Hidden magnetic order in CuNCN

We report a comprehensive experimental and theoretical study of the quasi-one-dimensional quantum magnet CuNCN. Based on magnetization measurements above room temperature as well as muon spin rotation and electron spin resonance measurements, we unequivocally establish the localized Cu+2-based magnetism and the magnetic transition around 70 K, both controversially discussed in the previous literature. Thermodynamic data conform to the uniform-spin-chain model with a nearest-neighbor intrachain coupling of about 2300 K, in remarkable agreement with the microscopic magnetic model based on density functional theory band-structure calculations. Using exact diagonalization and the coupled-cluster method, we derive a collinear antiferromagnetic order with a strongly reduced ordered moment of about 0.4 mu_B, indicating strong quantum fluctuations inherent to this quasi-one-dimensional spin system. We re-analyze the available neutron-scattering data, and conclude that they are not sufficient to resolve or disprove the magnetic order in CuNCN. By contrast, spectroscopic techniques indeed show signatures of long-range magnetic order below 70 K, yet with a rather broad distribution of internal field probed by implanted muons. We contemplate the possible structural origin of this effect and emphasize peculiar features of the microstructure studied with synchrotron powder x-ray diffraction.Comment: 17 pages, 17 figures, 1 tabl

Mitotic CDK Promotes Replisome Disassembly, Fork Breakage, and Complex DNA Rearrangements

DNA replication errors generate complex chromosomal rearrangements and thereby contribute to tumorigenesis and other human diseases. One mechanism that triggers these errors is mitotic entry before the completion of DNA replication. To address how mitosis might affect DNA replication, we used Xenopus egg extracts. When mitotic CDK (Cyclin B1-CDK1) is used to drive interphase egg extracts into a mitotic state, the replicative CMG (CDC45/MCM2-7/GINS) helicase undergoes ubiquitylation on its MCM7 subunit, dependent on the E3 ubiquitin ligase TRAIP. Whether replisomes have stalled or undergone termination, CMG ubiquitylation is followed by its extraction from chromatin by the CDC48/p97 ATPase. TRAIP-dependent CMG unloading during mitosis is also seen in C. elegans early embryos. At stalled forks, CMG removal results in fork breakage and end joining events involving deletions and templated insertions. Our results identify a mitotic pathway of global replisome disassembly that can trigger replication fork collapse and DNA rearrangements. Mitotic entry before completion of DNA replication causes genome instability via an unknown mechanism. Using Xenopus egg extracts, Deng et al. find that mitotic cyclin-dependent kinase triggers replication fork breakage and DNA rearrangements. The mechanism requires TRAIP-dependent ubiquitylation of the replicative helicase followed by p97 ATPase-dependent helicase removal from chromatin.</p

(18)F-FDG PET image biomarkers improve prediction of late radiation-induced xerostomia

BACKGROUND AND PURPOSE: Current prediction of radiation-induced xerostomia 12months after radiotherapy (Xer12m) is based on mean parotid gland dose and baseline xerostomia (Xerbaseline) scores. The hypothesis of this study was that prediction of Xer12m is improved with patient-specific characteristics extracted from (18)F-FDG PET images, quantified in PET image biomarkers (PET-IBMs). PATIENTS AND METHODS: Intensity and textural PET-IBMs of the parotid gland were collected from pre-treatment (18)F-FDG PET images of 161 head and neck cancer patients. Patient-rated toxicity was prospectively collected. Multivariable logistic regression models resulting from step-wise forward selection and Lasso regularisation were internally validated by bootstrapping. The reference model with parotid gland dose and Xerbaseline was compared with the resulting PET-IBM models. RESULTS: High values of the intensity PET-IBM (90th percentile (P90)) and textural PET-IBM (Long Run High Grey-level Emphasis 3 (LRHG3E)) were significantly associated with lower risk of Xer12m. Both PET-IBMs significantly added in the prediction of Xer12m to the reference model. The AUC increased from 0.73 (0.65-0.81) (reference model) to 0.77 (0.70-0.84) (P90) and 0.77 (0.69-0.84) (LRHG3E). CONCLUSION: Prediction of Xer12m was significantly improved with pre-treatment PET-IBMs, indicating that high metabolic parotid gland activity is associated with lower risk of developing late xerostomia. This study highlights the potential of incorporating patient-specific PET-derived functional characteristics into NTCP model development

The Xenopus Xmus101 protein is required for the recruitment of Cdc45 to origins of DNA replication

