Synthesis of epitaxial magnetic pyrochlore heterojunctions

The synthesis of stoichiometric and epitaxial pyrochlore iridate thin films presents significant challenges yet is critical for unlocking experimental access to novel topological and magnetic states. Towards this goal, we unveil an in-situ two-stage growth mechanism that facilitates the synthesis of high-quality oriented pyrochlore iridate thin films. The growth starts with the deposition of a pyrochlore titanate as an active iso-structural template, followed by the application of an in-situ solid phase epitaxy technique in the second stage to accomplish the formation of single crystalline, large-area films. This novel protocol ensures the preservation of stoichiometry and structural homogeneity, leading to a marked improvement in surface and interface qualities over previously reported methods. The success of this synthesis approach is attributed to the application of directional laser-heat annealing, which effectively reorganizes the continuous random network of ions into a crystalline structure, as evidenced by our comprehensive analysis of the growth kinetics. This new synthesis approach advances our understanding of pyrochlore iridate film fabrication and opens a new perspective for investigating their unique physical properties.Comment: 11 pages, 4 figures; supplementary materials (1 table, 6 figures

Ecological engineering projects increased vegetation cover, production, and biomass in semiarid and subhumid Northern China

Multiple ecological engineering projects have been implemented in semiarid and subhumid Northern China since 1978 with the purpose to combat desertification, control dust storms, and improve vegetation cover. Although a plethora of local studies exist, the effectiveness of these projects has not been studied in a systematic and comprehensive way. Here, we used multiple satellite-based time-series data as well as breakpoint analysis to assess shifts in leaf area index (a proxy for green vegetation cover), gross primary production, and aboveground biomass in Northern China. We documented increased vegetation growth in northwest and southeastern parts of the region, despite drought anomalies as documented by the standardized precipitation-evapotranspiration index during 1982–2016. Significant breakpoints in leaf area index were observed for over 72.5% of the southeastern and northwestern regions, and 70.6% of these breakpoints were detected after 1999, which correspond well to the areas with the highest ecological engineering efforts. Areas with negative trends were mainly located in the Inner Mongolian Plateau, Hulun Biur, Horqin Sand Land, and urban areas. The Loess Plateau had the largest increase in vegetation growth, followed by the north parts of Northern China where biomass increased more in the provinces of Shanxi, Liaoning, Shannxi, Hebei, and Beijing than Xinjiang, Inner Mongolia, Tianjin, and Qinghai. Our results show that multiple ecological engineering projects in the region have increased vegetation cover, production, and aboveground biomass that have led to improved environmental conditions in the study area

Minimal residual disease is an independent predictor for 10-year survival in CLL

Minimal residual disease (MRD) negativity, defined as <1 chronic lymphocytic leukemia (CLL) cell detectable per 10 000 leukocytes, has been shown to independently predict for clinical outcome in patients receiving combination chemoimmunotherapy in the frontline setting. However, the long-term prognostic value of MRD status in other therapeutic settings remains unclear. Here, we retrospectively analyzed, with up to 18 years follow-up, all patients at our institution who achieved at least a partial response (PR) with various therapies between 1996 and 2007, and received a bone marrow MRD assessment at the end of treatment according to the international harmonized approach. MRD negativity correlated with both progression-free survival (PFS) and overall survival (OS) independent of the type and line of treatment, as well as known prognostic factors including adverse cytogenetics. The greatest impact of achieving MRD negativity was seen in patients receiving frontline treatment, with 10-year PFS of 65% vs 10% and 10-year OS of 70% vs 30% for MRD-negative vs MRD-positive patients, respectively. Our results demonstrate the long-term benefit of achieving MRD negativity, regardless of the therapeutic setting and treatment modality, and support its use as a prognostic marker for long-term PFS and as a potential therapeutic goal in CLL

Anion-Sensitive Regions of L-Type CaV1.2 Calcium Channels Expressed in HEK293 Cells

L-type calcium currents (ICa) are influenced by changes in extracellular chloride, but sites of anion effects have not been identified. Our experiments showed that CaV1.2 currents expressed in HEK293 cells are strongly inhibited by replacing extracellular chloride with gluconate or perchlorate. Variance-mean analysis of ICa and cell-attached patch single channel recordings indicate that gluconate-induced inhibition is due to intracellular anion effects on Ca2+ channel open probability, not conductance. Inhibition of CaV1.2 currents produced by replacing chloride with gluconate was reduced from ∼75%–80% to ∼50% by omitting β subunits but unaffected by omitting α2δ subunits. Similarly, gluconate inhibition was reduced to ∼50% by deleting an α1 subunit N-terminal region of 15 residues critical for β subunit interactions regulating open probability. Omitting β subunits with this mutant α1 subunit did not further diminish inhibition. Gluconate inhibition was unchanged with expression of different β subunits. Truncating the C terminus at AA1665 reduced gluconate inhibition from ∼75%–80% to ∼50% whereas truncating it at AA1700 had no effect. Neutralizing arginines at AA1696 and 1697 by replacement with glutamines reduced gluconate inhibition to ∼60% indicating these residues are particularly important for anion effects. Expressing CaV1.2 channels that lacked both N and C termini reduced gluconate inhibition to ∼25% consistent with additive interactions between the two tail regions. Our results suggest that modest changes in intracellular anion concentration can produce significant effects on CaV1.2 currents mediated by changes in channel open probability involving β subunit interactions with the N terminus and a short C terminal region

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

The 7p15.3 (rs4487645) association for multiple myeloma shows strong allele-specific regulation of the MYC-interacting gene CDCA7L in malignant plasma cells

International audienceRecent genome-wide association studies have identified single nucleotide polymorphisms (SNPs) at 7 loci influencing multiple myeloma (MM) risk. We generated expression quantitative trait loci (eQTL) data on malignant plasma cells on 848 patients to fine map the risk loci associations and gain insight into their functional basis. At 7p15.3 the strongest association with MM risk is provided by rs4487645, which is associated with allele-specific cis-regulation of the MYC-interacting gene CDCA7L with P-value=4.1x10-25. rs4487645 resides within intron 80 of DNAH11 and only 47 kb upstream of the transcription start site of CDCA7L. rs4487645 maps within a binding site for interferon regulatory factor 4 (IRF4) in a strong enhancer element upstream of CDCA7L. IRF4 is a critical transcrip-tional regulator in B-cell development. Since rs4487645 represents the strongest signal for MM at 7p15.3 the data are compatible with increased expression of CDCA7L being the functional basis of the 7p15.3 association exerting its effects through an extended pathway involving IRF