Tracheal intubation in coronavirus disease 2019 (COVID-19) patients creates a risk to physiologically compromised patients and to attending healthcare providers. Clinical information on airway management and expert recommendations in these patients are urgently needed. By analysing a two-centre retrospective observational case series from Wuhan,

High mobility group box 1 (HMGB1) can be actively secreted by macrophages/monocytes in response to exogenous and endogenous inflammatory stimuli (such as bacterial endotoxin, TNF-α, IL-1, and IFN-γ) or passively released by necrotic cells and mediates innate and adaptive inflammatory responses to infection and injury. Here, we demonstrated that a reactive oxygen species, hydrogen peroxide (H 2 O 2 ), induces active and passive HMGB1 release from macrophage and monocyte cultures in a time-and dose-dependent manner. At nontoxic doses (e.g., 0.0125-0.125 mM), H 2 O 2 induced HMGB1 cytoplasmic translocation and active release within 3-24 h. At higher concentrations (e.g., 0.25 mM), however, H 2 O 2 exhibited cytotoxicity to macrophage and monocyte cell cultures and consequently, triggered active and passive HMGB1 release. In addition, H 2 O 2 stimulated potential interaction of HMGB1 with a nuclear export factor, CRM1, in macrophage/ monocyte cultures. Inhibitors specific for the JNK (SP600125) and MEK (PD98059), but not p38 MAPK (SB203580), abrogated H 2 O 2 -induced, active HMGB1 release. Together, these data establish an important role for oxidative stress in inducing active HMGB1 release, potentially through a MAPK-and CRM1-dependent mechanism.

Cutaneous squamous cell carcinoma (cuSCC) comprises 15–20% of all skin cancers, accounting for over 700,000 cases in USA annually. Most cuSCC arise in association with a distinct precancerous lesion, the actinic keratosis (AK). To identify potential targets for molecularly targeted chemoprevention, here we perform integrated cross-species genomic analysis of cuSCC development through the preneoplastic AK stage using matched human samples and a solar ultraviolet radiation-driven Hairless mouse model. We identify the major transcriptional drivers of this progression sequence, showing that the key genomic changes in cuSCC development occur in the normal skin to AK transition. Our data validate the use of this ultraviolet radiation-driven mouse cuSCC model for cross-species analysis and demonstrate that cuSCC bears deep molecular similarities to multiple carcinogen-driven SCCs from diverse sites, suggesting that cuSCC may serve as an effective, accessible model for multiple SCC types and that common treatment and prevention strategies may be feasible.

The performance of reduced-rank linear filtering is studied for the suppression of multiple-access interference. A reduced-rank filter resides in a lower dimensional space, relative to the full-rank filter, which enables faster convergence and tracking. We evaluate the large system output signal-to-interference plus noise ratio (SINR) as a function of filter rank for the multistage Wiener filter (MSWF) presented by Goldstein and Reed. The large system limit is defined by letting the number of users and the number of dimensions tend to infinity with fixed. For the case where all users are received with the same power, the reduced-rank SINR converges to the full-rank SINR as a continued fraction. An important conclusion from this analysis is that the rank needed to achieve a desired output SINR does not scale with system size. Numerical results show that = 8 is sufficient to achieve near-full-rank performance even under heavy loads (= 1). We also evaluate the large system output SINR for other reduced-rank methods, namely, Principal Components and Cross-Spectral, which are based on an eigendecomposition of the input covariance matrix, and Partial Despreading (PD). For those methods, the large system limit lets with fixed. Our results show that for large systems, the MSWF allows a dramatic reduction in rank relative to the other techniques considered.

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The roles of microRNAs (miRNAs) and the miRNA processing machinery in the regulation of stem cell biology are not well understood. Here, we show that the p53 family member and p63 isoform, ΔNp63, is a transcriptional activator of a cofactor critical for miRNA processing (DGCR8). This regulation gives rise to a unique miRNA signature resulting in reprogramming cells to multipotency. Strikingly, ΔNp63 −/− epidermal cells display profound defects in terminal differentiation and express a subset of markers and miRNAs present in embryonic stem cells and fibroblasts induced to pluripotency using Yamanaka factors. Moreover, ΔNp63 −/− epidermal cells transduced with an inducible DGCR8 plasmid can differentiate into multiple cell fates in vitro and in vivo. We found that human primary keratinocytes depleted of ΔNp63 or DGCR8 can be reprogrammed in 6 d and express a unique miRNA and gene expression signature that is similar but not identical to human induced pluripotent stem cells. Our data reveal a role for ΔNp63 in the transcriptional regulation of DGCR8 to reprogram adult somatic cells into multipotent stem cells.

