An Extracellular Domain of the Insulin Receptor β-Subunit with Regulatory Function on Protein-Tyrosine Kinase

Abstract Anti-insulin receptor monoclonal antibody MA-10 inhibits insulin receptor autophosphorylation of purified rat liver insulin receptors without affecting insulin binding (Cordera, R., Andraghetti, G., Gherzi, R., Adezati, L., Montemurro, A., Lauro, R., Goldfine, I. D., and De Pirro, R. (1987) Endocrinology 121, 2007-2010). The effect of MA-10 on insulin receptor autophosphorylation and on two insulin actions (thymidine incorporation into DNA and receptor down-regulation) was investigated in rat hepatoma Fao cells. MA-10 inhibits insulin-stimulated receptor autophosphorylation, thymidine incorporation into DNA, and insulin-induced receptor down-regulation without affecting insulin receptor binding. We show that MA-10 binds to a site of rat insulin receptors different from the insulin binding site in intact Fao cells. Insulin does not inhibit MA-10 binding, and MA-10 does not inhibit insulin binding to rat Fao cells. Moreover, MA-10 binding to down-regulated cells is reduced to the same extent as insulin binding. In rat insulin receptors the MA-10 binding site has been tentatively localized in the extracellular part of the insulin receptor beta-subunit based on the following evidence: (i) MA-10 binds to insulin receptor in intact rat cells; (ii) MA-10 immunoprecipitates isolated insulin receptor beta-subunits labeled with both [35S]methionine and 32P; (iii) MA-10 reacts with rat insulin receptor beta-subunits by the method of immunoblotting, similar to an antipeptide antibody directed against the carboxyl terminus of the insulin receptor beta-subunit. Moreover, MA-10 inhibits autophosphorylation and protein-tyrosine kinase activity of reduced and purified insulin receptor beta-subunits. The finding that MA-10 inhibits insulin-stimulated receptor autophosphorylation and reduces insulin-stimulated thymidine incorporation into DNA and receptor down-regulation suggests that the extracellular part of the insulin receptor beta-subunit plays a role in the regulation of insulin receptor protein-tyrosine kinase activity

Impact of Treatment With Protease Inhibitors on Aortic Stiffness in Adult Patients With Human Immunodeficiency Virus Infection

Background— The role of antiretroviral therapy in acceleration of atherosclerosis in patients with human immunodeficiency virus (HIV) infection is controversial. We hypothesized that aortic stiffness, an early marker of arteriosclerosis, may be increased in HIV patients treated with protease inhibitors. Methods and Results— In 32 HIV-infected patients treated with protease inhibitors and 32 age-, sex-, and blood pressure–matched HIV-uninfected control subjects, we obtained aortic pulse wave velocity and central aortic pressure waveform, from which aortic augmentation was calculated. HIV patients had a higher aortic pulse wave velocity (7.6±1.1 versus 6.8±1.2 m×s −1 , P =0.015) and aortic augmentation (6.8±5 versus 4.6±4 mm Hg, P =0.037) than control subjects. Age and HIV infection (both P <0.05) independently predicted aortic pulse wave velocity when a consistent number of cardiovascular risk factors was simultaneously controlled for. The cumulative duration of treatment was a predictor of aortic pulse wave velocity, each 5 years of treatment duration being independently related to a 1.35 m×s −1 increase in pulse wave velocity. Conclusions— Aortic stiffness is increased in HIV-positive individuals receiving antiretroviral therapy including a protease inhibitor. Pulse wave velocity increases with longer exposure to protease inhibitors. We hypothesize that arteriosclerosis is a side effect of antiretroviral treatment including a protease inhibitor

An improved non-invasive method for measuring heartbeat of intertidal animals

Since its emergence two decades ago, the use of infrared technology for noninvasively measuring the heartbeat rates of invertebrates has provided valuable insight into the physiology and ecology of intertidal organisms. During that time period, the hardware needed for this method has been adapted to currently available electronic components, making the original published description obsolete. This article reviews the history of heartbeat sensing technology, and describes the design and function of a modern and simplified infrared heartbeat rate sensing system compatible with many intertidal and marine invertebrates. This technique overcomes drawbacks and obstacles encountered with previous methods of heartbeat rate measurement, and due to the sensor’s small size, versatility, and noninvasive nature, it creates new possibilities for studies across a wide range of organismal type

Maraviroc Intensification Modulates Atherosclerotic Progression in HIV-Suppressed Patients at High Cardiovascular Risk. A Randomized, Crossover Pilot Study

