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Abstract Valosin-containing protein (VCP)/p97, an AAA+ ATPase critical for maintaining proteostasis, emerges as a promising target for cancer therapy. This study reveals that targeting VCP selectively eliminates breast cancer cells while sparing non-transformed cells by inducing paraptosis, a non-apoptotic cell death mechanism characterized by endoplasmic reticulum and mitochondria dilation. Intriguingly, oncogenic HRas sensitizes non-transformed cells to VCP inhibition-mediated paraptosis. The susceptibility of cancer cells to VCP inhibition is attributed to the non-attenuation and recovery of protein synthesis under proteotoxic stress. Mechanistically, mTORC2/Akt activation and eIF3d-dependent translation contribute to translational rebound and amplification of proteotoxic stress. Furthermore, the ATF4/DDIT4 axis augments VCP inhibition-mediated paraptosis by activating Akt. Given that hyperactive Akt counteracts chemotherapeutic-induced apoptosis, VCP inhibition presents a promising therapeutic avenue to exploit Akt-associated vulnerabilities in cancer cells by triggering paraptosis while safeguarding normal cells.

Angle estimation for low-altitude targets above the sea surface is a challenging problem due to multipath interference from surface reflection signals, and various approaches have been proposed. This paper proposes a matrix pencil method with multiple apertures. The matrix pencil method effectively responds to dynamic scenarios because it performs better when using a single snapshot than other methods. Also, employing multiple apertures is more economical than using one large aperture. Therefore, we propose a computationally efficient approach using this method and structures. The proposed two-stage MP method incrementally improves the resolution in two stages: in stage 1, we extract the denoised signals at each aperture level, and in stage 2, we further improve the resolution with those signals. In comparison with the angular resolution defined by the half-power beamwidth (HPBW) of a uniform linear array (ULA) antenna with an equivalent number of arrays, the proposed method demonstrated a superior resolution of less than 0.087 of the HPBW at a high signal-to-noise ratio (SNR) of 40 dB, and less than 0.31 of it even at a relatively low SNR of 15 dB, based on 90% of the resolving probability. For the multipath problem, the proposed scheme has the advantage of not requiring prior geometric information, and its performance is demonstrated through simulations to be better than the adaptive beamforming method and the composite monopulse method.

Primary angiitis of the central nervous system (PACNS) is a rare vasculitis in the central nervous system. Herein, we report a case of diagnosis and treatment of necrotic pattern PACNS, which was difficult to differentiate from a brain abscess. A 19-year-old male presented with blurred vision and a headache. Brain MRI revealed irregular rim-enhancing necrotic masses with central diffusion-high signal intensity in the corpus callosum and peripheral diffusion-high signal intensity in the left parietotemporal periventricular area. Susceptibility-weighted imaging revealed multiple punctate hemorrhages in the lesions. The patient was diagnosed with unusual abscess or tumefactive PACNS. Therefore, we initially treated the patient with antibiotics to rule out brain abscess. However, the brain lesions did not improve on follow-up MRI after the antibiotic treatment. Surgical biopsy was performed, and the histopathological diagnosis was PACNS with a necrotic pattern. The necrotic lesions became smaller on follow-up MRI after high-dose corticosteroid treatment.

Cerebral amyloid angiopathy-related inflammation (CAA-RI) is an encephalopathy caused by inflammation of β-amyloid peptide deposition in cerebrovascular vessels. It is a rare disease that mainly occurs in the elderly and is characterized by rapidly progressive dementia, headache, seizures, and focal neurologic deficits. CAA-RI can demonstrate characteristic brain MRI findings and can be reversed by steroids or other immunosuppressive therapies. Here, we report a case of CAA-RI, which was initially misdiagnosed as a subacute infarction but was diagnosed while reviewing follow-up brain MRI images, and spontaneous remission was achieved.

Brain arteriovenous malformations (bAVMs) substantially increase the risk for intracerebral hemorrhage (ICH), which is associated with significant morbidity and mortality. However, the treatment options for bAVMs are severely limited, primarily relying on invasive methods that carry their own risks for intraoperative hemorrhage or even death. Currently, there are no pharmaceutical agents shown to treat this condition, primarily due to a poor understanding of bAVM pathophysiology. For the last decade, bAVM research has made significant advances, including the identification of novel genetic mutations and relevant signaling in bAVM development. However, bAVM pathophysiology is still largely unclear. Further investigation is required to understand the detailed cellular and molecular mechanisms involved, which will enable the development of safer and more effective treatment options. Endothelial cells (ECs), the cells that line the vascular lumen, are integral to the pathogenesis of bAVMs. Understanding the fundamental role of ECs in pathological conditions is crucial to unraveling bAVM pathophysiology. This review focuses on the current knowledge of bAVM-relevant signaling pathways and dysfunctions in ECs, particularly the endothelial-to-mesenchymal transition (EndMT).

Letter to the Editor

Abstract The aggressive proliferation of tumor cells often requires increased glucose uptake and excessive anaerobic glycolysis, leading to the massive production and secretion of lactate to form a unique tumor microenvironment (TME). Therefore, regulating appropriate lactate levels in the TME would be a promising approach to control tumor cell proliferation and immune suppression. To effectively consume lactate in the TME, lactate oxidase (LOX) and catalase (CAT) were displayed onto Aquifex aeolicus lumazine synthase protein nanoparticles (AaLS) to form either AaLS/LOX or AaLS/LOX/CAT. These complexes successfully consumed lactate produced by CT26 murine colon carcinoma cells under both normoxic and hypoxic conditions. Specifically, AaLS/LOX generated a large amount of H2O2 with complete lactate consumption to induce drastic necrotic cell death regardless of culture condition. However, AaLS/LOX/CAT generated residual H2O2, leading to necrotic cell death only under hypoxic condition similar to the TME. While the local administration of AaLS/LOX to the tumor site resulted in mice death, that of AaLS/LOX/CAT significantly suppressed tumor growth without any severe side effects. AaLS/LOX/CAT effectively consumed lactate to produce adequate amounts of H2O2 which sufficiently suppress tumor growth and adequately modulate the TME, transforming environments that are favorable to tumor suppressive neutrophils but adverse to tumor-supportive tumor-associated macrophages. Collectively, these findings showed that the modular functionalization of protein nanoparticles with multiple metabolic enzymes may offer the opportunity to develop new enzyme complex-based therapeutic tools that can modulate the TME by controlling cancer metabolism. Graphical Abstract

