Low latency optical-based mode tracking with machine learning deployed on FPGAs on a tokamak.

Active feedback control in magnetic confinement fusion devices is desirable to mitigate plasma instabilities and enable robust operation. Optical high-speed cameras provide a powerful, non-invasive diagnostic and can be suitable for these applications. In this study, we process high-speed camera data, at rates exceeding 100 kfps, on in situ field-programmable gate array (FPGA) hardware to track magnetohydrodynamic (MHD) mode evolution and generate control signals in real time. Our system utilizes a convolutional neural network (CNN) model, which predicts the n = 1 MHD mode amplitude and phase using camera images with better accuracy than other tested non-deep-learning-based methods. By implementing this model directly within the standard FPGA readout hardware of the high-speed camera diagnostic, our mode tracking system achieves a total trigger-to-output latency of 17.6 µs and a throughput of up to 120 kfps. This study at the High Beta Tokamak-Extended Pulse (HBT-EP) experiment demonstrates an FPGA-based high-speed camera data acquisition and processing system, enabling application in real-time machine-learning-based tokamak diagnostic and control as well as potential applications in other scientific domains.

Inhibition of endosomal insulin-like growth factor-I processing by cysteine proteinase inhibitors blocks receptor-mediated functions.

The receptor for the type 1 insulin-like growth factor (IGF-I) has been implicated in cellular transformation and the acquisition of an invasive/metastatic phenotype in various tumors. Following ligand binding, the IGF-I receptor is internalized, and the receptor.ligand complex dissociates as the ligand is degraded by endosomal proteinases. In the present study we show that the inhibition of endosomal IGF-I-degrading enzymes in human breast and murine lung carcinoma cells by the cysteine proteinase inhibitors, E-64 and CA074-methyl ester, profoundly altered receptor trafficking and signaling. In treated cells, intracellular ligand degradation was blocked, and although the receptor and two substrates, Shc and Insulin receptor substrate, were hyperphosphorylated on tyrosine, IGF-I-induced DNA synthesis, anchorage-independent growth, and matrix metalloproteinase synthesis were inhibited. The results suggest that ligand processing by endosomal proteinases is a key step in receptor signaling and function and a potential target for therapy.

A G1 cell cycle arrest induced by ligands of the reovirus type 3 receptor is secondary to inactivation of p21ras and mitogen-activated protein kinase.

The reovirus type 3 S1 gene product (type 3 hemagglutinin; HA3) is the viral protein responsible for binding to a mammalian cell-surface receptor. It has been shown that HA3 binding to its receptor inhibits cell growth, even in the continuous presence of serum mitogens. Here, receptor-mediated signal transduction leading to growth arrest was studied after binding with synthetic or recombinant ligands in the absence of viral infection. Receptor ligation caused rapid inactivation of p21(ras), a decrease in Raf phosphorylation and in mitogen-activated protein kinase (MAPK) enzymatic activity, and G1 cell cycle arrest. Transfection and expression of constitutively active v-Has-ras prevented the G1 arrest, indicating that inactivation of p21(ras) is causative. Interestingly, v-Has-ras expression also decreased the efficiency of reoviridae replication, suggesting that inactivation of p21(ras) signals is required at some step of the viral cycle. This study may define new mechanisms regulating cell growth and support the approach of using viral proteins to identify and study cellular receptors. Synthetic receptor ligands with antiproliferative properties may be useful in drug development with the aim of blocking mitosis.

Effect of rhTNF-alpha injection into rat sciatic nerve.

To assess whether TNF-alpha causes inflammatory demyelination or axonal degeneration, we injected into rat sciatic nerve saline, 100 U and 1000 U of rhTNF-alpha and studied the electrophysiological and pathological effects. At day 1 electrophysiology showed a slight reduction of proximal compound muscle action potential amplitude and pathology showed edema, inflammatory infiltration of vessel walls and endoneurium only in nerves injected with 1000 U of rhTNF-alpha. At day 5, there was no demyelination and a percentage of degenerated fibers similar in the three groups. To study the blood-nerve barrier, fluorescein isothiocyanate-labelled albumin was given intravenously after intraneural injection. The nerves injected with 1000 U rhTNF-alpha showed a leakage of the tracer in the endoneurium. TNF-alpha does not appear, at the doses used, to have myelinotoxic or axonopathic properties. The electrophysiological effect at day 1 may be due to mechanical compression of nerve fibers as a result of the blood-nerve barrier damage with consequent endoneurial edema.

Uptake and metabolic fate of [HisA8,HisB4,GluB10,HisB27]insulin in rat liver in vivo.

