Mitochondrial dysfunction has been implicated in the pathogenesis of almost all neurological diseases, including Alzheimer’s disease (AD). Historically, a primary focus in this context has been the ...link between mitochondrial dynamics and amyloid β toxicity. Recent evidence suggests that dysregulation of mitochondrial calcium homeostasis is also related to tau and other risk factors in AD, although an ongoing challenge in the field is that data collected from different models or experimental settings have not always been consistent. We examine recent literature on mitochondrial dysregulation in AD, with special emphasis on mitochondrial calcium. We include data from in vitro systems, genetic animal models, and AD-derived human tissue, and discuss whether mitochondrial calcium transporters should be proposed as therapeutic candidates for the development of neuroprotective drugs against AD.
Ca2+ levels are tightly regulated in mitochondria. If excessive Ca2+ levels are reached within mitochondria, then key mitochondrial functions are impaired, leading to enhanced generation of reactive oxygen species and activation of apoptosis, processes that take place in AD.The combination of different technologies, such as RNA-seq, targeted fluorescent probes, multiphoton microscopy, and transgenic mouse models of AD, has made it possible to understand the underlying mechanisms of mitochondrial Ca2+ dysregulation and its contribution to a more general Ca2+ impairment in AD.Aβ causes cytosolic and mitochondrial Ca2+ overload both in vitro and in vivo. Misfolded and hyperphosphorylated tau protein also disrupts Ca2+ homeostasis in mitochondria.Identifying targets to maintain mitochondrial Ca2+ homeostasis and correct mitochondrial function, particularly mitochondrial Ca2+ transporters, could offer promising venues for the development of drugs against AD.
A fundamental goal of genomics is to identify the complete set of expressed proteins. Automated annotation strategies rely on assumptions about protein-coding sequences (CDSs), e.g., they are ...conserved, do not overlap, and exceed a minimum length. However, an increasing number of newly discovered proteins violate these rules. Here we present an experimental and analytical framework, based on ribosome profiling and linear regression, for systematic identification and quantification of translation. Application of this approach to lipopolysaccharide-stimulated mouse dendritic cells and HCMV-infected human fibroblasts identifies thousands of novel CDSs, including micropeptides and variants of known proteins, that bear the hallmarks of canonical translation and exhibit translation levels and dynamics comparable to that of annotated CDSs. Remarkably, many translation events are identified in both mouse and human cells even when the peptide sequence is not conserved. Our work thus reveals an unexpected complexity to mammalian translation suited to provide both conserved regulatory or protein-based functions.
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•ORF-RATER robustly identifies and quantifies translation from ribosome profiling data•ORF-RATER reveals thousands of novel micropeptides and variants of mammalian proteins•Hundreds of novel CDSs show evidence of protein-coding conservation among mammals•Many ORFs are translated in both mice and humans but lack protein-coding conservation
Fields et al. describe a ribosome profiling-based approach for empirical annotation of protein-coding regions of the genome. Of the thousands of previously unknown translated ORFs they identify in mouse and human, many are conserved or dynamically regulated. Surprisingly, a considerable subset is translated in both species despite weak sequence conservation.
Paravascular drainage of solutes, including β-amyloid (Aβ), appears to be an important process in brain health and diseases such as Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). ...However, the major driving force for clearance remains largely unknown. Here we used in vivo two-photon microscopy in awake head-fixed mice to assess the role of spontaneous vasomotion in paravascular clearance. Vasomotion correlated with paravascular clearance of fluorescent dextran from the interstitial fluid. Increasing the amplitude of vasomotion by means of visually evoked vascular responses resulted in increased clearance rates in the visual cortex of awake mice. Evoked vascular reactivity was impaired in mice with CAA, which corresponded to slower clearance rates. Our findings suggest that low-frequency arteriolar oscillations drive drainage of solutes. Targeting naturally occurring vasomotion in patients with CAA or AD may be a promising early therapeutic option for prevention of Aβ accumulation in the brain.
•Spontaneous low-frequency oscillations can be observed in arterioles in awake mice•Vasomotion drives paravascular clearance of solutes from the brain•Paravascular clearance is impaired in the context of cerebral amyloid angiopathy
van Veluw et al. demonstrate that vasomotion is a major driving force for paravascular clearance of solutes from the brain. Loss of vascular smooth muscle cells and reduced vasomotion in the context of amyloid deposition is associated with impaired clearance.
Mitochondria contribute to shape intraneuronal Ca
signals. Excessive Ca
taken up by mitochondria could lead to cell death. Amyloid beta (Aβ) causes cytosolic Ca
overload, but the effects of Aβ on ...mitochondrial Ca
levels in Alzheimer's disease (AD) remain unclear. Using a ratiometric Ca
indicator targeted to neuronal mitochondria and intravital multiphoton microscopy, we find increased mitochondrial Ca
levels associated with plaque deposition and neuronal death in a transgenic mouse model of cerebral β-amyloidosis. Naturally secreted soluble Aβ applied onto the healthy brain increases Ca
concentration in mitochondria, which is prevented by blockage of the mitochondrial calcium uniporter. RNA-sequencing from post-mortem AD human brains shows downregulation in the expression of mitochondrial influx Ca
transporter genes, but upregulation in the genes related to mitochondrial Ca
efflux pathways, suggesting a counteracting effect to avoid Ca
overload. We propose lowering neuronal mitochondrial Ca
by inhibiting the mitochondrial Ca
uniporter as a novel potential therapeutic target against AD.
