bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating corticosterone as a biomarker for amphibians exposed to increased salinity and ambient corticosterone
Authors: Tornabene Brian J , Hossack Blake R , Crespi Erica J , Breuner Creagh W
Published: June 2021

Physiological biomarkers are commonly used to assess the health of taxa exposed to natural and anthropogenic stressors. Glucocorticoid (GC) hormones are often used as indicators of physiological stress in wildlife because they affect growth, reproduction and survival. Increased salinity from human activities negatively influences amphibians and their corticosterone (CORT; the main amphibian GC) physiology; therefore, CORT could be a useful biomarker. We evaluated whether waterborne CORT could serve as a biomarker of salt stress for three free-living amphibian species that vary in their sensitivity to salinity: boreal chorus frogs (Pseudacris maculata), northern leopard frogs (Rana pipiens) and barred tiger salamanders (Ambystoma mavortium). Across a gradient of contamination from energy-related saline wastewaters, we tested the effects of salinity on baseline and stress-induced waterborne CORT of larvae. Stress-induced, but not baseline, CORT of leopard frogs increased with increasing salinity. Salinity was not associated with baseline or stress-induced CORT of chorus frogs or tiger salamanders. Associations between CORT and salinity were also not related to species-specific sensitivities to salinity. However, we detected background environmental CORT (ambient CORT) in all wetlands and spatial variation was high within and among wetlands. Higher ambient CORT was associated with lower waterborne CORT of larvae in wetlands. Therefore, ambient CORT likely confounded associations between waterborne CORT and salinity in our analysis and possibly influenced physiology of larvae. We hypothesize that larvae may passively take up CORT from their environment and downregulate endogenous CORT. Although effects of some hormones (e.g. oestrogen) and endocrine disruptors on aquatic organisms are well described, studies investigating the occurrence and effects of ambient CORT are limited. We provide suggestions to improve collection methods, reduce variability and avoid confounding effects of ambient CORT. By making changes to methodology, waterborne CORT could still be a promising, non-invasive conservation tool to evaluate effects of salinity on amphibians.
Comparison of recent ceramide-based coronary risk prediction scores in cardiovascular disease patients
Authors: Leiherer Andreas , Mündlein Axel , Laaksonen Reijo , Lääperi Mitja , Jylhä Antti , Fraunberger Peter , Drexel Heinz
Published: June 2021

Aim

Cholesterol-based risk prediction is often insufficient in cardiovascular disease (CVD) patients. Ceramides are a new kind of biomarkers for CVD. The Coronary Event Risk Test (CERT) is a validated cardiovascular risk predictor that uses only circulating ceramide levels, determined by coupled liquid chromatography–mass spectrometry, to allocate patients into one of four risk categories. This test has recently been modified (CERT2) by additionally including phosphatidylcholine levels.

Methods and results

In this observational cohort study, we have recruited 999 Austrian patients with CVD and followed them for up to 13 years. We found that CERT and CERT2 both predicted cardiovascular events, cardiovascular mortality, and overall mortality. CERT2 had the higher performance compared to CERT and also to the recent cardiovascular risk score of the ESC/EAS guidelines (Systematic COronary Risk Evaluation (SCORE)) for low-risk European countries. Combining CERT2 with the ESC/EAS-SCORE, predictive capacity was further increased leading to a hazard ratio of 3.58 (2.02–6.36; P < 0.001) for cardiovascular events, 11.60 (2.72–49.56; P = 0.001) for cardiovascular mortality, and 9.86 (4.23–22.99; P < 0.001) for overall mortality when patients with very high risk (category 4) were compared to those with low risk (category 1). The use of the combined score instead of the ESC/EAS-SCORE significantly improved the predictive power according to the integrated discrimination improvement index (P = 0.004).

Conclusion

We conclude that CERT and CERT2 are powerful predictors of cardiovascular events, cardiovascular mortality, and overall mortality in CVD patients. Including phosphatidylcholine to a ceramide-based score increases the predictive performance and is best in combination with classical risk factors as used in the ESC/EAS-SCORE.
Evidence for nutrient-dependent regulation of the COPII coat by O-GlcNAcylation
Authors: Bisnett Brittany J , Condon Brett M , Linhart Noah A , Lamb Caitlin H , Huynh Duc T , Bai Jingyi , Smith Timothy J , Hu Jimin , Georgiou George R , Boyce Michael
Published: June 2021

O-linked β-N-acetylglucosamine (O-GlcNAc) is a dynamic form of intracellular glycosylation common in animals, plants and other organisms. O-GlcNAcylation is essential in mammalian cells and is dysregulated in myriad human diseases, such as cancer, neurodegeneration and metabolic syndrome. Despite this pathophysiological significance, key aspects of O-GlcNAc signaling remain incompletely understood, including its impact on fundamental cell biological processes. Here, we investigate the role of O-GlcNAcylation in the coat protein II complex (COPII), a system universally conserved in eukaryotes that mediates anterograde vesicle trafficking from the endoplasmic reticulum. We identify new O-GlcNAcylation sites on Sec24C, Sec24D and Sec31A, core components of the COPII system, and provide evidence for potential nutrient-sensitive pathway regulation through site-specific glycosylation. Our work suggests a new connection between metabolism and trafficking through the conduit of COPII protein O-GlcNAcylation.
Karyopherin-βs play a key role as a phase separation regulator
Authors: Yoshizawa Takuya , Guo Lin
Published: June 2021

