Aims: Microglia are involved in neurodegeneration, are prime targets for anti‐inflammatory therapy and are potential biomarkers of disease progression. For example, positron emission tomography ...imaging employing radioligands for the mitochondrial translocator protein of 18 kDa (TSPO, formerly known as the peripheral benzodiazepine receptor) is being scrutinized to detect neuroinflammation in various diseases. TSPO is presumably present in activated microglia, but may be present in other neural cells. Methods: We sought to elucidate the protein expression in normal human central nervous system, several neurological diseases (HIV encephalitis, Alzheimer's disease, multiple sclerosis and stroke) and simian immunodeficiency virus encephalitis by performing immunohistochemistry with two anti‐TSPO antibodies. Results: Although the overall parenchymal staining was minimal in normal brain, endothelial and smooth muscle cells, subpial glia, intravascular monocytes and ependymal cells were TSPO‐positive. In disease states, elevated TSPO was present in parenchymal microglia, macrophages and some hypertrophic astrocytes, but the distribution of TSPO varied depending on the disease, disease stage and proximity to the lesion or relation to infection. Staining with the two antibodies correlated well in white matter, but one antibody also stained cortical neurones. Quantitative analysis demonstrated a significant increase in TSPO in the white matter of HIV encephalitis compared with brains without encephalitis. TSPO expression was also increased in simian immunodeficiency virus encephalitis. Conclusions: This report provides the first comprehensive immunohistochemical analysis of the expression of TSPO. The results are useful for informing the usage of positron emission tomography as an imaging modality and have an impact on the potential use of TSPO as an anti‐inflammatory pharmacological target.
MicroRNAs have been shown to play an important role in normal hematopoisis and leukemogenesis. Here, we report function and mechanisms of miR-181 family in myeloid differentiation and acute myeloid ...leukemia (AML). The aberrant overexpression of all the miR-181 family members (miR-181a/b/c/d) was detected in French-American-British M1, M2 and M3 subtypes of adult AML patients. By conducting gain- and loss-of-function experiments, we demonstrated that miR-181a inhibits granulocytic and macrophage-like differentiation of HL-60 cells and CD34+ hematopoietic stem/progenitor cells (HSPCs) by directly targeting and downregulating the expression of PRKCD (which then affected the PRKCD-P38-C/EBPα pathway), CTDSPL (which then affected the phosphorylation of retinoblastoma protein) and CAMKK1. The three genes were also demonstrated to be the targets of miR-181b, miR-181c and miR-181d, respectively. Significantly decreases in the expression levels of the target proteins were detected in AML patients. Inhibition of the expression of miR-181 family members owing to Lenti-miRZip-181a infection in bone marrow blasts of AML patients increased target protein expression levels and partially reversed myeloid differentiation blockage. In the mice implanted with AML CD34+ HSPCs, expression inhibition of the miR-181 family by Lenti-miRZip-181a injection improved myeloid differentiation, inhibited engraftment and infiltration of the leukemic CD34+ cells into the bone marrow and spleen, and released leukemic symptoms. In conclusion, our findings revealed new mechanism of miR-181 family in normal hematopoiesis and AML development, and suggested that expression inhibition of the miR-181 family could provide a new strategy for AML therapy.
A new N-functionalized strategy of nitrogen heterocycles was utilized for the synthesis of nitroazole-based energetic materials, giving rise to a new family of highly dense and oxygen-rich energetic ...materials. They were characterized by IR spectroscopy, NMR spectroscopy, elemental analysis, DSC, and X-ray diffraction. These new molecules exhibit high densities, moderate to good thermal stabilities, acceptable impact and friction sensitivities, and excellent detonation properties, which suggest potential applications as energetic materials or oxidizers. Interestingly, among tetrazole-based CHNO energetic materials compound 5 has the highest measured density of 1.97 g cm super(-3) to date. 5c is the first and the only heterocyclic CHNO energetic salt with a positive OB until now. Compounds 5 and 6 exhibit excellent detonation properties (38.5 GPa, 9.22 km s super(-1); 37.0 GPa, 9.05 km s super(-1)), comparable to the highly explosive HMX. With high OB, the specific impulses of 5, 5b, 5c, and 6c are superior to those of AP and ADN as neat compounds, and the ratio of oxidizer/aluminium/PBAN (%) is 80 : 20 : 0 or 80 : 13 : 7. Furthermore, computational results, BDEs, Mulliken charges and Wiberg bond orders also support the superior qualities of the newly prepared compounds and the design strategy.
Hydrographic data collected from research cruises, bottom‐anchored moorings, drifting Ice‐Tethered Profilers, and satellite altimetry in the Beaufort Gyre region of the Arctic Ocean document an ...increase of more than 6,400 km3 of liquid freshwater content from 2003 to 2018: a 40% growth relative to the climatology of the 1970s. This fresh water accumulation is shown to result from persistent anticyclonic atmospheric wind forcing (1997–2018) accompanied by sea ice melt, a wind‐forced redirection of Mackenzie River discharge from predominantly eastward to westward flow, and a contribution of low salinity waters of Pacific Ocean origin via Bering Strait. Despite significant uncertainties in the different observations, this study has demonstrated the synergistic value of having multiple diverse datasets to obtain a more comprehensive understanding of Beaufort Gyre freshwater content variability. For example, Beaufort Gyre Observational System (BGOS) surveys clearly show the interannual increase in freshwater content, but without satellite or Ice‐Tethered Profiler measurements, it is not possible to resolve the seasonal cycle of freshwater content, which in fact is larger than the year‐to‐year variability, or the more subtle interannual variations.
