Publications by authors named "A Kraus"

514 Publications

Antibody-guided in vivo imaging of Aspergillus fumigatus lung infections during antifungal azole treatment.

Nat Commun 2021 03 17;12(1):1707. Epub 2021 Mar 17.

Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany.

Invasive pulmonary aspergillosis (IPA) is a life-threatening lung disease of immunocompromised humans, caused by the opportunistic fungal pathogen Aspergillus fumigatus. Inadequacies in current diagnostic procedures mean that early diagnosis of the disease, critical to patient survival, remains a major clinical challenge, and is leading to the empiric use of antifungal drugs and emergence of azole resistance. A non-invasive procedure that allows both unambiguous detection of IPA and its response to azole treatment is therefore needed. Here, we show that a humanised Aspergillus-specific monoclonal antibody, dual labelled with a radionuclide and fluorophore, can be used in immunoPET/MRI in vivo in a neutropenic mouse model and 3D light sheet fluorescence microscopy ex vivo in the infected mouse lungs to quantify early A. fumigatus lung infections and to monitor the efficacy of azole therapy. Our antibody-guided approach reveals that early drug intervention is critical to prevent complete invasion of the lungs by the fungus, and demonstrates the power of molecular imaging as a non-invasive procedure for tracking IPA in vivo.
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http://dx.doi.org/10.1038/s41467-021-21965-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969596PMC
March 2021

Local criteria for the unit equation and the asymptotic Fermat's Last Theorem.

Proc Natl Acad Sci U S A 2021 Mar;118(12)

Mathematics Institute, University of Warwick, CV4 7AL Coventry, United Kingdom

Let F be a totally real number field of odd degree. We prove several purely local criteria for the asymptotic Fermat's Last Theorem to hold over F and also, for the nonexistence of solutions to the unit equation over F. For example, if two totally ramifies and three splits completely in F, then the asymptotic Fermat's Last Theorem holds over F.
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http://dx.doi.org/10.1073/pnas.2026449118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000273PMC
March 2021

Guinea fowl (Numida meleagris) eggs and free-range housing: a convenient alternative to laying hens' eggs in terms of food safety?

Poult Sci 2021 Apr 17;100(4):101006. Epub 2021 Jan 17.

Department of Animal Science, Czech University of Life Sciences Prague, 165 00 Prague, Czech Republic.

The aim of this study was to evaluate the impact of the genotype (guinea fowl, native breed Leghorn, and commercial hybrid hens), storage time (0, 14, 28 d) and storage temperature (fresh, 5, 20°C) on eggshell quality traits and microbiological contamination of eggshell, eggshell membranes, and albumen. A total of 150 hens (50 hens per genotype-divided into 2 equal groups because of the results replication) were used. There were 150 eggs (50 per genotype) used for microbial analysis and 600 eggs used for the analysis of eggshell quality. The effects of genotype, storage time, and storage temperature were observed. Moreover, interactions between these factors were calculated. The significant effect of genotype (P = 0.0001) was found in egg weight, in all observed parameters of eggshell quality (proportion, thickness, strength, surface, and index), eggshell contamination of Escherichia coli (EC) and total number of micro-organisms (TNM), penetration of TNM into eggshell membranes (P = 0.0014), and penetration of TNM into albumen (P = 0.0019). Storage time significantly affected egg weight and all parameters of eggshell quality except the eggshell strength and index. It also significantly affected count of Enterococcus (ENT) on eggshell, TNM in eggshell membranes and TNM in albumen. Storage temperature significantly influenced egg weight (P = 0.0001) and all parameters but eggshell thickness and surface. Regarding the microbial contamination, storage temperature significantly affected a count of ENT on shell, TNM in shell membranes, and TNM in albumen. Concerning significant interactions, the interaction among genotype and storage time was found significant (P = 0.0148). Fresh and 28-day-old commercial hybrid eggs were the most contaminated, whereas guinea fowl eggs (fresh and 14 d old) and Leghorn hen eggs (fresh, 14, 28 d old) had the lowest level of contamination by EC. When looking for an alternative to laying hens, guinea fowls should be taken into consideration due to their higher resistance to diseases, ability of adaptation to different environmental conditions, and especially in terms of eggshell quality and therefore egg safety.
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http://dx.doi.org/10.1016/j.psj.2021.01.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930637PMC
April 2021

Stroke increases the expression of ACE2, the SARS-CoV-2 binding receptor, in murine lungs.

Brain Behav Immun 2021 Feb 20. Epub 2021 Feb 20.

Institute for Experimental Immunology and Imaging, University Hospital Essen, University of Duisburg-Essen, DE-45147 Essen, Germany; Leibniz-Institut für Analytische Wissenschaften - ISAS -e.V., Dortmund, Germany. Electronic address:

Background: The newly emerged severe acute respiratory syndrome coronavirus (SARS-CoV-2) has caused a worldwide pandemic of human respiratory disease. Angiotensin-converting enzyme (ACE) 2 is the key receptor on lung epithelial cells to facilitate initial binding and infection of SARS-CoV-2. The binding to ACE2 is mediated via the spike glycoprotein present on the viral surface. Recent clinical data have demonstrated that patients with previous episodes of brain injuries are a high-risk group for SARS-CoV-2 infection. An explanation for this finding is currently lacking. Sterile tissue injuries including stroke induce the release of several inflammatory mediators that might modulate the expression levels of signaling proteins in distant organs. Whether systemic inflammation following brain injury can specifically modulate ACE2 expression in different vital tissues has not been investigated.

Methods: For the induction of brain stroke, mice were subjected to a surgical procedure for transient interruption of blood flow in the middle cerebral artery for 45 min and sacrificed after 1 and 3 days for analysis of brain, lung, heart, and kidney tissues. Gene expression and protein levels of ACE2, ACE, IL-6 and IL1β were measured by quantitative PCR and Western blot, respectively. The level of soluble ACE2 in plasma and bronchial alveolar lavage (BAL) was measured using an immunoassay. Immune cell populations in lymphoid organs were analyzed by flow cytometry. Post-stroke pneumonia in mice was examined by bacterial cultures from lung homogenates and whole blood.

