Liquid-liquid phase separation promotes the formation of membraneless condensates that mediate diverse cellular functions, including autophagy of misfolded proteins. However, how phase separation ...participates in autophagy of dysfunctional mitochondria (mitophagy) remains obscure. We previously discovered that nuclear receptor Nur77 (also called TR3, NGFI-B, or NR4A1) translocates from the nucleus to mitochondria to mediate celastrol-induced mitophagy through interaction with p62/SQSTM1. Here, we show that the ubiquitinated mitochondrial Nur77 forms membraneless condensates capable of sequestrating damaged mitochondria by interacting with the UBA domain of p62/SQSTM1. However, tethering clustered mitochondria to the autophagy machinery requires an additional interaction mediated by the N-terminal intrinsically disordered region (IDR) of Nur77 and the N-terminal PB1 domain of p62/SQSTM1, which confers Nur77-p62/SQSTM1 condensates with the magnitude and liquidity. Our results demonstrate how composite multivalent interaction between Nur77 and p62/SQSTM1 coordinates to sequester damaged mitochondria and to connect targeted cargo mitochondria for autophagy, providing mechanistic insight into mitophagy.
Low-dose post-transplant cyclophosphamide (PTCy) in conjunction with anti-thymocyte globulin (ATG) appears as a potentially effective graft-versus-host disease (GVHD) prevention strategy in ...haploidentical hematopoietic cell transplant (haplo-HCT). Our study aims to assess the efficacy of this regimen.
We extended our prospective study in patients treated with low-dose PTCy (14.5 mg/kg on days 3 and 4) in ATG/granulocyte colony-stimulating factor (G-CSF)-based regimen and compared the results to the contemporary cohort of patients without low-dose PTCy (ATG cohort). Both study cohort and control are transplanted from maternal donor or collateral relatives.
We identified 239 consecutive patients (ATG-PTCy cohort = 114; ATG cohort = 125). All patients but one in ATG cohort achieved myeloid engraftment by day 30 post-HCT. We found that both the cumulative incidence of 100-day grade III-IV aGvHD and non-relapse-mortality (NRM) in the ATG-PTCy cohort was significantly reduced than that in the ATG group (5% vs 18%; P = 0.003; and 6% vs 15%; P= 0.045); the 2-year cumulative incidences of relapse and overall survival were comparable between the two cohorts (13% vs 14%; P = 0.62; and 83% vs 77%; P = 0.18, respectively). Furthermore, GVHD-free, relapse-free survival (GRFS) was significantly improved in the ATG-PTCy arm (63% vs 48%; P = 0.039). In multivariate analysis, the joint treatment resulted in lower grade II-IV acute GVHD (HR 0.58; P = 0.036), grade III-IV aGvHD (HR 0.28; P = 0.006), chronic GVHD (HR 0.60; P = 0.047), NRM (HR 0.26; P = 0.014), and higher GRFS (HR 0.59; P = 0.021) but slower myeloid and platelet recovery (HR 0.29 and 0.30; both P < 0.001).
These results suggested that ATG/PTCy (low-dose) can reduce both acute and chronic GVHD as compared with standard ATG-based prophylaxis using maternal donor or collateral relatives at particular high GVHD risk.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
As a rapidly growing family of 2D transition metal carbides and nitrides, MXenes are recognized as promising materials for the development of future electronics and optoelectronics. So far, the ...reported patterning methods for MXene films lack efficiency, resolution, and compatibility, resulting in limited device integration and performance. Here, a high‐performance MXene image sensor array fabricated by a wafer‐scale combination patterning method of an MXene film is reported. This method combines MXene centrifugation, spin‐coating, photolithography, and dry‐etching and is highly compatible with mainstream semiconductor processing, with a resolution up to 2 µm, which is at least 100 times higher than other large‐area patterning methods reported previously. As a result, a high‐density integrated array of 1024‐pixel Ti3C2Tx/Si photodetectors with a detectivity of 7.73 × 1014 Jones and a light–dark current ratio (Ilight/Idark) of 6.22 × 106, which is the ultrahigh value among all reported MXene‐based photodetectors, is fabricated. This patterning technique paves a way for large‐scale high‐performance MXetronics compatible with mainstream semiconductor processes.
