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In the quest of new materials that can withstand severe irradiation and mechanical extremes for advanced applications ( e.g . fission & fusion reactors, space applications, etc.), design, prediction and control of advanced materials beyond current material designs become paramount. Here, through a combined experimental and simulation methodology, we design a nanocrystalline refractory high entropy alloy (RHEA) system. Compositions assessed under extreme environments and in situ electron-microscopy reveal both high thermal stability and radiation resistance. We observe grain refinement under heavy ion irradiation and resistance to dual-beam irradiation and helium implantation in the form of low defect generation and evolution, as well as no detectable grain growth. The experimental and modeling results—showing a good agreement—can be applied to design and rapidly assess other alloys subjected to extreme environmental conditions. Refractory high entropy alloys (RHEAs) have recently been developed in the context of high-temperature and severe environmental applications. Here the authors, by combining simulation and experiments, develop an irradiation resistant, thermally stable, and strong RHEA for nuclear application.

Respiratory viruses are among the first pathogens encountered by young children, and the significant impact of these viral infections on the developing lung is poorly understood. Circulating viruses are suited to the environment of the human lung and are different from those of viruses grown in cultured cells. We modeled respiratory virus infections that occur in children or infect the distal lung using lung organoids that represent the entire developing infant lung. These 3D lung organoids, derived from human pluripotent stem cells, develop into branching airway and alveolar structures and provide a tissue environment that maintains the authentic viral genome. The lung organoids can be genetically engineered prior to differentiation, thereby generating tissues bearing or lacking specific features that may be relevant to viral infection, a feature that may have utility for the study of host-pathogen interaction for a range of lung pathogens. Infectious viruses so precisely fit their hosts that the study of natural viral infection depends on host-specific mechanisms that affect viral infection. For human parainfluenza virus 3, a prevalent cause of lower respiratory tract disease in infants, circulating human viruses are genetically different from viruses grown in standard laboratory conditions; the surface glycoproteins that mediate host cell entry on circulating viruses are suited to the environment of the human lung and differ from those of viruses grown in cultured cells. Polarized human airway epithelium cultures have been used to represent the large, proximal airways of mature adult airways. Here we modeled respiratory virus infections that occur in children or infect the distal lung using lung organoids that represent the entire developing infant lung. These 3D lung organoids derived from human pluripotent stem cells contain mesoderm and pulmonary endoderm and develop into branching airway and alveolar structures. Whole-genome sequencing analysis of parainfluenza viruses replicating in the organoids showed maintenance of nucleotide identity, suggesting that no selective pressure is exerted on the virus in this tissue. Infection with parainfluenza virus led to viral shedding without morphological changes, while respiratory syncytial virus infection induced detachment and shedding of infected cells into the lung organoid lumens, reminiscent of parainfluenza and respiratory syncytial virus in human infant lungs. Measles virus infection, in contrast, induced syncytium formation. These human stem cell-derived lung organoids may serve as an authentic model for respiratory viral pathogenesis in the developing or infant lung, recapitulating respiratory viral infection in the host. IMPORTANCE Respiratory viruses are among the first pathogens encountered by young children, and the significant impact of these viral infections on the developing lung is poorly understood. Circulating viruses are suited to the environment of the human lung and are different from those of viruses grown in cultured cells. We modeled respiratory virus infections that occur in children or infect the distal lung using lung organoids that represent the entire developing infant lung. These 3D lung organoids, derived from human pluripotent stem cells, develop into branching airway and alveolar structures and provide a tissue environment that maintains the authentic viral genome. The lung organoids can be genetically engineered prior to differentiation, thereby generating tissues bearing or lacking specific features that may be relevant to viral infection, a feature that may have utility for the study of host-pathogen interaction for a range of lung pathogens.

