Publications by authors named "Martin Kaufmann"

95 Publications

The Human Leukocyte Antigen-DPB1 Degree of Compatibility Is Determined by Its Expression Level and Mismatch Permissiveness: A German Multicenter Analysis.

Front Immunol 2020 25;11:614976. Epub 2021 Jan 25.

Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service, Baden Wuerttemberg-Hessen, and University Hospital Ulm, Ulm, Germany.

T-cell epitope matching according to the TCE3 algorithm classifies HLA-DPB1 mismatches in permissive and non-permissive. This classification has been shown to be predictive for mortality and acute GvHD (aGvHD) events in large international cohorts. We retrospectively genotyped HLA-DPB1 in 3523 patients transplanted in Germany between 2000 and 2014 and in their unrelated donors using an Illumina amplicon-NGS based assay. Aim of the study was to evaluate DP-compatibility beyond the established TCE3 algorithm by assessing the combined effect of several DP-mismatch parameters on post-transplant outcome. We implemented an extended DP-mismatch assessment model where TCE3, DP allotype expression with respect to rs9277534, mismatch vector and number of mismatches were conjointly taken into consideration. In this model, non-permissive HLA-DPB1 mismatches showed significantly increased aGvHD risk if they were accompanied by two HLA-DPB1 mismatches in GvH direction (HR: 1.46) or one mismatched highly expressed patient allotype (HR: 1.53). As previously reported, non-permissive HLA-DPB1 mismatches associated with a significantly higher risk of aGvHD and non-relapse mortality (HR 1.36 and 1.21, respectively), which in turn translated into worse GvHD and relapse free survival (HR 1.13). Effects on GvL and GvHD appeared strongest in GvH-directed non-permissive mismatches. Our study results support the consideration of additional HLA-DPB1 mismatch parameters along with the established TCE3 matching algorithm for refinement of future donor selection. In particular, our findings suggest that DP non-permissiveness associated with two HLA-DPB1 mismatches or at least on highly expressed mismatched patient allotype should be avoided.
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http://dx.doi.org/10.3389/fimmu.2020.614976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868530PMC
January 2021

Photophysics of Ruthenium(II) Complexes with Thiazole π-Extended Dipyridophenazine Ligands.

Inorg Chem 2021 Jan 23;60(2):760-773. Epub 2020 Dec 23.

School of Chemical Sciences, National Centre for Sensor Research, Dublin City University, Dublin 9, Ireland.

Transition-metal-based donor-acceptor systems can produce long-lived excited charge-transfer states by visible-light irradiation. The novel ruthenium(II) polypyridyl type complexes and based on the dipyridophenazine ligand () directly linked to 4-hydroxythiazoles of different donor strengths were synthesized and photophysically characterized. The excited-state dynamics were investigated by femtosecond-to-nanosecond transient absorption and nanosecond emission spectroscopy complemented by time-dependent density functional theory calculations. These results indicate that photoexcitation in the visible region leads to the population of both metal-to-ligand charge-transfer (MLCT) and thiazole (tz)-induced intraligand charge-transfer (ILCT) states. Thus, the excited-state dynamics is described by two excited-state branches, namely, the population of (i) a comparably short-lived phenazine-centered MLCT state (τ ≈ 150-400 ps) and (ii) a long-lived ILCT state (τ ≈ 40-300 ns) with excess charge density localized on the phenazine and tz moieties. Notably, the ruthenium(II) complexes feature long-lived dual emission with lifetimes in the ranges τ ≈ 40-300 ns and τ ≈ 100-200 ns, which are attributed to emission from the ILCT and MLCT manifolds, respectively.
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http://dx.doi.org/10.1021/acs.inorgchem.0c02765DOI Listing
January 2021

Do the heterozygous carriers of a CYP24A1 mutation display a different biochemical phenotype than wild types?

J Clin Endocrinol Metab 2020 Nov 29. Epub 2020 Nov 29.

Department of Clinical and Experimental Medicine, Unit of Endocrinology, University of Pisa, Pisa, Italy.

Context: Human cytochrome P450 24 subfamily A member 1 (CYP24A1) loss-of-function mutations result in impaired activity of the 24-hydroxylase involved in vitamin D catabolism, thus inducing a vitamin D-dependent hypercalcemia. Homozygotes often present an overt clinical phenotype named Idiopathic Infantile hypercalcemia (IIH), whereas it is debated whether heterozygotes display an abnormal phenotype.

Objectives: To compare the clinical and biochemical features of heterozygous carriers of CYP24A1 variant and healthy wild-type controls, sharing the same genetic and environmental exposure.

Methods: A large family harboring the nonsense c.667A>T, p.Arg223* pathogenic variant in the CYP24A1 gene was evaluated. All subjects underwent clinical and biochemical evaluation and complete analysis of vitamin D metabolites using mass-spectroscopy including 1,24,25(OH)3D3. Subjects were divided according to their genotype in two groups: heterozygotes and wild-type for the CYP24A1 variant.

Results: The proband, a 40-year-old man, homozygous for p.Arg223* pathogenic variant, had a history of mild hypercalcemia with a seasonal trend, recurrent nephrolithiasis, and no episodes of acute hypercalcemia. He showed the highest serum levels of FGF23, the highest 25(OH)D3/24,25(OH)2D3 ratio and undetectable levels of 1,24,25(OH)3D3 which represent indicators of a loss-of function CYP24A1. Compared to the wild-types, heterozygotes had higher serum calcium and 25(OH)D3 concentrations (P=0.017 and P=0.025, respectively), without any difference in the other biochemical parameters and in the rate of nephrolithiasis.

Conclusions: Heterozygotes exhibit a biochemical phenotype different from that of wild-type subjects. In clinical practice, these individuals might require surveillance because of the potential risk of developing hypercalcemia and related clinical manifestations if exposed to triggering factors.
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http://dx.doi.org/10.1210/clinem/dgaa876DOI Listing
November 2020

Thermally stable monolithic Doppler asymmetric spatial heterodyne interferometer: optical design and laboratory performance.

