Search

Inherited retinal dystrophies (IRDs) are congenital retinal degenerative diseases that have various inheritance patterns, including dominant, recessive, X-linked, and mitochondrial. These diseases are most often the result of defects in rod and/or cone photoreceptor and retinal pigment epithelium function, development, or both. The genes associated with these diseases, when mutated, produce altered protein products that have downstream effects in pathways critical to vision, including phototransduction, the visual cycle, photoreceptor development, cellular respiration, and retinal homeostasis. The aim of this manuscript is to provide a comprehensive review of the underlying molecular mechanisms of pathogenesis of IRDs by delving into many of the genes associated with IRD development, their protein products, and the pathways interrupted by genetic mutation. [ABSTRACT FROM AUTHOR]

Dissolution (mixing or melting) of inhomogeneities formed during spinodal decomposition in binary polymer mixtures is studied both experimentally and theoretically. The details of the dissolution experiment with time-resolved light scattering on polystyrene/poly(vinylmethylether) are presented. The theoretical approach differs from that of Langer, Bar-on, and Miller in the way the fluctuations are treated in the nonlinear theory, and in the details of the calculations arising from the chain connectivity (polymer effect). The effect of mode coupling arising from nonlinearity on the relaxation rate is discussed. It is found both experimentally and theoretically that the wave number corresponding to peak intensity decreases in time asymptotically following a t-0.5 power law. [ABSTRACT FROM AUTHOR]

Equilibrium configurations of rigid building blocks with multiple embedded interaction sites are investigated, as a coarse-grained approach for conformational sampling of protein structures with known secondary structure. First, hypothetical structures of asymmetric shapes, and pairs of rods composed of multiple interaction sites are considered. The rods are either disconnected or joined by a flexible loop. The sites are assumed to interact with a classical 6-12 Lennard-Jones potential. Subsequently, the investigation is extended to the study of two disconnected α helices composed of homogeneous interaction sites and to the ROP monomer, a small protein consisting of two heterogeneous α helices connected by a loop. Residue-specific long-range and short-range potentials extracted from a protein database are used. A Monte Carlo procedure combined with an energy minimization algorithm, originally developed by Li and Scheraga [Proc. Natl. Acad. Sci. USA 84, 6611 (1987)] is used to generate a set of low energy conformations over the full conformational space. Results show that: (i) The potential of mean force between two rods as a whole exhibits an inverse linear dependence on the separation between rods despite the individual sites interacting via a 6-12 Lennard-Jones potential. (ii) As the length of the rods (or helices) increases, they tend to align parallel to one other. (iii) This tendency to become parallel is enhanced when the density of interaction sites is higher. (iv) The angle between the principal axes of the rods is found to scale as n-5/3 with the number n of sites. (v) The native conformation of the ROP monomer, including the detailed rotational states of the virtual bonds located in the loop connecting the α helices is correctly predicted. This lends support to the adoption of such a coarse-grained model and its parameters for future simulations. © 1997 American Institute of Physics. [ABSTRACT FROM AUTHOR]

Background: Descemet's membrane endothelial keratoplasty (DMEK) involves removal of the recipient's Descemet membrane (DM) prior to transplanting the donor's DM. When using balanced salt solution (BSS) or ophthalmic viscosurgical devices (OVDs), visualization of the host's DM during its stripping may be inadequate and may result in Descemet remnants and could lead to sub-optimal surgical results. Previous articles described excellent visualization when utilizing air injection but this requires repeated air injection into the anterior chamber (AC). We present a pilot study that compares different techniques under which DM stripping can be performed: with continuous automated air infusion, with manual air infusion, and with BSS. Methods: We retrospectively compared video footage of DM stripping with BSS, with continuous air and with manual injection of air into the AC to determine DM stripping duration and the number of times the surgeon had to insert and retrieve a surgical instrument from the AC. Results: Thirty videos of 10 consecutive cases of the three DM stripping techniques were evaluated. DM stripping duration was 3.26 (±1.32), 3.92 (±1.2) and 12.9 (±3.98) minutes for BSS, continuous air flow, and manual air injection, respectively. Frequency of instrument retrieval (FIR) was 3.6 (±1.71), 1.5 (±0.71) and 15.1 (±3.28) for BSS, continuous air flow, and manual air injection, respectively. Continuous air flow and BSS were both statistically different than manual air injection into the AC ( p < 0.05), but did not differ from one another statistically. Conclusion: DM stripping during posterior lamellar surgery is imperative for favorable post-operative results and prevention of complications. Performing this step under air in the AC contributes to better visualization and an efficient surgery. [ABSTRACT FROM AUTHOR]

