Metal chelation therapy and Parkinson\u2019s disease: A critical review on the thermodynamics of complex formation between relevant metal ions and promising or established drugs

The present review reports a list of approximately 800 compounds which have been used, tested or proposed for Parkinson\u2019s disease (PD) therapy in the year range 2014\u20132019 (April): name(s), chemical structure and references are given. Among these compounds, approximately 250 have possible or established metal-chelating properties towards Cu(II), Cu(I), Fe(III), Fe(II), Mn(II), and Zn(II), which are considered to be involved in metal dyshomeostasis during PD. Speciation information regarding the complexes formed by these ions and the 250 compounds has been collected or, if not experimentally available, has been estimated from similar molecules. Stoichiometries and stability constants of the complexes have been reported; values of the cologarithm of the concentration of free metal ion at equilibrium (pM), and of the dissociation constant Kd (both computed at pH = 7.4 and at total metal and ligand concentrations of 106 and 105 mol/L, respectively), charge and stoichiometry of the most abundant metal\u2013ligand complexes existing at physiological conditions, have been obtained. A rigorous definition of the reported amounts is given, the possible usefulness of this data is described, and the need to characterize the metal\u2013ligand speciation of PD drugs is underlined

Light effective hole mass in undoped Ge/SiGe quantum wells

We report density-dependent effective hole mass measurements in undoped germanium quantum wells. We are able to span a large range of densities ($2.0-11\times10^{11}$ cm$^{-2}$) in top-gated field effect transistors by positioning the strained buried Ge channel at different depths of 12 and 44 nm from the surface. From the thermal damping of the amplitude of Shubnikov-de Haas oscillations, we measure a light mass of $0.061m_e$ at a density of $2.2\times10^{11}$ cm$^{-2}$. We confirm the theoretically predicted dependence of increasing mass with density and by extrapolation we find an effective mass of $\sim0.05m_e$ at zero density, the lightest effective mass for a planar platform that demonstrated spin qubits in quantum dots

Low disordered, stable, and shallow germanium quantum wells: a playground for spin and hybrid quantum technology

Buried-channel semiconductor heterostructures are an archetype material platform to fabricate gated semiconductor quantum devices. Sharp confinement potential is obtained by positioning the channel near the surface, however nearby surface states degrade the electrical properties of the starting material. In this paper we demonstrate a two-dimensional hole gas of high mobility ($5\times 10^{5}$ cm$^2$/Vs) in a very shallow strained germanium channel, which is located only 22 nm below the surface. This high mobility leads to mean free paths $\approx6 \mu m$, setting new benchmarks for holes in shallow FET devices. Carriers are confined in an undoped Ge/SiGe heterostructure with reduced background contamination, sharp interfaces, and high uniformity. The top-gate of a dopant-less field effect transistor controls the carrier density in the channel. The high mobility, along with a percolation density of $1.2\times 10^{11}\text{ cm}^{-2}$, light effective mass (0.09 m$_e$), and high g-factor (up to $7$) highlight the potential of undoped Ge/SiGe as a low-disorder material platform for hybrid quantum technologies

Warburg effect and translocation-induced genomic instability: two yeast models for cancer cells

Yeast has been established as an efficient model system to study biological principles underpinning human health. In this review we focus on yeast models covering two aspects of cancer formation and progression (i) the activity of pyruvate kinase (PK), which recapitulates metabolic features of cancer cells, including the Warburg effect, and (ii) chromosome bridge-induced translocation (BIT) mimiking genome instability in cancer. Saccharomyces cerevisiae is an excellent model to study cancer cell metabolism, as exponentially growing yeast cells exhibit many metabolic similarities with rapidly proliferating cancer cells. The metabolic reconfiguration includes an increase in glucose uptake and fermentation, at the expense of respiration and oxidative phosphorylation (the Warburg effect), and involves a broad reconfiguration of nucleotide and amino acid metabolism. Both in yeast and humans, the regulation of this process seems to have a central player, PK, which is up-regulated in cancer, and to occur mostly on a post-transcriptional and post-translational basis. Furthermore, BIT allows to generate selectable translocation-derived recombinants ("translocants"), between any two desired chromosomal locations, in wild-type yeast strains transformed with a linear DNA cassette carrying a selectable marker flanked by two DNA sequences homologous to different chromosomes. Using the BIT system, targeted non-reciprocal translocations in mitosis are easily inducible. An extensive collection of different yeast translocants exhibiting genome instability and aberrant phenotypes similar to cancer cells has been produced and subjected to analysis. In this review, we hence provide an overview upon two yeast cancer models, and extrapolate general principles for mimicking human disease mechanisms in yeast

Morphological and physiological species-dependent characteristics of the rodent Grueneberg ganglion.