The sirtuins (SIRT 1–7) comprise a family of NAD + -dependent protein-modifying enzymes with activities in lysine deacetylation, adenosinediphospho(ADP)-ribosylation, and/or deacylation. These enzymes are involved in the cell’s stress response systems and in regulating gene expression, DNA damage repair, metabolism and survival. Sirtuins have complex roles in both promoting and/or suppressing tumorigenesis. This review presents recent research progress concerning sirtuins and cancer. On one hand, functional loss of sirtuin genes, particularly SIRT1 , involved in maintaining genome integrity and DNA repair will promote tumorigenesis because of genomic instability upon their loss. On the other hand, cancer cells tend to require sirtuins for these same processes to allow them to survive, proliferate, repair the otherwise catastrophic genomic events and evolve. The bifurcated roles of SIRT1, and perhaps several other sirtuins, in cancer may be in part a result of the nature of the genes that are involved in the cell’s genome maintenance systems. The in-depth understanding of sirtuin functions may have significant implication in designing precise modulation of selective sirtuin members to aid cancer prevention or treatment under defined conditions.

Metastasis of the cervical lymph nodes frequently leads to poor survival of patients with oral squamous cell carcinoma (OSCC). The underlying mechanisms of lymph node metastasis are unclear. Wingless-type MMTV integration site family, member 5B (WNT5B), one component of the WNT signal pathway, was markedly up-regulated in OSCC sublines with high potential of lymphatic metastasis compared to that in OSCC cells with low nodal metastasis. Increased WNT5B mRNA was demonstrated in human OSCC tissues in comparison with adjacent non-tumorous tissues. Interestingly, the high level of WNT5B protein in serum was associated with lymph node metastasis in OSCC patients. Knockdown of WNT5B expression in OSCC sublines did not affect tumour growth but impaired lymph node metastasis and tumour lymphangiogenesis of orthotopic transplantation. Conditioned medium from WNT5B knockdown cells reduced the tube formation of lymphatic endothelial cells (LECs). In contrast, recombinant WNT5B enhanced the tube formation, permeability and migration of LECs. In LECs stained with phalloidin, the morphology of those treated with recombinant WNT5B changed from flat to spindle-like. Recombinant WNT5B also increased α-smooth muscle actin and inhibited the expression of vascular endothelial-cadherin but retained characteristics of endothelial cells. The results suggest that WNT5B functions in the partial endothelial-mesenchymal transition (EndoMT). Furthermore, WNT5B-induced tube formation was impaired in the LECs following the knockdown of EndoMT-related transcription factor, SNAIL or SLUG. The WNT5B-induced expression of Snail or Slug was abolished by IWR-1-endo and Rac1 inhibitors, which are involved in the WNT/β-catenin and planar cell polarity pathways, respectively. Collectively, the data suggest that WNT5B induces tube formation by regulating the expression of Snail and Slug proteins through activation of canonical and non-canonical WNT signalling pathways.

Transforming growth factor-β (TGFβ) is enriched in the bone matrix and serves as a key factor in promoting bone metastasis in cancer. In addition, TGFβ signaling activates mammalian target of rapamycin (mTOR) functions, which is important for the malignant progression. Here, we demonstrate that TGFβ regulates the level of microRNA-96 (miR-96) through Smad-dependent transcription and that miR-96 promotes the bone metastasis in prostate cancer. The enhanced effects in cellular growth and invasiveness suggest that miR-96 functions as an oncomir/and metastamir. Supporting this idea, we identified a downstream target of the TGFβ-miR-96 signaling pathway to be AKT1S1 mRNA, whose translated protein is a negative regulator of mTOR kinase. Our findings provide a novel mechanism accounting for the TGFβ signaling and bone metastasis.

Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in regenerating nicotinamide adenine dinucleotide (NAD + ) from nicotinamide in mammals. NAMPT has crucial roles for many cellular functions by regulating NAD + -dependent SIRT1 deacetylase. However, roles of NAMPT in cancer are poorly defined. In this study, we show that NAMPT is prominently overexpressed in human prostate cancer cells along with SIRT1. Elevation of NAMPT expression occurs early for the prostate neoplasia. Inhibition of NAMPT significantly suppresses cell growth in culture, soft agar colony formation, cell invasion and growth of xenografted prostate cancer cells in mice. NAMPT knockdown sensitizes prostate cancer cells to oxidative stress caused by H 2 O 2 or chemotherapeutic treatment. Overexpression of NAMPT increases prostate cancer cell resistance to oxidative stress, which is partially blocked by SIRT1 knockdown. We demonstrate that in addition to modulating SIRT1 functions, the NAMPT inhibition reduces forkhead box, class ‘O’ (FOXO)3a protein expression and its downstream anti-oxidant genes catalase and manganese superoxide dismutase. Our results suggest important roles of concomitant upregulation of NAMPT and SIRT1 along with increased FOXO3a protein level for prostate carcinogenesis and their contribution to oxidative stress resistance of prostate cancer cells. These findings may have implications for exploring the NAMPT pathway for prostate cancer prevention and treatment.

