effects and avoid development of antibiotics multiresistance. In this research the use of liposomes to target two novel synthetic biofilm inhibitors is presented, focusing on a preformulation study to select a liposome composition for in vitro test. Five different liposome (LP) formulations, composed of phosphatidyl choline, cholesterol and charged surfactant (2:1:1, molar ratio) have been prepared by direct hydration and extrusion. As charged surfactants dicetyl phosphate didecyldimethylammonium chloride, di isobutyl phenoxy ethyl dimethyl benzyl ammonium chloride and stearylamine (SA) and have been used. Liposome charge, size and morphology were investigated by zeta potential, photon correlation spectroscopy, small angle x-ray spectroscopy and electron microscopy. LP-SA was selected for the loading of biofilm inhibitors and subjected to high performance liquid chromatography for entrapment capacity evaluation. LP-SA loaded inhibitors showed a higher diameter (223.6 nm) as compared to unloaded ones (205.7 nm) and a dose-dependent anti-biofilm effect mainly after 48 h of treatment, while free biofilm inhibitors loose activity. In conclusion, our data supported the use of liposomes as a strategy to enhance biofilm inhibitors effect.
Human Teeth-Derived Bioceramics for Improved Bone Regeneration
Authors: Lim Ki-Taek , Patel Dinesh K. , Dutta Sayan Deb , Choung Han-Wool , Jin Hexiu , Bhattacharjee Arjak , Chung Jong Hoon
Published: December 2020

Hydroxyapatite (HAp, Ca10(PO4)6(OH)2) is one of the most promising candidates of the calcium phosphate family, suitable for bone tissue regeneration due to its structural similarities with human hard tissues. However, the requirements of high purity and the non-availability of adequate synthetic techniques limit the application of synthetic HAp in bone tissue engineering. Herein, we developed and evaluated the bone regeneration potential of human teeth-derived bioceramics in mice′s defective skulls. The developed bioceramics were analyzed by X-ray diffraction (XRD), Fourier-transform infrared (FTIR) spectroscopy, and scanning electron microscopy (FE-SEM). The developed bioceramics exhibited the characteristic peaks of HAp in FTIR and XRD patterns. The inductively coupled plasma mass spectrometry (ICP-MS) technique was applied to determine the Ca/P molar ratio in the developed bioceramics, and it was 1.67. Cytotoxicity of the simulated body fluid (SBF)-soaked bioceramics was evaluated by WST-1 assay in the presence of human alveolar bone marrow stem cells (hABMSCs). No adverse effects were observed in the presence of the developed bioceramics, indicating their biocompatibility. The cells adequately adhered to the bioceramics-treated media. Enhanced bone regeneration occurred in the presence of the developed bioceramics in the defected skulls of mice, and this potential was profoundly affected by the size of the developed bioceramics. The bioceramics-treated mice groups exhibited greater vascularization compared to control. Therefore, the developed bioceramics have the potential to be used as biomaterials for bone regeneration application.
Simple New Method for the Preparation of La(IO3)3 Nanoparticles
Authors: Hebboul Zoulikha , Ghozlane Amira , Turnbull Robin , Benghia Ali , Allaoui Sara , Liang Akun , Errandonea Daniel , Touhami Amina , Rahmani Abdellah , Lefkaier Ibn Khaldoun
Published: December 2020

We present a cost- and time-efficient method for the controlled preparation of single phase La(IO3)3 nanoparticles via a simple soft-chemical route, which takes a matter of hours, thereby providing an alternative to the common hydrothermal method, which takes days. Nanoparticles of pure α-La(IO3)3 and pure δ-La(IO3)3 were synthesised via the new method depending on the source of iodate ions, thereby demonstrating the versatility of the synthesis route. The crystal structure, nanoparticle size-dispersal, and chemical composition were characterised via angle- and energy-dispersive powder X-ray diffraction, scanning electron microscopy, and Fourier-transform infrared spectroscopy.
Left Ventricular Mass Reduction by a Low-Sodium Diet in Treated Hypertensive Patients
Authors: Musso Natale , Gatto Federico , Nista Federica , Dotto Andrea , Shen Zhongyi , Ferone Diego
Published: December 2020

Objective: To evaluate the left ventricular mass (LVM) reduction induced by dietary sodium restriction. Patients and Methods: A simple sodium-restricted diet was advised in 138 treated hypertensives. They had to avoid common salt loads, such as cheese and salt-preserved meat, and were switched from regular to salt-free bread. Blood pressure (BP), 24-h urinary sodium (UNaV) and LVM were recorded at baseline, after 2 months. and after 2years. Results: In 76 patients UNaV decreased in the recommended range after 2 months and remained low at 2 years. In 62 patients UNaV levels decreased after 2 months and then increased back to baseline at 2 years. Initially the two groups did not differ in terms of BP (134.3 ± 16.10/80.84 ± 12.23 vs. 134.2 ± 16.67/81.55 ± 11.18 mmHg, mean ± SD), body weight (72.64 ± 15.17 vs. 73.79 ± 12.69 kg), UNaV (161.0 ± 42.22 vs. 158.2 ± 48.66 mEq/24 h), and LVM index (LVMI; 97.09 ± 20.42 vs. 97.31 ± 18.91 g/m2). After 2years. they did not differ in terms of BP (125.3 ± 10.69/74.97 ± 7.67 vs. 124.5 ± 9.95/75.21 ± 7.64 mmHg) and body weight (71.14 ± 14.29 vs. 71.50 ± 11.87 kg). Significant differences were seen for UNaV (97.3 ± 23.01 vs. 152.6 ± 49.96 mEq/24 h) and LVMI (86.38 ± 18.17 vs. 103.1 ± 21.06 g/m2). Multiple regression analysis: UNaV directly and independently predicted LVMI variations, either as absolute values (R2 = 0.369; β = 0.611; p < 0.001), or changes from baseline to +2years. (R2 = 0.454; β = 0.677; p < 0.001). Systolic BP was a weaker predictor of LVMI (R2 = 0.369; β = 0.168; p = 0.027; R2 = 0.454; β = 0.012; p = 0.890), whereas diastolic BP was not correlated with LVMI. The prevalence of left ventricular hypertrophy decreased (29/76 to 15/76) in the first group while it increased in the less compliant patients (25/62 to 36/62; Chi2p = 0.002). Conclusion: LVM seems linked to sodium consumption in patients already under proper BP control by medications.