Current Insights on Neurodegeneration by the Italian Proteomics Community

The growing number of patients affected by neurodegenerative disorders represents a huge problem for healthcare systems, human society, and economics. In this context, omics strategies are crucial for the identification of molecular factors involved in disease pathobiology, and for the discovery of biomarkers that allow early diagnosis, patients’ stratification, and treatment response prediction. The integration of different omics data is a required step towards the goal of personalized medicine. The Italian proteomics community is actively developing and applying proteomics approaches to the study of neurodegenerative disorders; moreover, it is leading the mitochondria-focused initiative of the Human Proteome Project, which is particularly important given the central role of mitochondrial impairment in neurodegeneration. Here, we describe how Italian research groups in proteomics have contributed to the knowledge of many neurodegenerative diseases, through the elucidation of the pathobiology of these disorders, and through the discovery of disease biomarkers. In particular, we focus on the central role of post-translational modifications analysis, the implementation of network-based approaches in functional proteomics, the integration of different omics in a systems biology view, and the development of novel platforms for biomarker discovery for the high-throughput quantification of thousands of proteins at a time

Manufacturing and characterization of III-V on silicon multijunction solar cells

Tandem GaInP/GaAs//Si(inactive) solar cells were manufactured by direct wafer bonding under vacuum. At this early stage, an inactive silicon substrate was used (i.e. n+ Si substrate instead of an active n-p Si junction). Bonded devices presented an Sshaped J-V curve with a kink close to Voc caused by a built-in potential barrier at the III-V//Si interface that reduces the fill factor and therefore the efficiency of the device by 7% compared to the stand-alone GaInP/GaAs tandem cells. Nevertheless, losses in Jsc and Voc caused by the bonding process, account for less than 10%. AlGaAs single junction cells, designed to be bonded on a silicon cell for low concentrator photovoltaics (LCPV), were also manufactured reaching an efficiency of 15.9% under one sun AM1.5G spectrum for a 2 cm² cell

Human interaural time difference thresholds for sine tones: The high-frequency limit

[EN] The smallest detectable interaural time difference (ITD) for sine tones was measured for four human listeners to determine the dependence on tone frequency. At low frequencies, 250 700 Hz, threshold ITDs were approximately inversely proportional to tone frequency. At mid-frequencies, 700 1000 Hz, threshold ITDs were smallest. At high frequencies, above 1000 Hz, thresholds increased faster than exponentially with increasing frequency becoming unmeasurably high justabove 1400 Hz. A model for ITD detection began with a biophysically based computational model for a medial superior olive (MSO) neuron that produced robust ITD responses up to 1000 Hz, and demonstrated a dramatic reduction in ITD-dependence from 1000 to 1500 Hz. Rate-ITD functions from the MSO model became inputs to binaural display models both place based and rate-differ-ence based. A place-based, centroid model with a rigid internal threshold reproduced almost all fea- tures of the human data. A signal-detection version of this model reproduced the high-frequence divergence but badly underestimated low-frequency thresholds. A rate-difference model incorporat- ing fast contralateral inhibition reproduced the major features of the human threshold data except for the divergence. A combined, hybrid model could reproduce all the threshold data.We are grateful to Dr. Les Bernstein for a useful discussion about the centroid display and to Dr. Steve Colburn for discussions about modeling. Zane Crawford provided valuable statistical help. This research was supported by The Vicerectorado de Profesorado y Ordenacion Academica of the Universitat Politecnica de Valencia (Spain), which brought L. D. to Michigan State, by the NIDCD Grant No. DC-00181 and the AFOSR Grant No. 11NL002. A. B. was supported by NIDCD Grant Nos. DC-00100 (H. S. Colburn) and P30-DC04663 (Core Center).Brughera, A.; Dunai ., L.; Hartmann, WM. (2013). Human interaural time difference thresholds for sine tones: The high-frequency limit. The Journal of the Acoustical Society of America. 133(5):2839-2855. https://doi.org/10.1121/1.4795778S28392855133

Asymmetric Excitatory Synaptic Dynamics Underlie Interaural Time Difference Processing in the Auditory System

In order to localize sounds in the environment, the auditory system detects and encodes differences in signals between each ear. The exquisite sensitivity of auditory brain stem neurons to the differences in rise time of the excitation signals from the two ears allows for neuronal encoding of microsecond interaural time differences

