Characterization of nanoparticle mediated laser transfection by femtosecond laser pulses for applications in molecular medicine

Background: In molecular medicine, the manipulation of cells is prerequisite to evaluate genes as therapeutic targets or to transfect cells to develop cell therapeutic strategies. To achieve these purposes it is essential that given transfection techniques are capable of handling high cell numbers in reasonable time spans. To fulfill this demand, an alternative nanoparticle mediated laser transfection method is presented herein. The fs-laser excitation of cell-adhered gold nanoparticles evokes localized membrane permeabilization and enables an inflow of extracellular molecules into cells. Results: The parameters for an efficient and gentle cell manipulation are evaluated in detail. Efficiencies of 90% with a cell viability of 93% were achieved for siRNA transfection. The proof for a molecular medical approach is demonstrated by highly efficient knock down of the oncogene HMGA2 in a rapidly proliferating prostate carcinoma in vitro model using siRNA. Additionally, investigations concerning the initial perforation mechanism are conducted. Next to theoretical simulations, the laser induced effects are experimentally investigated by spectrometric and microscopic analysis. The results indicate that near field effects are the initial mechanism of membrane permeabilization. Conclusion: This methodical approach combined with an automated setup, allows a high throughput targeting of several 100,000 cells within seconds, providing an excellent tool for in vitro applications in molecular medicine. NIR fs lasers are characterized by specific advantages when compared to lasers employing longer (ps/ns) pulses in the visible regime. The NIR fs pulses generate low thermal impact while allowing high penetration depths into tissue. Therefore fs lasers could be used for prospective in vivo applications.

High Quality Acoustic Time History Measurements of Rotor Harmonic Noise in Confined Spaces

A methodology has been developed and presented to enable the use of small to medium scale acoustic hover facilities for the quantitative measurement of rotor impulsive noise. The methodology was applied to the University of Maryland Acoustic Chamber resulting in accurate measurements of High Speed Impulsive (HSI) noise for rotors running at tip Mach numbers between 0.65 and 0.85 – with accuracy increasing as the tip Mach number was increased. Several factors contributed to the success of this methodology including: • High Speed Impulsive (HSI) noise is characterized by very distinct pulses radiated from the rotor. The pulses radiate high frequency energy – but the energy is contained in short duration time pulses. • The first reflections from these pulses can be tracked (using ray theory) and, through adjustment of the microphone position and suitably applied acoustic treatment at the reflected surface, reduced to small levels. A computer code was developed that automates this process. The code also tracks first bounce reflection timing, making it possible to position the first bounce reflections outside of a measurement window. • Using a rotor with a small number of blades (preferably one) reduces the number of interfering first bounce reflections and generally improves the measured signal fidelity. The methodology will help the gathering of quantitative hovering rotor noise data in less than optimal acoustic facilities and thus enable basic rotorcraft research and rotor blade acoustic design.

