Amyloid detection and typing yield of skin biopsy in systemic amyloidosis and polyneuropathy.

OBJECTIVE Disease-modifying therapies are available for amyloidosis but are ineffective if end-organ damage is severe. As small fiber neuropathy is an early and common feature of amyloidosis, we assessed detection and typing yield of skin biopsy for amyloid in patients with confirmed systemic amyloidosis and neuropathic symptoms. METHODS In this case-control study, patients with transthyretin and light chain amyloidosis (ATTRv, ATTRwt, and AL) were consecutively recruited. They were sex and age-matched to three control groups (1) non-neuropathic controls (NNC), (2) monoclonal gammopathy of undetermined significance (MGUS), and (3) other neuropathic disease controls (ONC). Patients underwent a double 3 mm skin biopsy in proximal and distal leg. Amyloid index and burden, protein typing by immuno-electron microscopy, intraepidermal nerve fiber density, electroneuromyography, and clinical characteristics were analyzed. RESULTS We studied 15 subjects with confirmed systemic amyloidosis, 20 NNC, 18 MGUS, and 20 ONC. Amyloid was detected in 100% of patients with amyloidosis (87% in ankle and 73% in thigh). It was not detected in any of the control groups. A small fiber neuropathy was encountered in 100% of amyloidosis patients, in 80% of MGUS, and in 78% of ONC. Amyloid burden was higher in ATTRv, followed by AL and ATTRwt. The ultrastructural examination allowed the identification of the precursor protein by immunotyping in most of the cases. INTERPRETATION Skin biopsy is a minimally invasive test with optimal sensitivity for amyloid. It allows amyloid typing by electron microscope to identify the precursor protein. The diagnostic work up of systemic amyloidosis should include a skin biopsy

The FAMU experiment at RIKEN-RAL to study the muon transfer rate from hydrogen to other gases

The aim of the FAMU (Fisica degli Atomi Muonici) experiment is to realize the first measurement of the hyperfine splitting (hfs) in the 1S state of muonic hydrogen _Ehf s 1S , by using the RIKEN-RAL intense pulsed muon beam and a high-energy mid-infrared tunable laser. This requires a detailed study of the muon transfer mechanism at different temperatures and hence at different epithermal states of the muonic system. The experimental setup involves a cryogenic pressurized gas target and a detection system based on silicon photomultipliers-fiber beam hodoscopes and high purity Germanium detectors and Cerium doped Lanthanium Bromide crystals, for X-rays detection at energies around 100 keV. Simulation, construction and detector performances of the FAMU apparatus at RAL are reported in this paper

The FAMU experiment at RIKEN-RAL to study the muon transfer rate from hydrogen to other gases

The aim of the FAMU (Fisica degli Atomi Muonici) experiment is to realize the first measurement of the hyperfine splitting (hfs) in the 1S state of muonic hydrogen _Ehf s 1S , by using the RIKEN-RAL intense pulsed muon beam and a high-energy mid-infrared tunable laser. This requires a detailed study of the muon transfer mechanism at different temperatures and hence at different epithermal states of the muonic system. The experimental setup involves a cryogenic pressurized gas target and a detection system based on silicon photomultipliers-fiber beam hodoscopes and high purity Germanium detectors and Cerium doped Lanthanium Bromide crystals, for X-rays detection at energies around 100 keV. Simulation, construction and detector performances of the FAMU apparatus at RAL are reported in this paper

First FAMU observation of muon transfer from \u3bcp atoms to higher-Z elements

Abstract: The FAMU experiment aims to accurately measure the hyperfine splitting of the ground state of the muonic hydrogen atom. A measurement of the transfer rate of muons from hydrogen to heavier gases is necessary for this purpose. In June 2014, within a preliminary experiment, a pressurized gas-target was exposed to the pulsed low-energy muon beam at the RIKEN RAL muon facility (Rutherford Appleton Laboratory, U.K.). The main goal of the test was the characterization of both the noise induced by the pulsed beam and the X-ray detectors. The apparatus, to some extent rudimental, has served admirably to this task. Technical results have been published that prove the validity of the choices made and pave the way for the next steps. This paper presents the results of physical relevance of measurements of the muon transfer rate to carbon dioxide, oxygen, and argon from non-thermalized excited \u3bcp atoms. The analysis methodology and the approach to the systematics errors are useful for the subsequent study of the transfer rate as function of the kinetic energy of the \u3bcp currently under way

Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly

Tau and Alpha Synuclein Synergistic Effect in Neurodegenerative Diseases: When the Periphery Is the Core

In neuronal cells, tau is a microtubule-associated protein placed in axons and alpha synuclein is enriched at presynaptic terminals. They display a propensity to form pathologic aggregates, which are considered the underlying cause of Alzheimer’s and Parkinson’s diseases. Their functional impairment induces loss of axonal transport, synaptic and mitochondrial disarray, leading to a “dying back” pattern of degeneration, which starts at the periphery of cells. In addition, pathologic spreading of alpha-synuclein from the peripheral nervous system to the brain through anatomical connectivity has been demonstrated for Parkinson’s disease. Thus, examination of the extent and types of tau and alpha-synuclein in peripheral tissues and their relation to brain neurodegenerative diseases is of relevance since it may provide insights into patterns of protein aggregation and neurodegeneration. Moreover, peripheral nervous tissues are easily accessible in-vivo and can play a relevant role in the early diagnosis of these conditions. Up-to-date investigations of tau species in peripheral tissues are scant and have mainly been restricted to rodents, whereas, more evidence is available on alpha synuclein in peripheral tissues. Here we aim to review the literature on the functional role of tau and alpha synuclein in physiological conditions and disease at the axonal level, their distribution in peripheral tissues, and discuss possible commonalities/diversities as well as their interaction in proteinopathies

Tau and Alpha Synuclein Synergistic Effect in Neurodegenerative Diseases: When the Periphery Is the Core.

In neuronal cells, tau is a microtubule-associated protein placed in axons and alpha synuclein is enriched at presynaptic terminals. They display a propensity to form pathologic aggregates, which are considered the underlying cause of Alzheimer's and Parkinson's diseases. Their functional impairment induces loss of axonal transport, synaptic and mitochondrial disarray, leading to a "dying back" pattern of degeneration, which starts at the periphery of cells. In addition, pathologic spreading of alpha-synuclein from the peripheral nervous system to the brain through anatomical connectivity has been demonstrated for Parkinson's disease. Thus, examination of the extent and types of tau and alpha-synuclein in peripheral tissues and their relation to brain neurodegenerative diseases is of relevance since it may provide insights into patterns of protein aggregation and neurodegeneration. Moreover, peripheral nervous tissues are easily accessible in-vivo and can play a relevant role in the early diagnosis of these conditions. Up-to-date investigations of tau species in peripheral tissues are scant and have mainly been restricted to rodents, whereas, more evidence is available on alpha synuclein in peripheral tissues. Here we aim to review the literature on the functional role of tau and alpha synuclein in physiological conditions and disease at the axonal level, their distribution in peripheral tissues, and discuss possible commonalities/diversities as well as their interaction in proteinopathies

Extracellular Vesicles as Promising Carriers in Drug Delivery: Considerations from a Cell Biologist’s Perspective

The use of extracellular vesicles as cell-free therapy is a promising approach currently investigated in several disease models. The intrinsic capacity of extracellular vesicles to encapsulate macromolecules within their lipid bilayer membrane-bound lumen is a characteristic exploited in drug delivery to transport active pharmaceutical ingredients. Besides their role as biological nanocarriers, extracellular vesicles have a specific tropism towards target cells, which is a key aspect in precision medicine. However, the little knowledge of the mechanisms governing the release of a cargo macromolecule in recipient cells and the Good Manufacturing Practice (GMP) grade scale-up manufacturing of extracellular vesicles are currently slowing their application as drug delivery nanocarriers. In this review, we summarize, from a cell biologist’s perspective, the main evidence supporting the role of extracellular vesicles as promising carriers in drug delivery, and we report five key considerations that merit further investigation before translating Extracellular Vesicles (EVs) to clinical applications