In the mouse, the Grueneberg ganglion (GG) is an olfactory subsystem implicated both in chemo- and thermo-sensing. It is specifically involved in the recognition of volatile danger cues such as alarm pheromones and structurally-related predator scents. No evidence for these GG sensory functions has been reported yet in other rodent species. In this study, we used a combination of histological and physiological techniques to verify the presence of a GG and investigate its function in the rat, hamster, and gerbil comparing with the mouse. By scanning electron microscopy (SEM) and transmitted electron microscopy (TEM), we found isolated or groups of large GG cells of different shapes that in spite of their gross anatomical similarities, display important structural differences between species. We performed a comparative and morphological study focusing on the conserved olfactory features of these cells. We found fine ciliary processes, mostly wrapped in ensheating glial cells, in variable number of clusters deeply invaginated in the neuronal soma. Interestingly, the glial wrapping, the amount of microtubules and their distribution in the ciliary processes were different between rodents. Using immunohistochemistry, we were able to detect the expression of known GG proteins, such as the membrane guanylyl cyclase G and the cyclic nucleotide-gated channel A3. Both the expression and the subcellular localization of these signaling proteins were found to be species-dependent. Calcium imaging experiments on acute tissue slice preparations from rodent GG demonstrated that the chemo- and thermo-evoked neuronal responses were different between species. Thus, GG neurons from mice and rats displayed both chemo- and thermo-sensing, while hamsters and gerbils showed profound differences in their sensitivities. We suggest that the integrative comparison between the structural morphologies, the sensory properties, and the ethological contexts supports species-dependent GG features prompted by the environmental pressure

The Grueneberg ganglion controls odor-driven food choices in mice under threat.

The ability to efficiently search for food is fundamental for animal survival. Olfactory messages are used to find food while being aware of the impending risk of predation. How these different olfactory clues are combined to optimize decision-making concerning food selection remains elusive. Here, we find that chemical danger cues drive the food selection in mice via the activation of a specific olfactory subsystem, the Grueneberg ganglion (GG). We show that a functional GG is required to decipher the threatening quality of an unfamiliar food. We also find that the increase in corticosterone, which is GG-dependent, enhances safe food preference acquired during social transmission. Moreover, we demonstrate that memory retrieval for food preference can be extinguished by activation of the GG circuitry. Our findings reveal a key function played by the GG in controlling contextual food responses and illustrate how mammalian organisms integrate environmental chemical stress to optimize decision-making

Lightly-strained germanium quantum wells with hole mobility exceeding one million

We demonstrate that a lightly-strained germanium channel ($\varepsilon_{//}$ = -0.41%) in an undoped Ge/Si$_{0.1}$Ge$_{0.9}$ heterostructure field effect transistor supports a 2D hole gas with mobility in excess of 1$\times$10$^{6}$ cm$^{2}$/Vs and percolation density less than 5$\times$10$^{10}$ cm$^{-2}$. This low disorder 2D hole system shows tunable fractional quantum Hall effect at low density and low magnetic field. The low-disorder and small effective mass (0.068$m_e$) defines lightly-strained germanium as a basis to tune the strength of the spin-orbit coupling for fast and coherent quantum hardware

Intrinsic aerobic capacity sets a divide for aging and longevity

<p><b>Rationale:</b> Low aerobic exercise capacity is a powerful predictor of premature morbidity and mortality for healthy adults as well as those with cardiovascular disease. For aged populations, poor performance on treadmill or extended walking tests indicates closer proximity to future health declines. Together, these findings suggest a fundamental connection between aerobic capacity and longevity.</p> <p><b>Objectives:</b> Through artificial selective breeding, we developed an animal model system to prospectively test the association between aerobic exercise capacity and survivability (aerobic hypothesis).</p> <p><b>Methods and Results:</b> Laboratory rats of widely diverse genetic backgrounds (N:NIH stock) were selectively bred for low or high intrinsic (inborn) treadmill running capacity. Cohorts of male and female rats from generations 14, 15, and 17 of selection were followed for survivability and assessed for age-related declines in cardiovascular fitness including maximal oxygen uptake (VO<sub>2max</sub>), myocardial function, endurance performance, and change in body mass. Median lifespan for low exercise capacity rats was 28% to 45% shorter than high capacity rats (hazard ratio, 0.06; P<0.001). VO<sub>2max</sub>, measured across adulthood was a reliable predictor of lifespan (P<0.001). During progression from adult to old age, left ventricular myocardial and cardiomyocyte morphology, contractility, and intracellular Ca<sup>2+</sup> handling in both systole and diastole, as well as mean blood pressure, were more compromised in rats bred for low aerobic capacity. Physical activity levels, energy expenditure (Vo<sub>2</sub>), and lean body mass were all better sustained with age in rats bred for high aerobic capacity.</p> <p><b>Conclusions:</b> These data obtained from a contrasting heterogeneous model system provide strong evidence that genetic segregation for aerobic exercise capacity can be linked with longevity and are useful for deeper mechanistic exploration of aging.</p&gt

