An Extracellular Cu2+ Binding Site in the Voltage Sensor of BK and Shaker Potassium Channels

Copper is an essential trace element that may serve as a signaling molecule in the nervous system. Here we show that extracellular Cu2+ is a potent inhibitor of BK and Shaker K+ channels. At low micromolar concentrations, Cu2+ rapidly and reversibly reduces macrosocopic K+ conductance (GK) evoked from mSlo1 BK channels by membrane depolarization. GK is reduced in a dose-dependent manner with an IC50 and Hill coefficient of ∼2 μM and 1.0, respectively. Saturating 100 μM Cu2+ shifts the GK-V relation by +74 mV and reduces GKmax by 27% without affecting single channel conductance. However, 100 μM Cu2+ fails to inhibit GK when applied during membrane depolarization, suggesting that Cu2+ interacts poorly with the activated channel. Of other transition metal ions tested, only Zn2+ and Cd2+ had significant effects at 100 μM with IC50s > 0.5 mM, suggesting the binding site is Cu2+ selective. Mutation of external Cys or His residues did not alter Cu2+ sensitivity. However, four putative Cu2+-coordinating residues were identified (D133, Q151, D153, and R207) in transmembrane segments S1, S2, and S4 of the mSlo1 voltage sensor, based on the ability of substitutions at these positions to alter Cu2+ and/or Cd2+ sensitivity. Consistent with the presence of acidic residues in the binding site, Cu2+ sensitivity was reduced at low extracellular pH. The three charged positions in S1, S2, and S4 are highly conserved among voltage-gated channels and could play a general role in metal sensitivity. We demonstrate that Shaker, like mSlo1, is much more sensitive to Cu2+ than Zn2+ and that sensitivity to these metals is altered by mutating the conserved positions in S1 or S4 or reducing pH. Our results suggest that the voltage sensor forms a state- and pH-dependent, metal-selective binding pocket that may be occupied by Cu2+ at physiologically relevant concentrations to inhibit activation of BK and other channels

Apparatus and methods for manipulation and optimization of biological systems

The invention provides systems and methods for manipulating, e.g., optimizing and controlling, biological systems, e.g., for eliciting a more desired biological response of biological sample, such as a tissue, organ, and/or a cell. In one aspect, systems and methods of the invention operate by efficiently searching through a large parametric space of stimuli and system parameters to manipulate, control, and optimize the response of biological samples sustained in the system, e.g., a bioreactor. In alternative aspects, systems include a device for sustaining cells or tissue samples, one or more actuators for stimulating the samples via biochemical, electromagnetic, thermal, mechanical, and/or optical stimulation, one or more sensors for measuring a biological response signal of the samples resulting from the stimulation of the sample. In one aspect, the systems and methods of the invention use at least one optimization algorithm to modify the actuator's control inputs for stimulation, responsive to the sensor's output of response signals. The compositions and methods of the invention can be used, e.g., to for systems optimization of any biological manufacturing or experimental system, e.g., bioreactors for proteins, e.g., therapeutic proteins, polypeptides or peptides for vaccines, and the like, small molecules (e.g., antibiotics), polysaccharides, lipids, and the like. Another use of the apparatus and methods includes combination drug therapy, e.g. optimal drug cocktail, directed cell proliferations and differentiations, e.g. in tissue engineering, e.g. neural progenitor cells differentiation, and discovery of key parameters in complex biological systems

Fast Fluid Antenna Multiple Access Enabling Massive Connectivity

Massive connectivity over wireless channels relies on aggressive spectrum sharing techniques. Conventionally, this may be achieved by sophisticated signal processing and optimization of applying multiple antennas and/or complex multiuser decoding at each user terminal (UT). Different from previous methods, this letter proposes a radical approach for massive connectivity, which employs fluid antenna at each UT to exploit the interference null, created naturally by multipath propagation and the randomness of UT’s data, on a symbol-by-symbol basis for multiple access. The proposed fast fluid antenna multiple access (f-FAMA) system adopts a large, distributed antenna array at the base station (BS) to transmit each UT’s signal from each of the BS antennas and lets each UT overcome the interference on its own using its fluid antenna. Our main contribution is a technique that estimates the best port of fluid antenna for reception at every symbol instance. The proposed approach needs only cross-correlation calculations and single-user decoding at each UT and requires no precoding at the BS. Simulation results demonstrate that for a BS with 16 antennas supporting 16 co-channel users, a multiplexing gain of 14.87 is achieved even when the channel has a strong line-of-sight (LoS) and multipath is few. The multiplexing gain can also rise to 24.36 if a 30-antenna BS is serving 30 co-channel users

