Publications by authors named "Carlos Aguilar"

108 Publications

Sestrins regulate muscle stem cell metabolic homeostasis.

Stem Cell Reports 2021 Sep 12;16(9):2078-2088. Epub 2021 Aug 12.

Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA; Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address:

The health and homeostasis of skeletal muscle are preserved by a population of tissue-resident muscle stem cells (MuSCs) that maintain a state of mitotic and metabolic quiescence in adult tissues. The capacity of MuSCs to preserve the quiescent state declines with aging and metabolic insults, promoting premature activation and stem cell exhaustion. Sestrins are a class of stress-inducible proteins that act as antioxidants and inhibit the activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling complex. Despite these pivotal roles, the role of Sestrins has not been explored in adult stem cells. We show that SESTRIN1,2 loss results in hyperactivation of the mTORC1 complex, increased propensity to enter the cell cycle, and shifts in metabolic flux. Aged SESTRIN1,2 knockout mice exhibited loss of MuSCs and a reduced ability to regenerate injured muscle. These findings demonstrate that Sestrins help maintain metabolic pathways in MuSCs that protect quiescence against aging.
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http://dx.doi.org/10.1016/j.stemcr.2021.07.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8452514PMC
September 2021

Murine muscle stem cell response to perturbations of the neuromuscular junction are attenuated with aging.

Elife 2021 07 29;10. Epub 2021 Jul 29.

Department of Biomedical Engineering, University of Michigan, Ann Arbor, United States.

During aging and neuromuscular diseases, there is a progressive loss of skeletal muscle volume and function impacting mobility and quality of life. Muscle loss is often associated with denervation and a loss of resident muscle stem cells (satellite cells or MuSCs); however, the relationship between MuSCs and innervation has not been established. Herein, we administered severe neuromuscular trauma to a transgenic murine model that permits MuSC lineage tracing. We show that a subset of MuSCs specifically engraft in a position proximal to the neuromuscular junction (NMJ), the synapse between myofibers and motor neurons, in healthy young adult muscles. In aging and in a mouse model of neuromuscular degeneration (Cu/Zn superoxide dismutase knockout - ), this localized engraftment behavior was reduced. Genetic rescue of motor neurons in mice reestablished integrity of the NMJ in a manner akin to young muscle and partially restored MuSC ability to engraft into positions proximal to the NMJ. Using single cell RNA-sequencing of MuSCs isolated from aged muscle, we demonstrate that a subset of MuSCs are molecularly distinguishable from MuSCs responding to myofiber injury and share similarity to synaptic myonuclei. Collectively, these data reveal unique features of MuSCs that respond to synaptic perturbations caused by aging and other stressors.
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http://dx.doi.org/10.7554/eLife.66749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360658PMC
July 2021

Biological significance of monoallelic and biallelic BIRC3 loss in del(11q) chronic lymphocytic leukemia progression.

Blood Cancer J 2021 Jul 9;11(7):127. Epub 2021 Jul 9.

University of Salamanca, IBSAL, IBMCC, CSIC, Cancer Research Center, Salamanca, Spain.

BIRC3 is monoallelically deleted in up to 80% of chronic lymphocytic leukemia (CLL) cases harboring del(11q). In addition, truncating mutations in the remaining allele of this gene can lead to BIRC3 biallelic inactivation, which has been shown to be a marker for reduced survival in CLL. Nevertheless, the biological mechanisms by which these lesions could contribute to del(11q) CLL pathogenesis and progression are partially unexplored. We implemented the CRISPR/Cas9-editing system to generate isogenic CLL cell lines harboring del(11q) and/or BIRC3 mutations, modeling monoallelic and biallelic BIRC3 loss. Our results reveal that monoallelic BIRC3 deletion in del(11q) cells promotes non-canonical NF-κB signaling activation via RelB-p52 nuclear translocation, being these effects allelic dose-dependent and therefore further enhanced in del(11q) cells with biallelic BIRC3 loss. Moreover, we demonstrate ex vivo in primary cells that del(11q) cases including BIRC3 within their deleted region show evidence of non-canonical NF-κB activation which correlates with high BCL2 levels and enhanced sensitivity to venetoclax. Furthermore, our results show that BIRC3 mutations in del(11q) cells promote clonal advantage in vitro and accelerate leukemic progression in an in vivo xenograft model. Altogether, this work highlights the biological bases underlying disease progression of del(11q) CLL patients harboring BIRC3 deletion and mutation.
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http://dx.doi.org/10.1038/s41408-021-00520-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270906PMC
July 2021

Benefits and pitfalls of data compression in visual working memory.

Atten Percept Psychophys 2021 Oct 15;83(7):2843-2864. Epub 2021 Jun 15.

Department of Psychology, Université Côte d'Azur, BCL UMR 7320, CNRS, Campus Saint Jean d'Angely, MSHS, 24 avenue des diables bleus, 06357, Nice, Cedex 4, France.

Data compression in memory is a cognitive process allowing participants to cope with complexity to reduce information load. However, previous studies have not yet considered the hypothesis that this process could also lead to over-simplifying information due to haphazard amplification of the compression process itself. For instance, we could expect that the over-regularized features of a visual scene could produce false recognition of patterns, not because of storage capacity limits but because of an errant compression process. To prompt memory compression in our participants, we used multielement visual displays for which the underlying information varied in compressibility. The compressibility of our material could vary depending on the number of common features between the multi-dimensional objects in the displays. We measured both accuracy and response times by probing memory representations with probes that we hypothesized could modify the participants' representations. We confirm that more compressible information facilitates performance, but a more novel finding is that compression can produce both typical memory errors and lengthened response times. Our findings provide clearer evidence of the forms of compression that participants carry out.
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http://dx.doi.org/10.3758/s13414-021-02333-xDOI Listing
October 2021

Metabolipidomic profiling reveals an age-related deficiency of skeletal muscle pro-resolving mediators that contributes to maladaptive tissue remodeling.