Results: Strikingly, 1 day after surgery, we observed a substantial increase in the protein levels of ACE2 in the lungs of stroke mice compared to sham-operated mice. However, the protein levels of ACE2 were found unchanged in the heart, kidney, and brain of these animals. In addition, we found increased transcriptional levels of alveolar ACE2 after stroke. The increased expression of ACE2 was significantly associated with the severity of behavioral deficits after stroke. The higher protein levels of alveolar ACE2 persisted until 3 days of stroke. Interestingly, we found reduced levels of soluble ACE2 in plasma but not in BAL in stroke-operated mice compared to sham mice. Furthermore, stroke-induced parenchymal and systemic inflammation was evident with the increased expression of IL-6 and IL-1β. Reduced numbers of T-lymphocytes were present in the blood and spleen as an indicator of sterile tissue injury-induced immunosuppression.

Conclusions: We demonstrate specific augmented alveolar ACE2 levels and inflammation in murine lungs after experimental stroke. These pre-clinical findings suggest that patients with brain injuries may have increased binding affinity to SARS-CoV-2 in their lungs which might explain why stroke is a risk factor for higher susceptibility to develop COVID-19.
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http://dx.doi.org/10.1016/j.bbi.2021.01.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896496PMC
February 2021

A LysR-type transcriptional regulator controls the expression of numerous small RNAs in Agrobacterium tumefaciens.

Mol Microbiol 2021 Feb 9. Epub 2021 Feb 9.

Microbial Biology, Ruhr University Bochum, Bochum, Germany.

Small RNAs (sRNAs) are universal posttranscriptional regulators of gene expression and hundreds of sRNAs are frequently found in each and every bacterium. In order to coordinate cellular processes in response to ambient conditions, many sRNAs are differentially expressed. Here, we asked how these small regulators are regulated using Agrobacterium tumefaciens as a model system. Among the best-studied sRNAs in this plant pathogen are AbcR1 regulating numerous ABC transporters and PmaR, a regulator of peptidoglycan biosynthesis, motility, and ampicillin resistance. We report that the LysR-type regulator VtlR (also known as LsrB) controls expression of AbcR1 and PmaR. A vtlR/lsrB deletion strain showed growth defects, was sensitive to antibiotics and severely compromised in plant tumor formation. Transcriptome profiling by RNA-sequencing revealed more than 1,200 genes with altered expression in the mutant. Consistent with the function of VtlR/LsrB as regulator of AbcR1, many ABC transporter genes were affected. Interestingly, the transcription factor did not only control the expression of AbcR1 and PmaR. In the mutant, 102 sRNA genes were significantly up- or downregulated. Thus, our study uncovered VtlR/LsrB as the master regulator of numerous sRNAs. Thereby, the transcriptional regulator harnesses the regulatory power of sRNAs to orchestrate the expression of distinct sub-regulons.
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http://dx.doi.org/10.1111/mmi.14695DOI Listing
February 2021

Determination of selected biochemical parameters in blood serum and egg quality of Czech and Slovak native hens depending on the housing system and hen age.

Poult Sci 2021 Feb 4;100(2):1142-1153. Epub 2020 Nov 4.

Czech University of Life Sciences Prague, Faculty of Agrobiology, Food and Natural Resources, Department of Veterinary Sciences, 165 00 Prague, Suchdol, Czech Republic.

The objective of this study was to determine and evaluate the impact of the age and housing system on blood indicators (triacylglycerides, total cholesterol, aspartate aminotransferase, total proteins, albumin, glucose) and physical egg quality parameters (egg weight, shape index and surface area, eggshell proportion, thickness, strength, and color, albumen proportion and index, Haugh units, yolk proportion, index and yolk-to-albumen ratio) in selected native breeds of the Czech Republic (the Czech Golden Spotted hens) and Slovakia (the Oravka hens). Furthermore, the concentration of cholesterol in the yolk was determined. A total of 132 animals were used. There were 60 eggs collected from each breed at each monitored period for the evaluation of egg quality. Blood samples were taken by puncture of a wing vein. The assessments were made when the hens were of 34, 42, and 50 weeks old. Enriched cages and floor pens with litter were used as housing systems. The effects of breed, housing system, and age were observed. Furthermore, interactions among these factors were calculated. The significant effect of housing system was found in total cholesterol (P = 0.098) and aspartate aminotransferase (P = 0.0343) and the significant effect of age in total protein (P = 0.0392). The significant effect of breed (P = 0.0199), housing system (P = 0.0001), and age (P = 0.0001) was found in concentration of cholesterol in the yolk. Regarding the egg quality, the significant effect of breed (P = 0.0001) was found in eggshell color, albumen index and Haugh units, whereas the significant effect of housing system was found in egg weight (P = 0.0002), egg surface area (P = 0.0003), eggshell proportion (P = 0.0460), thickness (P = 0.0216), strength (P = 0.0049), and color (P = 0.0009). The significant effect of age was determined in all parameters except for the eggshell proportion and strength. The results represent an interesting comparison of changes in biochemical blood and egg quality parameters. It is necessary to further evaluate these indicators, especially in other genetic resources of hens, where the data are often nonexisting.
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http://dx.doi.org/10.1016/j.psj.2020.10.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858131PMC
February 2021

Triphenylphosphonium derivatives disrupt metabolism and inhibit melanoma growth in vivo when delivered via a thermosensitive hydrogel.

PLoS One 2020 30;15(12):e0244540. Epub 2020 Dec 30.

Department of Radiology, Carver College of Medicine, The University of Iowa, Iowa City, IA, United States of America.

Despite dramatic improvements in outcomes arising from the introduction of targeted therapies and immunotherapies, metastatic melanoma is a highly resistant form of cancer with 5 year survival rates of <35%. Drug resistance is frequently reported to be associated with changes in oxidative metabolism that lead to malignancy that is non-responsive to current treatments. The current report demonstrates that triphenylphosphonium(TPP)-based lipophilic cations can be utilized to induce cytotoxicity in pre-clinical models of malignant melanoma by disrupting mitochondrial metabolism. In vitro experiments demonstrated that TPP-derivatives modified with aliphatic side chains accumulated in melanoma cell mitochondria; disrupted mitochondrial metabolism; led to increases in steady-state levels of reactive oxygen species; decreased total glutathione; increased the fraction of glutathione disulfide; and caused cell killing by a thiol-dependent process that could be rescued by N-acetylcysteine. Furthermore, TPP-derivative-induced melanoma toxicity was enhanced by glutathione depletion (using buthionine sulfoximine) as well as inhibition of thioredoxin reductase (using auranofin). In addition, there was a structure-activity relationship between the aliphatic side-chain length of TPP-derivatives (5-16 carbons), where longer carbon chains increased melanoma cell metabolic disruption and cell killing. In vivo bio-distribution experiments showed that intratumoral administration of a C14-TPP-derivative (12-carbon aliphatic chain), using a slow-release thermosensitive hydrogel as a delivery vehicle, localized the drug at the melanoma tumor site. There, it was observed to persist and decrease the growth rate of melanoma tumors. These results demonstrate that TPP-derivatives selectively induce thiol-dependent metabolic oxidative stress and cell killing in malignant melanoma and support the hypothesis that a hydrogel-based TPP-derivative delivery system could represent a therapeutic drug-delivery strategy for melanoma.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244540PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773266PMC
March 2021

Monocytic Cytokines in Autoimmune Polyglandular Syndrome Type 2 Are Modulated by Vitamin D and HLA-DQ.

