It was the best of times, it was the worst of times: a tale of two cities-Beijing and Shanghai-why the divergent COVID-19 control outcomes?

Coronavirus disease 2019 (COVID-19) both creates and complicates public health challenges. Yet, the pandemic also provides a unique lens for dissecting complex issues in global health that could benefit society in the long run. In this article, we discuss the underlying reasons that can help explain the divergent COVID-19 control outcomes between Beijing and Shanghai-two advanced metropolises that are similar in their municipal capacity, administrative capability and pandemic strategy. We hope insights from this investigation contribute to the development of disease prevention systems, such as context-specific and data-driven public health strategies that could yield optimal pandemic control outcomes with minimal unintended consequences, both amid and beyond COVID-19.

How to avoid future "Covid-19 origins" questions?

Origins debates regarding Covid-19 are gaining momentum again. In light of the continued infections and deaths of Covid-19 seen in countries rich and poor, rather than focusing the approach with "whodunit", developing solutions that can help societies become better prepared for future pandemics might be a more meaningful way to move forward. In this paper, we propose a solution that could help society better predict and prevent future pandemics. A system could allow humans to anonymously report potential infectious disease outbreaks without fearing backlash or prejudice and could automatically surveil for potential disease transfers or virus leaks. The proposed autonomous and anonymous pandemic reporting and surveillance system has the potential to help health officials locate infectious disease outbreaks before they form into pandemics. And in turn, it better prevents future pandemics and avoids Covid-19 origins debates.

Assessing heart disease using a novel magnetocardiography device.

The aim of this paper is to present the use of a portable, unshielded magnetocardiograph (MCG) and identify key characteristics of MCG scans that could be used in future studies to identify parameters that are sensitive to cardiac pathology. We recruited 50 patients with confirmed myocardial infarction (MI) within the past 12 weeks and 46 volunteers with no history of cardiac disease. A set of 38 parameters were extracted from MCG features including both signals from the sensor array and from magnetic images obtained from the device and principal component analysis was used to concentrate the information contained in these parameters into uncorrelated predictors. Linear fits of these parameters were then used to examine the ability of MCG to distinguish between sub-groups of patients. In the first instance, the primary aim of this study was to ensure that MCG has a basic ability to separate a highly polarised patient group (young controls from post infarction patients) and to identify parameters that could be used in future studies to build a formal diagnostic tool kit. Parameters that parameterised left ventricular ejection fraction (LVEF) were identified and an example is presented to show differential low and high ejection fractions.

Why is COVID-19 more deadly to nursing home residents?

COVID-19 is deadly to older adults, with research showing that being older and having underlying chronic diseases are significant risk factors for COVID-19 related deaths. However, though similarities exist between both nursing home residents and older community-dwelling people, nursing home residents are substantially more vulnerable to COVID-19. A closer review of both demographic groups provides clarity concerning the difference within the context of COVID-19. Therefore, to address the research gap, drawing insights from Maslow's hierarchy of needs model, this article aims to examine similarities and differences in COVID-19 risk factors experienced by nursing home residents and community-dwelling older people.

Cystine addiction of triple-negative breast cancer associated with EMT augmented death signaling.

This corrects the article DOI: 10.1038/onc.2016.394.

Identification badge lanyards as infection control risk: a cross-sectional observation study with epidemiological analysis.

Staphylococcus aureus cultures from name badge lanyards were phenotypically and genotypically indistinguishable from the wearer's nasal carrier strains by pulsed-field gel electrophoresis and antibiogram. Lanyards had a mean age of 22 months and hygiene was poor with only 9% ever having been laundered. Molecular analysis showed that 26% of S. aureus nasal carriers shared an indistinguishable strain on their lanyard. Lanyards should not be recommended for staff in frontline clinical care.

Cystine addiction of triple-negative breast cancer associated with EMT augmented death signaling.