FAF1 (FAS-associated factor 1) is involved in the activation of Fas cell surface death receptors and plays a role in apoptosis and necrosis. In patients with Parkinson’s disease, FAF1 is overexpressed in dopaminergic neurons in the substantia nigra. KM-819, an FAF1 inhibitor, has shown potential for preventing dopaminergic neuronal cell death, promoting the degradation of α-synuclein and preventing its accumulation. This study aimed to develop and validate a quantitative analytical method for determining KM-819 levels in rat plasma using liquid chromatography–tandem mass spectrometry. This method was then applied to pharmacokinetic (PK) studies in rats. The metabolic stability of KM-819 was assessed in rat, dog, and human hepatocytes. In vitro metabolite identification and metabolic pathways were investigated in rat, dog, and human hepatocytes. The structural analog of KM-819, namely N-[1-(4-bromobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(phenylsulfanyl) acetamide, served as the internal standard (IS). Proteins were precipitated from plasma samples using acetonitrile. Analysis was carried out using a reverse-phase C18 column with a mobile phase consisting of 0.1% formic acid in distilled water and 0.1% formic acid in acetonitrile. The analytical method developed for KM-819 exhibited linearity within the concentration range of 0.002–10 μg/mL in rat plasma. The precision and accuracy of the intra- and inter-day measurements were

A high-frequency surface wave radar (HFSWR) is the only sensor that provides inexpensive surveillance for up to 200 nautical miles (NM) of the exclusive economic zone in the 3–5 MHz band. However, because of its long wavelength, its angular resolution is low. Multiple-input multiple-output (MIMO) technology is an attractive method to improve angular resolution. This paper proposes MIMO waveforms and their processing that can be used in HFSWR systems. This dual modulation method applies linear frequency modulation to each pulse and orthogonal polyphase codes for a few consecutive pulses to enable MIMO processing. The proposed method can effectively remove the correlation of mutual interference and exhibits excellent performance in removing multiple-time-around echoes.

Abstract The plant toxin ricin, especially its cytotoxic A chain (RTA), can be genetically engineered with targeting ligands to develop specific anti-cancer recombinant immunotoxins (RITs). Here, we used affibody molecules targeting two cancer biomarkers, the receptors HER2 and EGFR, along with the KDEL signal peptide to construct two cancer-specific ricin-based RITs, HER2Afb-RTA-KDEL and EGFRAfb-RTA-KDEL. The affibodies successfully provided target-specificity and subsequent receptor-mediated endocytosis and the KDEL signal peptide routed the RITs through the retrograde transport pathway, effectively delivering RTA to the cytosol as well as avoiding the alternate recycling pathway that typical cancer cells frequently have. The in vivo efficacy of RITs was enhanced by introducing the albumin binding domain (AlBD) to construct AlBD/HER2Afb/RTA-KDEL. Systemic administration of AlBD-containing RITs to tumor-bearing mice significantly suppressed tumor growth without any noticeable side-effects. Collectively, combining target-selective affibody molecules, a cytotoxic RTA, and an intracellularly designating peptide, we successfully developed cancer-specific and efficacious ricin-based RITs. This approach can be applied to develop novel protein-based “magic bullets” to effectively suppress tumors that are resistant to conventional anti-cancer drugs. Graphical Abstract

ABSTRACT: Three different medicinal plants that consisted of the formulated mixture (CAVAC-1901) have been traditionally used for distinct medicinal purposes in different areas. Angelica dahurica has been used as an important ingredient of a prescription, Gumiganghwal-tang, for the common cold and influenza. Curcuma longa has been utilized for the treatment of asthma, and jaundice. Pinus densiflora (Korean red pine) has been used to improve memory and brain function for the treatment of vascular. Industrial livestock, which are characterized by dense breeding, are vulnerable to influenza infection, causing severe economic loss and social problems. However, there are no viable alternatives due to the risk of the occurrence of variants. Therefore, the aim of this study was to discover anti-influenza combinations of different medicinal plants with the concept of a multicomponent and multitarget (MCMT) strategy in traditional Chinese medicine (TCM). As part of a continuous project, 3 medicinal plants whose inhibitory activity against influenza A was previously reported at the compound level, and the inhibition of cytopathic effects (CPEs) by these formulated mixtures was evaluated against influenza A virus H1N1. A selected combination with an optimal ratio exhibiting synergistic activity was assessed for its antiviral activity in chickens against the highly pathogenic avian influenza (HPAI) H5N6. The selected combination (CAVAC-1901) showed potent inhibitory effects on the expression of neuraminidase and nucleoprotein, by RT-qPCR, Western blot, and immunofluorescence assays. The antiviral activity was more evident in chickens infected with H5N6. The sample-treated group (50 mg/kg/d) decreased mortality and virus titers in various organs. Our results indirectly suggest synergistic inhibitory activity of the combination of 3 different medicinal plants with different modes of action. Taken together, an optimally formulated mixture (CAVAC-1901) could serve as an effective alternative to current measures to minimize damage caused by HPAIs.

Abstract Objective Although COVID-19 is a respiratory disease, all organs can be affected including the brain. To date, specific investigations of brain injury markers (BIM) and endothelial injury markers (EIM) have been limited. Additionally, a male bias in disease severity and mortality after COVID-19 is evident globally. Sex differences in the immune response to COVID-19 may mediate this disparity. We investigated BIM, EIM and inflammatory cytokine/chemokine (CC) levels after COVID-19 and in across sexes. Methods Plasma samples from 57 subjects at

Abstract Alzheimer’s Disease (AD) is one of the most prevalent neurodegenerative chronic diseases. As it progresses, patients become increasingly dependent, and their caregivers are burdened with the increasing demand for managing their care. Mobile health (mHealth) technology, such as smartphone applications, can support the need of these caregivers. This paper examines the published academic literature of mHealth applications that support the caregivers of AD patients. Following the PRISMA for scoping reviews, we searched published literature in five electronic databases between January 2014 and January 2021. Twelve articles were included in the final review. Six themes emerged based on the functionalities provided by the reviewed applications for caregivers. They are tracking, task management, monitoring, caregiver mental support, education, and caregiver communication platform. The review revealed that mHealth applications for AD patients’ caregivers are inadequate. There is an opportunity for industry, government, and academia to fill the unmet need of these caregiver.

