Modulation by internal protons of native cyclic nucleotide-gated channels from retinal rods

Ion channels directly activated by cyclic nucleotides are present in the plasma membrane of retinal rod outer segments. These channels can be modulated by several factors including internal pH (pH(i)). Native cyclic nucleotide-gated channels were studied in excised membrane patches from the outer segment of retinal rods of the salamander. Channels were activated by cGMP or cAMP and currents as a function of voltage and cyclic nucleotide concentrations were measured as pH(i) was varied between 7.6 and 5.0. Increasing internal proton concentrations reduced the current activated by cGMP without modifying the concentration (K(1/2)) of cGMP necessary for half-activation of the maximal current. This effect could be well described as a reduction of single-channel current by protonation of a single acidic residue with a pK(1) of 5.1. When channels were activated by cAMP a more complex phenomenon was observed. K(1/2) for cAMP decreased by increasing internal proton concentration whereas maximal currents activated by cAMP increased by lowering pH(i) from 7.6 to 5.7-5.5 and then decreased from pH(i) 5.5 to 5.0. This behavior was attributed both to a reduction in single-channel current as measured with cGMP and to an increase in channel open probability induced by the binding of three protons to sites with a pK(2) of 6

Pre-torsors and Galois comodules over mixed distributive laws

We study comodule functors for comonads arising from mixed distributive laws. Their Galois property is reformulated in terms of a (so-called) regular arrow in Street's bicategory of comonads. Between categories possessing equalizers, we introduce the notion of a regular adjunction. An equivalence is proven between the category of pre-torsors over two regular adjunctions $(N_A,R_A)$ and $(N_B,R_B)$ on one hand, and the category of regular comonad arrows $(R_A,\xi)$ from some equalizer preserving comonad ${\mathbb C}$ to $N_BR_B$ on the other. This generalizes a known relationship between pre-torsors over equal commutative rings and Galois objects of coalgebras.Developing a bi-Galois theory of comonads, we show that a pre-torsor over regular adjunctions determines also a second (equalizer preserving) comonad ${\mathbb D}$ and a co-regular comonad arrow from ${\mathbb D}$ to $N_A R_A$, such that the comodule categories of ${\mathbb C}$ and ${\mathbb D}$ are equivalent.Comment: 34 pages LaTeX file. v2: a few typos correcte

Hygienic and dietetic guidelines for implant-supported full-arch immediate loading prostheses

Introduction: Proper oral hygiene and diet are important considerations for success in implant prosthodontics. However, detailed hygienic and dietetic guidelines for patients rehabilitated with implant-supported, immediate loading prostheses are lacking in the literature. Methods: The authors have developed a dietary and hygienic protocol for patients rehabilitated with implant-supported, full-arch, immediate loading prostheses in order to avoid occlusal overloads during osseointegration and optimize healing. Results: The dietary and hygienic guidelines provided in this paper emphasize the importance of maintaining proper oral hygiene and diet to support osseointegration and soft tissue healing during postsurgery healing periods. Conclusions: The protocol presented has been an effective instrument to obtain and maintain osseointegration in patients rehabilitated with full-arch, immediate loading prostheses

Ergonomics and Workflow Evaluation of Automatic Doppler Angle Technology Implemented in a Diagnostic Ultrasound System

AbstractCommonly available Pulsed Wave Doppler (PW) flow velocity measurements for Ultrasound (US) investigation require the operator to manually set the direction of the flow velocity vector along the blood vessel axis on the US image, in order to determine the Doppler angle and then to estimate the real flow velocity. The present work investigates the possibility to implement on a commercially available US system an innovative Automatic Doppler Angle (ADA) Technology by analyzing the best workflow in terms of higher execution speed, lower keystrokes/adjustments helping in the prevention of Work-related Musculoskeletal Disorders (WRMSD) and a Doppler angle correction precision, comparable to the one obtained manually by expert sonographer. Ergonomics and workflow tests, then accuracy and repeatability evaluations of the Doppler velocity measurement, were performed on a portable US system (MyLabAlpha, Esaote S.p.A., Florence, Italy) by an expert sonographer. Ergonomics and workflow Tests were performed to analyze the potential of ADA in terms of reduction of muscular activation applied (by SEMG), number of activations (by cameras optoelectronic system) and time needed using ADA, in comparison to manual procedure. Accuracy and intra-operator repeatability tests of the velocity measurement were performed to evaluate the precision of the obtained PW trace velocity measurements with ADA technology, compared to manual ones. Results provided evidence that ADA tool allowed: a reduction of muscular activation (from 12% for trapezius descendens, to 25% for deltoideus anterior) a lower total number of keystrokes and a reduction of the US scan time of about 56%. The maximal variation between PW Doppler trace velocity measurement set automatically by ADA and set manually by sonographer was 11%. ADA technology can provide a Doppler angle correction precision comparable to the manual one, while decreasing the risk of WRMSD

