Follistatin regulates the specification of the apical cochlea responsible for low-frequency hearing in mammals.

The cochlea's ability to discriminate sound frequencies is facilitated by a special topography along its longitudinal axis known as tonotopy. Auditory hair cells located at the base of the cochlea respond to high-frequency sounds, whereas hair cells at the apex respond to lower frequencies. Gradual changes in morphological and physiological features along the length of the cochlea determine each region's frequency selectivity, but it remains unclear how tonotopy is established during cochlear development. Recently, sonic hedgehog (SHH) was proposed to initiate the establishment of tonotopy by conferring regional identity to the primordial cochlea. Here, using mouse genetics, we provide in vivo evidence that regional identity in the embryonic cochlea acts as a framework upon which tonotopy-specific properties essential for frequency selectivity in the mature cochlea develop. We found that follistatin (FST) is required for the maintenance of apical cochlear identity, but dispensable for its initial induction. In a fate-mapping analysis, we found that FST promotes expansion of apical cochlear cells, contributing to the formation of the apical cochlear domain. SHH, in contrast, is required both for the induction and maintenance of apical identity. In the absence of FST or SHH, mice produce a short cochlea lacking its apical domain. This results in the loss of apex-specific anatomical and molecular properties and low-frequency-specific hearing loss.

External Validation of Deep Learning-Based Cardiac Arrest Risk Management System for Predicting In-Hospital Cardiac Arrest in Patients Admitted to General Wards Based on Rapid Response System Operating and Nonoperating Periods: A Single-Center Study.

OBJECTIVES: The limitations of current early warning scores have prompted the development of deep learning-based systems, such as deep learning-based cardiac arrest risk management systems (DeepCARS). Unfortunately, in South Korea, only two institutions operate 24-hour Rapid Response System (RRS), whereas most hospitals have part-time or no RRS coverage at all. This study validated the predictive performance of DeepCARS during RRS operation and nonoperation periods and explored its potential beyond RRS operating hours. DESIGN: Retrospective cohort study. SETTING: In this 1-year retrospective study conducted at Yonsei University Health System Severance Hospital in South Korea, DeepCARS was compared with conventional early warning systems for predicting in-hospital cardiac arrest (IHCA). The study focused on adult patients admitted to the general ward, with the primary outcome being IHCA-prediction performance within 24 hours of the alarm. PATIENTS: We analyzed the data records of adult patients admitted to a general ward from September 1, 2019, to August 31, 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Performance evaluation was conducted separately for the operational and nonoperational periods of the RRS, using the area under the receiver operating characteristic curve (AUROC) as the metric. DeepCARS demonstrated a superior AUROC as compared with the Modified Early Warning Score (MEWS) and the National Early Warning Score (NEWS), both during RRS operating and nonoperating hours. Although the MEWS and NEWS exhibited varying performance across the two periods, DeepCARS showed consistent performance. CONCLUSIONS: The accuracy and efficiency for predicting IHCA of DeepCARS were superior to that of conventional methods, regardless of whether the RRS was in operation. These findings emphasize that DeepCARS is an effective screening tool suitable for hospitals with full-time RRS, part-time RRS, and even those without any RRS.

Understanding experiences of cancer-related fatigue in patients with lung cancer after their cancer treatment: a qualitative content analysis.

PURPOSE: Cancer-related fatigue (CRF) is an important symptom affecting the quality of life of patients with lung cancer. However, research on the characteristics of CRF in lung cancer and their relationship to cancer treatment is limited. We aimed to explore the unique features of CRF in patients with lung cancer, and investigate the influencing factors. METHODS: Semi-structured interviews were conducted with 21 adult patients with lung cancer until data saturation was reached. The collected data were analyzed using qualitative content analysis. An inductive coding process and deductive content analysis incorporating the established CRF domains were employed. Patient data from electronic medical records were used for data triangulation. RESULTS: The analysis revealed five themes of CRF: (1) energy depletion, the double burden of illness and treatment, and daily life impediments; (2) feeling down and anxious; (3) neurovascular disturbances and changes in sensory perception; (4) cognitive impairment; and (5) personal and social isolation. CRF tended to improve over time, except for persistent emotional fatigue beyond 6 months. Patients who underwent surgery followed by adjuvant cancer treatment exhibited the most diverse CRF symptoms. The concurrent chemoradiation therapy group experienced significant physical fatigue, whereas the radiosurgery group reported distinct emotional fatigue. Certain factors, such as exercise, can serve as both alleviating and aggravating factors for CRF. CONCLUSION: Tailored interventions that take into account the multidimensional symptoms of CRF and patient characteristics are crucial. These findings will guide healthcare professionals when implementing patient-centered symptom management and patient education.

mTORC1 Coordinates Protein Synthesis and Immunoproteasome Formation via PRAS40 to Prevent Accumulation of Protein Stress.

