Enhancement of the physical, mechanical, and thermal properties of epoxy-based bamboo nanofiber nanocomposites

Epoxy-based nanocomposites were prepared by incorporating 0.3%, 0.5%, 0.7%, 1%, and 2% cellulose nanofibers (CNF) through a hand lay-up technique. The influence of the CNF as a reinforcement material on the morphology, and the physical, mechanical, and thermal properties of epoxy-based nanocomposites were investigated using scanning electron microscopy (SEM), density, void content, water absorption, tensile, flexural, impact strength, and thermogravimetric analyses. Compatibility between the nano-reinforcement and epoxy matrix was confirmed using SEM, which demonstrated that the CNF was homogeneously dispersed throughout the epoxy matrix. The mechanical properties were enhanced by increasing the CNF loading up to 1%. Moreover, the incorporation of CNF into the composites reduced the water uptake of the substrates in the water absorption test and resulted in a high thermal stability when exposed to a high temperature. Bamboo-CNF could be used as a potential reinforcement material to improve the properties of epoxy-based nanocomposites

Cell fate and metabolic reprogramming of tumor-initiating stem-like cells

Background & Aims: Tumor-initiating stem-like cells (TICs) are defective in maintaining asymmetric cell division and responsible for tumor recurrence. Stem cell markers such as Nanog have been implicated in various cancer, but whether they are functionally contributing to cancer pathogenesis has remained unclear. Novel NOTCH/NUMB-interacting protein, TBC1D15, is overexpressed and contributes to p53 degradation in TICs. Aims are to identify NANOG- or TBC1D15-mediated oncogenic mechanisms and to test tumorigenic roles. Methods: We determined novel targets of NANOG in tumor-initiating cells (TICs) from patient and mouse-models of hepatocellular carcinoma (HCC) using genome-wide NANOG-binding site analysis (ChIP-seq) and how Nanog is regulated at the transcriptional to promote oncogenesis and self-renewal in TICs. TBC1D15 interacting proteins were searched by large-scale immunoaffinity purification and LC-MS analysis. We examined HCC development in alcohol Western diet (AWD)-fed HCV NS5A Tg mice with hepatocyte-specific TBC1D15 deficiency or hepatocyte-specific expression of non-phosphorylatable NUMB mutations (non-p-NUMB). Results: Silencing NANOG inhibits tumor development in HCC mouse-models and genesis of TICs. NANOG binds genes of oxidative phosphorylation and b-oxidation in mitochondria. Silencing NANOG promotes oxidative phosphorylation and b-oxidation, indicating that NANOG is a suppressor of mitochondria-mediated energy production. We identified NuMA1, RANGAP1 and NOTCH1-4 as TBC1D15-interacting proteins. TBC1D15-NuMA1 association impaired NuMA1-LAN interaction which is essential for an asymmetric division machinery, thereby promoting TIC self-renewal. TBC1D15-NOTCH1 interaction activated and stabilized NOTCH1 and NOTCH1 Intracellular Domain (N1ICD) which in turn upregulated transcription of Nanog essential for TICs. Conclusions: These results suggest that NANOG-mediated metabolic reprogramming through suppression of mitochondria function in both experimental and clinical HCC downstream of TLR4/ NANOG generates TICs and drives liver tumorigenesis. TBC1D15 and p-NUMB are required for liver tumor development in vivo

Cell fate and metabolic reprogramming of tumor-initiating stem-like cells

Background & Aims: Tumor-initiating stem-like cells (TICs) are defective in maintaining asymmetric cell division and responsible for tumor recurrence. Stem cell markers such as Nanog have been implicated in various cancer, but whether they are functionally contributing to cancer pathogenesis has remained unclear. Novel NOTCH/NUMB-interacting protein, TBC1D15, is overexpressed and contributes to p53 degradation in TICs. Aims are to identify NANOG- or TBC1D15-mediated oncogenic mechanisms and to test tumorigenic roles. Methods: We determined novel targets of NANOG in tumor-initiating cells (TICs) from patient and mouse-models of hepatocellular carcinoma (HCC) using genome-wide NANOG-binding site analysis (ChIP-seq) and how Nanog is regulated at the transcriptional to promote oncogenesis and self-renewal in TICs. TBC1D15 interacting proteins were searched by large-scale immunoaffinity purification and LC-MS analysis. We examined HCC development in alcohol Western diet (AWD)-fed HCV NS5A Tg mice with hepatocyte-specific TBC1D15 deficiency or hepatocyte-specific expression of non-phosphorylatable NUMB mutations (non-p-NUMB). Results: Silencing NANOG inhibits tumor development in HCC mouse-models and genesis of TICs. NANOG binds genes of oxidative phosphorylation and b-oxidation in mitochondria. Silencing NANOG promotes oxidative phosphorylation and b-oxidation, indicating that NANOG is a suppressor of mitochondria-mediated energy production. We identified NuMA1, RANGAP1 and NOTCH1-4 as TBC1D15-interacting proteins. TBC1D15-NuMA1 association impaired NuMA1-LAN interaction which is essential for an asymmetric division machinery, thereby promoting TIC self-renewal. TBC1D15-NOTCH1 interaction activated and stabilized NOTCH1 and NOTCH1 Intracellular Domain (N1ICD) which in turn upregulated transcription of Nanog essential for TICs. Conclusions: These results suggest that NANOG-mediated metabolic reprogramming through suppression of mitochondria function in both experimental and clinical HCC downstream of TLR4/ NANOG generates TICs and drives liver tumorigenesis. TBC1D15 and p-NUMB are required for liver tumor development in vivo

Review of guidelines and recommendations from 17 countries highlights the challenges that clinicians face caring for neonates born to mothers with COVID-19.