Plain Language
The Beaufort Gyre centered in the Canada Basin of the Arctic Ocean is the major reservoir of fresh water in the Arctic. The primary focus of this study is on quantifying variability and trends in liquid (water) and solid (sea ice) freshwater content in this region. The Beaufort Gyre Exploration Program was initiated in 2003 to synthesize results of historical data analysis, design and conduct long‐term observations, and to provide information for numerical modeling under the umbrella of the FAMOS (Forum for Arctic Observing and Modeling Synthesis) project. The data collected from research cruises, moorings, Ice‐Tethered Profiler observations, and satellite altimetry document an increase of more than 6,400 km3 of liquid freshwater content from 2003 to 2018, a 40% growth relative to the climatology of the 1970s. This fresh water volume is comparable to the fresh water volume released to the sub‐arctic seas during the Great Salinity Anomaly episode of the 1970s. Thus, since the 2000s, the stage has been set for another possible release of fresh water to lower latitudes with accompanying climate impacts, including changes to sea ice conditions, ocean circulation, and ecosystems of the Sub‐Arctic similar to the influence of the Great Salinity Anomaly observed in the 1970s.
Key Points
Beaufort Gyre freshwater content time series (2003–2018) from different data sets are updated, compared, and analyzed
Qualitative and quantitative estimates of factors and mechanisms driving freshwater content changes are provided
In 2003–2018, the major sources of accumulated fresh water were sea ice melt, Mackenzie River runoff, and Bering Strait transport
Contents
Vitrification has been shown to decrease the developmental capacity of mammalian oocytes, and this is closely associated with the abnormal mRNA expressions of vitrified oocytes. However, the ...effect of vitrification on transcriptional machinery of oocytes examined by RNA sequencing (RNA‐seq) has yet to be defined. In the present study, the mRNA transcriptomes of fresh and vitrified bovine oocytes were analysed by Smart‐seq2 with the differently expressed genes determined by DEseq2 (an adjusted p‐value of .05 and a minimum fold change of 2). The differentially expressed mRNAs were then searched against the Gene Ontology (GO) and Genomes (KEGG) database. Finally, the mRNA expressions of 10 candidate genes were validated using quantitative real‐time PCR (qRT‐PCR). Approximately 12,000 genes were detected in each sample of fresh or vitrified oocytes. Of these, the expression levels of 102 genes differed significantly in vitrified groups: 12 genes mainly involved in cell cycle, fertilization and glucose metabolism were upregulated, and 90 genes mainly involved in mitochondria, ribosomal protein, cytoskeleton, transmembrane protein, cell cycle and calcium ions were downregulated. GO analysis showed that these genes were mainly enriched in terms of membrane‐bounded organelles, macromolecular complex, and intracellular part. The mRNA expression levels of 10 candidate genes selected randomly were in agreement with the results of the RNA‐seq. In conclusion, our results showed that vitrification affected the mRNA transcriptome of bovine oocytes by downregulating genes, which contributed to the decreased developmental capacity of vitrified oocytes. Our findings will be useful in determining approaches to improve the efficiency of vitrified oocytes.
This paper explores the influence of the confining stress on rock fragmentation under the cutter of tunnel boring machine (TBM) by indentation test. Acoustic emission (AE) system was employed for ...real-time monitoring the rock fragmentation process during the indentation test. Granite and marble samples were used in the indentation test. The rock fragmentation processes with the different confining stress levels was studied based on the characteristics of force–penetration depth curve and the AE parameters, including AE energy rate, hit counts, amplitude and location of AE events. After the indentation test, the rock samples were cut along the centerline of rock samples and subsequently the crack distribution and the size of crushed zone were measured. The test results showed that the force for crack initiation and crushed zone size increased with increasing confining stress. The cracks tend to propagate to the free surface as the confining stress increases. But for the marble samples, there exists a critical confining stress condition, such that if the confining stress is more than the critical value, the force for crack initiation and crushed zone size decrease dramatically. Moreover, it was found that rock slabbing induced by confining stress had occurred before TBM cutter indentation. Such confining stress condition promotes rock fragmentation.
•Influence of confining stress on rock fragmentation by a TBM cutter is studied by indentation test.•AE technique is used for real-time monitoring rock fragmentation during indentation test.•The damage zone and crack distribution are observed by the cross-section of the failed samples.
Laser powder bed fusion (LPBF) is a 3D printing technology that can print parts with complex geometries that are unachievable by conventional manufacturing technologies. However, pores formed during ...the printing process impair the mechanical performance of the printed parts, severely hindering their widespread application. Here, we report six pore formation mechanisms that were observed during the LPBF process. Our results reconfirm three pore formation mechanisms - keyhole induced pores, pore formation from feedstock powder and pore formation along the melting boundary during laser melting from vaporization of a volatile substance or an expansion of a tiny trapped gas. We also observe three new pore formation mechanisms: (1) pore trapped by surface fluctuation, (2) pore formation due to depression zone fluctuation when the depression zone is shallow and (3) pore formation from a crack. The results presented here provide direct evidence and insight into pore formation mechanisms during the LPBF process, which may guide the development of pore elimination/mitigation approaches. Since certain laser processing conditions studied here are similar to the situations in high energy density laser welding, the results presented here also have implications for laser welding.
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•Direct observation of pore formation dynamics during LPBF additive manufacturing.•Revealed three new pore formation mechanisms.•Reconfirmed three previously studied pore formation mechanisms
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