Reduction of translational fidelity often occurs in cells with high rates of protein synthesis, generating defective ribosomal products. If not removed, such aberrant proteins can be a major source of cellular stress causing human diseases. Here, we demonstrate that mTORC1 promotes the formation of immunoproteasomes for efficient turnover of defective proteins and cell survival. mTORC1 sequesters precursors of immunoproteasome ß subunits via PRAS40. When activated, mTORC1 phosphorylates PRAS40 to enhance protein synthesis and simultaneously to facilitate the assembly of the ß subunits for forming immunoproteasomes. Consequently, the PRAS40 phosphorylations play crucial roles in clearing aberrant proteins that accumulate due to mTORC1 activation. Mutations of RAS, PTEN, and TSC1, which cause mTORC1 hyperactivation, enhance immunoproteasome formation in cells and tissues. Those mutations increase cellular dependence on immunoproteasomes for stress response and survival. These results define a mechanism by which mTORC1 couples elevated protein synthesis with immunoproteasome biogenesis to protect cells against protein stress.

Comparative Effectiveness of Personal Sound Amplification Products Versus Hearing Aids for Unilateral Hearing Loss: A Prospective Randomized Crossover Trial.

BACKGROUND: This study compared hearing outcomes with use of personal sound amplification products (PSAPs) and hearing aids (HAs) in patients with moderate to moderately severe unilateral hearing loss. METHODS: Thirty-nine participants were prospectively enrolled, and randomly assigned to use either one HA (basic or premium type) or one PSAP (basic or high-end type) for the first 8 weeks and then the other device for the following 8 weeks. Participants underwent a battery of examinations at three visits, including sound-field audiometry, word recognition score (WRS), speech perception in quiet and in noise, real-ear measurement, and self-report questionnaires. RESULTS: Functional gain was significantly higher with HAs across all frequencies (P < 0.001). While both PSAPs and HAs improved WRS from the unaided condition, HAs were superior to PSAPs. The speech recognition threshold in quiet conditions and signal-to-noise ratio in noisy conditions were significantly lower in the HA-aided condition than in the PSAP-aided condition, and in the PSAP-aided condition than in the unaided condition. Subjective satisfaction also favored HAs than PSAPs in questionnaires, Abbreviated Profile of Hearing Aid Benefit, International Outcome Inventory for Hearing Aids, and Host Institutional Questionnaire. CONCLUSION: While PSAPs provide some benefit for moderate to moderately severe unilateral hearing loss, HAs are more effective. This underscores the potential role of PSAPs as an accessible, affordable first-line intervention in hearing rehabilitation, particularly for individuals facing challenges in accessing conventional HAs.

Titration-based normalization of antibody amount improves consistency of ChIP-seq experiments.

Chromatin immunoprecipitation (ChIP) is an antibody-based approach that is frequently utilized in chromatin biology and epigenetics. The challenge in experimental variability by unpredictable nature of usable input amounts from samples and undefined antibody titer in ChIP reaction still remains to be addressed. Here, we introduce a simple and quick method to quantify chromatin inputs and demonstrate its utility for normalizing antibody amounts to the optimal titer in individual ChIP reactions. For a proof of concept, we utilized ChIP-seq validated antibodies against the key enhancer mark, acetylation of histone H3 on lysine 27 (H3K27ac), in the experiments. The results indicate that the titration-based normalization of antibody amounts improves assay outcomes including the consistency among samples both within and across experiments for a broad range of input amounts.

Modafinil exerts anti-inflammatory and anti-fibrotic effects by upregulating adenosine A2A and A2B receptors.

