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A perfect anomalous reflector is designed by employing the receiving and scattering array antenna theory to optimize the scattering characteristics of a planar reflecting surface. For periodic reflectors with a supercell consisting of a relatively few reactively loaded radiating elements, reflection amplitudes into propagating Floquet modes are controlled in an algebraic optimization of the load reactances, avoiding brute-force optimization via electromagnetic simulations. Wide-angle reflectors are numerically designed and compared with the conventional reflectarray designs, showing that the proposed design approach achieves reflection efficiencies higher than the linear reflection phase gradient method in a computationally efficient manner.

High-voltage direct-current (HVDC) systems using voltage source converters (VSCs) have been developed to suppress voltage fluctuations in offshore grids due to the intermittent power generation of offshore wind farms (OWFs). This paper proposes a new strategy for the optimal secondary voltage control of HVDC-linked OWFs. In the proposed strategy, optimal coordinated control of an HVDC system and OWFs is achieved to minimize real-time voltage fluctuations throughout an offshore grid. A full-order dynamic model of HVDC-linked OWFs is implemented, and its unobservable and uncontrollable state variables are then eliminated using a model reduction algorithm. Given the dynamic model, a linear quadratic Gaussian regulator is designed for optimal coordinated control, and an eigenvalue analysis is conducted focusing on the effects of communication time delays on the stability of the proposed strategy. Simulation case studies are also carried out to verify that the proposed strategy more effectively improves real-time regulation of offshore grid voltages, compared to conventional strategies, while ensuring voltage stability even for relatively large delays in communications systems.

Crosstalk between ion channels and small GTPases is critical during homeostasis and disease1, but little is known about the structural underpinnings of these interactions. TRPV4 is a polymodal, calcium-permeable cation channel that has emerged as a potential therapeutic target in multiple conditions2–5. Gain-of-function mutations also cause hereditary neuromuscular disease6–11. Here, we present cryo-EM structures of human TRPV4 in complex with RhoA in the apo, antagonist-bound closed, and agonist-bound open states. These structures reveal the mechanism of ligand-dependent TRPV4 gating. Channel activation is associated with rigid-body rotation of the intracellular ankyrin repeat domain, but state-dependent interaction with membrane-anchored RhoA constrains this movement. Notably, many residues at the TRPV4-RhoA interface are mutated in disease and perturbing this interface by introducing mutations into either TRPV4 or RhoA increases TRPV4 channel activity. Together, these results suggest that the interaction strength between TRPV4 and RhoA tunes TRPV4-mediated calcium homeostasis and actin remodeling, and that disruption of TRPV4-RhoA interactions leads to TRPV4-related neuromuscular disease, findings that will guide TRPV4 therapeutics development.

Ischemic stroke, caused by vessel blockage, results in cerebral infarction, the death of brain tissue. Previously, quantitative trait locus (QTL) mapping of cerebral infarct volume and collateral vessel number identified a single, strong genetic locus regulating both phenotypes. Additional studies identified RAB GTPase-binding effector protein 2 (Rabep2) as the casual gene. However, there is yet no evidence that variation in the human ortholog of this gene plays any role in ischemic stroke outcomes. We established an in vivo evaluation platform in mice by using adeno-associated virus (AAV) gene replacement and verified that both mouse and human RABEP2 rescue the mouse Rabep2 knockout ischemic stroke volume and collateral vessel phenotypes. Importantly, this cross-species complementation enabled us to experimentally investigate the functional effects of coding sequence variation in human RABEP2. We chose four coding variants from the human population that are predicted by multiple in silico algorithms to be damaging to RABEP2 function. In vitro and in vivo analyses verify that all four led to decreased collateral vessel connections and increased infarct volume. Thus, there are naturally occurring loss-of-function alleles. This cross-species approach will expand the number of targets for therapeutics development for ischemic stroke.

Transient receptor potential vanilloid member 1 (TRPV1) is a Ca2+-permeable cation channel that serves as the primary heat and capsaicin sensor in humans. Using cryo-EM, we have determined the structures of apo and capsaicin-bound full-length rat TRPV1 reconstituted into lipid nanodiscs over a range of temperatures. This has allowed us to visualize the noxious heat-induced opening of TRPV1 in the presence of capsaicin. Notably, noxious heat-dependent TRPV1 opening comprises stepwise conforma- tional transitions. Global conformational changes across multiple subdomains of TRPV1 are followed by the rearrangement of the outer pore, leading to gate opening. Solvent-accessible surface area analyses and functional studies suggest that a subset of residues form an interaction network that is directly involved in heat sensing. Our study provides a glimpse of the molecular principles underlying noxious physical and chemical stimuli sensing by TRPV1, which can be extended to other thermal sensing ion channels.