MXenes are promising for future electronics and optoelectronics; however, previously reported patterning methods lack efficiency, resolution, and compatibility with mainstream semiconductor processing. Here, a wafer‐scale combination patterning method with a resolution up to the micrometer scale is developed, resulting in an integrated array of 1024‐pixel Ti3C2Tx/Si photodetectors with a record‐high detectivity of 7.73 × 1014 Jones.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
14.
Long-Term Efficacy of a Hepatitis E Vaccine Zhang, Jun; Zhang, Xue-Feng; Huang, Shou-Jie ...
The New England journal of medicine,
03/2015, Volume:
372, Issue:
10
Journal Article
Peer reviewed
Open access
Hepatitis E virus is a common cause of illness worldwide and is associated with severe complications, especially in pregnant women. In this report, the long-term efficacy, immunogenicity, and safety ...of a hepatitis E vaccine are described.
Hepatitis E virus (HEV) is a common cause of acute hepatitis worldwide.
1
,
2
HEV infection occurs in two distinct epidemiologic patterns.
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The most common pattern is waterborne infection, which is caused by HEV genotype 1 or 2 and occurs mainly in resource-limited countries, often in large, protracted outbreaks or in sporadic cases associated with high mortality among pregnant women.
4
–
6
The other pattern is transmission from animals and humans, which is caused by HEV genotype 3 or 4 and occurs widely in both resource-limited and developed countries.
1
,
7
–
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Rein et al.
10
estimated the incidence of hepatitis E in areas . . .
This study compared the effects of pre-transplantation minimal residual disease (pre-MRD) on outcomes in AML patients who underwent human leukocyte antigen-matched sibling donor transplantation ...(MSDT) or who received unmanipulated haploidentical allografts.
A retrospective study (n = 339) and a prospective study (n = 340) were performed. MRD was determined using multiparameter flow cytometry.
Either after retrospective or prospective analysis, patients with negative pre-MRD (pre-MRDneg) had a lower incidence of relapse than those with positive pre-MRD (pre-MRDpos) in MSDT settings (P < 0.001 for all), but relapse was comparable in Haplo-SCT settings for patients with pre-MRDneg versus pre-MRDpos (P = 0.866 and 0.161, respectively). In either the retrospective (n = 65) or the prospective study (n = 76), pre-MRDpos subjects receiving Haplo-SCT experienced a lower incidence of relapse than those who underwent MSDT (P < 0.001 and p = 0.017, respectively). Of the patients with pre-MRDpos in either the total (n = 141) or the subgroup excluding cases which received donor lymphocyte infusion (DLI; n = 105), those who underwent MSDT had a higher incidence of relapse than those receiving haplo-SCT (P < 0.01 for all). Multivariate analysis showed that, for pre-MRDpos cases, haplo-SCT was associated with a low incidence of relapse and with better LFS and OS in either retrospective group, prospective group, combination groups, or subgroup not including cases which received DLI.