Adenosine receptor (AR) suppresses inflammation and fibrosis by activating cyclic adenosine monophosphate (cAMP) signaling. We investigated whether altered AR expression contributes to the development of fibrotic diseases and whether A2AAR and A2BAR upregulation inhibits fibrotic responses. Primary human lung fibroblasts (HLFs) from normal (NHLFs) or patients with idiopathic pulmonary fibrosis (DHLF) were used for in vitro testing. Murine models of fibrotic liver or pulmonary disease were developed by injecting thioacetamide intraperitoneally, by feeding a high-fat diet, or by intratracheal instillation of bleomycin. Modafinil, which activates cAMP signaling via A2AAR and A2BAR, was administered orally. The protein amounts of A2AAR, A2BAR, and exchange protein directly activated by cAMP (Epac) were reduced, while collagen and α-smooth muscle actin (α-SMA) were elevated in DHLFs compared to NHLFs. In liver or lung tissue from murine models of fibrotic diseases, A2AAR and A2BAR were downregulated, but A1AR and A3AR were not. Epac amounts decreased, and amounts of collagen, α-SMA, KCa2.3, and KCa3.1 increased compared to the control. Modafinil restored the amounts of A2AAR, A2BAR, and Epac, and reduced collagen, α-SMA, KCa2.3, and KCa3.1 in murine models of fibrotic diseases. Transforming growth factor-ß reduced the amounts of A2AAR, A2BAR, and Epac, and elevated collagen, α-SMA, KCa2.3, and KCa3.1 in NHLFs; however, these alterations were inhibited by modafinil. Our investigation revealed that A2AAR and A2BAR downregulation induced liver and lung fibrotic diseases while upregulation attenuated fibrotic responses, suggesting that A2AAR and A2BAR-upregulating agents, such as modafinil, may serve as novel therapies for fibrotic diseases.

Anti-Neuroinflammatory Effect of the Ethanolic Extract of Black Ginseng through TLR4-MyD88-Regulated Inhibition of NF-κB and MAPK Signaling Pathways in LPS-Induced BV2 Microglial Cells.

Korean ginseng (Panax ginseng) contains various ginsenosides as active ingredients, and they show diverse biological activities. Black ginseng is manufactured by repeated steaming and drying of white ginseng, which alters the polarity of ginsenosides and improves biological activities. The aim of the present investigation was to examine the anti-neuroinflammatory effects of the ethanolic extract of black ginseng (BGE) in lipopolysaccharide (LPS)-induced BV2 microglial cells. Pre-treatment with BGE inhibited the overproduction of pro-inflammatory mediators including nitric oxide (NO), prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in LPS-induced BV2 cells. In addition, BGE reduced the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), p38 mitogen-activated protein kinase (MAPK), and c-jun N-terminal kinase (JNK) MAPK signaling pathways induced by LPS. These anti-neuroinflammatory effects were mediated through the negative regulation of the toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88 (MyD88) signaling pathway. Among the four ginsenosides contained in BGE, ginsenosides Rd and Rg3 inhibited the production of inflammatory mediators. Taken together, this investigation suggests that BGE represents potential anti-neuroinflammatory candidates for the prevention and treatment of neurodegenerative diseases.

Acetylcorynoline Induces Apoptosis and G2/M Phase Arrest through the c-Myc Signaling Pathway in Colon Cancer Cells.

Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide, and despite advances in treatment, survival rates are still low; therefore, the development of novel drugs is imperative. Acetylcorynoline (ACN) is derived from Corydalis ambigua Cham. et Schltdl tubers. The effect of ACN on colon cancer is still unknown. Therefore, we investigated its potential effects. Our data showed that ACN inhibited cell viability and proliferation. Moreover, ACN induced apoptosis and cell cycle arrest by inhibiting cell growth. In the present study, we hypothesized that ACN regulates c-Myc through CNOT2 or MID1IP1. ACN reduced the protein expression of oncogenic genes, decreased c-Myc half-life, and rapidly inhibited the serum stimulation response. Moreover, knockdown of CNOT2 and MID1IP1 with ACN increased apoptosis and further reduced the expression of oncogenes. In addition, ACN exhibited a synergistic effect with low-dose 5-fluorouracil (5-FU) and doxorubicin (Dox). Collectively, our data demonstrate that ACN inhibited c-Myc expression through CNOT2 and MID1IP1, and induced apoptosis. These findings indicate the potential of ACN as a therapeutic agent against colon cancer.

A 7-Hydroxy 4-Methylcoumarin Enhances Melanogenesis in B16-F10 Melanoma Cells.

