Daily changes in spatial accessibility to ICU beds and their relationship with the case-fatality ratio of COVID-19 in the state of Texas, USA.

During the COVID-19 pandemic, many patients could not receive timely healthcare services due to limited availability and access to healthcare resources and services. Previous studies found that access to intensive care unit (ICU) beds saves lives, but they overlooked the temporal dynamics in the availability of healthcare resources and COVID-19 cases. To fill this gap, our study investigated daily changes in ICU bed accessibility with an enhanced two-step floating catchment area (E2SFCA) method in the state of Texas. Along with the increased temporal granularity of measurements, we uncovered two phenomena: 1) aggravated spatial inequality of access during the pandemic, and 2) the retrospective relationship between insufficient ICU bed accessibility and the high case-fatality ratio of COVID-19 in rural areas. Our findings suggest that those locations should be supplemented with additional healthcare resources to save lives in future pandemic scenarios.

QUANTITATIVE ANALYSIS OF CHOROIDAL MORPHOLOGY USING MULTIMODAL IMAGING IN ACUTE AND PERSISTENT CENTRAL SEROUS CHORIORETINOPATHY.

PURPOSE: To analyze quantitative differences in choroidal morphology between acute and persistent central serous chorioretinopathy using multimodal images. METHODS: Ultra-widefield indocyanine green angiography (UWICGA) and optical coherence tomography images of 72 eyes of 72 patients with acute (32 eyes) and persistent (40 eyes) central serous chorioretinopathy were collected. Choroidal thickness, area, vessel density, symmetry, and intervortex anastomosis were assessed. RESULTS: The choroidal area on optical coherence tomography B-scan images was smaller and the choroidal vessel density on UWICGA images was lower in the persistent group ( P < 0.001 and P = 0.028, respectively). Choroidal vessel density on UWICGA showed positive correlation with that of vortex ampullae (all P ≤ 0.046). The constitution of the intervortex anastomosis and dominant vessels in the macular area showed differences between the groups ( P = 0.014 and P = 0.010, respectively), with greater inferonasal vessel participation in the anastomosis and combined superotemporal and inferotemporal vessels as dominant vessels in the persistent groups. CONCLUSION: Acute and persistent central serous chorioretinopathy differed in subfoveal choroidal area, choroidal vessel density, and intervortex anastomosis constitution on UWICGA images. Choroidal vessel density on UWICGA images correlated with that of vortex ampullae. These findings enhance our understanding of the pathophysiology of central serous chorioretinopathy subtypes.

Choroidal Morphology on Ultra-Widefield Indocyanine Green Angiography and Response to Aflibercept in Pachychoroid Neovasculopathy.

Purpose: This study assessed the relationship between the choroidal morphology and short-term response to aflibercept treatment in pachychoroid neovasculopathy (PNV). Methods: This was a retrospective case-control study. Ultra-widefield indocyanine green angiography (UWICGA) and optical coherence tomography (OCT) images of 90 PNV eyes of 90 patients treated with aflibercept were enrolled. Responsiveness to aflibercept was defined as a complete resolution of sub- or intra-retinal fluid after three loading doses (50 dry and 40 non-dry eyes). Subfoveal choroidal thickness (SFCT) was measured on OCT images, and choroidal vessel density (CVD), CVD asymmetry, intervortex anastomosis, and choroidal vascular hyperpermeability (CVH) were assessed on UWICGA images. Results: CVD on UWICGA differed between groups in terms of the total area (0.323 ± 0.034 in dry vs. 0.286 ± 0.038 in non-dry, p < 0.001) and area of each quadrant (superotemporal: 0.317 ± 0.040 vs. 0.283 ± 0.040, superonasal: 0.334 ± 0.040 vs. 0.293 ± 0.045, inferonasal: 0.306 ± 0.051 vs. 0.278 ± 0.052, inferotemporal: 0.334 ± 0.047 vs. 0.290 ± 0.046; all p ≤ 0.010). The CVH grade differed between groups (mean 1.480 ± 0.735 vs. 1.875 ± 0.822, p = 0.013). ST and IT intervortex anastomoses were common in the dry group, while SN, ST, and IT were most common in the non-dry group (p = 0.001). Conclusions: A poor short-term response to aflibercept treatment in PNV eyes was associated with a lower Haller vessel density, higher CVH grade, and intervortex anastomosis involving more quadrants on UWICGA.

Mosaic RBD nanoparticles induce intergenus cross-reactive antibodies and protect against SARS-CoV-2 challenge.