The results indicated that, for pre-MRD-positive AML patients, haplo-SCT was associated with lower incidence of relapse and better survival, suggesting a stronger anti-leukemia effect.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
This study evaluated the effects of pretransplantation minimal residual disease (pre‐MRD) on outcomes of patients with acute lymphoblastic leukemia (ALL) who underwent unmanipulated haploidentical ...stem cell transplantation (haplo‐SCT). A retrospective study including 543 patients with ALL was performed. MRD was determined using multiparametric flow cytometry. Both in the entire cohort of patients and in subgroup cases with T‐ALL or B‐ALL, patients with positive pre‐MRD had a higher incidence of relapse (CIR) than those with negative pre‐MRD in MSDT settings (P < 0.01 for all). Landmark analysis at 6 months showed that MRD positivity was significantly and independently associated with inferior rates of relapse (HR, 1.908; P = 0.007), leukemia‐free survival (LFS) (HR, 1.559; P = 0.038), and OS (HR, 1.545; P = 0.049). The levels of pre‐MRD according to a logarithmic scale were also associated with leukemia relapse, LFS, and OS, except that cases with MRD <0.01% experienced comparable CIR and LFS to those with negative pre‐MRD. A risk score for CIR was developed using the variables pre‐MRD, disease status, and immunophenotype of ALL. The CIR was 14%, 26%, and 59% for subjects with scores of 0, 1, and 2‐3, respectively (P < 0.001). Three‐year LFS was 75%, 64%, and 42%, respectively (P < 0.001). Multivariate analysis confirmed the association of the risk score with CIR and LFS. The results indicate that positive pre‐MRD, except for low level one (MRD < 0.01%), is associated with poor outcomes in patients with ALL who underwent unmanipulated haplo‐SCT.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Long noncoding RNAs (lncRNAs) are emerging as important regulators of multiple cellular processes such as cell invasion, growth, apoptosis and differentiation. LncRNAs can function as competing ...endogenous RNAs (ceRNAs) which sponge and sequester microRNA (miRNA) to regulate specific targets. Previously, we found that the target genes of several miRNAs, including FADD, Fas, Casp and Bax, are related to neuronal apoptosis and form a regulatory network. Among several factors, microRNA‐296‐5p expression was found to be negatively correlated with caspase activity and apoptosis. Here, we aimed to investigate the role of miR‐296‐5p in neuroblastoma (NB) cells. By performing quantitative real‐time PCR (qRT‐PCR), western blot and flow cytometry assays we analysed the expression of apoptotic markers in NB cells transfected with miR‐296‐5p mimics or inhibitor. Pathway‐specific PCR array allowed us to identify the target genes of miR‐296‐5p. Using LncBase online tool, we predicted lncRNA KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1) as an upstream regulator of miR‐296‐5p. The binding of KCNQ1OT1 and miR‐296‐5p was validated via RNA immunoprecipitation and Biotin pull‐down assays. We also demonstrate that miR‐296‐5p suppresses apoptosis of NB cells in vitro and in vivo. Mechanistically, miR‐296‐5p directly bound the 3′UTR of Bax mRNA, thus repressing Bax at the mRNA and protein level. Moreover, through bioinformatic analysis and molecular experiments, we showed that KCNQ1OT1 sponged miR‐296‐5p and impaired its effect on NB cell apoptosis. In summary, KCNQ1OT1 is a potent promoting factor of cell apoptosis, which acts by sponging miR‐296‐5p and upregulating Bax. Our findings identify a regulatory axis of cell fate in NB cells.
Increasing evidence shows that long noncoding RNAs (lncRNAs) can function as competing endogenous RNAs by sponging microRNAs in a sequence‐specific manner and impairing their functions of binding and suppressing target mRNAs. Through bioinformatic analysis and subsequent molecular experiments, we implied that lncRNA KCNQ1 opposite strand/antisense transcript 1 promotes Bax expression and neuroblastoma cells apoptosis by direct binding with miR‐296‐5p.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Two novel polyoxovanadate-based metal-organic frameworks (MOFs), Co(bib){V
2
O
6
} (V-Co-MOF) and Ni(en)(bib){V
2
O
6
}·2H
2
O (V-Ni-MOF) (bib = 1,4-bis(1
H
-imidazoly-1-yl)benzene, en = ...ethylenediamine) were facilely synthesized under mild hydrothermal conditions. Single-crystal X-ray diffraction analysis shows that the V sites in both compounds adopt {VO
4
} tetrahedral coordination geometries, and the Co center in the V-Co-MOF presents a four-coordinated distorted tetrahedron configuration (coordinatively unsaturated metal sites, CUMS), while the Ni center in the V-Ni-MOF exhibits six-coordinated octahedral geometry (coordinatively saturated metal sites, CSMS). Given that the CUMS can generally be used as active sites for catalytic reactions, we explored the catalytic activities of these two compounds for the oxidation of a mustard gas simulant, 2-chloroethyl ethyl sulfide (CEES). The experimental results indicate that they can catalyze the oxidation of CEES to give the only nontoxic product, 2-chloroethyl ethyl sulfoxide (CEESO). Significantly, the V-Co-MOF exhibits higher catalytic activity; it converts 100% of CEES in 10 min, whereas V-Ni-MOF converts only 47.5% of CEES under identical conditions. Researching the mechanism of the catalytic reaction revealed that the excellent catalytic performance of the V-Co-MOF was attributed to the two-site synergetic effect: (1) the oxidant H
2
O
2
interacts with the V site to produce peroxovanadium with higher oxidation activity; (2) the S atom in CEES coordinates with the four-coordinated Co(
ii
) center to obtain 2-chloroethyl ethyl sulfonium cation (CEES+), which makes the CEES more easily oxidize to CEESO based on the oxidation mechanism of peroxovanadium and shortens the molecular size distance between CEES and the obtained peroxovanadium, thereby greatly improving the rate of the catalytic reaction. To our knowledge, this is the first dual-active-site polyoxometalate-based MOF catalyst for catalysing the oxidative detoxification of CEES.