Recent studies have revealed that cells utilize liquid–liquid phase separation (LLPS) as a mechanism in assembly of membrane-less organelles, such as RNP granules. The nucleus is a well-known membrane-bound organelle surrounded by the nuclear envelope; the nuclear pore complex on the nuclear envelope likely applies LLPS in the central channel to facilitate selective biological macromolecule exchange. Karyopherin-β family proteins exclusively pass through the central channel with cargos by dissolving the phase separated hydrogel formed by the phenylalanine-glycine (FG) repeats-containing nucleoporins. Karyopherin-βs also exhibit dissolution activity for the phase separation of cargo proteins. Many cargos, including RNA-binding proteins containing intrinsically disordered regions (IDRs), undergo phase separation; however, aberrant phase separation is linked to fatal neurodegenerative diseases. Multiple weak interactions between karyopherin-βs and phase separation-prone proteins, such as FG repeats-containing nucleoporins or IDR-containing karyopherin-β cargos, are likely to be important for passing through the nuclear pore complex and maintaining the soluble state of cargo, respectively. In this review, we discuss how karyopherin-βs regulate phase separation to function.
Fragments of Quasi-Nelson: The Algebraizable Core
Authors: Rivieccio Umberto
Published: June 2021

This is the second of a series of papers that investigate fragments of quasi-Nelson logic (QNL) from an algebraic logic standpoint. QNL, recently introduced as a common generalization of intuitionistic and Nelson’s constructive logic with strong negation, is the axiomatic extension of the substructural logic $FL_{ew}$ (full Lambek calculus with exchange and weakening) by the Nelson axiom. The algebraic counterpart of QNL (quasi-Nelson algebras) is a class of commutative integral residuated lattices (a.k.a. $FL_{ew}$-algebras) that includes both Heyting and Nelson algebras and can be characterized algebraically in several alternative ways. The present paper focuses on the algebraic counterpart (a class we dub quasi-Nelson implication algebras, QNI-algebras) of the implication–negation fragment of QNL, corresponding to the connectives that witness the algebraizability of QNL. We recall the main known results on QNI-algebras and establish a number of new ones. Among these, we show that QNI-algebras form a congruence-distributive variety (Cor. 3.15) that enjoys equationally definable principal congruences and the strong congruence extension property (Prop. 3.16); we also characterize the subdirectly irreducible QNI-algebras in terms of the underlying poset structure (Thm. 4.23). Most of these results are obtained thanks to twist representations for QNI-algebras, which generalize the known ones for Nelson and quasi-Nelson algebras; we further introduce a Hilbert-style calculus that is algebraizable and has the variety of QNI-algebras as its equivalent algebraic semantics.
Root mass carbon costs to acquire nitrogen are determined by nitrogen and light availability in two species with different nitrogen acquisition strategies
Authors: Perkowski Evan A , Waring Elizabeth F , Smith Nicholas G
Published: June 2021

Plant nitrogen acquisition requires carbon to be allocated belowground to build roots and sustain microbial associations. This carbon cost to acquire nitrogen varies by nitrogen acquisition strategy; however, the degree to which these costs vary due to nitrogen availability or demand has not been well tested under controlled conditions. We grew a species capable of forming associations with nitrogen-fixing bacteria (Glycine max) and a species not capable of forming such associations (Gossypium hirsutum) under four soil nitrogen levels to manipulate nitrogen availability and four light levels to manipulate nitrogen demand in a full-factorial greenhouse experiment. We quantified carbon costs to acquire nitrogen as the ratio of total root carbon to whole-plant nitrogen within each treatment combination. In both species, light availability increased carbon costs due to a larger increase in root carbon than whole-plant nitrogen, while nitrogen fertilization generally decreased carbon costs due to a larger increase in whole-plant nitrogen than root carbon. Nodulation data indicated that G. max shifted relative carbon allocation from nitrogen fixation to direct uptake with increased nitrogen fertilization. These findings suggest that carbon costs to acquire nitrogen are modified by changes in light and nitrogen availability in species with and without associations with nitrogen-fixing bacteria.
Particle diffusion and acceleration in magnetorotational instability turbulence
Authors: Sun Xiaochen , Bai Xue-Ning
Published: June 2021

Hot accretion flows contain collisionless plasmas that are believed to be capable of accelerating particles to very high energies, as a result of turbulence generated by the magnetorotational instability (MRI). We conduct unstratified shearing-box simulations of the MRI turbulence in ideal magnetohydrodynamic (MHD), and inject energetic relativistic test particles in simulation snapshots to conduct a detailed investigation on particle diffusion and stochastic acceleration. We consider different amount of net vertical magnetic flux, with sufficiently high resolution to resolve the gyro-radii (Rg) of most particles. Particles with large Rg (≳ 0.03 disc scale height H) show spatial diffusion coefficients of ∼30 and ∼5 times Bohm values in the azimuthal and poloidal directions, respectively. We further measure particle momentum diffusion coefficient D(p) by applying the Fokker–Planck equation, finding that contribution from turbulent fluctuations scales as D(p) ∝ p, and shear acceleration takes over when Rg ≳ 0.1H, characterized by D(p) ∝ p3. For particles with smaller Rg (≲ 0.03H), their spatial diffusion coefficients roughly scale as ∼p−1, and show evidence of D(p) ∝ p2 scaling in momentum diffusion but with large uncertainties. We find that multiple effects contribute to stochastic acceleration/deceleration, and the process is likely affected by intermittency in the MRI turbulence. We also discuss the potential of accelerating PeV cosmic rays in hot accretion flows around supermassive black holes.
Schistosome W-Linked Genes Inform Temporal Dynamics of Sex Chromosome Evolution and Suggest Candidate for Sex Determination
Authors: Elkrewi Marwan , Moldovan Mikhail A , Picard Marion A L , Vicoso Beatriz
Published: June 2021

