Publications by authors named "Martin Frank"

242 Publications

Genome sequencing in congenital cataracts improves diagnostic yield.

Hum Mutat 2021 Jun 8. Epub 2021 Jun 8.

Eye Genetics Research Unit, The Children's Hospital at Westmead, Save Sight Institute, Children's Medical Research Institute, University of Sydney, Sydney, New South Wales, Australia.

Congenital cataracts are one of the major causes of childhood-onset blindness around the world. Genetic diagnosis provides benefits through avoidance of unnecessary tests, surveillance of extraocular features, and genetic family information. In this study, we demonstrate the value of genome sequencing in improving diagnostic yield in congenital cataract patients and families. We applied genome sequencing to investigate 20 probands with congenital cataracts. We examined the added value of genome sequencing across a total cohort of 52 probands, including 14 unable to be diagnosed using previous microarray and exome or panel-based approaches. Although exome or genome sequencing would have detected the variants in 35/52 (67%) of the cases, specific advantages of genome sequencing led to additional diagnoses in 10% (5/52) of the overall cohort, and we achieved an overall diagnostic rate of 77% (40/52). Specific benefits of genome sequencing were due to detection of small copy number variants (2), indels in repetitive regions (2) or single-nucleotide variants (SNVs) in GC-rich regions (1), not detectable on the previous microarray, exome sequencing, or panel-based approaches. In other cases, SNVs were identified in cataract disease genes, including those newly identified since our previous study. This study highlights the additional yield of genome sequencing in congenital cataracts.
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http://dx.doi.org/10.1002/humu.24240DOI Listing
June 2021

Dynamic Interactions of Fully Glycosylated SARS-CoV-2 Spike Protein with Various Antibodies.

bioRxiv 2021 May 11. Epub 2021 May 11.

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a public health crisis, and the vaccines that can induce highly potent neutralizing antibodies are essential for ending the pandemic. The spike (S) protein on the viral envelope mediates human angiotensin-converting enzyme 2 (ACE2) binding and thus is the target of a variety of neutralizing antibodies. In this work, we built various S trimer-antibody complex structures on the basis of the fully glycosylated S protein models described in our previous work, and performed all-atom molecular dynamics simulations to get insight into the structural dynamics and interactions between S protein and antibodies. Investigation of the residues critical for S-antibody binding allows us to predict the potential influence of mutations in SARS-CoV-2 variants. Comparison of the glycan conformations between S-only and S-antibody systems reveals the roles of glycans in S-antibody binding. In addition, we explored the antibody binding modes, and the influences of antibody on the motion of S protein receptor binding domains. Overall, our analyses provide a better understanding of S-antibody interactions, and the simulation-based S-antibody interaction maps could be used to predict the influences of S mutation on S-antibody interactions, which will be useful for the development of vaccine and antibody-based therapy.
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http://dx.doi.org/10.1101/2021.05.10.443519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132224PMC
May 2021

Effects of anti-resorptive treatment on the material properties of individual canine trabeculae in cyclic tensile tests.

Bone 2021 Sep 1;150:115995. Epub 2021 May 1.

Institute of Lightweight Design and Structural Biomechanics, TU Wien, Gumpendorfer Straße 7, 1060 Vienna, Austria. Electronic address:

Osteoporosis is defined as a decrease of bone mass and strength, as well as an increase in fracture risk. It is conventionally treated with antiresorptive drugs, such as bisphosphonates (BPs) and selective estrogen receptor modulators (SERMs). Although both drug types successfully decrease the risk of bone fractures, their effect on bone mass and strength is different. For instance, BP treatment causes an increase of bone mass, stiffness and strength of whole bones, whereas SERM treatment causes only small (4%) increases of bone mass, but increased bone toughness. Such improved mechanical behavior of whole bones can be potentially related to the bone mass, bone structure or material changes. While bone mass and architecture have already been investigated previously, little is known about the mechanical behavior at the tissue/material level, especially of trabecular bone. As such, the goal of the work presented here was to fill this gap by performing cyclic tensile tests in a wet, close to physiologic environment of individual trabeculae retrieved from the vertebrae of beagle dogs treated with alendronate (a BP), raloxifene (a SERM) or without treatments. Identification of material properties was performed with a previously developed rheological model and of mechanical properties via fitting of envelope curves. Additionally, tissue mineral density (TMD) and microdamage formation were analyzed. Alendronate treatment resulted in a higher trabecular tissue stiffness and strength, associated with higher levels of TMD. In contrast, raloxifene treatment caused a higher trabecular toughness, pre-dominantly in the post-yield region. Microdamage formation during testing was not affected by either anti-resorptive treatment regimens. These findings highlight that the improved mechanical behavior of whole bones after anti-resorptive treatment is at least partly caused by improved material properties, with different mechanisms for alendronate and raloxifene. This study further shows the power of performing a mechanical characterization of trabecular bone at the level of individual trabeculae for better understanding of clinically relevant mechanical behavior of bone.
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http://dx.doi.org/10.1016/j.bone.2021.115995DOI Listing
September 2021

VANTAGE6: an open source priVAcy preserviNg federaTed leArninG infrastructurE for Secure Insight eXchange.

AMIA Annu Symp Proc 2020 25;2020:870-877. Epub 2021 Jan 25.