Opt Express 2020 Jul;28(14):19887-19900

We report on a thermally stable monolithic Doppler asymmetric spatial heterodyne (DASH) interferometer with field-widening prisms for thermospheric wind measurements by observing the Doppler shift of the airglow emission. Analytical deduction and numerical simulation are applied to determine the central optical path difference, the thermal compensation condition and the field-widening design. A monolithic interferometer with optimized configuration was built and tested in the laboratory. Laboratory tests show that the best visibility of 0.94 was realized with the 9 field-of-view illumination, while the thermal responses of the spatial frequency and the optical phase offset are 0.0154 cm/C and 0.469 rad/C, respectively.
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http://dx.doi.org/10.1364/OE.394101DOI Listing
July 2020

PTH suppression by calcitriol does not predict off-target actions in experimental CKD.

Pharmacol Res Perspect 2020 06;8(3):e00605

Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.

Vitamin D receptor agonist (VDRA) therapy for PTH suppression is a mainstay for patients with severe CKD. Calcitriol (1,25-(OH) D ) is a former first-line VDRA in CKD treatment. However, a consequence of its use in CKD is accelerated vascular calcification (VC). An experimental CKD model was used to determine whether altering the calcitriol delivery profile to obtain different PTH suppression levels could improve vascular health outcomes. High adenine diet (0.25%) was used to generate experimental CKD in rats. CKD rats were treated using different calcitriol dosing strategies: (a) 20 ng/kg SD (n = 8), (b) 80 ng/kg SD (n = 8), (c) 5 ng/kg QID (n = 9), or (d) 20 ng/kg QID (n = 9). Multiple targets of calcitriol were assessed which include arterial calcium and phosphate as well as circulating calcium, phosphate, PTH, FGF-23, VWF, and vitamin D metabolome. PTH suppression occurred dose-dependently after 1-week calcitriol treatment (P < .01), but the suppressive effect was lost over time. Both VC and circulating FGF-23 increased > 10× in all calcitriol-treated rats (P < .05 and P < .001, respectively); similarly, circulating VWF increased at all time points (P < .05). Ad-hoc analysis of CKD morbidities in treated rats indicated no differences in negative outcomes based on PTH suppression level (minimal-, target-, and over-). Comparing different calcitriol dosing strategies revealed the following: (a) despite initial calcitriol-influenced PTH suppression across all treatments, the ability to continually suppress PTH was markedly reduced by study conclusion and (b) PTH suppression level is not an adequate proxy for improvements in overall CKD morbidity. These findings show (a) a more holistic approach to evaluate CKD treatment efficacy aside from PTH suppression is needed and (b) that other VDRA therapies should be examined in CKD treatment.
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http://dx.doi.org/10.1002/prp2.605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283992PMC
June 2020

Preclinical safety and efficacy of 24R,25-dihydroxyvitamin D or lactosylceramide treatment to enhance fracture repair.

J Orthop Translat 2020 Jul 27;23:77-88. Epub 2020 Apr 27.

Research Centre, Shriners Hospitals for Children - Canada, Montreal, Quebec, H4A 0A9, Canada.

Background/objective: -null mice deficient in 24,25(OH)D display impaired callus formation during the endochondral phase of bone fracture repair. The 24,25(OH)D metabolite acted by binding to the TLC domain containing 3B isoform 2 (TLCD3B2, previously named FAM57B2) effector protein, which then synthesizes lactosylceramide (LacCer). Treatment with 24,25(OH)D or LacCer restored callus size and mechanical properties in -null mice.

Methods: To assess the safety of these molecules and test their efficacy for bone healing in wild-type, non-genetically modified mice, we treated 12-week-old, osteotomized C57BL/6 female mice with each compound for up to 21 days post-osteotomy. Control cohorts were injected with vehicle.

Results: Neither compound was found to exhibit any nephro- nor hepato-toxicity. Calcemia remained stable throughout the experiment and was unaffected by either treatment. Supplementation with 24,25(OH)D increased circulating levels of this metabolite about 8-fold, decreased 1,25(OH)D levels, and significantly increased circulating 1,24,25(OH)D levels, suggesting 1?-hydroxylation of 24,25(OH)D. TLCD3B2 was found to be expressed in fracture callus at the surface of unmineralized or pre-mineralized cartilage on day 10 and day 12 post-osteotomy and to progressively recede to become undetectable by day 18. Treatment with 24,25(OH)D or LacCer reduced the number of TLCD3B2-positive cells. Both treatments also significantly increased stiffness and elastic modulus of the healing bone callus.

Conclusion: Exogenous administration of 24,25(OH)D or LacCer improved the biomechanical properties of repaired bones in wild-type animals without affecting circulating calcium levels or other blood parameters, demonstrating preclinical safety and efficacy.

Translational Potential: Our data suggest the use of 24R,25-dihydroxyvitamin D or lactosylceramide for ameliorating fracture healing in clinical practice.
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http://dx.doi.org/10.1016/j.jot.2020.03.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270532PMC
July 2020

Does time from diagnosis to treatment affect the prognosis of patients with newly diagnosed acute myeloid leukemia?

Blood 2020 Aug;136(7):823-830

Medizinische Klinik und Poliklinik I, Universitätsklinikum Dresden, Dresden, Germany.

In fit patients with newly diagnosed acute myeloid leukemia (AML), immediate treatment start is recommended due to the poor prognosis of untreated acute leukemia. We explored the relationship between time from diagnosis to treatment start (TDT) and prognosis in a large real-world data set from the German Study Alliance Leukemia-Acute Myeloid Leukemia (SAL-AML) registry. All registered non-acute promyelocytic leukemia patients with intensive induction treatment and a minimum 12 months of follow-up were selected (n = 2263). We analyzed influence of TDT on remission, early death, and overall survival (OS) in univariable analyses for each day of treatment delay, in groups of 0 to 5, 6 to 10, 11 to 15, and >15 days of TDT, adjusted for influence of established prognostic variables on outcomes. Median TDT was 3 days (interquartile range, 2-7). Unadjusted 2-year OS rates, stratified by TDT of 0 to 5, 6 to 10, 11 to 15, and >15 days, were 51%, 48%, 44%, and 50% (P = .211). In multivariable Cox regression analysis accounting for established prognostic variables, the TDT hazard ratio as a continuous variable was 1.00 (P = .617). In OS analyses, separately stratified for age ≤60 and >60 years and for high vs lower initial white blood cell count, no significant differences between TDT groups were observed. Our study suggests that TDT is not related to survival. As stratification in intensive first-line AML treatment evolves, TDT data suggest that it may be a feasible approach to wait for genetic and other laboratory test results so that clinically stable patients are assigned the best available treatment option. This trial was registered at www.clinicaltrials.gov as #NCT03188874.
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http://dx.doi.org/10.1182/blood.2019004583DOI Listing
August 2020

Navigated tissue characterization during skin cancer surgery.