OBJECTIVE The current grading system for moyamoya disease (MMD) is focused on angiographic studies with limited clinical application. The authors aimed to determine relevant factors that may impact postoperative outcome and establish a scoring system to predict the functional outcome. METHODS Adult patients with MMD who underwent treatment between 1998 and 2016 were included. Factors such as age, sex, comorbidity, smoking, MMD family history, initial presentation, multimodal imaging modalities, and types of surgical revascularization were thoroughly reviewed. These factors were analyzed to determine possible risk factors related to unfavorable 6-month postoperative outcomes using the modified Rankin Scale (mRS) (unfavorable: mRS score ≥ 3). A scoring system was developed using these independent risk factors to predict the outcome and validated using prospectively collected data from multiple centers between 2017 and 2018. RESULTS Of 302 patients for whom applications were submitted, 260 patients (321 hemispheres) met the diagnostic criteria. In multivariate analysis, hyperlipidemia, smoking, cerebral infarction on preoperative CT or MRI, and moderately to severely reduced regional cerebrovascular reserve results from Diamox SPECT were significantly related to unfavorable outcome. The authors developed a scoring system and stratified patients into risk groups according to their scores: low-risk (score 0–3), intermediate-risk (score 4–6), and high-risk (score 7–9) groups. This model demonstrated both good discrimination and calibration using C-statistics and the Hosmer-Lemeshow goodness-of-fit test showing 0.812 (95% CI 0.743–0.881) (p = 0.568) for the development and 0.954 (95% CI 0.896–1) (p = 0.097) for the temporal and external validation cohort. CONCLUSIONS The authors’ scoring system is readily adoptable to predict the postoperative outcome for MMD. Their data revealed the importance of smoking and hyperlipidemia, which were the only modifiable factors included in the scoring system. The authors validated their scoring system both internally and externally and maintained good performance, highlighting the system’s generalizability and reliability.

Ischemic stroke, caused by vessel blockage, results in cerebral infarction; the death of brain tissue. Previously, quantitative trait locus mapping (QTL) of cerebral infarct volume and collateral vessel number identified a single, strong genetic locus regulating both phenotypes. Additional studies identified the causative gene, encoding RAB GTPase Binding Effector Protein 2 (Rabep2). However, there is yet no evidence that variation in the human ortholog of this gene plays any role in ischemic stroke outcomes. We established an in vivo evaluation platform in mice using adeno-associated virus (AAV) gene replacement and verified that both mouse and human RABEP2 rescue the mouse Rabep2 KO ischemic stroke volume and collateral vessel phenotypes. Importantly, this cross-species complementation enabled us to experimentally investigate the functional effects of coding sequence variation in the human RABEP2 gene. We chose four coding variants from the human population that are predicted by multiple in silico algorithms to be damaging to RABEP2 function. In vitro and in vivo analyses verify that all four led to decreased collateral vessel connections and increased infarct volume. Thus, there are naturally occurring loss-of-function alleles. This cross-species approach will expand the number of targets for therapeutics development for ischemic stroke.

The ClpP serine peptidase is a tetradecameric degradation molecular machine involved in many physiological processes. It becomes a competent ATP-dependent protease when coupled with Clp-ATPases. Small chemical compounds, acyldepsipeptides (ADEPs), are known to cause the dysregulation and activation of ClpP without ATPases and have potential as novel antibiotics. Previously, structural studies of ClpP from various species revealed its structural details, conformational changes, and activation mechanism. Although product release through side exit pores has been proposed, the detailed driving force for product release remains elusive. Herein, we report crystal structures of ClpP from Bacillus subtilis (BsClpP) in unforeseen ADEP-bound states. Cryo-electron microscopy structures of BsClpP revealed various conformational states under different pH conditions. To understand the conformational change required for product release, we investigated the relationship between substrate hydrolysis and the pH-lowering process. The production of hydrolyzed peptides from acidic and basic substrates by proteinase K and BsClpP lowered the pH values. Our data, together with those of previous findings, provide insight into the molecular mechanism of product release by the ClpP self-compartmentalizing protease.