The objectives of this study were to investigate the melanogenetic potentials of the naturally occurring 7-hydroxy coumarin derivatives 7-hydroxy 5,6-dimethoxycoumarin (7H-5,6DM), 7-hydroxy 6,8-dimethoxycoumarin (7H-6,8DM), 7-hydroxy 6-methoxycoumarin (7H-6M), and 7-hydroxy 4-methylcoumarin (7H-4M) in the melanogenic cells model for murine B16F10 melanoma cells. The initial results indicated that melanin production and intracellular tyrosinase activity were significantly stimulated by 7H-4M but not by 7H-5,6DM, 7H-6,8DM, or 7H-6M. Therefore, our present study further investigated the melanogenic effects of 7H-4M in B16-F10 cells, as well as its mechanisms of action. In a concentration-dependent manner, 7H-4M increased intracellular tyrosinase activity, leading to the accumulation of melanin without affecting the viability of B16-F10 cells. Our study further investigated the effects of 7H-4M on melanogenesis, including its ability to promote tyrosinase activity, increase melanin content, and activate molecular signaling pathways. The results indicate that 7H-4M effectively stimulated tyrosinase activity and significantly increased the expression of melanin synthesis-associated proteins, such as microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase-related protein-1 (TRP1), and TRP2. Based on our findings, we can conclude that 7H-4M has the ability to activate the melanogenesis process through the upregulation of cAMP-dependent protein kinase (PKA) and the cAMP response element-binding protein (CREB). Additionally, our study showed that 7H-4M induced melanogenic effects by downregulating the extracellular signal-regulated kinase (ERK) and the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt)/glycogen synthesis kinase-3ß (GSK-3ß) cascades, while upregulating the JNK and p38 signaling pathways. Finally, the potential of using 7H-4M in topical applications was tested through primary human skin irritation tests. During these tests, no adverse reactions were induced by 7H-4M. In summary, our results indicate that 7H-4M regulates melanogenesis through various signaling pathways such as GSK3ß/ß-catenin, AKT, PKA/CREB, and MAPK. These findings suggest that 7H-4M has the potential to prevent the development of pigmentation diseases.

Synthetic Glabridin Derivatives Inhibit LPS-Induced Inflammation via MAPKs and NF-κB Pathways in RAW264.7 Macrophages.

Glabridin is a polyphenolic compound with reported anti-inflammatory and anti-oxidative effects. In the previous study, we synthesized glabridin derivatives-HSG4112, (S)-HSG4112, and HGR4113-based on the structure-activity relationship study of glabridin to improve its biological efficacy and chemical stability. In the present study, we investigated the anti-inflammatory effects of the glabridin derivatives in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. We found that the synthetic glabridin derivatives significantly and dose-dependently suppressed the production of nitric oxide (NO) and prostaglandin E2 (PGE2), and decreased the level of inducible nitric oxygen synthase (iNOS) and cyclooxygenase-2 (COX-2) and the expression of pro-inflammatory cytokines interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor alpha (TNF-α). The synthetic glabridin derivatives inhibited the nuclear translocation of the NF-κB by inhibiting phosphorylation of the inhibitor of κB alpha (IκB-α), and distinctively inhibited the phosphorylation of ERK, JNK, and p38 MAPKs. In addition, the compounds increased the expression of antioxidant protein heme oxygenase (HO-1) by inducing nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) through ERK and p38 MAPKs. Taken together, these results indicate that the synthetic glabridin derivatives exert strong anti-inflammatory effects in LPS-stimulated macrophages through MAPKs and NF-κB pathways, and support their development as potential therapeutics against inflammatory diseases.

New in vitro multiple cardiac ion channel screening system for preclinical Torsades de Pointes risk prediction under the Comprehensive in vitro Proarrhythmia Assay concepta.