Receptor-mediated endocytosis and subsequent endosomal proteolysis of [125I]TyrA14-[HisA8,HisB4,GluB10,HisB27]in sulin ([125I]TyrA14-H2 analogue), an insulin analogue exhibiting a high affinity for the insulin receptor, has been studied in liver parenchymal cells by quantitative subcellular fractionation and compared with that of wild-type [125I]TyrA14-insulin. Whereas the kinetics of uptake of the H2 analogue by liver was not different from that of insulin, the H2 analogue radioactivity after the 2 min peak declined significantly more slowly. A significant retention of the H2 analogue compared with insulin in both plasma membrane and endosomal fractions was observed and corresponded to decreased processing and dissociation of the H2 analogue. Cell-free endosomes preloaded in vivo with radiolabelled ligands and incubated in vitro processed insulin and extraluminally released insulin intermediates at a 2-3-fold higher rate than the H2 analogue. In vitro proteolysis of both non-radiolabelled and monoiodinated molecules by endosomal lysates showed a decreased response to the endosomal proteolytic machinery for the H2 analogue. However, in cross-linking and competition studies the H2 analogue exhibited an affinity for insulin-degrading enzyme identical with that of wild-type insulin. Brij-35-permeabilized endosomes revealed a 2-fold higher rate of dissociation of insulin from internalized receptors compared with the H2 analogue. After the administration of a saturating dose of both ligands, a rapid and reversible ligand-induced translocation of insulin receptor was observed, but without receptor loss. The H2 analogue induced a higher receptor concentration and tyrosine autophosphorylation of the receptor beta subunit in endosomes. Moreover, a prolonged temporal interaction of the in vivo injected H2 analogue with receptor was observed by direct binding assays performed on freshly prepared subcellular fractions. These results indicate that endosomal proteolysis for the H2 analogue is slowed as a result of an increased residence time of the analogue on the insulin receptor and a low affinity of endosomal acidic insulinase for the dissociated H2 molecule.

Insulin receptor internalization and signalling.

The insulin receptor kinase (IRK) is a tyrosine kinase whose activation, subsequent to insulin binding, is essential for insulin-signalling in target tissues. Insulin binding to its cell surface receptor is rapidly followed by internalization of insulin-IRK complexes into the endosomal apparatus (EN) of the cell. Internalization of insulin into target organs, especially liver, is implicated in effecting insulin clearance from the circulation. Internalization mediates IRK downregulation and hence attenuation of insulin sensitivity although most internalized IRKs readily recycle to the plasma membrane at physiological levels of insulin. A role for internalization in insulin signalling is indicated by the accumulation of activated IRKs in ENs. Furthermore, the maximal level of IRK activation has been shown to exceed that attained at the cell surface. Using an in vivo rat liver model in which endosomal IRKs are exclusively activated has revealed that IRKs at this intracellular locus are able by themselves to promote IRS-1 tyrosine phosphorylation and induce hypoglycemia. Furthermore, studies with isolated rat adipocytes reveal the EN to be the principle site of insulin-stimulated IRS-1 tyrosine phosphorylation and associated PI3K activation. Key steps in the termination of the insulin signal are also operative in ENs. Thus, an endosomal acidic insulinase has been identified which limits the extent of IRK activation. Furthermore, IRK dephosphorylation is effected in ENs by an intimately associated phosphotyrosine phosphatase(s) which, in rat liver, appears to regulate IRK activity in both a positive and negative fashion. Thus, insulin-mediated internalization of IRKs into ENs plays a crucial role in effecting and regulating signal transduction in addition to modulating the levels of circulating insulin and the cellular concentration of IRK in target tissues.

Low back pain due to hypertrophic roots as presenting symptom of CIDP.

Attention has recently been drawn to chronic inflammatory demyelinating polyneuropathy (CIDP) with symptomatic nerve root hypertrophy. A 31-year-old woman had fluctuating and worsening low back pain. Absent tendon jerks and a slight weakness of the hand interossei muscles suggested a diffuse neuropathy. The electrophysiological and histological findings were diagnostic for CIDP. Lumbar spine MRI showed marked nerve root enlargement with gadolinium enhancement. This case widens the range of the clinical presentations of CIDP. Further studies are warranted to ascertain whether cauda equina gadolinium enhancement may be a useful tool in the diagnosis of CIDP and a marker of disease activity for monitoring response to therapy.

Conduction block and segmental velocities in carpal tunnel syndrome.

In carpal tunnel syndrome (CTS) standard measurement of median distal motor latency and sensory conduction does not distinguish whether low amplitude responses are due to axonal degeneration or demyelination. In 88 control and 294 CTS hands we recorded amplitude and duration of compound muscle action potential (CMAP) and of antidromic sensory nerve action potential (SNAP) after palm and wrist stimulation to determine wrist to palm amplitude, duration ratios and segmental conduction velocities. In 16% of CTS hands there was an abnormal amplitude reduction without increased duration of CMAP or SNAP from wrist stimulation indicating partial conduction block. In 148 hands distal motor latency to abductor pollicis brevis and/or sensory conduction to digit 2 were abnormal. In the remaining 146 hands wrist to palm motor conduction was less than 35 m/s in 22.6% and wrist to palm sensory conduction was less than 45 m/s in 13%. At least one segmental conduction was abnormal in 27% of hands. Segmental studies allow the discrimination between conduction block and axonal degeneration, increase diagnostic yield in CTS, and might be useful in addressing treatment and predicting outcome.

Acute motor axonal neuropathy with high titer IgG and IgA anti-GD1a antibodies following Campylobacter enteritis.

