Cosmological models in which dark matter consists of cold elementary particles predict that the dark halo population should extend to masses many orders of magnitude below those at which galaxies can ...form
. Here we report a cosmological simulation of the formation of present-day haloes over the full range of observed halo masses (20 orders of magnitude) when dark matter is assumed to be in the form of weakly interacting massive particles of mass approximately 100 gigaelectronvolts. The simulation has a full dynamic range of 30 orders of magnitude in mass and resolves the internal structure of hundreds of Earth-mass haloes in as much detail as it does for hundreds of rich galaxy clusters. We find that halo density profiles are universal over the entire mass range and are well described by simple two-parameter fitting formulae
. Halo mass and concentration are tightly related in a way that depends on cosmology and on the nature of the dark matter. For a fixed mass, the concentration is independent of the local environment for haloes less massive than those of typical galaxies. Haloes over the mass range of 10
to 10
solar masses contribute about equally (per logarithmic interval) to the luminosity produced by dark matter annihilation, which we find to be smaller than all previous estimates by factors ranging up to one thousand
.
ABSTRACT
We present a general method to compute the non-linear matter power spectrum for dark energy (DE) and modified gravity scenarios with per cent-level accuracy. By adopting the halo model and ...non-linear perturbation theory, we predict the reaction of a lambda cold dark matter (ΛCDM) matter power spectrum to the physics of an extended cosmological parameter space. By comparing our predictions to N-body simulations we demonstrate that with no-free parameters we can recover the non-linear matter power spectrum for a wide range of different w0–wa DE models to better than 1 per cent accuracy out to k ≈ 1 $h \,{\rm Mpc}^{-1}$. We obtain a similar performance for both DGP and f(R) gravity, with the non-linear matter power spectrum predicted to better than 3 per cent accuracy over the same range of scales. When including direct measurements of the halo mass function from the simulations, this accuracy improves to 1 per cent. With a single suite of standard ΛCDM N-body simulations, our methodology provides a direct route to constrain a wide range of non-standard extensions to the concordance cosmology in the high signal-to-noise non-linear regime.
Steroid hormones are essential for carbohydrate metabolism, stress management, and reproduction and are synthesized from cholesterol in mitochondria of adrenal glands and gonads/ovaries. In acute ...stress or hormonal stimulation, steroidogenic acute regulatory protein (StAR) transports substrate cholesterol into the mitochondria for steroidogenesis by an unknown mechanism. Here, we report for the first time that StAR interacts with voltage-dependent anion channel 2 (VDAC2) at the mitochondria-associated endoplasmic reticulum membrane (MAM) prior to its translocation to the mitochondrial matrix. In the MAM, StAR interacts with mitochondrial proteins Tom22 and VDAC2. However, Tom22 knockdown by siRNA had no effect on pregnenolone synthesis. In the absence of VDAC2, StAR was expressed but not processed into the mitochondria as a mature 30-kDa protein. VDAC2 interacted with StAR via its C-terminal 20 amino acids and N-terminal amino acids 221–229, regulating the mitochondrial processing of StAR into the mature protein. In the absence of VDAC2, StAR could not enter the mitochondria or interact with MAM-associated proteins, and therefore steroidogenesis was inhibited. Furthermore, the N terminus was not essential for StAR activity, and the N-terminal deletion mutant continued to interact with VDAC2. The endoplasmic reticulum-targeting prolactin signal sequence did not affect StAR association with the MAM and thus its mitochondrial targeting. Therefore, VDAC2 controls StAR processing and activity, and MAM is thus a central location for initiating mitochondrial steroidogenesis.
Background: Steroidogenic acute regulatory protein (StAR) fosters cholesterol into the adrenal and gonadal mitochondria to initiate steroidogenesis.
Results: Voltage-dependent anion channel 2 (VDAC2) knockdown ablated pregnenolone synthesis and StAR processing into the mitochondria.
