Acidithiobacillus ferrooxidans are acidophilic chemolithoautotrophs that are commonly reported to exhibit diauxic population growth behavior where ferrous iron is oxidized before elemental sulfur when both are available, despite the higher energy content of sulfur. We have discovered sulfur dispersion formulations that enables sulfur oxidation before ferrous iron oxidation. The oxidation of dispersed sulfur can lower the culture pH within days below the range where aerobic ferrous iron oxidation can occur so that ferric iron reduction occurs which had previously been reported over extended incubation periods with untreated sulfur. Therefore, we demonstrate that this substrate utilization pattern is strongly dependent on the cell loading in relation to sulfur concentration, sulfur surface hydrophobicity, and the pH of the culture. Our dispersed sulfur formulation, lig-sulfur, can be used to support the rapid antibiotic selection of plasmid-transformed cells, which is not possible in liquid cultures where ferrous iron is the main source of energy for these acidophiles. Furthermore, we find that media containing lig-sulfur supports higher production of green fluorescent protein (GFP) compared to media containing ferrous iron. The use of dispersed sulfur is a valuable new tool for the development of engineered A. ferrooxidans strains and it provides a new method to control iron and sulfur oxidation behaviors.

In this work we study the existence of positive solutions to the following fractional elliptic systems with Hardy-type singular potentials, and coupled by critical homogeneous nonlinearities \begin{equation*} \begin{cases} (-\Delta)^{s}u-\mu_{1}\frac{u}{|x|^{2s}}=|u|^{2^{\ast}_{s}-2}u+\frac{\eta\alpha}{2^{\ast}_{s}}|u|^{\alpha-2} |v|^{\beta}u+\frac{1}{2}Q_{u}(u,v) \ \ in \ \Omega, \\[2mm] (-\Delta)^{s}v-\mu_{2}\frac{v}{|x|^{2s}}=|v|^{2^{\ast}_{s}-2}v+\frac{\eta\beta}{2^{\ast}_{s}}|u|^{\alpha} |v|^{\beta-2}v+\frac{1}{2}Q_{v}(u,v) \ \ in \ \Omega, \\[2mm] \ \ u, \ v>0 \ \ \ \ \ in \ \ \Omega, \\[2mm] \ u=v=0 \ \ \ \ in \ \ \mathbb{R}^{N}\backslash\Omega, \end{cases} \end{equation*} where $(-\Delta)^{s}$ denotes the fractional Laplace operator, $\Omega\subset\mathbb{R}^{N}$ is a smooth bounded domain such that $0\in\Omega$, $\mu_{1}, \mu_{2}\in [0,\Lambda_{N,s})$, $\Lambda_{N,s}=2^{2s}\frac{\Gamma^{2}(\frac{N+2s}{4})}{\Gamma^{2}(\frac{N-2s}{4})}$ is the best constant of the fractional Hardy inequality and $2^{*}_{s}=\frac{2N}{N-2s}$ is the fractional critical Sobolev exponent. In order to prove the main result, we establish some refined estimates on the extremal functions of the fractional Hardy-Sobolev type inequalities and we get the existence of positive solutions to the systems through variational methods.

In this study we adapted WRF-Hydro to the Cape Fear River basin (CFRB) to assess its performance during Hurricane Florence (2018). The model was first calibrated with a strategy of mixture of automatic and manual calibration during Florence and then evaluated with an independent hurricane event. With satisfactory NSE values (>0.4) achieved at all gages for hourly simulation, the model demonstrates its potential in simulating the flood response at both basin and sub-basin scale during hurricane events. The model’s capability in reproducing rainfall and properly translating it to hydrological response was further evaluated. The analysis suggests that the calibrated WRF-Hydro in combination with a series of WRF simulation using different microphysics schemes can provide reasonable flood simulations. The model reproduced peak streamflow observed at gage stations with acceptable errors in timing and amplitude. Meanwhile, positive(negative) bias in rainfall input is likely to be amplified (reduced) in streamflow forecast when simulated rainfall volume is larger than the “model true”. And the timing bias mostly inherited from rainfall simulation and calibration process.

Central vision loss, photopsia, floaters, and macular edema in a highly myopic patient can easily be misrelated to high myopia complications. However, in atypical cases, detailed examination along with a thorough diagnostic is required to establish the right diagnosis, which is often beyond the limits of the condition originally considered.