This study examines utterances--either words, phrases, or sentences--that instructors initiate and students later appropriate for their own purposes and interests in different sequential contexts. We name these utterances "shared codes" because they occur repeatedly in classroom interactions and gradually take on meanings unique to class members. Simply put, they serve as codes, or "keys," for unlocking the interactional history (but not necessarily for explaining the original meaning). Such shared codes were employed for making humor and building relationships. Indeed, students' use of the codes seems to exhibit learner agency in selecting and appropriating utterances. We examined classroom interactions of two English as a second language (ESL) courses, taught by two instructors in university-based English-language programs in the U.S. Following Cameron and Deignan (2006), this study analyzes interactional contexts where shared codes emerge by employing complex dynamic systems theory perspectives. From our corpus of ESL writing classrooms, we selected four utterances that emerged as shared codes by tracking instances longitudinally, visualizing "patterns" among which the codes emerged. We also employed multimodal conversation analysis to "illuminate" processes during which students adapted their teachers' utterances, thus contributing to those utterances becoming temporarily stable, or in an "attractor state" (Larsen--Freeman, 2017).

Diabetic patients have larger infarcts, worse neurological deficits, and higher mortality rate after an ischemic stroke. Evidence shows that in diabetes, the hypothalamic–pituitary–adrenal (HPA) axis was dysregulated and levels of cortisol increased. Based on the role of the HPA axis in immunity, we hypothesized that diabetes-dysregulated stress response exacerbates stroke outcomes via regulation of inflammation. To test this hypothesis, we assessed the regulation of the HPA axis in diabetic mice before and after stroke and determined its relevance in the regulation of post-stroke injury and inflammation. Diabetes was induced in C57BL/6 mice by feeding a high-fat diet and intraperitoneal injection of streptozotocin (STZ), and then the mice were subjected to 30 min of middle cerebral artery occlusion (MCAO). Infarct volume and neurological scores were measured in the ischemic mice. The inflammatory cytokine and chemokine levels were also determined in the ischemic brain. To assess the effect of diabetes on the stroke-modulated HPA axis, we measured the expression of components in the HPA axis including corticotropin-releasing hormone (CRH) in the hypothalamus, proopiomelanocortin (POMC) in the pituitary, and plasma adrenocorticotropic hormone (ACTH) and corticosterone. Diabetic mice had larger infarcts and worse neurological scores after stroke. The exacerbated stroke outcomes in diabetic mice were accompanied by the upregulated expression of inflammatory factors (including IL-1β, TNF-α, IL-6, CCR2, and MCP-1) in the ischemic brain. We also confirmed increased levels of hypothalamic CRH, pituitary POMC, and plasma corticosterone in diabetic mice before and after stroke, suggesting the hyper-activated HPA axis in diabetic conditions. Finally, we confirmed that post-stroke treatment of metyrapone (an inhibitor of glucocorticoid synthesis) reduced IL-6 expression and the infarct size in the ischemic brain of diabetic mice. These results elucidate the mechanisms in which the HPA axis in diabetes exacerbates ischemic stroke. Maintaining an optimal level of the stress response by regulating the HPA axis may be an effective approach to improving stroke outcomes in patients with diabetes.

Abstract Tumor suppressive microRNAs (miRNAs) are increasingly implicated in the development of anti-tumor therapy by reprogramming gene network that are aberrantly regulated in cancer cells. This study aimed to determine the therapeutic potential of putative tumor suppressive miRNA, miR-138, against glioblastoma (GBM). Whole transcriptome and miRNA expression profiling analyses on human GBM patient tissues identified miR-138 as one of the significantly downregulated miRNAs with an inverse correlation with CD44 expression. Transient overexpression of miR-138 in GBM cells inhibited cell proliferation, cell cycle, migration, and wound healing capability. We unveiled that miR-138 negatively regulates the expression of CD44 by directly binding to the 3′ UTR of CD44. CD44 inhibition by miR-138 resulted in an inhibition of glioblastoma cell proliferation in vitro through cell cycle arrest as evidenced by a significant induction of p27 and its translocation into nucleus. Ectopic expression of miR-138 also increased survival rates in mice that had an intracranial xenograft tumor derived from human patient-derived primary GBM cells. In conclusion, we demonstrated a therapeutic potential of tumor suppressive miR-138 through direct downregulation of CD44 for the treatment of primary GBM.

Multi-band antennas have received significant interest because they can support multiple wireless communication services with a single antenna. However, an array antenna consisting of these element antennas can suffer from non-periodic arrangement due to the irregular sizes of the elements. In this paper, various shapes of patch antennas with fractal antennas are used to ensure the periodic arrangement of the array antenna, and antenna array incorporated with a feed network is proposed. Four different antenna arrays operating at 2.45/3.7/4.3/5.0 GHz are aggregated in an antenna with interleaved disposition of the different element antennas. It is observed that mutual couplings between two elements are sufficiently low, at less than −23 dB. Peak antenna gain ranging from 11.1 dBi to 14.4 dBi at the four different bands is obtained.

In accordance with the new healthcare policy of government (Moon Jae-In Care) to strengthen health insurance coverage, the National Health Insurance (NHI) coverage of brain magnetic resonance imaging (MRI), brain/neck MR angiography (MRA), and head and neck MRI have been expanded since 2018 in Korea. This article has been reviewed focusing on the “Detailed matter concerning criteria and method for providing reimbursed services in the NHI. Some revisions” regarding reimbursement for MRI, which was revised from October 2018 to April 2020 and is currently in effect. It included the MRI reimbursement system in Korea, recent adjustment of the reimbursement coverage for patients with headache or dizziness, and reimbursement coverage, standard imaging, and radiologic report of brain MRI, brain/neck MRA and head and neck MRI. This article could help radiologists gain knowledge on health insurance to protect the expertise of the radiologist and to play a leading role in the hospital. As the policy changes, detailed matter concerning criteria and method for providing reimbursed services in the NHI may be revised. Therefore, radiologists should update issues related to insurance reimbursement for MRI continuously.