Netherlands Comprehensive Cancer Organization (IKNL), Eindhoven, NL.

Answering many of the research questions in the field of cancer informatics requires incorporating and centralizing data that are hosted by different parties. Federated Learning (FL) has emerged as a new approach in which a global model can be generated without disclosing private patient data by keeping them at their original location. Flexible, user-friendly, and robust infrastructures are crucial for bringing FL solutions to the day-to-day work of the cancer epidemiologist. In this paper, we present an open source priVAcy preserviNg federaTed leArninG infrastructurE for Secure Insight eXchange, VANTAGE6. We provide a detailed description of its conceptual design, modular architecture, and components. We also show a few examples where VANTAGE6 has been successfully used in research on observational cancer data. Developing and deploying technology to support federated analyses - such as VANTAGE6 - will pave the way for the adoption and mainstream practice of this new approach for analyzing decentralized data.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075508PMC
June 2021

Site-Specific O-Glycosylation Analysis of SARS-CoV-2 Spike Protein Produced in Insect and Human Cells.

Viruses 2021 03 25;13(4). Epub 2021 Mar 25.

Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen, Denmark.

Enveloped viruses hijack not only the host translation processes, but also its glycosylation machinery, and to a variable extent cover viral surface proteins with tolerogenic host-like structures. SARS-CoV-2 surface protein S presents as a trimer on the viral surface and is covered by a dense shield of N-linked glycans, and a few O-glycosites have been reported. The location of O-glycans is controlled by a large family of initiating enzymes with variable expression in cells and tissues and hence is difficult to predict. Here, we used our well-established O-glycoproteomic workflows to map the precise positions of O-linked glycosylation sites on three different entities of protein S-insect cell or human cell-produced ectodomains, or insect cell derived receptor binding domain (RBD). In total 25 O-glycosites were identified, with similar patterns in the two ectodomains of different cell origin, and a distinct pattern of the monomeric RBD. Strikingly, 16 out of 25 O-glycosites were located within three amino acids from known N-glycosites. However, O-glycosylation was primarily found on peptides that were unoccupied by N-glycans, and otherwise had low overall occupancy. This suggests possible complementary functions of O-glycans in immune shielding and negligible effects of O-glycosylation on subunit vaccine design for SARS-CoV-2.
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http://dx.doi.org/10.3390/v13040551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064498PMC
March 2021

Comparative cohorts of retinopathy of prematurity outcomes of differing oxygen saturation: real-world outcomes.

BMJ Open Ophthalmol 2021 8;6(1):e000626. Epub 2021 Mar 8.

Ophthalmology, The University of Sydney Save Sight Institute, Sydney, New South Wales, Australia.

Objective: An ongoing third epidemic of retinopathy of prematurity (ROP) is contributed largely by developing nations. We describe a cohort of infants in a single neonatal unit where two limits of oxygen saturation were administered, to show real-world outcomes from trend in neonatology for higher oxygen to improve survival.

Methods And Analysis: This retrospective, comparative study of prospectively collected data in an ROP screening programme included infants indicated by gestational age ≤32 weeks, birth weight <1501 g, ventilation for 7 days or requiring oxygen >1 month, who underwent dilated fundoscopic examination from age 4 weeks, every 2 weeks until full retinal vascularisation. Infants with ROP were examined weekly and treated where indicated. Data were divided into two epochs. Epoch 1 oxygen saturation targets were [88-92%], epoch 2 targets [90-95% (99%)] with allowance of increase to 20% for several hours after procedures. Outcome measures included development of ROP, treatment, mortality, sepsis and intraventricular haemorrhage.

Results: A total of 651 infants underwent examination between 2003 and 2016. The incidence of ROP in epoch 1 was 29.1% and epoch 2 was 29.3% (p=0.24). ROP progression doubled in epoch 2 (5 vs 11%, p=0.006), proportion of cases treated halved (14% vs 6%, p=0.0005), sepsis was halved (78.5% vs 41.2%, p<0.0001) and intraventricular haemorrhage doubled (20.2% vs 43.8%, p=0.0001) in epoch 2. Mortality was 4% and 0% in epochs 1 and 2, respectively.

Conclusion: Incidence of ROP did not differ, although ROP cases that worsened doubled with higher oxygen targets. ROP cases requiring treatment decreased, as did sepsis and mortality. Intraventricular haemorrhage cases doubled.
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http://dx.doi.org/10.1136/bmjophth-2020-000626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942244PMC
March 2021

Site-specific steric control of SARS-CoV-2 spike glycosylation.

bioRxiv 2021 Mar 9. Epub 2021 Mar 9.

A central tenet in the design of vaccines is the display of native-like antigens in the elicitation of protective immunity. The abundance of N-linked glycans across the SARS-CoV-2 spike protein is a potential source of heterogeneity between the many different vaccine candidates under investigation. Here, we investigate the glycosylation of recombinant SARS-CoV-2 spike proteins from five different laboratories and compare them against infectious virus S protein. We find patterns which are conserved across all samples and this can be associated with site-specific stalling of glycan maturation which act as a highly sensitive reporter of protein structure. Molecular dynamics (MD) simulations of a fully glycosylated spike support s a model of steric restrictions that shape enzymatic processing of the glycans. These results suggest that recombinant spike-based SARS-CoV-2 immunogen glycosylation reproducibly recapitulates signatures of viral glycosylation.
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http://dx.doi.org/10.1101/2021.03.08.433764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986994PMC
March 2021

Structure, Dynamics, Receptor Binding, and Antibody Binding of the Fully Glycosylated Full-Length SARS-CoV-2 Spike Protein in a Viral Membrane.