Int J Comput Assist Radiol Surg 2020 Oct 31;15(10):1665-1672. Epub 2020 May 31.

School of Computing, Queen's University, Kingston, ON, Canada.

Purpose: Basal cell carcinoma (BCC) is the most commonly diagnosed skin cancer and is treated by surgical resection. Incomplete tumor removal requires surgical revision, leading to significant healthcare costs and impaired cosmesis. We investigated the clinical feasibility of a surgical navigation system for BCC surgery, based on molecular tissue characterization using rapid evaporative ionization mass spectrometry (REIMS).

Methods: REIMS enables direct tissue characterization by analysis of cell-specific molecules present within surgical smoke, produced during electrocautery tissue resection. A tissue characterization model was built by acquiring REIMS spectra of BCC, healthy skin and fat from ex vivo skin cancer specimens. This model was used for tissue characterization during navigated skin cancer surgery. Navigation was enabled by optical tracking and real-time visualization of the cautery relative to a contoured resection volume. The surgical smoke was aspirated into a mass spectrometer and directly analyzed with REIMS. Classified BCC was annotated at the real-time position of the cautery. Feasibility of the navigation system, and tissue classification accuracy for ex vivo and intraoperative surgery were evaluated.

Results: Fifty-four fresh excision specimens were used to build the ex vivo model of BCC, normal skin and fat, with 92% accuracy. While 3 surgeries were successfully navigated without breach of sterility, the intraoperative performance of the ex vivo model was low (< 50%). Hypotheses are: (1) the model was trained on heterogeneous mass spectra that did not originate from a single tissue type, (2) during surgery mixed tissue types were resected and thus presented to the model, and (3) the mass spectra were not validated by pathology.

Conclusion: REIMS-navigated skin cancer surgery has the potential to detect and localize remaining tumor intraoperatively. Future work will be focused on improving our model by using a precise pencil cautery tip for burning localized tissue types, and having pathology-validated mass spectra.
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http://dx.doi.org/10.1007/s11548-020-02200-4DOI Listing
October 2020

Perioperative margin detection in basal cell carcinoma using a deep learning framework: a feasibility study.

Int J Comput Assist Radiol Surg 2020 May 22;15(5):887-896. Epub 2020 Apr 22.

School of Computing, Queen's University, Kingston, ON, Canada.

Purpose: Basal cell carcinoma (BCC) is the most commonly diagnosed cancer and the number of diagnosis is growing worldwide due to increased exposure to solar radiation and the aging population. Reduction of positive margin rates when removing BCC leads to fewer revision surgeries and consequently lower health care costs, improved cosmetic outcomes and better patient care. In this study, we propose the first use of a perioperative mass spectrometry technology (iKnife) along with a deep learning framework for detection of BCC signatures from tissue burns.

Methods: Resected surgical specimen were collected and inspected by a pathologist. With their guidance, data were collected by burning regions of the specimen labeled as BCC or normal, with the iKnife. Data included 190 scans of which 127 were normal and 63 were BCC. A data augmentation approach was proposed by modifying the location and intensity of the peaks of the original spectra, through noise addition in the time and frequency domains. A symmetric autoencoder was built by simultaneously optimizing the spectral reconstruction error and the classification accuracy. Using t-SNE, the latent space was visualized.

Results: The autoencoder achieved an accuracy (standard deviation) of 96.62 (1.35%) when classifying BCC and normal scans, a statistically significant improvement over the baseline state-of-the-art approach used in the literature. The t-SNE plot of the latent space distinctly showed the separability between BCC and normal data, not visible with the original data. Augmented data resulted in significant improvements to the classification accuracy of the baseline model.

Conclusion: We demonstrate the utility of a deep learning framework applied to mass spectrometry data for surgical margin detection. We apply the proposed framework to an application with light surgical overhead and high incidence, the removal of BCC. The learnt models can accurately separate BCC from normal tissue.
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http://dx.doi.org/10.1007/s11548-020-02152-9DOI Listing
May 2020

Vitamin D supplementation in pregnancy: A word of caution. Familial hypercalcaemia due to disordered vitamin D metabolism.

Ann Clin Biochem 2020 03 19;57(2):186-191. Epub 2020 Jan 19.

Department of Biomedical and Molecular Sciences, Queen's University, Ontario, Canada.

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http://dx.doi.org/10.1177/0004563219897691DOI Listing
March 2020

Allogeneic transplantation in multiple myeloma: long-term follow-up and cytogenetic subgroup analysis.

Leukemia 2019 11 28;33(11):2710-2719. Epub 2019 Aug 28.

Department of Internal Medicine II, Division of Hematology and Medical Oncology, Würzburg University Medical Centre, Würzburg, Germany.

This phase 3 trial compared tandem autologous stem cell transplantation (autoSCT) versus autoSCT followed by reduced-intensity conditioning allogeneic stem cell transplantation (auto/alloSCT) in patients with newly diagnosed multiple myeloma (MM) with deletion of (del) chromosome 13q (del13q). The availability/absence of a human leukocyte antigen-matched-related or matched-unrelated donor (MUD) determined the nature of the second SCT. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population (n = 199). Auto/alloSCT was performed in 126 patients; 74 received MUD allografts. After 91 months median follow-up, median PFS with auto/allo versus tandem autoSCT was 34.5 versus 21.8 months (P = 0.003; adjusted hazard ratio 0.55, 95% confidence interval 0.36-0.84). Median overall survival (OS) was 70.2 versus 71.8 months (P = 0.856). Two-year non-relapse mortality with auto/allo versus tandem autoSCT was 14.3% versus 4.1% (P = 0.008). In patients harboring both del13q and del17p, median PFS and OS were 37.5 and 61.5 months with auto/allo (n = 19) versus 6.1 and 23.4 months with tandem autoSCT (n = 6) (P = 0.0002 and 0.032). Our findings suggest that auto/alloSCT significantly extends PFS versus tandem autoSCT in del13q MM, and indicate some survival benefit for first-line alloSCT in high-risk MM.
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http://dx.doi.org/10.1038/s41375-019-0537-2DOI Listing
November 2019

A chromatin-based mechanism controls differential regulation of the cytochrome P450 gene in renal and non-renal tissues.