Conclusion: Interaction between StAR and VDAC2 is critical for steroidogenesis.
Significance: VDAC2 is a crucial regulator for initiating steroidogenesis.
Can the most "classical-like" of all quantum states, namely the Schrödinger coherent state of a harmonic oscillator, exhibit nonclassical behavior? We find that for an oscillating object initially in ...a coherent state, merely by observing at various instants which spatial region the object is in, the Leggett-Garg inequality (LGI) can be violated through a genuine negative result measurement, thereby repudiating the everyday notion of macrorealism. This violation thus reveals an unnoticed nonclassicality of the very state which epitomizes classicality within the quantum description. It is found that for any given mass and oscillator frequency, a significant quantum violation of LGI can be obtained by suitably choosing the initial peak momentum of the coherent state wave packet. It thus opens up potentially the simplest way (without coupling with any ancillary quantum system or using nonlinearity) for testing whether various recently engineered and sought after macroscopic oscillators, such as feedback cooled thermal trapped nanocrystals of ∼10^{6}-10^{9} amu mass, are indeed bona fide nonclassical objects.
ABSTRACT
We present observations of ASASSN-19dj, a nearby tidal disruption event (TDE) discovered in the post-starburst galaxy KUG 0810+227 by the All-Sky Automated Survey for Supernovae (ASAS-SN) at ...a distance of d ≃ 98 Mpc. We observed ASASSN-19dj from −21 to 392 d relative to peak ultraviolet (UV)/optical emission using high-cadence, multiwavelength spectroscopy and photometry. From the ASAS-SN g-band data, we determine that the TDE began to brighten on 2019 February 6.8 and for the first 16 d the rise was consistent with a flux ∝t2 power law. ASASSN-19dj peaked in the UV/optical on 2019 March 6.5 (MJD = 58548.5) at a bolometric luminosity of L = (6.2 ± 0.2) × 1044 erg s−1. Initially remaining roughly constant in X-rays and slowly fading in the UV/optical, the X-ray flux increased by over an order of magnitude ∼225 d after peak, resulting from the expansion of the X-ray emitting region. The late-time X-ray emission is well fitted by a blackbody with an effective radius of ∼1 × 1012 cm and a temperature of ∼6 × 105 K. The X-ray hardness ratio becomes softer after brightening and then returns to a harder state as the X-rays fade. Analysis of Catalina Real-Time Transient Survey images reveals a nuclear outburst roughly 14.5 yr earlier with a smooth decline and a luminosity of LV ≥ 1.4 × 1043 erg s−1, although the nature of the flare is unknown. ASASSN-19dj occurred in the most extreme post-starburst galaxy yet to host a TDE, with Lick HδA = 7.67 ± 0.17 Å.
Based on genomic analysis, 50% of high-grade serous ovarian cancers (HGSC) are predicted to have DNA repair defects. Whether this substantial subset of HGSCs actually have functional repair defects ...remains unknown. Here, we devise a platform for functional profiling of DNA repair in short-term patient-derived HGSC organoids. We tested 33 organoid cultures derived from 22 patients with HGSC for defects in homologous recombination (HR) and replication fork protection. Regardless of DNA repair gene mutational status, a functional defect in HR in the organoids correlated with PARP inhibitor sensitivity. A functional defect in replication fork protection correlated with carboplatin and CHK1 and ATR inhibitor sensitivity. Our results indicate that a combination of genomic analysis and functional testing of organoids allows for the identification of targetable DNA damage repair defects. Larger numbers of patient-derived organoids must be analyzed to determine whether these assays can reproducibly predict patient response in the clinic.
Patient-derived ovarian tumor organoids grow rapidly and match the tumors from which they are derived, both genetically and functionally. These organoids can be used for DNA repair profiling and therapeutic sensitivity testing and provide a rapid means of assessing targetable defects in the parent tumor, offering more suitable treatment options.