J Chem Theory Comput 2021 Apr 10;17(4):2479-2487. Epub 2021 Mar 10.

Departments of Biological Sciences, Chemistry, Bioengineering, and Computer Science and Engineering, Lehigh University, Bethlehem, Pennsylvania 18015, United States.

The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mediates host cell entry by binding to angiotensin-converting enzyme 2 (ACE2) and is considered the major target for drug and vaccine development. We previously built fully glycosylated full-length SARS-CoV-2 S protein models in a viral membrane including both open and closed conformations of the receptor-binding domain (RBD) and different templates for the stalk region. In this work, multiple μs-long all-atom molecular dynamics simulations were performed to provide deeper insights into the structure and dynamics of S protein and glycan functions. Our simulations reveal that the highly flexible stalk is composed of two independent joints and most probable S protein orientations are competent for ACE2 binding. We identify multiple glycans stabilizing the open and/or closed states of the RBD and demonstrate that the exposure of antibody epitopes can be captured by detailed antibody-glycan clash analysis instead of commonly used accessible surface area analysis that tends to overestimate the impact of glycan shielding and neglect possible detailed interactions between glycan and antibodies. Overall, our observations offer structural and dynamic insights into the SARS-CoV-2 S protein and potentialize for guiding the design of effective antiviral therapeutics.
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http://dx.doi.org/10.1021/acs.jctc.0c01144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047829PMC
April 2021

A multiplex TaqMan qPCR assay for detection and quantification of clade 1 and clade 2 isolates of and .

Plant Dis 2021 Feb 16. Epub 2021 Feb 16.

USDA ARS, 17123, Salinas, California, United States;

The ability to detect and quantify aerially dispersed plant pathogens is essential for developing effective disease control measures and epidemiological models that optimize the timing for control . There is an acute need for managing the downy mildew pathogens infecting cucurbits and hop incited by members of the genus ( clade 1 and 2 isolates and , respectively). A highly specific multiplex TaqMan qPCR assay targeting unique sequences in the pathogens' mitochondrial genomes was developed that enables detection of all three taxa in a single multiplexed amplification. An internal control included in the reaction evaluated if results were influenced by PCR inhibitors that can make it through the DNA extraction process. Reliable quantification of inoculum as low as three sporangia in a sample was observed. The multiplexed assay was tested with DNA extracted from purified sporangia, infected plant tissue and environmental samples collected on impaction spore traps samplers. The ability to accurately detect and simultaneously quantify all three pathogens in a single multiplexed amplification should improve management options for controlling the diseases they cause.
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http://dx.doi.org/10.1094/PDIS-11-20-2339-REDOI Listing
February 2021

Site-specific O-glycosylation analysis of SARS-CoV-2 spike protein produced in insect and human cells.

bioRxiv 2021 Feb 4. Epub 2021 Feb 4.

Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen, Denmark.

Enveloped viruses hijack not only the host translation processes, but also its glycosylation machinery, and to a variable extent cover viral surface proteins with tolerogenic host-like structures. SARS-CoV-2 surface protein S presents as a trimer on the viral surface and is covered by a dense shield of N-linked glycans, and a few O-glycosites have been reported. The location of O-glycans is controlled by a large family of initiating enzymes with variable expression in cells and tissues and hence difficult to predict. Here, we used our well-established O-glycoproteomic workflows to map the precise positions of O-linked glycosylation sites on three different entities of protein S - insect cell or human cell-produced ectodomains, or insect cell derived receptor binding domain (RBD). In total 25 O-glycosites were identified, with similar patterns in the two ectodomains of different cell origin, and a distinct pattern of the monomeric RBD. Strikingly, 16 out of 25 O-glycosites were located within three amino acids from known N-glycosites. However, O-glycosylation was primarily found on peptides that were unoccupied by N-glycans, and otherwise had low overall occupancy. This suggests possible complimentary functions of O-glycans in immune shielding and negligible effects of O-glycosylation on subunit vaccine design for SARS-CoV-2.
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http://dx.doi.org/10.1101/2021.02.03.429627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872350PMC
February 2021

A novel ACE2 isoform is expressed in human respiratory epithelia and is upregulated in response to interferons and RNA respiratory virus infection.

Nat Genet 2021 02 11;53(2):205-214. Epub 2021 Jan 11.

Faculty of Medicine, School of Clinical and Experimental Sciences, University of Southampton, Southampton, UK.

Angiotensin-converting enzyme 2 (ACE2) is the main entry point in airway epithelial cells for SARS-CoV-2. ACE2 binding to the SARS-CoV-2 protein spike triggers viral fusion with the cell plasma membrane, resulting in viral RNA genome delivery into the host. Despite ACE2's critical role in SARS-CoV-2 infection, full understanding of ACE2 expression, including in response to viral infection, remains unclear. ACE2 was thought to encode five transcripts and one protein of 805 amino acids. In the present study, we identify a novel short isoform of ACE2 expressed in the airway epithelium, the main site of SARS-CoV-2 infection. Short ACE2 is substantially upregulated in response to interferon stimulation and rhinovirus infection, but not SARS-CoV-2 infection. This short isoform lacks SARS-CoV-2 spike high-affinity binding sites and, altogether, our data are consistent with a model where short ACE2 is unlikely to directly contribute to host susceptibility to SARS-CoV-2 infection.
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http://dx.doi.org/10.1038/s41588-020-00759-xDOI Listing
February 2021

Evidence for increasing anthropogenic Pb concentrations in Indian shelf sediments during the last century.