Sensory Communication

Contains table of contents for Section 2, an introduction and reports on twelve research projects.National Institutes of Health Grant R01 DC00117National Institutes of Health Grant R01 DC02032National Institutes of Health/National Institute of Deafness and Other Communication Disorders Grant 2 R01 DC00126National Institutes of Health Grant 2 R01 DC00270National Institutes of Health Contract N01 DC-5-2107National Institutes of Health Grant 2 R01 DC00100U.S. Navy - Office of Naval Research Grant N61339-96-K-0002U.S. Navy - Office of Naval Research Grant N61339-96-K-0003U.S. Navy - Office of Naval Research Grant N00014-97-1-0635U.S. Navy - Office of Naval Research Grant N00014-97-1-0655U.S. Navy - Office of Naval Research Subcontract 40167U.S. Navy - Office of Naval Research Grant N00014-96-1-0379U.S. Air Force - Office of Scientific Research Grant F49620-96-1-0202National Institutes of Health Grant RO1 NS33778Massachusetts General Hospital, Center for Innovative Minimally Invasive Therapy Research Fellowship Gran

Sensory Communication

Contains table of contents for Section 2, an introduction and reports on fourteen research projects.National Institutes of Health Grant RO1 DC00117National Institutes of Health Grant RO1 DC02032National Institutes of Health/National Institute on Deafness and Other Communication Disorders Grant R01 DC00126National Institutes of Health Grant R01 DC00270National Institutes of Health Contract N01 DC52107U.S. Navy - Office of Naval Research/Naval Air Warfare Center Contract N61339-95-K-0014U.S. Navy - Office of Naval Research/Naval Air Warfare Center Contract N61339-96-K-0003U.S. Navy - Office of Naval Research Grant N00014-96-1-0379U.S. Air Force - Office of Scientific Research Grant F49620-95-1-0176U.S. Air Force - Office of Scientific Research Grant F49620-96-1-0202U.S. Navy - Office of Naval Research Subcontract 40167U.S. Navy - Office of Naval Research/Naval Air Warfare Center Contract N61339-96-K-0002National Institutes of Health Grant R01-NS33778U.S. Navy - Office of Naval Research Grant N00014-92-J-184

Sensory Communication

Contains table of contents for Section 2, an introduction and reports on fifteen research projects.National Institutes of Health Grant RO1 DC00117National Institutes of Health Grant RO1 DC02032National Institutes of Health Contract P01-DC00361National Institutes of Health Contract N01-DC22402National Institutes of Health/National Institute on Deafness and Other Communication Disorders Grant 2 R01 DC00126National Institutes of Health Grant 2 R01 DC00270National Institutes of Health Contract N01 DC-5-2107National Institutes of Health Grant 2 R01 DC00100U.S. Navy - Office of Naval Research/Naval Air Warfare Center Contract N61339-94-C-0087U.S. Navy - Office of Naval Research/Naval Air Warfare Center Contract N61339-95-K-0014U.S. Navy - Office of Naval Research/Naval Air Warfare Center Grant N00014-93-1-1399U.S. Navy - Office of Naval Research/Naval Air Warfare Center Grant N00014-94-1-1079U.S. Navy - Office of Naval Research Subcontract 40167U.S. Navy - Office of Naval Research Grant N00014-92-J-1814National Institutes of Health Grant R01-NS33778U.S. Navy - Office of Naval Research Grant N00014-88-K-0604National Aeronautics and Space Administration Grant NCC 2-771U.S. Air Force - Office of Scientific Research Grant F49620-94-1-0236U.S. Air Force - Office of Scientific Research Agreement with Brandeis Universit

Sensitivity to interaural time differences across sound frequency: models of auditory-brainstem neurons