Aging Cell 2021 06 2;20(6):e13393. Epub 2021 Jun 2.

Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.

Specialized pro-resolving mediators actively limit inflammation and support tissue regeneration, but their role in age-related muscle dysfunction has not been explored. We profiled the mediator lipidome of aging muscle via liquid chromatography-tandem mass spectrometry and tested whether treatment with the pro-resolving mediator resolvin D1 (RvD1) could rejuvenate the regenerative ability of aged muscle. Aged mice displayed chronic muscle inflammation and this was associated with a basal deficiency of pro-resolving mediators 8-oxo-RvD1, resolvin E3, and maresin 1, as well as many anti-inflammatory cytochrome P450-derived lipid epoxides. Following muscle injury, young and aged mice produced similar amounts of most pro-inflammatory eicosanoid metabolites of cyclooxygenase (e.g., prostaglandin E ) and 12-lipoxygenase (e.g., 12-hydroxy-eicosatetraenoic acid), but aged mice produced fewer markers of pro-resolving mediators including the lipoxins (15-hydroxy-eicosatetraenoic acid), D-resolvins/protectins (17-hydroxy-docosahexaenoic acid), E-resolvins (18-hydroxy-eicosapentaenoic acid), and maresins (14-hydroxy-docosahexaenoic acid). Similar absences of downstream pro-resolving mediators including lipoxin A , resolvin D6, protectin D1/DX, and maresin 1 in aged muscle were associated with greater inflammation, impaired myofiber regeneration, and delayed recovery of strength. Daily intraperitoneal injection of RvD1 had minimal impact on intramuscular leukocyte infiltration and myofiber regeneration but suppressed inflammatory cytokine expression, limited fibrosis, and improved recovery of muscle function. We conclude that aging results in deficient local biosynthesis of specialized pro-resolving mediators in muscle and that immunoresolvents may be attractive novel therapeutics for the treatment of muscular injuries and associated pain in the elderly, due to positive effects on recovery of muscle function without the negative side effects on tissue regeneration of non-steroidal anti-inflammatory drugs.
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http://dx.doi.org/10.1111/acel.13393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208786PMC
June 2021

B-Cell Regeneration Profile and Minimal Residual Disease Status in Bone Marrow of Treated Multiple Myeloma Patients.

Cancers (Basel) 2021 Apr 3;13(7). Epub 2021 Apr 3.

Translational and Clinical Research Program, Cancer Research Center (IBMCC, USAL-CSIC), Cytometry Service (NUCLEUS) and Department of Medicine, University of Salamanca, Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain.

B-cell regeneration during therapy has been considered as a strong prognostic factor in multiple myeloma (MM). However, the effects of therapy and hemodilution in bone marrow (BM) B-cell recovery have not been systematically evaluated during follow-up. MM (n = 177) and adult (≥50y) healthy donor (HD; n = 14) BM samples were studied by next-generation flow (NGF) to simultaneously assess measurable residual disease (MRD) and residual normal B-cell populations. BM hemodilution was detected in 41 out of 177 (23%) patient samples, leading to lower total B-cell, B-cell precursor (BCP) and normal plasma cell (nPC) counts. Among MM BM, decreased percentages (vs. HD) of BCP, transitional/naïve B-cell (TBC/NBC) and nPC populations were observed at diagnosis. BM BCP increased after induction therapy, whereas TBC/NBC counts remained abnormally low. At day+100 postautologous stem cell transplantation, a greater increase in BCP with recovered TBC/NBC cell numbers but persistently low memory B-cell and nPC counts were found. At the end of therapy, complete response (CR) BM samples showed higher CD19 nPC counts vs. non-CR specimens. MRD positivity was associated with higher BCP and nPC percentages. Hemodilution showed a negative impact on BM B-cell distribution. Different BM B-cell regeneration profiles are present in MM at diagnosis and after therapy with no significant association with patient outcome.
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http://dx.doi.org/10.3390/cancers13071704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038337PMC
April 2021

Engineered Tools to Study Intercellular Communication.

Adv Sci (Weinh) 2021 Feb 21;8(3):2002825. Epub 2020 Dec 21.

Department of Biomedical Engineering and Biointerfaces Institute 2800 Plymouth Road, North Campus Research Complex Ann Arbor MI A10-183 USA.

All multicellular organisms rely on intercellular communication networks to coordinate physiological functions. As members of a dynamic social network, each cell receives, processes, and redistributes biological information to define and maintain tissue homeostasis. Uncovering the molecular programs underlying these processes is critical for prevention of disease and aging and development of therapeutics. The study of intercellular communication requires techniques that reduce the scale and complexity of in vivo biological networks while resolving the molecular heterogeneity in "omic" layers that contribute to cell state and function. Recent advances in microengineering and high-throughput genomics offer unprecedented spatiotemporal control over cellular interactions and the ability to study intercellular communication in a high-throughput and mechanistic manner. Herein, this review discusses how salient engineered approaches and sequencing techniques can be applied to understand collective cell behavior and tissue functions.
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http://dx.doi.org/10.1002/advs.202002825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856891PMC
February 2021

The inhibitory effect of word neighborhood size when reading with central field loss is modulated by word predictability and reading proficiency.

Sci Rep 2020 12 11;10(1):21792. Epub 2020 Dec 11.

CNRS UMR 7290, Aix-Marseille Univ., Marseille, France.