Front Immunol 2020 7;11:583709. Epub 2020 Dec 7.

Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany.

Context: Autoimmune polyglandular syndrome (APS-2: autoimmune Addison's disease or type 1 diabetes) is conferred by predisposing HLA molecules, vitamin D deficiency, and heritable susceptibility. Organ destruction is accompanied by cytokine alterations. We addressed the monocytic cytokines of two distinct APS-2 cohorts, effects of vitamin D and HLA DQ risk.

Methods: APS-2 patients (n = 30) and healthy controls (n = 30) were genotyped for HLA DQA1/DQB1 and their CD14+ monocytes stimulated with IL1β and/or 1,25(OH)D for 24 h. Immune regulatory molecules (IL-6, IL-10, IL-23A, IL-15, CCL-2, PD-L1), vitamin D pathway gene transcripts (CYP24A1, CYP27B1, VDR), and CD14 were analyzed by enzyme-linked immunosorbent assay and RTqPCR.

Results: Pro-inflammatory CCL-2 was higher in APS-2 patients than in controls (p = 0.001), whereas IL-6 showed a trend - (p = 0.1). In vitro treatment with 1,25(OH)D reduced proinflammatory cytokines (IL-6, CCL-2, IL-23A, IL-15) whereas anti-inflammatory cytokines (IL-10 and PD-L1) rose both in APS-type 1 diabetes and APS-Addison´s disease. Patients with adrenal autoimmunity showed a stronger response to vitamin D. Expression of IL-23A and vitamin D pathway genes VDR and CYP27B1 varied by HLA genotype and was lower in healthy individuals with high-risk HLA (p = 0.0025; p = 0.04), while healthy controls with low-risk HLA showed a stronger IL-10 and CD14 expression (p = 0.01; p = 0.03).

Conclusion: 1,25(OH)D regulates the monocytic response in APS-2 disorders type 1 diabetes or Addison´s disease. The monocytic cytokine profile of individuals carrying HLA high-risk alleles is proinflammatory, enhances polyglandular autoimmunity and can be targeted by vitamin D.
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http://dx.doi.org/10.3389/fimmu.2020.583709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750404PMC
December 2020

The Fabp5/calnexin complex is a prerequisite for sensitization of mice to experimental autoimmune encephalomyelitis.

FASEB J 2020 Dec 30;34(12):16662-16675. Epub 2020 Oct 30.

School of Human Nutrition, McGill University, Ste. Anne de Bellevue, QC, Canada.

We previously showed that calnexin (Canx)-deficient mice are desensitized to experimental autoimmune encephalomyelitis (EAE) induction, a model that is frequently used to study inflammatory demyelinating diseases, due to increased resistance of the blood-brain barrier to immune cell transmigration. We also discovered that Fabp5, an abundant cytoplasmic lipid-binding protein found in brain endothelial cells, makes protein-protein contact with the cytoplasmic C-tail domain of Canx. Remarkably, both Canx-deficient and Fabp5-deficient mice commonly manifest resistance to EAE induction. Here, we evaluated the importance of Fabp5/Canx interactions on EAE pathogenesis and on the patency of a model blood-brain barrier to T-cell transcellular migration. The results demonstrate that formation of a complex comprised of Fabp5 and the C-tail domain of Canx dictates the permeability of the model blood-brain barrier to immune cells and is also a prerequisite for EAE pathogenesis.
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http://dx.doi.org/10.1096/fj.202001539RRDOI Listing
December 2020

Arginine-Rich Small Proteins with a Domain of Unknown Function, DUF1127, Play a Role in Phosphate and Carbon Metabolism of Agrobacterium tumefaciens.

J Bacteriol 2020 10 22;202(22). Epub 2020 Oct 22.

Microbial Biology, Ruhr University Bochum, Bochum, Germany

In any given organism, approximately one-third of all proteins have a yet-unknown function. A widely distributed domain of unknown function is DUF1127. Approximately 17,000 proteins with such an arginine-rich domain are found in 4,000 bacteria. Most of them are single-domain proteins, and a large fraction qualifies as small proteins with fewer than 50 amino acids. We systematically identified and characterized the seven DUF1127 members of the plant pathogen They all give rise to authentic proteins and are differentially expressed as shown at the RNA and protein levels. The seven proteins fall into two subclasses on the basis of their length, sequence, and reciprocal regulation by the LysR-type transcription factor LsrB. The absence of all three short DUF1127 proteins caused a striking phenotype in later growth phases and increased cell aggregation and biofilm formation. Protein profiling and transcriptome sequencing (RNA-seq) analysis of the wild type and triple mutant revealed a large number of differentially regulated genes in late exponential and stationary growth. The most affected genes are involved in phosphate uptake, glycine/serine homeostasis, and nitrate respiration. The results suggest a redundant function of the small DUF1127 paralogs in nutrient acquisition and central carbon metabolism of They may be required for diauxic switching between carbon sources when sugar from the medium is depleted. We end by discussing how DUF1127 might confer such a global impact on cell physiology and gene expression. Despite being prevalent in numerous ecologically and clinically relevant bacterial species, the biological role of proteins with a domain of unknown function, DUF1127, is unclear. Experimental models are needed to approach their elusive function. We used the phytopathogen , a natural genetic engineer that causes crown gall disease, and focused on its three small DUF1127 proteins. They have redundant and pervasive roles in nutrient acquisition, cellular metabolism, and biofilm formation. The study shows that small proteins have important previously missed biological functions. How small basic proteins can have such a broad impact is a fascinating prospect of future research.
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http://dx.doi.org/10.1128/JB.00309-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585064PMC
October 2020

Modulation of band alignment with water redox potentials by biaxial strain on orthorhombic NaTaO thin films.

