An Optimized Structure-Function Design Principle Underlies Efficient Signaling Dynamics in Neurons.

Dynamic signaling on branching axons is critical for rapid and efficient communication between neurons in the brain. Efficient signaling in axon arbors depends on a trade-off between the time it takes action potentials to reach synaptic terminals (temporal cost) and the amount of cellular material associated with the wiring path length of the neuron's morphology (material cost). However, where the balance between structural and dynamical considerations for achieving signaling efficiency is, and the design principle that neurons optimize to preserve this balance, is still elusive. In this work, we introduce a novel analysis that compares morphology and signaling dynamics in axonal networks to address this open problem. We show that in Basket cell neurons the design principle being optimized is the ratio between the refractory period of the membrane, and action potential latencies between the initial segment and the synaptic terminals. Our results suggest that the convoluted paths taken by axons reflect a design compensation by the neuron to slow down signaling latencies in order to optimize this ratio. Deviations in this ratio may result in a breakdown of signaling efficiency in the cell. These results pave the way to new approaches for investigating more complex neurophysiological phenomena that involve considerations of neuronal structure-function relationships

SiNW-based Biosensors for Profiling Biomarkers in Breast Tumor Tissues

Breast cancer is the most common life-threatening malignancy in women of most developed countries today, with approximately 200,000 new cases diagnosed every year. About 30% of these cases progress to metastatic disease and death. Considering that one-third of these cancer deaths could be decreased if detected and treated early, new strategies for early breast cancer detection are needed to improve the efficacy of current diagnostics. The sensitive analysis of proteins such as breast cancer biomarkers has become the focus of intensive research due to its relevance to tumor diagnosis. However, the state-of-the-art diagnostic tools still lack the level of resolution needed for the detection of biomarkers at the very early stage of the disease, when treatments have more probability of success, and when protein concentration in tumor tissue is still very low. Nanotechnologies have shown great potential for the development of high-sensitive, portable devices for clinical applications. In particular, SiNWs with their unique properties such as the high surface-to-volume ratio and size, combined with the specificity of immune-sensing, are natural candidates for the fabrication of nanosensors. Thanks to their compatibility with conventional CMOS technology, SiNWs have been incorporated in standard FETs. In biosensing, SiNW-FETs have been shown a promising method for the label-free detection of trace amounts of biomolecules. However, detection of Antigen using Antibody immobilized SiNW-FETs is limited by ionic screening effects that reduce the sensor responsiveness and limit their applicability in tumor tissue. Here, we propose novel SiNW-based biosensing strategies with the aim of overcoming current sensitivity limitations of conventional SiNW-FET biosensors for the detection of breast cancer biomarkers in real human samples. Specifically, we address this goal by investigating two different approaches of biosensing. In the first method, we push the sensitivity of SiNW-FETs to their limits by proposing an alternative way of doing sensing in dry conditions. We show that in-air electrical measurements of Ab-Ag binding have the big advantage of increased Debye screening length in non-bulk solutions, and enable highly sensitive and specific measurements in breast tumor extract. Then, we present a completely novel biosensing paradigm that shows, for the first time, the use of memristive effects in fabricated SiNWs for biodetection purposes. This novel detection method has been named Voltage Gap (VoG)-biosensing as it is based on the changes of the VoG parameter, observed in the hysteretic characteristic of memristive devices, as a function of biomolecules. In this research, we demonstrate the use of the memristive-based VoG effect in Schottky Barrier SiNWs for the high-resolution sensing of ionic and biological species both in ideal buffer solutions and in tumor tissue extracts. Moreover, we propose an original theory enabling the physical interpretation and prediction of the mechanisms underlying the VoG-biosensing method in memristive devices. Finally, we demonstrate the potential of our system for future integration in a multi-panel VoG-biosensing platform. We fabricated a PDMS microfluidics enabling selective and high-quality functionalization of the NWs. We also realized a CMOS readout circuit for multiplexed VoG acquisition. The simulations demonstrate the feasibility of the approach and the potential for the integration of the reader with a portable and automated biosensing platform. Microfluidics and VoG reader will enable fast, concurrent detection ofmultiple angiogenic and inflammatory ligands in tumor tissue. This will highly improve the level of knowledge of the cancer disease by capturing the heterogeneity and the complexity of the tumor microenvironment, thus leading to novel opportunities in breast cancer diagnosis