Apparatus and Methods for Manipulation and Optimization of Biological Systems

The invention provides systems and methods for manipulating biological systems, for example to elicit a more desired biological response from a biological sample, such as a tissue, organ, and/or a cell. In one aspect, the invention operates by efficiently searching through a large parametric space of stimuli and system parameters to manipulate, control, and optimize the response of biological samples sustained in the system. In one aspect, the systems and methods of the invention use at least one optimization algorithm to modify the actuator's control inputs for stimulation, responsive to the sensor's output of response signals. The invention can be used, e.g., to optimize any biological system, e.g., bioreactors for proteins, and the like, small molecules, polysaccharides, lipids, and the like. Another use of the apparatus and methods includes is for the discovery of key parameters in complex biological systems

Port Selection for Fluid Antenna Systems

Fluid antenna system promises to obtain enormous diversity in the small space of a mobile device by switching the position of the radiating element to the most desirable position from a large number of prescribed locations of the given space. Previous researches have revealed the promising performance of fluid antenna systems if the position with the maximum received signal-to-noise ratio (SNR) is chosen. However, selecting the best position, referred to as port selection, requires a huge number of SNR observations from the ports and may prove to be infeasible. This letter tackles this problem by devising a number of fast port selection algorithms utilizing a combination of machine learning methods and analytical approximation when the system observes only a few ports. Simulation results illustrate that with only 10% of the ports observed, more than an order of magnitude reduction in the outage probability can be achieved. Even in the extreme cases where only one port is observed, considerable performance improvements are possible using the proposed algorithms

Opportunistic Fluid Antenna Multiple Access

Multiple access can be realized by utilizing the spatial moments of deep fades, using fluid antennas. The interference immunity for fluid antenna multiple access (FAMA), nevertheless, comes with the requirement of a large number of ports at each user. To alleviate this, we study the synergy between opportunistic scheduling and FAMA. A large pool of users permits selection of favourable users for FAMA and decreases the outage probability at each selected user. Our objective is to characterize the benefits of opportunistic scheduling in FAMA. In particular, we derive the multiplexing gain of the opportunistic FAMA network in closed form and upper bound the required number of users in the pool to achieve a given multiplexing gain. Also, we find a lower bound on the required outage probability at each user for achieving a given network multiplexing gain, from which the advantage of opportunistic scheduling is illustrated. In addition, we investigate the rate of increase of the multiplexing gain with respect to the number of users in the pool, and derive a tight approximation to the multiplexing gain, expressed in closed form. As a key result of our analysis, we obtain an operating condition on the product of the number of users in the pool and the number of ports at each fluid antenna that ensures a high multiplexing gain. Numerical results demonstrate clear benefits of opportunistic scheduling in FAMA networks, and corroborate our analytical results

Local structures of free-standing AlₓGa₁ˍₓN thin films studied by extended x-ray absorption fine structure

Local structural information for the first two atomic shells surrounding Ga atoms in free standing AlₓGa₁ˍₓN alloy films has been obtained by extended x-ray absorption fine structure spectroscopy. For an AlN mole fraction ranging from 0 to 0.6, we found that the first shell Ga–N bond length had only a weak composition dependence, roughly one quarter of that predicted by Vegard’s Law. In the second shell, the Ga–Ga bond length was significantly longer than that of Ga–Al (Δ∼0.04–0.065 Å). A bond-type specific composition dependence was observed for the second shell cation–cation distances. While the composition dependence of the Ga–Ga bond length is ∼70% of that predicted by Vegard’s Law, the Ga–Al bond length was essentially composition independent. These results suggested that local strain in AlₓGa₁ˍₓN was also accommodated by lattice distortion in the Al cation sublattice.This work was supported by the Director, Office of Science, Of- fice of Basic Energy Sciences, Materials Science Division of the U.S. Department of Energy under Contract No. DE-AC03-76SF00098. The LLO work was performed at the UC Berkeley Integrated Materials Laboratory which was supported in part by the National Science Foundation. C.J.G. and M.C.R. were supported by the Australian Synchrotron Research Program, funded by the Commonwealth of Australia via the Major National Research Facilities Program. SSRL was supported by the Office of Basic Energy Sciences of the U.S. Department of Energy

Cross-disciplinary collaboration through WuZhiQiao Project to foster cultural exchange and community engagement

In 2013, students of the Technological and Higher Education Institute of Hong Kong (THEi), with the support of WuZhiQiao (WZQ) Charitable Foundation, formed a core team of 11 students to organize and participate in social service projects to help the underprivileged in the Chinese mainland. WuZhiQiao (WZQ) projects, the first cross-region social service engagement by THEi students, bring together students from Hong Kong and the Mainland. WZQ Charitable Foundation aims to help the Chinese traditional village in building Pedestrian Bridge and organizing community projects. Since there are Chinese villages facing flooding during rainy seasons, the local villagers will be trapped inside the village without the chance to go outside or wade outside the village. There are hundreds of such villages and they highly need our help. Each project mainly involves two or three institutes from Hong Kong and the Mainland, and they organize the whole volunteer project including planning, investigation, design, promotion and operation. Through involvement in different states or provinces, WZQ projects provide good chance of communication and interaction between Hong Kong teams and the Mainland teams and advocate intercultural social services. The projects can foster the cultural exchange between Hong Kong and the Mainland. Moreover, the majority of WZQ project members are coming from the fields of engineering, architecture and health care. We can practice our learning from lectures through the project implementation. Different parties are involved in the engineering projects including clients, consultants, contractors, surveyors, engineers and workers. Engineering students can gain good understanding of the holistic picture of a real-life engineering project. We visited the location village for investigation to learn more about the local culture, geometry and the people’s needs and discussed with the Mainland Team through online chatting tools in order to propose the optimal pedestrian building design and other community projects. Having spent over six months in planning and preparation, THEi students will implement a bridge-building and community project in Chongqing in January 2015. Through engagement in this service-learning project, not only the undergraduates of THEi can benefit through personal development but the life quality of the disadvantaged can also be improved

Hemodynamic variability and cerebrovascular control after transient cerebral ischemia

We investigated if hemodynamic variability, cerebral blood flow (CBF) regulation, and their interrelationships differ between patients with transient ischemic attack (TIA) and controls. We recorded blood pressure (BP) and bilateral middle cerebral artery flow velocity (MCAv) in a cohort of TIA patients (n = 17), and age?matched controls (n = 15). Spontaneous fluctuations in BP and MCAv were characterized by spectral power analysis, and CBF regulation was assessed by wavelet phase synchronization analysis in the very low? (0.02–0.07 Hz), low? (0.07–0.20 Hz), and high?frequency (0.20–0.40 Hz) ranges. Furthermore, cerebrovascular CO2 reactivity was assessed as a second metric of CBF regulation by inducing hypercapnia with 8% CO2 inhalation followed by hyperventilation driven hypocapnia. We found that TIA was associated with higher BP power (group effect, P < 0.05), but not MCAv power (P = 0.11). CBF regulation (assessed by wavelet phase synchronization and CO2 reactivity) was intact in patients (all P ? 0.075) across both hemispheres (all P ? 0.51). Pooled data (controls and affected hemisphere of patients) showed that BP and MCAv power were positively correlated at all frequency ranges (R2 = 0.20–0.80, all P < 0.01). Furthermore, LF phase synchronization index was a significant determinant of MCAv power (P < 0.05), while VLF and HF phase synchronization index, and TIA were not (all P ? 0.50). These results indicate that CBF stability and control is maintained in TIA patients, but BPV is markedly elevated. BPV attenuation may be an important therapeutic strategy for enhancing secondary stroke prevention in patients who suffer a TIA