This review examined how applicable national and regional clinical practice guidelines and recommendations for managing neonates born to mothers with COVID-19 mothers were to the evolving pandemic. A systematic search and review identified 20 guidelines and recommendations that had been published by May 25, 2020. We analysed documents from 17 countries: Australia, Brazil, Canada, China, France, India, Italy, Japan, Saudi Arabia, Singapore, South Africa, South Korea, Spain, Sweden, Switzerland, the UK and the United States. The documents were based on expert consensus with limited evidence and were of variable, low methodological rigour. Most did not provide recommendations for delivery methods or managing symptomatic infants. None provided recommendations for post-discharge assimilation of potentially infected infants into the community. The majority encouraged keeping mothers and infants together, subject to infection control measures, but one-third recommended separation. Although breastfeeding or using breastmilk was widely encouraged, two countries specifically prohibited this. The guidelines and recommendations for managing infants affected by COVID-19 were of low, variable quality and may be unsustainable. It is important that transmission risks are not increased when new information is incorporated into clinical recommendations. Practice guidelines should emphasise the extent of uncertainty and clearly define gaps in the evidence

Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis

Somatic mutations in UBA1 cause VEXAS (Vacuoles, E1 ubiquitin activating enzyme, X-linked, Autoinflammatory Somatic) syndrome, an adult-onset inflammatory disease with an overlap of hematologic manifestations. VEXAS syndrome is characterized by a high mortality rate and significant clinical heterogeneity. We sought to determine independent predictors of survival in VEXAS and to understand the mechanistic basis for these factors. We analyzed 83 patients with somatic pathogenic variants in UBA1 at p.Met41 (p.Met41Leu/Thr/Val), the start codon for translation of the cytoplasmic isoform of UBA1 (UBA1b). Patients with the p.Met41Val genotype were most likely to have an undifferentiated inflammatory syndrome. Multivariate analysis showed ear chondritis was associated with increased survival, while transfusion dependence and the p.Met41Val variant were independently associated with decreased survival. Using in vitro models and patient-derived cells, we demonstrate that p.Met41Val variant supports less UBA1b translation than either p.Met41Leu or p.Met41Thr, providing a molecular rationale for decreased survival. In addition, we show that these three canonical VEXAS variants produce more UBA1b than any of the six other possible single nucleotide variants within this codon. Finally, we report a patient, clinically diagnosed with VEXAS syndrome, with two novel mutations in UBA1 occurring in cis on the same allele. One mutation (c.121 A>T; p.Met41Leu) caused severely reduced translation of UBA1b in a reporter assay, but co-expression with the second mutation (c.119 G>C; p.Gly40Ala) rescued UBA1b levels to those of canonical mutations. We conclude that regulation of residual UBA1b translation is fundamental to the pathogenesis of VEXAS syndrome and contributes to disease prognosis

The long non-coding RNA Morrbid regulates Bim and short-lived myeloid cell lifespan.

Neutrophils, eosinophils and \u27classical\u27 monocytes collectively account for about 70% of human blood leukocytes and are among the shortest-lived cells in the body. Precise regulation of the lifespan of these myeloid cells is critical to maintain protective immune responses and minimize the deleterious consequences of prolonged inflammation. However, how the lifespan of these cells is strictly controlled remains largely unknown. Here we identify a long non-coding RNA that we termed Morrbid, which tightly controls the survival of neutrophils, eosinophils and classical monocytes in response to pro-survival cytokines in mice. To control the lifespan of these cells, Morrbid regulates the transcription of the neighbouring pro-apoptotic gene, Bcl2l11 (also known as Bim), by promoting the enrichment of the PRC2 complex at the Bcl2l11 promoter to maintain this gene in a poised state. Notably, Morrbid regulates this process in cis, enabling allele-specific control of Bcl2l11 transcription. Thus, in these highly inflammatory cells, changes in Morrbid levels provide a locus-specific regulatory mechanism that allows rapid control of apoptosis in response to extracellular pro-survival signals. As MORRBID is present in humans and dysregulated in individuals with hypereosinophilic syndrome, this long non-coding RNA may represent a potential therapeutic target for inflammatory disorders characterized by aberrant short-lived myeloid cell lifespan. Nature 2016 Aug 15; 537(7619):239-243