The momentum dependence of the nematic order parameter is an important ingredient in the microscopic description of iron-based high-temperature superconductors. While recent reports on FeSe indicate ...that the nematic order parameter changes sign between electron and hole bands, detailed knowledge is still missing for other compounds. Combining angle-resolved photoemission spectroscopy with uniaxial strain tuning, we measure the nematic band splitting in both FeSe and BaFe_{2}As_{2} without interference from either twinning or magnetic order. We find that the nematic order parameter exhibits the same momentum dependence in both compounds with a sign change between the Brillouin center and the corner. This suggests that the same microscopic mechanism drives the nematic order in spite of the very different phase diagrams.
The PROTAC (proteolysis-targeting chimera) ARV-825 recruits bromodomain and extraterminal (BET) proteins to the E3 ubiquitin ligase cereblon, leading to degradation of BET proteins, including BRD4. ...Although the BET-protein inhibitor (BETi) OTX015 caused accumulation of BRD4, treatment with equimolar concentrations of ARV-825 caused sustained and profound depletion (>90%) of BRD4 and induced significantly more apoptosis in cultured and patient-derived (PD) CD34+ post-MPN sAML cells, while relatively sparing the CD34+ normal hematopoietic progenitor cells. RNA-Seq, Reverse Phase Protein Array and mass cytometry 'CyTOF' analyses demonstrated that ARV-825 caused greater perturbations in messenger RNA (mRNA) and protein expressions than OTX015 in sAML cells. Specifically, compared with OTX015, ARV-825 treatment caused more robust and sustained depletion of c-Myc, CDK4/6, JAK2, p-STAT3/5, PIM1 and Bcl-xL, while increasing the levels of p21 and p27. Compared with OTX015, PROTAC ARV-771 treatment caused greater reduction in leukemia burden and further improved survival of NSG mice engrafted with luciferase-expressing HEL92.1.7 cells. Co-treatment with ARV-825 and JAK inhibitor ruxolitinib was synergistically lethal against established and PD CD34+ sAML cells. Notably, ARV-825 induced high levels of apoptosis in the in vitro generated ruxolitinib-persister or ruxolitinib-resistant sAML cells. These findings strongly support the in vivo testing of the BRD4-PROTAC based combinations against post-MPN sAML.
Several transition-metal dichalcogenides exhibit a striking crossover from indirect to direct band gap semiconductors as they are thinned down to a single monolayer. Here, we demonstrate how an ...electronic structure characteristic of the isolated monolayer can be created at the surface of a bulk MoS2 crystal. This is achieved by intercalating potassium in the interlayer van der Waals gap, expanding its size while simultaneously doping electrons into the conduction band. Our angle-resolved photoemission measurements reveal resulting electron pockets centered at the K̅ and K′ points of the Brillouin zone, providing the first momentum-resolved measurements of how the conduction band dispersions evolve to yield an approximately direct band gap of ∼1.8 eV in quasi-freestanding monolayer MoS2. As well as validating previous theoretical proposals, this establishes a novel methodology for manipulating electronic structure in transition-metal dichalcogenides, opening a new route for the generation of large-area quasi-freestanding monolayers for future fundamental study and use in practical applications.
Bromodomain extraterminal protein (BETP) inhibitors transcriptionally repress oncoproteins and nuclear factor-κB (NF-κB) target genes that undermines the growth and survival of mantle cell lymphoma ...(MCL) cells. However, BET bromodomain inhibitor (BETi) treatment causes accumulation of BETPs, associated with reversible binding and incomplete inhibition of BRD4 that potentially compromises the activity of BETi in MCL cells. Unlike BETi, BET-PROTACs (proteolysis-targeting chimera) ARV-825 and ARV-771 (Arvinas, Inc.) recruit and utilize an E3-ubiquitin ligase to effectively degrade BETPs in MCL cells. BET-PROTACs induce more apoptosis than BETi of MCL cells, including those resistant to ibrutinib. BET-PROTAC treatment induced more perturbations in the mRNA and protein expressions than BETi, with depletion of c-Myc, CDK4, cyclin D1 and the NF-κB transcriptional targets Bcl-xL, XIAP and BTK, while inducing the levels of HEXIM1, NOXA and CDKN1A/p21. Treatment with ARV-771, which possesses superior pharmacological properties compared with ARV-825, inhibited the in vivo growth and induced greater survival improvement than the BETi OTX015 of immune-depleted mice engrafted with MCL cells. Cotreatment of ARV-771 with ibrutinib or the BCL2 antagonist venetoclax or CDK4/6 inhibitor palbociclib synergistically induced apoptosis of MCL cells. These studies highlight promising and superior preclinical activity of BET-PROTAC than BETi, requiring further in vivo evaluation of BET-PROTAC as a therapy for ibrutinib-sensitive or -resistant MCL.
Summary Objective Immune cells are involved in the pathogenesis of osteoarthritis (OA). We examined the effects of T helper (Th) cells, which induce the expression of macrophage inflammatory protein ...(MIP-1γ), on the progression of OA. Design Using anterior cruciate ligament-transection (ACLT), we induced OA in one hind-leg knee joint of B6 mice. The CD4+ T cells from splenocytes and synovium were flow-cytometrically and immunochemically evaluated, respectively. The knee joints were histologically assessed for manifestations of OA. MIP-1γ levels and nuclear factor-κB (NF-κB) in the knee joints were measured using enzyme-linked immunosorbent and immunoblotting assays, respectively; osteoclastogenesis was detected by tartrate-resistant acid phosphatase (TRAP) staining. The inflammatory responses and MIP-1γ expression were examined using immunohistochemistry. Results The number of CD4+ T cells and the expression of interferon-γ (IFN-γ) increased during OA onset (30 days after ACLT) and then decreased at a later stage of OA (90 days after ACLT). Tissue damage induced by CD4+ T cells was evident at the later stage. The activation of CD4+ T cells induced the expression of MIP-1γ and NF-κB. The expression of MIP-1γ can be detected in synovium which CD4+ T cells were infiltrated. The increased MIP-1γ expression caused an increase in the number of osteoclasts in joints. The regulation of CD4+ T cells was accompanied by increased macrophage infiltration and matrix metalloproteinase (MMP)-9 expression. Histopathological examinations revealed that CD4+ T cell knockout (CD4−/− ) mice had less expression of MIP-1γ and slower cartilage degeneration than control mice had. Conclusions CD4+ T cells were activated during the onset of OA, but cartilage damage was more prominent at a later stage. CD4+ T cells were involved in the pathogenesis of OA: they induced MIP-1γ expression and subsequent osteoclast formation.