Background Experimental CCR5 antagonism with maraviroc in atherosclerosis-prone mice and preliminary data in humans suggest an anti-atherosclerotic effect of the drug. We assessed the impact of maraviroc treatment in persons living with HIV on subclinical indicators of atherosclerosis. Methods Persons living with HIV on effective antiretroviral therapy (ART) including only protease inhibitors were recruited if they had a Framingham risk score &gt;20% and brachial flow-mediated dilation (bFMD) &lt;4%, as indices of high cardiovascular risk. Maraviroc (300 mg per os for 24 weeks) was administered, in addition to ongoing ART, to all patients using a crossover design. Brachial FMD, carotid-femoral pulse wave velocity (cfPWV), and carotid intima-media thickness (cIMT) were measured as markers of atherosclerosis. Vascular competence—as expressed by the ratio of circulating endothelial microparticles (EMPs) to endothelial progenitor cells (EPCs)—and markers of systemic inflammation and monocyte and platelet activation were assessed. Results Maraviroc treatment significantly improved bFMD, cfPWV, and cIMT by 66%, 11%, and 13%, respectively (P = .002, P = .022, P = .038, respectively). We also found a beneficial effect of maraviroc on the EMP/EPC ratio (P &lt; .001) and platelet/leucocyte aggregates (P = .013). No significant changes in markers of systemic inflammation, monocyte activation, and microbial translocation were observed. Conclusions Maraviroc led to significant improvements in several markers for cardiovascular risk, endothelial dysfunction, arterial stiffness, and early carotid atherosclerosis, which was accompanied by an increase of vascular competence, without seeming to affect systemic inflammation. Our data support the need for larger studies to test for any effects of maraviroc on preventing atherosclerosis-driven pathologies

A New Limit on the Neutrinoless DBD of 130Te

We report the present results of CUORICINO a cryogenic experiment on neutrinoless double beta decay (DBD) of 130Te consisting of an array of 62 crystals of TeO2 with a total active mass of 40.7 kg. The array is framed inside of a dilution refrigerator, heavily shielded against environmental radioactivity and high-energy neutrons, and operated at a temperature of ~8 mK in the Gran Sasso Underground Laboratory. Temperature pulses induced by particle interacting in the crystals are recorded and measured by means of Neutron Transmutation Doped thermistors. The gain of each bolometer is stabilized with voltage pulses developed by a high stability pulse generator across heater resistors put in thermal contact with the absorber. The calibration is performed by means of two thoriated wires routinely inserted in the set-up. No evidence for a peak indicating neutrinoless DBD of 130Te is detected and a 90% C.L. lower limit of 1.8E24 years is set for the lifetime of this process. Taking largely into account the uncertainties in the theoretical values of nuclear matrix elements, this implies an upper boud on the effective mass of the electron neutrino ranging from 0.2 to 1.1 eV. This sensitivity is similar to those of the 76Ge experiments.Comment: 4 pages, 2 figure

Overview of Plasma Lens Experiments and Recent Results at SPARC_LAB

Beam injection and extraction from a plasma module is still one of the crucial aspects to solve in order to produce high quality electron beams with a plasma accelerator. Proper matching conditions require to focus the incoming high brightness beam down to few microns size and to capture a high divergent beam at the exit without loss of beam quality. Plasma-based lenses have proven to provide focusing gradients of the order of kT/m with radially symmetric focusing thus promising compact and affordable alternative to permanent magnets in the design of transport lines. In this paper an overview of recent experiments and future perspectives of plasma lenses is reported

A Cryogenic Underground Observatory for Rare Events: Cuore, an Update

CUORE is a proposed tightly packed array of 1000 TeO_{2} bolometers, each being a cube 5 cm on a side with a mass of 750 gms. The array consists of 25 vertical towers, arranged in a square, of 5 towers by 5 towers, each containing 10 layers of 4 crystals. The design of the detector is optimized for ultralow- background searches for neutrinoless double beta decay of ^{130}Te (33.8% abundance), cold dark matter, solar axions, and rare nuclear decays. A preliminary experiment involving 20 crystals of various sizes (MIBETA) has been completed, and a single CUORE tower is being constructed as a smaller scale experiment called CUORICINO. The expected performance and sensitivity, based on Monte Carlo simulations and extrapolations of present results, are reported.Comment: in press: Nucl. Phys. of Russian Academy of Sc

Genome-wide association study of primary open-angle glaucoma in continental and admixed African populations.