Cardiotoxicity, particularly drug-induced Torsades de Pointes (TdP), is a concern in drug safety assessment. The recent establishment of human induced pluripotent stem cell-derived cardiomyocytes (human iPSC-CMs) has become an attractive human-based platform for predicting cardiotoxicity. Moreover, electrophysiological assessment of multiple cardiac ion channel blocks is emerging as an important parameter to recapitulate proarrhythmic cardiotoxicity. Therefore, we aimed to establish a novel in vitro multiple cardiac ion channel screening-based method using human iPSC-CMs to predict the drug-induced arrhythmogenic risk. To explain the cellular mechanisms underlying the cardiotoxicity of three representative TdP high- (sotalol), intermediate- (chlorpromazine), and low-risk (mexiletine) drugs, and their effects on the cardiac action potential (AP) waveform and voltage-gated ion channels were explored using human iPSC-CMs. In a proof-of-principle experiment, we investigated the effects of cardioactive channel inhibitors on the electrophysiological profile of human iPSC-CMs before evaluating the cardiotoxicity of these drugs. In human iPSC-CMs, sotalol prolonged the AP duration and reduced the total amplitude (TA) via selective inhibition of IKr and INa currents, which are associated with an increased risk of ventricular tachycardia TdP. In contrast, chlorpromazine did not affect the TA; however, it slightly increased AP duration via balanced inhibition of IKr and ICa currents. Moreover, mexiletine did not affect the TA, yet slightly reduced the AP duration via dominant inhibition of ICa currents, which are associated with a decreased risk of ventricular tachycardia TdP. Based on these results, we suggest that human iPSC-CMs can be extended to other preclinical protocols and can supplement drug safety assessments.

Validation of a Quantification Method for Curcumin Derivatives and Their Hepatoprotective Effects on Nonalcoholic Fatty Liver Disease.

Curcumin (CM), demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC) are major curcumin derivatives found in the rhizome of turmeric (Curcuma longa L.), and have yielded impressive properties to halt various diseases. In the present study, we carried out a method validation for curcumin derivatives and analyzed the contents simultaneously using HPLC with UV detection. For validation, HPLC was used to estimate linearity, range, specificity, accuracy, precision, limit of detection (LOD), and limit of quantification (LOQ). Results showed a high linearity of the calibration curve, with a coefficient of correlation (R2) for CM, DMC, and BDMC of 0.9999, 0.9999, and 0.9997, respectively. The LOD values for CM, DMC, and BDMC were 1.16, 1.03, and 2.53 ng/µL and LOQ values were 3.50, 3.11, and 7.67 ng/µL, respectively. Moreover, to evaluate the ability of curcumin derivatives to reduce liver lipogenesis and compare curcumin derivatives' therapeutic effects, a HepG2 cell model was established to analyze their hepatoprotective properties. Regarding the in vivo study, we investigated the effect of DMC, CM, and BDMC on nonalcoholic fatty liver disease (NAFLD) caused by a methionine choline deficient (MCD)-diet in the C57BL/6J mice model. From the in vitro and in vivo results, curcumin derivatives alleviated MCD-diet-induced lipid accumulation as well as high triglyceride (TG) and total cholesterol (TC) levels, and the protein and gene expression of the transcription factors related to liver adipogenesis were suppressed. Furthermore, in MCD-diet mice, curcumin derivatives suppressed the upregulation of toll-like receptors (TLRs) and the production of pro-inflammatory cytokines. In conclusion, our findings indicated that all of the three curcuminoids exerted a hepatoprotective effect in the HepG2 cell model and the MCD-diet-induced NAFLD model, suggesting a potential for curcuminoids derived from turmeric as novel therapeutic agents for NAFLD.

Remarkable enantioselectivity enhancement of the extractors with nonaxial chirality in liquid-liquid extraction of underivatized amino acids by introducing t-butyl group.

A class of carbonyl extractors, (R)-3, (R)-4, and (R)-5, with nonaxial chirality containing asymmetric carbons has been synthesized and studied for their efficiencies in enantioselective liquid-liquid extraction for underivatized amino acids. The bulky t-butyl ketone extractors, (R)-4 and (R)-5, showed the stereoselectivities ranging 5.4-9.4 of l/d ratio much better than those of the aldehyde extractor, (R)-3, ranging 2.4-5.2. The imine formation rates and yields of the t-butyl ketones were not significantly affected by their bulkiness and even in the absence of resonance-assisted hydrogen bond. This work confirms that a bulky t-butyl ketone can be a good choice in the development of an extractor not only with axial chirality but also with nonaxial chirality for the enantioselective extraction of unprotected amino acids.

Laparoscopic cholecystectomy in a swine model using a novel near-infrared fluorescent IV dye (BL-760).