Components and circuits for tunneling diode based high frequency sources

Terahertz (THz) technology has been generating a lot of interest because of the potential applications for systems working in this frequency range. However, to fully achieve this potential, effective and efficient ways of generating controlled signals in the terahertz range are required. Devices that exhibit negative differential resistance (NDR) in a region of their current-voltage (I-V ) characteristics have been used in circuits for the generation of radio frequency signals. Of all of these NDR devices, resonant tunneling diode (RTD) oscillators, with their ability to oscillate in the THz range are considered as one of the most promising solid-state sources for terahertz signal generation at room temperature. There are however limitations and challenges with these devices, from inherent low output power usually in the range of micro-watts (uW) for RTD oscillators when milli-watts (mW) are desired. At device level, parasitic oscillations caused by the biasing line inductance when the device is biased in the NDR region prevent accurate device characterisation, which in turn prevents device modelling for computer simulations. This thesis describes work on I-V characterisation of tunnel diode (TD) and RTD (fabricated by Dr. Jue Wang) devices, and the radio frequency (RF) characterisation and small signal modelling of RTDs. The thesis also describes the design and measurement of hybrid TD oscillators for higher output power and the design and measurement of a planar Yagi antenna (fabricated by Khalid Alharbi) for THz applications. To enable oscillation free current-voltage characterisation of tunnel diodes, a commonly employed method is the use of a suitable resistor connected across the device to make the total differential resistance in the NDR region positive. However, this approach is not without problems as the value of the resistor has to satisfy certain conditions or else bias oscillations would still be present in the NDR region of the measured I-V characteristics. This method is difficult to use for RTDs which are fabricated on wafer due to the discrepancies in designed and actual resistance values of fabricated resistors using thin film technology. In this work, using pulsed DC rather than static DC measurements during device characterisation were shown to give accurate characteristics in the NDR region without the need for a stabilisation resistor. This approach allows for direct oscillation free characterisation for devices. Experimental results show that the I-V characterisation of tunnel diodes and RTD devices free of bias oscillations in the NDR region can be made. In this work, a new power-combining topology to address the limitations of low output power of TD and RTD oscillators is presented. The design employs the use of two oscillators biased separately, but with the combined output power from both collected at a single load. Compared to previous approaches, this method keeps the frequency of oscillation of the combined oscillators the same as for one of the oscillators. Experimental results with a hybrid circuit using two tunnel diode oscillators compared with a single oscillator design with similar values shows that the coupled oscillators produce double the output RF power of the single oscillator. This topology can be scaled for higher (up to terahertz) frequencies in the future by using RTD oscillators. Finally, a broadband Yagi antenna suitable for wireless communication at terahertz frequencies is presented in this thesis. The return loss of the antenna showed that the bandwidth is larger than the measured range (140-220 GHz). A new method was used to characterise the radiation pattern of the antenna in the E-plane. This was carried out on-wafer and the measured radiation pattern showed good agreement with the simulated pattern. In summary, this work makes important contributions to the accurate characterisation and modelling of TDs and RTDs, circuit-based techniques for power combining of high frequency TD or RTD oscillators, and to antennas suitable for on chip integration with high frequency oscillators.

High performance terahertz resonant tunnelling diode sources and broadband antenna for air-side radiation

Resonant tunnelling diode (RTD) is known to be the fastest electronics device that can be fabricated in compact form and operate at room temperature with potential oscillation frequency up to 2.5 THz. The RTD device consists of a narrow band gap quantum well layer sandwiched between two thin wide band gap barriers layers. It exhibits negative differential resistance (NDR) region in its current-voltage (I-V) characteristics which is utilised in making oscillators. Up to date, the main challenge is producing high output power at high frequencies in particular. Although oscillation frequencies of ~ 2 THz have been already reported, the output power is in the range of micro-Watts. This thesis describes the systematic work on the design, fabrication, and characterisation of RTD-based oscillators in microwave/millimetre-wave monolithic integrated circuits (MMIC) form that can produce high output power and high oscillation frequency at the same time. Different MMIC RTD oscillator topologies were designed, fabricated, and characterised in this project which include: single RTD oscillator which employs one RTD device, double RTDs oscillator which employs two RTD devices connected in parallel, and coupled RTD oscillators which combine the powers of two oscillators over a single load, based on mutual coupling and which can employ up to four RTD devices. All oscillators employed relatively large size RTD devices for high power operation. The main challenge was to realise high oscillation frequency (~ 300 GHz) in MMIC form with the employed large sized RTD devices. To achieve this aim, proper designs of passive structures that can provide small values of resonating inductances were essential. These resonating inductance structures included shorted coplanar wave guide (CPW) and shorted microstrip transmission lines of low characteristics impedances Zo. Shorted transmission line of lower Zo has lower inductance per unit length. Thus, the geometrical dimensions would be relatively large and facilitate fabrication by low cost photolithography. A series of oscillators with oscillation frequencies in the J-band (220 – 325 GHz) range and output powers from 0.2 – 1.1 mW have been achieved in this project, and all were fabricated using photolithography. Theoretical estimation showed that higher oscillation frequencies (> 1 THz) can be achieved with the proposed MMIC RTD oscillators design in this project using photolithography with expected high power operation. Besides MMIC RTD oscillators, reported planar antennas for RTD-based oscillators were critically reviewed and the main challenges in designing high performance integrated antennas on large dielectric constant substrates are discussed in this thesis. A novel antenna was designed, simulated, fabricated, and characterised in this project. It was a bow-tie antenna with a tuning stub that has very wide bandwidth across the J-band. The antenna was diced and mounted on a reflector ground plane to alleviate the effect of the large dielectric constant substrate (InP) and radiates upwards to the air-side direction. The antenna was also investigated for integration with the all types of oscillators realised in this project. One port and two port antennas were designed, simulated, fabricated, and characterised and showed the suitability of integration with the single/double oscillator layout and the coupled oscillator layout, respectively.