Primary open angle glaucoma (POAG) is a complex disease with a major genetic contribution. Its prevalence varies greatly among ethnic groups, and is up to five times more frequent in black African populations compared to Europeans. So far, worldwide efforts to elucidate the genetic complexity of POAG in African populations has been limited. We conducted a genome-wide association study in 1113 POAG cases and 1826 controls from Tanzanian, South African and African American study samples. Apart from confirming evidence of association at TXNRD2 (rs16984299; OR[T] 1.20; P = 0.003), we found that a genetic risk score combining the effects of the 15 previously reported POAG loci was significantly associated with POAG in our samples (OR 1.56; 95% CI 1.26-1.93; P = 4.79 × 10-5). By genome-wide association testing we identified a novel candidate locus, rs141186647, harboring EXOC4 (OR[A] 0.48; P = 3.75 × 10-8), a gene transcribing a component of the exocyst complex involved in vesicle transport. The low frequency and high degree of genetic heterogeneity at this region hampered validation of this finding in predominantly West-African replication sets. Our results suggest that established genetic risk factors play a role in African POAG, however, they do not explain the higher disease load. The high heterogeneity within Africans remains a challenge to identify the genetic commonalities for POAG in this ethnicity, and demands studies of extremely large size

Proposal for taking data with the KLOE-2 detector at the DAΦ\PhiNE collider upgraded in energy

This document reviews the physics program of the KLOE-2 detector at DA$\Phi$NE upgraded in energy and provides a simple solution to run the collider above the $\phi$-peak (up to 2, possibly 2.5 GeV). It is shown how a precise measurement of the multihadronic cross section in the energy region up to 2 (possibly 2.5) GeV would have a major impact on the tests of the Standard Model through a precise determination of the anomalous magnetic moment of the muon and the effective fine-structure constant at the $M_Z$ scale. With a luminosity of about $10^{32}$cm$^{-2}$s$^{-1}$, DA$\Phi$NE upgraded in energy can perform a scan in the region from 1 to 2.5 GeV in one year by collecting an integrated luminosity of 20 pb$^{-1}$ (corresponding to a few days of data taking) for single point, assuming an energy step of 25 MeV. A few years of data taking in this region would provide important tests of QCD and effective theories by $\gamma\gamma$ physics with open thresholds for pseudo-scalar (like the $\eta'$), scalar ($f_0,f'_0$, etc...) and axial-vector ($a_1$, etc...) mesons; vector-mesons spectroscopy and baryon form factors; tests of CVC and searches for exotics. In the final part of the document a technical solution for the energy upgrade of DA$\Phi$NE is proposed.Comment: 19 pages, 8 figure

Calcium Channel Blocker Use and Associated Glaucoma and Related Traits Among UK Biobank Participants

IMPORTANCE: Calcium channel blocker (CCB) use has been associated with an increased risk of glaucoma in exploratory studies. OBJECTIVE: To examine the association of systemic CCB use with glaucoma and related traits among UK Biobank participants. DESIGN, SETTING, AND PARTICIPANTS: This population-based cross-sectional study included UK Biobank participants with complete data (2006-2010) for analysis of glaucoma status, intraocular pressure (IOP), and optical coherence tomography (OCT)-derived inner retinal layer thicknesses. Data analysis was conducted in January 2023. EXPOSURE: Calcium channel blocker use was assessed in a baseline touchscreen questionnaire and confirmed during an interview led by a trained nurse. MAIN OUTCOMES AND MEASURES: The primary outcome measures included glaucoma status, corneal-compensated IOP, and 2 OCT-derived inner retinal thickness parameters (macular retinal nerve fiber layer [mRNFL] and macular ganglion cell-inner plexiform layer [mGCIPL] thicknesses). We performed logistic regression and linear regression analyses to test for associations with glaucoma status and IOP and OCT-derived inner retinal thickness parameters, respectively. RESULTS: This study included 427 480 adults. Their median age was 58 (IQR, 50-63) years, and more than half (54.1%) were women. There were 33 175 CCB users (7.8%). Participants who had complete data for glaucoma status (n = 427 480), IOP (n = 97 100), and OCT-derived inner retinal layer thicknesses (n = 41 023) were eligible for respective analyses. After adjustment for key sociodemographic, medical, anthropometric, and lifestyle factors, use of CCBs (but not other antihypertensive agents) was associated with greater odds of glaucoma (odds ratio [OR], 1.39 [95% CI, 1.14 to 1.69]; P = .001). Calcium channel blocker use was also associated with thinner mGCIPL (-0.34 μm [95% CI, -0.54 to -0.15 μm]; P = .001) and mRNFL (-0.16 μm [95% CI, -0.30 to -0.02 μm]; P = .03) thicknesses but not IOP (-0.01 mm Hg [95% CI, -0.09 to 0.07 mm Hg]; P = .84). CONCLUSIONS AND RELEVANCE: In this study, an adverse association between CCB use and glaucoma was observed, with CCB users having, on average, 39% higher odds of glaucoma. Calcium channel blocker use was also associated with thinner mGCIPL and mRNFL thicknesses, providing a structural basis that supports the association with glaucoma. The lack of association of CCB use with IOP suggests that an IOP-independent mechanism of glaucomatous neurodegeneration may be involved. Although a causal relationship has not been established, CCB replacement or withdrawal may be considered should glaucoma progress despite optimal care