Recurrent spillovers of α- and ß-coronaviruses (CoV) such as severe acute respiratory syndrome (SARS)-CoV, Middle East respiratory syndrome-CoV, SARS-CoV-2, and possibly human CoV have caused serious morbidity and mortality worldwide. In this study, six receptor-binding domains (RBDs) derived from α- and ß-CoV that are considered to have originated from animals and cross-infected humans were linked to a heterotrimeric scaffold, proliferating cell nuclear antigen (PCNA) subunits, PCNA1, PCNA2, and PCNA3. They assemble to create a stable mosaic multivalent nanoparticle, 6RBD-np, displaying a ring-shaped disk with six protruding antigens, like jewels in a crown. Prime-boost immunizations with 6RBD-np in mice induced significantly high Ab titers against RBD antigens derived from α- and ß-CoV and increased interferon (IFN-γ) production, with full protection against the SARS-CoV-2 wild type and Delta challenges. The mosaic 6RBD-np has the potential to induce intergenus cross-reactivity and to be developed as a pan-CoV vaccine against future CoV spillovers.

An integrated cyberGIS and machine learning framework for fine-scale prediction of Urban Heat Island using satellite remote sensing and urban sensor network data.

Due to climate change and rapid urbanization, Urban Heat Island (UHI), featuring significantly higher temperature in metropolitan areas than surrounding areas, has caused negative impacts on urban communities. Temporal granularity is often limited in UHI studies based on satellite remote sensing data that typically has multi-day frequency coverage of a particular urban area. This low temporal frequency has restricted the development of models for predicting UHI. To resolve this limitation, this study has developed a cyber-based geographic information science and systems (cyberGIS) framework encompassing multiple machine learning models for predicting UHI with high-frequency urban sensor network data combined with remote sensing data focused on Chicago, Illinois, from 2018 to 2020. Enabled by rapid advances in urban sensor network technologies and high-performance computing, this framework is designed to predict UHI in Chicago with fine spatiotemporal granularity based on environmental data collected with the Array of Things (AoT) urban sensor network and Landsat-8 remote sensing imagery. Our computational experiments revealed that a random forest regression (RFR) model outperforms other models with the prediction accuracy of 0.45 degree Celsius in 2020 and 0.8 degree Celsius in 2018 and 2019 with mean absolute error as the evaluation metric. Humidity, distance to geographic center, and PM2.5 concentration are identified as important factors contributing to the model performance. Furthermore, we estimate UHI in Chicago with 10-min temporal frequency and 1-km spatial resolution on the hottest day in 2018. It is demonstrated that the RFR model can accurately predict UHI at fine spatiotemporal scales with high-frequency urban sensor network data integrated with satellite remote sensing data.

Melatonin Protects Chronic Kidney Disease Mesenchymal Stem/Stromal Cells against Accumulation of Methylglyoxal via Modulation of Hexokinase-2 Expression.

Treatment options for patients with chronic kidney disease (CKD) are currently limited; therefore, there has been significant interest in applying mesenchymal stem/stromal cell (MSC)-based therapy to treat CKD. However, MSCs harvested from CKD patients tend to show diminished viability and proliferation due to sustained exposure to uremic toxins in the CKD environment, which limits their utility for cell therapy. The application of melatonin has been demonstrated to improve the therapeutic efficacy of MSCs derived from and engrafted to tissues in patients suffering from CKD, although the underlying biological mechanism has not been elucidated. In this study, we observed overexpression of hexokinase-2 (HK2) in serum samples of CKD patients and MSCs harvested from an adenine-fed CKD mouse model (CKD-mMSCs). HK2 upregulation led to increased production levels of methylglyoxal (MG), a toxic metabolic intermediate of abnormal glycolytic processes. The overabundance of HK2 and MG was associated with impaired mitochondrial function and low cell proliferation in CKD-mMSCs. Melatonin treatment inhibited the increases in HK2 and MG levels, and further improved mitochondrial function, glycolytic metabolism, and cell proliferation. Our findings suggest that identifying and characterizing metabolic regulators such as HK2 in CKD may improve the efficacy of MSCs for treating CKD and other kidney disorders.

Topical Administration of Melatonin-Loaded Extracellular Vesicle-Mimetic Nanovesicles Improves 2,4-Dinitrofluorobenzene-Induced Atopic Dermatitis.