The article discusses notions of Jewish identity among a number of German scholars (tagged as Jewish by the Nazi government) who settled in Turkey because of Nazi persecution in Germany. The author describes the relationship of these scholars to Turkey's Jewish community while analyzing their identification as Germans. Possible motivations for Turkey's inviting of the scholars are provided, with the author questioning whether or not these motivations were humanitarian in nature or politically driven. The role of the Turkish national interest (raison d'etat) in the invitation is analyzed.

Aim: To compare the outcomes of IntraLase-enabled top hat penetrating keratoplasty (IEK( versus retrospective results of manual top hat penetrating keratoplasty (THPKP) and conventional PKP. Patients/methods: This non-randomised prospective study included 94 eyes: 23 eyes underwent IEK, 36 THPKP and 35 conventional PKP. Preoperative and postoperative manifest refraction, uncorrected and best-spectacle corrected visual acuity (BSCVA(, high-order ocular aberrations (HOA), endothelial cell counts and complications were analysed. Results: At 12 months of follow-up, the mean log MAR BSCVA was 0.32 (SD 0.31( in the IEK group, 0.53 (0.36) in the TH PKP group (p = 0.03( and 0.39 (0.30) in the conventional PKP group (p = 0.4). The mean spherical equivalent was similar between the groups and was less than -2.2 dioptres. The mean cylinder was similar in the IEK and conventional PKP group (3.6 (1.9) dioptres and 4.1 (1.8( dioptres, respectively), and was significantly lower than the TH-PKP group (5.1 (3.2( dioptres, p = 0.04). The complications rate and high-order ocular aberrations were similar between the three groups studied. The mean endothelial cell loss was significantly lower at 12 months of follow-up in the IEK and the THPKP groups versus conventional PKP (32.4% and 22.3% vs 40.8%, respectively) (p = 0.05(. The mean time to suture removal was 4.1 (1.2( months in the IEK group and 3.9 (1.5( months in the TH-PKP group versus 9.7 (1.1( months in the conventional PKP group (p<0.0001(. Conclusions: IEK is a safe and stable procedure. It results in higher endothelial counts and faster suture removal in comparison with the conventional PKP, and has less astigmatism and better BSCVA in comparison with the manual TH-PKP. [ABSTRACT FROM AUTHOR]

Aims: To examine the wound configuration after penetrating keratoplasty (PKP) using anterior segment optical coherence tomography (OCT). Methods: All PKP patients who were examined for routine follow-up, between November and December 2006, after having all their sutures removed were included. Patients underwent clinical examination, refraction, corneal topography, aberrometry and Visante anterior segment OCT. Results: 204 graft-host sections from 27 eyes 125 patients, mean age 51.6 (SD 17.7) years) were analysed. Although all the graft-host junctions had continuous smooth epithelial surfaces, 124 of them (60.8%) had internal graft-host malappositions such as gapes (15.7%), steps 130%) or protrusions (15.2%). Keratoconus patients had significantly more graft steps (p<0.05) while those transplanted for endothelial dysfunctions had more protrusions (p<0.01). Graft oversizing significantly increased the size of malappositions. Internal gapes or steps significantly reduced the graft-host touch. Intraocular pressure (IOP), final refraction and final keratometric cylinder were all significantly correlated with the presence and size of the malapposition, while steeper keratometry and tilt aberrations correlated with diminished graft-host touch. Conclusions: After PKP, internal graft-host malapposition is relatively common and associated with increased ametropia, astigmatism, lop and optical tilt aberrations. [ABSTRACT FROM AUTHOR]