Aims: The objective of this retrospective cohort study was to provide an overview of the utilization of originator and biosimilar infliximab in the Netherlands. Methods: All infliximab dispensings were selected from the PHARMO In-patient Pharmacy Database from 2002-2018. Descriptive analyses were performed in order to characterise initiators and to describe switching patterns over time. Results: Overall, 3,840 patients with 61,274 infliximab dispensings were identified. 2,496 patients initiated an originator infliximab and 777 patients initiated a biosimilar infliximab. Overall, 57% of the patients was female and mean age was 43.2 years. Both originators and biosimilars were mostly prescribed by gastroenterologists, followed by internists and rheumatologists. After market authorization of the first biosimilar the proportion of new patients initiating the biosimilar increased from 39% in 2015 to 91% in 2018. Out of 704 patients eligible for switching 34% switched. Among switchers, the proportion of females was 60% and mean age at index was 45.1 years. Among non-switchers, 55% was female and mean age was 39.8 years. The median time to switch was 1.7 years and switchers were most frequently initiated on infliximab by a rheumatologist (42%), while non-switchers were most frequently initiated by a gastroenterologist (42%). Conclusions: The results of this large population-based cohort show an increase in biosimilar initiation in daily clinical practice. The number of switchers remains relatively low as non-medical switch is not encouraged in the Netherlands.

Seagrasses play a vital role in structuring coastal marine ecosystems, but their distributional range and genetic diversity have declined rapidly over the past decades. In order to improve conservation of seagrass species, it is important to predict how climate change may impact their ranges. Such predictions are typically made with correlative species distribution models (SDMs), which can estimate a species’ potential distribution under present and future climatic scenarios given species’ presence data and climatic predictor variables. However, these models are typically constructed with species-level data, and thus ignore intraspecific genetic variability of populations that potentially have adaptations to heterogeneous climatic conditions. Here, we explore the link between intraspecific adaptation and niche differentiation in Thalassia hemprichii, a seagrass broadly distributed in the tropical Indo-Pacific Ocean and a crucial provider of habitat for numerous marine species. Using microsatellite-based genotyping, we identified two distinct phylogeographical lineages within the nominal species and found an intermediate level of differentiation in their multidimensional environmental niches, suggesting the possibility for local adaptation. We then compared projections of the species’ habitat suitability under climate change scenarios using species-level and lineage-level SDMs. In the Central Tropical Indo-Pacific region, both models predicted considerable range contraction in the future, but the lineage-level model predicted more severe habitat loss. The two modelling approaches predicted opposite pattern in habitat change in the Western Tropical Indo-Pacific region. Our results highlight the necessity of conserving distinct populations and genetic pools under climate change and have important implications for guiding future management of seagrasses.

Abstract Aim: To evaluate the respiratory functions of children with nephrotic syndrome (NS) by IOS and its correlation with spirometry. Methods: Fifty-five NS patients aged 3–18 years were included as the study group and 40 healthy children of the same age formed the control group. Patients were divided into nephrotic phase (first attack and relapse) and remission. Demographic, anthropometric and laboratory data of the children were recorded. Respiratory functions were evaluated by IOS and spirometry. Children over 6 years old performed both IOS and spirometry while children under 6 years performed only IOS. Results: The R (R5%, R10%, R5-20) and AX and Z5% values of IOS in patients with nephrotic phase were higher than remission patients and control group while spirometry indices of FEV1%, FEV1/FVC, PEF% and MEF25-75% were lower. FEV1% showed negative correlation with R5%, R10%, R15%, X10% and X15% results, FEV1/FVC% showed negative correlation with R5%, R5-20 and X15% results, FVC showed negative correlation with X10% results, MEF25-75% showed negative correlation with, R5%, R10%, R5-20, X15%, F res, Z5% and AX results. Conclusion: Our study demonstrated that respiratory functions measured by IOS and spirometry were affected at the time of nephrotic phase in NS patients. And IOS, a novel method easily applicable even in small children, is a valuable and reliable tool to detect this condition; given its good correlation with spirometry. Keywords Nephrotic syndrome, Respiratory functions, Spirometry, Impulse Oscillometry

S-ICD: Is it time for radiological follow-ups?