Sensory adaptation to chemical cues by vomeronasal sensory neurons

Sensory adaptation is a source of experience-dependent feedback that impacts responses to environmental cues. In the mammalian main olfactory system (MOS), adaptation influences sensory coding at its earliest processing stages. Sensory adaptation in the accessory olfactory system (AOS) remains incompletely explored, leaving many aspects of the phenomenon unclear. We investigated sensory adaptation in vomeronasal sensory neurons (VSNs) using a combination of in situ Ca2+ imaging and electrophysiology. Parallel studies revealed prominent short-term sensory adaptation in VSNs upon repeated stimulation with mouse urine and monomolecular bile acid ligands at interstimulus intervals (ISIs) less than 30 s. In such conditions, Ca2+ signals and spike rates were often reduced by more than 50%, leading to dramatically reduced chemosensory sensitivity. Short-term adaptation was reversible over the course of minutes. Population Ca2+ imaging experiments revealed the presence of a slower form of VSN adaptation that accumulated over dozens of stimulus presentations delivered over tens of minutes. Most VSNs showed strong adaptation, but in a substantial VSN subpopulation adaptation was diminished or absent. Investigation of same-and opposite-sex urine responses in male and female VSNs revealed that adaptation to same-sex cues occurred at ISIs up to 180 s, conditions that did not induce adaptation to opposite-sex cues. This result suggests that VSN sensory adaptation can be modulated by sensory experience. These studies comprehensively establish the presence of VSN sensory adaptation and provide a foundation for future inquiries into the molecular and cellular mechanisms of this phenomenon and its impact on mammalian behavior

Diabetes promotes invasive pancreatic cancer by increasing systemic and tumour carbonyl stress in Kras G12D/+mice

Background: Type 1 and 2 diabetes confer an increased risk of pancreatic cancer (PaC) of similar magnitude, suggesting a common mechanism. The recent finding that PaC incidence increases linearly with increasing fasting glucose levels supports a central role for hyperglycaemia, which is known to cause carbonyl stress and advanced glycation end-product (AGE) accumulation through increased glycolytic activity and non-enzymatic reactions. This study investigated the impact of hyperglycaemia on invasive tumour development and the underlying mechanisms involved. Methods: Pdx1-Cre;LSL-Kras G12D/+ mice were interbred with mitosis luciferase reporter mice, rendered diabetic with streptozotocin and treated or not with carnosinol (FL-926-16), a selective scavenger of reactive carbonyl species (RCS) and, as such, an inhibitor of AGE formation. Mice were monitored for tumour development by in vivo bioluminescence imaging. At the end of the study, pancreatic tissue was collected for histology/immunohistochemistry and molecular analyses. Mechanistic studies were performed in pancreatic ductal adenocarcinoma cell lines challenged with high glucose, glycolysis- and glycoxidation-derived RCS, their protein adducts AGEs and sera from diabetic patients. Results: Cumulative incidence of invasive PaC at 22 weeks of age was 75% in untreated diabetic vs 25% in FL-926-16-gtreated diabetic and 8.3% in non-diabetic mice. FL-926-16 treatment suppressed systemic and pancreatic carbonyl stress, extracellular signal-regulated kinases (ERK) 1/2 activation, and nuclear translocation of Yes-associated protein (YAP) in pancreas. In vitro, RCS scavenging and AGE elimination completely inhibited cell proliferation stimulated by high glucose, and YAP proved essential in mediating the effects of both glucose-derived RCS and their protein adducts AGEs. However, RCS and AGEs induced YAP activity through distinct pathways, causing reduction of Large Tumour Suppressor Kinase 1 and activation of the Epidermal Growth Factor Receptor/ERK signalling pathway, respectively. Conclusions: An RCS scavenger and AGE inhibitor prevented the accelerating effect of diabetes on PainINs progression to invasive PaC, showing that hyperglycaemia promotes PaC mainly through increased carbonyl stress. In vitro experiments demonstrated that both circulating RCS/AGEs and tumour cell-derived carbonyl stress generated by excess glucose metabolism induce proliferation by YAP activation, hence providing a molecular mechanism underlying the link between diabetes and PaC (and cancer in general)

Evaluation of polyneuropathy markers in type 1 diabetic kidney transplant patients and effects of islet transplantation: Neurophysiological and skin biopsy longitudinal analysis

OBJECTIVE - The purpose of this study was to evaluate whether islet transplantation may stabilize polyneuropathy in uremic type 1 diabetic patients (end-stage renal disease [ESRD] and type 1 diabetes), who received a successful islet-after-kidney transplantation (KI-s). RESEARCH DESIGN AND METHODS - Eighteen KI-s patients underwent electroneurographic tests of sural, peroneal, ulnar, and median nerves: the nerve conduction velocity (NCV) index and amplitudes of both sensory action potentials (SAPs) and compound motor action potentials (CMAPs) were analyzed longitudinally at 2, 4, and 6 years after islet transplantation. Skin content of advanced glycation end products (AGEs) and expression of their specific receptors (RAGE) were also studied at the 4-year follow-up. Nine patients with ESRD and type 1 diabetes who received kidney transplantation alone (KD) served as control subjects. RESULTS - The NCV score improved in the KI-s group up to the 4-year time point (P = 0.01 versus baseline) and stabilized 2 years later, whereas the same parameter did not change significantly in the KD group throughout the follow-up period or when a cross-sectional analysis between groups was performed. Either SAP or CMAP amplitudes recovered in the KI-s group, whereas they continued worsening in KD control subjects. AGE and RAGE levels in perineurium and vasa nervorum of skin biopsies were lower in the KI-s than in the KD group (P < 0.01 for RAGE). CONCLUSIONS - Islet transplantation seems to prevent long-term worsening of polyneuropathy in patients with ESRD and type 1 diabetes who receive islets after kidney transplantation. No statistical differences between the two groups were evident on cross-sectional analysis. A reduction in AGE/RAGE expression in the peripheral nervous system was shown in patients receiving islet transplantation. © 2007 by the American Diabetes Association