Schistosomes, the human parasites responsible for snail fever, are female-heterogametic. Different parts of their ZW sex chromosomes have stopped recombining in distinct lineages, creating “evolutionary strata” of various ages. Although the Z-chromosome is well characterized at the genomic and molecular level, the W-chromosome has remained largely unstudied from an evolutionary perspective, as only a few W-linked genes have been detected outside of the model species Schistosoma mansoni. Here, we characterize the gene content and evolution of the W-chromosomes of S. mansoni and of the divergent species S. japonicum. We use a combined RNA/DNA k-mer based pipeline to assemble around 100 candidate W-specific transcripts in each of the species. About half of them map to known protein coding genes, the majority homologous to S. mansoni Z-linked genes. We perform an extended analysis of the evolutionary strata present in the two species (including characterizing a previously undetected young stratum in S. japonicum) to infer patterns of sequence and expression evolution of W-linked genes at different time points after recombination was lost. W-linked genes show evidence of degeneration, including high rates of protein evolution and reduced expression. Most are found in young lineage-specific strata, with only a few high expression ancestral W-genes remaining, consistent with the progressive erosion of nonrecombining regions. Among these, the splicing factor u2af2 stands out as a promising candidate for primary sex determination, opening new avenues for understanding the molecular basis of the reproductive biology of this group.

Keywords: sex chromosomes, evolutionary strata, W-linked gene, sex determining gene, schistosome parasites.
Molecular characterization of both transesterification reactions of the group II intron circularization pathway
Authors: LaRoche-Johnston Félix , Monat Caroline , Verreault Erika , Cousineau Benoit
Published: June 2021

Group II introns can self-splice from RNA transcripts through branching, hydrolysis and circularization, being released as lariats, linear introns and circles, respectively. In contrast to branching, the circularization pathway is mostly based on assumptions and has been largely overlooked. Here, we address the molecular details of both transesterification reactions of the group II intron circularization pathway in vivo. We show that free E1 is recruited by the intron through base pairing interactions and that released intron circles can generate free E1 by the spliced exon reopening reaction. The first transesterification reaction was found to be induced inaccurately by the 3′OH of the terminal residue of free E1 at the 3′ splice site, producing circularization intermediates with heterogeneous 3′ ends. Nevertheless, specific terminal 3′OH, selected by a molecular ruler, was shown to precisely attack the 5′ splice site and release intron circles with 3′–5′ rather than 2′–5′ bonds at their circularization junction. Our work supports a circularization model where the recruitment of free E1 and/or displacement of cis-E1 induce a conformational change of the intron active site from the pre-5′ to the pre-3′ splice site processing conformation, suggesting how circularization might initiate at the 3′ instead of the 5′ splice site.
Detrital Chromite from Jack Hills, Western Australia: Signatures of Metamorphism and Constraints on Provenance
Authors: Staddon Leanne G , Parkinson Ian J , Cavosie Aaron J , Elliott Tim , Valley John W , Fournelle John , Kemp Anthony I S , Shirey Steven B
Published: June 2021

Detrital chromites are commonly reported within Archean metasedimentary rocks, but have thus far garnered little attention for use in provenance studies. Systematic variations of Cr–Fe spinel mineral chemistry with changing tectonic setting have resulted in the extensive use of chromite as a petrogenetic indicator, and so detrital chromites represent good candidates to investigate the petrogenesis of eroded Archean mafic and ultramafic crust. Here, we report the compositions of detrital chromites within fuchsitic (Cr-muscovite rich) metasedimentary rocks from the Jack Hills, situated within the Narryer Terrane, Yilgarn Craton, Western Australia, which are geologically renowned for hosting Hadean (>4000 Ma) zircons. We highlight signatures of metamorphism, including highly elevated ZnO and MnO, coupled with lowered Mg# in comparison with magmatic chromites, development of pitted domains, and replacement of primary inclusions by phases that are part of the metamorphic assemblages within host metasedimentary rocks. Oxygen isotope compositions of detrital chromites record variable exchange with host metasedimentary rocks. The variability of metamorphic signatures between chromites sampled only meters apart further indicates that modification occurred in situ by interaction of detrital chromites with metamorphic fluids and secondary mineral assemblages. Alteration probably occurred during upper greenschist to lower amphibolite facies metamorphism and deformation of host metasedimentary rocks at ∼2650 Ma. Regardless of metamorphic signatures, sampling location or grain shape, chromite cores yield a consistent range in Cr#. Although other key petrogenetic indices, such as Fe2O3 and TiO2 contents, are complicated in Jack Hills chromites by mineral non-stoichiometry and secondary mobility within metasedimentary rocks, we demonstrate that the Cr# of chromite yields significant insights into their provenance. Importantly, moderate Cr# (typically 55–70) precludes a komatiitic origin for the bulk of chromites, reflecting a dearth of komatiites and intrusive equivalents within the erosional catchment of the Jack Hills metasedimentary units. We suggest that the Cr# of Jack Hills chromite fits well with chromites derived from layered intrusions, and that a single layered intrusion may account for the observed chemical compositions of Jack Hills detrital chromites. Where detailed characterization of key metamorphic signatures is undertaken, detrital chromites preserved within Archean metasedimentary rocks may therefore yield valuable information on the petrogenesis and geodynamic setting of poorly preserved mafic and ultramafic crust.
Novel electrospun poly-hydroxybutyrate scaffolds as carriers for the wound healing agents alkannins and shikonins
Authors: Arampatzis Athanasios S , Giannakoula Konstantina , Kontogiannopoulos Konstantinos N , Theodoridis Konstantinos , Aggelidou Eleni , Rat Angélique , Kampasakali Elli , Willems Anne , Christofilos Dimitrios , Kritis Aristeidis , Papageorgiou Vassilios P , Tsivintzelis Ioannis , Assimopoulou Andreana N
Published: June 2021