Abstract Background Fas-associated factor 1 (FAF1) has been implicated in Parkinson’s disease (PD) and activates the cell death machinery in the cytosol. However, the presence of extracellular FAF1 has not been studied. Methods Serum-free conditioned medium (CM) from FAF1-transfected SH-SY5Y cells was concentrated and analyzed by western blotting. Exosomes were isolated from CM by ultracentrifugation and analyzed by western blotting, electron microscopy and nanoparticle tracking analysis. Soluble FAF1 from CM was immunodepleted using anti-FAF1 antibody. Transmission of secreted FAF1 was examined by transwell assay under a confocal microscope. CM-induced cell death was determined by measuring propidium iodide (PI) uptake using a flow cytometer. Results FAF1 was secreted from SH-SY5Y cells via exocytosis and brefeldin A (BFA)-resistant secretory pathways. Furthermore, FAF1 was secreted as a vesicle-free form and a genuine exosome cargo in the lumen of exosomes. In addition, FAF1 increased the number of exosomes, suggesting a regulatory role in exosome biogenesis. Extracellular FAF1 was transmitted via endocytosis to neighboring cells, where it induced cell death through apoptotic and necrotic pathways. Conclusions This study presents a novel route by which FAF1 induces neuronal death through cell-to-cell transmission. Video Abstract

Objective: Phenotypic (Sensititre Myco, pDST) and genotypic drug susceptibility testing (GenoType NTM DR, gDST) in M. avium complex (MAC) have become available as standardized assays, but comparable data is needed. This study aimed to investigate the phenotypic and genotypic drug susceptibility patterns in MAC clinical isolates. Methods: Overall, 98 isolates from 85 patients were included. pDST and gDST were performed on all isolates and results compared regarding specificity and sensitivity using pDST as a reference method. The impact of drug instability on pDST results was studied using a biological assay over 14 days. In addition, the evolution of antimicrobial resistance was investigated in sequential isolates of 13 patients. Results: Macrolide resistance was rare, 1.2% (95% CI 0.7–7.3) of isolates in the base cohort. No aminoglycoside resistances were found, but 14.1% of the studied isolates (95% CI 7.8–23.8) showed intermediate susceptibility. The GenoType NTM DR identified two out of four macrolide-resistant isolates. Antibiotic stability was demonstrated to be poor in rifampicin, rifabutin, and doxycycylin. Conclusions: pDST results in NTM for unstable antibiotics must be interpreted with care. A combination of pDST and gDST will be useful for the guidance of antimicrobial therapy in MAC-disease. Keywords: NTM, Non-tuberculous mycobacteria, M. avium complex, M. avium, M. chimaera, M. Intracellulare, Drug susceptibility testing, DST

Multiple-input multiple-output (MIMO) technology has recently attracted attention with regard to improving the angular resolution of small antennas such as automotive radars. If appropriately placed, the co-located transmit and receive arrays can make a large virtual aperture. This paper proposes a new method for designing arrays by adopting a structure with minimum redundancy. The proposed structure can significantly increase the virtual array aperture while keeping the transmit and receive antennas at the same size. We describe the application of the proposed method to subarray-type antennas using multi-channel transceivers, which is essential for arranging RF hardware in a small antenna operating at high frequency. Further, we present an analysis of the final beam pattern and discuss its benefits and limitations.

Noise radar has become attractive owing to progress in hardware technology. Aside from the low probability of exploitation, the use of noise waveform is likely to grow due to its low interference features, especially in circumstances where multiple radars operate in the same band. In this study, we developed and tested a wideband noise radar for a ground-moving vehicle. It operates in the X-band with an instantaneous bandwidth of 1.5 GHz. The true time delay (TTD) was applied to correct the distortion of the beam pattern by the wide bandwidth, and the correlators were implemented by high-speed parallel processing using a field programmable gate array (FPGA). The outdoor experimental results were presented.

Abstract Here, we develop a flexible microrobot enhancing the steerability of a conventional guidewire. To improve steerability, a microrobot is attached to the tip of the guidewire and guided using an external magnetic field generated by an electromagnetic coil system. The flexible microrobot is fabricated via replica-molding and features a body made of polydimethylsiloxane (PDMS) and a single permanent magnet. As the robot is made of a deformable material, it can be steered using a low-intensity external magnetic field; the robot can potentially be guided into the coronary artery. To study steering performance, we employed mathematical modeling and a finite element model (FEM), and performed experiments under various magnetic fields. We found that a mathematical model using the Euler–Bernoulli beam could not precisely calculate the deformation angles. The FEM more accurately estimated those angles. The deformation angle can be controlled from 0 to 80° at a magnetic field intensity of 15 mT. The trackability at angles of 45 and 80° of the guidewire-based microrobot was confirmed in vitro using a two-dimensional blood vessel phantom.

Paraptosis is a type of programmed cell death that is characterized by dilation of the endoplasmic reticulum (ER) and/or mitochondria. Since paraptosis is morphologically and biochemically different from apoptosis, understanding its regulatory mechanisms may provide a novel therapeutic strategy in malignant cancer cells that have proven resistant to conventional pro-apoptotic treatments. Relatively little is known about the molecular basis of paraptosis, but perturbations of cellular proteostasis and ion homeostasis appear to critically contribute to the process. Ca2+ transport has been shown to be important in the paraptosis induced by several natural products, metal complexes, and co-treatment with proteasome inhibitors and certain Ca2+-modulating agents. In particular, the Ca2+-mediated communication between the ER and mitochondria plays a crucial role in paraptosis. Mitochondrial Ca2+ overload from the intracellular Ca2+-flux system located at the ER–mitochondrial axis can induce mitochondrial dilation during paraptosis, while the accumulation of misfolded proteins within the ER lumen is believed to exert an osmotic force and draw water from the cytoplasm to distend the ER lumen. In this process, Ca2+ release from the ER also critically contributes to aggravating ER stress and ER dilation. This review focuses on the role of Ca2+ transport in paraptosis by summarizing the recent findings related to the actions of Ca2+-modulating paraptosis-inducing agents and discussing the potential cancer therapeutic strategies that may effectively induce paraptosis via Ca2+ signaling.