Phys Chem Chem Phys 2020 Nov 16;22(41):23810-23815. Epub 2020 Oct 16.

Center for Engineering, Modeling and Applied Social Sciences - CECS, Federal University of ABC - UFABC, Santo André - SP, Brazil.

Photocatalysis-assisted water splitting using semiconductor materials greatly depends on the bandgap size and the alignment of band edges relative to the reaction potentials. We used ab initio computational methods to show that the biaxial strain on [100]-oriented orthorhombic NaTaO thin films grants the modulation of surface states, favoring either the hydrogen evolution reaction (HER) or the oxygen evolution reaction (OER), which basically rules the perovskite photocatalytic performance. Under compression, the outermost TaO and TaO polyhedra become more distorted, and electrostatic repulsion increases the energy of Ta 5d surface states. As they overcome the O/HO potential, they cease to contribute to the OER. At the same time, the H/H remains below the conduction band, leveraging the HER over the OER. The tensile strain lowers the outermost polyhedra distortions, stabilizing both Ta 5d surface and conduction band states, and increasing the charge centered around surface Ta atoms. Consequently, the bands are better aligned with O/HO and H/H potentials, which benefits the overall water splitting photocatalysis. Our results evidence that combining facet and strain engineering is an effective way of altering the photocatalytic activity of orthorhombic [100] NaTaO thin films.
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http://dx.doi.org/10.1039/d0cp04322bDOI Listing
November 2020

Preparing for the Second Surge: Preventing Posttraumatic Stress Disorder and Building Resilience for Health Care Workers in the Face of COVID-19.

Disaster Med Public Health Prep 2020 Oct 13:1-4. Epub 2020 Oct 13.

Beth Israel Deaconess Medical Center Fellowship in Disaster Medicine COVID-19 Taskforce, Beth Israel Deaconess Medical Center, Brookline, MA, USA.

The global community needs to be aware of the potential psychosocial consequences that may be experienced by health care workers who are actively managing patients with coronavirus disease (COVID-19). These health care workers are at increased risk for experiencing mood and trauma-related disorders, including posttraumatic stress disorder (PTSD). In this concept article, strategies are recommended for individual health care workers and hospital leadership to aid in mitigating the risk of PTSD, as well as to build resilience in light of a potential second surge of COVID-19.
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http://dx.doi.org/10.1017/dmp.2020.371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684017PMC
October 2020

Timing of Emergency Postpartum Hospital Visits in the Fourth Trimester.

Am J Perinatol 2021 Mar 29;38(4):319-325. Epub 2020 Sep 29.

Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas.

Objective:  The concept of the "fourth trimester" emphasizes the importance of individualized postpartum follow-up. Women seek care for urgent issues during this critical time period. Our objective was to evaluate trends in presenting complaints and admissions in an emergency setting over the first 42 days following delivery.

Study Design:  Postpartum hospital encounters within 42 days of delivery at our institution from 2015 to 2019 were studied. Demographic information, delivery route, and emergent hospital encounter details were obtained from the electronic medical record. The postpartum encounters were analyzed by week of presentation. Statistical analysis included Student's -test and Mantel-Haenszel test with <0.05 considered significant.

Results:  Of the 8,589 deliveries, 491 (5.7%) were complicated by an emergent hospital presentation within 42 days of delivery resulting in 576 hospital encounters. 35.9% of these visits occurred in the first week and 75.5% occurred within the first 3 weeks. Women presenting to the hospital were more commonly African American, higher body mass index, and delivered via cesarean. The most common chief complaints were fever, headache, abdominal pain, vaginal bleeding, hypertension, and wound concerns with temporal trends noted. 72% of admissions occur within 14 days of delivery and drop dramatically thereafter ( = 0.001). The most common diagnoses were hypertension/preeclampsia with severe features, vaginal bleeding/delayed postpartum hemorrhage, and wound infection.

Conclusion:  We observed important trends in presenting complaints and admission diagnoses of emergency postpartum visits in the first 42 days. The majority of hospital visits and admissions occur within the first 2 weeks postpartum. Understanding maternal conditions and reasons for accessing care through an emergency setting allows for tailoring of routine postpartum follow-up.

Key Points: · Women presenting in the postpartum period most commonly seek care within 3 weeks of delivery.. · Postpartum presentations requiring admission most frequently occur within 2 weeks of delivery.. · The most common diagnoses on presentation were hypentension, vaginal bleeding, and wound infections..
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http://dx.doi.org/10.1055/s-0040-1716842DOI Listing
March 2021

ND-13, a DJ-1-Derived Peptide, Attenuates the Renal Expression of Fibrotic and Inflammatory Markers Associated with Unilateral Ureter Obstruction.

Int J Mol Sci 2020 Sep 24;21(19). Epub 2020 Sep 24.

Molecular Inflammation Group, Biomedical Research Institute of Murcia (IMIB), University Clinical Hospital Virgen Arrixaca, 30120 Murcia, Spain.

DJ-1 is a redox-sensitive chaperone with reported antioxidant and anti-inflammatory properties in the kidney. The 20 amino acid (aa) peptide ND-13 consists of 13 highly conserved aas from the DJ-1 sequence and a TAT-derived 7 aa sequence that helps in cell penetration. This study aimed to determine if ND-13 treatment prevents the renal damage and inflammation associated with unilateral ureter obstruction (UUO). Male C57Bl/6 and mice underwent UUO and were treated with ND-13 or vehicle for 14 days. ND-13 attenuated the renal expression of fibrotic markers and () and inflammatory markers and in C57Bl/6 mice. mice treated with ND-13 presented similar decreased expression of , and . However, in contrast to C57Bl/6 mice, ND-13 failed to prevent renal fibrosis or to ameliorate the expression of in this genotype. Further, UUO led to elevated urinary levels of the proximal tubular injury marker neutrophil gelatinase-associated lipocalin (NGAL) in mice, which were blunted by ND-13. Our results suggest that ND-13 protects against UUO-induced renal injury, inflammation and fibrosis. These are all crucial mechanisms in the pathogenesis of kidney injury. Thus, ND-13 may be a new therapeutic approach to prevent renal diseases.
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http://dx.doi.org/10.3390/ijms21197048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582723PMC
September 2020

Cholestasis: A Prospective Study of Perinatal Outcomes and Time to Symptom Improvement.

Am J Perinatol 2021 Apr 24;38(5):414-420. Epub 2020 Sep 24.

Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas.