We describe the first two European cases of acute axonal motor neuropathy with both IgG and IgA anti-GD1a antibodies following Campylobacter enteritis. Both patients acutely developed severe weakness without sensory involvement, had antibodies to Campylobacter jejuni and polyclonal IgG and IgA titers > or = 12,800 to GD1a at onset, which decreased during follow-up. Serial electrophysiologic studies showed: 1, normal or only slightly slowed motor conductions; 2, evidence of a progressive loss of excitability and conduction failure in nerve fibers undergoing axonal degeneration in intermediate nerve segments and evidence of distal axonal involvement in one nerve; 3, normal sensory conductions, sensory potential amplitudes and somatosensory evoked potentials. Although we cannot exclude that axonal degeneration followed demyelination, we think that anti-GD1a antibodies account for the axonal involvement because GD1a is present in the axolemma and exposed at the node of Ranvier and in nerve terminals. The exclusive motor involvement could be explained by the fact that GD1a has a different internal structure in motor and sensory fibers.

Compartmentalized signal transduction by receptor tyrosine kinases.

Signal transduction through receptor tyrosine kinases is believed to occur mainly at the plasma membrane. Ligands bind to their cognate receptors and trigger autophosphorylation events, which are detected by intracellular signalling molecules. However, ligands, such as epidermal growth factor and insulin, induce the rapid internalization of their receptors into endosomes. Although this event is traditionally thought to attenuate the ligand-induced response, in this article the authors discuss an alternative scenario in which selective and regulated signal transduction from receptor tyrosine kinases occurs within the endosome.

Endosomes, receptor tyrosine kinase internalization and signal transduction.

Upon the binding of insulin or epidermal growth factor to their cognate receptors on the liver parenchymal plasmalemma, signal transduction and receptor internalization are near co-incident. Indeed, the rapidity and extent of ligand mediated receptor internalization into endosomes in liver as well as other organs predicts that signal transduction is regulated at this intracellular locus. Although internalization has been thought as a mechanism to attenuate ligand mediated signal transduction responses, detailed studies of internalized receptors in isolated liver endosomes suggest an alternative scenario whereby selective signal transduction pathways can be accessed at this locus.

Differential electrophysiological features of neuropathies associated with 17p11.2 deletion and duplication.

UNLABELLED: Hereditary neuropathy with liability to pressure palsies (HNPP) and hereditary motor-sensory neuropathy type IA (HMSN IA) are quite distinct clinical entities recently associated to deletion and duplication, respectively, of the 17p11.2 segment including the gene for peripheral myelin protein 22 (PMP-22). We studied the electrophysiological features of 48 HNPP and 62 HMSN IA motor nerves. Conduction velocities (CV) and compound muscle action potential amplitudes were significantly reduced and distal latencies prolonged in HMSN IA compared to HNPP. CV was uniformly slowed in HMSN IA nerves whereas in HNPP it was focally slowed in 80% of ulnar and 12% of peroneal nerves at usual compression sites. Conduction block was present in 6% of HNPP nerves but in none of HMSN IA. IN CONCLUSION: (1) HMSN IA with 17p11.2 duplication presents marked, diffuse, and uniform slowing; (2) HNPP with 17p11.2 deletion presents focal electrophysiological abnormalities possibly correlated with the presence of tomaculae; and (3) under- and overexpression of PMP-22 in concurrence with environmental factors might be responsible for the distinctive features of HNPP and HMSN IA.

Compartmentalization of SHC, GRB2 and mSOS, and hyperphosphorylation of Raf-1 by EGF but not insulin in liver parenchyma.

Rat liver parenchyma harbors equal numbers of epidermal growth factor (EGF) and insulin receptors. Following administration of a saturating dose of EGF (10 micrograms/100 g body weight), there was a rapid (t1/2 approximately 1.1 min) internalization of receptor coincident with its tyrosine phosphorylation at residue 1173 and receptor recruitment of the adaptor protein SHC, its tyrosine phosphorylation and its association with GRB2 and the Ras guanine nucleotide exchange factor, mSOS, largely in endosomes. This led to a cytosolic pool of a complex of tyrosine-phosphorylated SHC, GRB2 and mSOS. It was demonstrated that these constituents were linked to Ras activation by the characteristic decrease in Raf-1 mobility on SDS-PAGE, which was maintained for 60 min after a single bolus of administered EGF. While insulin administration (15 micrograms/100 g body weight) led to insulin receptor beta-subunit tyrosine phosphorylation and internalization, there was little detectable tyrosine phosphorylation of SHC, recruitment of GRB2, association of a complex with mSOS or any detectable change in the mobility of Raf-1. Therefore, in normal physiological target cells in vivo, distinct signaling pathways are realized after EGF or insulin receptor activation, with regulation of this specificity most probably occurring at the locus of the endosome.

Chondrodysplasia punctata after warfarin. Case report with 18-month follow-up.

Administration of warfarin during pregnancy may cause a rare syndrome characterized by nasal hypoplasia, usually associated with stippled epiphyseal and extraepiphyseal calcifications resembling chondrodysplasia punctata. A case of chondrodysplasia punctata after warfarin with 18 months follow-up is reported.