The aim of this study was to investigate the potential of novel electrospun fiber mats loaded with alkannin and shikonin (A/S) derivatives, using as carrier a highly biocompatible, bio-derived, eco-friendly polymer such as poly[(R)-3-hydroxybutyric acid] (PHB). PHB fibers containing a mixture of A/S derivatives at different ratios were successfully fabricated via electrospinning. Αs evidenced by scanning electron microscopy, the fibers formed a bead-free mesh with average diameters from 1.25 to 1.47 μm. Spectroscopic measurements suggest that electrospinning marginally increases the amorphous content of the predominantly crystalline PHB in the fibers, while a significant drug amount lies near the fiber surface for samples of high total A/S content. All scaffolds displayed satisfactory characteristics, with the lower concentrations of A/S mixture-loaded PHB fiber mats achieving higher porosity, water uptake ratios, and entrapment efficiencies. The in vitro dissolution studies revealed that all samples released more than 70% of the encapsulated drug after 72 h. All PHB scaffolds tested by cell viability assay were proven non-toxic for Hs27 fibroblasts, with the 0.15 wt.% sample favoring cell attachment, spreading onto the scaffold surface, as well as cell proliferation. Finally, the antimicrobial activity of PHB meshes loaded with A/S mixture was documented for Staphylococcus epidermidis and S. aureus.
Quantitative ultrasound to monitor the vascular response to tocilizumab in giant cell arteritis
Authors: Seitz Luca , Christ Lisa , Lötscher Fabian , Scholz Godehard , Sarbu Adela-Cristina , Bütikofer Lukas , Kollert Florian , Schmidt Wolfgang A , Reichenbach Stephan , Villiger Peter M
Published: June 2021

Objectives

To characterize the effect of ultra-short glucocorticoids followed by Tocilizumab monotherapy on the intima-media thickness (IMT) in GCA.

Methods

Eighteen GCA patients received 500 mg for 3 consecutive days (total of 1500mg) i.v. methylprednisolone on days 0–2, followed by i.v. Tocilizumab (8 mg/kg) on day 3 and thereafter weekly s.c. Tocilizumab injections (162 mg) over 52 weeks. US of temporal (TAs), axillary (AAs) and subclavian (SAs) arteries was performed at baseline, on days 2–3, and at weeks 4, 8, 12, 24 and 52. The largest IMT of all segments and IMT at landmarks of AA/SA were recorded. IMT was scaled by mean normal values and averaged. Each segment was classified according to diagnostic cut-offs.

Results

Of the 18 GCA patients, 16 patients had TA and 6 had extracranial large artery involvement. The IMT showed a sharp decline on day 2/3 in the TAs and AAs/SAs. In TAs, this was followed by an increase to baseline levels at week 4 and a subsequent slow decrease, which was paralleled by decreasing symptoms and achievement of clinical remission. The AAs/SAs showed a new signal of vasculitis at week 4 in three patients, with an IMT increase up to week 8.

Conclusion

Glucocorticoid pulse therapy induced a transient decrease of the IMT in TAs and AAs/SAs. Tocilizumab monotherapy resulted in a slow and steady decrease in IMT of the TAs and a smaller and delayed effect on the AAs/SAs. The data strongly support a remission-inducing effect of Tocilizumab and argue the case for US having an important role in monitoring disease activity in GCA.

Trial registration

ClinicalTrials.gov, www.clinicaltrials.gov, NCT03745586.
Species-Specific Urothelial Toxicity With an Anti-HIV Noncatalytic Site Integrase Inhibitor (NCINI) Is Related to Unusual pH-Dependent Physicochemical Changes
Authors: Roberts Ruth A , Campbell Richard A , Sikakana Phumzile , Sadler Claire , Osier Mark , Xu Yili , Feng Joy Y , Mitchell Michael , Sakowicz Roman , Chester Anne , Paoli Eric , Wang Jianhong , Burns-Naas Leigh Ann
Published: June 2021