Aims: To describe a new, simpler method of achieving the advantages of a lamellar wound configuration in penetrating keratoplasty (PKP)—the half-top-hat (HTH) configuration. Methods: The donor corneal button was prepared in a top-hat configuration, as previously described. It consisted of a central, full-thickness part, 7-8 mm in diameter, surrounded by a peripheral lamellar wing of deep stroma and endothelium that was 0.5 mm in width (wing diameter 8-9 mm). The recipient bed was prepared by a straight full thickness trephination with a suction trephine. The donor button was positioned by sliding the peripheral wing under the recipient bed. Sixteen 10-0 interrupted sutures and a single continuous 16-bite 11-0 nylon sutures were placed. The interrupted sutures were passed so as to go through the wing, in order to ensure a good apposition of the wing to the inner corneal surface of the recipient. Anterior segment optical coherence tomography (Visante OCT) was used to image the position and alignment of the corneal graft postoperatively. Results: Ten eyes of 10 patients (mean (SD) age: 73.7 (11.4) years, 7 females) underwent HTH PKP. The donor lenticule diameter was 7.7 (0.3) mm (wing diameter 8.7 (0.3) mm). The mean follow-up time was 2.4 (0.7) months. The last median visual acuity was 20/200 (range 20/80-counting fingers), and the last lOP was 18.2 (8.8) mm Hg. No major intraoperative complications were noted. No postoperative events of graft rejection were documented. No anterior surface misalignment was noted either clinically or by OCT. One patient had a rise in lOP postoperatively. Conclusions: Half-top-hat wound configuration is a valid alternative in penetrating keratoplasty. Its advantages include better apposition of donor and recipient corneas, improved tectonic strength to prevent graft dehiscence, the possibility of early sutures removal and being a simpler procedure to perform. [ABSTRACT FROM AUTHOR]

Investigates the dynamics of the bacterial chaperonin GroEL and its cofactor GroES. Revelation of a variety of motions dependent upon the central cavity of the structure; Cooperative cross-correlations between subunits; Provision of a variable binding surfaces and variable cavities.

Develops an analytical model based on local residue packing densities for describing the conformational fluctations of proteins in their folded state. Application of the Gaussian network model to interprete the behavior of proteins; Calculations performed for five proteins; Methodology used in the study; Results of the study.

Studies the dynamics of proteins using a low-resolution model combined with knowledge-based potentials. Generation of configurations with the use of a Monte Carlo/Metropolis scheme partnered with a singular value decomposition (SVD) technique; Characterization of the cooperative motions by the approach; Global-scale dynamics of T4 lysozyme (T4L).

A letter to the editor is presented about a study on the use of human fibrin adhesive for scleral as well as conjuctival wound closure in penetrating trabeculectomy.

Serum levels of interleukin(IL)-8, IL-6, and (TNF)-α were measured in 25 patients during active uveitis and uveitis in remission and compared to age-matched controls. Levels of IL-8 and IL-6 were significantly elevated in patients with active disease and were decreased during remission. IL-8 levels were highest in patients with anterior uveitis, with greatest difference between active disease and remission. No consistent pattern was observed for TNF-α. In conclusion, serum cytokine levels are elevated in active noninfectious uveitis. The rise in IL-8 may suggest innate immune mechanisms in the acute disease, while IL-6 participates in modulation of inflammation in the chronic disease. [ABSTRACT FROM AUTHOR]

Information on protein dynamics has been usually inferred from spectroscopic studies of parts of the proteins, or indirectly from the comparison of the conformations assumed in the presence of different substrates or ligands. While molecular simulations also provide information on protein dynamics, they usually suffer from incomplete sampling of conformational space, and become prohibitively expensive when exploring the collective dynamics of large macromolecular structures. Here, we explore the dynamics of a well-studied allosteric protein, hemoglobin (Hb), to show that a simple mechanical model based on Gaussian fluctuations of residues can efficiently predict the transition between the tense (T, unliganded) and relaxed (R or R2, O2 or CO-bound) forms of Hb. The passage from T into R2 is shown to be favored by the global mode of motion, which, in turn is driven by entropic effects. The major difference between the dynamics of the T and R2 forms is the loss of the hinge-bending role of α1–β2 (or α2–β1) interfacial residues at αPhe36-His45 and βThr87-Asn102 in the R2 form, which implies a decreased cooperativity in the higher affinity (R2) form of Hb, consistent with many experimental studies. The involvement of the proximal histidine βHis92 in this hinge region suggests that the allosteric propagation of the local structural changes (induced upon O2 binding) into global ones occur via hinge regions. This is the first demonstration that there is an intrinsic tendency of Hb to undergo T→R2 transition, induced by purely elastic forces of entropic origin that are uniquely defined for the particular contact topology of the T form. [Copyright &y& Elsevier]

