Diabetes and Parkinson\u27s Disease: Understanding Shared Molecular Mechanisms

\ua9 2024-The authors.Aging is a major risk factor for Parkinson\u27s disease (PD). Genetic mutations account for a small percentage of cases and the majority appears to be sporadic, with yet unclear causes. However, various environmental factors have been linked to an increased risk of developing PD and, therefore, understanding the complex interplay between genetic and environmental factors is crucial for developing effective disease-modifying therapies. Several studies identified a connection between type 2 diabetes (T2DM) and PD. T2DM is characterized by insulin resistance and failure of β-cells to compensate, leading to hyperglycemia and serious comorbidities. Both PD and T2DM share misregulated processes, including mitochondrial dysfunction, oxidative stress, chronic inflammation, altered proteostasis, protein aggregation, and misregulation of glucose metabolism. Chronic or recurring hyperglycemia is a T2DM hallmark and can lead to increased methylglyoxal (MGO) production, which is responsible for protein glycation. Glycation of alpha-synuclein (aSyn), a central player in PD pathogenesis, accelerates the deleterious aSyn effects. Interestingly, MGO blood plasma levels and aSyn glycation are significantly elevated in T2DM patients, suggesting a molecular mechanism underlying the T2DM-PD link. Compared to high constant glucose levels, glycemic variability (fluctuations in blood glucose levels), can be more detrimental for diabetic patients, causing oxidative stress, inflammation, and endothelial damage. Accordingly, it is imperative for future research to prioritize the exploration of glucose variability\u27s influence on PD development and progression. This involves moving beyond the binary classification of patients as diabetic or non-diabetic, aiming to pave the way for the development of enhanced therapeutic interventions

Quantum Spin Hall Insulator State in HgTe Quantum Wells

Recent theory predicted that the Quantum Spin Hall Effect, a fundamentally novel quantum state of matter that exists at zero external magnetic field, may be realized in HgTe/(Hg,Cd)Te quantum wells. We have fabricated such sample structures with low density and high mobility in which we can tune, through an external gate voltage, the carrier conduction from n-type to the p-type, passing through an insulating regime. For thin quantum wells with well width d < 6.3 nm, the insulating regime shows the conventional behavior of vanishingly small conductance at low temperature. However, for thicker quantum wells (d > 6.3 nm), the nominally insulating regime shows a plateau of residual conductance close to 2e^2/h. The residual conductance is independent of the sample width, indicating that it is caused by edge states. Furthermore, the residual conductance is destroyed by a small external magnetic field. The quantum phase transition at the critical thickness, d = 6.3 nm, is also independently determined from the magnetic field induced insulator to metal transition. These observations provide experimental evidence of the quantum spin Hall effect.Comment: 16 pages, 5 figure

The role of Cahn and Sivers effects in Deep Inelastic Scattering

The role of intrinsic \bfk_\perp in inclusive and semi-inclusive Deep Inelastic Scattering processes ($\ell p \to \ell h X$) is studied with exact kinematics within QCD parton model at leading order; the dependence of the unpolarized cross section on the azimuthal angle between the leptonic and the hadron production planes (Cahn effect) is compared with data and used to estimate the average values of $k_\perp$ both in quark distribution and fragmentation functions. The resulting picture is applied to the description of the weighted single spin asymmetry $A_{UT}^{\sin(\phi_\pi - \phi_S)}$ recently measured by the HERMES collaboration at DESY; this allows to extract some simple models for the quark Sivers functions. These are compared with the Sivers functions which succeed in describing the data on transverse single spin asymmetries in \pup p \to \pi X processes; the two sets of functions are not inconsistent. The extracted Sivers functions give predictions for the COMPASS measurement of $A_{UT}^{\sin(\phi_\pi - \phi_S)}$ in agreement with recent preliminary data, while their contribution to HERMES $A_{UL}^{\sin\phi_\pi}$ is computed and found to be small. Predictions for $A_{UT}^{\sin(\phi_K - \phi_S)}$ for kaon production at HERMES are also given.Comment: 21 pages, 12 figures, revtex, version published in PRD, one figure, comments and references adde

Response to combination therapy with interferon alfa-2a and ribavirin in chronic hepatitis C according to a TNF-alpha promoter polymorphism