The neurophysiological mechanisms in the human amygdala that underlie post-traumatic stress disorder (PTSD) remain poorly understood. In a first-of-its-kind pilot study, we recorded intracranial electroencephalographic data longitudinally (over one year) in two male individuals with amygdala electrodes implanted for the management of treatment-resistant PTSD (TR-PTSD) under clinical trial NCT04152993. To determine electrophysiological signatures related to emotionally aversive and clinically relevant states (trial primary endpoint), we characterized neural activity during unpleasant portions of three separate paradigms (negative emotional image viewing, listening to recordings of participant-specific trauma-related memories, and at-home-periods of symptom exacerbation). We found selective increases in amygdala theta (5–9 Hz) bandpower across all three negative experiences. Subsequent use of elevations in low-frequency amygdala bandpower as a trigger for closed-loop neuromodulation led to significant reductions in TR-PTSD symptoms (trial secondary endpoint) following one year of treatment as well as reductions in aversive-related amygdala theta activity. Altogether, our findings provide early evidence that elevated amygdala theta activity across a range of negative-related behavioral states may be a promising target for future closed-loop neuromodulation therapies in PTSD. Neurostimulation has been proposed as a potential approach for treatment-resistant PTSD. Here in a pilot study the authors show that amygdala theta activity is heightened during aversive and symptomatic experiences in patients with treatment-resistant post-traumatic stress disorder, and reduced following significant clinical improvement associated with closed-loop stimulation.

Current therapeutic regimens for prostate cancer focus on targeting androgen receptor (AR) signaling. However, the AR is a key factor in luminal epithelium differentiation and was shown to have a role as a tumor suppressor. Thus, its inhibition may activate oncogenic pathways that contribute to metastatic castration-resistant prostate cancer (CRPC). Herein, we report a novel tumor promoter, ZBTB46, which is negatively regulated by AR signaling via microRNA (miR)-1-mediated downregulation. ZBTB46 is associated with malignant prostate cancer and is essential for metastasis. Its overexpression can overcome the antitumor effects of miR-1 and promote androgen-independent proliferation. We demonstrated that ZBTB46 can transcriptionally regulate SNAI1, a key epithelial-to-mesenchymal transition (EMT) driver, which could contribute to induction of the EMT after androgen-deprivation therapy and metastasis. Our findings are supportive of the model that disruption of AR’s function may predispose prostate cancer to progress to metastatic CRPC.

Electromagnetic energy harvesting holds a promising future for energizing low power electronic devices in wireless communication circuits. This article presents an RF energy harvesting system that can harvest energy from the ambient surroundings at the downlink radio frequency range of GSM-900 band. The harvesting system is aimed to provide an alternative source of energy for energizing low power devices. The system design consists of three modules: a single wideband 377Ω E-shaped patch antenna, a pi matching network and a 7-stage voltage doubler circuit. These three modules were fabricated on a single printed circuit board. The antenna and Pi matching network have been optimized through electromagnetic simulation software, Agilent ADS 2009 environment. The uniqueness of the system lies in the partial ground plane and the alignment of induced electric field for maximum current flow in the antenna that maximizes the captured RF energy. The design and simulation of the voltage doubler circuit were performed using Multisim software. All the three modules were integrated and fabricated on a double sided FR 4 printed circuit board. The DC voltage obtained from the harvester system in the field test at an approximate distance of 50 m from GSM cell tower was 2.9 V. This voltage was enough to power the STLM20 temperature sensor.