A new DC current-voltage droop control method for a hybrid high-voltage direct-current (HVDC) system featuring a voltage-sourced converter (VSC) rectifier and a line-commutated converter (LCC) inverter is presented. The proposed method utilizes DC voltage droop control to reduce the AC voltage fluctuation at the inverter side, to exploit the hybrid HVDC system for connecting offshore wind farms to weak grids without necessitating continuous reactive power compensation facilities. Additionally, an optimal droop coefficient calculation method is proposed to keep the AC voltage constant for wind power fluctuations. To evaluate the stability of the proposed method, a small-signal state-space (SS) model of the target system is derived and the root locus analysis is given. Simulation case studies are performed using an electromagnetic transient model in PSCAD and an SS model in MATLAB. The results demonstrate that a hybrid HVDC system with the proposed method successfully integrates offshore wind energy and weak grids without additional facilities because the AC voltage can be maintained at a near constant during wind fluctuations.

Different from voltage-source converter (VSC), reactive power absorption of line-commutated converters (LCCs) changes depending on DC voltage level. Therefore, the amount of AC voltage fluctuations at inverter side are different according to $I$ – $V$ droop constants in hybrid multi-terminal high-voltage direct current (MT-HVDC) system. This paper proposes a method for calculating the $I$ – $V$ droop constants in a hybrid MT-HVDC system to suppress these AC voltage fluctuations, based on the sensitivity of AC and DC networks. Simulations performed using PSCAD demonstrate the effectiveness of the proposed method.

Aberrantly elevated steroid receptor coactivator-1 (SRC-1) expression and activity are strongly correlated with cancer progression and metastasis. Here we report, for the first time, the development of a proteolysis targeting chimera (PROTAC) that is composed of a selective SRC-1 binder linked to a specific ligand for UBR box, a unique class of E3 ligases recognizing N-degrons. We showed that the bifunctional molecule efficiently and selectively induced the degradation of SRC-1 in cells through the N-degron pathway. Importantly, given the ubiquitous expression of the UBR protein in most cells, PROTACs targeting the UBR box could degrade a protein of interest regardless of cell types. We also showed that the SRC-1 degrader significantly suppressed cancer cell invasion and migration in vitro and in vivo. Together, these results demonstrate that the SRC-1 degrader can be an invaluable chemical tool in the studies of SRC-1 functions. Moreover, our findings suggest PROTACs based on the N-degron pathway as a widely useful strategy to degrade disease-relevant proteins.

A design technique for modulated surface reactances for 1-D leaky-wave antenna applications based on complete aperture field synthesis is presented. For a given visible-region spectrum corresponding to desired radiation and polarization patterns, the evanescent or invisible-region spectrum is introduced and systematically optimized to render the antenna surface passive and lossless everywhere, while generating the specified far-zone characteristics. Design techniques for linear and circular polarizations excited by a TM-polarized feed surface wave are provided together with design examples with simulation validation. Not based on local periodicity, the proposed technique does not suffer from limitations associated with the traditional sinusoidally modulated reactance surfaces.

In this paper, a new control method for a line-commutated converter-based (LCC) high-voltage direct current (HVDC) system to support the frequency and AC voltage was proposed. For coordinated control of the inverter and rectifier, droop-based controllers are adopted for the outer loop of conventional controllers, and DC voltage is used to transfer the frequency information so that communication is not required. A method to determine the droop constants of the proposed controller is presented to emulate the conventional $f$ / $P$ droop characteristic and suppress the AC voltage fluctuations. Furthermore, a small-signal state-space model of the LCC HVDC system with the proposed scheme is derived, and root locus analysis is carried out to evaluate its stability. The effects of the proposed method are verified based on case studies, using the well-known CIGRE BENCHMARK model. The advantages of the proposed method can be summarized as follows: 1) system reliability is enhanced because there is no risk of communication failure during frequency information transfer and 2) voltage stability at the inverter side is enhanced as AC voltage fluctuation during frequency support is minimized.