GS-9695 and GS-9822 are next-generation noncatalytic site integrase inhibitors (NCINIs) with significantly improved potency against human immunodeficiency virus compared with previous drugs such as BI-224436. Development stopped due to vacuolation of the bladder urothelium seen in cynomolgus monkey but not in rat; this lesion was absent in equivalent preclinical studies with BI-224436 (tested in dog and rat). Lesions were unlikely to be attributable to target because NCINIs specifically target viral integrase protein and no mammalian homologue is known. Secondary pharmacology studies, mitochondrial toxicity studies, immunophenotyping, and analysis of proteins implicated in cell-cell interactions and/or bladder integrity (E-cadherin, pan-cytokeratin, uroplakins) failed to offer any plausible explanation for the species specificity of the lesion. Because it was characterized by inflammation and disruption of urothelial morphology, we investigated physicochemical changes in the bladder of cynomolgus monkey (urinary pH 5.5–7.4) that might not occur in the bladder of rats (urinary pH 7.3–8.5). In measurements of surface activity, GS-9822 showed an unusual transition from a monolayer to a bilayer at the air/water interface with decreasing pH, attributed to the strong association between drug molecules in adjacent bilayer leaflets and expected to be highly disruptive to the urothelium. Structural analysis of GS-9822 and GS-9695 showed zwitterionic characteristics over the range of pH expected in cynomolgus monkey but not rat urine. This exotic surface behavior is unlikely with BI-224436 since it would transition from neutral to cationic (never zwitterionic) with decreasing pH. These data provide useful insights to guide discovery and development of NCINIs, related compounds, and zwitterions.
Mechanistic Computational Model for Extrapolating In Vitro Thyroid Peroxidase (TPO) Inhibition Data to Predict Serum Thyroid Hormone Levels in Rats
Authors: Handa Sakshi , Hassan Iman , Gilbert Mary , El-Masri Hisham
Published: June 2021

High-throughput in vitro assays are developed to screen chemicals for their potential to inhibit thyroid hormones (THs) synthesis. Some of these experiments, such as the thyroid peroxidase (TPO) inhibition assay, are based on thyroid microsomal extracts. However, the regulation of thyroid disruption chemicals is based on THs in vivo serum levels. This necessitates the estimation of thyroid disruption chemicals in vivo tissue levels in the thyroid where THs synthesis inhibition by TPO takes place. The in vivo tissue levels of chemicals are controlled by pharmacokinetic determinants such as absorption, distribution, metabolism, and excretion, and can be described quantitatively in physiologically based pharmacokinetic (PBPK) models. An integrative computational model including chemical-specific PBPK and TH kinetics models provides a mechanistic quantitative approach to translate thyroidal high-throughput in vitro assays to in vivo measures of circulating THs serum levels. This computational framework is developed to quantitatively establish the linkage between applied dose, chemical thyroid tissue levels, thyroid TPO inhibition potential, and in vivo TH serum levels. Once this link is established quantitatively, the overall model is used to calibrate the TH kinetics parameters using experimental data for THs levels in thyroid tissue and serum for the 2 drugs, propylthiouracil and methimazole. The calibrated quantitative framework is then evaluated against literature data for the environmental chemical ethylenethiourea. The linkage of PBPK and TH kinetics models illustrates a computational framework that can be extrapolated to humans to screen chemicals based on their exposure levels and potential to disrupt serum THs levels in vivo.
Selection of Artificial Dermis for Shortening Treatment Period: Integra versus Pelnac
Authors: Kashimura Tsutomu , Nagasaki Keito , Horigome Michio , Yoshida Kotoku , Soejima Kazutaka
Published: June 2021

Background:

Skin reconstruction of full-thickness skin defect wounds using artificial dermis is performed using secondary split-thickness skin grafting. For the selection of artificial dermis to shorten the treatment period, the waiting time until secondary skin grafting was investigated when the dermis-like tissue was constructed with Pelnac or Integra.

Methods:

We evaluated 26 patients who underwent secondary skin grafting after dermis reconstruction with Pelnac (18 patients) or Integra (8 patients) for full-thickness skin defects between 2006 and 2017. The waiting period from artificial dermis application to closure of the full-thickness skin defect with a secondary skin graft was investigated retrospectively.

Results:

Skin grafts survived well in all cases, and no complications of grafts or donors were observed. The mean waiting period was 17.5 ± 4.2 and 22.0 ± 4.6 days for the Pelnac and Integra groups, respectively (significantly shorter in the Pelnac group).

Conclusions:

The difference in waiting period is presumed to be due to the structural differences between the collagen sponge layer, which is the dermal replacement layer of Pelnac and Integra grafts. In cases where shortening the treatment period is important, Pelnac should be the first choice. In addition, in pediatric cases and widespread burns where it is difficult to control the infection during the waiting period, Pelnac is considered to be the first choice because the risk can be reduced by shortening the waiting period.
Serial Excision for Treatment of Non-melanoma Skin Cancer
Authors: Dekker Paige K. , Mishu Mark D. , Youn Richard , Baker Stephen B.
Published: June 2021

Background:

Mohs micrographic surgery (MMS) has become the predominant modality of excision for non-melanoma skin cancers (NMSC). Patients are referred for MMS under the assumption that it is the most effective procedure for definitive removal of the cancer while also allowing for maximal tissue preservation to achieve optimal cosmesis. The objective of this study was to investigate outcomes of serial excision (SE) as an alternative excision modality for NMSC.

Methods:

Patients undergoing SE for basal cell carcinoma or squamous cell carcinoma by the senior author from 2009 to 2020 were retrospectively reviewed. Patient demographics, lesion characteristics, and excision characteristics were recorded. The primary outcome was the number of excisions required to achieve negative margins.

Results:

In total, 129 patients with 205 NMSC lesions were retrospectively reviewed. An estimated 69 lesions (33.7%) were located in high risk areas, as defined by the National Comprehensive Cancer Network. Negative margins were achieved in 191 (93.2%) lesions. In 88.3% of lesions (n = 181/205), negative margins were achieved in 2 or less excisions. 12 lesions (5.9%) were referred for MMS.