BACKGROUND AND OBJECTIVES: Bile duct injury during laparoscopic cholecystectomy has an incidence rate of 1%-2% and commonly appears under conditions of severe inflammation, adhesion, or unexpected anatomical variations. Despite the difficulties and rising concerns of identifying bile duct during surgeries, surgeons do not have a specific modality to identify bile duct except intraoperative cholangiography. While no biliary-specific fluorescent dye exists for clinical use, our team has previously described the development of a preclinical biliary-specific dye, BL-760. Here, we present our study of laparoscopic cholecystectomy using the fluorescent dye in a swine model. STUDY DESIGN/MATERIALS AND METHODS: With an approval from Institutional Animal Care and Use Committee, two 20-25 kg swine underwent laparoscopic abdominal surgery using a Food and Drug Administration-cleared fluorescent laparoscopic system. Images of the liver and gallbladder were taken both before and after intravenous injection of the novel fluorescent dye. The dye was dosed at 60 µg/kg and injected via the ear vein. The amount of time taken to visualize fluorescence in the biliary tract was measured. Fluorescent signal was observed after injection, and target-to-background ratio (TBR) of the biliary tract to surrounding cystic artery and liver parenchyma was measured. RESULTS: Biliary tract visualization under fluorescent laparoscopy was achieved within 5 min after the dye injection without any adverse effects. Cystic duct and extrahepatic duct were clearly visualized and identified with TBR values of 2.19 and 2.32, respectively, whereas no fluorescent signal was detected in liver. Cystic duct and artery were successfully ligated by an endoscopic clip applier with the visual assistance of highlighted biliary tract images. Laparoscopic cholecystectomy was completed within 30 min in each case without any complications. CONCLUSIONS: BL-760 is a novel preclinical fluorescent dye useful for intraoperative identification and visualization of biliary tract. Such fluorescent dye that is exclusively metabolized by liver and rapidly excreted into biliary tract would be beneficial for all types of hepato-biliary surgeries. With the validation of additional preclinical data, this novel dye has potential to be a valuable tool to prevent any iatrogenic biliary injuries and/or bile leaks during laparoscopic abdominal and liver surgeries.

Racial and Neighborhood-Level Disparities in COVID-19 Incidence among Patients on Hemodialysis in New York City.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has disproportionately affected socially disadvantaged populations. Whether disparities in COVID-19 incidence related to race/ethnicity and socioeconomic factors exist in the hemodialysis population is unknown. METHODS: Our study involved patients receiving in-center hemodialysis in New York City. We used a validated index of neighborhood social vulnerability, the Social Vulnerability Index (SVI), which comprises 15 census tract-level indicators organized into four themes: socioeconomic status, household composition and disability, minority status and language, and housing type and transportation. We examined the association of race/ethnicity and the SVI with symptomatic COVID-19 between March 1, 2020 and August 3, 2020. COVID-19 cases were ascertained using PCR testing. We performed multivariable logistic regression to adjust for demographics, individual-level social factors, dialysis-related medical history, and dialysis facility factors. RESULTS: Of the 1378 patients on hemodialysis in the study, 247 (17.9%) developed symptomatic COVID-19. In adjusted analyses, non-Hispanic Black and Hispanic patients had significantly increased odds of COVID-19 compared with non-Hispanic White patients. Census tract-level overall SVI, modeled continuously or in quintiles, was not associated with COVID-19 in unadjusted or adjusted analyses. Among non-Hispanic White patients, the socioeconomic status SVI theme, the minority status and language SVI theme, and housing crowding were significantly associated with COVID-19 in unadjusted analyses. CONCLUSIONS: Among patients on hemodialysis in New York City, there were substantial racial/ethnic disparities in COVID-19 incidence not explained by neighborhood-level social vulnerability. Neighborhood-level socioeconomic status, minority status and language, and housing crowding were positively associated with acquiring COVID-19 among non-Hispanic Whites. Our findings suggest that socially vulnerable patients on dialysis face disparate COVID-19-related exposures, requiring targeted risk-mitigation strategies.

Macluraxanthone B inhibits LPS-induced inflammatory responses in RAW264.7 and BV2 cells by regulating the NF-κB and MAPK signaling pathways.

