Young-onset Parkinson's disease (YOPD), defined by onset at <50 years, accounts for approximately 10% of all Parkinson's disease cases and, while some cases are associated with known genetic ...mutations, most are not. Here induced pluripotent stem cells were generated from control individuals and from patients with YOPD with no known mutations. Following differentiation into cultures containing dopamine neurons, induced pluripotent stem cells from patients with YOPD showed increased accumulation of soluble α-synuclein protein and phosphorylated protein kinase Cα, as well as reduced abundance of lysosomal membrane proteins such as LAMP1. Testing activators of lysosomal function showed that specific phorbol esters, such as PEP005, reduced α-synuclein and phosphorylated protein kinase Cα levels while increasing LAMP1 abundance. Interestingly, the reduction in α-synuclein occurred through proteasomal degradation. PEP005 delivery to mouse striatum also decreased α-synuclein production in vivo. Induced pluripotent stem cell-derived dopaminergic cultures reveal a signature in patients with YOPD who have no known Parkinson's disease-related mutations, suggesting that there might be other genetic contributions to this disorder. This signature was normalized by specific phorbol esters, making them promising therapeutic candidates.
Neuronal microcircuits in the superficial layers of the mammalian cortex provide the substrate for associative cortical computation. Inhibitory interneurons constitute an essential component of the ...circuitry and are fundamental to the integration of local and long-range information. Here we report that, during early development, superficially positioned Reelin-expressing neurogliaform interneurons in the mouse somatosensory cortex receive afferent innervation from both cortical and thalamic excitatory sources. Attenuation of ascending sensory, but not intracortical, excitation leads to axo-dendritic morphological defects in these interneurons. Moreover, abrogation of the NMDA receptors through which the thalamic inputs signal results in a similar phenotype, as well as in the selective loss of thalamic and a concomitant increase in intracortical connectivity. These results suggest that thalamic inputs are critical in determining the balance between local and long-range connectivity and are fundamental to the proper integration of Reelin-expressing interneurons into nascent cortical circuits.
Over the last couple of decades, deep eutectic solvents (DESs) have emerged as novel alternatives to ionic liquids that are extensively used in the synthesis of innovative materials, metal ...processing, catalysis, etc. However, their usage is limited, primarily because of their large viscosity and poor conductivity. Therefore, an understanding of the molecular origin of these transport properties is essential to improve their industrial applicability. Here, we present the report of the nanoscopic diffusion mechanism of acetamide in a DES synthesized with lithium perchlorate as studied using neutron scattering and molecular dynamics (MD) simulation techniques. A diffusion model is constructed with the help of MD simulation data comprising two distinct processes, corresponding to long-range jump diffusion and localized diffusion within a restricted volume. This diffusion model is validated through the analysis of neutron scattering data in the acetamide based DES (ADES) and molten acetamide. Although ADES has a remarkably lower freezing point compared to pure acetamide, the molecular mobility is found to be enormously restricted in the former. Particularly, the long-range jump diffusion process of acetamide is slower by a factor of 3 in ADES in comparison with molten acetamide. Further, the geometry of localized diffusion is found to be unaltered, but the dynamics is observed to be slightly slower in ADES. The diffusion model is found to be consistent over a wide temperature range for the ADES. Both long-range and localized diffusion show Arrhenius dependence with temperature in ADES. MD simulation analysis reveals that the long-range diffusion in ADES is restricted mainly due to the formation of hydrogen bond mediated complexes between the ionic species of the salt and acetamide molecules. Hence, the origin of higher viscosity observed in ADES can be attributed to the complexation in the ADES. The complex formation also explains the inhibition of the crystallization process while cooling and thereby results in depression of the freezing point of ADES.
•Vitamin D3 was successfully encapsulated in nanostructured lipid carriers (NLCs).•Hot high pressure homogenization produced small and stable NLCs.•A high encapsulation efficiency of 85.6% was ...achieved.•The NLCs protected the vitamin D3 in simulated gastric conditions.•Most of the vitamin was released after 8h digestion in simulated intestinal medium.