Atopic dermatitis (AD) is caused by multiple factors that trigger chronic skin inflammation, including a defective skin barrier, immune cell activation, and microbial exposure. Although melatonin has an excellent biosafety profile and a potential to treat AD, there is limited clinical evidence from controlled trials that support the use of melatonin as an AD treatment. The delivery of melatonin via the transdermal delivery system is also a challenge in designing melatonin-based AD treatments. In this study, we generated melatonin-loaded extracellular vesicle-mimetic nanoparticles (MelaNVs) to improve the transdermal delivery of melatonin and to evaluate their therapeutic potential in AD. The MelaNVs were spherical nanoparticles with an average size of 100 nm, which is the optimal size for the transdermal delivery of drugs. MelaNVs showed anti-inflammatory effects by suppressing the release of TNF-α and ß-hexosaminidase in LPS-treated RAW264.7 cells and compound 48/80-treated RBL-2H3 cells, respectively. MelaNVs showed a superior suppressive effect compared to an equivalent concentration of free melatonin. Treating a 2,4-dinitrofluorobenzene (DNCB)-induced AD-like mouse model with MelaNVs improved AD by suppressing local inflammation, mast cell infiltration, and fibrosis. In addition, MelaNVs effectively suppressed serum IgE levels and regulated serum IFN-γ and IL-4 levels. Taken together, these results suggest that MelaNVs are novel and efficient transdermal delivery systems of melatonin and that MelaNVs can be used as a treatment to improve AD.

Multifaceted C-terminus of HSP70-interacting protein regulates tumorigenesis via protein quality control.

C-terminus of heat shock protein 70 (HSP70)-interacting protein (CHIP) is an E3 ligase involved in a variety of protein homeostasis events implicated in diverse signaling pathways. Its involvement in varied and even opposite signaling circuits might be due to its hallmark signature of associating with molecular chaperones, including HSP90 and HSP70. Together, these proteins may be pivotal in implementing protein quality control. A curious and puzzling aspect of the function of CHIP is its capability to induce protein degradation via the proteasome- or lysosome-dependent pathways. In addition, these pathways are combined with ubiquitin-dependent or -independent pathways. This review focuses on the role of CHIP in the development or suppression of tumorigenesis. CHIP can act as a tumor suppressor by downregulating various oncogenes. CHIP also displays an oncogenic feature involving the inhibition of diverse tumor suppressors, including proteins related to intrinsic and extrinsic apoptotic pathways. The ability of CHIP to exhibit dual roles in determining the fate of cells has not been studied analytically. However, its association with various proteins involved in protein quality control might play a major role. In this review, the mechanistic roles of CHIP in tumor formation based on the regulation of diverse proteins are discussed.

Loss of the E3 ubiquitin ligase MKRN1 represses diet-induced metabolic syndrome through AMPK activation.

AMP-activated protein kinase (AMPK) plays a key role in controlling energy metabolism in response to physiological and nutritional status. Although AMPK activation has been proposed as a promising molecular target for treating obesity and its related comorbidities, the use of pharmacological AMPK activators has been met with contradictory therapeutic challenges. Here we show a regulatory mechanism for AMPK through its ubiquitination and degradation by the E3 ubiquitin ligase makorin ring finger protein 1 (MKRN1). MKRN1 depletion promotes glucose consumption and suppresses lipid accumulation due to AMPK stabilisation and activation. Accordingly, MKRN1-null mice show chronic AMPK activation in both liver and adipose tissue, resulting in significant suppression of diet-induced metabolic syndrome. We demonstrate also its therapeutic effect by administering shRNA targeting MKRN1 into obese mice that reverses non-alcoholic fatty liver disease. We suggest that ubiquitin-dependent AMPK degradation represents a target therapeutic strategy for metabolic disorders.

Regulatory Network of ARF in Cancer Development.

ARF is a tumor suppressor protein that has a pivotal role in the prevention of cancer development through regulating cell proliferation, senescence, and apoptosis. As a factor that induces senescence, the role of ARF as a tumor suppressor is closely linked to the p53-MDM2 axis, which is a key process that restrains tumor formation. Thus, many cancer cells either lack a functional ARF or p53, which enables them to evade cell oncogenic stress-mediated cycle arrest, senescence, or apoptosis. In particular, the ARF gene is a frequent target of genetic and epigenetic alterations including promoter hyper-methylation or gene deletion. However, as many cancer cells still express ARF, pathways that negatively modulate transcriptional or post-translational regulation of ARF could be potentially important means for cancer cells to induce cellular proliferation. These recent findings of regulators affecting ARF protein stability along with its low levels in numerous human cancers indicate the significance of an ARF post-translational mechanism in cancers. Novel findings of regulators stimulating or suppressing ARF function would provide new therapeutic targets to manage cancer- and senescence-related diseases. In this review, we present the current knowledge on the regulation and alterations of ARF expression in human cancers, and indicate the importance of regulators of ARF as a prognostic marker and in potential therapeutic strategies.