For normally sighted readers, word neighborhood size (i.e., the total number of words that can be formed from a single word by changing only one letter) has a facilitator effect on word recognition. When reading with central field loss (CFL) however, individual letters may not be correctly identified, leading to possible misidentifications and a reverse neighborhood size effect. Here we investigate this inhibitory effect of word neighborhood size on reading performance and whether it is modulated by word predictability and reading proficiency. Nineteen patients with binocular CFL from 32 to 89 years old (mean ± SD = 75 ± 15) read short sentences presented with the self-paced reading paradigm. Accuracy and reading time were measured for each target word read, along with its predictability, i.e., its probability of occurrence following the two preceding words in the sentence using a trigram analysis. Linear mixed effects models were then fit to estimate the individual contributions of word neighborhood size, predictability, frequency and length on accuracy and reading time, while taking patients' reading proficiency into account. For the less proficient readers, who have given up daily reading as a consequence of their visual impairment, we found that the effect of neighborhood size was reversed compared to normally sighted readers and of higher amplitude than the effect of frequency. Furthermore, this inhibitory effect is of greater amplitude (up to 50% decrease in reading speed) when a word is not easily predictable because its chances to occur after the two preceding words in a specific sentence are rather low. Severely impaired patients with CFL often quit reading on a daily basis because this task becomes simply too exhausting. Based on our results, we envision lexical text simplification as a new alternative to promote effective rehabilitation in these patients. By increasing reading accessibility for those who struggle the most, text simplification might be used as an efficient rehabilitation tool and daily reading assistive technology, fostering overall reading ability and fluency through increased practice.
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http://dx.doi.org/10.1038/s41598-020-78420-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733451PMC
December 2020

Forward genetics identifies a novel sleep mutant with sleep state inertia and REM sleep deficits.

Sci Adv 2020 Aug 12;6(33):eabb3567. Epub 2020 Aug 12.

Mammalian Genetics Unit, MRC Harwell Institute, Harwell Science and Innovation Campus, Oxfordshire, UK.

Switches between global sleep and wakefulness states are believed to be dictated by top-down influences arising from subcortical nuclei. Using forward genetics and in vivo electrophysiology, we identified a recessive mouse mutant line characterized by a substantially reduced propensity to transition between wake and sleep states with an especially pronounced deficit in initiating rapid eye movement (REM) sleep episodes. The causative mutation, an Ile102Asn substitution in the synaptic vesicular protein, VAMP2, was associated with morphological synaptic changes and specific behavioral deficits, while in vitro electrophysiological investigations with fluorescence imaging revealed a markedly diminished probability of vesicular release in mutants. Our data show that global shifts in the synaptic efficiency across brain-wide networks leads to an altered probability of vigilance state transitions, possibly as a result of an altered excitability balance within local circuits controlling sleep-wake architecture.
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http://dx.doi.org/10.1126/sciadv.abb3567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423362PMC
August 2020

Resolvin D1 supports skeletal myofiber regeneration via actions on myeloid and muscle stem cells.

JCI Insight 2020 09 17;5(18). Epub 2020 Sep 17.

Department of Molecular & Integrative Physiology.

Specialized proresolving mediators (SPMs) actively limit inflammation and expedite its resolution by modulating leukocyte recruitment and function. Here we profiled intramuscular lipid mediators via liquid chromatography-tandem mass spectrometry-based metabolipidomics following myofiber injury and investigated the potential role of SPMs in skeletal muscle inflammation and repair. Both proinflammatory eicosanoids and SPMs increased following myofiber damage induced by either intramuscular injection of barium chloride or synergist ablation-induced functional muscle overload. Daily systemic administration of the SPM resolvin D1 (RvD1) as an immunoresolvent limited the degree and duration of inflammation, enhanced regenerating myofiber growth, and improved recovery of muscle strength. RvD1 suppressed inflammatory cytokine expression, enhanced polymorphonuclear cell clearance, modulated the local muscle stem cell response, and polarized intramuscular macrophages to a more proregenerative subset. RvD1 had minimal direct impact on in vitro myogenesis but directly suppressed myokine production and stimulated macrophage phagocytosis, showing that SPMs can modulate both infiltrating myeloid and resident muscle cell populations. These data reveal the efficacy of immunoresolvents as a novel alternative to classical antiinflammatory interventions in the management of muscle injuries to modulate inflammation while stimulating tissue repair.
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http://dx.doi.org/10.1172/jci.insight.137713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526543PMC
September 2020

Dissecting Murine Muscle Stem Cell Aging through Regeneration Using Integrative Genomic Analysis.

Cell Rep 2020 07;32(4):107964

Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA; Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address:

During aging, there is a progressive loss of volume and function in skeletal muscle that impacts mobility and quality of life. The repair of skeletal muscle is regulated by tissue-resident stem cells called satellite cells (or muscle stem cells [MuSCs]), but in aging, MuSCs decrease in numbers and regenerative capacity. The transcriptional networks and epigenetic changes that confer diminished regenerative function in MuSCs as a result of natural aging are only partially understood. Herein, we use an integrative genomics approach to profile MuSCs from young and aged animals before and after injury. Integration of these datasets reveals aging impacts multiple regulatory changes through significant differences in gene expression, metabolic flux, chromatin accessibility, and patterns of transcription factor (TF) binding activities. Collectively, these datasets facilitate a deeper understanding of the regulation tissue-resident stem cells use during aging and healing.
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http://dx.doi.org/10.1016/j.celrep.2020.107964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025697PMC
July 2020

Chronic lymphocytic leukemia patients with IGH translocations are characterized by a distinct genetic landscape with prognostic implications.

Int J Cancer 2020 11 4;147(10):2780-2792. Epub 2020 Sep 4.

Universidad de Salamanca, IBSAL, Centro de Investigación del Cáncer, IBMCC-CSIC, Salamanca, Spain.