Nanostructured lipid carriers (NLCs) for encapsulating vitamin D3 (VD3), a lipophilic vitamin, were successfully fabricated by hot high pressure homogenization. The physicochemical properties of the VD3-NLCs were characterized, and the release profiles of VD3 in simulated gastrointestinal fluids were investigated. Optimum VD3-NLCs were obtained with a small diameter (132.9nm), a high zeta potential (−41.90mV), and a high encapsulation efficiency (85.6%). The stability of the VD3-NLCs was tested during 20days of storage at 25°C under a wide range of pHs. In vitro digestion in simulated gastrointestinal fluids demonstrated their capability for controlled release because the NLCs were able to remain stable and protect the VD3 in simulated stomach fluid, but released more than 90% of the VD3 in simulated intestinal fluid. Therefore, the developed NLCs are promising carriers for increasing the oral bioavailability of VD3.
We have developed an efficient simulation tool 'GOLLUM' for the computation of electrical, spin and thermal transport characteristics of complex nanostructures. The new multi-scale, multi-terminal ...tool addresses a number of new challenges and functionalities that have emerged in nanoscale-scale transport over the past few years. To illustrate the flexibility and functionality of GOLLUM, we present a range of demonstrator calculations encompassing charge, spin and thermal transport, corrections to density functional theory such as local density approximation +U (LDA+U) and spectral adjustments, transport in the presence of non-collinear magnetism, the quantum Hall effect, Kondo and Coulomb blockade effects, finite-voltage transport, multi-terminal transport, quantum pumps, superconducting nanostructures, environmental effects, and pulling curves and conductance histograms for mechanically-controlled break-junction experiments.
Organic electronics is emerging for large-area applications such as photovoltaic cells, rollable displays or electronic paper. Its future development and integration will require a simple, low-power ...organic memory, that can be written, erased and readout electrically. Here we demonstrate a non-volatile memory in which the ferroelectric polarisation state of an organic tunnel barrier encodes the stored information and sets the readout tunnel current. We use high-sensitivity piezoresponse force microscopy to show that films as thin as one or two layers of ferroelectric poly(vinylidene fluoride) remain switchable with low voltages. Submicron junctions based on these films display tunnel electroresistance reaching 1,000% at room temperature that is driven by ferroelectric switching and explained by electrostatic effects in a direct tunnelling regime. Our findings provide a path to develop low-cost, large-scale arrays of organic ferroelectric tunnel junctions on silicon or flexible substrates.
Phase separation is a cooperative process, the kinetics of which underpin the orderly morphogenesis of domain patterns on mesoscopic scales
. Systems of highly degenerate frozen states may exhibit ...the rare and counterintuitive inverse-symmetry-breaking phenomenon
. Proposed a century ago
, inverse transitions have been found experimentally in disparate materials, ranging from polymeric and colloidal compounds to high-transition-temperature superconductors, proteins, ultrathin magnetic films, liquid crystals and metallic alloys
, with the notable exception of ferroelectric oxides, despite extensive theoretical and experimental work on the latter. Here we show that following a subcritical quench, the non-equilibrium self-assembly of ferroelectric domains in ultrathin films of Pb(Zr
Ti
)O
results in a maze, or labyrinthine pattern, featuring meandering stripe domains. Furthermore, upon increasing the temperature, this highly degenerate labyrinthine phase undergoes an inverse transition whereby it transforms into the less-symmetric parallel-stripe domain structure, before the onset of paraelectricity at higher temperatures. We find that this phase sequence can be ascribed to an enhanced entropic contribution of domain walls, and that domain straightening and coarsening is predominantly driven by the relaxation and diffusion of topological defects. Computational modelling and experimental observation of the inverse dipolar transition in BiFeO
suggest the universality of the phenomenon in ferroelectric oxides. The multitude of self-patterned states and the various topological defects that they embody may be used beyond current domain and domain-wall-based
technologies by enabling fundamentally new design principles and topologically enhanced functionalities within ferroelectric films.