Sci Total Environ 2021 Mar 20;760:143833. Epub 2020 Nov 20.

Geological Oceanography Division, National Institute of Oceanography (CSIR), Dona Paula, 403004, Goa, India.

India is industrializing rapidly and with this there comes higher releases of contaminants into the environment. Change in Pb deposition over the last century on the eastern (off Andhra Pradesh) and western (off Karnataka) shelves of India was investigated based on the data extracted from two sediment cores covering the past ~114 and ~145 yrs. The variations of the total Pb content, its enrichment factor, and concentrations of non-residual Pb in both the sediment cores document that there was a gradual increase in anthropogenic Pb input into the coastal sediments of India over the last century. Sediment leachates were used to monitor the increase in anthropogenic Pb input and its Pb isotope composition. The anthropogenic end member composition of the western shelf sediment location (Pb/Pb: 1.105; Pb/Pb: 2.149) was significantly less radiogenic than the eastern shelf isotopic composition (Pb/Pb: 1.145; Pb/Pb:2.120). A binary mixing model suggests that Pb emitted from the heavy industries (e.g., ore mining, Pb processing and smelting plants) of India has been the major source of anthropogenic Pb to the sediments of western continental shelf. In contrast, the isotopic signatures suggest that coal combustion is responsible for elevated anthropogenic Pb levels in the sediments from the eastern shelf of India.
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http://dx.doi.org/10.1016/j.scitotenv.2020.143833DOI Listing
March 2021

Microdamage formation in individual bovine trabeculae during fatigue testing.

J Biomech 2021 01 17;115:110131. Epub 2020 Nov 17.

Institute of Lightweight Design and Structural Biomechanics, TU Wien, Gumpendorfer Str. 7, BE02, 1060 Vienna, Austria. Electronic address:

Ageing, disease and osteoporosis treatment have been linked to accumulation of microdamage, which is caused by repetitive loading and may eventually causes fatigue failure of bones. Post-hoc investigations for in vivo loading and in vitro experiments have been developed to better understand microdamage formation. In this context, previous studies were not able to discriminate the effects caused by structural changes of the trabecular network from differences of tissue/material properties on microdamage formation. In the present study a fatigue test protocol was established to induce microdamage at a defined tensile stress state of individual trabeculae. Further, a thorough analysis of microdamage analysis was presented for 2D and 3D confocal images, enabling a comparison between the tissue and the meso-scale. Eight individual trabeculae were tested for 1500 cycles, six for 2100 cycles and seven for 3000 cycles (close to failure). Microdamage increased slowly from 1500 to 2100 cycles and showed a rapid increase at 3000 cycles. Diffuse damage was mainly present, although also linear microcracks were visible at 2100 and 3000 cycles. Average microcrack length was 93 µm and diffuse damage density was 4.4% for samples tested for 3000 cycles, comparable to previous studies on trabecular bone cores. Only one to three large microdamage sites were observed in the central region, connected to the trabecular surface with small straight cracks. The presented procedure is a first step to better understand how microdamage formation is influenced by material properties in aged and diseased bone, independently of deteriorated trabecular microarchitecture.
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http://dx.doi.org/10.1016/j.jbiomech.2020.110131DOI Listing
January 2021

Phylogenomic analysis of a 55.1 kb 19-gene dataset resolves a monophyletic Fusarium that includes the Fusarium solani Species Complex.

Phytopathology 2020 Nov 17. Epub 2020 Nov 17.

University of Cordoba, Genetics, Campus Rabanales, Edif. C5, Cordoba, Spain, 14071;

Scientific communication is facilitated by a data-driven, scientifically sound taxonomy that considers the end-user's needs and established successful practice. Previously (Geiser et al. 2013; Phytopathology 103:400-408. 2013), the Fusarium community voiced near unanimous support for a concept of Fusarium that represented a clade comprising all agriculturally and clinically important Fusarium species, including the F. solani Species Complex (FSSC). Subsequently, this concept was challenged by one research group (Lombard et al. 2015 Studies in Mycology 80: 189-245) who proposed dividing Fusarium into seven genera, including the FSSC as the genus Neocosmospora, with subsequent justification based on claims that the Geiser et al. (2013) concept of Fusarium is polyphyletic (Sandoval-Denis et al. 2018; Persoonia 41:109-129). Here we test this claim, and provide a phylogeny based on exonic nucleotide sequences of 19 orthologous protein-coding genes that strongly support the monophyly of Fusarium including the FSSC. We reassert the practical and scientific argument in support of a Fusarium that includes the FSSC and several other basal lineages, consistent with the longstanding use of this name among plant pathologists, medical mycologists, quarantine officials, regulatory agencies, students and researchers with a stake in its taxonomy. In recognition of this monophyly, 40 species recently described as Neocosmospora were recombined in Fusarium, and nine others were renamed Fusarium. Here the global Fusarium community voices strong support for the inclusion of the FSSC in Fusarium, as it remains the best scientific, nomenclatural and practical taxonomic option available.
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http://dx.doi.org/10.1094/PHYTO-08-20-0330-LEDOI Listing
November 2020

RPA-PCR couple: an approach to expedite plant diagnostics and overcome PCR inhibitors.

