Francoriley5177

We investigated the seismological structure beneath the equatorial Melanesian region, where is tectonically unique because an immense oceanic plateau, a volcanic chain and subduction zones meet. We conducted a multi-frequency P-wave tomography using data collected from an approximately 2-year-long seismic experiment around the Ontong Java Plateau (OJP). High-velocity anomalies were revealed beneath the center of the OJP at a depth of ~ 150 km, the middle-eastern edge of the OJP at depths of 200-300 km, and in the mantle transition zone beneath and around the OJP; low-velocity anomalies were observed along the Caroline volcanic island chain above 450 km depth. These anomalies are considered to be associated with the thick lithosphere of the OJP, remnant dipping Pacific slab, stagnant Pacific slab, and a sheet-like upwelling. The broad stagnant slab was formed due to rapid trench retreat from 48 to 25 Ma until when the OJP with thick lithosphere collided with a subduction boundary of the Pacific and Australian plates. This collision triggered slab breakoff beneath the arc where the dipping slab remained. The stagnant Pacific slab in the mantle transition zone restricted the plume upwelling from the lower mantle causing sheet-like deformed upwelling in the upper mantle.Traceability of patients who are candidates for Hematopoietic cell transplant (HCT) is crucial to ensure HCT program quality. Continuous knowledge of both a detailed registry from a HCT program and final exclusion causes can contribute to promoting a real-life vision and optimizing patient and donor selection. We analyzed epidemiological data reported in a 4 year-monocentric prospective registry, which included all patients presented as candidates for autologous (Auto) and/or allogeneic (Allo) HCT. A total of 543 patients were considered for HCT 252 (42.4%) for Allo and 291 (57.6%) for Auto. Tanespimycin order A total of 98 (38.9%) patients were excluded from AlloHCT due to basal disease progression more commonly (18.2%). Seventy-six (30.2%) patients had an HLA identical sibling, whereas 147 (58.3%) patients had only Haplo. UD research was performed in 106 (42%) cases, significantly more often in myeloid than lymphoid malignancies (57% vs 28.7%, p  less then  0.001) but 61.3% were finally canceled, due to donor or disease causes in 72.4%. With respect to Auto candidates, a total of 60 (20.6%) patients were finally excluded; progression was the most common cause (12%). Currently, Haplo is the most frequent donor type. The high cancellation rate of UD research should be revised to optimize further donor algorithms.MI-773 is a recently developed small-molecule inhibitor of the mouse double minute 2 (MDM2) proto-oncogene. Preclinical data on the anti-tumour activity of MI-773 are limited and indicate that tumour cell lines (CLs) with mutated TP53 are more resistant to MI-773 than wild type TP53. Here, we explored the compound's therapeutic potential in vitro using a panel of 274 annotated CLs derived from a diversity of tumours. MI-773 exhibited a pronounced selectivity and moderate potency, with anti-tumour activity in the sub-micromolar range in about 15% of the CLs. The most sensitive tumour types were melanoma, sarcoma, renal and gastric cancers, leukaemia, and lymphoma. A COMPARE analysis showed that the profile of MI-773 was similar to that of Nutlin-3a, the first potent inhibitor of p53-MDM2 interactions, and, in addition, had a superior potency. In contrast, it poorly correlates with profiles of compounds targeting the p53 pathway with another mechanism of action. OMICS analyses confirmed that MI-773 was primarily active in CLs with wild type TP53. In silico biomarker investigations revealed that the TP53 mutation status plus the aggregated expression levels of 11 genes involved in the p53 signalling pathway predicted sensitivity or resistance of CLs to inhibitors of p53-MDM2 interactions reliably. The results obtained for MI-773 could help to refine the selection of cancer patients for therapy.Non-alcoholic fatty liver disease (NAFLD) is the most frequent liver disease worldwide and can progress to non-alcoholic steatohepatitis (NASH), which is characterized by triglyceride accumulation, inflammation, and fibrosis. No pharmacological agents are currently approved to treat these conditions, but it is clear now that modulation of lipid synthesis and autophagy are key biological mechanisms that could help reduce or prevent these liver diseases. The folliculin (FLCN) protein has been recently identified as a central regulatory node governing whole body energy homeostasis, and we hypothesized that FLCN regulates highly metabolic tissues like the liver. We thus generated a liver specific Flcn knockout mouse model to study its role in liver disease progression. Using the methionine- and choline-deficient diet to mimic liver fibrosis, we demonstrate that loss of Flcn reduced triglyceride accumulation, fibrosis, and inflammation in mice. In this aggressive liver disease setting, loss of Flcn led to activation of transcription factors TFEB and TFE3 to promote autophagy, promoting the degradation of intracellular lipid stores, ultimately resulting in reduced hepatocellular damage and inflammation. Hence, the activity of FLCN could be a promising target for small molecule drugs to treat liver fibrosis by specifically activating autophagy. Collectively, these results show an unexpected role for Flcn in fatty liver disease progression and highlight new potential treatment strategies.Reconstructing the behavior of extinct species is challenging, particularly for those with no living analogues. However, damage preserved as paleopathologies on bone can record how an animal moved in life, potentially