Chromosome 14q32 rearrangements/translocations involving the immunoglobulin heavy chain (IGH) are rarely detected in chronic lymphocytic leukemia (CLL). The prognostic significance of the IGH translocation is controversial and its mutational profile remains unknown. Here, we present for the first time a comprehensive next-generation sequencing (NGS) analysis of 46 CLL patients with IGH rearrangement (IGHR-CLLs) and we demonstrate that IGHR-CLLs have a distinct mutational profile with recurrent mutations in NOTCH1, IGLL5, POT1, BCL2, FBXW7, ZMYM3, MGA, BRAF and HIST1H1E genes. Interestingly, BCL2 and FBXW7 mutations were significantly associated with this subgroup and almost half of BCL2, IGLL5 and HISTH1E mutations reported were previously identified in non-Hodgkin lymphomas. Notably, IGH/BCL2 rearrangements were associated with a lower mutation frequency and carried BCL2 and IGLL5 mutations, while the other IGHR-CLLs had mutations in genes related to poor prognosis (NOTCH1, SF3B1 and TP53) and shorter time to first treatment (TFT). Moreover, IGHR-CLLs patients showed a shorter TFT than CLL patients carrying 13q-, normal fluorescence in situ hybridization (FISH) and +12 CLL, being this prognosis particularly poor when NOTCH1, SF3B1, TP53, BIRC3 and BRAF were also mutated. The presence of these mutations not only was an independent risk factor within IGHR-CLLs, but also refined the prognosis of low-risk cytogenetic patients (13q-/normal FISH). Hence, our study demonstrates that IGHR-CLLs have a distinct mutational profile from the majority of CLLs and highlights the relevance of incorporating NGS and the status of IGH by FISH analysis to refine the risk-stratification CLL model.
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http://dx.doi.org/10.1002/ijc.33235DOI Listing
November 2020

Co-occurrence of cohesin complex and Ras signaling mutations during progression from myelodysplastic syndromes to secondary acute myeloid leukemia.

Haematologica 2021 08 1;106(8):2215-2223. Epub 2021 Aug 1.

Institute of Biomedical Research of Salamanca, Cancer Research Center-University of Salamanca, Spain.

Myelodysplastic syndromes (MDS) are hematological disorders at high risk of progression to secondary acute myeloid leukemia (sAML). However, the mutational dynamics and clonal evolution underlying disease progression are poorly understood at present. To elucidate the mutational dynamics of pathways and genes occurring during the evolution to sAML, next generation sequencing was performed on 84 serially paired samples of MDS patients who developed sAML (discovery cohort) and 14 paired samples from MDS patients who did not progress to sAML during follow-up (control cohort). Results were validated in an independent series of 388 MDS patients (validation cohort). We used an integrative analysis to identify how mutations, alone or in combination, contribute to leukemic transformation. The study showed that MDS progression to sAML is characterized by greater genomic instability and the presence of several types of mutational dynamics, highlighting increasing (STAG2) and newly-acquired (NRAS and FLT3) mutations. Moreover, we observed cooperation between genes involved in the cohesin and Ras pathways in 15-20% of MDS patients who evolved to sAML, as well as a high proportion of newly acquired or increasing mutations in the chromatin-modifier genes in MDS patients receiving a disease-modifying therapy before their progression to sAML.
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http://dx.doi.org/10.3324/haematol.2020.248807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327724PMC
August 2021

Pre-innervated tissue-engineered muscle promotes a pro-regenerative microenvironment following volumetric muscle loss.

Commun Biol 2020 06 25;3(1):330. Epub 2020 Jun 25.

Center for Brain Injury & Repair, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Volumetric muscle loss (VML) is the traumatic or surgical loss of skeletal muscle beyond the inherent regenerative capacity of the body, generally leading to severe functional deficit. Formation of appropriate somato-motor innervations remains one of the biggest challenges for both autologous grafts as well as tissue-engineered muscle constructs. We aim to address this challenge by developing pre-innervated tissue-engineered muscle comprised of long aligned networks of spinal motor neurons and skeletal myocytes on aligned nanofibrous scaffolds. Motor neurons led to enhanced differentiation and maturation of skeletal myocytes in vitro. These pre-innervated tissue-engineered muscle constructs when implanted in a rat VML model significantly increased satellite cell density, neuromuscular junction maintenance, graft revascularization, and muscle volume over three weeks as compared to myocyte-only constructs and nanofiber scaffolds alone. These pro-regenerative effects may enhance functional neuromuscular regeneration following VML, thereby improving the levels of functional recovery following these devastating injuries.
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http://dx.doi.org/10.1038/s42003-020-1056-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316777PMC
June 2020

Glutamine chelation governs the selective inhibition of Staphylococcus aureus and Salmonella typhi growth by cis-dichloro-bis(8-quinolinolato)zirconium(IV): Theory and experiment.

Eur J Pharm Sci 2020 Aug 13;151:105427. Epub 2020 Jun 13.

Division de Ingeniería en Nanotecnología, Universidad Politécnica del Valle de México, Av. Mexiquense s/n esquina Av. Universidad Politécnica, Tultitlan, Estado de México, CP 54910, México.

Quinolone-based Schiff base zirconium(IV) complex was studied as potential bacterial inhibitor against Gram-positive Staphylococcus aureus and Gram-negative Salmonella typhi growth, showing that the interaction of the complex with L-glutamine which presents in the membrane of wall leads cell death, and the mode of bacterial interaction was analyzed theoretically by DFT. Furthermore, the interaction of different amino acid residues L-alanine, D-alanine, L-lysine and D-glutamine with the metal complex through UV-vis docking studies was conducted observing that D-glutamine interacts efficiently among other amino acid residues. This observation is consistent with the interaction of the metal complex that was effective when participating in an insight of the peptidoglycan cell wall since the binding nature of glutamine potentially inhibits these microorganisms.
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http://dx.doi.org/10.1016/j.ejps.2020.105427DOI Listing
August 2020

Neuronal mechanisms for sequential activation of memory items: Dynamics and reliability.