Biotechniques 2020 10 20;69(4):270-280. Epub 2020 Aug 20.

Department of Environmental & Biological Sciences, University of Eastern Finland, Kuopio 70211, Finland.

DNA extraction can be lengthy and sometimes ends up with amplification inhibitors. We present the potential of recombinase polymerase amplification (RPA) to replace plant DNA extraction. In our rapid 'RPA-PCR couple' concept, RPA is tuned to slower reaction kinetics to promote amplification of long targets. RPA primers amplify target and some flanking regions directly from simple plant macerates. Then PCR primers exponentially amplify the target directly from the RPA reaction. We present the coupling of RPA with conventional, TaqMan and SYBR Green PCR assays. We applied the concept to strawberry pathogens and the identification marker . We found RPA-PCR couple specific, sensitive and reliable. The approach may also benefit other difficult samples such as food, feces and ancient samples.
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http://dx.doi.org/10.2144/btn-2020-0065DOI Listing
October 2020

C-Mannosylation Enhances the Structural Stability of Human RNase 2.

iScience 2020 Aug 16;23(8):101371. Epub 2020 Jul 16.

Bijvoet Center, Division of Bio-Organic Chemistry, Utrecht University, Padualaan 8, Utrecht 3584 CH, The Netherlands. Electronic address:

C-Mannosylation is a relatively rare form of protein glycosylation involving the attachment of an α-mannopyranosyl residue to C-2 of the indole moiety of the amino acid tryptophan. This type of linkage was initially discovered in RNase 2 from human urine but later confirmed to be present in many other important proteins. Based on NMR experiments and extensive molecular dynamics simulations on the hundred microsecond timescale we demonstrate that, for isolated glycopeptides and denatured RNase 2, the C-linked mannopyranosyl residue exists as an ensemble of conformations, among which C is the most abundant. However, for native RNase 2, molecular dynamics and NMR studies revealed that the mannopyranosyl residue favors a specific conformation, which optimally stabilizes the protein fold through a network of hydrogen bonds and which leads to a significant reduction of the protein dynamics on the microsecond timescale. Our findings contribute to the understanding of the biological role of C-mannosylation.
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http://dx.doi.org/10.1016/j.isci.2020.101371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399192PMC
August 2020

Correction to: A two‑layer elasto‑visco‑plastic rheological model for the material parameter identification of bone tissue.

Biomech Model Mechanobiol 2020 10;19(5):1977

Division Biomechanics, Department of Anatomy and Biomechanics, Karl Landsteiner University of Health Sciences, Krems an der Donau, Austria.

In the original publication of the article.
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http://dx.doi.org/10.1007/s10237-020-01356-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502445PMC
October 2020

On relaxation systems and their relation to discrete velocity Boltzmann models for scalar advection-diffusion equations.

Philos Trans A Math Phys Eng Sci 2020 Jul 22;378(2175):20190400. Epub 2020 Jun 22.

Lattice Boltzmann Research Group, Karlsruhe Institute of Technology, 76131 Karlsruhe, Germany.

The connection of relaxation systems and discrete velocity models is essential to the progress of stability as well as convergence results for lattice Boltzmann methods. In the present study we propose a formal perturbation ansatz starting from a scalar one-dimensional target equation, which yields a relaxation system specifically constructed for its equivalence to a discrete velocity Boltzmann model as commonly found in lattice Boltzmann methods. Further, the investigation of stability structures for the discrete velocity Boltzmann equation allows for algebraic characterizations of the equilibrium and collision operator. The methods introduced and summarized here are tailored for scalar, linear advection-diffusion equations, which can be used as a foundation for the constructive design of discrete velocity Boltzmann models and lattice Boltzmann methods to approximate different types of partial differential equations. This article is part of the theme issue 'Fluid dynamics, soft matter and complex systems: recent results and new methods'.
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http://dx.doi.org/10.1098/rsta.2019.0400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333944PMC
July 2020

Use and importance of different information sources among patients with rare diseases and their relatives over time: a qualitative study.

BMC Public Health 2020 Jun 5;20(1):860. Epub 2020 Jun 5.

Center for Health Economics Research Hannover (CHERH), Leibniz University Hannover, Otto-Brenner-Straße 7, 30159, Hannover, Germany.

Background: Finding reliable information on one of more than 7000 rare diseases is a major challenge for those affected. Since rare diseases are defined only by the prevalence criterion, a multitude of heterogeneous diseases are included. Common to all, however, are difficulties regarding information access. Even though various quantitative studies have analyzed the use of different information sources for specific rare diseases, little is known about the use of information sources for different rare diseases, how users rate these information sources based on their experiences, and how the use and importance of these information sources change over time.

Methods: Fifty-five patients with a variety of rare diseases and 13 close relatives participated in qualitative interviews. For these interviews, a semi-structured guideline was developed, piloted, and revised. Data analysis involved a qualitative content analysis developed by Philipp Mayring.