J Biol Chem 2019 09 22;294(39):14467-14481. Epub 2019 Aug 22.

Department of Biochemistry, University of Wisconsin, Madison, Wisconsin 53706

Cytochrome P450 family 27 subfamily B member 1 (CYP27B1) and CYP24A1 function to maintain physiological levels of 1,25-dihydroxyvitamin D (1,25(OH)D) in the kidney. Renal and expression levels are transcriptionally regulated in a highly reciprocal manner by parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and 1,25(OH)D In contrast, regulation in nonrenal target cells (NRTCs) is limited to induction by 1,25(OH)D Herein, we used ChIP-Seq analyses of mouse tissues to identify regulatory regions within the gene locus. We found an extended region downstream of containing a cluster of sites, termed C24-DS1, binding PTH-sensitive cAMP-responsive element-binding protein (CREB) and a cluster termed C24-DS2 binding the vitamin D receptor (VDR). VDR-occupied sites were present in both the kidney and NRTCs, but pCREB sites were occupied only in the kidney. We deleted each segment in the mouse and observed that although the overt phenotypes of both cluster deletions were unremarkable, RNA analysis in the C24-DS1-deleted strain revealed a loss of basal renal expression, total resistance to FGF23 and PTH regulation, and secondary suppression of renal ; 1,25(OH)D induction remained unaffected in all tissues. In contrast, loss of the VDR cluster in the C24-DS2-deleted strain did not affect 1,25(OH)D induction of renal expression yet reduced but did not eliminate responses in NRTCs. We conclude that a chromatin-based mechanism differentially regulates in the kidney and NRTCs and is essential for the specific functions of in these two tissue types.
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http://dx.doi.org/10.1074/jbc.RA119.010173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768633PMC
September 2019

Reliable identification of prostate cancer using mass spectrometry metabolomic imaging in needle core biopsies.

Lab Invest 2019 10 3;99(10):1561-1571. Epub 2019 Jun 3.

Cancer Biology & Genetics, Queen's Cancer Research Institute, Queen's University, Kingston, ON, K7L 3N6, Canada.

Metabolomic profiling can aid in understanding crucial biological processes in cancer development and progression and can also yield diagnostic biomarkers. Desorption electrospray ionization coupled to mass spectrometry imaging (DESI-MSI) has been proposed as a potential adjunct to diagnostic surgical pathology, particularly for prostate cancer. However, due to low resolution sampling, small numbers of mass spectra, and little validation, published studies have yet to test whether this method is sufficiently robust to merit clinical translation. We used over 900 spatially resolved DESI-MSI spectra to establish an accurate, high-resolution metabolic profile of prostate cancer. We identified 25 differentially abundant metabolites, with cancer tissue showing increased fatty acids (FAs) and phospholipids, along with utilization of the Krebs cycle, and benign tissue showing increased levels of lyso-phosphatidylethanolamine (PE). Additionally, we identified, for the first time, two lyso-PEs with abundance that decreased with cancer grade and two phosphatidylcholines (PChs) with increased abundance with increasing cancer grade. Importantly, we developed and internally validated a multivariate metabolomic classifier for prostate cancer using 534 spatial regions of interest (ROIs) in the training cohort and 430 ROIs in the test cohort. With excellent statistical power, the training cohort achieved a balanced accuracy of 97% and validation on testing data set demonstrated 85% balanced accuracy. Given the validated accuracy of this classifier and the correlation of differentially abundant metabolites with established patterns of prostate cancer cell metabolism, we conclude that DESI-MSI is an effective tool for characterizing prostate cancer metabolism with the potential for clinical translation.
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http://dx.doi.org/10.1038/s41374-019-0265-2DOI Listing
October 2019

Hereditary Hypercalcemia Caused by a Homozygous Pathogenic Variant in the Gene: A Case Report and Review of the Literature.

Case Rep Endocrinol 2019 8;2019:4982621. Epub 2019 Apr 8.

Department of Clinical and Experimental Medicine, Unit of Endocrinology, University of Pisa, Pisa, Italy.

Introduction: Loss of function mutations of CYP24A1 gene, which is involved in vitamin D catabolism, cause vitamin D-mediated PTH-independent hypercalcemia. The phenotype varies from life-threatening forms in the infancy to milder forms in the adulthood.

Case Presentation: We report a case of a 17-year-old woman with a history of nephrolithiasis, mild PTH-independent hypercalcemia (10,5mg/dL), and high serum 1,25(OH)D concentrations (107pg/mL). Other causes of hypercalcemia associated with the above biochemical signature were excluded. Family history revealed nephrolithiasis in the sister. Blood testing in first-degree relatives showed serum PTH in the low-normal range and 1,25(OH)D at the upper normal limit or slightly elevated. The CYP24A1 gene analysis revealed a known homozygous loss-of-function pathogenic variant (c.428_430delAAG, rs777676129, p.Glu143del). The panel of vitamin D metabolites evaluated by liquid chromatography showed the typical profile of CYP24A1 mutations, namely, low 24,25(OH)D, elevated 25(OH)D:24,25(OH)D ratio, and undetectable 1,24,25(OH)D. The parents and both the siblings harbored the same variant in heterozygosis. We decided for a watchful waiting approach and the patient remained clinically and biochemically stable over a 24-month followup.

Conclusion: gene mutations should be considered in cases of PTH-independent hypercalcemia, once that more common causes (hypercalcemia of malignancy, granulomatous diseases, and vitamin D intoxication) have been ruled out.
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http://dx.doi.org/10.1155/2019/4982621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6476011PMC
April 2019

Targeted genomic deletions identify diverse enhancer functions and generate a kidney-specific, endocrine-deficient pseudo-null mouse.

J Biol Chem 2019 06 3;294(24):9518-9535. Epub 2019 May 3.