The development of planar high-K/III-V p-channel MOSFETs for post-silicon CMOS

Conventional Si complementary-metal-oxide-semiconductor (CMOS) scaling is fast approaching its limits. The extension of the logic device roadmap for future enhancements in transistor performance requires non-Si materials and new device architectures. III-V materials, due to their superior electron transport properties, are well poised to replace Si as the channel material beyond the 10nm technology node to mitigate the performance loss of Si transistors from further reductions in supply voltage to minimise power dissipation in logic circuits. However several key challenges, including a high quality dielectric/III-V gate stack, a low-resistance source/drain (S/D) technology, heterointegration onto a Si platform and a viable III-V p-metal-oxide-semiconductor field-effect-transistor (MOSFET), need to be addressed before III-Vs can be employed in CMOS. This Thesis specifically addressed the development and demonstration of planar III-V p-MOSFETs, to complement the n-MOSFET, thereby enabling an all III-V CMOS technology to be realised. This work explored the application of InGaAs and InGaSb material systems as the channel, in conjunction with Al2O3/metal gate stacks, for p-MOSFET development based on the buried-channel flatband device architecture. The body of work undertaken comprised material development, process module development and integration into a robust fabrication flow for the demonstration of p-channel devices. The parameter space in the design of the device layer structure, based around the III-V channel/barrier material options of In_x≥0.53Ga_1-xAs/In_0.52Al_0.48As and In_x≥0.1Ga_1-xSb/AlSb, was systematically examined to improve hole channel transport. A mobility of 433 cm²/Vs, the highest room temperature hole mobility of any InGaAs quantum-well channel reported to date, was obtained for the In_0.85Ga_0.15As (2.1% strain) structure. S/D ohmic contacts were developed based on thermally annealed Au/Zn/Au metallisation and validated using transmission line model test structures. The effects of metallisation thickness, diffusion barriers and de-oxidation conditions were examined. Contacts to InGaSb-channel structures were found to be sensitive to de-oxidation conditions. A fabrication process, based on a lithographically-aligned double ohmic patterning approach, was realised for deep submicron gate-to-source/drain gap (L_side) scaling to minimise the access resistance, thereby mitigating the effects of parasitic S/D series resistance on transistor performance. The developed process yielded gaps as small as 20nm. For high-k integration on GaSb, ex-situ ammonium sulphide ((NH₄)₂S) treatments, in the range 1%-22%, for 10min at 295K were systematically explored for improving the electrical properties of the Al₂O₃/GaSb interface. Electrical and physical characterisation indicated the 1% treatment to be most effective with interface trap densities in the range of 4 - 10×10¹²cm^-2eV^-1 in the lower half of the bandgap. An extended study, comprising additional immersion times at each sulphide concentration, was further undertaken to determine the surface roughness and the etching nature of the treatments on GaSb. A number of p-MOSFETs based on III-V-channels with the most promising hole transport and integration of the developed process modules were successfully demonstrated in this work. Although the non-inverted InGaAs-channel devices showed good current modulation and switch-off characteristics, several aspects of performance were non-ideal; depletion-mode operation, modest drive current (I_d,sat=1.14mA/mm), double peaked transconductance (g_m=1.06mS/mm), high subthreshold swing (SS=301mV/dec) and high on-resistance (R_on=845kΩ.μm). Despite demonstrating substantial improvement in the on-state metrics of I_d,sat (11×), g_m (5.5×) and R_on (5.6×), inverted devices did not switch-off. Scaling gate-to-source/drain gap (L_side) from 1μm down to 70nm improved I_d,sat (72.4mA/mm) by a factor of 3.6 and gm (25.8mS/mm) by a factor of 4.1 in inverted InGaAs-channel devices. Well-controlled current modulation and good saturation behaviour was observed for InGaSb-channel devices. In the on-state In_0.3Ga_0.7Sb-channel (I_d,sat=49.4mA/mm, g_m=12.3mS/mm, R_on=31.7kΩ.μm) and In_0.4Ga_0.6Sb-channel (I_d,sat=38mA/mm, g_m=11.9mS/mm, R_on=73.5kΩ.μm) devices outperformed the InGaAs-channel devices. However the devices could not be switched off. These findings indicate that III-V p-MOSFETs based on InGaSb as opposed to InGaAs channels are more suited as the p-channel option for post-Si CMOS.