Objective:  Although intrahepatic cholestasis of pregnancy (ICP) remains poorly understood, there are several perinatal complications associated with this condition. This study aimed to examine perinatal outcomes of women with ICP, evaluate outcomes according to severity of disease, and monitor time to symptom improvement following diagnosis.

Study Design:  It involves a prospective, observational study of women with ICP at a single institution. Women with new-onset pruritus without rash were referred to a high-risk obstetrics clinic and evaluated with fasting total bile acids (TBA). Laboratory-confirmed ICP was defined as fasting TBA ≥10 µmol/L. Following diagnosis, a standardized protocol was utilized, including treatment with ursodeoxycholic acid (UDCA). Perinatal outcomes were compared amongst those with and without ICP, and to the general population. Women with ICP were further analyzed based on maximum TBA: 10 to 39, 40 to 99, and ≥100 µmol/L. A Kaplan-Meier survival curve was used to analyze time to symptom improvement.

Results:  A total of 404 patients were evaluated and 212 (52%) were diagnosed with ICP. The mean gestational age at diagnosis was 34.1 ± 3.3 weeks. When comparing those with ICP to those not confirmed, and to the general population, there were no differences in age, parity, mode of delivery, preeclampsia, or stillbirth ( > 0.05). Preterm birth was significantly associated with ICP ( < 0.01). This relationship was significant across increasing severity of TBA ( < 0.01) and persisted when examining rates of spontaneous preterm birth ( < 0.01). All women with fasting TBA ≥40 µmol/L delivered preterm due to premature rupture of membranes or spontaneous labor. Time to symptom improvement after diagnosis was over 2 weeks on average; however, this time increased with worsening severity of disease.

Conclusion:  Despite treatment with UDCA, women with ICP are at increased risk for spontaneous preterm birth, and this risk significantly increased with severity of disease. Although not significant, a trend exists between increasing time to symptom improvement and worsening severity of disease.

Key Points: · Preterm birth is significantly increased in patients diagnosed with intrahepatic cholestasis of pregnancy.. · The risk of preterm birth in women with ICP increases across increasing strata of disease.. · Following initiation of treatment in patients with ICP, symptom improvement takes more than 2 weeks..
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http://dx.doi.org/10.1055/s-0040-1717076DOI Listing
April 2021

Macrophage migration inhibitory factor is regulated by HIF-1α and cAMP and promotes renal cyst cell proliferation in a macrophage-independent manner.

J Mol Med (Berl) 2020 11 4;98(11):1547-1559. Epub 2020 Sep 4.

Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nuernberg, Ulmenweg 18, D - 91054, Erlangen, Germany.

Progressive cyst growth leads to decline of renal function in polycystic kidney disease. Macrophage migration inhibitory factor (MIF) was found to be upregulated in cyst-lining cells in a mouse model of polycystic kidney disease and to promote cyst growth. In addition, MIF can be secreted by tubular cells and may contribute to cyst growth in an autocrine manner. However, the underlying mechanisms leading to induction of MIF in cyst-lining cells remained elusive. Here, we demonstrate that hypoxia-inducible transcription factor (HIF) 1α upregulates MIF in cyst-lining cells in a tubule-specific PKD1 knockout mouse. Pharmacological stabilization of HIF-1α resulted in significant increase of MIF in cyst epithelial cells whereas tubule-specific knockout of HIF-1α prevented MIF upregulation. Identical regulation could be found for ABCA1, which has been shown to act as a transport protein for MIF. Furthermore, we show that MIF and ABCA1 are direct target genes of HIF-1α in human primary tubular cells. Next to HIF-1α and hypoxia, we found MIF being additionally regulated by cAMP which is a strong promotor of cyst growth. In line with these findings, HIF-1α- and cAMP-dependent in vitro cyst growth could be decreased by the MIF-inhibitor ISO-1 which resulted in reduced cyst cell proliferation. In conclusion, HIF-1α and cAMP regulate MIF in primary tubular cells and cyst-lining epithelial cells, and MIF promotes cyst growth in the absence of macrophages. In line with these findings, the MIF inhibitor ISO-1 attenuates HIF-1α- and cAMP-dependent in vitro cyst enlargement. KEY MESSAGES: • MIF is upregulated in cyst-lining cells in a polycystic kidney disease mouse model. • MIF upregulation is mediated by hypoxia-inducible transcription factor (HIF) 1α. • ABCA1, transport protein for MIF, is also regulated by HIF-1α in vitro and in vivo. • MIF is additionally regulated by cAMP, a strong promotor of cyst growth. • MIF-inhibitor ISO-1 reduces HIF-1α- and cAMP-dependent cyst growth.
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http://dx.doi.org/10.1007/s00109-020-01964-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591438PMC
November 2020

Biallelic variants in the small optic lobe calpain CAPN15 are associated with congenital eye anomalies, deafness and other neurodevelopmental deficits.

Hum Mol Genet 2020 Nov;29(18):3054-3063

Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada.

Microphthalmia, coloboma and cataract are part of a spectrum of developmental eye disorders in humans affecting ~12 per 100 000 live births. Currently, variants in over 100 genes are known to underlie these conditions. However, at least 40% of affected individuals remain without a clinical genetic diagnosis, suggesting variants in additional genes may be responsible. Calpain 15 (CAPN15) is an intracellular cysteine protease belonging to the non-classical small optic lobe (SOL) family of calpains, an important class of developmental proteins, as yet uncharacterized in vertebrates. We identified five individuals with microphthalmia and/or coloboma from four independent families carrying homozygous or compound heterozygous predicted damaging variants in CAPN15. Several individuals had additional phenotypes including growth deficits, developmental delay and hearing loss. We generated Capn15 knockout mice that exhibited similar severe developmental eye defects, including anophthalmia, microphthalmia and cataract, and diminished growth. We demonstrate widespread Capn15 expression throughout the brain and central nervous system, strongest during early development, and decreasing postnatally. Together, these findings demonstrate a critical role of CAPN15 in vertebrate developmental eye disorders, and may signify a new developmental pathway.
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http://dx.doi.org/10.1093/hmg/ddaa198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645705PMC
November 2020

Cyst growth in ADPKD is prevented by pharmacological and genetic inhibition of TMEM16A in vivo.

Nat Commun 2020 08 28;11(1):4320. Epub 2020 Aug 28.

Department of Nephrology and Hypertension, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.