From the Department of Biochemistry, University of Wisconsin, Madison, Wisconsin 53706.

Vitamin D is terminally bioactivated in the kidney to 1α,25-dihydroxyvitamin D (1,25(OH)D) via cytochrome P450 family 27 subfamily B member 1 (CYP27B1), whose gene is regulated by parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and 1,25(OH)D Our recent genomic studies in the mouse have revealed a complex kidney-specific enhancer module within the introns of adjacent methyltransferase-like 1 () and that mediate basal and PTH-induced expression of and FGF23- and 1,25(OH)D-mediated repression. Gross deletion of these segments in mice has severe effects on regulation and skeletal phenotype but does not affect expression in nonrenal target cells (NRTCs). Here, we report a bimodal activity in the intronic enhancer with components responsible for PTH-mediated induction and 1,25(OH)D-mediated repression and additional activities, including FGF23 repression, within the enhancers. Deletion of both submodules eliminated basal expression and regulation in the kidney, leading to systemic and skeletal phenotypes similar to those of -null mice. However, basal expression and lipopolysaccharide-induced regulation of in NRTCs was unperturbed. Importantly, dietary normalization of calcium, phosphate, PTH, and FGF23 rescued the skeletal phenotype of this mutant mouse, creating an ideal model to study nonrenal 1,25(OH)D production in health and disease. Finally, we confirmed a conserved chromatin landscape in human kidney that is similar to that in mouse. These findings define a finely balanced homeostatic mechanism involving PTH and FGF23 together with protection from 1,25(OH)D toxicity that is responsible for both adaptive vitamin D metabolism and mineral regulation.
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http://dx.doi.org/10.1074/jbc.RA119.008760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6579472PMC
June 2019

Analysis and correction of distortions in a spatial heterodyne spectrometer system.

Appl Opt 2019 Mar;58(9):2190-2197

In this paper a method for correcting the radial distortion of interferograms generated by a spatial heterodyne spectrometer system is presented. Instead of utilizing calibration patterns, the distortion model parameters are estimated based on the distorted fringe features generated by projecting the straight interference stripes onto the detector. Comparisons between polynomial models and division models indicate that division models can deliver competitive performance on the reconstructed image with fewer parameters. Simulated interferograms based on ray-tracing are used to demonstrate the correction of errors in the spatial, phase, and spectral domain caused by optical distortion.
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http://dx.doi.org/10.1364/AO.58.002190DOI Listing
March 2019

Autonomous Supramolecular Interface Self-Healing Monitored by Restoration of UV/Vis Absorption Spectra of Self-Assembled Thiazole Layers.

Chemistry 2019 Jun 30;25(36):8630-8634. Epub 2019 May 30.

Institute of Physical Chemistry, Friedrich Schiller University Jena, Helmholtzweg 4, 07743, Jena, Germany.

Longevity of complex organic devices critically depends on the supramolecular integrity of the constituting layers and interfaces. Because the latter are soft matter, they can structurally respond to perturbation of their supramolecular structure by relaxing back to a thermodynamically favorable state. To use this response for self-healing of optoelectronically active layers and particularly interfaces, the degraded dyes in these layers need to be exchanged with non-degraded ones. Here, we present a dye layer interfaced between a solid surface and a dye reservoir that autonomously self-heals after photo-degradation of single molecules to restore its optical function. Surface sensitive in situ photothermal deflection spectroscopy reveals that this supramolecular self-healing approach critically depends on the thermodynamic stability of the layer, the chemical change of the dye upon degradation, and the medium dissolving the degraded dye and providing the reservoir dyes. Hence, the interplay of these parameters is key to successfully using this supramolecular self-healing approach to thin layers and interfaces in organic device for increased sustainability of organic optoelectronics and related fields.
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http://dx.doi.org/10.1002/chem.201901549DOI Listing
June 2019

Assembly of T-Shaped Amphiphilic Thiazoles on the Air-Water Interface: Impact of Polar Chromophore Moieties, as Well as Dipolarity and π-Extension of the Chromophore on the Supramolecular Structure.

Langmuir 2019 Feb 11;35(7):2587-2600. Epub 2019 Feb 11.

Institute of Physical Chemistry , Friedrich Schiller University Jena , Helmholtzweg 4 , 07743 Jena , Germany.

The supramolecular structure essentially determines the properties of organic thin films. In this work, we systematically investigate the influence of the chromophore on the supramolecular structure formation at air-water interfaces by means of the Langmuir-Blodgett technique. Therefore, we focus on the recently introduced class of double-anchor T-shaped amphiphilic dyes, namely, 4-hydroxy-thiazole chromophores that are centrally equipped with an amphiphilicity-inducing hexanoic acid. The thiazoles contain hydrophilic subphase-anchor groups in the 2-position (4- N, N-dimethylaminophenyl (Am), 2-pyridyl (Py), and 4-nitrophenyl (Ni)), whereas the chromophores are systematically extended in the 5-position with various substituents. The combination of the Langmuir technique with online fluorescence measurements revealed that the π-π interactions that are pronounced in the case of 4-methoxybiphenyl derivatives yield the most distinct supramolecular structures. Whereas in the case of Py and Ni derivatives ordered J-type supramolecular structures in microdomains are formed, the Am derivative forms ordered supramolecular structures that are more homogeneous, which are, however, not stabilized by J-type dipolar interactions. Because of the synergetic π-π and dipolar stabilizations, the Ni derivative bearing the 4-methoxybiphenyl unit forms exceptionally stable quasi-two-dimensional Langmuir monolayers reaching very high surface pressures beyond 60 mN/m without any sign of disturbance of the Langmuir monolayer.
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http://dx.doi.org/10.1021/acs.langmuir.8b04063DOI Listing
February 2019

Calcioic acid: In vivo detection and quantification of the terminal C24-oxidation product of 25-hydroxyvitamin D and related intermediates in serum of mice treated with 24,25-dihydroxyvitamin D.

J Steroid Biochem Mol Biol 2019 04 13;188:23-28. Epub 2018 Dec 13.

Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada. Electronic address:

Calcitroic acid, the excretory form of vitamin D, is the terminal product of a 5-step pathway catalyzed by CYP24A1, commencing with C24-hydroxylation of 1,25-dihydroxyvitamin D (1,25-(OH)D). Catabolism of 25-hydroxyvitamin D (25-OH-D) proceeds via analogous steps culminating in calcioic acid; however this C23-truncated acid has not been reported in the circulation. It has recently been shown that 24,25-dihydroxyvitamin D (24,25-(OH)D) is an important factor in optimal bone fracture healing acting via an effector molecule FAM57B2 to produce lactosylceramide. Administration of 24,25-(OH)D was found to restore normal fracture repair in Cyp24a1 mice devoid of 24,25-(OH)D. We set out to study the multi-step catabolism of D metabolites in vivo using LC-MS/MS methods in vehicle or 24,25-(OH)D-treated mice. Vehicle-treated Cyp24a1 mice possessed normal levels of serum 24,25-(OH)D (7 ng/mL) and 25-OH-D-26,23-lactone (4 ng/mL). We also detected 24-oxo-25-OH-D (3 ng/mL) and 24-oxo-23,25-(OH)D (0.4 ng/mL); which were not detectable in vehicle-treated Cyp24a1 mice. In 24,25-(OH)D-treated Cyp24a1 mice, serum 24,25-(OH)D rose to 200 ng/mL while 25-OH-D-26,23-lactone remained unchanged in comparison to vehicle-treated Cyp24a1 mice Concentration of serum 24-oxo-25-OH-D and 24-oxo-23,25-(OH)D rose by 10-fold, when Cyp24a1 mice were treated with 24,25-(OH)D Calcioic acid was increased to 0.030 ng/mL for 24,25-(OH)D-treated Cyp24a1 mice. In 24,25-(OH)D-treated Cyp24a1 mice, serum 24,25-(OH)D rose further to a striking 830 ng/mL due to lack of catabolism of the 24,25-(OH)D dose. Serum 1,25-(OH)D levels were suppressed in 24,25-(OH)D-treated Cyp24a1 and Cyp24a1 mice. Circulating 1,24,25-(OH)D rose from 73 pg/mL to 106 pg/mL when Cyp24a1 mice were treated with 24,25-(OH)D. While undetectable in vehicle-treated Cyp24a1 mice, 1,24,25-(OH)D rose unexpectedly to 153 pg/mL in 24,25-(OH)D-treated nulls suggesting conversion of 24,25-(OH)D to 1,24,25-(OH)D via 1-hydroxylation. Taken together, amplification of 24,25-(OH)D catabolism by exogenous doses of this metabolite have enabled detection of downstream C24-oxidation pathway products in vivo, including calcioic acid; and provides a platform for studying alternative routes of vitamin D metabolism that may occur in pathological states including hypervitaminosis D and idiopathic infantile hypercalcemia caused by mutations of CYP24A1.
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http://dx.doi.org/10.1016/j.jsbmb.2018.12.001DOI Listing
April 2019

Mineral Homeostasis in Murine Fetuses Is Sensitive to Maternal Calcitriol but Not to Absence of Fetal Calcitriol.

J Bone Miner Res 2019 04 2;34(4):669-680. Epub 2019 Jan 2.

Faculty of Medicine-Endocrinology, Memorial University of Newfoundland, St. John's, Canada.

Vitamin D receptor (VDR) null fetuses have normal serum minerals, parathyroid hormone (PTH), skeletal morphology, and mineralization but increased serum calcitriol, placental calcium transport, and placental expression of Pthrp, Trpv6, and (as reported in this study) Pdia3. We examined Cyp27b1 null fetal mice, which do not make calcitriol, to determine if loss of calcitriol has the same consequences as loss of VDR. Cyp27b1 null and wild-type (WT) females were mated to Cyp27b1 males, which generated Cyp27b1 null and Cyp27b1 fetuses from Cyp27b1 null mothers, and Cyp27b1 and WT fetuses from WT mothers. Cyp27b1 null fetuses had undetectable calcitriol but normal serum calcium and phosphorus, PTH, fibroblast growth factor 23 (FGF23), skeletal mineral content, tibial lengths and morphology, placental calcium transport, and expression of Trpv6 and Pthrp; conversely, placental Pdia3 was downregulated. However, although Cyp27b1 and null fetuses of Cyp27b1 null mothers were indistinguishable, they had higher serum and amniotic fluid calcium, lower amniotic fluid phosphorus, lower FGF23, and higher 25-hydroxyvitamin D and 24,25-dihydroxyvitamin D than in WT and Cyp27b1 fetuses of WT mothers. In summary, loss of fetal calcitriol did not alter mineral or bone homeostasis, but Cyp27b1 null mothers altered mineral homeostasis in their fetuses independent of fetal genotype. Cyp27b1 null fetuses differ from Vdr null fetuses, possibly through high levels of calcitriol acting on Pdia3 in Vdr nulls to upregulate placental calcium transport and expression of Trpv6 and Pthrp. In conclusion, maternal calcitriol influences fetal mineral metabolism, whereas loss of fetal calcitriol does not. © 2018 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3642DOI Listing
April 2019

Photoannealing of Merocyanine Aggregates.

J Phys Chem A 2018 Dec 14;122(51):9821-9832. Epub 2018 Dec 14.

Institute of Physical Chemistry , Friedrich Schiller University Jena , Helmholtzweg 4 , 07743 Jena , Germany.

In this work we elucidate the fundamental difference between aggregate formation of donor-π-acceptor merocyanines in their electronic ground and excited states. While increasing the π-bridge size favors formation of π-stacked aggregates in the dark, irradiation with visible light causes reorientation of the dyes to form prototype H-aggregates with compensating dipole moments. This photoannealing changes the supramolecular structure and its UV-vis spectroscopic properties dramatically, thus being of importance for the function of active layers composed of these dyes. Aggregates of the ground state dyes are bound cooperatively through ππ-London dispersion interactions and hydrogen bonds between the polar α-cyano-carboxylic acid groups. However, charge transfer upon photoexcitation leads to repulsion of the polar acid groups. Electronic excitation of the dyes approximately doubles the ground state dipole moment, thus driving molecular reorientation into prototype H-aggregate structures. We show that this photoinduced supramolecular rearrangement can disrupt the large polymeric aggregates formed in the dark. The photoinduced supramolecular structural changes reported in this work will influence the performance of optoelectronic devices composed of these structures and must be controlled to avoid morphological decomposition of active layers upon operation.
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http://dx.doi.org/10.1021/acs.jpca.8b09048DOI Listing
December 2018

Effective wind and temperature retrieval from Doppler asymmetric spatial heterodyne spectrometer interferograms.