The phenomenon of electron tunneling has been known since the advent of quantum mechanics, but continues to enrich our understanding of many fields of physics, as well as creating sub-fields on its ...own. Spin-dependent tunneling in magnetic tunnel junctions has aroused considerable interest and development. In parallel with this endeavor, recent advances in thin-film ferroelectrics have demonstrated the possibility of achieving stable and switchable ferroelectric polarization in nanometer-thick films. This discovery opened the possibility of using thin-film ferroelectrics as barriers in magnetic tunnel junctions, thus merging the fields of magnetism, ferroelectricity, and spin-polarized transport into an exciting and promising area of novel research. Nowadays, this research has become an important constituent of a broader effort in multiferroic materials and heterostructures that involves rich fundamental science and offers a potential for applications in novel multifunctional devices. The purpose of this article is to review recent developments in ferroelectric and multiferroic tunnel junctions. Starting from the concept of electron tunneling, we first discuss the key properties of magnetic tunnel junctions and then assess key functional characteristics of ferroelectric and multiferroic tunnel junctions. We discuss the recent demonstrations of giant resistive switching observed in ferroelectric tunnel junctions and the new concept of electrically controlling the spin polarization in magnetic tunnel junctions with a ferroelectric tunnel barrier.
The single-arm, phase 2 ENESTfreedom trial assessed the potential for treatment-free remission (TFR; i.e., the ability to maintain a molecular response after stopping therapy) following frontline ...nilotinib treatment. Patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase with MR
(BCR-ABL1⩽0.0032% on the International Scale (BCR-ABL1
)) and ⩾2 years of frontline nilotinib therapy were enrolled. Patients with sustained deep molecular response during the 1-year nilotinib consolidation phase were eligible to stop treatment and enter the TFR phase. Patients with loss of major molecular response (MMR; BCR-ABL1
⩽0.1%) during the TFR phase reinitiated nilotinib. In total, 215 patients entered the consolidation phase, of whom 190 entered the TFR phase. The median duration of nilotinib before stopping treatment was 43.5 months. At 48 weeks after stopping nilotinib, 98 patients (51.6%; 95% confidence interval, 44.2-58.9%) remained in MMR or better (primary end point). Of the 86 patients who restarted nilotinib in the treatment reinitiation phase after loss of MMR, 98.8% and 88.4%, respectively, regained MMR and MR
by the data cutoff date. Consistent with prior reports of imatinib-treated patients, musculoskeletal pain-related events were reported in 24.7% of patients in the TFR phase (consolidation phase, 16.3%).
CACNA1C, encoding the Ca
1.2 subunit of L-type Ca
channels, has emerged as one of the most prominent and highly replicable susceptibility genes for several neuropsychiatric disorders. Ca
1.2 channels ...play a crucial role in calcium-mediated processes involved in brain development and neuronal function. Within the CACNA1C gene, disease-associated single-nucleotide polymorphisms have been associated with impaired social and cognitive processing and altered prefrontal cortical (PFC) structure and activity. These findings suggest that aberrant Ca
1.2 signaling may contribute to neuropsychiatric-related disease symptoms via impaired PFC function. Here, we show that mice harboring loss of cacna1c in excitatory glutamatergic neurons of the forebrain (fbKO) that we have previously reported to exhibit anxiety-like behavior, displayed a social behavioral deficit and impaired learning and memory. Furthermore, focal knockdown of cacna1c in the adult PFC recapitulated the social deficit and elevated anxiety-like behavior, but not the deficits in learning and memory. Electrophysiological and molecular studies in the PFC of cacna1c fbKO mice revealed higher E/I ratio in layer 5 pyramidal neurons and lower general protein synthesis. This was concurrent with reduced activity of mTORC1 and its downstream mRNA translation initiation factors eIF4B and 4EBP1, as well as elevated phosphorylation of eIF2α, an inhibitor of mRNA translation. Remarkably, systemic treatment with ISRIB, a small molecule inhibitor that suppresses the effects of phosphorylated eIF2α on mRNA translation, was sufficient to reverse the social deficit and elevated anxiety-like behavior in adult cacna1c fbKO mice. ISRIB additionally normalized the lower protein synthesis and higher E/I ratio in the PFC. Thus this study identifies a novel Ca
1.2 mechanism in neuropsychiatric-related endophenotypes and a potential future therapeutic target to explore.
PDF