Allergic inflammation after allergen challenge – insights from the tissueTo the Editor,Limited data exist on the infiltration of eosinophils in direct response to allergen exposure in asthmatic patients. The experimental procedure of segmental allergen provocation (SAP) in mild asthmatic subjects is an extremely valuable study tool to investigate mechanisms of bronchial asthma in patients in general and in particular for the role of eosinophils. In this procedure, BAL and bronchial mucosa can be analysed simultaneously after the induction of allergic inflammation. Older studies yielded data on different time points after the challenge with contradictory results. Eosinophils were studied in mucosa and airway lumen of mild asthmatics undergoing segmental allergen provocation1,2. Here, eosinophils and their release products were investigated in thick sections of the bronchial biopsies. Subject data, methods and detailed results are given in the supplement. All subjects showed a clear eosinophilic response in the airway lumen and mucosa 24 hours after the challenge (Figure 1, S1). The data on neutrophils were inconclusive (Figure 1, S2). There was an increase of eosinophils in the mucosa and in the BAL. In the BAL the concentrations of IL‑5 and ECP were elevated (supplement). In the mucosa ECP stained areas were found elevated as well as signs of eosinophil activation and degranulation (Figure 2). ECP staining was associated with cellular structures, small granules or dispersed over a large area beneath the epithelium. The degree of released mediators into the tissue is an important parameter investigating new drugs for asthma. In the presented study not cell associated, free ECP positive granules were seen at baseline but only to a small extent. However, after allergen challenge the ECP volume was significantly increased and only few distinct cells could be detected being positive for ECP. These results suggest that in human tissue eosinophils degranulate to a significant amount after a single allergen challenge and therefore release all their toxic content into the surrounding tissue. This is in contrast to animal models of asthma where eosinophilic degranulation after allergen challenge does not occur extensively 3,4. In the present study, subjects with a strong IL-5 reaction in BAL showed a strong eosinophilic response in the lumen. However, BAL IL-5 levels did not correlate with eosinophil numbers in the mucosa or volume of ECP positive surfaces in the mucosa (Figure S3). It is a long known fact that IL-5 levels in the BAL correlate highly with absolute numbers of eosinophils in the same compartment 5. In the present study the allergic reaction is comparable to those of other studies. The missing correlation between IL-5 in the BAL and numbers of tissue eosinophils showed that the relationship between both compartments is not as simple as assumed. Here, the data for the volume of ECP positive surfaces may give an important hint. Interestingly, the volume of ECP positive surfaces was inversely correlated with TNF-α and IL-8. TNF-α enhances migration of eosinophils from mucosa to lumen shown in an in vitro cell culture model 6. Therefore, one possible explanation is the more TNF-α is found in the BAL the less activated eosinophils are found in the mucosa. In conclusion, the findings in subjects with mild asthma are in alignment with other published results and suggest that 1) human tissue eosinophils release their granules in non-provoked state, and 2) toxic content of these cells is significantly released into the surrounding tissue after a single allergen challenge whereas the distribution and the degree of activation and degranulation of eosinophils differs widely between subjects. Many eosinophils in the airways indicate many eosinophils in the mucosa. Three-dimensional analysis in thick tissue sections using confocal microscopy is a valuable tool in the investigation of bronchial biopsies from patients suffering from bronchial asthma.(Abbreviations: BAL=bronchoalveolar lavage, ECP=eosinophilic cation protein, IL=interleukin, MBP=major basic protein, NE=neutrophilic elastase, SAP=segmental allergen provocation, TNF=tumor necrosis factor)References1. Erpenbeck VJ, Hagenberg A, Dulkys Y, et al. Natural porcine surfactant augments airway inflammation after allergen challenge in patients with asthma. Am J Respir Crit Care Med.2004;169(5):578-586.2. Schaumann F, Muller M, Braun A, et al. Endotoxin augments myeloid dendritic cell influx into the airways in patients with allergic asthma.Am J Respir Crit Care Med. 2008;177(12):1307-1313.3. Denzler KL, Borchers MT, Crosby JR, et al. Extensive eosinophil degranulation and peroxidase-mediated oxidation of airway proteins do not occur in a mouse ovalbumin-challenge model of pulmonary inflammation. J Immunol. 2001;167(3):1672-1682.4. Malm-Erjefält M, Persson CG, Erjefält JS. Degranulation status of airway tissue eosinophils in mouse models of allergic airway inflammation. Am J Respir Cell Mol Biol. 2001;24(3):352-359.5. Sur S, Kita H, Gleich GJ, Chenier TC, Hunt LW. Eosinophil recruitment is associated with IL-5, but not with RANTES, twenty-four hours after allergen challenge. J Allergy Clin Immunol. 1996;97(6):1272-1278.6. Kikuchi I, Kikuchi S, Kobayashi T, et al. Eosinophil trans-basement membrane migration induced by interleukin-8 and neutrophils. Am J Respir Cell Mol Biol. 2006;34(6):760-765.Frauke Prenzler1, Thomas Tschernig2, Katherina Sewald1,5, Tibor Z Veres1,3, Susanne Rittinghausen1, Norbert Krug1,5, Jens M. Hohlfeld1,4,5, Armin Braun1,4,51Fraunhofer Institute for Toxicology and Experimental Medicine2Institute for Cell Biology and Anatomy, Saarland University, Homburg/Saar, Germany3Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA4 Institute of Immunology, Hannover Medical School, Hannover, Germany5 Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease (BREATH) research network, Hannover, GermanyCorrespondence: Armin BraunPreclinical Pharmacology and ToxicologyFraunhofer Institute for Toxicology and Experimental Medicine (ITEM)Nikolai-Fuchs-Str. 1, 30625 Hannover, Germanyemail: [email protected]: +49(0)511/5350-263Acknowledgements: We would like to thank Isabelle Bleeker for processing the biopsy samples of the classical immunohistology.Funding: Supported by Deutsche Forschungsgemeinschaft (SFB587/ B8 und B4)Conflict of Interest: None of the authors has any financial interest.Contributions: AB, JH and NK planned and conducted the study. FP, AB and TT wrote the manuscript, all other authors read, corrected and approved the manuscript. TZV, KS, SR and FP established and performed the morphology and made the evaluation of tissue data.