reflecting behavioral patterns. Here, we assess hypothesized etiologies of pathology in a pelvis and associated right femur of a Smilodon fatalis saber-toothed cat, one of the best-studied species from the Pleistocene-age Rancho La Brea asphalt seeps, California, USA, using visualization by computed tomography (CT). The pelvis exhibits massive destruction of the right hip socket that was interpreted, for nearly a century, to have developed from trauma and infection. CT imaging reveals instead that the pathological distortions characterize chronic remodeling that began at birth and led to degeneration of the joint over the animal's life. These results suggest that this individual suffered from hip dysplasia, a congenital condition common in domestic dogs and cats. This individual reached adulthood but could not have hunted properly nor defended territory on its own, likely relying on a social group for feeding and protection. While extant social felids are rare, these fossils and others with similar pathologies are consistent with a spectrum of social strategies in Smilodon supported by a predominance of previous studies.In this work, mode-locked thulium-doped fiber lasers operating in the 2 µm wavelength region were demonstrated using tantalum aluminum carbide (Ta2AlC)-based saturable absorbers (SAs) utilizing the evanescent wave interaction. The Ta2AlC MAX Phase was prepared by dissolving the Ta2AlC powder in isopropyl alcohol and then deposited onto three different evanescent field-based devices, which were the tapered fiber, side-polished fiber, and arc-shaped fiber. Flame-brushing and wheel-polishing techniques were used to fabricate the tapered and arc-shaped fibers, respectively, while the side-polished fiber was purchased commercially. All three SA devices generated stable mode-locked pulses at center wavelengths of 1937, 1931, and 1929 nm for the tapered, side-polished, and arc-shaped fibers. The frequency of the mode-locked pulses was 10.73 MHz for the tapered fiber, 9.58 MHz for the side-polished fiber, and 10.16 MHz for the arc-shaped fiber. The measured pulse widths were 1.678, 1.734, and 1.817 ps for each of the three SA devices. The long-term stability of the mode-locked lasers was tested for each configuration over a 2-h duration. The lasers also showed little to no fluctuations in the center wavelengths and the peak optical intensities, demonstrating a reliable, ultrafast laser system.In this paper, laser welding-brazing of TC4 Titanium (Ti) alloy and Al2O3 ceramic dissimilar material was carried. The results showed that the Ti alloy and Al2O3 were joined by melting filler metal when the laser was concentrated in the Ti alloy side of the joint. The joint with one fusion weld and one brazed weld separated by remaining unmelted Ti alloy. Laser beam offset the Ti alloy 1.5 mm, Ti alloy would not be completely melted in joint. Through heat conduction, the filler metal melted occurred at the Ti-ceramic interface. A brazed weld was formed at the Ti-ceramic interface with the main microstructure of β-CuZn + Ti2Zn3, β-CuZn and Al2Cu + β-CuZn. The joint fractured at the brazed weld with the maximum tensile strength of 169 MPa.Neuromyelitis optica spectrum disorder (NMOSD) is a rare inflammatory CNS disease that primarily manifests as relapsing episodes of severe optic neuritis and myelitis. Diagnosis of NMOSD is supported by the detection of IgG autoantibodies that target the aquaporin 4 (AQP4) water channel, which, in the CNS, is an astrocyte-specific protein. AQP4 antibody binding leads to AQP4 internalization, complement-dependent and antibody-dependent cellular cytotoxicity, and water channel dysfunction. Cumulative attack-related injury causes disability in NMOSD, so the prevention of attacks is expected to prevent disability accrual. Until recently, no regulator-approved therapies were available for NMOSD. Traditional immunosuppressant therapies, including mycophenolate mofetil, azathioprine and rituximab, were widely used but their benefits have not been assessed in controlled studies. In 2019 and 2020, five phase II and III randomized placebo-controlled trials of four mechanism-based therapies for NMOSD were published and demonstrated that all four effectively prolonged the time to first relapse. All four drugs were monoclonal antibodies the complement C5 antibody eculizumab, the IL-6 receptor antibody satralizumab, the B cell-depleting antibody inebilizumab, which targets CD19, and rituximab, which targets CD20. We review the pathophysiology of NMOSD, the rationale for the development of these mechanism-based drugs, the methodology and outcomes of the five trials, and the implications of these findings for the treatment of NMOSD.A proteome-wide study of the virus kingdom based on 1.713 million protein sequences from 19,128 virus proteomes was conducted to construct an overall proteome map of the virus kingdom. Viral proteomes encode an average of 386.214 amino acids per protein with the variation in the number of protein-coding sequences being host-specific. The proteomes of viruses of fungi hosts (882.464) encoded the greatest number of amino acids, while the viral proteome of bacterial host (210.912) encoded the smallest number of amino acids. Viral proteomes were found to have a host-specific amino acid composition. Leu (8.556%) was the most abundant and Trp (1.274%) the least abundant amino acid in the collective proteome of viruses. Viruses were found to exhibit a host-dependent molecular weight and isoelectric point of encoded proteins. The isoelectric point (pI) of viral proteins was found in the acidic range, having an average pI of 6.89. However, the pI of viral proteins of algal (pI 7.08) and vertebrate (pI 7.09) hosts was in the basic range.