In autosomal dominant polycystic kidney disease (ADPKD) multiple bilateral renal cysts gradually enlarge, leading to a decline in renal function. Transepithelial chloride secretion through cystic fibrosis transmembrane conductance regulator (CFTR) and TMEM16A (anoctamin 1) are known to drive cyst enlargement. Here we demonstrate that loss of Pkd1 increased expression of TMEM16A and CFTR and Cl secretion in murine kidneys, with TMEM16A essentially contributing to cyst growth. Upregulated TMEM16A enhanced intracellular Ca signaling and proliferation of Pkd1-deficient renal epithelial cells. In contrast, increase in Ca signaling, cell proliferation and CFTR expression was not observed in Pkd1/Tmem16a double knockout mice. Knockout of Tmem16a or inhibition of TMEM16A in vivo by the FDA-approved drugs niclosamide and benzbromarone, as well as the TMEM16A-specific inhibitor Ani9 largely reduced cyst enlargement and abnormal cyst cell proliferation. The present data establish a therapeutic concept for the treatment of ADPKD.
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http://dx.doi.org/10.1038/s41467-020-18104-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455562PMC
August 2020

Defining the Protein Seeds of Neurodegeneration using Real-Time Quaking-Induced Conversion Assays.

Biomolecules 2020 08 25;10(9). Epub 2020 Aug 25.

Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.

Neurodegenerative diseases are characterized by the accumulation of disease-related misfolded proteins. It is now widely understood that the characteristic self-amplifying (i.e., seeding) capacity once only attributed to the prions of transmissible spongiform encephalopathy diseases is a feature of other misfolded proteins of neurodegenerative diseases, including tau, Aβ, and αSynuclein (αSyn). Ultrasensitive diagnostic assays, known as real-time quaking-induced conversion (RT-QuIC) assays, exploit these seeding capabilities in order to exponentially amplify protein seeds from various biospecimens. To date, RT-QuIC assays have been developed for the detection of protein seeds related to known prion diseases of mammals, the αSyn aggregates of Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, and the tau aggregates of Alzheimer's disease, chronic traumatic encephalopathy, and other tauopathies including progressive supranuclear palsy. Application of these assays to premortem human biospecimens shows promise for diagnosis of neurodegenerative disease and is an area of active investigation. RT-QuIC assays are also powerful experimental tools that can be used to dissect seeding networks within and between tissues and to evaluate how protein seed distribution and quantity correlate to disease-related outcomes in a host. As well, RT-QuIC application may help characterize molecular pathways influencing protein seed accumulation, transmission, and clearance. In this review we discuss the application of RT-QuIC assays as diagnostic, experimental, and structural tools for detection and discrimination of PrP prions, tau, and αSyn protein seeds.
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http://dx.doi.org/10.3390/biom10091233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564261PMC
August 2020

Practical Solutions for Healthcare Worker Protection During the COVID-19 Pandemic Response in the Ambulatory, Emergency, and Inpatient Settings.

J Occup Environ Med 2020 Nov;62(11):e616-e624

Beth Israel Deaconess Medical Center Fellowship in Disaster Medicine COVID-19 Taskforce, Beth Israel Deaconess Medical Center, Brookline, Massachusetts.

Objective: Protecting healthcare workers is an essential component of a successful response to the COVID-19 pandemic. The resource intensive nature of infectious disease protection, budgetary constraints, and global shortages of personal protective equipment (PPE) make this a daunting task. Practical, easily implemented strategies for healthcare workers (HCW) protection are needed.

Methods: We cross-reference the "Systems, Space, Staff, and Stuff" paradigm from disaster management and the "Hierarchy of Controls" approach to infection prevention from the Center for Disease Control and Prevention (CDC) to generate a narrative overview of worker protection strategies relevant to COVID-19.

Results: Alternative types of PPE, management of hazards, and reorganizing how people work can optimize HCWs protection.

Conclusions: A comprehensive PPE strategy can utilize the "systems, space, staff, stuff" paradigm of disaster management to identify new or underutilized solutions to HCWs protection.
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http://dx.doi.org/10.1097/JOM.0000000000002008DOI Listing
November 2020

Remote monitoring of cardiac implanted electronic devices: legal requirements and ethical principles - ESC Regulatory Affairs Committee/EHRA joint task force report.

Europace 2020 11;22(11):1742-1758

School of Medicine, Cardiff University, Cardiff, UK.

The European Union (EU) General Data Protection Regulation (GDPR) imposes legal responsibilities concerning the collection and processing of personal information from individuals who live in the EU. It has particular implications for the remote monitoring of cardiac implantable electronic devices (CIEDs). This report from a joint Task Force of the European Heart Rhythm Association and the Regulatory Affairs Committee of the European Society of Cardiology (ESC) recommends a common legal interpretation of the GDPR. Manufacturers and hospitals should be designated as joint controllers of the data collected by remote monitoring (depending upon the system architecture) and they should have a mutual contract in place that defines their respective roles; a generic template is proposed. Alternatively, they may be two independent controllers. Self-employed cardiologists also are data controllers. Third-party providers of monitoring platforms may act as data processors. Manufacturers should always collect and process the minimum amount of identifiable data necessary, and wherever feasible have access only to pseudonymized data. Cybersecurity vulnerabilities have been reported concerning the security of transmission of data between a patient's device and the transceiver, so manufacturers should use secure communication protocols. Patients need to be informed how their remotely monitored data will be handled and used, and their informed consent should be sought before their device is implanted. Review of consent forms in current use revealed great variability in length and content, and sometimes very technical language; therefore, a standard information sheet and generic consent form are proposed. Cardiologists who care for patients with CIEDs that are remotely monitored should be aware of these issues.
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http://dx.doi.org/10.1093/europace/euaa168DOI Listing
November 2020

A Gap in Care? Postpartum Women Presenting to the Emergency Room and Getting Readmitted.

Am J Perinatol 2020 12 30;37(14):1385-1392. Epub 2020 May 30.

Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas.

Objective: Emergent postpartum hospital encounters in the first 42 days after birth are estimated to complicate 5 to 12% of births. Approximately 2% of these visits result in admission. Data on emergent visits and admissions are critically needed to address the current maternal morbidity crisis. Our objective is to characterize trends in emergent postpartum hospital encounters and readmissions through chief complaints and admission diagnoses over a 4.5-year period.

Study Design: All postpartum hospital encounters within 42 days of delivery at our institution from 2015 to 2019 were included. We reviewed demographic information, antepartum, intrapartum, and postpartum care and postpartum hospital encounters. Trends in hospital presentation and admission over the study period were analyzed. Comparisons between women who were admitted to those managed outpatient were performed. Statistical analysis included Chi-square, student's -test, and Mantel-Haenszel test for trend and ANOVA, as appropriate. A -value <0.05 considered significant.