Appl Opt 2018 Oct;57(30):8829-8835

This paper presents a method for wind velocity and Doppler temperature retrieval from interferograms of a Doppler asymmetric spatial heterodyne spectrometer. This method is based on the analytic representation of the signal and the subsequent algorithms. It turns out to be more robust than the conventional Fourier transform method at low SNR. The influence of optical dispersion on the accuracy of the retrieved parameters is also characterized. The effective optical path difference is suggested for use in wind and temperature retrieval routines. Computer simulations are used to characterize the accuracy of the proposed method, in particular regarding the influence of optical dispersion.
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http://dx.doi.org/10.1364/AO.57.008829DOI Listing
October 2018

2-Deoxyglucosone: A New C-α-Dicarbonyl Compound in the Maillard Reaction of d-Fructose with γ-Aminobutyric Acid.

J Agric Food Chem 2018 Nov 26;66(44):11806-11811. Epub 2018 Oct 26.

Fachgebiet Lebensmittelchemie und Analytik, Institut für Lebensmitteltechnologie und Lebensmittelchemie , Technische Universität Berlin , Gustav-Meyer-Allee 25 , 13355 Berlin , Germany.

In this study, α-dicarbonyl compounds consisting of a backbone with six carbon atoms resulting from the Maillard reaction of d-fructose with γ-aminobutyric acid were determined. The reaction was carried out under mild reaction conditions at 50 °C and water contents between 0 and 90%. A thus far unknown α-dicarbonyl compound was found as the main product in the first 24 h at water contents below 50%. After isolation of its stable quinoxaline derivative, it was possible to identify the compound as 2-deoxy-d- glycero-hexo-3,4-diulose (2-deoxyglucosone). For the first time, the four C-α-dicarbonyl compounds, 1-deoxyglucosone, 2-deoxyglucosone, 3-deoxyglucosone, and 4-deoxyglucosone, could be identified in the Maillard reaction of a hexose at the same time. This indicates the formation of a 2,3-eneaminol from the Schiff base of d-fructose and the formation of 2-amino-2-deoxy-3-ketose as an alternative to the Heyns product.
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http://dx.doi.org/10.1021/acs.jafc.8b03629DOI Listing
November 2018

Update on pharmacologically-relevant vitamin D analogues.

Br J Clin Pharmacol 2019 06 22;85(6):1095-1102. Epub 2018 Nov 22.

Department of Biomedical & Molecular Sciences, Queen's University, Kingston, Ontario, Canada.

Pharmacologists have been interested in vitamin D since its metabolism was elucidated in the early 1970s. Despite the synthesis of thousands of vitamin D analogues in the hope of separating its calcemic and anti-proliferative properties, few molecules have reached the market for use in the treatment of clinical conditions from psoriasis to chronic kidney disease. This review discusses vitamin D drugs, recently developed or still under development, for use in various diseases, but in particular bone disease. In the process we explore the mechanisms postulated to explain the action of these vitamin D analogues including action through the vitamin D receptor, action through other receptors e.g. FAM57B2 and dual action on transcriptional processes.
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http://dx.doi.org/10.1111/bcp.13781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533488PMC
June 2019

Optimal bone fracture repair requires 24R,25-dihydroxyvitamin D3 and its effector molecule FAM57B2.

J Clin Invest 2018 08 16;128(8):3546-3557. Epub 2018 Jul 16.

Research Centre, Shriners Hospitals for Children - Canada, Montreal, Quebec, Canada.

The biological activity of 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3] remains controversial, but it has been suggested that it contributes to fracture healing. Cyp24a1-/- mice, synthesizing no 24R,25(OH)2D3, show suboptimal endochondral ossification during fracture repair, with smaller callus and reduced stiffness. These defects were corrected by 24R,25(OH)2D3 treatment, but not by 1,25-dihydroxyvitamin D3. Microarrays with Cyp24a1-/- callus mRNA identified FAM57B2 as a mediator of the 24R,25(OH)2D3 effect. FAM57B2 produced lactosylceramide (LacCer) upon specific binding of 24R,25(OH)2D3. Fam57b inactivation in chondrocytes (Col2-Cre Fam57bfl/fl) phenocopied the callus formation defect of Cyp24a1-/- mice. LacCer or 24R,25(OH)2D3 injections restored callus volume, stiffness, and mineralized cartilage area in Cyp24a1-null mice, but only LacCer rescued Col2-Cre Fam57bfl/fl mice. Gene expression in callus tissue suggested that the 24R,25(OH)2D3/FAM57B2 cascade affects cartilage maturation. We describe a previously unrecognized pathway influencing endochondral ossification during bone repair through LacCer production upon binding of 24R,25(OH)2D3 to FAM57B2. Our results identify potential new approaches to ameliorate fracture healing.
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http://dx.doi.org/10.1172/JCI98093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063485PMC
August 2018

Determination of Free 25(OH)D Concentrations and Their Relationships to Total 25(OH)D in Multiple Clinical Populations.

J Clin Endocrinol Metab 2018 09;103(9):3278-3288

Department of Medicine, University of California, San Francisco, California.

Context: The optimal measure of vitamin D status is unknown.

Objective: To directly measure circulating free 25-hydroxyvitamin D [25(OH)D] concentrations and relationships to total 25(OH)D in a clinically diverse sample of humans.

Design: Cross-sectional analysis.

Setting: Seven academic sites.

Patients: A total of 1661 adults: healthy (n = 279), prediabetic (n = 479), outpatients (n = 714), cirrhotic (n = 90), pregnant (n = 20), nursing home resident (n = 79).

Interventions: Merge research data on circulating free 25(OH)D (directly-measured immunoassay), total 25(OH)D (liquid chromatography/tandem mass spectrometry), D-binding protein [DBP; by radial (polyclonal) immunodiffusion assay], albumin, creatinine, intact parathyroid hormone, and DBP haplotype.