Conclusions:

Our results demonstrate that SE is an effective modality for definitive removal of NMSC. Recent research reveals that SE is much less expensive than MMS, and therefore places a smaller financial burden on the patient and the healthcare system as a whole. Relative to MMS, SE offers similar if not increased benefits for lower cost. Our findings highlight the need to critically reassess the select indications for MMS.
Arteriovenous Malformation of the Upper Eyelid: A Case Report
Authors: Alsabbagh Badriah M. , Alfaqeeh Faisal A. , Ajlan Abdulrazag M. , Yaghmoor Faris , Essbaiheen Fahad , Arab Khalid A.
Published: June 2021

Arteriovenous malformations (AVMs) are rare lesions formed by direct connection of arteries and veins bypassing capillary beds. AVM locations can vary; however, extracranial AVMs remain the least common. The vast majority of these malformations are congenital and can be triggered by hormonal changes. A 49-year-old woman presented with a progressive right-sided upper eyelid swelling over the past 12 years. The patient had mechanical ptosis and mild impairment of the right visual field. The swelling was compressible with a thrill, and bruits were heard. The patient was diagnosed with AVM using cerebral angiography. Preoperative endovascular embolization was not possible; however, surgical excision was successfully done with no complications. AVMs and fistulas are high-flow vascular lesions that usually occur during childhood and progress with time. Only a few cases of face and eyelid AVMs have been reported in the literature. Diagnosis of these anomalies is mostly made based on clinical presentation and radiographic imaging such as angiography. Treatment options remain controversial, and management should be individualized for each patient. Endovascular embolization followed by surgical excision is advisable in many cases. Due to its rare entity, information regarding the best management options for AVMs is limited. Reducing the risk of bleeding and achieving total resection is the goal of treatment. Long-term follow-up is required in these patients because recurrent cases of AVMs have been reported.
Three-dimensional Printing Technology for Deep Circumflex Iliac Artery Flap: From Recipient to Donor Sites
Authors: Zhu Wang-Yong , Choi Wing Shan , Su Yu-Xiong
Published: June 2021

The deep circumflex iliac artery (DCIA) flap is one of the most commonly used vascularized free flaps for jaw reconstruction; however, its clinical application is limited by donor site complications. We aimed to describe a new technique of using 3-dimensionally (3D) printed patient-specific devices for mandibular reconstruction with DCIA flap and simultaneous dental implants, and for donor site restoration after harvesting the DCIA flap. One patient with mandible ameloblastoma underwent mandibular reconstruction using a DCIA flap with the “jaw-in-a-day” approach. The 3D-printed patient-specific devices included mandibular cutting guides, DCIA harvesting and dental implant guide, surgical plate, and iliac prosthesis. The postoperative 1-month accuracy measurement showed the mean distance deviations of the mandible, transferred bone grafts, dental implants and iliac prosthesis were 1.8 mm, 2.1 mm, 0.9 mm, and 1.2 mm, respectively. Three-dimensionally printed iliac prosthesis satisfactorily restored the contour of the iliac crest after DCIA flap harvesting. No complication of donor site was recorded during the follow-up of 12 months. We successfully used 3D-printed patient-specific implants in both donor and recipient sites for DCIA flap jaw reconstruction. Further studies with a larger sample size and long-term follow-up are needed.
Feasibility and safety of a rapid-access transient ischemic attack clinic
Authors: Hermanson Sarah , Vora Nirali , Blackmore C. Craig , Williams Barbara , Isenberg Nancy
Published: June 2021

Background:

In the United States, patients with transient ischemic attacks (TIAs) are commonly admitted to the hospital despite evidence that low-risk TIA patients achieve improved outcomes at lower costs at specialized rapid-access TIA clinics (RATCs).

Local problem:

All patients experiencing TIAs at a hospital system in the Pacific Northwest were being admitted to the hospital. This project aimed to implement an RATC to relocate care for low-risk TIA patients, showing feasibility and safety.

Methods:

Following implementation of the RATC, a retrospective chart review was performed. Outcomes included days to RATC; days to magnetic resonance imaging (MRI); final diagnosis; stroke-related admissions and deaths within 90 days of the RATC visit.

Interventions:

From 2016 to 2018, implementation of an RATC included patient triage tools; multidisciplinary collaboration between departments; a direct scheduling pathway; and emphasis on stroke prevention.

Results:

Ninety-nine patients were evaluated in the RATC, 69% (69/99) were referred from the emergency department. Sixty-six percent of patients were seen in the TIA clinic in 2 days or less, 19% at 3 days, and 15% at 4 days or more. Mean days to TIA clinic was 2.5 days (SD 2.4). Mean days (SD) to MRI was 2.1 days (SD 2.3). Forty-eight percent (48/99) had a final diagnosis of probable TIA, followed by 32% (32/99) who had other diagnoses; 15% (15/99) migraine variant; 4% (4/99) with stroke. Two percent (2/99) of patients had a stroke-related admission within 90 days, another 2% (2/99) died of non–stroke-related causes within 90 days of the RATC visit.