Poly (ADP-ribose) polymerase 1 (PARP1)-dependent cell death in the retinal pigment epithelium (RPE) is implicated in dry age-related macular degeneration (AMD). Although PARP1 inhibitors are available for treating dry AMD, their delivery route is not ideal for patients. The aim of this study was to test the efficacy of a novel PARP1-inhibitory compound (PIC) in vitro and in vivo. This study presents PIC, a novel small molecule, with superior efficacy to PARP1 inhibitors in the market. PIC demonstrated a distinctive inhibitory profile against PARP isotypes than the FDA-approved PARP1 inhibitors. PIC inhibited PARP1 activation at an IC50 of 0.41 ± 0.15 nM in an enzyme-based assay in vitro and at IC50 and EC50 in ARPE-19 cells of 0.11 ± 0.02 nM and 0.22 ± 0.02 nM, respectively, upon H2O2 insult. PIC also moderated mitochondrial fission and depolarization and maintained cellular energy levels under oxidative stress in ARPE-19 cells. Furthermore, PIC demonstrated good corneal penetration in a rat model, presenting PIC as a promising candidate for eye drop therapeutics for dry AMD. When PIC was administered as an eye drop formulation, RPE morphology was preserved, maintaining the thickness of the outer nuclear layers under sodium iodate (SI) treatment in rats. In SI-treated rabbits, eye drop administration of PIC also retained the structural and functional integrity when analyzed using funduscopy and electroretinogram. Collectively, our data portray PIC as an attractive treatment measure for dry AMD.

Co-located MIMO is used to enlarge the antenna aperture virtually and increase the angular resolution. This paper shows FMCW radar using MIMO VAA. Polyphase codes are designed for modulating the successive chirps of transmitting signals. The codes are optimized to have low cross-correlations regardless of the Doppler filter mismatch. Compared with orthogonal codes, the designed codes show robust performance for Doppler mismatch and lower angle estimation errors. The entire procedure is explained, and the simulation results are provided.

Fas-associated factor 1 (FAF1), a Fas-binding protein, is implicated in neuronal cell death in Parkinson’s disease (PD). We examined the effects of a novel FAF1 inhibitor, KM-819, in dopaminergic neurons in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model using [18F]FE-PE2I positron emission tomography (PET). The MPTP model was generated with subacute MPTP treatment (20 mg/kg/day, i.p.) for 5 consecutive days in C57bl/6J mice. This study included three groups: the control group (treatment with saline only), the MPTP model group with KM-819 treatment (20 mg/kg/day p.o.) for 6 days, and the MPTP model group without KM-819 treatment. [18F]FE-PE2I PET studies were conducted in the same animals before and after MPTP with or without KM-819 treatment to monitor changes in striatal dopamine transporter activity indicated by non-displaceable binding potential (BPND) of [18F]FE-PE2I, and the expression levels of tyrosine hydroxylase were assessed using immunohistochemistry before and after KM-819 treatment. After MPTP injection, decreased striatal BPND was observed in the MPTP model group compared with the control group. Striatal BPND increased in the MPTP model group with KM-819 treatment, but not in the MPTP model group without KM-819 treatment. The tyrosine hydroxylase expression levels also significantly increased in the MPTP model group with KM-819 treatment compared with the control group. This study indicates that inhibition of the Fas-mediated cell death pathway by KM-819 has neurorestorative effects in striatal dopamine neurons in the MPTP model. Further studies would be needed to investigate the potential of KM-819 as a therapeutic drug for PD treatment.

Abstract Background Aberrant cell death induced by ischemic stress is implicated in the pathogenesis of ischemic diseases. Fas-associated factor 1 (FAF1) has been identified as a death-promoting protein. This study demonstrates that FAF1 functions in death signaling triggered by ischemic insult. Methods The expression changes of FAF1 and phophorylated JNK1 were detected by Western blotting. Immunoprecipitation was employed to investigate protein-protein interaction. We determined the cell death using flow cytometry and lactate dehydrogenase release measurement. To validate the death-promoting role of FAF1 in the retina, we generated conditional retinal FAF1 knockout mice. We used hematoxylin and eosin staining to detect retinal cell death in retinal ganglion cell layer. Results FAF1 was found to function upstream of c-Jun N-terminal kinase 1 (JNK1), followed by mitochondrial dysregulation and necrotic cell death processes upon ischemic insult. We investigated whether FAF1 is involved in the pathogenesis of ischemic diseases using a retinal ischemia model. Indeed, FAF1 potentiated necrosis through JNK1 activation upon ischemic stress in retinal cells demonstrating retinal ganglion–like character. Conditional FAF1 depletion attenuated JNK1 activation in the retinas of Dkk3-Cre;Faf1 flox/flox mice and ameliorated death of retinal cells due to elevated intraocular pressure (IOP). Conclusions Our results show that FAF1 plays a key role in ischemic retinal damage and may be implicated in the pathogenesis of retinal ischemic disease.