OBJECTIVE: The prenylated xanthones compounds, macluraxanthone B (MCXB) was isolated from the MeOH extracts of Cudrania tricuspidata. In this study, we investigated the effect of MCXB on inflammatory response. MATERIALS AND METHODS: Anti-inflammatory effects of MCXB were examined in lipopolysaccharide (LPS)-stimulated RAW264.7 and BV2 cells. We observed their anti-inflammatory effects by ELISA, western blot analysis, and immunofluorescence. RESULTS: MCXB significantly inhibited the LPS-stimulated production of nitric oxide (NO), prostaglandin E2 (PGE2), interleukin-6 (IL-6), and tumor necrosis factor (TNF)-α in RAW264.7 and BV2 cells. MCXB also reduced the LPS-induced expression of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 proteins. Incubating cells with MCXB prevented subsequent activation of the nuclear factor kappa B (NF-κB) signaling pathway by inhibiting the nuclear localization and DNA-binding activity of the p65 subunit induced by LPS. MCXB inhibited the phosphorylation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38 mitogen-activated protein kinases (MAPKs) in RAW264.7 and BV2 cells. MCXB induced the expression of heme oxygenase (HO)-1 protein, and the inhibitory effect of MCXB on nitric oxide production was partially reversed by a selective HO-1 inhibitor. DISCUSSION AND CONCLUSIONS: Our results suggested that the anti-inflammatory effect of MCXB is partly regulated by HO-1 induction. In conclusion, MCXB could be a useful candidate for the development of therapeutic and preventive agents to treat inflammatory diseases.

Post-CMOS Compatible Aluminum Scandium Nitride/2D Channel Ferroelectric Field-Effect-Transistor Memory.

Recent advances in oxide ferroelectric (FE) materials have rejuvenated the field of low-power, nonvolatile memories and made FE memories a commercial reality. Despite these advances, progress on commercial FE-RAM based on lead zirconium titanate has stalled due to process challenges. The recent discovery of ferroelectricity in scandium-doped aluminum nitride (AlScN) presents new opportunities for direct memory integration with logic transistors due to the low temperature of AlScN deposition (approximately 350 °C), making it compatible with back end of the line integration on silicon logic. Here, we present a FE-FET device composed of an FE-AlScN dielectric layer integrated with a two-dimensional MoS2 channel. Our devices show an ON/OFF ratio of ∼106, concurrent with a normalized memory window of 0.3 V/nm. The devices also demonstrate stable memory states up to 104 cycles and state retention up to 105 s. Our results suggest that the FE-AlScN/2D combination is ideal for embedded memory and memory-based computing architectures.

The Antitumor Effect of Timosaponin A3 through c-Myc Inhibition in Colorectal Cancer Cells and Combined Treatment Effect with 5-FU or Doxorubicin.

Timosaponin A3 (TA3), extracted from the rhizome of Anemarrhenaasphodeloides Bunge, has been reported to affect various diseases, such as cancer, Alzheimer's disease, and allergies. However, the underlying molecular mechanisms and impacts are largely unknown. In the present study, we hypothesized that TA3 induces apoptosis through the inhibition of c-Myc expression via CNOT2 or MID1IP1 in HCT116. An MTT assay and colony formation assay were used to measure cell viability and proliferation. The protein expression of apoptotic markers and oncogenes was measured using immunoblotting and immunofluorescence assays. The interaction between MID1IP1 and c-Myc was confirmed by performing an immunoprecipitation assay. TA3 markedly inhibited colon cancer cell proliferation. Consistently, TA3 regulated the apoptotic proteins pro-PARP and caspase 3. TA3 inhibited the half-life of c-Myc and suppressed its expression in response to serum stimulation. In addition, TA3 enhanced the apoptotic effects of doxorubicin and 5-FU in colon cancer cells. Altogether, our results reveal a mechanism by which TA3 induces apoptosis through inhibiting c-Myc expression via CNOT2 or MID1IP1 in HCT116, which may help in the development of new therapies for colon cancer based on TA3 in the future.

Comparison of the Characteristics of Recycled Carbon Fibers/Polymer Composites by Different Recycling Techniques.

In this study, three recycling methods, namely, mechanical grinding, steam pyrolysis, and the supercritical solvent process, which are used to acquire recycled carbon fibers (RCFs), were compared for their application in synthesizing polymer-matrix composites. RCF-reinforced polyethylene (PE) composites were prepared to compare the mechanical properties of the composites generated using the three recycling methods. The PE/RCF composites exhibited 1.5 times higher mechanical strength than the RCF-reinforced PE composites, probably because of the surface oxidation effects during the recycling processes that consequently enhanced interfacial forces between the RCF and the matrix. Further, the steam pyrolysis process showed the highest energy efficiency and can thus be applied on a large production scale in domestic recycled CF markets.