The effect of subinhibitory concentrations (1/2–1/32×MIC) of ciprofloxacin, ofloxacin and levofloxacin on the adherence of three strains of Escherichia coli (a mannose-resistant haemagglutinating clinical isolate, a non-haemagglutinating clinical isolate and the mannose-resistant haemagglutinating ATCC 25922 strain) were studied. Ciprofloxacin had the lowest MIC values but only the 1/2 MIC concentration inhibited adherence of mannose-resistant haemagglutinating strains after exposure to subMIC values. Significant inhibition of adherence was observed with 1/4×MIC ofloxacin for both haemagglutinating isolate (27096) and the ATCC strain. Levofloxacin might be more effective and safer than ciprofloxacin and ofloxacin as a long acting fluoroquinolone at subMIC values in patients with UTI. [Copyright &y& Elsevier]

One of the major complications in diabetes is impaired wound healing. Unfortunately, effective therapies are currently lacking. Epithelial to mesenchymal transition (EMT) is a critical process involved in cutaneous wound healing. In response to injury, EMT is required to activate and mobilize stationary keratinocytes in the skin toward the wound bed, which allows for re-epithelialization. This process is stalled in diabetic wounds. In this study, we investigate the role of long non-coding RNA (lncRNA), MALAT1, in transforming growth factor beta 1(TGF-β1)-induced EMT of human keratinocyte (HaCaT) cells. Initially, we detected MALAT1 and TGF-β1 expression in non-diabetic and diabetic wounds and found that these expression are significantly up-regulated in diabetic wounds. Then, HaCaT cells were cultured and exposed to TGF-β1. The EMT of HaCaT cells were confirmed by the increased expression of CDH2, KRT10, and ACTA2, in addition to the down-regulation of CDH1. Knockdown of MALAT1 was achieved by transfecting a small interfering RNA (SiRNA). MALAT1 silencing attenuates TGFβ1-induced EMT. Mechanistically, MALAT1 is involved in TGF-β1 mediated EMT through significantly induced ZEB1 expression, a critical transcription factor for EMT. In summary, lncRNA MALAT1 is involved in TGFβ1-induced EMT of human HaCaT cells and provides new understanding for the pathogenesis of diabetic wounds. [ABSTRACT FROM AUTHOR]

The Anton supercomputing technology recently developed for efficient molecular dynamics simulations permits us to examine micro- to milli-second events at full atomic resolution for proteins in explicit water and lipid bilayer. It also permits us to investigate to what extent the collective motions predicted by network models (that have found broad use in molecular biophysics) agree with those exhibited by full-atomic long simulations. The present study focuses on Anton trajectories generated for two systems: the bovine pancreatic trypsin inhibitor, and an archaeal aspartate transporter, GltPh. The former, a thoroughly studied system, helps benchmark the method of comparative analysis, and the latter provides new insights into the mechanism of function of glutamate transporters. The principal modes of motion derived from both simulations closely overlap with those predicted for each system by the anisotropic network model (ANM). Notably, the ANM modes define the collective mechanisms, or the pathways on conformational energy landscape, that underlie the passage between the crystal structure and substates visited in simulations. In particular, the lowest frequency ANM modes facilitate the conversion between the most probable substates, lending support to the view that easy access to functional substates is a robust determinant of evolutionarily selected native contact topology. [ABSTRACT FROM AUTHOR]

Background/aim: Alterations of the immune system may have a role in thrombogenesis. Ailety sites occluded with thrombi apparently release pro-inflammatory cytokines. Non-arteritic anterior ischaemic optic neuropathy (NAION) results from occlusion of the blood supply to the optic nerve. The aim of this study was to analyse levels of pro- inflammatory cytokines in patients with acute event of NMON. Methods: Study participants included 10 patients (12 eyes) with NAJON and 20 age matched controls with the same risk factors for atherosderosis disease. Peripheral blood samples were obtained immediately at the acute onset of NA1ON. Plasma interleukin 8 (11-8), 11-6, and tumour necrosis factor alpha (TNF-α) levels were measured immediately following diagnosis and during the follow up intervals. Results: The plasma Levels of 11-8 were significantly higher in NAION patients at the time of diagnosis in comparison to the control group (p = 0.002), and decreased during the follow up period (6-12 months) (p=0.05). There were no differences in plasma levels of 11-6 and TNF-α between NAION patients and controls, either in the acute phase or during the follow up period. Conclusion: Plasma levels of 11-8 are elevated during the acute phase of NAION, but not 11-6 and TNF-α. These elevated levels are in accordance with other acute vascular thrombosis. The clinical significance of these findings should be further evaluated. [ABSTRACT FROM AUTHOR]