PLoS One 2020 16;15(4):e0231165. Epub 2020 Apr 16.

Université Côte d'Azur, CNRS-BCL, Nice, France.

In this article we present a biologically inspired model of activation of memory items in a sequence. Our model produces two types of sequences, corresponding to two different types of cerebral functions: activation of regular or irregular sequences. The switch between the two types of activation occurs through the modulation of biological parameters, without altering the connectivity matrix. Some of the parameters included in our model are neuronal gain, strength of inhibition, synaptic depression and noise. We investigate how these parameters enable the existence of sequences and influence the type of sequences observed. In particular we show that synaptic depression and noise drive the transitions from one memory item to the next and neuronal gain controls the switching between regular and irregular (random) activation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231165PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161983PMC
July 2020

Tuning Macrophage Phenotype to Mitigate Skeletal Muscle Fibrosis.

J Immunol 2020 04 11;204(8):2203-2215. Epub 2020 Mar 11.

Department of Surgery, University of Michigan, Ann Arbor, MI 48109;

Myeloid cells are critical to the development of fibrosis following muscle injury; however, the mechanism of their role in fibrosis formation remains unclear. In this study, we demonstrate that myeloid cell-derived TGF-β1 signaling is increased in a profibrotic ischemia reperfusion and cardiotoxin muscle injury model. We found that myeloid-specific deletion of abrogates the fibrotic response in this injury model and reduces fibro/adipogenic progenitor cell proliferation while simultaneously enhancing muscle regeneration, which is abrogated by adaptive transfer of normal macrophages. Similarly, a murine TGFBRII-Fc ligand trap administered after injury significantly reduced muscle fibrosis and improved muscle regeneration. This study ultimately demonstrates that infiltrating myeloid cell TGF-β1 is responsible for the development of traumatic muscle fibrosis, and its blockade offers a promising therapeutic target for preventing muscle fibrosis after ischemic injury.
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http://dx.doi.org/10.4049/jimmunol.1900814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080967PMC
April 2020

Unraveling the Influence of Common von Willebrand factor variants on von Willebrand Disease Phenotype: An Exploratory Study on the Molecular and Clinical Profile of von Willebrand Disease in Spain Cohort.

Thromb Haemost 2020 Mar 5;120(3):437-448. Epub 2020 Mar 5.

Department of Hematology, Hospital Sta Creu i St Pau, Barcelona, Spain.

The clinical diagnosis of von Willebrand disease (VWD), particularly type 1, can be complex because several genetic and environmental factors affect von Willebrand factor (VWF) plasma levels. An estimated 60% of the phenotypic variation is attributable to hereditary factors, with the ABO blood group locus being the most influential. However, recent studies provide strong evidence that nonsynonymous single nucleotide variants (SNVs) contribute to VWF and factor VIII phenotypic variability in healthy individuals. This study aims to investigate the role of common VWF SNVs on VWD phenotype by analyzing data from 219 unrelated patients included in the "Molecular and Clinical Profile of von Willebrand Disease in Spain project." To that end, generalized linear mixed-effects regression models were fitted, and additive and epistatic analyses, and haplotype studies were performed, considering five VWD-related measures (bleeding score, VWF:Ag, VWF:RCo, factor VIII:C, and VWF:CB). According to these analyses, homozygotes: for p.Thr789Ala(C) would be expected to show 39% higher VWF:Ag levels; p.Thr1381Ala(C), 27% lower VWF:Ag levels; and p.Gln852Arg(C), 52% lower VWF:RCo levels. Homozygotes for both p.Thr789Ala(C) and p.Gln852Arg(T) were predicted to show 185% higher VWF:CB activity, and carriers of two copies of the p.Thr1381Ala(T)/p.Gln852Arg(T) haplotype would present a 100% increase in VWF:RCo activity. These results indicate a substantial effect of common variation on VWD phenotype. Although additional studies are needed to determine the true magnitude of the effects of SNVs on , these findings provide new evidence regarding the contribution of common variants to VWD, which should be taken into account to enhance the accuracy of the diagnosis and classification of this condition. ClinicalTrials.gov identifier: NCT02869074.
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http://dx.doi.org/10.1055/s-0040-1702227DOI Listing
March 2020

Clarin-2 is essential for hearing by maintaining stereocilia integrity and function.

EMBO Mol Med 2019 09 26;11(9):e10288. Epub 2019 Aug 26.

Department of Biomedical Science, University of Sheffield, Sheffield, UK.

Hearing relies on mechanically gated ion channels present in the actin-rich stereocilia bundles at the apical surface of cochlear hair cells. Our knowledge of the mechanisms underlying the formation and maintenance of the sound-receptive structure is limited. Utilizing a large-scale forward genetic screen in mice, genome mapping and gene complementation tests, we identified Clrn2 as a new deafness gene. The Clrn2 mice (p.Trp4* mutation) exhibit a progressive, early-onset hearing loss, with no overt retinal deficits. Utilizing data from the UK Biobank study, we could show that CLRN2 is involved in human non-syndromic progressive hearing loss. Our in-depth morphological, molecular and functional investigations establish that while it is not required for initial formation of cochlear sensory hair cell stereocilia bundles, clarin-2 is critical for maintaining normal bundle integrity and functioning. In the differentiating hair bundles, lack of clarin-2 leads to loss of mechano-electrical transduction, followed by selective progressive loss of the transducing stereocilia. Together, our findings demonstrate a key role for clarin-2 in mammalian hearing, providing insights into the interplay between mechano-electrical transduction and stereocilia maintenance.
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http://dx.doi.org/10.15252/emmm.201910288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728604PMC
September 2019

Linguistic processes do not beat visuo-motor constraints, but they modulate where the eyes move regardless of word boundaries: Evidence against top-down word-based eye-movement control during reading.