Despite the advances in the diagnosis and treatment of breast cancer, breast cancers still cause significant mortality. For some patients, especially those with triple-negative breast cancer, current treatments continue to be limited and ineffective. Therefore, there remains an unmet need for a novel therapeutic approach. One potential strategy is to target the altered metabolic state that is rewired by oncogenic transformation. Specifically, this rewiring may render certain outside nutrients indispensable. To identify such a nutrient, we performed a nutrigenetic screen by removing individual amino acids to identify possible addictions across a panel of breast cancer cells. This screen revealed that cystine deprivation triggered rapid programmed necrosis, but not apoptosis, in the basal-type breast cancer cells mostly seen in TNBC tumors. In contrast, luminal-type breast cancer cells are cystine-independent and exhibit little death during cystine deprivation. The cystine addiction phenotype is associated with a higher level of cystine-deprivation signatures noted in the basal type breast cancer cells and tumors. We found that the cystine-addicted breast cancer cells and tumors have strong activation of TNFα and MEKK4-p38-Noxa pathways that render them susceptible to cystine deprivation-induced necrosis. Consistent with this model, silencing of TNFα and MEKK4 dramatically reduces cystine-deprived death. In addition, the cystine addiction phenotype can be abrogated in the cystine-addictive cells by miR-200c, which converts the mesenchymal-like cells to adopt epithelial features. Conversely, the introduction of inducers of epithelial-mesenchymal transition (EMT) in cystine-independent breast cancer cells conferred the cystine-addiction phenotype by modulating the signaling components of cystine addiction. Together, our data reveal that cystine-addiction is associated with EMT in breast cancer during tumor progression. These findings provide the genetic and mechanistic basis to explain how cystine deprivation triggers necrosis by activating pre-existing oncogenic pathways in cystine-addicted TNBC with prominent mesenchymal features.

The estrogen receptor as a mediator of the pathological actions of cholesterol in breast cancer.

Despite increased survivorship among patients, breast cancer remains the most common cancer among women and is the second leading cause of cancer death in women. The magnitude of this problem provides a strong impetus for new chemopreventative strategies and/or lifestyle changes that reduce cancer incidence. It is of significance, therefore, that several studies positively correlate obesity to the development of breast cancer. Importantly, obesity is also highly associated with elevated cholesterol, and cholesterol itself is a risk factor for breast cancer. Furthermore, patients taking statins demonstrate a lower breast cancer incidence and decreased recurrence. The recent observation that 27-hydroxycholesterol (27HC) is produced in a stoichiometric manner from cholesterol, together with our recent demonstration that it exerts partial agonist activity on both the estrogen and liver X receptors, suggested a potential mechanistic link between hyper-cholesterolemia and breast cancer incidence. Using genetic and pharmacological approaches, we have recently shown that elevation of circulating 27HC significantly increases tumor growth and metastasis in murine models of breast cancer. Further, we have demonstrated in appropriate animal models that the impact of high-fat diet on tumor pathogenesis can be mitigated by statins or by small molecule inhibitors of CYP27A1. These findings suggest that pharmacological or dietary modifications that lower total cholesterol, and by inference 27HC, are likely to reduce the impact of obesity/metabolic syndrome on breast cancer incidence.

ELF3 is a repressor of androgen receptor action in prostate cancer cells.

The androgen receptor (AR) has a critical role in the development and progression of prostate cancer (PC) and is a major therapeutic target in this disease. The transcriptional activity of AR is modulated by the coregulators with which it interacts, and consequently deregulation of cofactor expression and/or activity impacts the expression of genes whose products can have a role in PC pathogenesis. Here we report that E74-like factor 3 (ELF3), a member of the ETS family of transcription factors, is a repressor of AR transcriptional activity. Exogenous expression of ELF3 represses AR transcriptional activity when assessed using reporter-based transfection assays or when evaluated on endogenous AR target genes. Conversely, ELF3 knock down increases the AR transcriptional activity. Biochemical dissection of this activity indicates that it results from the physical interaction between ELF3 and AR and that this interaction inhibits the recruitment of AR to specific androgen response elements within target gene promoters. Significantly, we observed that depletion of ELF3 expression in LNCaP cells promotes cell migration, whereas increased ELF3 expression severely inhibits tumor growth in vitro and in a mouse xenograft model. Taken together, these results suggest that modulation of ELF3 expression and/or AR/ELF3 interaction may have utility in the treatment of PC.

Assessing the infrequent oral supplementation of olanzapine long-acting injection in the treatment of schizophrenia.