Main Outcome Measures: Distribution of free 25(OH)D (ANOVA with Bonferroni correction for post hoc comparisons) and relationships between free and total 25(OH)D (mixed-effects modeling incorporating clinical condition, DBP haplotype with sex, race, estimated glomerular filtration rate (eGFR), body mass index (BMI), and other covariates).

Results: Free 25(OH)D was 4.7 ± 1.8 pg/mL (mean ± SD) in healthy persons and 4.3 ± 1.9 pg/mL in outpatients, with levels of 0.5 to 8.1 pg/mL and 0.9 to 8.1 pg/mL encompassing 95% of healthy persons and outpatients, respectively. Free 25(OH)D was higher in patients with cirrhosis (7.1 ± 3.0 pg/mL; P < 0.0033) and nursing home residents (7.9 ± 2.1 pg/mL; P < 0.0033) than in other groups and differed between whites and blacks (P < 0.0033) and between DBP haplotypes (P < 0.0001). Mixed-effects modeling of relationships between free and total 25(OH)D identified clinical conditions (patients with cirrhosis > nursing home residents > patients with prediabetes > outpatients > pregnant women) and BMI (lesser effect) as covariates affecting relationships but not eGFR, sex, race, or DBP haplotype.

Conclusions: Total 25(OH)D, health condition, race, and DBP haplotype affected free 25(OH)D, but only health conditions and BMI affected relationships between total and free 25(OH)D. Clinical importance of free 25(OH)D needs to be established in studies assessing outcomes.
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http://dx.doi.org/10.1210/jc.2018-00295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126881PMC
September 2018

Calcitriol Accelerates Vascular Calcification Irrespective of Vitamin K Status in a Rat Model of Chronic Kidney Disease with Hyperphosphatemia and Secondary Hyperparathyroidism.

J Pharmacol Exp Ther 2018 09 14;366(3):433-445. Epub 2018 Jun 14.

Departments of Biomedical and Molecular Sciences (K.M.M., J.G.Z., M.K., K.L., E.W., H.B., G.J., M.A.A.) and Medicine (G.J., R.M.H.), Queen's University, Kingston, Ontario, Canada

Patients with chronic kidney disease (CKD) have a markedly increased risk for developing cardiovascular disease. Nontraditional risk factors, such as increased phosphate retention, increased serum fibroblast growth factor 23 (FGF-23), and deficiencies in vitamins D and K metabolism, likely play key roles in the development of vascular calcification during CKD progression. Calcitriol [1,25-(OH)-D] is a key transcriptional regulator of matrix Gla protein, a vitamin K-dependent protein that inhibits vascular calcification. We hypothesized that calcitriol treatment would inhibit the development of vascular calcification and this inhibition would be dependent on vitamin K status in a rat model of CKD. Rats were treated with dietary adenine (0.25%) to induce CKD, with either 0, 20, or 80 ng/kg of calcitriol with low or high dietary vitamin K1 (0.2 or 100 mg/kg) for 7 weeks. Calcitriol at both lower (20 ng/kg) and moderate (80 ng/kg) doses increased the severity of vascular calcification, and contrary to our hypothesis this was not significantly improved by high dietary vitamin K1. Calcitriol had a dose-dependent effect on: 1) lowering serum parathyroid hormone, 2) increasing serum calcium, and 3) increasing serum FGF-23. Calcitriol treatment significantly increased aortic expression of the calcification genes and These data also implicate impaired vitamin D catabolism in CKD, which may contribute to the development of calcitriol toxicity and increased vascular calcification. The present findings demonstrate that in an adenine-induced rat model of CKD calcitriol treatment at doses as low as 20 ng/kg can increase the severity of vascular calcification regardless of vitamin K status.
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http://dx.doi.org/10.1124/jpet.117.247270DOI Listing
September 2018

NMR analyses of complex d-glucose anomerization.

Food Chem 2018 Nov 23;265:222-226. Epub 2018 May 23.

Berlin Institute of Technology, Department of Food Chemistry and Food Analysis, Gustav-Meyer-Allee 25, TIB 4/3-1, D-13355 Berlin, Germany. Electronic address:

Analyzing the H NMR spectrum of d-glucose, the resonance frequencies of the anomeric protons of five d-glucose anomers could be determined in dependence on temperature. Besides, the relative concentrations of all cyclic d-glucose anomers could be quantified. Based on that, thermodynamic parameters were calculated. In addition, ring opening rate constants of all cyclic d-glucose anomers were measured for the first time using H selective blind saturation transfer NMR spectroscopy. The results presented here give rise to the assumption that furanoid anomers highly influence the reactivity of total d-glucose. Finally, the complex anomeric equilibration curves for a freshly prepared solution of crystalline α-d-glucopyranose are presented. Based on that, it is hypothesized that the reactivity of a solution of a reducing sugar in general and d-glucose in particular depends on time until the thermodynamic equilibrium state is reached.
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http://dx.doi.org/10.1016/j.foodchem.2018.05.100DOI Listing
November 2018

General acid/base catalysis of sugar anomerization.

Food Chem 2018 Nov 23;265:216-221. Epub 2018 May 23.

Berlin Institute of Technology, Department of Food Chemistry and Food Analysis, Gustav-Meyer-Allee 25, TIB 4/3-1, D-13355 Berlin, Germany. Electronic address:

Based on theoretical and mechanistical considerations, an equation is presented that describes the observed rate of a pH sensitive reaction. In contrast to the commonly used catalytic catenary, the new approach enables the calculation of non-biased thermodynamic activation parameters. Applying this model, the general acid/base catalysis of the ring opening of β-d-fructopyranose was analyzed polarimetrically. Thereby, it could be shown that acids (bases) catalyze the ring opening of anionic (cationic) sugar species. Since anomerization rate constants correlate with the rate of sugar degradation, catalysts of anomerization will increase the sugar's reactivity as well. The most effective catalysts of the ring opening of β-d-fructopyranose in the food relevant pH milieu are weak acids and their conjugated bases. Consequently, the enhanced reactivity of reducing sugars in the presence of amino acids is not solely due to classical Maillard reaction but primarily due to carboxylic acid catalysis of degradation reactions.
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http://dx.doi.org/10.1016/j.foodchem.2018.05.101DOI Listing
November 2018