Abstract Background Neuroinflammation is implicated in the development and progression of many neurodegenerative diseases. Conditions that lead to a peripheral immune response are often associated with inflammation in the central nervous system (CNS), suggesting a communication between the peripheral immune system and the neuroimmune system. The underlying mechanism of this relationship remains largely unknown; however, experimental studies have demonstrated that exposure to infectious stimuli, such as lipopolysaccharide (LPS) or high-fat diet (HFD) feeding, result in profound peripheral- and neuro-inflammation. Methods Using the model of endotoxemia with LPS, we studied the role of serum-derived exosomes in mediating neuroinflammation. We purified circulating exosomes from the sera of LPS-challenged mice, which were then intravenously injected into normal adult mice. Results We found that the recipient mice that received serum-derived exosomes from LPS-challenged mice exhibited elevated microglial activation. Moreover, we observed astrogliosis, increased systemic pro-inflammatory cytokine production, and elevated CNS expression of pro-inflammatory cytokine mRNA and the inflammation-associated microRNA (miR-155) in these recipient mice. Gene expression analysis confirmed that many inflammatory microRNAs were significantly upregulated in the purified exosomes under LPS-challenged conditions. We observed accumulated signaling within the microglia of mice that received tail-vein injections of fluorescently labeled exosomes though the percentage of those microglial cells was found low. Finally, purified LPS-stimulated exosomes from blood when infused directly into the cerebral ventricles provoked significant microgliosis and, to a lesser extent, astrogliosis. Conclusions The experimental results suggest that circulating exosomes may act as a neuroinflammatory mediator in systemic inflammation.

Abstract Microprobes are used to repair neuronal injury by recording electrical signals from neuronal cells around the surface of the device. Following implantation into the brain, the immune response results in formation of scar tissue around the microprobe. However, neurons must be in close proximity to the microprobe to enable signal recording. A common reason for failure of microprobes is impaired signal recording due to scar tissue, which is not related to the microprobe itself. Therefore, the device–cell interface must be improved to increase the number of neurons in contact with the surface. In this study, we developed nanostructured SU-8 microprobes to support neuronal growth. Nanostructures of 200 nm diameter and depth were applied to the surface of microprobes, and the attachment and neurite outgrowth of PC12 cells on the microprobes were evaluated. Neuronal attachment and neurite outgrowth on the nanostructured microprobes were significantly greater than those on non-nanostructured microprobes. The enhanced neuronal attachment and neurite outgrowth on the nanostructured microprobes occurred in the absence of an adhesive coating, such as poly-l-lysine, and so may be useful for implantable devices for long-term use. Therefore, nanostructured microprobes can be implanted without adhesive coating, which can cause problems in vivo over the long term.

While the role of ASLX1 in haematopoiesis and leukaemia has been heavily studied, the role of ASLX2 is unclear. Here the authors show that ASLX2 is required for normal haematopoietic stem cell self-renewal whereas Asxl2 loss promotes leukemogenesis, thus explaining the frequently observed mutations in AML patients

Abstract Harmful materials in the blood are prevented from entering the healthy brain by a highly selective blood–brain barrier (BBB), and impairment of barrier function has been associated with a variety of neurological diseases. In Alzheimer's disease (AD), BBB breakdown has been shown to occur even before cognitive decline and brain pathology. To investigate the role of the cerebral vasculature in AD, a physiologically relevant 3D human neural cell culture microfluidic model is developed having a brain endothelial cell monolayer with a BBB‐like phenotype. This model is shown to recapitulate several key aspects of BBB dysfunction observed in AD patients: increased BBB permeability, decreased expression of claudin‐1, claudin‐5, and VE‐cadherin, increased expression of matrix‐metalloproteinase‐2 and reactive oxygen species, and deposition of β‐amyloid (Aβ) peptides at the vascular endothelium. Thus, it provides a well‐controlled platform for investigating BBB function as well as for screening of new drugs that need to pass the BBB to gain access to neural tissues.

Fas-associated factor 1 is a death-promoting protein that induces apoptosis by interacting with the Fas receptor. Until now, FAF1 was reported to interact potentially with diverse proteins and to function as a negative and/or positive regulator of several cellular possesses. However, the role of FAF1 in defense against bacterial infection remains unclear. Here, we show that FAF1 plays a pivotal role in activating NADPH oxidase in macrophages during Listeria monocytogenes infection. Upon infection by L. monocytogenes, FAF1 interacts with p67phox (an activator of the NADPH oxidase complex), thereby facilitating its stabilization and increasing the activity of NADPH oxidase. Consequently, knockdown or ectopic expression of FAF1 had a marked effect on production of ROS, proinflammatory cytokines, and antibacterial activity, in macrophages upon stimulation of TLR2 or after infection with L. monocytogenes. Consistent with this, FAF1gt/gt mice, which are knocked down in FAF1, showed weaker inflammatory responses than wild-type mice; these weaker responses led to increased replication of L. monocytogenes. Collectively, these findings suggest that FAF1 positively regulates NADPH oxidase-mediated ROS production and antibacterial defenses.

What are the most significant factors that motivate and inhibit faculty with regard to teaching in online environments? And what are the specific kinds of experiences that underlie and explain the importance of these factors? One goal of this study was to add to the understanding of these issues, but the primary purpose of this study is determining how well these questions can be answered using the method of structured focus groups. This paper describes the methods and results of a pilot study conducted using four focus group interviews of faculty experienced in teaching using “Asynchronous Learning Networks” (ALN) at one university, and a single focus group at a second university in order to explore generalizability. For the university at which four group interviews were conducted, the rank orders of leading motivators and demotivators were quite consistent. Leading motivators include the flexibility allowed by being able to teach “anytime/anywhere;” better/more personal interaction and community building supported by the medium; the technical and creativity challenges offered by this mode of teaching; being able to reach more (and more diverse) students; and better course management. Major sources of dissatisfaction are more work, medium limitations, lack of adequate support and policies for teaching online, and the fact that the medium is not a good fit for some students. Very similar results were found through the replication focus group conducted at a different institution.

OBJECTIVES This study aimed to reveal the epidemiologic characteristics of the outbreak of gastroenteritis caused by Salmonella enterica serovar Thompson in Busan Metropolitan City and to identify points for improvement to prevent of food-borne disease outbreak. METHODS This was a case-control study. The control group comprised asymptomatic students in the same classes of the cases. The presence or absence of symptoms, ingestion of each food provided by school meal service, and commonly ingested foods in addition to those foods in meal service were investigated. Moreover, specimens collected from rectal swab, preserved foods, and environmental surface were tested. RESULTS Of the 6,092 subjects, 1,111 (1,083 students, 22 school personnel, and 6 foodservice employees) were included in the case group; this corresponded to an 18.4% attack rate. Symptoms included diarrhea (n=1,051, 94.6%), abdominal pain (n=931, 83.8%), febrile sensation (n=502, 45.2%), and vomiting (n=275, 24.8%). The epidemic curves of each 10 schools were unimodal. Investigation of food intake showed a significantly high odds ratio for chocolate cake in 5 out of the 10 schools. Laboratory test detected Salmonella enterica serovar Thompson both in rectal swab specimens of 9 schools and in collected preserved chocolate cakes of 9 schools. Pulsed-field gel electrophoresis test result showed that Salmonella enterica seorvar Thompson isolated from human and foods were the same. CONCLUSIONS The source of infection for the Salmonella enterica serovar Thompson outbreak in the 10 schools of Busan Metropolitan City is chocolate cake. Traceback investigation for origin of contaminated food in food-borne disease outbreak and safety control during food production should be more enhanced.