Methylammonium lead iodide (MAPbI3) perovskite shows an outstanding performance in photovoltaic devices. However, certain material properties, especially the possible ferroic behavior, remain ...unclear. We observed distinct nanoscale periodic domains in the piezoresponse of MAPbI3(Cl) grains. The structure and the orientation of these striped domains indicate ferroelasticity as their origin. By correlating vertical and lateral piezoresponse force microscopy experiments performed at different sample orientations with X-ray diffraction, the preferred domain orientation is suggested to be the a 1 –a 2-phase. The observation of these ferroelastic fingerprints appears to strongly depend on the film texture and thus the preparation route. The ferroelastic twin domains could form due to the introduction of strain during the cubic−tetragonal phase transition.
Fundamental mechanisms of energy storage, corrosion, sensing, and multiple biological functionalities are directly coupled to electrical processes and ionic dynamics at solid-liquid interfaces. In ...many cases, these processes are spatially inhomogeneous taking place at grain boundaries, step edges, point defects, ion channels, etc and possess complex time and voltage dependent dynamics. This necessitates time-resolved and real-space probing of these phenomena. In this review, we discuss the applications of force-sensitive voltage modulated scanning probe microscopy (SPM) for probing electrical phenomena at solid-liquid interfaces. We first describe the working principles behind electrostatic and Kelvin probe force microscopies (EFM & KPFM) at the gas-solid interface, review the state of the art in advanced KPFM methods and developments to (i) overcome limitations of classical KPFM, (ii) expand the information accessible from KPFM, and (iii) extend KPFM operation to liquid environments. We briefly discuss the theoretical framework of electrical double layer (EDL) forces and dynamics, the implications and breakdown of classical EDL models for highly charged interfaces or under high ion concentrations, and describe recent modifications of the classical EDL theory relevant for understanding nanoscale electrical measurements at the solid-liquid interface. We further review the latest achievements in mapping surface charge, dielectric constants, and electrodynamic and electrochemical processes in liquids. Finally, we outline the key challenges and opportunities that exist in the field of nanoscale electrical measurements in liquid as well as providing a roadmap for the future development of liquid KPFM.
Semiconductor–graphene oxide-based surface-enhanced Raman spectroscopy substrates represent a new frontier in the field of surface-enhanced Raman spectroscopy (SERS). However, the application of ...graphene oxide has had limited success because of the poor Raman enhancement factors that are achievable in comparison to noble metals. In this work, we report chemical SERS enhancement enabled by the application of an electric field (10–25 V/mm) to aligned semiconducting peptide nanotube–graphene oxide composite structures during Raman measurements. The technique enables nanomolar detection sensitivity of glucose and nucleobases with up to 10-fold signal enhancement compared to metal-based substrates, which, to our knowledge, is higher than that previously reported for semiconductor-based SERS substrates. The increased Raman scattering is assigned to enhanced charge-transfer resonance enabled by work function lowering of the peptide nanotubes. These results provide insight into how semiconductor organic peptide nanotubes interact with graphene oxide, which may facilitate chemical biosensing, electronic devices, and energy-harvesting applications.
Peptide self-assemblies show intriguing and tunable physicochemical properties, and thus have been attracting increasing interest over the last two decades. However, the micro/nano-scale dimensions ...of the self-assemblies severely restrict their extensive applications. Inspired by nature, to genuinely realize the practical utilization of the bio-organic super-architectures, it is beneficial to further organize the peptide self-assemblies to integrate the properties of the individual supermolecules and fabricate higher-level organizations for smart functional devices. Therefore, cumulative studies have been reported on peptide microfabrication giving rise to diverse properties. This review summarizes the recent development of the microfabrication of peptide self-assemblies, discussing each methodology along with the diverse properties and practical applications of the engineered peptide large-scale, highly-ordered organizations. Finally, the current limitations of the state-of-the-art microfabrication strategies are critically assessed and alternative solutions are suggested.
In this review, the development of microfabrication of peptide self-assemblies, including methodologies along with the diverse properties and applications of the engineered large-scale, highly-ordered peptide arrays, are summarized.
Cell migration is a universal and crucial mechanism for life. It is required in a series of physiological processes, in wound repair and immune response and is involved in several pathological ...conditions, including cancer and virus dissemination. Among the several biochemical and biophysical routes, changing cell membrane elasticity holds the promise to be a universal strategy to alter cell mobility. Due to their affinity with cell membranes, ionic liquids (ILs) may play an important role. This work focuses on the effect of subtoxic amounts of imidazolium-ILs on the migration of the model cancer cell line MDA-MB-231. Here we show that ILs are able to enhance cell mobility by reducing the elasticity of the cellular lipid membrane, and that both mobility and elasticity can be tuned by IL-concentration and IL-cation chain length. This biochemical–physical mechanism is potentially valid for all mammalian cells, and its impact in bionanomedicine and bionanotechnology is discussed.
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