Voltage and current spectra for matrix power converters

Matrix power converters are used for transforming one alternating-current power supply to another, with different peak voltage and frequency. There are three input lines, with sinusoidally varying voltages which are 120◦ out of phase one from another, and the output is to be delivered as a similar three-phase supply. The matrix converter switches rapidly, to connect each output line in sequence to each of the input lines in an attempt to synthesize the prescribed output voltages. The switching is carried out at high frequency and it is of practical importance to know the frequency spectra of the output voltages and of the input and output currents. We determine in this paper these spectra using a new method, which has significant advantages over the prior default method (a multiple Fourier series technique), leading to a considerably more direct calculation. In particular, the determination of the input current spectrum is feasible here, whereas it would be a significantly more daunting procedure using the prior method instead.

Interface properties and capacitance-voltage behaviour of diamond devices prepared by microwave-assisted CVD

Free standing diamond films were used to study the effect of diamond surface morphology and microstructure on the electrical properties of Schottky barrier diodes. By using free standing films both the rough top diamond surface and the very smooth bottom surface are available for post-metal deposition. Rectifying electrical contacts were then established either with the smooth or the rough surface. The estimate of doping density from the capacitance-voltage plots shows that the smooth surface has a lower doping density when compared with the top layers of the same film. The results also show that surface roughness does not contribute significantly to the frequency dispersion of the small signal capacitance. The electrical properties of an abrupt asymmetric n(+)(silicon)-p(diamond) junction have also been measured. The I-V curves exhibit at low temperatures a plateau near zero bias, and show inversion of rectification. Capacitance-voltage characteristics show a capacitance minimum with forward bias, which is dependent on the environment conditions. It is proposed that this anomalous effect arises from high level injection of minority carriers into the bulk.

Interface properties and capacitance-voltage behaviour of diamond devices prepared by microwave-assisted CVD

Free standing diamond films were used to study the effect of diamond surface morphology and microstructure on the electrical properties of Schottky barrier diodes. By using free standing films both the rough top diamond surface and the very smooth bottom surface are available for post-metal deposition. Rectifying electrical contacts were then established either with the smooth or the rough surface. The estimate of doping density from the capacitance-voltage plots shows that the smooth surface has a lower doping density when compared with the top layers of the same film. The results also show that surface roughness does not contribute significantly to the frequency dispersion of the small signal capacitance. The electrical properties of an abrupt asymmetric n(+)(silicon)-p(diamond) junction have also been measured. The I-V curves exhibit at low temperatures a plateau near zero bias, and show inversion of rectification. Capacitance-voltage characteristics show a capacitance minimum with forward bias, which is dependent on the environment conditions. It is proposed that this anomalous effect arises from high level injection of minority carriers into the bulk.