Irisin is a myokine that is generated by cleavage of the membrane protein fibronectin type III domain-containing protein 5 (FNDC5) in response to physical exercise. Studies reveal that irisin/FNDC5 has neuroprotective functions against Alzheimer’s disease, the most common form of dementia in the elderly, by improving cognitive function and reducing amyloid-β and tau pathologies as well as neuroinflammation in cell culture or animal models of Alzheimer’s disease. Although current and ongoing studies on irisin/FNDC5 show promising results, further mechanistic studies are required to clarify its potential as a meaningful therapeutic target for alleviating Alzheimer’s disease. We recently found that irisin treatment reduces amyloid-β pathology by increasing the activity/levels of amyloid-β-degrading enzyme neprilysin secreted from astrocytes. Herein, we present an overview of irisin/FNDC5’s protective roles and mechanisms against Alzheimer’s disease.

Aortic pseudoaneurysm after cardiac surgery is a rare entity, but it is potentially fatal due to its clinical course along with higher morbidity and mortality rates. Instead of open surgical repair, percutaneous procedures have been introduced as other options for managing an aortic pseudoaneurysm. In this case report, we describe transesophageal echocardiography guidance for successful percutaneous closure of an aortic pseudoaneurysm located in the left ventricular outflow tract by using a type II Amplatzer vascular plug in a patient in whom open surgical repair was not recommended.

Isolated left ventricular noncompaction (LVNC) is a rare primary genetic cardiomyopathy characterized by prominent trabeculation of the left ventricular wall and intertrabecular recesses. Perioperative management of the patient with LVNC might be challenging due to the clinical symptoms of heart failure, systemic thromboembolic events, and fatal left ventricular arrhythmias. We conducted real time intraoperative transesophageal echocardiography in a patient with LVNC undergoing general anesthesia for ovarian cystectomy.

Pinus densiflora was screened in an ongoing project to discover anti-influenza candidates from natural products. An extensive phytochemical investigation provided 26 compounds, including two new megastigmane glycosides (1 and 2), 21 diterpenoids (3–23), and three flavonoids (24–26). The chemical structures were elucidated by a series of chemical reactions, including modified Mosher’s analysis and various spectroscopic measurements such as LC/MS and 1D- and 2D-NMR. The anti-influenza A activities of all isolates were screened by cytopathic effect (CPE) inhibition assays and neuraminidase (NA) inhibition assays. Ten candidates were selected, and detailed mechanistic studies were performed by various assays, such as Western blot, immunofluorescence, real-time PCR and flow cytometry. Compound 5 exerted its antiviral activity not by direct neutralizing virion surface proteins, such as HA, but by inhibiting the expression of viral mRNA. In contrast, compound 24 showed NA inhibitory activity in a noncompetitive manner with little effect on viral mRNA expression. Interestingly, both compounds 5 and 24 were shown to inhibit nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) expression in a dose-dependent manner. Taken together, these results provide not only the chemical profiling of P. densiflora but also anti-influenza A candidates.

[This corrects the article DOI: 10.1371/journal.ppat.1006398.].

Background and Purpose Quantitative magnetic resonance angiography (Q-MRA) enables direct measurement of volume flow rate (VFR) of intracranial arteries. We aimed to evaluate the collateral flows in internal carotid artery (ICA) occlusion with primary collateral pathway via circle of Willis using Q-MRA, and to compare them between patients who recently developed ipsilateral symptomatic ischemia and those who did not. Methods Between 2012 and 2014, 505 patients underwent Q-MRA in our institution. Among these, 33 patients who had unilateral ICA occlusion with primary collateral pathway were identified, and grouped into asymptomatic patients, stable patients with chronic infarction, and symptomatic patients with acute/subacute infarction. Mean VFR (mVFR) in intracranial arteries was measured and compared between the patients’ groups. Kruskal-Wallis test was used for statistical analysis. Results Six patients were asymptomatic, fifteen with chronic infarction were stable, and twelve with acute/subacute infarction were symptomatic. The mVFR of ipsilateral middle cerebral artery in symptomatic patients was significantly lower than those in stable or asymptomatic patients (73.7±45.6 mL/min vs. 119.9±36.1 mL/min vs. 121.8±42.0 mL/min; P = 0.04). Total sum of the mVFR of ipsilateral anterior, middle, and posterior cerebral arteries was significantly lower in symptomatic patients than those in other groups (229.3 ± 51.3 mL/min vs. 282.0±68.6 mL/min vs. 314.0±44.4 mL/min; P = 0.02). Conclusions Q-MRA could be helpful to demonstrate the difference in the degree of primary collateral flow in ICA occlusion between the patients with recent symptomatic ischemia and those without.