Conclusions:

Utilization of RATCs is feasible and safe. Nurse practitioners are integral in delivering this innovative, cost-effective model of care.
rMAP: the Rapid Microbial Analysis Pipeline for ESKAPE bacterial group whole-genome sequence data
Authors: Sserwadda Ivan , Mboowa Gerald
Published: June 2021

The recent re-emergence of multidrug-resistant pathogens has exacerbated their threat to worldwide public health. The evolution of the genomics era has led to the generation of huge volumes of sequencing data at an unprecedented rate due to the ever-reducing costs of whole-genome sequencing (WGS). We have developed the Rapid Microbial Analysis Pipeline (rMAP), a user-friendly pipeline capable of profiling the resistomes of ESKAPE pathogens (

Enterococcus faecium

,

Staphylococcus aureus

,

Klebsiella pneumoniae

,

Acinetobacter baumannii

,

Pseudomonas aeruginosa

and

Enterobacter

species) using WGS data generated from Illumina’s sequencing platforms. rMAP is designed for individuals with little bioinformatics expertise, and automates the steps required for WGS analysis directly from the raw genomic sequence data, including adapter and low-quality sequence read trimming, de novo genome assembly, genome annotation, single-nucleotide polymorphism (SNP) variant calling, phylogenetic inference by maximum likelihood, antimicrobial resistance (AMR) profiling, plasmid profiling, virulence factor determination, multi-locus sequence typing (MLST), pangenome analysis and insertion sequence characterization (IS). Once the analysis is finished, rMAP generates an interactive web-like html report. rMAP installation is very simple, it can be run using very simple commands. It represents a rapid and easy way to perform comprehensive bacterial WGS analysis using a personal laptop in low-income settings where high-performance computing infrastructure is limited.
Social inequalities in hostility toward vaccination against Covid-19
Authors: Spire Alexis , Bajos Nathalie , Silberzan Léna
Published: June 2021

In recent decades, France has appeared as a country particularly hostile to vaccination in general. When asked in November 2020 about the intention to take the Covid-19 vaccine, the French public showed, once again, reluctance. Therefore, France appeared as an ideal case study to analyze whether the hostility toward the Covid-19 vaccine has its own reasons or whether it is related to the reluctance to the principle of vaccination itself. Our objective was to determine the specificity of the social determinants of the intention to get the Covid-19 vaccine. Thanks to the use of a large random sample of the general population in France (86,000 individuals), the reluctant to Covid-19 vaccine could be clearly distinguished from the hesitant and the convinced, and thereby thoroughly analyzed. Our analysis highlighted a gendered reluctance toward vaccination in general but even more so regarding vaccination against Covid-19. It might refer to women being more concerned about the possible effects of an injection in their body, especially at the age of maternity and a differentiated socialization making them more sensitive than men to long-term risks and more apprehensive toward rapid technological change. We also found that people at the bottom of the social hierarchy, in terms of level of education, financial resources, and immigration status, were more likely to refuse the Covid-19 vaccine. Nevertheless, this reluctance was less prominent than for vaccination in general, reflecting the actual spread of the epidemic in various social milieux. Finally, our analysis showed that trust in the government’s actions was significantly associated with reluctance toward the Covid-19 vaccine, even more than toward vaccination in general.

Specific campaigns should be thought beforehand to reach women and people at the bottom of the social hierarchy to avoid furthering social inequalities in terms of morbidity and mortality.
Evolutionary epidemiology consequences of trait-dependent control of heterogeneous parasites
Authors: Miele Leonardo , Evans R M L , Cunniffe Nik , Torres-Barcelo Clara , Bevacqua Daniele
Published: June 2021

Disease control can induce both demographic and evolutionary responses in host-parasite systems. Foreseeing the outcome of control therefore requires knowledge of the eco-evolutionary feedback between control and system. Previous work has assumed that control strategies have a homogeneous effect on the parasite population. However, this is not true when control targets those traits that confer to the parasite heterogeneous levels of resistance, which can additionally be related to other key parasite traits, through evolutionary trade-offs. In this work, we develop a minimal model coupling epidemiological and evolutionary dynamics to explore possible trait-dependent effects of control strategies. Particularly, we consider a parasite expressing continuous levels of a trait determining resource exploitation, and a control treatment that can be either positively or negatively correlated with that trait. We demonstrate the potential of trait-dependent control by considering that the decision maker may want to minimise both the damage caused by the disease and the use of treatment, due to possible environmental or economic costs. We identify efficient strategies showing that the optimal type of treatment depends on the amount applied. Our results pave the way for the study of control strategies based on evolutionary constraints, such as collateral sensitivity and resistance costs, which are receiving increasing attention for both public health and agricultural purposes.
Prediction of the effect of pH on the aggregation and conditional folding of intrinsically disordered proteins with SolupHred and DispHred
Authors: Iglesias Valentín , Pintado-Grima Carlos , Santos Jaime , Fornt Marc , Ventura Salvador
Published: June 2021

Proteins microenvironments modulate their structures. Binding partners, organic molecules, or dissolved ions can alter the protein’s compaction, inducing aggregation or order-disorder conformational transitions. Surprisingly, bioinformatic platforms often disregard the protein context in their modeling. In recent work, we proposed that modeling how pH affects protein net charge and hydrophobicity might allow us to forecast pH-dependent aggregation and conditional disorder in intrinsically disordered proteins (IDPs). As these approaches showed remarkable success in recapitulating the available bibliographical data, we made these prediction methods available for the scientific community as two user-friendly web servers. SolupHred is the first dedicated software to predict pH-dependent aggregation, and DispHred is the first pH-dependent predictor of protein disorder. Here we dissect the features of these two software applications to train and assist scientists in studying pH-dependent conformational changes in IDPs.
Imaging flow cytometry challenges the usefulness of classically used EV labelling dyes and qualifies that of a novel dye, named Exoria™ for the labelling of MSC-EV preparations
Authors: Tertel Tobias , Schoppet Melanie , Stambouli Oumaima , Al-Jipouri Ali , James Patrick F. , Giebel Bernd
Published: June 2021