Towards person-centered neuroimaging markers for resilience and vulnerability in Bipolar Disorder

Improved clinical care for Bipolar Disorder (BD) relies on the identification of diagnostic markers that can reliably detect disease-related signals in clinically heterogeneous populations. At the very least, diagnostic markers should be able to differentiate patients with BD from healthy individuals and from individuals at familial risk for BD who either remain well or develop other psychopathology, most commonly Major Depressive Disorder (MDD). These issues are particularly pertinent to the development of translational applications of neuroimaging as they represent challenges for which clinical observation alone is insufficient. We therefore applied pattern classification to task-based functional magnetic resonance imaging (fMRI) data of the n-back working memory task, to test their predictive value in differentiating patients with BD (n=30) from healthy individuals (n=30) and from patients' relatives who were either diagnosed with MDD (n=30) or were free of any personal lifetime history of psychopathology (n=30). Diagnostic stability in these groups was confirmed with 4-year prospective follow-up. Task-based activation patterns from the fMRI data were analyzed with Gaussian Process Classifiers (GPC), a machine learning approach to detecting multivariate patterns in neuroimaging datasets. Consistent significant classification results were only obtained using data from the 3-back versus 0-back contrast. Using contrast, patients with BD were correctly classified compared to unrelated healthy individuals with an accuracy of 83.5%, sensitivity of 84.6% and specificity of 92.3%. Classification accuracy, sensitivity and specificity when comparing patients with BD to their relatives with MDD, were respectively 73.1%, 53.9% and 94.5%. Classification accuracy, sensitivity and specificity when comparing patients with BD to their healthy relatives were respectively 81.8%, 72.7% and 90.9%. We show that significant individual classification can be achieved using whole brain pattern analysis of task-based working memory fMRI data. The high accuracy and specificity achieved by all three classifiers suggest that multivariate pattern recognition analyses can aid clinicians in the clinical care of BD in situations of true clinical uncertainty regarding the diagnosis and prognosis.

High Frequency Class DE Converter Using a Multilayer Coreless PCB Transformer

In modern power electronics equipment, it is desirable to design a low profile, high power density, and fast dynamic response converter. Increases in switching frequency reduce the size of the passive components such as transformers, inductors, and capacitors which results in compact size and less requirement for the energy storage. In addition, the fast dynamic response can be achieved by operating at high frequency. However, achieving high frequency operation while keeping the efficiency high, requires new advanced devices, higher performance magnetic components, and new circuit topology. These are required to absorb and utilize the parasitic components and also to mitigate the frequency dependent losses including switching loss, gating loss, and magnetic loss. Required performance improvements can be achieved through the use of Radio Frequency (RF) design techniques. To reduce switching losses, resonant converter topologies like resonant RF amplifiers (inverters) combined with a rectifier are the effective solution to maintain high efficiency at high switching frequencies through using the techniques such as device parasitic absorption, Zero Voltage Switching (ZVS), Zero Current Switching (ZCS), and a resonant gating. Gallium Nitride (GaN) device technologies are being broadly used in RF amplifiers due to their lower on- resistance and device capacitances compared with silicon (Si) devices. Therefore, this kind of semiconductor is well suited for high frequency power converters. The major problems involved with high frequency magnetics are skin and proximity effects, increased core and copper losses, unbalanced magnetic flux distribution generating localized hot spots, and reduced coupling coefficient. In order to eliminate the magnetic core losses which play a crucial role at higher operating frequencies, a coreless PCB transformer can be used. Compared to the conventional wire-wound transformer, a planar PCB transformer in which the windings are laid on the Printed Board Circuit (PCB) has a low profile structure, excellent thermal characteristics, and ease of manufacturing. Therefore, the work in this thesis demonstrates the design and analysis of an isolated low profile class DE resonant converter operating at 10 MHz switching frequency with a nominal output of 150 W. The power stage consists of a class DE inverter using GaN devices along with a sinusoidal gate drive circuit on the primary side and a class DE rectifier on the secondary side. For obtaining the stringent height converter, isolation is provided by a 10-layered coreless PCB transformer of 1:20 turn’s ratio. It is designed and optimized using 3D Finite Element Method (FEM) tools and radio frequency (RF) circuit design software. Simulation and experimental results are presented for a 10-layered coreless PCB transformer operating in 10 MHz.