Results: The participants considered internet as the most important and widespread information source, especially for early information. Although patients have difficulty dealing with information obtained online, they consider online searching a quick and practical option to gather information. During the course of the disease, personal contact partners, especially self-help associations and specialized doctors, become more important. This is also because information provided online is sometimes insufficiently detailed to answer their information needs, which can be complemented by information from doctors and self-help.

Conclusions: People rarely use just one type of source, but rather refer to different sources and informants. The source used depends on the type of information sought as well as other person-related factors such as preexisting knowledge and the disease stage. To improve people's information searching and connect them with medical specialists in rare diseases, a central information portal on rare diseases might be a suitable access point to provide free and quality assured information for patients, caregivers, and physicians. This would allow not only patients but also doctors to find quality assured information on symptoms and therapies as well as patient associations and specialized doctors.
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http://dx.doi.org/10.1186/s12889-020-08926-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275578PMC
June 2020

Revealing hidden genetic diagnoses in the ocular anterior segment disorders.

Genet Med 2020 10 5;22(10):1623-1632. Epub 2020 Jun 5.

Eye Genetics Research Unit, The Children's Hospital at Westmead, Save Sight Institute, Children's Medical Research Institute, University of Sydney, Sydney, NSW, Australia.

Purpose: Ocular anterior segment disorders (ASDs) are clinically and genetically heterogeneous, and genetic diagnosis often remains elusive. In this study, we demonstrate the value of a combined analysis protocol using phenotypic, genomic, and pedigree structure data to achieve a genetic conclusion.

Methods: We utilized a combination of chromosome microarray, exome sequencing, and genome sequencing with structural variant and trio analysis to investigate a cohort of 41 predominantly sporadic cases.

Results: We identified likely causative variants in 54% (22/41) of cases, including 51% (19/37) of sporadic cases and 75% (3/4) of cases initially referred as familial ASD. Two-thirds of sporadic cases were found to have heterozygous variants, which in most cases were de novo. Approximately one-third (7/22) of genetic diagnoses were found in rarely reported or recently identified ASD genes including PXDN, GJA8, COL4A1, ITPR1, CPAMD8, as well as the new phenotypic association of Axenfeld-Rieger anomaly with a homozygous ADAMTS17 variant. The remainder of the variants were in key ASD genes including FOXC1, PITX2, CYP1B1, FOXE3, and PAX6.

Conclusions: We demonstrate the benefit of detailed phenotypic, genomic, variant, and segregation analysis to uncover some of the previously "hidden" heritable answers in several rarely reported and newly identified ocular ASD-related disease genes.
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http://dx.doi.org/10.1038/s41436-020-0854-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521990PMC
October 2020

A two-layer elasto-visco-plastic rheological model for the material parameter identification of bone tissue.

Biomech Model Mechanobiol 2020 Dec 6;19(6):2149-2162. Epub 2020 May 6.

Division Biomechanics, Department of Anatomy and Biomechanics, Karl Landsteiner University of Health Sciences, Krems an der Donau, Austria.

The ability to measure bone tissue material properties plays a major role in diagnosis of diseases and material modeling. Bone's response to loading is complex and shows a viscous contribution to stiffness, yield and failure. It is also ductile and damaging and exhibits plastic hardening until failure. When performing mechanical tests on bone tissue, these constitutive effects are difficult to quantify, as only their combination is visible in resulting stress-strain data. In this study, a methodology for the identification of stiffness, damping, yield stress and hardening coefficients of bone from a single cyclic tensile test is proposed. The method is based on a two-layer elasto-visco-plastic rheological model that is capable of reproducing the specimens' pre- and postyield response. The model's structure enables for capturing the viscously induced increase in stiffness, yield, and ultimate stress and for a direct computation of the loss tangent. Material parameters are obtained in an inverse approach by optimizing the model response to fit the experimental data. The proposed approach is demonstrated by identifying material properties of individual bone trabeculae that were tested under wet conditions. The mechanical tests were conducted according to an already published methodology for tensile experiments on single trabeculae. As a result, long-term and instantaneous Young's moduli were obtained, which were on average 3.64 GPa and 5.61 GPa, respectively. The found yield stress of 16.89 MPa was lower than previous studies suggest, while the loss tangent of 0.04 is in good agreement. In general, the two-layer model was able to reproduce the cyclic mechanical test data of single trabeculae with an root-mean-square error of 2.91 ± 1.77 MPa. The results show that inverse rheological modeling can be of great advantage when multiple constitutive contributions shall be quantified based on a single mechanical measurement.
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http://dx.doi.org/10.1007/s10237-020-01329-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603462PMC
December 2020

Validation of a Preformulated, Field Deployable, Recombinase Polymerase Amplification Assay for Species.

Plants (Basel) 2020 Apr 7;9(4). Epub 2020 Apr 7.

Department of Plant, Soil and Microbial Sciences, Michigan State University, East Lansing, MI 48824, USA.