Results: Among 8,589 deliveries, 491 (5.7%) presented emergently to the hospital within 42 days of delivery, resulting in 576 hospital encounters. From 2015 to 2019, annual rates of presentation were stable, ranging from 5.0 to 6.4% ( = 0.09). Of the 576 hospital encounters, 224 (38.9%) resulted in an admission with increasing rates from 2.0% in 2015 to 3.4% in 2019 ( = 0.005). Primiparous women with higher body mass index, cesarean delivery, and blood loss ≥1, 000 mL during delivery were significantly more likely to be admitted to the hospital. Women with psychiatric illnesses increasingly utilized the emergency room in the postpartum period (6.7-17.2%,  = 0.03). The most common presenting complaints were fever, abdominal pain, headache, vaginal bleeding, wound concerns, and high blood pressure. Admitting diagnoses were predominantly hypertensive disorder (22.9%), wound complications (12.8%), endometritis (9.6%), headache (6.9%), and delayed postpartum hemorrhage (5.6%).

Conclusion: The average proportion of women presenting for an emergent hospital encounter in the immediate 42-day postpartum period is 5.7%. Nearly 40% of emergent hospital encounters resulted in admission and the rate increased from to 2.0 to 3.4% over the study period. The most common reasons for presentation were fever, abdominal pain, headache, vaginal bleeding, wound concerns, and hypertension. Hypertension, wound complications, and endometritis accounted for the top three admission diagnoses.
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http://dx.doi.org/10.1055/s-0040-1712170DOI Listing
December 2020

Dermatomyositis induced by the secretion of Phyllomedusa bicolor or Kambô frog - A case report.

Toxicon 2020 Sep 28;184:57-61. Epub 2020 May 28.

Internal Medicine and Rheumatology Department, The American British Cowdray Medical Center, Sur 136 116, Las Americas, 01120, Mexico City, Mexico. Electronic address:

The Amazonian Kambô frog, Phyllomedusa bicolor, is commonly known for the potential benefits of its secretion. The Kambô ritual consists in applying the toxin directly to a freshly burnt skin area, since it is believed by natives and shamans to purify and strengthen the body and mind of the user. We describe a 33-year old female with a history of periodic use of Kambô toxin who presented with a 3-week course of asthenia, malaise, myalgia, and proximal muscle weakness predominantly in the lower limbs. She had elevated muscle enzymes and an abnormal electromyography. We used the 2017 European League Against Rheumatism and American College of Rheumatology classification criteria to establish the diagnosis of dermatomyositis. The patient demonstrated clinical response to prednisone, with a complete recovery of signs and symptoms after 8 weeks of treatment. To our knowledge, this is the first case report of dermatomyositis possibly associated with the use of Kambô. The Kambô cleansing ritual is becoming popular in first world countries, but its use may lead to serious side-effects, sometimes life-threatening. In patients presenting with signs and symptoms suggestive of dermatomyositis and a skin line of circle-shaped burns, Phyllomedusa bicolor skin secretion exposure should be suspected.
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http://dx.doi.org/10.1016/j.toxicon.2020.05.018DOI Listing
September 2020

Parameter estimation for discretely observed linear birth-and-death processes.

Biometrics 2021 Mar 8;77(1):186-196. Epub 2020 May 8.

Department of Mathematics and Statistics, Masaryk University, Brno, Czech Republic.

Birth-and-death processes are widely used to model the development of biological populations. Although they are relatively simple models, their parameters can be challenging to estimate, as the likelihood can become numerically unstable when data arise from the most common sampling schemes, such as annual population censuses. A further difficulty arises when the discrete observations are not equi-spaced, for example, when census data are unavailable for some years. We present two approaches to estimating the birth, death, and growth rates of a discretely observed linear birth-and-death process: via an embedded Galton-Watson process and by maximizing a saddlepoint approximation to the likelihood. We study asymptotic properties of the estimators, compare them on numerical examples, and apply the methodology to data on monitored populations.
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http://dx.doi.org/10.1111/biom.13282DOI Listing
March 2021

Current and Investigational Therapeutics for Fabry Disease.

Kidney Int Rep 2020 Apr 6;5(4):407-413. Epub 2019 Dec 6.

Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Fabry disease (FD) is an X-linked lysosomal storage disease caused by a deficiency in the lysosomal enzyme α-galactosidase (α-GAL). This in turn leads to the buildup of globotriaosylceramide, resulting classically in progressive kidney disease, peripheral neuropathy, early-onset cerebrovascular disease, gastrointestinal symptoms, hypertrophic cardiomyopathy, arrhythmias, corneal whorls, and angiokeratomas. The diagnosis of FD relies on identification of a low α-GAL enzyme activity, identification of a genetic mutation, or histologic evidence of disease. With more than 900 mutations identified, there is phenotypic variability deriving from both mutational effects as well as the effect of skewed X-inactivation in females. Treatment of this disease has relied on intravenous replacement of the deficient enzyme with agalsidase α or agalsidase β. However, treatment options for some patients with FD have recently expanded, with the approval of migalastat, an oral molecular chaperone. In addition to chaperone-based therapies, there are several additional therapies under development that could substantially reshape treatment options for patients with FD. Four approaches to gene therapy, through both and methods, are under development. Another approach is through the administration of α-GAL mRNA to help stimulate production of α-GAL, which is another unique form of therapy. Finally, substrate reduction therapies act as inhibitors of glucosylceramide synthase, thus inhibiting the production of GB-3, promise another oral option to treat FD. This article will review the literature around current therapies as well as these newer therapeutics agents in the pipeline for FD.
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http://dx.doi.org/10.1016/j.ekir.2019.11.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136345PMC
April 2020

A case of upper lip necrosis after cosmetic injection of hyaluronic acid soft-tissue filler-Does capillary infarction play a role in the development of vascular compromise, and what are the implications?

J Cosmet Dermatol 2020 Jun 8;19(6):1316-1320. Epub 2020 Apr 8.

Department of Plastic, Aesthetic and Hand Surgery, Otto-von-Guericke University, Magdeburg, Germany.