The initiation of eukaryotic DNA replication involves origin recruitment and activation of the MCM2-7 complex, the putative replicative helicase. Mini-chromosome maintenance (MCM)2-7 recruitment to origins in G1 requires origin recognition complex (ORC), Cdt1, and Cdc6, and activation at G1/S requires MCM10 and the protein kinases Cdc7 and S-Cdk, which together recruit Cdc45, a putative MCM2-7 cofactor required for origin unwinding. Here, we show that the Xenopus BRCA1 COOH terminus repeat–containing Xmus101 protein is required for loading of Cdc45 onto the origin. Xmus101 chromatin association is dependent on ORC, and independent of S-Cdk and MCM2-7. These results define a new factor that is required for Cdc45 loading. Additionally, these findings indicate that the initiation complex assembly pathway bifurcates early, after ORC association with the origin, and that two parallel pathways, one controlled by MCM2-7, and the other by Xmus101, cooperate to load Cdc45 onto the origin

Impact of Th1 CD4 Follicular Helper T Cell Skewing on Antibody Responses to an HIV-1 Vaccine in Rhesus Macaques.

Generating durable humoral immunity through vaccination depends upon effective interactions of follicular helper T (Tfh) cells with germinal center (GC) B cells. Th1 polarization of Tfh cells is an important process shaping the success of Tfh-GC B cell interactions by influencing costimulatory and cytokine-dependent Tfh help to B cells. However, the question remains as to whether adjuvant-dependent modulation of Tfh cells enhances HIV-1 vaccine-induced antienvelope (anti-Env) antibody responses. We investigated whether an HIV-1 vaccine platform designed to increase the number of Th1-polarized Tfh cells enhances the magnitude and quality of anti-Env antibodies. Utilizing a novel interferon-induced protein 10 (IP-10)-adjuvanted HIV-1 DNA prime followed by a monophosphoryl lipid A and QS-21 (MPLA+QS-21)-adjuvanted Env protein boost (DIP-10 PALFQ) in macaques, we observed higher anti-Env serum IgG titers with greater cross-clade reactivity, specificity for V1V2, and effector functions than in macaques primed with DNA lacking IP-10 and boosted with MPLA-plus-alum-adjuvanted Env protein (DPALFA) The DIP-10 PALFQ vaccine regimen elicited higher anti-Env IgG1 and lower IgG4 antibody levels in serum, showing for the first time that adjuvants can dramatically impact the IgG subclass profile in macaques. The DIP-10 PALFQ regimen also increased vaginal and rectal IgA antibodies to a greater extent. Within lymph nodes, we observed augmented GC B cell responses and the promotion of Th1 gene expression profiles in GC Tfh cells. The frequency of GC Tfh cells correlated with both the magnitude and avidity of anti-Env serum IgG. Together, these data suggest that adjuvant-induced stimulation of Th1-Tfh cells is an effective strategy for enhancing the magnitude and quality of anti-Env antibody responses.IMPORTANCE The results of the RV144 trial demonstrated that vaccination could prevent HIV transmission in humans and that longevity of anti-Env antibodies may be key to this protection. Efforts to improve upon the prime-boost vaccine regimen used in RV144 have indicated that booster immunizations can increase serum anti-Env antibody titers but only transiently. Poor antibody durability hampers efforts to develop an effective HIV-1 vaccine. This study was designed to identify the specific elements involved in the immunological mechanism necessary to produce robust HIV-1-specific antibodies in rhesus macaques. By clearly defining immune-mediated pathways that improve the magnitude and functionality of the anti-HIV-1 antibody response, we will have the foundation necessary for the rational development of an HIV-1 vaccine

A massive proto-cluster of galaxies at a redshift of z {\approx} 5.3

Massive clusters of galaxies have been found as early as 3.9 Billion years (z=1.62) after the Big Bang containing stars that formed at even earlier epochs. Cosmological simulations using the current cold dark matter paradigm predict these systems should descend from "proto-clusters" - early over-densities of massive galaxies that merge hierarchically to form a cluster. These proto-cluster regions themselves are built-up hierarchically and so are expected to contain extremely massive galaxies which can be observed as luminous quasars and starbursts. However, observational evidence for this scenario is sparse due to the fact that high-redshift proto-clusters are rare and difficult to observe. Here we report a proto-cluster region 1 billion years (z=5.3) after the Big Bang. This cluster of massive galaxies extends over >13 Mega-parsecs, contains a luminous quasar as well as a system rich in molecular gas. These massive galaxies place a lower limit of >4x10^11 solar masses of dark and luminous matter in this region consistent with that expected from cosmological simulations for the earliest galaxy clusters.Comment: Accepted to Nature, 16 Pages, 6 figure