OBJECTIVE: Adding another antipsychotic to a treatment regimen was previously used in evaluating the medication's efficacy. Supplementation of depot antipsychotics with oral antipsychotics is particularly meaningful because depot formulations are typically chosen for patients struggling with adherence to oral antipsychotics. This post-hoc analysis assessed supplementation of olanzapine long-acting injection (olanzapine-LAI) with oral olanzapine. SUBJECTS AND METHODS: We used 12 months of data from an open-label, single-arm extension study of patients with schizophrenia or schizoaffective disorder (N=931) treated with olanzapine-LAI. The prevalence, duration, time to first supplementation, and best predictors of oral supplementation were assessed. RESULTS: Oral supplementation occurred in 21% of patients for a median of 31 days with mean modal dose of 10.8 mg/day. Mean time to first supplementation was shorter for patients who were at least moderately ill at baseline compared to less ill patients (47 vs. 97 days, p<0.001). Best predictors of oral supplementation included a more severe illness profile at baseline, lower olanzapine-LAI dose prior to oral supplementation, supervised living arrangements, and being African-American. CONCLUSION: Supplementation of olanzapine-LAI appears to be infrequent, of relatively short duration, and reserved for more severely ill patients who may require a targeted rescue medication due to signs of impending relapse.

Estrogen-related receptor alpha as a therapeutic target in cancer.

The orphan receptor estrogen-related receptor alpha (ERR alpha) is a member of the nuclear receptor superfamily of ligand-regulated transcription factors. This protein is structurally most related to the canonical estrogen receptor and has been shown to modulate estrogen signaling in some contexts. These observations have heightened interest in ERR alpha as a therapeutic target in both breast and ovarian cancer and in other estrogenopathies. This review details our present understanding of ERR alpha action with a view to highlight specific aspects of its signal-transduction pathway in breast cancer that may be amenable to pharmaceutical manipulation.

Intraosseous mandibular lipoma (IML): a case report and review of the literature.

Intraosseous mandibular lipoma (IML) is a rare benign tumour and is infrequently associated with unerupted teeth. This report describes an IML associated with an unerupted impacted mandibular wisdom tooth.

Ligand-selective interactions of ER detected in living cells by fluorescence resonance energy transfer.

Some aspects of ligand-regulated transcription activation by the estrogen receptor (ER) are associated with the estrogen-dependent formation of a hydrophobic cleft on the receptor surface. At least in vitro, this cleft is required for direct interaction of ER with an alpha helix, containing variants of the sequence LXXLL, found in many coactivators. In cells, it is unknown whether ER interactions with the different LXXLL-containing helices are uniformly similar or whether they vary with LXXLL sequence or activating ligand. Using fluorescence resonance energy transfer (FRET), we confirm in the physiological environment a direct interaction between the estradiol (E2)-bound ER and LXXLL peptides expressed in living cells as fusions with spectral variants of the green fluorescent protein. This interaction was blocked by a single amino acid mutation in the hydrophobic cleft. No FRET was detected when cells were incubated with the antiestrogenic ligands tamoxifen and ICI 182,780. E2, diethylstilbestrol, ethyl indenestrol A, and 6,4'-dihydroxyflavone all promoted FRET and activated ER-dependent transcription. Measurement of the level of FRET of ER with different LXXLL-containing peptides suggested that the orientations or affinities of the LXXLL interactions with the hydrophobic cleft were globally similar but slightly different for some activating ligands.

Indirect digital images: limit of image compression for diagnosis in endodontics.

AIM: To analyse the impact of the loss of information that results from the compression of a file containing a radiographic image. METHODOLOGY: Fourteen intraoral radiographs were digitized employing an AGFA ARCUS II scanner at an optical resolution of 300 ppi and with a grey scale of 8 bytes. The images were stored in Tagged Image File Format (TIFF). The files were compressed with no information loss with the WinZip 8.0 program. Compression with information loss was performed using the Photoshop 5.0 program (Adobe Systems Inc., San José, CA. USA) and the Joint Photograph Expert (Group (JPEG) format. Each of the images was compressed to one of the 11 qualities available (10-0). An expert performed the qualitative analysis. The quantitative analysis involved digital subtraction with each of the JPEG images to yield a new image using Photoshop 5.). The histograms of grey values were submitted to statistical analysis. The mean and standard deviation were calculated for each image. RESULTS: The data revealed that a JPEG lossy compression, six times smaller than the original TIFF, is compatible with diagnostic applications. CONCLUSIONS: The compression ratio calculated as the quotient between the file sizes and the standard deviation of the values corresponding to the image that resulted from digital subtraction may be employed to assess the outcome of the compression process and guarantee adequate quality.