Abstract Duality of iron as an essential cofactor of many enzymatic metabolic processes and as a catalyst of poorly controlled redox-cycling reactions defines its possible biological beneficial and hazardous role in the body. In this review, we discuss these two "faces" of iron in a newly conceptualized program of regulated cell death, ferroptosis. Ferroptosis is a genetically programmed iron-dependent form of regulated cell death driven by enhanced lipid peroxidation and insufficient capacity of thiol-dependent mechanisms (glutathione peroxidase 4, GPX4) to eliminate hydroperoxy-lipids. We present arguments favoring the enzymatic mechanisms of ferroptotically engaged non-heme iron of 15-lipoxygenases (15-LOX) in complexes with phosphatidylethanolamine binding protein 1 (PEBP1) as a catalyst of highly selective and specific oxidation reactions of arachidonoyl- (AA) and adrenoyl-phosphatidylethanolamines (PE). We discuss possible role of iron chaperons as control mechanisms for guided iron delivery directly to their "protein clients" thus limiting non-enzymatic redox-cycling reactions. We also consider opportunities of loosely-bound iron to contribute to the production of pro-ferroptotic lipid oxidation products. Finally, we propose a two-stage iron-dependent mechanism for iron in ferroptosis by combining its catalytic role in the 15-LOX-driven production of 15-hydroperoxy-AA-PE (HOO-AA-PE) as well as possible involvement of loosely-bound iron in oxidative cleavage of HOO-AA-PE to oxidatively truncated electrophiles capable of attacking nucleophilic targets in yet to be identified proteins leading to cell demise. Graphical abstract fx1 Highlights • Phospholipid peroxidation in ferroptosis. • Lipoxygenase oxidation of arachidonoyl phosphatidylethanolamine. • Guided transportation of iron to target destinations in cells. • GPX4 reduction of hydroperoxy-arachidonoyl-phosphatidylethanolamine. • ACSL4 biosynthesis of arachidonoyl phosphatidylethanolamine is required for. [ABSTRACT FROM AUTHOR]

Single‐particle analysis by electron microscopy is a well established technique for analyzing the three‐dimensional structures of biological macromolecules. Besides its ability to produce high‐resolution structures, it also provides insights into the dynamic behavior of the structures by elucidating their conformational variability. Here, the different image‐processing methods currently available to study continuous conformational changes are reviewed. In this paper, the existing image‐processing approaches in electron microscopy for the analysis of continuous conformational changes of biological macromolecules are reviewed. [ABSTRACT FROM AUTHOR]

Background: There is no specific quality of life (QoL) measurement tool to quantify QoL in patients with biliary tract cancer. Quality of life measurement is an increasingly crucial trial end point and is now being incorporated into clinical practice.Methods: This International Multicentre Phase IV Validation Study assessed the QLQ-BIL21 module in 172 patients with cholangiocarcinoma and 91 patients with cancer of the gallbladder. Patients completed the questionnaire at baseline pretherapy and subsequently at 2 months. Following this, the psychometric properties of reliability, validity, scale structure and responsiveness to change were analysed.Results: Analysis of the QLQ-BIL21 scales showed appropriate reliability with Cronbach's α-coefficients >0.70 for all scales overall. Intraclass correlations exceeded 0.80 for all scales. Convergent validity >0.40 was demonstrated for all items within scales, and discriminant validity was confirmed with values <0.70 for all scales compared with each other. Scale scores changed in accordance with Karnofsky performance status and in response to clinical change.Conclusions: The QLQ-BIL21 is a valid tool for the assessment of QoL in patients with cholangiocarcinoma and cancer of the gallbladder. [ABSTRACT FROM AUTHOR]

Src-family kinases are modular signaling proteins involved in a diverse array of cellular processes. All members of the Src family share the same domain organization, with modular SH3, SH2 and kinase domains followed by a C-terminal negative regulatory tail. X-ray crystallographic analyses of several Src family members have revealed critical roles for the SH3 and SH2 domains in the down-regulation of the kinase domain. This review focuses on biological, biophysical, and computational studies that reveal conformationally distinct active states within this unique kinase family. [ABSTRACT FROM AUTHOR]