Beneficial effects of long-term treatment with bosentan on the development of pulmonary arterial hypertension in patients with systemic sclerosis

OBJECTIVE: To investigate the effects of long-term treatment with bosentan on pulmonary arterial hypertension (PAH) in patients with systemic sclerosis. METHODS: Patients with systemic sclerosis were followed between 2003 and 2014; those who developed digital ulcers were treated with standard regimens of bosentan. Patients were assessed at baseline and every 12\u2009months using transthoracic Doppler echocardiography, 6-min walking distance test, Borg dyspnoea index and monitoring of plasma levels of 76-amino-acid N-terminal probrain natriuretic peptide. Patients who developed PAH underwent right heart catheterization to confirm the diagnosis. RESULTS: Sixty-nine patients with systemic sclerosis were enrolled in the study. Of these, 25 developed digital ulcers and received treatment with bosentan; the remaining 44 comprised the control group. None of the patients treated with bosentan developed PAH during the follow-up period. Furthermore, in these patients the mean\u2009\ub1\u2009SD systolic pulmonary arterial pressure significantly decreased from 33.64\u2009\ub1\u20092.91\u2009mmHg at baseline to 26.20\u2009\ub1\u20091.78\u2009mmHg at the end of the follow-up period. In contrast, in the control group, seven patients developed PAH during the follow-up period, with the mean\u2009\ub1\u2009SD systolic pulmonary arterial pressure significantly increasing from 33.57\u2009\ub1\u20092.75\u2009mmHg at baseline to 39.41\u2009\ub1\u20094.11\u2009mmHg at the end of the follow-up period. CONCLUSION: Long-term treatment with bosentan reduces the risk of developing PAH in patients with systemic sclerosis

expression of membrane bound human leucocyte antigen g in systemic sclerosis and systemic lupus erythematosus

Abstract Human leucocyte antigen-G (HLA-G) is a nonclassical class I major histocompatibility complex (MHC) molecule characterized by complex immunoregulatory and tolerogenic functions. Membrane-bound HLA-G is expressed on the surface of different cell populations in both physiological and pathological conditions. Systemic sclerosis (SSc) is a multisystem autoimmune disease characterized by widespread tissue fibrosis, vascular lesions and immunological alterations. Systemic lupus erythematosus is the prototypic systemic autoimmune disease affecting virtually any organ system, such as skin, joints, central nervous system, or kidneys. In SSc and SLE patients, the membrane expression of HLA-G on monocytes (0.88 ± 1.54 and 0.43 ± 0.75, respectively), CD4+ (0.42 ± 0.78 and 0.63 ± 0.48, respectively), CD8+ (2.65 ± 3.47 and 1.29 ± 1.34, respectively) and CD4+ CD8+ double-positive cells (13.87 ± 15.97 and 3.79 ± 3.11, respectively) was significantly higher than in healthy controls (0.12 ± 0.07; 0.01 ± 0.01; 0.14 ± 0.20 and 0.32 ± 0.38, respectively) (

Nuclear Run-On Assay Using Biotin Labeling, Magnetic Bead Capture and Analysis by Fluorescence-Based RT-PCR

In this report, we present a fluorescencebased approach to the assessment of cellular gene expression and transcription rates. Nuclear run-on was performed by supplying biotin-16-UTP to nuclei, and labeled transcripts were bound to streptavidin-coated magnetic beads. Total cDNA was then synthesized by means of random hexamer primed reverse transcription of captured molecules. To monitor transcript abundance in cDNA, both from nuclear run-on and total RNA, we propose a semiquantitative PCR approach based on the use of fluorescent primers