Oncogene-induced senescence mediated by c-Myc requires USP10 dependent deubiquitination and stabilization of p14ARF.

Oncogene-induced senescence (OIS) is a critical tumor-suppressor mechanism, which prevents hyper-proliferation and transformation of cells. c-Myc promotes OIS through the transcriptional activation of p14ARF followed by p53 activation. Although the oncogene-mediated transcriptional regulation of p14ARF has been well addressed, the post-translational modification of p14ARF regulated by oncogenic stress has yet to be investigated. Here, we found that c-Myc increased p14ARF protein stability by inducing the transcription of ubiquitin-specific protease 10 (USP10). USP10, in turn, mediated the deubiquitination of p14ARF, preventing its proteasome-dependent degradation. USP10-null mouse embryonic fibroblasts and human primary cells depleted of USP10 bypassed c-Myc-induced senescence via the destabilization of p14ARF, and these cells displayed accelerated hyper-proliferation and transformation. Clinically the c-Myc-USP10-p14ARF axis was disrupted in non-small cell lung cancer patients, resulting in significantly worse overall survival. Our studies indicate that USP10 induced by c-Myc has a crucial role in OIS by maintaining the stability of key tumor suppressor p14ARF.

Molecular Chaperone HSP90 Is Necessary to Prevent Cellular Senescence via Lysosomal Degradation of p14ARF.

The tumor suppressor function of p14ARF is regulated at a posttranslational level via mechanisms yet to be fully understood. Here, we report the identification of an unconventional p14ARF degradation pathway induced by the chaperone HSP90 in association with the E3 ubiquitin ligase C-terminus of HSP70-interacting protein (CHIP). The ternary complex of HSP90, CHIP, and p14ARF was required to induce the lysosomal degradation of p14ARF by an ubiquitination-independent but LAMP2A-dependent mechanism. Depletion of HSP90 or CHIP induced p14ARF-dependent senescence in human fibroblasts. Premature senescence observed in cells genetically deficient in CHIP was rescued in cells that were doubly deficient in CHIP and p14ARF. Notably, non-small cell lung cancer cells (NSCLC) positive for p14ARF were sensitive to treatment with the HSP90 inhibitor geldanamycin. Furthermore, overexpression of HSP90 and CHIP with a concomitant loss of p14ARF correlated with poor prognosis in patients with NSCLC. Our findings identify a relationship between p14ARF and its chaperones that suggest new therapeutic strategies in cancers that overexpress HSP90. Cancer Res; 77(2); 343-54. ©2016 AACR.

Tumorigenicity Evaluation of Umbilical Cord Blood-derived Mesenchymal Stem Cells.

Mesenchymal stem cells (MSCs) have been identified in multiple types of tissue and exhibit characteristic self-renewal and multi-lineage differentiation abilities. However, the possibility of oncogenic transformation after transplantation is concerning. In this study, we investigated the tumorigenic potential of umbilical cord blood-derived MSCs (hUCB-MSCs) relative to MRC-5 and HeLa cells (negative and positive controls, respectively) both in vitro and in vivo. To evaluate tumorigenicity in vitro, anchorage-independent growth was assessed using the soft agar colony formation assay. hUCB-MSCs and MRC-5 cells formed few colonies, while HeLa cells formed a greater number of larger colonies, indicating that hUCB-MSCs and MRC-5 cells do not have anchorage-independent proliferation potential. To detect tumorigenicity in vivo, hUCB-MSCs were implanted as a single subcutaneous injection into BALB/c-nu mice. No tumor formation was observed in mice transplanted with hUCB-MSCs or MRC-5 cells based on macroand microscopic examinations; however, all mice transplanted with HeLa cells developed tumors that stained positive for a human gene according to immunohistochemical analysis. In conclusion, hUCB-MSCs do not exhibit tumorigenic potential based on in vitro and in vivo assays under our experimental conditions, providing further evidence of their safety for clinical applications.

Dynamics of ARF regulation that control senescence and cancer.