PLoS One 2019 22;14(7):e0219666. Epub 2019 Jul 22.

Aix-Marseille Univ, CNRS, LPC (Laboratoire de Psychologie Cognitive), Fédération de Recherche 3C, Marseille, France.

Where readers move their eyes, while proceeding forward along lines of text, has long been assumed to be determined in a top-down word-based manner. According to this classical view, readers of alphabetic languages would invariably program their saccades towards the center of peripheral target words, as selected based on the (expected) needs of ongoing (word-identification) processing, and the variability in within-word landing positions would exclusively result from systematic and random errors. Here we put this predominant hypothesis to a strong test by estimating the respective influences of language-related variables (word frequency and word predictability) and lower-level visuo-motor factors (word length and saccadic launch-site distance to the beginning of words) on both word-skipping likelihood and within-word landing positions. Our eye-movement data were collected while forty participants read 316 pairs of sentences, that differed only by one word, the prime; this was either semantically related or unrelated to a following test word of variable frequency and length. We found that low-level visuo-motor variables largely predominated in determining which word would be fixated next, and where in a word the eye would land. In comparison, language-related variables only had tiny influences. Yet, linguistic variables affected both the likelihood of word skipping and within-word initial landing positions, all depending on the words' length and how far on average the eye landed from the word boundaries, but pending the word could benefit from peripheral preview. These findings provide a strong case against the predominant word-based account of eye-movement guidance during reading, by showing that saccades are primarily driven by low-level visuo-motor processes, regardless of word boundaries, while being overall subject to subtle, one-off, language-based modulations. Our results also suggest that overall distributions of saccades' landing positions, instead of truncated within-word landing-site distributions, should be used for a better understanding of eye-movement guidance during reading.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0219666PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6645505PMC
February 2020

The influence of word frequency on word reading speed when individuals with macular diseases read text.

Vision Res 2019 02 4;155:1-10. Epub 2019 Jan 4.

Aix-Marseille University, Marseille, France; Laboratoire de Psychologie Cognitive, CNRS, Marseille, France.

People with central field loss (CFL) use peripheral vision to identify words. Eccentric vision provides ambiguous visual inputs to the processes leading to lexical access. Our purpose was to explore the hypothesis that this ambiguity leads to strong influences of inferential processes, our prediction being that increasing word frequency would decrease word reading time. Individuals with bilateral CFL induced by macular diseases read French sentences displayed with a self-paced reading method. Reading time of the last word of each sentence (target word) was recorded. Each target word (in sentence n) was matched with a synonym word (in sentence n+1) of the same length. When using absolute frequency value (Analysis 1), we found that reading time of target words decreased when word frequency increases, even when controlling for word length. The amplitude of this effect is larger than reported in previous investigations of reading with normal subjects. When comparing the effect of relative frequency (low vs. high) within each pair of synonyms (Analysis 2), results show the same pattern as the one observed in Analysis 1. Our results demonstrate clear-cut frequency effects on word reading time and suggest that inferential processes are stronger in CFL readers than in normally sighted observers. These results might also help design text simplification tools tailored for low-vision patients.
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http://dx.doi.org/10.1016/j.visres.2018.12.002DOI Listing
February 2019

A Wars2 Mutant Mouse Model Displays OXPHOS Deficiencies and Activation of Tissue-Specific Stress Response Pathways.

Cell Rep 2018 12;25(12):3315-3328.e6

MRC Harwell Institute, Mammalian Genetics Unit and Mary Lyon Centre, Harwell Campus, Oxfordshire OX11 0RD, UK. Electronic address:

Mutations in genes essential for mitochondrial function have pleiotropic effects. The mechanisms underlying these traits yield insights into metabolic homeostasis and potential therapies. Here we report the characterization of a mouse model harboring a mutation in the tryptophanyl-tRNA synthetase 2 (Wars2) gene, encoding the mitochondrial-localized WARS2 protein. This hypomorphic allele causes progressive tissue-specific pathologies, including hearing loss, reduced adiposity, adipose tissue dysfunction, and hypertrophic cardiomyopathy. We demonstrate the tissue heterogeneity arises as a result of variable activation of the integrated stress response (ISR) pathway and the ability of certain tissues to respond to impaired mitochondrial translation. Many of the systemic metabolic effects are likely mediated through elevated fibroblast growth factor 21 (FGF21) following activation of the ISR in certain tissues. These findings demonstrate the potential pleiotropy associated with Wars2 mutations in patients.
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http://dx.doi.org/10.1016/j.celrep.2018.11.080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6315286PMC
December 2018

Efficiency of Different Disinfectants on Sensu Stricto Biofilms on Stainless-Steel Surfaces in Contact With Milk.

Front Microbiol 2018 28;9:2934. Epub 2018 Nov 28.

Department of Veterinary Medicine, School of Animal Science and Food Engineering, University of São Paulo, São Paulo, Brazil.