We present a new reactive power control method for hybrid high-voltage direct-current (HVDC) systems that features a line-commutated converter-based (LCC) rectifier and a voltage-sourced converter-based (VSC) inverter. Our principal objective is to regulate the reactive power of the LCC rectifier side via co-operative control of the DC voltage and switched shunt devices (SSDs) such as capacitors and reactors. To achieve these objectives, we used three operative modes: reactive power, voltage, and power factor control. For each mode, we show how to determine the DC reference voltage. Also, to maintain the voltage within operational bounds and enhance the range over which reactive power is controllable, our method features the cooperation of SSDs. Furthermore, we show how to determine the required SSD capacities. MATLAB and PSCAD simulations confirmed that our method improves reactive power controllability at the LCC rectifier side of a hybrid HVDC system.

Background: To analysis the role of gamma knife radiosurgery (GKRS) in treatment of the recurrent or residual World Health Organization (WHO) grade II and III meningiomas.Methods: Between 1995 and ...

Background We investigated the risk factors for leptomeningeal carcinomatosis (LMC) and compared clinical efficacies of various treatment modalities including intrathecal (IT) chemotherapy in patients with lung adenocarcinoma harboring epidermal growth factor receptor (EGFR) mutations. Methods Using clinical research data from the Asan Medical Center, we retrospectively analyzed data of patients diagnosed with LMC, confirmed via cerebrospinal fluid (CSF) analysis from January 2008 to December 2017. Results We identified 1189 patients with lung adenocarcinoma harboring EGFR mutations. Among these, 9.8% had a median duration of 13.5 (interquartile range [IQR] 6.8–23.6) months from the initial lung cancer diagnosis to LMC occurrence. Younger age (hazard ratio [HR] 1.043, P

The N-degron pathway, formerly the N-end rule pathway, is a protein degradation process that determines the half-life of proteins based on their N-terminal residues. In contrast to the well-established in vivo studies over decades, in vitro studies of this pathway, including biochemical characterization and high-resolution structures, are relatively limited. In this study, we have developed a unique fusion technique using microtubule-associated protein 1A/1B light chain 3B, a key marker protein of autophagy, to tag the N terminus of the proteins involved in the N-degron pathway, which enables high yield of homogeneous target proteins with variable N-terminal residues for diverse biochemical studies including enzymatic and binding assays and substrate identification. Intriguingly, crystallization showed a markedly enhanced probability, even for the N-degron complexes. To validate our results, we determined the structures of select proteins in the N-degron pathway and compared them with the Protein Data Bank–deposited proteins. Furthermore, several biochemical applications of this technique were introduced. Therefore, this technique can be used as a general tool for the in vitro study of the N-degron pathway.

This paper proposes multilevel linear polarization shift keying (MLPolSK) modulation, based on a high polarization-dependent gain optical amplifier (PDG-OA), for spectral efficient free-space optical (FSO) communication. At the transmitter end, multiple linear states of polarization (SOPs) are adopted, and different SOPs are mapped for MLPolSK modulation according to the PDG-OA. First, in the receiver, scintillation is effectively mitigated by a polarization-independent semiconductor optical amplifier (SOA) with gain saturation. Next, various SOPs are transformed into different signal intensity levels by an OA with high PDG characteristics. Finally, transformed signal is directly detected by a single photodiode (PD) with multilevel-thresholds decision. The feasibility of the proposed technique is evaluated experimentally using a reflective semiconductor optical amplifier (RSOA), with a high PDG-up to 20 dB. A Mach–Zehnder modulator (MZM)-based fading simulator is used to accommodate lognormal distribution simulated turbulence effects into experiments. Experimental results illustrate that multilevel linear SOPs can be distinguished effectively by the proposed technique. Consequently, the MLPolSK detection is simplified, and the spectral efficiency (SE) is improved by up to 2 bit/s/Hz with effective scintillation mitigation in FSO.

Single particle cryo-EM often yields multiple protein conformations within a single dataset, but experimentally deducing the temporal relationship of these conformers within a conformational trajectory is not trivial. Here, we use thermal titration methods and cryo-EM in an attempt to obtain temporal resolution of the conformational trajectory of the vanilloid receptor TRPV1 with resiniferatoxin (RTx) bound. Based on our cryo-EM ensemble analysis, RTx binding to TRPV1 appears to induce intracellular gate opening first, followed by selectivity filter dilation, then pore loop rearrangement to reach the final open state. This apparent conformational wave likely arises from the concerted, stepwise, additive structural changes of TRPV1 over many subdomains. Greater understanding of the RTx-mediated long-range allostery of TRPV1 could help further the therapeutic potential of RTx, which is a promising drug candidate for pain relief associated with advanced cancer or knee arthritis.