Introduction The dissection of perirenal fat is of critical importance to kidney surgery and ease of dissection is more important when using minimally invasive approaches. This study aimed to determine the clinical, radiological, and pathological significance of adherent perirenal fat(APF). Materials and Methods This prospective study included 22 patients scheduled for partial nephrectomy and 40 patients for donor nephrectomy. Intra-operative fat dissection time was recorded and the complexity of perirenal fat dissection was surgeon-classified as easy, moderate, and difficult. Perirenal fat and subcutaneous fat thickness was measured. Measurement of perirenal fat depth, and the Hounsfield unit(HU) for both perirenal and subcutaneous fields was performed using CT images. All specimens were submitted for histopatological analysis. Researchers in each arm were blinded to other researchers’ data. Results Mean age of the patients was 51.3±12.7years. Mean perirenal fat dissection time was 15.0±13.5min. Patient demographics, BMI, nor occupational status differed between the 3 complexity of perirenal fat dissection groups. Radiological findings showed that there was a significant correlation between perirenal fat depth and complexity of perirenal fat dissection(p<0.05), but not with HU measurements or subcutaneous fat thickness. Surgeon classification of the complexity of perirenal fat dissection was in accordance with the duration of dissection(p<0.05). Perinephric fat contained more fibrous tissue in the patients with histologically proven APF than in those without(p<0.05). Conclusions APF is a challenge during kidney surgery. Difficult dissection prolongs the duration of surgery, which can lead to complications. Perirenal fat thickness measured via pre-operative CT might be used to predict APF.

High power, short duration ablation: at least for the right pulmonary vein carina, maybe not so fastGustavo S. Guandalini, MD a and Francis E. Marchlinski, MD aa Section of Cardiac Electrophysiology, Hospital of the University of Pennsylvania, Philadelphia, PACorresponding author: Dr. Francis E. Marchlinski, Division of Cardiovascular Medicine, Electrophysiology Section, Hospital of the University of Pennsylvania, 3400 Spruce Street, 9 Founders Pavilion, Philadelphia, Pennsylvania 19104. E-mail: [email protected] authors have no conflicts to disclose.Word count: 1,170.This research was supported by the Richard T and Angela Clark Innovation Fund in Cardiovascular Medicine.

Kozyrev et al. report their results in a modified technique for coarctation of aorta with hypoplastic distal aortic arch (1). This paper represents a quality initiative as much as a technical manuscript. The authors included 32 patients during a three year time period from 2016 until 2019.