The species of the group have the ability to adhere to and form biofilms on solid surfaces, including stainless steel, a material widely used in food industries. Biofilms allow for recontamination during food processing, and the "clean-in-place" (CIP) system is largely used by industries to control them. This study thus proposes to evaluate the efficacy of peracetic acid and sodium hypochlorite against biofilms induced on stainless-steel surfaces. The SAMN07414939 isolate (BioProject PRJNA390851), a recognized biofilm producer, was selected for biofilm induction on AISI 304 stainless steel. Biofilm induction was performed and classified into three categories: TCP (Tindalized, Contaminated, and Pasteurized milk), TCS (Tindalized milk Contaminated with Spores), and TCV (Tindalized milk Contaminated with Vegetative cells). Subsequently, the coupons were sanitized simulating a CIP procedure, on a pilot scale, using alkaline and acid solutions followed by disinfectants (peracetic acid and sodium hypochlorite). Microorganism adhesion on the surfaces reached 6.3 × 10 to 3.1 × 10 CFU/cm. Results did not show significant differences ( > 0.05) for surface adhesion between the three tested categories (TCP, TCS, and TCV) or ( > 0.05) between the two disinfectants (peracetic acid and sodium hypochlorite). Microbial populations adhered to the stainless-steel coupons are equally reduced after treatment with peracetic acid and sodium hypochlorite, with no differences in the control of biofilms on AISI 304 stainless-steel surfaces.
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http://dx.doi.org/10.3389/fmicb.2018.02934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280812PMC
November 2018

New Technologies To Enhance In Vivo Reprogramming for Regenerative Medicine.

Trends Biotechnol 2019 06 6;37(6):604-617. Epub 2018 Dec 6.

Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA; Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI, USA. Electronic address:

Cellular identity and state are determined by a collection of molecular components that are specified during development and stabilized thereafter to maintain and protect tissue functions. Alteration of the molecular elements (gene expression program and chromatin state) as a result of disease or age can induce somatic cells to assume different identities or modulate functions. Therapeutic use of this technique, called 'cellular reprogramming', is very promising for regenerative medicine, but implementation of reprogramming-based strategies in vivo has been precluded by technological and safety limitations. Recent advances in transcriptional control and improved transmembrane delivery strategies now offer exciting potential to more efficiently reprogram cell fates as well as to control the reprogramming timeline and scale of delivery to improve safety.
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http://dx.doi.org/10.1016/j.tibtech.2018.11.003DOI Listing
June 2019

Unraveling the effect of silent, intronic and missense mutations on splicing: contribution of next generation sequencing in the study of mRNA.

Haematologica 2019 03 25;104(3):587-598. Epub 2018 Oct 25.

Hospital San Pedro de Alcántara, Cáceres, Spain.

Large studies in von Willebrand disease patients, including Spanish and Portuguese registries, led to the identification of >250 different mutations. It is a challenge to determine the pathogenic effect of potential splice site mutations on mRNA. This study aimed to elucidate the true effects of 18 mutations on mRNA processing, investigate the contribution of next-generation sequencing to mRNA study in von Willebrand disease, and compare the findings with prediction. RNA extracted from patient platelets and leukocytes was amplified by RT-PCR and sequenced using Sanger and next generation sequencing techniques. Eight mutations affected splicing: c.1533+1G>A, c.5664+2T>C and c.546G>A (p.=) prompted exon skipping; c.3223-7_3236dup and c.7082-2A>G resulted in activation of cryptic sites; c.3379+1G>A and c.7437G>A) demonstrated both molecular pathogenic mechanisms simultaneously; and the p.Cys370Tyr missense mutation generated two aberrant transcripts. Of note, the complete effect of three mutations was provided by next generation sequencing alone because of low expression of the aberrant transcripts. In the remaining 10 mutations, no effect was elucidated in the experiments. However, the differential findings obtained in platelets and leukocytes provided substantial evidence that four of these would have an effect on VWF levels. In this first report using next generation sequencing technology to unravel the effects of mutations on splicing, the technique yielded valuable information. Our data bring to light the importance of studying the effect of synonymous and missense mutations on splicing to improve the current knowledge of the molecular mechanisms behind von Willebrand disease. .
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http://dx.doi.org/10.3324/haematol.2018.203166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395343PMC
March 2019

A Vision Enhancement System to Improve Face Recognition with Central Vision Loss.

Optom Vis Sci 2018 09;95(9):738-746

Laboratoire de Psychologie Cognitive, Aix-Marseille University, Marseille, France.

Significance: The overall goal of this work is to validate a low vision aid system that uses gaze as a pointing tool and provides smart magnification. We conclude that smart visual enhancement techniques as well as gaze contingency should improve the efficiency of assistive technology for the visually impaired.

Purpose: A low vision aid, using gaze-contingent visual enhancement and primarily intended to help reading with central vision loss, was recently designed and tested with simulated scotoma. Here, we present a validation of this system for face recognition in age-related macular degeneration patients.

Methods: Twelve individuals with binocular central vision loss were recruited and tested on a face identification-matching task. Gaze position was measured in real time, thanks to an eye tracker. In the visual enhancement condition, at any time during the screen exploration, the fixated face was segregated from background and considered as a region of interest that could be magnified into a region of augmented vision by the participant, if desired. In the natural exploration condition, participants also performed the matching task but without the visual aid. Response time and accuracy were analyzed with mixed-effects models to (1) compare the performance with and without visual aid and (2) estimate the usability of the system.

Results: On average, the percentage of correct response for the natural exploration condition was 41%. This value was significantly increased to 63% with visual enhancement (95% confidence interval, 45 to 78%). For the large majority of our participants (83%), this improvement was accompanied by moderate increase in response time, suggesting a real functional benefit for these individuals.

Conclusions: Without visual enhancement, participants with age-related macular degeneration performed poorly, confirming their struggle for face recognition and the need to use efficient visual aids. Our system significantly improved face identification accuracy by 55%, proving to be helpful under laboratory conditions.
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http://dx.doi.org/10.1097/OPX.0000000000001263DOI Listing
September 2018

Validation of the STA-Liatest DDi assay for exclusion of proximal deep vein thrombosis according to the latest Clinical and Laboratory Standards Institute/Food and Drug Administration guideline: results of a multicenter management study.