Facial rejuvenation with injectable filler substances is a frequently applied outpatient procedure. However, light, moderate, and even severe complications may occur. A case of tissue necrosis at the upper lip after injection of highly cross-linked hyaluronic acid together with the following salvage procedure is presented here. We discuss this complication with respect to relevant anatomy and physicochemical properties of the filler substance and review the recommendations given in literature for decreasing the likelihood of such an adverse event.
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http://dx.doi.org/10.1111/jocd.13391DOI Listing
June 2020

Distinct roles for H4 and H2A.Z acetylation in RNA transcription in African trypanosomes.

Nat Commun 2020 03 20;11(1):1498. Epub 2020 Mar 20.

Department of Veterinary Sciences, Experimental Parasitology, Ludwig-Maximilians-Universität München, 80752, Munich, Germany.

Despite histone H2A variants and acetylation of histones occurring in almost every eukaryotic organism, it has been difficult to establish direct functional links between canonical histones or H2A variant acetylation, deposition of H2A variants and transcription. To disentangle these complex interdependent processes, we devised a highly sensitive strategy for quantifying histone acetylation levels at specific genomic loci. Taking advantage of the unusual genome organization in Trypanosoma brucei, we identified 58 histone modifications enriched at transcription start sites (TSSs). Furthermore, we found TSS-associated H4 and H2A.Z acetylation to be mediated by two different histone acetyltransferases, HAT2 and HAT1, respectively. Whereas depletion of HAT2 decreases H2A.Z deposition and shifts the site of transcription initiation, depletion of HAT1 does not affect H2A.Z deposition but reduces total mRNA levels by 50%. Thus, specifically reducing H4 or H2A.Z acetylation levels enabled us to reveal distinct roles for these modifications in H2A.Z deposition and RNA transcription.
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http://dx.doi.org/10.1038/s41467-020-15274-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083915PMC
March 2020

A single ultrasensitive assay for detection and discrimination of tau aggregates of Alzheimer and Pick diseases.

Acta Neuropathol Commun 2020 02 22;8(1):22. Epub 2020 Feb 22.

LPVD, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, MT, 59840, USA.

Multiple neurodegenerative diseases are characterized by aggregation of tau molecules. Adult humans express six isoforms of tau that contain either 3 or 4 microtubule binding repeats (3R or 4R tau). Different diseases involve preferential aggregation of 3R (e.g Pick disease), 4R (e.g. progressive supranuclear palsy), or both 3R and 4R tau molecules [e.g. Alzheimer disease and chronic traumatic encephalopathy]. Three ultrasensitive cell-free seed amplification assays [called tau real-time quaking induced conversion (tau RT-QuIC) assays] have been developed that preferentially detect 3R, 4R, or 3R/4R tau aggregates in biospecimens. In these reactions, low-fg amounts of a given self-propagating protein aggregate (the seed) are incubated with a vast excess of recombinant tau monomers (the substrate) in multi-well plates. Over time, the seeds incorporate the substrate to grow into amyloids that can then be detected using thioflavin T fluorescence. Here we describe a tau RT-QuIC assay (K12 RT-QuIC) that, using a C-terminally extended recombinant 3R tau substrate (K12CFh), enables sensitive detection of Pick disease, Alzheimer disease, and chronic traumatic encephalopathy seeds in brain homogenates. The discrimination of Pick disease from Alzheimer disease and chronic traumatic encephalopathy cases is then achieved through the quantitative differences in K12 RT-QuIC assay thioflavin T responses, which correlate with structural properties of the reaction products. In particular, Fourier transform infrared spectroscopy analysis of the respective K12CFh amyloids showed distinct β-sheet conformations, suggesting at least partial propagation of the original seed conformations in vitro. Thus, K12 RT-QuIC provides a single assay for ultrasensitive detection and discrimination of tau aggregates comprised mainly of 3R, or both 3R and 4R, tau isoforms.
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http://dx.doi.org/10.1186/s40478-020-0887-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036215PMC
February 2020

Short-term effects of simulated microgravity on morphology and gene expression in human breast cancer cells.

Physiol Int 2019 Dec 3;106(4):311-322. Epub 2020 Jan 3.

Department of Plastic, Aesthetic and Hand Surgery, Otto-von-Guericke-University, Magdeburg, Germany.

Introduction: Microgravity has been shown to impose various effects on breast cancer cells. We exposed human breast cancer cells to simulated microgravity and studied morphology and alterations in gene expression.

Materials And Methods: Human breast cancer cells were exposed to simulated microgravity in a random positioning machine (RPM) for 24 h. Morphology was observed under light microscopy, and gene alteration was studied by qPCR.

Results: After 24 h, formation of three-dimensional structures (spheroids) occurred. BRCA1 expression was significantly increased (1.9×,  < 0.05) in the adherent cells under simulated microgravity compared to the control. Expression of KRAS was significantly decreased (0.6×,  < 0.05) in the adherent cells compared to the control. VCAM1 was significantly upregulated (6.6×, 2.0×,  < 0.05 each) in the adherent cells under simulated microgravity and in the spheroids. VIM expression was significantly downregulated (0.45×, 0.44×,  < 0.05 each) in the adherent cells under simulated microgravity and in the spheroids. There was no significant alteration in the expression of , , , and .

Conclusions: Simulated microgravity induces spheroid formation in human breast cancer cells within 24 h and alters gene expression toward modified adhesion properties, enhanced cell repair, and phenotype preservation. Further insights into the underlying mechanisms could open up the way toward new therapies.
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December 2019

Sexual and gender minority youth's perspectives on sharing de-identified data in sexual health and HIV prevention research.

Sex Res Social Policy 2019 Mar 10;16(1):1-11. Epub 2019 Jan 10.

Department of Medical Social Sciences & Institute for Sexual and Gender Minority Health and Wellbeing, Northwestern University Feinberg School of Medicine (Chicago, IL).

Funding agencies encourage and sometimes require data sharing. However, there is limited empirical research on participant perspectives on sharing de-identified data from research on sensitive topics (e.g., HIV, sexual health) with other researchers, and virtually none from adolescents or sexual and gender minority (SGM) participants. SGM teens (N = 197) ages 14-17 completed an online survey with multiple choice and open-ended items assessing perspectives toward sharing survey responses and blood samples from sexual health and HIV testing studies with other researchers. SGM youth were willing to share data but frequently cited confidentiality and privacy concerns, including fears about parents finding out about their identities even after de-identification was explained. Researchers need to ensure youth understand explanations of data security protections in order to make well-informed decisions about participating in research.
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http://dx.doi.org/10.1007/s13178-018-0372-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936765PMC
March 2019