TRAIP is a master regulator of DNA interstrand crosslink repair

Cells often use multiple pathways to repair the same DNA lesion, and the choice of pathway has substantial implications for the fidelity of genome maintenance. DNA interstrand crosslinks covalently link the two strands of DNA, and thereby block replication and transcription; the cytotoxicity of these crosslinks is exploited for chemotherapy. In Xenopus egg extracts, the collision of replication forks with interstrand crosslinks initiates two distinct repair pathways. NEIL3 glycosylase can cleave the crosslink; however, if this fails, Fanconi anaemia proteins incise the phosphodiester backbone that surrounds the interstrand crosslink, generating a double-strand-break intermediate that is repaired by homologous recombination. It is not known how the simpler NEIL3 pathway is prioritized over the Fanconi anaemia pathway, which can cause genomic rearrangements. Here we show that the E3 ubiquitin ligase TRAIP is required for both pathways. When two replisomes converge at an interstrand crosslink, TRAIP ubiquitylates the replicative DNA helicase CMG (the complex of CDC45, MCM2–7 and GINS). Short ubiquitin chains recruit NEIL3 through direct binding, whereas longer chains are required for the unloading of CMG by the p97 ATPase, which enables the Fanconi anaemia pathway. Thus, TRAIP controls the choice between the two known pathways of replication-coupled interstrand-crosslink repair. These results, together with our other recent findings establish TRAIP as a master regulator of CMG unloading and the response of the replisome to obstacles

Pre-treatment radiomic features predict individual lymph node failure for head and neck cancer patients

Background and purpose: To develop and validate a pre-treatment radiomics-based prediction model to identify pathological lymph nodes (pLNs) at risk of failures after definitive radiotherapy in head and neck squamous cell carcinoma patients. Materials and methods: Training and validation cohorts consisted of 165 patients with 558 pLNs and 112 patients with 467 pLNs, respectively. All patients were primarily treated with definitive radiotherapy, with or without systemic treatment. The endpoint was the cumulative incidence of nodal failure. For each pLN, 82 pre-treatment CT radiomic features and 7 clinical features were included in the Cox proportional-hazard analysis. Results: There were 68 and 23 nodal failures in the training and validation cohorts, respectively. Multivariable analysis revealed three clinical features (T-stage, gender and WHO Performance-status) and two radiomic features (Least-axis-length representing nodal size and gray level co-occurrence matrix based - Correlation representing nodal heterogeneity) as independent prognostic factors. The model showed good discrimination with a c-index of 0.80 (0.69–0.91) in the validation cohort, significantly better than models based on clinical features (p < 0.001) or radiomics (p = 0.003) alone. High- and low-risk groups were defined by using thresholds of estimated nodal failure risks at 2-year of 60% and 10%, resulting in positive and negative predictive values of 94.4% and 98.7%, respectively. Conclusion: A pre-treatment prediction model was developed and validated, integrating the quantitative radiomic features of individual lymph nodes with generally used clinical features. Using this prediction model, lymph nodes with a high failure risk can be identified prior to treatment, which might be used to select patients for intensified treatment strategies targeted on individual lymph nodes

Ceramide Analog [\u3csup\u3e18\u3c/sup\u3eF]F-HPA-12 Detects Sphingolipid Disbalance in the Brain of Alzheimer’s Disease Transgenic Mice by Functioning as a Metabolic Probe

The metabolism of ceramides is deregulated in the brain of Alzheimer’s disease (AD) patients and is associated with apolipoprotein (APO) APOE4 and amyloid-β pathology. However, how the ceramide metabolism changes over time in AD, in vivo, remains unknown. Distribution and metabolism of [18F]F-HPA-12, a radio-fluorinated version of the ceramide analog N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl) dodecanamide, was investigated in the brain of AD transgenic mouse models (FAD) on an APOE4 or APOE3 genetic background, by positron emission tomography and by gamma counter. We found that FAD mice displayed a higher uptake of [18F]F-HPA-12 in the brain, independently from the APOE4 or APOE3 genetic background. FAD mice could be distinguished from littermate control animals with a sensitivity of 85.7% and a specificity of 87.5%, by gamma counter measurements. Metabolic analysis of [18F]F-HPA-12 in the brain suggested that the tracer is degraded less efficiently in the FAD mice. Furthermore, the radioactive signal registered in the hippocampus correlated with an increase of Cer d18:1/20:2 levels measured in the same brain region by mass spectrometry. Our data gives additional proof that ceramide metabolism is different in FAD mice compared to controls. Ceramide analogs like HPA-12 may function as metabolic probes to study ceramide disbalance in the brain