Highly differentiated sex chromosomes create a lethal imbalance in gene expression in one sex. To accommodate hemizygosity of the X chromosome in male fruit flies, expression of X-linked genes increases twofold. This is achieved by the male-specific lethal (MSL) complex, which modifies chromatin to increase expression. Mutations that disrupt the X localization of this complex decrease the expression of X-linked genes and reduce male survival. The mechanism that restricts the MSL complex to X chromatin is not understood. We recently reported that the siRNA pathway contributes to localization of the MSL complex, raising questions about the source of the siRNAs involved. The X-linked 1.688 g/cm 3 satellite related repeats (1.688 X repeats) are restricted to the X chromosome and produce small RNA, making them an attractive candidate. We tested RNA from these repeats for a role in dosage compensation and found that ectopic expression of singlestranded RNAs from 1.688 X repeats enhanced the male lethality of mutants with defective X recognition. In contrast, expression of double-stranded hairpin RNA from a 1.688 X repeat generated abundant siRNA and dramatically increased male survival. Consistent with improved survival, X localization of the MSL complex was largely restored in these males. The striking distribution of 1.688 X repeats, which are nearly exclusive to the X chromosome, suggests that these are cis-acting elements contributing to identification of X chromatin.ales and females of many species have an unequal number of X chromosomes, producing a potentially fatal imbalance in X-linked gene expression (1). The process by which balance is restored is called dosage compensation. In the male fruit fly, Drosophila melanogaster, the male-specific lethal (MSL) complex modifies the chromatin of X-linked genes to increase expression by twofold, equalizing expression between XX females and XY males (2). The long noncoding roX RNAs assemble with the MSL proteins to form the intact MSL complex. roX RNA is required for exclusive X-chromosome binding of the complex and for increased expression of X-linked genes (3, 4).How the MSL complex selectively recognizes X chromatin is not fully understood, but an elegant model for X recognition proposes that the complex is first recruited to chromatin entry sites (CESs), then spreads into nearby active genes through a cotranscriptional mechanism (5). The CESs, defined by elevated affinity for the MSL proteins, are limited to the X chromosome (6). A 21-bp motif, termed the MSL recognition element (MRE), is enriched within the CES and binds CLAMP, a protein essential for MSL recruitment (7, 8); however, MREs are only modestly enriched on the X chromosome, and CLAMP binds autosomal MREs without recruiting the MSL complex. These observations indicate that additional factors must contribute to X identification.The siRNA pathway contributes to X chromosome recognition during dosage compensation (9). This suggests that siRNAproducing sequences on the X chromosome might participate in the ...

High-mobility-group box 1 (HMGB1), a nuclear protein, has recently been identified as an important mediator of local and systemic inflammatory diseases when released into the extracellular milieu. Anti-inflammatory regulation by the stress response is an effective autoprotective mechanism when the host encounters harmful stimuli, but the mechanism of action remains incompletely delineated. In this study, we demonstrate that increases in levels of a major stress-inducible protein, heat shock protein 72 (Hsp72) by gene transfection attenuated LPS- or TNF-α-induced HMGB1 cytoplasmic translocation and release. The mechanisms involved inhibition of the chromosome region maintenance 1 (CRM1)-dependent nuclear export pathway. Overexpression of Hsp72 inhibited CRM1 translocation and interaction between HMGB1 and CRM1 in macrophages post-LPS and TNF-α treatment. In addition, overexpression of Hsp72 strongly inhibited HMGB1-induced cytokine (TNF-α, IL-1β) expression and release, which correlated closely with: 1) inhibition of the MAP kinases (p38, JNK, and ERK); and 2) inhibition of the NF-κB pathway. Taken together, these experiments suggest that the anti-inflammatory activity of Hsp72 is achieved by interfering with both the release and proinflammatory function of HMGB1. Our experimental data provide important insights into the anti-inflammatory mechanisms of heat shock protein protection.