Extracellular vesicles (EVs) are involved in mediating intercellular communication processes. An important goal within the EV field is the study of the biodistribution of EVs and the identification of their target cells. Considering that EV uptake is central for mediating the EVs role in intercellular communication processes, labelling with fluorescent dyes has emerged as a broadly distributed strategy for the identification of the EVs target cells and tissues. However, the accuracy and specificity of commonly utilized labelling dyes has not been sufficiently analyzed. By combining recent advancements in imaging flow cytometry for the phenotypic analysis of single EVs and aiming to identify target cells for EVs within therapeutically relevant MSC-EV preparations, we explored the EV labelling efficacy of various fluorescent dyes, specifically of CFDA-SE, Calcein AM, PKH67, BODIPY-TR-Ceramide and a novel lipid dye named Exoria. Our analyses qualified Exoria as the only dye which specifically labels EVs within our MSC-EV preparations. Furthermore, we demonstrate Exoria labelling does not interfere with the immunomodulatory properties of the MSC-EV preparations as tested in a multi-donor mixed lymphocyte reaction assay. Within this assay, labelled EVs were differentially taken-up by different immune cell types. Overall, our results qualify Exoria as an appropriate dye for the labelling of EVs derived from our MSC-EV preparations, this study also demonstrates the need for the development of next generation EV characterization tools which are able to localize and confirm specificity of EV labelling.
Multi-Level DBSCAN: A Hierarchical Density-Based Clustering Method for Analyzing Molecular Dynamics Simulation Trajectories
Authors: Liu Song , Cao Siqin , Suarez Michael , Goonetillek Eshani C. , Huang Xuhui
Published: June 2021

Molecular Dynamic (MD) simulations have been extensively used as a powerful tool to investigate dynamics of biological molecules in recent decades. Generally, MD simulations generate high-dimensional data that is very hard to visualize and comprehend. As a result, clustering algorithms have been commonly used to reduce the dimensionality of MD data with the key benefit being their ability to reduce the dimensionality of MD data without prior knowledge of structural details or dynamic mechanisms. In this paper, we propose a new algorithm, the Multi-Level Density-Based Spatial Clustering of Applications with Noise (ML-DBSCAN), which combines the clustering results at different resolution of density levels to obtain the hierarchical structure of the free energy landscape and the metastable state assignment. At relatively low resolutions, the ML-DBSCAN can efficiently detect high population regions that contain all metastable states, while at higher resolutions, the ML-DBSCAN can find all metastable states and structural details of the free energy landscape. We demonstrate the powerfulness of the ML-DBSCAN in generating metastable states with a particle moving in a Mexican hat-like potential, and four peptide and protein examples are used to demonstrate how hierarchical structures of free energy landscapes can be found. Furthermore, we developed a GPU implementation of the ML-DBSCAN, which allows the algorithm to handle larger MD datasets and be up to two orders of magnitude faster than the CPU implementation. We demonstrate the power of the ML-DBSCAN on MD simulation datasets of five systems: a 2D-potential, alanine dipeptide, β-hairpin Tryptophan Zipper 2 (Trpzip2), Human Islet Amyloid Polypeptide (hIAPP), and Maltose Binding Protein (MBP). Our code is available at https://github.com/liusong299/ML-DBSCAN.
Detection ofNeisseria meningitidisin Saliva and Oropharyngeal Samples from College Students
Authors: Miellet Willem R. , Mariman Rob , Pluister Gerlinde , de Jong Lieke J. , Grift Ivo , Wijkstra Stijn , van Logchem Elske , van Veldhuizen Janieke , Immink Marie-Monique , Wijmenga-Monsuur Alienke J. , Rots Nynke Y. , Sanders Elisabeth A.M. , Bosch Thijs , Trzciński Krzysztof
Published: June 2021

Objectives

Since conjugated polysaccharide vaccines reduce carriage of vaccine-typeNeisseria meningitidisstrains, meningococcal carriage is an accepted endpoint in monitoring vaccine effects. We have assessed vaccine-type genogroup carriage prevalence in students at the time of MenACWY vaccine introduction in The Netherlands. In addition, we evaluated the feasibility of saliva sampling and qPCR-based detection method for the surveillance of meningococcal carriage.

Methods

Paired saliva and oropharyngeal samples, collected from 299 students, were cultured for meningococcus. The DNA extracted from all bacterial growth was subjected to qPCRs quantifying meningococcal presence and genogroup-specific genes. Samples negative by culture yet positive for qPCR were cultured again for meningococcus. Results for saliva were compared with oropharyngeal samples.

Results

Altogether 74 (25% of 299) students were identified as meningococcal carrier by any method used. Sixty-one students (20%) were identified as carriers with qPCR. The difference between number of qPCR-positive oropharyngeal (n=59) and saliva (n=52) samples was not significant (McNemar’s test,p=0.07). Meningococci were cultured from 72 students (24%), with a significantly higher (p<0.001) number of oropharyngeal (n=70) compared with saliva (n=54) samples. The prevalence of genogroups A, B, C, W, and Y was none, 9%, 1% and 6%, respectively, and 8% of students carried MenACWY vaccine-type genogroup meningococci.

Conclusions

We show that the detected prevalence of meningococcal carriage between oropharyngeal and saliva samples was nondifferent with qPCR and moreover, detection with both samples was highly concordant. Saliva is easy to collect and when combined with qPCR detection can be considered for meningococcal carriage studies.