High bandwidth freestanding semipolar (11–22) InGaN/GaN light-emitting diodes

Freestanding semipolar (11–22) indium gallium nitride (InGaN) multiplequantum-well light-emitting diodes (LEDs) emitting at 445 nm have been realized by the use of laser lift-off (LLO) of the LEDs from a 50- m-thick GaN layer grown on a patterned (10–12) r -plane sapphire substrate (PSS). The GaN grooves originating from the growth on PSS were removed by chemical mechanical polishing. The 300 m × 300 m LEDs showed a turn-on voltage of 3.6 V and an output power through the smooth substrate of 0.87 mW at 20 mA. The electroluminescence spectrum of LEDs before and after LLO showed a stronger emission intensity along the [11–23]InGaN/GaN direction. The polarization anisotropy is independent of the GaN grooves, with a measured value of 0.14. The bandwidth of the LEDs is in excess of 150 MHz at 20 mA, and back-to-back transmission of 300 Mbps is demonstrated, making these devices suitable for visible light communication (VLC) applications.

Aging assessment of polyethylene-based insulated low-voltage cables for nuclear applications

This thesis aims at investigating the evolution of physico-chemical and electrical properties relevant to low-voltage power cables for nuclear application when subjected to typical nuclear power plant (NPP) environments i.e., to gamma radiation and high temperature. This research is part of the European Project Horizon 2020 TeaM Cables, which aims at providing a novel methodology for efficient and reliable NPP cable aging management to NPP operators. The analyzed samples consist of both coaxial and twisted pair cables with different polymeric compounds used as primary insulation. Insulating materials are based on the same silane cross-linked polyethylene matrix with different additives and fillers. In order to characterize the material response to the environmental stresses, various experimental techniques have been used. These characterizations range from the microscale chemical response e.g. by FTIR, OIT and DSC, to the macroscale electrical and mechanical behavior. A significant part of this Thesis is given to the correlation of the response to aging among the different measured properties. It has been shown that it could be possible to connect both the chemical and mechanical properties of the investigated XLPE cables with the electrical ones. In particular, the high-frequency dielectric response allows an effective monitoring of both the early periods of aging, controlled by the antioxidant consumption kinetics, and then the subsequent oxidation of the polymer matrix. Therefore, dielectric spectroscopy showed to be capable of assessing the LV cable aging state and, it might be used as an aging marker for cable diagnostic. The last part of the manuscript focuses on the building of a predictive modelling approach of LV cable conditions subjected to radio-chemical aging. It resulted into obtaining a lifetime curve which relates the aging factor to which the cable is subjected to, namely the dose rate, with the limit value of the considered electrical property (tanδ).

Wireless Power Link Design for Both High-Power Inductive Coupling and Smart Metasurfaces Exploitation