Food preference acquired by social transmission is altered by the absence of the olfactory marker protein in mice.

Food preference is conserved from the most primitive organisms to social animals including humans. A continuous integration of olfactory cues present both in food and in the different environmental and physiological contexts favors the intake of a given source of food or its avoidance. Remarkably, in mice, food preference can also be acquired by olfactory communication in-between conspecifics, a behavior known as the social transmission of food preference (STFP). STFP occurs when a mouse sniffs the breath of a conspecific who has previously eaten a novel food emitting specific odorants and will then develop a preference for this never encountered food. The efficient discrimination of odorants is performed by olfactory sensory neurons (OSNs). It is essential and supports many of the decision-making processes. Here, we found that the olfactory marker protein (OMP), an enigmatic protein ubiquitously expressed in all mature olfactory neurons, is involved in the fine regulation of OSNs basal activity that directly impacts the odorant discrimination ability. Using a previously described Omp null mouse model, we noticed that although odorants and their hedonic-associated values were still perceived by these mice, compensatory behaviors such as a higher number of sniffing events were displayed both in the discrimination of complex odorant signatures and in social-related contexts. As a consequence, we found that the ability to differentiate the olfactory messages carried by individuals such as those implicated in the social transmission of food preference were significantly compromised in Omp null mice. Thus, our results not only give new insights into the role of OMP in the fine discrimination of odorants but also reinforce the fundamental implication of a functional olfactory system for food decision-making

When ring makes the difference: coordination properties of Cu2+/Cu+ complexes with sulfur-pendant polyazamacrocycles for radiopharmaceutical applications

Three polyazamacrocyclic ligands, i.e. 1,5,9-tris[2-(methylsulfanyl)ethyl]-1,5,9-triazacyclododecane (TACD3S), 1,4,7,10-tetrakis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetrazacyclotridecane (TRI4S) and 1,4,8,11-tetrakis[2-(methylsulfanyl)ethyl]-1,4,8,11-tetrazacyclotetradecane (TE4S), were considered as potential chelators for the medically relevant copper radioisotopes. The ligands have been synthesized through facile, single-step reactions, and their acidity constants have been measured in aqueous solution at 25 degrees C. The kinetic, thermodynamic, electrochemical and structural properties of their Cu2+ and Cu+ complexes were investigated in aqueous solution at 25 degrees C using spectroscopic (UV-Visible, EPR, NMR) and electrochemical techniques (pH-potentiometric titrations, cyclic voltammetry and electrolysis). TACD3S was demonstrated to be unable to stabilize Cu2+, whereas for TRI4S and TE4S the formation of stable monocupric (CuL2+) and monocuprous (CuL+) complexes was detected. TRI4S coordinates Cu(2+)via a [4N] and a [4N]S array of donor atoms while with TE4S only the latter geometry exists. The thermodynamic stability and the kinetic inertness of the copper complexes formed by TACD3S, TRI4S and TE4S were compared with those previously reported for 1,4,7,10-tetrakis-[2-(methylsulfanyl)ethyl]-1,4,7,10-tetrazacyclododecane (DO4S) to unravel the influence of the ring size and the nitrogen donor array on the copper chelation properties of these sulfur-rich macrocycles. The copresence of four nitrogen atoms is an essential feature to allow effective copper coordination when a 12-member ring is employed, as the Cu2+-DO4S complexes were far more stable than those of Cu2+-TACD3S. Furthermore, the larger ring size of TRI4S and TE4S, when compared to DO4S, progressively increases the rate of the Cu2+ complexation reactions but decreases the thermodynamic stability of the Cu2+ complexes. Despite this, the ability of TRI4S and TE4S to stably accommodate both copper oxidation states makes them very attractive for application in nuclear medicine as they could avoid the demetallation after the biologically triggered Cu2+/Cu+ reduction