Blood Coagul Fibrinolysis 2018 Sep;29(6):562-566

Department of Vascular Medicine, Grenoble-Alpes University Hospital, Universite Grenoble Alpes CNRS/TIMC-IMAG UMR 5525/Themas, Grenoble, F-CRIN, INNOVTE (Investigation Network On Venous Thrombo-Embolism), France.

: Recommended strategy for venous thromboembolism (VTE) diagnosis includes the use of sensitive D-dimer (DDi) assays along with pretest probability (PTP) assessment. The Clinical and Laboratory Standards Institute (CLSI) recently issued a guideline (US FDA endorsed) on DDi in VTE exclusion. Such guideline specifies the ideal D-dimer assay characteristics and target population. Demonstrate STA-LiatestD-Di performance combined with a PTP score for proximal deep vein thrombosis (pDVT) exclusion in a CLSI compliant study. International, multicenter, prospective nonrandomized, noninterventional clinical outcome management study conducted in a standard-of-care setting. DDi was measured in DVT-suspected consecutive low/moderate PTP outpatients, without conditions possibly impacting DDi values independently of thrombosis presence (age >80, pregnancy, postoperative, cancer) using a 0.5 μg/ml (FEU) threshold for DVT exclusion. Results were used to determine test performance. One thousand two hundred and thirty-four patients (17 centers) signed informed consent. Nine hundred and eighty (mean age: 55) with valid results (494 negative DDi) completed the study (DVT prevalence: 8.7%). STA-LiatestD-Di performance exceeded CLSI/FDA requirements: sensitivity: 100% (95% CI 95.8-100%), NPV: 100% (95% CI 99.3-100%). STA-LiatestD-Di associated with PTP score showed excellent performance for pDVT exclusion, as recently demonstrated for pulmonary embolism. The assay allows safe VTE exclusion, avoiding unnecessary imaging tests.
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http://dx.doi.org/10.1097/MBC.0000000000000750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6200385PMC
September 2018

Correction: Multiscale analysis of a regenerative therapy for treatment of volumetric muscle loss injury.

Cell Death Discov 2018 23;4:16. Epub 2018 Jul 23.

2Extremity Trauma and Regenerative Medicine, United States Army Institute of Surgical Research, Fort Sam Houston, San Antonio, TX USA.

[This corrects the article DOI: 10.1038/s41420-018-0027-8.].
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http://dx.doi.org/10.1038/s41420-018-0080-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056478PMC
July 2018

Ibrutinib-related bleeding: pathogenesis, clinical implications and management.

Authors:
Carlos Aguilar

Blood Coagul Fibrinolysis 2018 Sep;29(6):481-487

Department of Haematology, Hospital General Santa Barbara, Paseo Santa Bárbara s/n, Soria, Spain.

: Ibrutinib is the first drug of a new family of Bruton's tyrosine kinases (Btk)-inhibiting agents, which have proved to be useful for the treatment of several B-cell lymphoid malignancies. This drug is associated to an increased bleeding risk from initial clinical trials especially in association with warfarin. Although Btk plays an important role in platelet signalling, increased bleeding tendency in patients on ibrutinib is more complex than Btk inhibition alone and is because of several antiplatelet mechanisms, namely inhibition of Btk and Tec kinases, which play a key role in platelet activation downstream of the collagen GPVI and Glycoprotein Ib. This risk is increased by concomitant antiplatelet and anticoagulant therapy; both dual antiplatelet therapy and vitamin K antagonists are contraindicated in these patients. Potential ibrutinib users often have age-associated cardiovascular risk factors or conditions and the drug itself may trigger atrial fibrillation requiring antithrombotic therapy. Aspirin and direct oral anticoagulants can be regarded as the antithrombotic therapies of choice if required. Heparin and fondaparinux have also been used in clinical trials. Therefore, the need and duration of antithrombotic therapy must be carefully evaluated and treatment individualized according to clinical circumstances. Ibrutinib withdrawal and platelet transfusion are key for the management of major bleeding not involving the central nervous system.
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http://dx.doi.org/10.1097/MBC.0000000000000749DOI Listing
September 2018

Role of multimeric analysis of von Willebrand factor (VWF) in von Willebrand disease (VWD) diagnosis: Lessons from the PCM-EVW-ES Spanish project.

PLoS One 2018 20;13(6):e0197876. Epub 2018 Jun 20.

Servicio Hematología, Hospital Universitario Fundación Alcorcón, Madrid, Spain.

The multimeric analysis (MA) of plasma von Willebrand factor (VWF) evaluates structural integrity and helps in the diagnosis of von Willebrand disease (VWD). This assay is a matter of controversy, being considered by some investigators cumbersome and only slightly informative. The centralised study 'Molecular and Clinical Profile of von Willebrand Disease in Spain (PCM-EVW-ES)' has been carried out by including the phenotypic assessment and the genetic analysis by next generation sequencing (NGS) of the VWF gene (VWF). The aim of the present study was to evaluate the role of MA to the diagnosis of these patients and their potential discrepancies. Two hundred and seventy out of 480 patients centrally diagnosed with VWD had normal multimers, 168 had abnormal multimers and 42 a total absence of multimers. VWF MA was of great significance in the diagnosis of 83 patients (17.3%), it was also of help in the diagnosis achieved in 365 additional patients (76%) and was not informative in 32 cases (6.7%). With regard to discrepancies, 110 out of 480 (23%) patients centrally diagnosed with VWD presented some kind of discordance between VWF:RCo/VWF:Ag and/or VWF:CB/VWF:Ag ratios, multimeric study and/or genetic results. The VWF MA was key in the presence of novel mutations as well as in cases with phenotypic discrepancies. A comparison between the contribution of MA and VWF:CB showed a clearly higher contribution of the former in the diagnostic process. These data seem to reinforce the relevance of the VWF MA in VWD diagnosis, despite all its limitations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0197876PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010290PMC
December 2018
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