The Small East African (SEA) goat (Capra hircus) breeds are widely distributed in different agro-ecological zones of Tanzania. We report the genetic diversity, maternal origin, and phylogenetic relationship among the 12 Tanzanian indigenous goats populations, namely Fipa (n = 44), Songwe (n = 34), Tanga (n = 33), Pwani (n = 40), Newala (n = 49), Lindi (n = 46), Gogo (n = 73), Pare (n = 67), Maasai (n = 72), Sukuma (n = 67), and Ujiji (n = 67), based on the mitochondrial DNA (mtDNA) D-loop. High haplotype (Hd = 0.9619-0.9945) and nucleotide (π = 0.0120-0.0162) diversities were revealed from a total of 389 haplotypes. The majority of the haplotypes (h = 334) drawn from all the goat populations belonged to Haplogroup A which was consistent with the global scenario on the genetic pattern of maternal origin of all goat breeds in the world. Haplogroup G comprised of 45 haplotypes drawn from all populations except the Ujiji goat population while Haplogroup B with 10 haplotypes was dominated by Ujiji goats (41%). Tanzanian goats shared four haplotypes with the Kenyan goats and two with goats from South Africa, Namibia, and Mozambique. There was no sharing of haplotypes observed between individuals from Tanzanian goat populations with individuals from North or West Africa. The indigenous goats in Tanzania have high genetic diversity defined by 389 haplotypes and multiple maternal origins of haplogroup A, B and G. There is a lot of intermixing and high genetic variation within populations which represent an abundant resource for selective breeding in the different agro-ecological regions of the country.

We describe the role of three-dimensional echocardiography in the assessment of the aortic valve and the aorta. The manuscript is heavily illustrated with figures and movie clips.

In this paper, we apply the resolvent operator theory and an approximating technique to derive the existence and controllability results for nonlocal impulsive neutral integro-differential equations with finite delay in a Hilbert space. To establish the results, we take the impulsive functions as a continuous function only, and we assume that the nonlocal initial condition is Lipschitz continuous function in the first case and continuous functions only in the second case. The main tools applied in our analysis are semigroup theory, the resolvent operator theory, an approximating technique, and fixed point theorems. Finally, we illustrate the main results with the help of two examples.

We introduce new reproducing kernel Hilbert spaces on a trapezoidal semi-infinite domain $B_{\infty}$ in the plane. We establish uniform approximation results in terms of the number of nodes on compact subsets of $B_{\infty}$ for solutions to nonhomogeneous hyperbolic partial differential equations in one of these spaces, $\widetilde{W}(B_{\infty})$. Furthermore, we demonstrate the stability of such solutions with respect to the driver. Finally, we give an example to illustrate the efficiency and accuracy of our results.

The interface fracture toughness of SnSb11Cu6/20steel was measured by calculating the critical energy release rate and stress phase angle of the interface crack. A three-point bending test was used to introduce cracks into the bonding interface, and the cohesion model of the bonding interface was established through experimental data. Through finite element analysis of load-deflection curves with and without interface crack propagation, the crack initiation point is found. Then the energy calculation model of crack propagation is established, and the critical energy release rate is obtained using the virtual crack growth criterion. The calculation results of the stress phase angle show that the crack propagation is greatly affected by the normal stress after the babbitt alloy layer fractures. If the strength of the substrate material is weaker, the crack will continue to expand in the tangent perpendicular to the crack tip.

A robust monoclonal antibody (mAb) bioprocess requires physiological parameters such as temperature, pH, or dissolved oxygen (DO) to be well-controlled as even small variations in them could potentially impact the final product quality. For instance, pH substantially affects N-glycosylation, protein aggregation and charge variant profiles, as well as mAb productivity. However, relatively less is known about how pH jointly influences product quality and titer. In this study, we investigated the effect of pH on culture performance, product titer and quality profiles by applying longitudinal multi-omics profiling, including transcriptomics, proteomics, metabolomics and glycomics, at three different culture pH set points. The subsequent systematic analysis of multi-omics data showed that pH set points differentially regulated various intracellular pathways including intracellular vesicular trafficking, cell cycle, and apoptosis, thereby resulting in differences in specific productivity, product titer and quality profiles. In addition, a time-dependent variation in mAb N-glycosylation profiles, independent of pH was identified to be mainly due to the accumulation of mAb proteins in the endoplasmic reticulum (ER) over culture time, disrupting cellular homeostasis. Overall, this multi-omics-based study provides an in-depth understanding of the intracellular processes in mAb-producing CHO cell line under varied pH conditions and could serve as a baseline for enabling the quality optimization and control of mAb production.