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.
Glioblastoma-initiating cells (GICs) are self-renewing tumorigenic sub-populations, contributing to therapeutic resistance via decreased sensitivity to ionizing radiation (IR). GIC survival following ...IR is attributed to an augmented response to genotoxic stress. We now report that GICs are primed to handle additional stress due to basal activation of single-strand break repair (SSBR), the main DNA damage response pathway activated by reactive oxygen species (ROS), compared with non-GICs. ROS levels were higher in GICs and likely contributed to the oxidative base damage and single-strand DNA breaks found elevated in GICs. To tolerate constitutive DNA damage, GICs exhibited a reliance on the key SSBR mediator, poly-ADP-ribose polymerase (PARP), with decreased viability seen upon small molecule inhibition to PARP. PARP inhibition (PARPi) sensitized GICs to radiation and inhibited growth, self-renewal, and DNA damage repair. In vivo treatment with PARPi and radiotherapy attenuated radiation-induced enrichment of GICs and inhibited the central cancer stem cell phenotype of tumor initiation. These results indicate that elevated PARP activation within GICs permits exploitation of this dependence, potently augmenting therapeutic efficacy of IR against GICs. In addition, our results support further development of clinical trials with PARPi and radiation in glioblastoma.
The ability to manipulate quantum systems lies at the heart of the development of quantum technology. The ultimate goal of quantum control is to realize arbitrary quantum operations (AQUOs) for all ...possible open quantum system dynamics. However, the demanding extra physical resources impose great obstacles. Here, we experimentally demonstrate a universal approach of AQUO on a photonic qudit with the minimum physical resource of a two-level ancilla and a log2d -scale circuit depth for a d-dimensional system. The AQUO is then applied in a quantum trajectory simulation for quantum subspace stabilization and quantum Zeno dynamics, as well as incoherent manipulation and generalized measurements of the qudit. Therefore, the demonstrated AQUO for complete quantum control would play an indispensable role in quantum information science.
Aerosol‐planetary boundary layer (PBL) interactions have been found to enhance air pollution in megacities in China. We show that black carbon (BC) aerosols play the key role in modifying the PBL ...meteorology and hence enhancing the haze pollution. With model simulations and data analysis from various field observations in December 2013, we demonstrate that BC induces heating in the PBL, particularly in the upper PBL, and the resulting decreased surface heat flux substantially depresses the development of PBL and consequently enhances the occurrences of extreme haze pollution episodes. We define this process as the “dome effect” of BC and suggest an urgent need for reducing BC emissions as an efficient way to mitigate the extreme haze pollution in megacities of China.
Key Points
BC plays an important role in enhancing surface haze pollution in megacities in China
Upper PBL heating and surface cooling by BC are two comparable processes in the PBL feedback
Reducing BC emission cobenefits the mitigations of haze pollution and global warming
Toroidal dipole resonance can significantly reduce radiation loss of materials, potentially improving sensor sensitivity. Generally, toroidal dipole response is suppressed by electric and magnetic ...dipoles in natural materials, making it difficult to observe experimentally. However, as 2D metamaterials, metasurfaces can weaken the electric and magnetic dipole, enhancing toroidal dipole response. Here, we propose a new graphene-integrated toroidal resonance metasurface as an ultra-sensitive chemical sensor, capable of qualitative detection of chlorothalonil in the terahertz region, down to a detection limit of 100 pg/mL. Our results demonstrate graphene-integrated toroidal resonance metasurfaces as a promising basis for ultra-sensitive, qualitative detection in chemical and biological sensing.
No randomized controlled trials have evaluated the comparative outcomes of cefazolin versus nafcillin for methicillin-susceptible Staphylococcus aureus (MSSA) bacteraemia.
A prospective observational ...cohort study including all S. aureus bacteraemia was conducted at 10 hospitals. Patients (≥15 years) with MSSA bacteraemia who received cefazolin or nafcillin as definitive antibiotics were included. The rates of treatment failure (premature discontinuation of antibiotics because of adverse effects, switching of antibiotics because of clinical failure, all-cause mortality within 1 month, or recurrence) were compared between the cefazolin and nafcillin groups. Propensity score matching analyses were performed to balance the factors influencing the selection of antibiotics.
Among the 242 included cases, the bones and joints (36.8%) were the most common sites of infection and 60.7% of the patients had sepsis. The overall treatment failure rate was 43.8% (106/242). All-cause mortality within 1 month was 6.2% (15/242). After propensity score matching, the treatment failure rate of cefazolin was lower than that of nafcillin (30.4% (24/79) vs. 49.4% (39/79), p 0.015) because of a higher rate of discontinuation caused by adverse events. When the data were limited to patients with sepsis, the treatment failure rates of both groups were not significantly different. Approximately 22% (24/110) of MSSA isolates exhibited a cefazolin-inoculum effect (CIE) that had significant impact on the failure rate and mortality of the cefazolin group.
Cefazolin might be recommended as an adequate and better-tolerated treatment for MSSA bacteraemia in the absence of CIE.