Normal-hearing listeners can locate sound sources, using binaural cues for azimuth angle. These binaural differences in the timing and intensity of sound arriving at the two ears, interaural time differences (ITDs) and interaural intensity differences (IIDs), also support selective listening in multi-talker environments. Auditory-brainstem neurons of the medial superior olive (MSO) and lateral superior olive (LSO) encode ITD in the envelope of sound (ITDENV) and in the temporal fine structure of low-frequency sound (ITDTFS); LSO neurons encode IID. Bilateral-cochlear-implant (bCI) listeners generally receive only IID and ITDENV. Experimental bCI pulse-bursts overcome adaptation, and convey electrical ITDTFS. Improving the understanding of mechanisms for ITD sensitivity can help bCI developers convey acoustic ITDTFS. In this dissertation, models for auditory-brainstem neurons are developed that explain human ability to detect small differences in ITD, as neuronal and MSO population mechanisms. Promoting binaural-coincidence detection and limiting backpropagation, model MSO ion-channels set resting potentials that reproduce dendritic and somatic KLT activation, somatic Na+ inactivation, and a lower amount of axonal Na+ inactivation. Sensitivity to ITDTFS in moderately fast and very fast model MSO neurons collectively match physiological data from 150 to 2000 Hz. The best-ITD (the ITD of highest spike rate) can be made contralateral-leading, by contralateral inhibition of moderate speed, or by asymmetric axon location, leveraging dendritic filtering. Leveraging standard binaural-display models, neuronal populations based on these model MSO neurons match normal-hearing human discrimination thresholds for ITDTFS in sine tones from 39 to 1500 Hz. Adaptation before binaural interaction helps model MSO neurons glimpse the ITDTFS of sound direct from a source, before reflected sound arrives from different directions. With inputs from adapting model spherical bushy cells, a moderately fast model MSO neuron reproduces in vivo responses to amplitude-modulated binaural beats, with a frequency-dependent emphasis of rising vs. peak sound-pressure for ITDTFS encoding, which reflects human ITD detection and reverberation times in outdoor environments. Distinct populations of model LSO neurons, spanning the range of electrical membrane impedance as a function of frequency in LSO neurons, collectively reflect discrimination thresholds for ITDENV in transposed tones across carrier frequency (4-10 kHz) and modulation rate (32-800 Hz).2022-09-28T00:00:00

Sensitivity to Envelope Interaural Time Differences: Modeling Auditory Modulation Filtering

For amplitude-modulated sound, the envelope interaural time difference (ITDENV) is a potential cue for sound-source location. ITDENV is encoded in the lateral superior olive (LSO) of the auditory brainstem, by excitatory-inhibitory (EI) neurons receiving ipsilateral excitation and contralateral inhibition. Between human listeners, sensitivity to ITDENV varies considerably, but ultimately decreases with increasing stimulus carrier frequency, and decreases more strongly with increasing modulation rate. Mechanisms underlying the variation in behavioral sensitivity remain unclear. Here, with increasing carrier frequency (4–10 kHz), as we phenomenologically model the associated decrease in ITDENV sensitivity using arbitrarily fewer neurons consistent across populations, we computationally model the variable sensitivity across human listeners and modulation rates (32–800 Hz) as the decreasing range of membrane frequency responses in LSO neurons. Transposed tones stimulate a bilateral auditory-periphery model, driving model EI neurons where electrical membrane impedance filters the frequency content of inputs driven by amplitude-modulated sound, evoking modulation filtering. Calculated from Fisher information in spike-rate functions of ITDENV, for model EI neuronal populations distinctly reflecting the LSO range in membrane frequency responses, just-noticeable differences in ITDENV collectively reproduce the largest variation in ITDENV sensitivity across human listeners. These slow to fast model populations each generally match the best human ITDENV sensitivity at a progressively higher modulation rate, by membrane-filtering and spike-generation properties producing realistically less than Poisson variance. Non-resonant model EI neurons are also sensitive to interaural intensity differences. With peripheral filters centered between carrier frequency and modulation sideband, fast resonant model EI neurons extend ITDENV sensitivity above 500-Hz modulation.Fil: Brughera, Andrew. Boston University; Estados Unidos. Macquarie University; AustraliaFil: Ballestero, Jimena Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: McAlpine, David. Macquarie University; Australi

The Role of Rab Proteins in Mitophagy: Insights into Neurodegenerative Diseases

Mitochondrial dysfunction and vesicular trafficking alterations have been implicated in the pathogenesis of several neurodegenerative diseases. It has become clear that pathogenetic pathways leading to neurodegeneration are often interconnected. Indeed, growing evidence suggests a concerted contribution of impaired mitophagy and vesicles formation in the dysregulation of neuronal homeostasis, contributing to neuronal cell death. Among the molecular factors involved in the trafficking of vesicles, Ras analog in brain (Rab) proteins seem to play a central role in mitochondrial quality checking and disposal through both canonical PINK1/Parkin-mediated mitophagy and novel alternative pathways. In turn, the lack of proper elimination of dysfunctional mitochondria has emerged as a possible causative/early event in some neurodegenerative diseases. Here, we provide an overview of major findings in recent years highlighting the role of Rab proteins in dysfunctional mitochondrial dynamics and mitophagy, which are characteristic of neurodegenerative diseases. A further effort should be made in the coming years to clarify the sequential order of events and the molecular factors involved in the different processes. A clear cause–effect view of the pathogenetic pathways may help in understanding the molecular basis of neurodegeneration