Memristive sensors for pH measure in dry conditions

A large progress in pH sensing with nanowire based ion-sensitive field-effect transistors (ISFETs) has been demonstrated over the years. The electrochemical reactions occurring at the wire surface-to-electrolyte interface play a key role in the detection of ions. In this letter, we show that pH sensing can also be performed on dried samples, through electrical measurements in air with a new kind of memristive sensor. The detection of different concentrations of [H+] is confirmed by both the increased conductance and hysteretic voltage gap of the wires. The observed change in the electrical properties with pH in dry conditions is related to the formation of a wet film at the nanowire surface. Ions from the initial solution are free to move in the final water thin film at the sensing interface with consequent polarization of the NW surface

Novel Readout Circuit for Memristive Biosensors in Cancer Detection

We present a novel circuit for the automated and quick characterization of an array of experimental memristive nanowires that are functionalized as biosensors. Successfully functionalized nanowires will express the concentration of target molecules by hysteretic gaps of the zero crossing of their mem- ristive I/V characteristics as the voltage across them is swept up and down. The width of the voltage gap is directly proportional to the target molecule concentration. The characterization circuit sorts out faulty, i.e. non-conducting nanowires in the array, and performs an analog to digital conversion of the voltage gap to assess successful functionalization of the others, and thus significantly reduces the time for functional testing. Many of the test parameters are configurable: the speed and range of the voltage sweep and the resolution of the measurements. An initial prototype 2x2 array of the circuit has been layed out in 0.35μm CMOS technology within an area of 0.429 mm2 and has been thoroughly characterized in simulation, has been layed out, and is ready for fabrication

Modeling Memristive Biosensors

In the present work, a computational study is carried out investigating the relationship between the biosensing and the electrical characteristics of two-terminal Schottky- barrier silicon nanowire devices. The model suggested successfully reproduces computationally the experimentally obtained electrical behavior of the devices prior to and after the surface bio-modification. Throughout modeling and simulations, it is confirmed that the nanofabricated devices present electrical behavior fully equivalent to that of a memristor device, according to literature. Furthermore, the model introduced successfully reproduces computationally the voltage gap appearing in the current to voltage characteristics for nanowire devices with bio- modified surface. Overall, the present study confirms the implication of the memristive effect for bio sensing applications, therefore demonstrating the Memristive Biosensors

Autoimmune central diabetes insipidus in a patient with ureaplasma urealyticum infection and review on new triggers of immune response

Diabetes insipidus is a disease in which large volumes of dilute urine (polyuria) are excreted due to vasopressin (AVP) deficiency [central diabetes insipidus (CDI)] or to AVP resistance (nephrogenic diabetes insipidus). In the majority of patients, the occurrence of CDI is related to the destruction or degeneration of neurons of the hypothalamic supraoptic and paraventricular nuclei. The most common and well recognized causes include local inflammatory or autoimmune diseases, vascular disorders, Langerhans cell histiocytosis (LCH), sarcoidosis, tumors such as germinoma/craniopharyngioma or metastases, traumatic brain injuries, intracranial surgery, and midline cerebral and cranial malformations. Here we have the opportunity to describe an unusual case of female patient who developed autoimmune CDI following ureaplasma urealyticum infection and to review the literature on this uncommon feature. Moreover, we also discussed the potential mechanisms by which ureaplasma urealyticum might favor the development of autoimmune CDI

Memristor-Based Devices for Sensing

In this paper we propose CMOS-compatible Memristive-Biosensors as label-free, highly sensitive sensors for in-air detection of Vascular Endothelial Growth Factor (VEGF) molecules. The memristive behavior of the fabricated devices is strongly affected by molecules in proximity of the wire surface. In this paper, we demonstrate the reproducibility of the measurement based on the memristive voltage gap. We also show the successful sensing of femto-molar amounts of VEGF. Specifically, we demonstrate a correlation between the decreasing behavior of the voltage gap and the increasing concentrations of VEGF. The voltage gap dependence on the pH of the initial solution is also shown as a further proof of the ionic interactions occurring at the SiNW surface. All measurements are performed in air, under controlled humidity; this makes our approach more sensitive thanks to the lowered Debye screening effect of counterions