Background. Tumor necrosis factor-alpha (TNF-alpha) is involved in the pathogenesis of chronic active hepatitis C. Polymorphisms in the promoter region of the TNF-alpha gene can alter the TNF-alpha expression and modify the host immune response. The present study aimed at the correlation of the G308A TNF-alpha polymorphism with the response to antiviral combination therapy in chronic hepatitis C. Patients and Methods: 62 patients with HCV and 119 healthy unrelated controls were genotyped for the G308A TNF-alpha promoter polymorphism. The patients received 3 x 3 million units of interferon alfa-2a and 1,0001,200 mg ribavirin daily according to their body weight. A response was defined as absence of HCV-RNA and normalization of S-ALT after 6 months of combination therapy. Results:With respect to the allele and genotype frequency, a significant difference was not observed between controls and patients with chronic hepatitis C. Furthermore, such a difference was also not observed if responders and non-responders to antiviral therapy were compared. Conclusions: The promoter polymorphism of the TNF-alpha gene investigated herein is equally distributed in healthy individuals and patients with hepatitis C and does not seem to predict the response to therapy with interferon alfa-2a and ribavirin. Copyright (C) 2003 S. Karger AG, Basel

High-speed tunable photonic crystal fiber-based femtosecond soliton source without dispersion pre-compensation

We present a high-speed wavelength tunable photonic crystal fiber-based source capable of generating tunable femtosecond solitons in the infrared region. Through measurements and numerical simulation, we show that both the pulsewidth and the spectral width of the output pulses remain nearly constant over the entire tuning range from 860 to 1160 nm. This remarkable behavior is observed even when pump pulses are heavily chirped (7400 fs^2), which allows to avoid bulky compensation optics, or the use of another fiber, for dispersion compensation usually required by the tuning device.Comment: 8 pages, 11 figure

A large-deviations principle for all the cluster sizes of a sparse Erdős–Rényi graph

Let (Formula presented.) be the Erdős–Rényi graph with connection probability (Formula presented.) as N → ∞ for a fixed t ∈ (0, ∞). We derive a large-deviations principle for the empirical measure of the sizes of all the connected components of (Formula presented.), registered according to microscopic sizes (i.e., of finite order), macroscopic ones (i.e., of order N), and mesoscopic ones (everything in between). The rate function explicitly describes the microscopic and macroscopic components and the fraction of vertices in components of mesoscopic sizes. Moreover, it clearly captures the well known phase transition at t = 1 as part of a comprehensive picture. The proofs rely on elementary combinatorics and on known estimates and asymptotics for the probability that subgraphs are connected. We also draw conclusions for the strongly related model of the multiplicative coalescent, the Marcus–Lushnikov coagulation model with monodisperse initial condition, and its gelation phase transition

Quantitative Imaging of Protein-Protein Interactions by Multiphoton Fluorescence Lifetime Imaging Microscopy using a Streak camera

Fluorescence Lifetime Imaging Microscopy (FLIM) using multiphoton excitation techniques is now finding an important place in quantitative imaging of protein-protein interactions and intracellular physiology. We review here the recent developments in multiphoton FLIM methods and also present a description of a novel multiphoton FLIM system using a streak camera that was developed in our laboratory. We provide an example of a typical application of the system in which we measure the fluorescence resonance energy transfer between a donor/acceptor pair of fluorescent proteins within a cellular specimen.Comment: Overview of FLIM techniques, StreakFLIM instrument, FRET application

MicroRNA-519a is a novel oncomir conferring tamoxifen resistance by targeting a network of tumour-suppressor genes in ER+ breast cancer

Cataloged from PDF version of article.Tamoxifen is an endocrine therapy which is administered to up to 70% of all breast cancer patients with oestrogen receptor alpha (ERα) expression. Despite the initial response, most patients eventually acquire resistance to the drug. MicroRNAs (miRNAs) are a class of small non-coding RNAs which have the ability to post-transcriptionally regulate genes. Although the role of a few miRNAs has been described in tamoxifen resistance at the single gene/target level, little is known about how concerted actions of miRNAs targeting biological networks contribute to resistance. Here we identified the miRNA cluster, C19MC, which harbours around 50 mature miRNAs, to be up-regulated in resistant cells, with miRNA-519a being the most highly up-regulated. We could demonstrate that miRNA-519a regulates tamoxifen resistance using gain- and loss-of-function testing. By combining functional enrichment analysis and prediction algorithms, we identified three central tumour-suppressor genes (TSGs) in PI3K signalling and the cell cycle network as direct target genes of miR-519a. Combined expression of these target genes correlated with disease-specific survival in a cohort of tamoxifen-treated patients. We identified miRNA-519a as a novel oncomir in ER+ breast cancer cells as it increased cell viability and cell cycle progression as well as resistance to tamoxifen-induced apoptosis. Finally, we could show that elevated miRNA-519a levels were inversely correlated with the target genes' expression and that higher expression of this miRNA correlated with poorer survival in ER+ breast cancer patients. Hence we have identified miRNA-519a as a novel oncomir, co-regulating a network of TSGs in breast cancer and conferring resistance to tamoxifen. Using inhibitors of such miRNAs may serve as a novel therapeutic approach to combat resistance to therapy as well as proliferation and evasion of apoptosis in breast cancer. © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland