Voltage-Dependent Anion Selective Channel 3: Unraveling Structural and Functional Features of the Least Known Porin Isoform

Voltage-dependent anion-selective channels (VDAC) are pore-forming proteins located in the outer mitochondrial membrane. Three isoforms are encoded by separate genes in mammals (VDAC1-3). These proteins play a crucial role in the cell, forming the primary interface between mitochondrial and cellular metabolisms. Research on the role of VDACs in the cell is a rapidly growing field, but the function of VDAC3 remains elusive. The high-sequence similarity between isoforms suggests a similar pore-forming structure. Electrophysiological analyzes revealed that VDAC3 works as a channel; however, its gating and regulation remain debated. A comparison between VDAC3 and VDAC1-2 underlines the presence of a higher number of cysteines in both isoforms 2 and 3. Recent mass spectrometry data demonstrated that the redox state of VDAC3 cysteines is evolutionarily conserved. Accordingly, these residues were always detected as totally reduced or partially oxidized, thus susceptible to disulfide exchange. The deletion of selected cysteines significantly influences the function of the channel. Some cysteine mutants of VDAC3 exhibited distinct kinetic behavior, conductance values and voltage dependence, suggesting that channel activity can be modulated by cysteine reduction/oxidation. These properties point to VDAC3 as a possible marker of redox signaling in the mitochondrial intermembrane space. Here, we summarize our current knowledge about VDAC3 predicted structure, physiological role and regulation, and possible future directions in this research field.

Enabling User Relaying In MCM-NOMA Under Doubly Selective Channels Using Iterative Interference Cancellation Schemes For Wireless IoT Networks

<div>Cell-edge users of the future cellular internet of things (IoT) with massive IoT sensors can suffer from extremely severe channel conditions, especially under very high-speed scenarios. In this paper, we present a performance improvement method for cell-edge users of multi-carrier modulation (MCM)-based non-orthogonal multiple access (NOMA) downlink systems. To this end, we consider the implementation of cooperative user relaying NOMA (CUR-NOMA) and derive its lower bound end-to-end bit error rate (E2E-BER) under doubly selective channels. In addition, the imperfect successive interference cancellation (SIC) process is analyzed, wherein two interference cancellation schemes are combined to remove the NOMA induced inter-user interference (IUI) and the doubly selective channel induced inter-carrier interference (ICI). Furthermore, numerical simulations are performed to prove the efficiency of the introduced schemes with imperfect channel state information (CSI) when compared to the theoretical perfect SIC with a perfect CSI case. </div>

Molecular Mechanism of Hyperactivation Conferred by a Truncated TRPA1 Disease Mutant Suggests New Gating Insights

The wasabi receptor, TRPA1, is a non-selective homotetrameric cation channel expressed in primary sensory neurons of the pain pathway, where it is activated by diverse chemical irritants. A direct role for TRPA1 in human health has been highlighted by the discovery of genetic variants associated with severe pain disorders. One such TRPA1 mutant was identified in a father-son pair with cramp fasciculation syndrome (CFS) and neuronal hyperexcitability-hypersensitivity symptoms that may be caused by aberrant channel activity, though the mechanism of action for this mutant is unknown. Here, we show the CFS-associated R919* TRPA1 mutant is functionally inactive when expressed alone in heterologous cells, which is not surprising since it lacks the 201 C-terminal amino acids that house critical channel gating machinery including the pore-lining transmembrane helix. Interestingly, the R919* mutant confers enhanced agonist sensitivity when co-expressed with wild type (WT) TRPA1. This channel hyperactivation mechanism is conserved in distant TRPA1 species orthologues and can be recapitulated in the capsaicin receptor, TRPV1. Using a combination of ratiometric calcium imaging, immunostaining, surface biotinylation, pulldown assays, fluorescence size exclusion chromatography, and proximity biotinylation assays, we show that the R919* mutant co-assembles with WT subunits into heteromeric channels. Within these heteromers, we postulate that R919* TRPA1 subunits contribute to hyperactivation by lowering energetic barriers to channel activation contributed by the missing regions. Additionally, we show heteromer activation can originate from the R919* TRPA1 subunits, which suggests an unexpected role for the ankyrin repeat and coiled coil domains in concerted channel gating. Our results demonstrate the R919* TRPA1 mutant confers gain-of-function thereby expanding the physiological impact of nonsense mutations, reveals a novel and genetically tractable mechanism for selective channel sensitization that may be broadly applicable to other receptors, and uncovers new gating insights that may explain the molecular mechanism of temperature sensing by some TRPA1 orthologues.

Enabling User Relaying In MCM-NOMA Under Doubly Selective Channels Using Iterative Interference Cancellation Schemes For Wireless IoT Networks

<div>Cell-edge users of the future cellular internet of things (IoT) with massive IoT sensors can suffer from extremely severe channel conditions, especially under very high-speed scenarios. In this paper, we present a performance improvement method for cell-edge users of multi-carrier modulation (MCM)-based non-orthogonal multiple access (NOMA) downlink systems. To this end, we consider the implementation of cooperative user relaying NOMA (CUR-NOMA) and derive its lower bound end-to-end bit error rate (E2E-BER) under doubly selective channels. In addition, the imperfect successive interference cancellation (SIC) process is analyzed, wherein two interference cancellation schemes are combined to remove the NOMA induced inter-user interference (IUI) and the doubly selective channel induced inter-carrier interference (ICI). Furthermore, numerical simulations are performed to prove the efficiency of the introduced schemes with imperfect channel state information (CSI) when compared to the theoretical perfect SIC with a perfect CSI case. </div>

Blind Adaptive Equalization for Aerospace Communication Channels

In some communication systems, it is desirable for the receiver to synchronize to the received signal and to adjust the equalizer without having knowledge of a training sequence. Blind equalization uses the initial adjustment of the coefficients without making use of a training sequence. Different adaptive blind equalization algorithms have been developed over the past four decades. In this paper, we investigate the effect of blind equalization on space communication channels. The space channel under investigation is considered to be a multipath frequency selective channel having four paths. The channel is subjected to the phenomenon of InterSymbol Interference (ISI) which severely degrades the performance of the space communication system. Two blind algorithms are used in equalizer adjustment. The impulse responses of the space channel, the blind equalizer and the combination of channel and equalizer for QPSK and 16-QAM transmission are shown. The scatter diagrams for the transmitted sequence, received sequence, and the output of the equalizer using two of the blind algorithms are shown.

Redox-Sensitive VDAC: A Possible Function as an Environmental Stress Sensor Revealed by Bioinformatic Analysis

Voltage-dependent anion-selective channel (VDAC) allows the exchange of small metabolites and inorganic ions across the mitochondrial outer membrane. It is involved in complex interactions that regulate mitochondrial and cellular functioning. Many organisms have several VDAC paralogs that play distinct but poorly understood roles in the life and death of cells. It is assumed that such a large diversity of VDAC-encoding genes might cause physiological plasticity to cope with abiotic and biotic stresses known to impact mitochondrial function. Moreover, cysteine residues in mammalian VDAC paralogs may contribute to the reduction–oxidation (redox) sensor function based on disulfide bond formation and elimination, resulting in redox-sensitive VDAC (rsVDAC). Therefore, we analyzed whether rsVDAC is possible when only one VDAC variant is present in mitochondria and whether all VDAC paralogs present in mitochondria could be rsVDAC, using representatives of currently available VDAC amino acid sequences. The obtained results indicate that rsVDAC can occur when only one VDAC variant is present in mitochondria; however, the possibility of all VDAC paralogs in mitochondria being rsVDAC is very low. Moreover, the presence of rsVDAC may correlate with habitat conditions as rsVDAC appears to be prevalent in parasites. Thus, the channel may mediate detection and adaptation to environmental conditions.

Screening for Activity Against AMPA Receptors Among Anticonvulsants—Focus on Phenytoin

The interest in AMPA receptors as a target for epilepsy treatment increased substantially after the approval of perampanel, a negative AMPA receptor allosteric antagonist, for the treatment of partial-onset seizures and generalized tonic-clonic seizures. Here we performed a screening for activity against native calcium-permeable AMPA receptors (CP-AMPARs) and calcium-impermeable AMPA receptors (CI-AMPARs) among different anticonvulsants using the whole-cell patch-clamp method on isolated Wistar rat brain neurons. Lamotrigine, topiramate, levetiracetam, felbamate, carbamazepine, tiagabin, vigabatrin, zonisamide, and gabapentin in 100-µM concentration were practically inactive against both major subtypes of AMPARs, while phenytoin reversibly inhibited them with IC50 of 30 ± 4 μM and 250 ± 60 µM for CI-AMPARs and CP-AMPARs, respectively. The action of phenytoin on CI-AMPARs was attenuated in experiments with high agonist concentrations, in the presence of cyclothiazide and at pH 9.0. Features of phenytoin action matched those of the CI-AMPARs pore blocker pentobarbital, being different from classical competitive inhibitors, negative allosteric inhibitors, and CP-AMPARs selective channel blockers. Close 3D similarity between phenytoin and pentobarbital also suggests a common binding site in the pore and mechanism of inhibition. The main target for phenytoin in the brain, which is believed to underlie its anticonvulsant properties, are voltage-gated sodium channels. Here we have shown for the first time that phenytoin inhibits CI-AMPARs with similar potency. Thus, AMPAR inhibition by phenytoin may contribute to its anticonvulsant properties as well as its side effects.

Data Acquisition and Dissemination for the Internet of Nano Things

<p>Electromagnetic-based Wireless NanoSensor Networks (EM-WNSNs) operating in the Terahertz band (0.1 THz – 10 THz) will enable nano-scale applications and stimulate the evolution from the Internet of Things (IoT) to the Internet of Nano Things (IoNT). Data delivery, which is one of the key functionalities of EM-WNSNs, faces three major challenges that will affect network performance: the frequency-selective channel in the THz band due to molecular absorption, the limited ability to support networking functions due to their small size, and the limited bandwidth of the existing infrastructure for transferring sensed data to the Internet. However, to date, limited amount of research on data delivery has been done to address the peculiarities of IoNT from the networking perspective. To fill the gap, in this thesis, data acquisition and dissemination solutions are studied for IoNT to improve the resource utilization efficiency during data delivery. Different from existing literatures that focus on standalone nanonetworks, this thesis investigates solutions for connecting nanodevices to the Internet. In detail, the contributions of this thesis are composed of four components: First, a preliminary study namely the Channel-aware Forwarding (CForward) is conducted on multi-hop forwarding for THz networks; second, the On-demand Probabilistic polling (OP polling) is developed for IoNT with dynamic IoT bandwidth and channel conditions; third, a TTLbased Efficient Forwarding (TEForward) is designed for the polling-based nanonetworks under dynamic channel conditions; fourth, the Enhanced Adaptive Pulse Interval Scheduling (EAPIS) is implemented to collect data from event-based nanonetworks under limited IoT bandwidth.</p>

Data Acquisition and Dissemination for the Internet of Nano Things

<p>Electromagnetic-based Wireless NanoSensor Networks (EM-WNSNs) operating in the Terahertz band (0.1 THz – 10 THz) will enable nano-scale applications and stimulate the evolution from the Internet of Things (IoT) to the Internet of Nano Things (IoNT). Data delivery, which is one of the key functionalities of EM-WNSNs, faces three major challenges that will affect network performance: the frequency-selective channel in the THz band due to molecular absorption, the limited ability to support networking functions due to their small size, and the limited bandwidth of the existing infrastructure for transferring sensed data to the Internet. However, to date, limited amount of research on data delivery has been done to address the peculiarities of IoNT from the networking perspective. To fill the gap, in this thesis, data acquisition and dissemination solutions are studied for IoNT to improve the resource utilization efficiency during data delivery. Different from existing literatures that focus on standalone nanonetworks, this thesis investigates solutions for connecting nanodevices to the Internet. In detail, the contributions of this thesis are composed of four components: First, a preliminary study namely the Channel-aware Forwarding (CForward) is conducted on multi-hop forwarding for THz networks; second, the On-demand Probabilistic polling (OP polling) is developed for IoNT with dynamic IoT bandwidth and channel conditions; third, a TTLbased Efficient Forwarding (TEForward) is designed for the polling-based nanonetworks under dynamic channel conditions; fourth, the Enhanced Adaptive Pulse Interval Scheduling (EAPIS) is implemented to collect data from event-based nanonetworks under limited IoT bandwidth.</p>