Glucocorticoids manifest androgenic activity in a cell line derived from a metastatic prostate cancer.

The pathophysiological mechanism(s) by which androgen independence develops in prostate cancer remains to be determined. The identification in many prostate cancer specimens of a mutant androgen receptor, T877A, with altered ligand specificity has provided an explanation for some treatment failures. The T877A mutant androgen receptor recognizes a number of nonandrogenic compounds, including certain estrogens, progestins, and even antiandrogens as androgens. However, a comprehensive screen for hormonal agents which display agonist activity on this mutant has not been performed. In this study, we characterized this clinically important receptor mutant further and found that it can be activated by a wide range of compounds, including a number of endogenous glucocorticoids. Among the most clinically relevant compounds identified are DOC and corticosterone, both of which can effectively activate the mutant receptor at concentrations normally found in blood. Dexamethasone, a synthetic glucocorticoid frequently used in various contexts for prostate cancer therapy, is also recognized as an androgen by the mutant receptor. These unexpected findings suggest the need to: (a) reassess the role of adrenally derived glucocorticoids in prostate cancer disease progression; and (b) recognize the potential for iatrogenic stimulation of disease progression with certain glucocorticoid interventions.

Development of an ER action indicator mouse for the study of estrogens, selective ER modulators (SERMs), and Xenobiotics.

We have developed a transgenic mouse that functions as a reporter of ER activity, termed ER action indicator (ERIN), by incorporating a transgene with an estrogen-responsive promoter (three copies of the vitellogenin estrogen response element with a minimal thymidine kinase promoter) linked to the reporter gene beta-galactosidase. Evaluation of ER activity in female ERIN mice demonstrated estrogen-inducible expression of the reporter gene in the uterus, pituitary, and hypothalamus; established targets of estrogen action. Importantly, we also identified ER activity in a number of nonclassical estrogen target tissues, including kidney, liver, adrenal, and thyroid gland. ERIN provides a system to measure the same end point (transgene regulation) in different target tissues, permitting separation of the contributions of cell- and promoter-specific factors in determining ER pharmacology. In this regard we observed that on this specific promoter the pituitary gland was 25-fold more sensitive than the uterus to the estrogen diethylstilbestrol, implying the existence of cell-specific factors that influence ligand sensitivity. Our studies also identified considerable difference in the efficacy and potency of ER ligands in the uterus when ER transcriptional activity was assayed vs. uterine weight gain. Specifically, we observed that the environmental estrogen bisphenol A was a potent agonist in stimulating ER transcriptional activity, whereas it exhibited little uterotropic activity. In contrast to bisphenol A, tamoxifen significantly increased uterine weight, but minimally induced ER reporter activity in this tissue. Given the results of these studies, we believe that ERIN will be a useful model to evaluate ER ligand pharmacology and will assist in defining the cellular and molecular mechanisms that determine agonist and antagonist activity.

The human estrogen receptor-alpha is a ubiquitinated protein whose stability is affected differentially by agonists, antagonists, and selective estrogen receptor modulators.

The human estrogen receptor alpha-isoform (ERalpha) is a nuclear transcription factor that displays a complex pharmacology. In addition to classical agonists and antagonists, the transcriptional activity of ERalpha can be regulated by selective estrogen receptor modulators, a new class of drugs whose relative agonist/antagonist activity is determined by cell context. It has been demonstrated that the binding of different ligands to ERalpha results in the formation of unique ERalpha-ligand conformations. These conformations have been shown to influence ERalpha-cofactor binding and, therefore, have a profound impact on ERalpha pharmacology. In this study, we demonstrate that the nature of the bound ligand also influences the stability of ERalpha, revealing an additional mechanism by which the pharmacological activity of a compound is determined. Of note we found that although all ERalpha-ligand complexes can be ubiquitinated and degraded by the 26 S proteasome in vivo, the mechanisms by which they are targeted for proteolysis appear to be different. Specifically, for agonist-activated ERalpha, an inverse relationship between transcriptional activity and receptor stability was observed. This relationship does not extend to selective estrogen receptor modulators and pure antagonists. Instead, it appears that with these compounds, the determinant of receptor stability is the ligand-induced conformation of ERalpha. We conclude that the different conformational states adopted by ERalpha in the presence of different ligands influence transcriptional activity directly by regulating cofactor binding and indirectly by modulating receptor stability.