As future technologies are going to be autonomous under the umbrella of the Internet of things (IoT) we can expect WPT to be the solution for intelligent devices. WPT has many industrial and medical applications both in the near-field and far-field domains. Considering the impact of WPT, this thesis is an attempt to design and realize both near-field and far-field WPT solutions for different application scenarios. A 27 MHz high frequency inductive wireless power link has been designed together with the Class-E switching inverter to compensate for the efficiency loss because of the varying weak coupling between transmitter and receiver because of their mutual misalignment. Then a system of three coils was introduced for SWIPT. The outer coil for WPT and the inner two coils were designed to fulfil the purpose of communication and testing, operating at frequencies different from the WPT coil. In addition to that, a trapping filter technique has also been adopted to ensure the EM isolation of the coils. Moreover, a split ring resonator-based dual polarization converter has been designed with good efficiency over a wide frequency range. The gap or cuts have been introduced in the adjacent sides of the square ring to make it a dual-polarization converter. The converter is also stable over a wide range of incident angles. Furthermore, a meta-element based intelligent surface has been designed to work in the reflection mode at 5 GHz. In this research activity, interdigital capacitors (IDCs) instead of ICs are introduced and a thin layer of the HfZrO between substrate and meta elements is placed whose response can be tuned and controlled with the applied voltage to achieve IRS.

Impaired Compensatory Beta-cell Function And Growth In Response To High-fat Diet In Ldl Receptor Knockout Mice.

In this study, we investigated the effect of low density lipoprotein receptor (LDLr) deficiency on gap junctional connexin 36 (Cx36) islet content and on the functional and growth response of pancreatic beta-cells in C57BL/6 mice fed a high-fat (HF) diet. After 60 days on regular or HF diet, the metabolic state and morphometric islet parameters of wild-type (WT) and LDLr-/- mice were assessed. HF diet-fed WT animals became obese and hypercholesterolaemic as well as hyperglycaemic, hyperinsulinaemic, glucose intolerant and insulin resistant, characterizing them as prediabetic. Also they showed a significant decrease in beta-cell secretory response to glucose. Overall, LDLr-/- mice displayed greater susceptibility to HF diet as judged by their marked cholesterolaemia, intolerance to glucose and pronounced decrease in glucose-stimulated insulin secretion. HF diet induced similarly in WT and LDLr-/- mice, a significant decrease in Cx36 beta-cell content as revealed by immunoblotting. Prediabetic WT mice displayed marked increase in beta-cell mass mainly due to beta-cell hypertrophy/replication. Nevertheless, HF diet-fed LDLr-/- mice showed no significant changes in beta-cell mass, but lower islet-duct association (neogenesis) and higher beta-cell apoptosis index were seen as compared to controls. The higher metabolic susceptibility to HF diet of LDLr-/- mice may be explained by a deficiency in insulin secretory response to glucose associated with lack of compensatory beta-cell expansion.

Taurine Supplementation Increases K(atp) Channel Protein Content, Improving Ca2+ Handling And Insulin Secretion In Islets From Malnourished Mice Fed On A High-fat Diet.

Pancreatic β-cells are highly sensitive to suboptimal or excess nutrients, as occurs in protein-malnutrition and obesity. Taurine (Tau) improves insulin secretion in response to nutrients and depolarizing agents. Here, we assessed the expression and function of Cav and KATP channels in islets from malnourished mice fed on a high-fat diet (HFD) and supplemented with Tau. Weaned mice received a normal (C) or a low-protein diet (R) for 6 weeks. Half of each group were fed a HFD for 8 weeks without (CH, RH) or with 5% Tau since weaning (CHT, RHT). Isolated islets from R mice showed lower insulin release with glucose and depolarizing stimuli. In CH islets, insulin secretion was increased and this was associated with enhanced KATP inhibition and Cav activity. RH islets secreted less insulin at high K(+) concentration and showed enhanced KATP activity. Tau supplementation normalized K(+)-induced secretion and enhanced glucose-induced Ca(2+) influx in RHT islets. R islets presented lower Ca(2+) influx in response to tolbutamide, and higher protein content and activity of the Kir6.2 subunit of the KATP. Tau increased the protein content of the α1.2 subunit of the Cav channels and the SNARE proteins SNAP-25 and Synt-1 in CHT islets, whereas in RHT, Kir6.2 and Synt-1 proteins were increased. In conclusion, impaired islet function in R islets is related to higher content and activity of the KATP channels. Tau treatment enhanced RHT islet secretory capacity by improving the protein expression and inhibition of the KATP channels and enhancing Synt-1 islet content.