ARF is an alternative reading frame product of the INK4a/ARF locus, inactivated in numerous human cancers. ARF is a key regulator of cellular senescence, an irreversible cell growth arrest that suppresses tumor cell growth. It functions by sequestering MDM2 (a p53 E3 ligase) in the nucleolus, thus activating p53. Besides MDM2, ARF has numerous other interacting partners that induce either cellular senescence or apoptosis in a p53-independent manner. This further complicates the dynamics of the ARF network. Expression of ARF is frequently disrupted in human cancers, mainly due to epigenetic and transcriptional regulation. Vigorous studies on various transcription factors that either positively or negatively regulate ARF transcription have been carried out. However, recent focus on posttranslational modifications, particularly ubiquitination, indicates wider dynamic controls of ARF than previously known. In this review, we discuss the role and dynamic regulation of ARF in senescence and cancer. [BMB Reports 2016; 49(11): 598-606].

CHIP controls necroptosis through ubiquitylation- and lysosome-dependent degradation of RIPK3.

Receptor-interacting protein kinase 3 (RIPK3) functions as a key regulator of necroptosis. Here, we report that the RIPK3 expression level is negatively regulated by CHIP (carboxyl terminus of Hsp70-interacting protein; also known as STUB1) E3 ligase-mediated ubiquitylation. Chip(-/-) mouse embryonic fibroblasts and CHIP-depleted L929 and HT-29 cells exhibited higher levels of RIPK3 expression, resulting in increased sensitivity to necroptosis induced by TNF (also known as TNFα). These phenomena are due to the CHIP-mediated ubiquitylation of RIPK3, which leads to its lysosomal degradation. Interestingly, RIPK1 expression is also negatively regulated by CHIP-mediated ubiquitylation, validating the major role of CHIP in necrosome formation and sensitivity to TNF-mediated necroptosis. Chip(-/-) mice (C57BL/6) exhibit inflammation in the thymus and massive cell death and disintegration in the small intestinal tract, and die within a few weeks after birth. These phenotypes are rescued by crossing with Ripk3(-/-) mice. These results imply that CHIP is a bona fide negative regulator of the RIPK1-RIPK3 necrosome formation leading to desensitization of TNF-mediated necroptosis.

Do Global Cities Enable Global Views? Using Twitter to Quantify the Level of Geographical Awareness of U.S. Cities.

Dynamic social media content, such as Twitter messages, can be used to examine individuals' beliefs and perceptions. By analyzing Twitter messages, this study examines how Twitter users exchanged and recognized toponyms (city names) for different cities in the United States. The frequency and variety of city names found in their online conversations were used to identify the unique spatiotemporal patterns of "geographical awareness" for Twitter users. A new analytic method, Knowledge Discovery in Cyberspace for Geographical Awareness (KDCGA), is introduced to help identify the dynamic spatiotemporal patterns of geographic awareness among social media conversations. Twitter data were collected across 50 U.S. cities. Thousands of city names around the world were extracted from a large volume of Twitter messages (over 5 million tweets) by using the Twitter Application Programming Interface (APIs) and Python language computer programs. The percentages of distant city names (cities located in distant states or other countries far away from the locations of Twitter users) were used to estimate the level of global geographical awareness for Twitter users in each U.S. city. A Global awareness index (GAI) was developed to quantify the level of geographical awareness of Twitter users from within the same city. Our findings are that: (1) the level of geographical awareness varies depending on when and where Twitter messages are posted, yet Twitter users from big cities are more aware of the names of international cities or distant US cities than users from mid-size cities; (2) Twitter users have an increased awareness of other city names far away from their home city during holiday seasons; and (3) Twitter users are more aware of nearby city names than distant city names, and more aware of big city names rather than small city names.

The Korean version of the Connor-Davidson Resilience Scale: an extended validation.

The Connor-Davidson Resilience Scale (CD-RISC) is a brief self-rating questionnaire for measuring resilience. The aims of the present study were to describe the development of a Korean version of the CD-RISC (K-CD-RISC) and to more firmly establish its psychometric properties in terms of reliability and validity. The participants consisted of a general population sample (n=194) and psychiatric outpatients (n=127) with non-psychotic mood or anxiety disorders. The K-CD-RISC score means (standard deviation) were 65.9 (13.6) in the general population and 50.4 (20.5) in the psychiatric outpatients. The mean score of the general population was significantly higher than that of the psychiatric outpatients. Exploratory factor analysis revealed five factors, and the obtained factor structure was verified through confirmatory factor analysis. In the general population, the Cronbach's α coefficient of the K-CD-RISC was found to be 0.92. Greater resilience was found to be associated with less perceived stress, anxiety and depression and with higher levels of positive affect and purpose in life. Taken together, our findings suggest that the K-CD-RISC has good psychometric properties and is a valid and reliable tool for assessing resilience.