.
Alterations in DNA damage response (DDR) genes are common in advanced prostate tumors and are associated with unique genomic and clinical features. ATM is a DDR kinase that has a central role in ...coordinating DNA repair and cell-cycle response following DNA damage, and
alterations are present in approximately 5% of advanced prostate tumors. Recently, inhibitors of PARP have demonstrated activity in advanced prostate tumors harboring DDR gene alterations, particularly in tumors with
alterations. However, the role of alterations in DDR genes beyond
in mediating PARP inhibitor sensitivity is poorly understood. To define the role of
loss in prostate tumor DDR function and sensitivity to DDR-directed agents, we created a series of
-deficient preclinical prostate cancer models and tested the impact of
loss on DNA repair function and therapeutic sensitivities.
loss altered DDR signaling, but did not directly impact homologous recombination function. Furthermore,
loss did not significantly impact sensitivity to PARP inhibition but robustly sensitized to inhibitors of the related DDR kinase ATR. These results have important implications for planned and ongoing prostate cancer clinical trials and suggest that patients with tumor
alterations may be more likely to benefit from ATR inhibitor than PARP inhibitor therapy. SIGNIFICANCE: ATM loss occurs in a subset of prostate tumors. This study shows that deleting ATM in prostate cancer models does not significantly increase sensitivity to PARP inhibition but does sensitize to ATR inhibition.
PARP inhibitors are approved for the treatment of high-grade serous ovarian cancers (HGSOC). Therapeutic resistance, resulting from restoration of homologous recombination (HR) repair or replication ...fork stabilization, is a pressing clinical problem. We assessed the activity of prexasertib, a checkpoint kinase 1 (CHK1) inhibitor known to cause replication catastrophe, as monotherapy and in combination with the PARP inhibitor olaparib in preclinical models of HGSOC, including those with acquired PARP inhibitor resistance.
Prexasertib was tested as a single agent or in combination with olaparib in 14 clinically annotated and molecularly characterized luciferized HGSOC patient-derived xenograft (PDX) models and in a panel of ovarian cancer cell lines. The ability of prexasertib to impair HR repair and replication fork stability was also assessed.
Prexasertib monotherapy demonstrated antitumor activity across the 14 PDX models. Thirteen models were resistant to olaparib monotherapy, including 4 carrying
mutation. The combination of olaparib with prexasertib was synergistic and produced significant tumor growth inhibition in an olaparib-resistant model and further augmented the degree and durability of response in the olaparib-sensitive model. HGSOC cell lines, including those with acquired PARP inhibitor resistance, were also sensitive to prexasertib, associated with induction of DNA damage and replication stress. Prexasertib also sensitized these cell lines to PARP inhibition and compromised both HR repair and replication fork stability.
Prexasertib exhibits monotherapy activity in PARP inhibitor-resistant HGSOC PDX and cell line models, reverses restored HR and replication fork stability, and synergizes with PARP inhibition.
Business incubators have emerged worldwide as highly popular methods for promotion of economic development in the industrialised and emerging economies. The present study tries to analyse the role of ...Networking; linkage with university and Facilities on Technology Business Incubation (TBI) performance. The study uses PLS-SEM to design a model collecting data from 60 managers of TBIs in India. Prior studies have taken Networking; Linkage with University and Facilities as independent variables and the mediating role of facilities has not been examined earlier. This motivated the researchers' to examine this. The findings support the role of networking on TBI performance. In case of Linkage with University with facilities as mediating variable the indirect effect is 0.54 and direct effect becomes negative and insignificant highlighting full mediation of facilties. Networking and linkage with University emerge as important predictors to stimulate TBI performance. Implications of the study: The present model can help the TBI managers to execute their functions in an effective and productive way with due focus on linkage with universities through facilities to stimulate TBI performance. The results of positive and significant impact of networking on TBI performance can serve to help TBI managers better serve their clients.
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