The unfolded protein response (UPR) in the endoplasmic reticulum (ER) and the cytoplasmic heat stress response are two major stress response systems necessary for maintaining proteostasis for cellular health. Failure of either of these systems, such as in sustained UPR activation or in insufficient heat shock response activation, can lead to the development of neurodegeneration. Alleviation of ER stress and enhancement of heat shock response through heat shock factor 1 (HSF1) activation have previously been considered as attractive potential therapeutic targets for Alzheimer's disease (AD)-a prevalent and devastating tauopathy. Understanding the interplay of the two aforementioned systems and their cooperative role in AD remain elusive. Here we report studies in human brain and tau pathogenic mouse models (rTg4510, PS19, and rTg21221), identifying HSF1 degradation and UPR activation as precursors of aberrant tau pathogenesis. We demonstrate that chemical ER stress inducers caused autophagy-lysosomal HSF1 degradation, resulting in tau hyperphosphorylation in rat primary neurons. In addition, permanent HSF1 loss reversely causes chronic UPR activation, leading to aberrant tau phosphorylation and aggregation in the hippocampus of aged HSF1 heterozygous knock-out mice. The deleterious interplay of UPR activation and HSF1 loss is exacerbated in N2a cells stably overexpressing a pro-aggregation mutant TauRD ΔK280 (N2a-TauRD ΔK280). We provide evidence of how these two stress response systems are intrinsically interweaved by showing that the gene encoding C/EBP-homologous protein (CHOP) activation in the UPR apoptotic pathway facilitates HSF1 degradation, which likely further contributes to prolonged UPR via ER chaperone HSP70 a5 (BiP/GRP78) suppression. Upregulating HSF1 relieves the tau toxicity in N2a-TauRD ΔK280 by reducing CHOP and increasing HSP70 a5 (BiP/GRP78). Our work reveals how the bidirectional crosstalk between the two stress response systems promotes early tau pathology and identifies HSF1 being one likely key player in both systems.

FAS-associated factor-1 (FAF1) is a component of the death-inducing signaling complex involved in Fas-mediated apoptosis. It regulates NF-κB activity, ubiquitination, and proteasomal degradation. Here, we found that FAF1 positively regulates the type I interferon pathway. FAF1gt/gt mice, which deficient in FAF1, and FAF1 knockdown immune cells were highly susceptible to RNA virus infection and showed low levels of inflammatory cytokines and type I interferon (IFN) production. FAF1 was bound competitively to NLRX1 and positively regulated type I IFN signaling by interfering with the interaction between NLRX1 and MAVS, thereby freeing MAVS to bind RIG-I, which switched on the MAVS-RIG-I-mediated antiviral signaling cascade. These results highlight a critical role of FAF1 in antiviral responses against RNA virus infection.

Acute kidney injury (AKI) after pediatric cardiac surgery is associated with high morbidity and mortality. Modifiable risk factors for postoperative AKI including perioperative anesthesia-related parameters were assessed. The authors conducted a single-center, retrospective cohort study of 220 patients (aged 10 days to 19 years) who underwent congenital cardiac surgery between January and December 2012. The incidence of AKI within 7 days postoperatively was determined using the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Ninety-two patients (41.8%) developed AKI and 18 (8.2%) required renal replacement therapy within the first postoperative week. Among patients who developed AKI, 57 patients (25.9%) were KDIGO stage 1, 27 patients (12.3%) were KDIGO stage 2, and eight patients (3.6%) were KDIGO stage 3. RACHS-1 (Risk-Adjusted classification for Congenital Heart Surgery) category, perioperative transfusion and fluid administration as well as fluid overload were compared between patients with and without AKI. Multivariable logistic regression analyses determined the risk factors for AKI. AKI was associated with longer hospital stay or ICU stay, and frequent sternal wound infections. Younger age (3 g/dl) from preoperative level on POD1 was entered into the multivariable analysis, it was independently associated with postoperative AKI (OR, 6.51; 95% CI, 2.23-19.03 compared with no increase). This association was significant after adjustment with patient demographics, medication history and RACHS-1 category (hemoglobin increase >3g/dl vs. no increase: adjusted OR, 6.94; 95% CI, 2.33-20.69), regardless of different age groups and cyanotic or non-cyanotic heart disease. Prospective trials are required to evaluate whether correction of preoperative anemia and prevention of hemoconcentration may ameliorate postoperative AKI in patients who underwent congenital cardiac surgery.

To find the faster and easier way than the existing intubating technique for double-lumen tube, we modified the angle of double-lumen tube according to an individual's upper airway anatomy and compared the time needed and the number of attempts for successful intubation between individually angle-modified and non-modified double-lumen tubes. Adult patients undergoing elective thoracic surgery were randomly allocated in either non-angle-modified (Group N, n = 54) or angle-modified (Group M, n = 54) groups. During mask ventilation in the sniffing position, angle-modification was performed in Group M as follows: the distal tip of the tube was placed at the level of the cricoid cartilage and the shaft was bent at the intersection of the oral and pharyngeal axes estimated from the patient's surface anatomy. The time needed and the number of attempts for successful intubation and Cormack and Lehane (C-L) grade were recorded. Overall median intubation time (sec) was significantly shorter in Group M than in Group N [10.2 vs. 15.1, P

A 47-day-old male infant presented with fever, poor oral intake, irritability, and right-sided bluish buccal swelling. Contrast-enhanced computed tomography of the neck showed a round mass lesion of about 2.0×1.5 cm that suggested abscess formation in the right masticator space. Ultrasound-guided extraoral aspiration of the abscess at the right masseter muscle was successful. Staphylococcus aureus was identified in the culture from the aspirated pus and blood. Appropriate antibiotics were given and the patient recovered. The patient underwent follow-up ultrasonography that showed an improved state of the previously observed right masseter muscle swelling at about 1 month after hospital discharge. A masticator space abscess usually originates from an odontogenic infection in adults. We report a case of masticator space abscess in a 47-day-old infant in whom septicemia without odontogenic infection was suspected.

Determination of 5-d biochemical oxygen demand (BOD5) is the most commonly practiced test to assess the water quality of surface waters and the waste loading. However, BOD5 is not a good parameter for the control of water or wastewater treatment processes because of its long test period. It is very difficult to produce consistent and reliable BOD5 results without using careful laboratory quality control practices. This study was performed to develop software sensors to predict the BOD5 of river water and wastewater. The software sensors were based on the multiple regression analysis using the dissolved organic carbon (DOC) concentration, UV light absorbance at 254 nm, and synchronous fluorescence spectra. River water samples and wastewater treatment plant (WWTP) effluents were collected at 1-hour interval to evaluate the feasibility of the software sensors. In short, the software sensors developed in this study could well predict the BOD5 of river water (r=0.78) and for the WWTP effluent (r=0.90).