| 1. |
- Chelban, V., et al.
(författare)
-
PDXK mutations cause polyneuropathy responsive to pyridoxal 5′-phosphate supplementation
- 2019
-
Ingår i: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 86:2, s. 225-240
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: To identify disease-causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy. Methods: We performed genome-wide sequencing, homozygosity mapping, and segregation analysis for novel disease-causing gene discovery. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the impact of variants on adenosine triphosphate (ATP) binding. Pathogenicity was further supported by enzymatic assays and mass spectroscopy on recombinant protein, patient-derived fibroblasts, plasma, and erythrocytes. Response to supplementation was measured with clinical validated rating scales, electrophysiology, and biochemical quantification. Results: We identified biallelic mutations in PDXK in 5 individuals from 2 unrelated families with primary axonal polyneuropathy and optic atrophy. The natural history of this disorder suggests that untreated, affected individuals become wheelchair-bound and blind. We identified conformational rearrangement in the mutant enzyme around the ATP-binding pocket. Low PDXK ATP binding resulted in decreased erythrocyte PDXK activity and low pyridoxal 5′-phosphate (PLP) concentrations. We rescued the clinical and biochemical profile with PLP supplementation in 1 family, improvement in power, pain, and fatigue contributing to patients regaining their ability to walk independently during the first year of PLP normalization. Interpretation: We show that mutations in PDXK cause autosomal recessive axonal peripheral polyneuropathy leading to disease via reduced PDXK enzymatic activity and low PLP. We show that the biochemical profile can be rescued with PLP supplementation associated with clinical improvement. As B6 is a cofactor in diverse essential biological pathways, our findings may have direct implications for neuropathies of unknown etiology characterized by reduced PLP levels. ANN NEUROL 2019;86:225–240. © 2019 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.
|
|
| 2. |
- Block, Keith I., et al.
(författare)
-
Designing a broad-spectrum integrative approach for cancer prevention and treatment
- 2015
-
Ingår i: Seminars in Cancer Biology. - : Academic Press. - 1044-579X .- 1096-3650. ; 35, s. S276-S304
-
Forskningsöversikt (refereegranskat)abstract
- Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity "broadspectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested, many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered. (C) 2015 The Authors. Published by Elsevier Ltd.
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
- Tzolov, M, et al.
(författare)
-
Modification of the structure of ZnO : Al films by control of the plasma parameters
- 2001
-
Ingår i: Thin Solid Films. - 0040-6090 .- 1879-2731. ; 396:1-2, s. 274-279
-
Tidskriftsartikel (refereegranskat)abstract
- ZnO:Al films were deposited by RF magnetron sputtering in triode configuration applying an external DC electric field to the substrates. Reflection high-energy electron diffraction measurements characterized the different films as consisting of randomly-oriented zinc blende crystallites or randomly and texture-oriented wurtzite crystallites, as well as of the amorphous phase. The non-resonant Raman spectra are strongly influenced by the presence of a built-in electric field at the grain boundaries and they do not depend on the symmetry of the microcrystallites. The Raman spectra taken at resonant excitation are more sensitive to the presence of the amorphous phase in the films. (C) 2001 Elsevier Science B.V. All rights reserved.
|
|
| 6. |
- Tzolov, M., et al.
(författare)
-
Vibrational properties and structure of undoped and Al-doped ZnO films deposited by RF magnetron sputtering
- 2000
-
Ingår i: Thin Solid Films. - 0040-6090 .- 1879-2731. ; 379:1-2, s. 28-36
-
Tidskriftsartikel (refereegranskat)abstract
- Highly conductive and transparent in the visible range Al-doped ZnO (ZnO:Al) and undoped ZnO films have been deposited by RF magnetron sputtering. Reflection high-energy electron diffraction observations characterized them as textured. The habitus of the microcrystallites forming the texture depends on the Al doping. The layer texture of undoped ZnO films has texture axis parallel to the substrate. The ZnO:Al films, instead, show a columnar texture with texture axis perpendicular to the substrate. The Raman spectra of the films obtained by non-resonant excitation are completely different from those of the target material which is polycrystalline ZnO. For the interpretation of the different bands in the Raman spectra the existence of a depletion region near the grain boundaries has been assumed. The most intensive band in the Raman spectra at approximately 570 cm-1 has been assigned to electric field-induced Raman scattering on longitudinal optical phonons. The built-in electric field in the depletion region induces the Raman activity of the B2 modes and a band at 276 cm-1 appears in the spectra. Phonon modes highly localized near the grain boundaries have been detected at 516 cm-1 and 468 cm-1 which are well pronounced in the Raman spectra for the doped samples. Localized modes were observed also in the infrared reflection spectra of the doped films. Surface enhanced Raman scattering has been applied and the band in the range 830-920 cm-1 has been interpreted as due to adsorbates from the ambient air. It has been shown that the non-resonant Raman scattering can be used for qualitative study of some details of the microstructure of the zinc oxide films like the built-in electric field and the adsorbates in the films.
|
|
| 7. |
|
|
| 8. |
- Marinova, Ts., et al.
(författare)
-
XPS depth profiling of laser-annealed Zn+-implanted GaAs
- 1997
-
Ingår i: Applied Surface Science. - 0169-4332 .- 1873-5584. ; 109/110, s. 80-86
-
Tidskriftsartikel (refereegranskat)abstract
- Data on the effects of 140 keV Zn+-implantation in (100) GaAs and the consequent low power pulsed laser annealing (LPPLA) on the As/Ga ratio and the chemical states of the elements at the surface and in the subsurface region are presented. The results include the depth distribution of the elements for virgin, as-implanted and implanted+LPPLA [30×(4.5/7.5) MW/cm2] samples. The X-ray photoelectron spectra of as-implanted samples show that a low-intensity Zn 2p peak is observed after 20 min of Ar+ sputtering with an energy of 3 keV, corresponding to about 20 nm of etched material. The depth profiling XPS analysis confirms the ‘recovering' of the stoichiometry of Zn+-implanted specimens after LPPLA with laser pulses of a power density in the energy window of (5–7 MW/cm2). At laser pulse power densities outside of this energy window (4.5 and 7.5 MW/cm2) Zn appears again in the XP spectra after 20 min sputtering as in the case of as-implanted GaAs.
|
|