Recombinase polymerase amplification (RPA) assays are valuable molecular diagnostic tools that can detect and identify plant pathogens in the field without time-consuming DNA extractions. Historically, RPA assay reagents were commercially available as a lyophilized pellet in microfuge strip tubes, but have become available in liquid form more recently-both require the addition of primers and probes prior to use, which can be challenging to handle in a field setting. Lyophilization of primers and probes, along with RPA reagents, contained within a single tube limits the risk of contamination, eliminates the need for refrigeration, as the lyophilized reagents are stable at ambient temperatures, and simplifies field use of the assays. This study investigates the potential effect of preformulation on assay performance using a previously validated genus-specific RPA assay, lyophilized with primers and probes included with the RPA reagents. The preformulated lyophilized RPA assay was compared with a quantitative polymerase chain reaction (qPCR) assay and commercially available RPA kits using three qPCR platforms (BioRad CFX96, QuantStudio 6 and Applied Biosystems ViiA7) and one isothermal platform (Axxin T16-ISO RPA), with experiments run in four separate labs. The assay was tested for sensitivity (ranging from 500 to 0.33 pg of DNA) and specificity using purified oomycete DNA, as well as crude extracts of -infected and non-infected plants. The limit of detection (LOD) using purified DNA was 33 pg in the CFX96 and ViiA7 qPCR platforms using the preformulated kits, while the Axxin T16-ISO RPA chamber and the QuantStudio 6 platform could detect down to 3.3 pg with or without added plant extract. The LOD using a crude plant extract for the BioRad CFX96 was 330 pg, whereas the LOD for the ViiA7 system was 33 pg. These trials demonstrate the consistency and uniformity of pathogen detection with preformulated RPA kits for detection when conducted by different labs using different instruments for measuring results.
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http://dx.doi.org/10.3390/plants9040466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238109PMC
April 2020

Proteomics-based screening of the endothelial heparan sulfate interactome reveals that C-type lectin 14a (CLEC14A) is a heparin-binding protein.

J Biol Chem 2020 02 21;295(9):2804-2821. Epub 2020 Jan 21.

Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California 92093. Electronic address:

Animal cells express heparan sulfate proteoglycans that perform many important cellular functions by way of heparan sulfate-protein interactions. The identification of membrane heparan sulfate-binding proteins is challenging because of their low abundance and the need for extensive enrichment. Here, we report a proteomics workflow for the identification and characterization of membrane-anchored and extracellular proteins that bind heparan sulfate. The technique is based on limited proteolysis of live cells in the absence of denaturation and fixation, heparin-affinity chromatography, and high-resolution LC-MS/MS, and we designate it LPHAMS. Application of LPHAMS to U937 monocytic and primary murine and human endothelial cells identified 55 plasma membrane, extracellular matrix, and soluble secreted proteins, including many previously unidentified heparin-binding proteins. The method also facilitated the mapping of the heparin-binding domains, making it possible to predict the location of the heparin-binding site. To validate the discovery feature of LPHAMS, we characterized one of the newly-discovered heparin-binding proteins, C-type lectin 14a (CLEC14A), a member of the C-type lectin family that modulates angiogenesis. We found that the C-type lectin domain of CLEC14A binds one-to-one to heparin with nanomolar affinity, and using molecular modeling and mutagenesis, we mapped its heparin-binding site. CLEC14A physically interacted with other glycosaminoglycans, including endothelial heparan sulfate and chondroitin sulfate E, but not with neutral or sialylated oligosaccharides. The LPHAMS technique should be applicable to other cells and glycans and provides a way to expand the repertoire of glycan-binding proteins for further study.
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http://dx.doi.org/10.1074/jbc.RA119.011639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049958PMC
February 2020

Assembly, annotation, and comparison of Macrophomina phaseolina isolates from strawberry and other hosts.

BMC Genomics 2019 Nov 4;20(1):802. Epub 2019 Nov 4.

Crop Improvement and Protection Research Unit, USDA-ARS, Salinas, California, USA.

Background: Macrophomina phaseolina is a fungal plant pathogen with a broad host range, but one genotype was shown to exhibit host preference/specificity on strawberry. This pathogen lacked a high-quality genome assembly and annotation, and little was known about genomic differences among isolates from different hosts.

Results: We used PacBio sequencing and Hi-C scaffolding to provide nearly complete genome assemblies for M. phaseolina isolates representing the strawberry-specific genotype and another genotype recovered from alfalfa. The strawberry isolate had 59 contigs/scaffolds with an N50 of 4.3 Mb. The isolate from alfalfa had an N50 of 5.0 Mb and 14 nuclear contigs with half including telomeres. Both genomes were annotated with MAKER using transcript evidence generated in this study with over 13,000 protein-coding genes predicted. Unique groups of genes for each isolate were identified when compared to closely related fungal species. Structural comparisons between the isolates reveal large-scale rearrangements including chromosomal inversions and translocations. To include isolates representing a range of pathogen genotypes, an additional 30 isolates were sequenced with Illumina, assembled, and compared to the strawberry genotype assembly. Within the limits of comparing Illumina and PacBio assemblies, no conserved structural rearrangements were identified among the isolates from the strawberry genotype compared to those from other hosts, but some candidate genes were identified that were largely present in isolates of the strawberry genotype and absent in other genotypes.