A polyoxovanadate-based cobalt organic framework (V-Co-MOF) was synthesized and it, as a heterogeneous catalyst, can catalyze the rapid selective oxidation of a mustard gas simulant to a non-toxic product by the two-site synergistic effect of V
V
and Co
II
.
Adoptive therapy with cytomegalovirus (CMV)‐specific cytotoxic T lymphocytes (CMV‐CTLs) has emerged as an effective method for CMV infection. However, the efficacy reportedly ranges from 50% to 90%, ...and factors affecting anti‐CMV efficacy have not been established. We investigated the safety and efficacy of adoptive therapy with CMV‐CTLs for CMV infection in 190 patients after haploidentical stem cell transplantation (haplo‐SCT), and importantly, we analyzed the main factors affecting antiviral efficacy. The CMV peak titer decreased from 19 (range, 1.0–503.0) × 103 copies/mL to 3.9 (range, 0–112) × 103 copies/mL after CMV‐CTL infusion. The cumulative complete response (CR) rates in the first, fourth, and sixth weeks after the first CMV‐CTL infusion were 37.9% (95% CI 35.0–40.8), 76.8% (95% CI 70.7–82.9), and 89.5% (95% CI 85.2–93.8), respectively. In multivariate analysis, persistent CMV infection prior to CMV‐CTL infusion (hazard ratio HR 2.29, 95% CI 1.29–4.06, p = .005) and basiliximab treatment within 2 weeks of CMV‐CTL infusion (HR 1.87, 95% CI 1.06–3.81, p = .031) were independent predictors of poor antiviral efficacy of CMV‐CTL therapy. Our data showed that adoptive therapy with CMV‐CTLs is a safe and effective treatment for CMV infection after haplo‐SCT. Persistent CMV infection and basiliximab treatment are correlated with poor anti‐CMV efficacy of CMV‐CTL therapy.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
•The topology optimization method is firstly employed for bionic heat sinks.•The performance of the heat sinks are studied by numerically and experimentally.•Different optimization goals for ...temperature uniformity can lead to different results.•The optimal heat sinks is superior to the conventional heat sinks in terms of the performance.•The CFD results agree well with the experimental results.
In this paper, topology optimization method is applied to bionic domain, and in order to improve the thermal performance of heat sinks, two topological heat sinks are obtained under two objectives. One objective is minimize the temperature difference and pressure drop, and another is minimize the average temperature and pressure drop. The topological heat sink designed by topology optimization with the minimum temperature difference and the pressure drop as a goal is named as M2, while that designed with the minimum average temperature and the pressure drop as a goal is called M3. The flow and thermal performance of these two topological flow channel heat sinks are investigated numerically. The results show that for Re = 2056.8, the temperature difference of the topological heat sink M2 is reduced by 57.35% compared to conventional spider web heat sink M1, while that of the topological heat sink M3 is reduced by 10.64% compared to M1. In addition, the thermal resistance of the topological heat sinks are smaller than the conventional spider web heat sink. Through analysis, it can be known that M2 has the best comprehensive heat dissipation capacity. In order to verify the correctness of the numerical simulation, M2 is manufactured, and the heat transfer performance of M2 is investigated experimentally. The experimental results of the optimal heat sink agree well with the calculated results.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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