Summary
Background
The rs738409 GG variant in patatin‐like phospholipase 3 (PNPLA3) is associated with non‐alcoholic fatty liver disease (NAFLD) and disease severity. However, it remains unclear if ...it contributes to the development of NAFLD through affecting dietary pattern.
Aim
To examine the association among PNPLA3 gene polymorphism, dietary pattern, metabolic factors and NAFLD.
Methods
Liver fat and fibrosis were assessed by proton‐magnetic resonance spectroscopy and transient elastography in 920 subjects from a population screening project (251 had NAFLD). Dietary nutrient intake was recorded using a locally validated food‐frequency questionnaire.
Results
The prevalence of GG genotype in NAFLD subjects was 20.7%, compared to 10.6% in controls (P < 0.001). Macronutrient intake was similar among subjects with different PNPLA3 genotypes. The presence of G allele was a predictor of NAFLD independent of nutrient intake and other metabolic factors (adjusted odds ratio to CC: CG, 2.00; GG, 2.68). In subjects without metabolic syndrome, G allele was even more closely correlated with NAFLD diagnosis (adjusted odds ratio to CC: CG, 2.22; GG, 3.39). The prevalence of NAFLD was only 12% in subjects with CC genotype and no metabolic syndrome, and increased to 34% in those with GG genotype and no metabolic syndrome. While NAFLD subjects had significantly lower fibre intake, there was no significant interaction between PNPLA3 and dietary pattern.
Conclusions
The G allele in PNPLA3 rs738409 increases the risk of NAFLD in the general population, especially in subjects without metabolic syndrome, independent of dietary pattern and metabolic factors.
Summary
The effects of cigarette smoking on the risk of herpes zoster (HZ) infection remain unclear. This study aimed to examine the association between cigarette smoking and HZ. Participants were ...collected from four rounds (2001, 2005, 2009 and 2013) of the Taiwan National Health Interview Survey. Incident cases of HZ were identified from the Taiwanese National Health Insurance database. Of the 57 641 participants, 3346 developed HZ during the observation period. After controlling for confounders, current smokers had a lower risk of incident HZ than never‐smokers (adjusted hazard ratio 0.69; 95% CI 0.62–0.77). There was a trend toward a decreased risk of HZ with increasing numbers of cigarettes per day, years of smoking and cumulative pack‐years of smoking among current smokers (Ptrend < 0.001). Former smoking was not associated with risk of HZ. In conclusion, current smoking was significantly associated with a decreased risk of developing HZ.
Many-body interactions in transition-metal oxides give rise to a wide range of functional properties, such as high-temperature superconductivity, colossal magnetoresistance or multiferroicity . The ...seminal recent discovery of a two-dimensional electron gas (2DEG) at the interface of the insulating oxides LaAlO(3) and SrTiO(3) (ref. 4) represents an important milestone towards exploiting such properties in all-oxide devices. This conducting interface shows a number of appealing properties, including a high electron mobility, superconductivity and large magnetoresistance, and can be patterned on the few-nanometre length scale. However, the microscopic origin of the interface 2DEG is poorly understood. Here, we show that a similar 2DEG, with an electron density as large as 8×10(13) cm(-2), can be formed at the bare SrTiO(3) surface. Furthermore, we find that the 2DEG density can be controlled through exposure of the surface to intense ultraviolet light. Subsequent angle-resolved photoemission spectroscopy measurements reveal an unusual coexistence of a light quasiparticle mass and signatures of strong many-body interactions.
We aimed to determine the effect of dementia and Parkinson's disease on one, three and 12-month mortality following surgery for fracture of the hip in elderly patients from an Asian population.
Using ...a random sample of patients taken from the Taiwan National Health Insurance Research Database, this retrospective cohort study analyzed the data on 6626 elderly patients who sustained a fracture of the hip between 1997 and 2012 who had ICD-9 codes within the general range of hip fracture (820.xx). We used Cox regression to estimate the risk of death associated with dementia, Parkinson's disease or both, adjusting for demographic, clinical, treatment, and provider factors.
Among 6626 hip fracture patients, 10.20% had dementia alone, 5.60% had Parkinson's disease alone, and 2.67% had both. Corresponding one-year mortality rates were 15.53%, 11.59%, and 15.82%, compared with 9.22% for those without neurological illness. Adjusted hazard ratio for one-year mortality was 1.45 (95% confidence intervals (CI) 1.17 to 1.79) for those with dementia, and 1.57 (95% CI 1.07 to 2.30) with both dementia and Parkinson's disease versus patients with neither. There was no significant association with death for Parkinson's disease alone. Age, male gender and comorbidities were also associated with a higher risk of mortality.
Dementia, with or without Parkinson's disease, is an independent predictor of mortality following surgery for fractures of the hip. Age, male gender and comorbidities also increase the risk of death. Parkinson's disease alone has no significant effect. Cite this article: Bone Joint J 2018;100-B:1220-6.
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