Ambient total OH reactivity was measured at the Finnish boreal forest station SMEAR II in Hyytiälä (Latitude 61°51' N; Longitude 24°17' E) in July and August 2010 using the Comparative Reactivity ...Method (CRM). The CRM - total OH reactivity method - is a direct, in-situ determination of the total loss rate of hydroxyl radicals (OH) caused by all reactive species in air. During the intensive field campaign HUMPPA-COPEC 2010 (Hyytiälä United Measurements of Photochemistry and Particles in Air - Comprehensive Organic Precursor Emission and Concentration study) the total OH reactivity was monitored both inside (18 m) and directly above the forest canopy (24 m) for the first time. The comparison between these two total OH reactivity measurements, absolute values and the temporal variation have been analyzed here. Stable boundary layer conditions during night and turbulent mixing in the daytime induced low and high short-term variability, respectively. The impact on total OH reactivity from biogenic emissions and associated photochemical products was measured under "normal" and "stressed" (i.e. prolonged high temperature) conditions. The advection of biomass burning emissions to the site caused a marked change in the total OH reactivity vertical profile. By comparing the OH reactivity contribution from individually measured compounds and the directly measured total OH reactivity, the size of any unaccounted for or "missing" sink can be deduced for various atmospheric influences. For "normal" boreal conditions a missing OH reactivity of 58%, whereas for "stressed" boreal conditions a missing OH reactivity of 89% was determined. Various sources of not quantified OH reactive species are proposed as possible explanation for the high missing OH reactivity.
Increased demand for timber, the reduction in the available timber resources, and more frequent and severe forest fires under a changing climate have increased the use of salvage logging in North ...American forests despite concerns regarding impacts on biodiversity and long-term forest productivity. We aimed to complement previous approaches that used bird species richness or individual abundance in salvage-logged habitats to assess the sustainability of this practice. We looked for commonalities in the taxonomic, functional, and phylogenetic components of bird assemblages among these three post-disturbance habitats across a broad geographic range. We compiled six North American datasets selected from primary and grey literature that documented species composition of avian assemblages in habitats after recent fire, post-fire salvage logging, and traditional logging. Our results revealed contrasting patterns of bird trait assemblage among burned, post-fire salvage, and traditionally logged habitats. In salvage-logged habitats, taxonomic diversity, functional diversity, and functional and phylogenetic redundancy were significantly lower than in both burned and traditionally logged habitats. The frequency of insectivores was significantly lower after salvage logging than after both fire and traditional logging. These findings suggest that cumulative disturbances have a negative effect on early assembly of bird communities. The outcomes of this study encourage further assessments, at landscape level, of salvage logging intensity, burn size, and fire severity on bird functional structure to better plan for their conservation.
Phosphorus (P) is an essential nutrient for living organisms and cannot be replaced or substituted. In this paper, we present a simple yet efficient membrane free electrochemical system for P removal ...and recovery as calcium phosphate (CaP). This method relies on in situ formation of hydroxide ions by electro mediated water reduction at a titanium cathode surface. The in situ raised pH at the cathode provides a local environment where CaP will become highly supersaturated. Therefore, homogeneous and heterogeneous nucleation of CaP occurs near and at the cathode surface. Because of the local high pH, the P removal behavior is not sensitive to bulk solution pH and therefore, efficient P removal was observed in three studied bulk solutions with pH of 4.0 (56.1%), 8.2 (57.4%), and 10.0 (48.4%) after 24 h of reaction time. While P removal efficiencies are not generally affected by bulk solution pH, the chemical-physical properties of CaP solids collected on the cathode are still related to bulk solution pH, as confirmed by structure characterizations. High initial solution pH promotes the formation of more crystalline products with relatively high Ca/P molar ratio. The Ca/P molar ratio increases from 1.30 (pH 4.0) to 1.38 (pH 8.2) and further increases to 1.55 (pH 10.0). The formation of CaP precipitates was a typical crystallization process, with an amorphous phase formed at the initial stage which then transforms to the most stable crystal phase, hydroxyapatite, which is inferred from the increased Ca/P molar ratio from 1.38 (day 1) to the theoretical 1.76 (day 11) and by the formation of needle-like crystals. Finally, we demonstrated the efficiency of this system for real wastewater. This, together with the fact that the electrochemical method can work at low bulk pH, without dosing chemicals and a need for a separation process, highlights the potential application of the electrochemical method for P removal and recovery.
Cancer is characterised by DNA hypermethylation and gene silencing of CpG island-associated promoters, including tumour-suppressor genes. The methyl-CpG-binding domain (MBD) family of proteins bind ...to methylated DNA and can aid in the mediation of gene silencing through interaction with histone deacetylases and histone methyltransferases. However, the mechanisms responsible for eliciting CpG island hypermethylation in cancer, and the potential role that MBD proteins play in modulation of the methylome remain unclear. Our previous work demonstrated that MBD2 preferentially binds to the hypermethylated GSTP1 promoter CpG island in prostate cancer cells. Here, we use functional genetic approaches to investigate if MBD2 plays an active role in reshaping the DNA methylation landscape at this locus and genome-wide. First, we show that loss of MBD2 results in inhibition of both maintenance and spread of de novo methylation of a transfected construct containing the GSTP1 promoter CpG island in prostate cancer cells and Mbd2-/- mouse fibroblasts. De novo methylation was rescued by transient expression of Mbd2 in Mbd2-/- cells. Second, we show that MBD2 depletion triggers significant hypomethylation genome-wide in prostate cancer cells with concomitant loss of MBD2 binding at promoter and enhancer regulatory regions. Finally, CpG islands and shores that become hypomethylated after MBD2 depletion in LNCaP cancer cells show significant hypermethylation in clinical prostate cancer samples, highlighting a potential active role of MBD2 in promoting cancer-specific hypermethylation. Importantly, co-immunoprecipiation of MBD2 shows that MBD2 associates with DNA methyltransferase enzymes 1 and 3A. Together our results demonstrate that MBD2 has a critical role in 'rewriting' the cancer methylome at specific regulatory regions.
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