Conclusions: High-quality reference genomes of M. phaseolina have allowed for the identification of structural changes associated with a genotype that has a host preference toward strawberry and will enable future comparative genomics studies. Having more complete assemblies allows for structural rearrangements to be more fully assessed and ensures a greater representation of all the genes. Work with Illumina data from additional isolates suggests that some genes are predominately present in isolates of the strawberry genotype, but additional work is needed to confirm the role of these genes in pathogenesis. Additional work is also needed to complete the scaffolding of smaller contigs identified in the strawberry genotype assembly and to determine if unique genes in the strawberry genotype play a role in pathogenicity.
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http://dx.doi.org/10.1186/s12864-019-6168-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829926PMC
November 2019

20/20 Hindsight - A chance to reflect upon my career.

Authors:
Martin Frank

Dev Biol 2020 03 18;459(1):19-21. Epub 2019 Oct 18.

Frankly Physiology Consulting, 12609 Triple Crown Road, North Potomac, MD 20878, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ydbio.2019.10.014DOI Listing
March 2020

Miocene restriction of the Pacific-North Atlantic throughflow strengthened Atlantic overturning circulation.

Nat Commun 2019 09 6;10(1):4025. Epub 2019 Sep 6.

GEOMAR Helmholtz Centre for Ocean Research Kiel, Kiel, Germany.

Export of warm and salty waters from the Caribbean to the North Atlantic is an essential component of the Atlantic Meridional Overturning Circulation (AMOC). However, there was also an active AMOC during the Miocene, despite evidence for an open Central American Seaway (CAS) that would have allowed low-salinity Pacific waters to enter the Caribbean. To address this apparent contradiction and to constrain the timing of CAS closure we present the first continuous Nd isotope record of intermediate waters in the Florida Strait over the past 12.5 million years. Our results indicate that there was no direct intermediate water mass export from the Caribbean to the Florida Strait between 11.5 and 9.5 Ma, at the same time as a strengthened AMOC. After 9 Ma a strong AMOC was maintained due to a major step in CAS closure and the consequent cessation of low-salinity Pacific waters entering the Caribbean.
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http://dx.doi.org/10.1038/s41467-019-12034-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731301PMC
September 2019

Late Eocene onset of the Proto-Antarctic Circumpolar Current.

Sci Rep 2019 07 12;9(1):10125. Epub 2019 Jul 12.

GEOMAR Helmholtz Centre for Ocean Research, Kiel, 24148, Germany.

The formation of the Antarctic Circumpolar Current (ACC) is critical for the evolution of the global climate, but the timing of its onset is not well constrained. Here, we present new seismic evidence of widespread Late Eocene to Oligocene marine diagenetic chert in sedimentary drift deposits east of New Zealand indicating prolonged periods of blooms of siliceous microorganisms starting ~36 million years ago (Ma). These major blooms reflect the initiation of the arrival and upwelling of northern-sourced, nutrient-rich deep equatorial Pacific waters at the high latitudes of the South Pacific. We show that this change in circulation was linked to the initiation of a proto-ACC, which occurred ~6 Ma earlier than the currently estimated onset of the ACC at 30 Ma. We propose that the associated increased primary productivity and carbon burial facilitated atmospheric carbon dioxide reduction contributing to the expansion of Antarctic Ice Sheet at the Eocene-Oligocene Transition.
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http://dx.doi.org/10.1038/s41598-019-46253-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626031PMC
July 2019

Two-step closure of the Miocene Indian Ocean Gateway to the Mediterranean.

Sci Rep 2019 06 20;9(1):8842. Epub 2019 Jun 20.

Dr. Moses Strauss Department of Marine Geosciences, The Leon H. Charney School of Marine Sciences, University of Haifa, Carmel, 31905, Israel.

The Tethys Ocean was compartmentalized into the Mediterranean Sea and Indian Ocean during the early Miocene, yet the exact nature and timing of this disconnection are not well understood. Here we present two new neodymium isotope records from isolated carbonate platforms on both sides of the closing seaway, Malta (outcrop sampling) and the Maldives (IODP Site U1468), to constrain the evolution of past water mass exchange between the present day Mediterranean Sea and Indian Ocean via the Mesopotamian Seaway. Combining these data with box modeling results indicates that water mass exchange was reduced by ~90% in a first step at ca. 20 Ma. The terminal closure of the seaway then coincided with the sea level drop caused by the onset of permanent glaciation of Antarctica at ca. 13.8 Ma. The termination of meridional water mass exchange through the Tethyan Seaway resulted in a global reorganization of currents, paved the way to the development of upwelling in the Arabian Sea and possibly led to a strengthening of South Asian Monsoon.
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http://dx.doi.org/10.1038/s41598-019-45308-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586870PMC
June 2019

Updates to the Symbol Nomenclature for Glycans guidelines.

Glycobiology 2019 08;29(9):620-624

Complex Carbohydrate Research Center, University of Georgia, 315 Riverbend Rd, Athens, GA, 30602, USA.

The Symbol Nomenclature for Glycans (SNFG) is a community-curated standard for the depiction of monosaccharides and complex glycans using various colored-coded, geometric shapes, along with defined text additions. It is hosted by the National Center for Biotechnology Information (NCBI) at the NCBI-Glycans Page (www.ncbi.nlm.nih.gov/glycans/snfg.html). Several changes have been made to the SNFG page in the past year to update the rules for depicting glycans using the SNFG, to include more examples of use, particularly for non-mammalian organisms, and to provide guidelines for the depiction of ambiguous glycan structures. This Glycoforum article summarizes these recent changes.
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http://dx.doi.org/10.1093/glycob/cwz045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335484PMC
August 2019