Sustained alternate-day fasting potentiates doxorubicin cardiotoxicity

Fasting strategies are under active clinical investigation in patients receiving chemotherapy. Prior murine studies suggest that alternate-day fasting may attenuate doxorubicin cardiotoxicity and stimulate nuclear translocation of transcription factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis. In this study, human heart tissue from patients with doxorubicin-induced heart failure demonstrated increased nuclear TFEB protein. In mice treated with doxorubicin, alternate-day fasting or viral TFEB transduction increased mortality and impaired cardiac function. Mice randomized to alternate-day fasting plus doxorubicin exhibited increased TFEB nuclear translocation in the myocardium. When combined with doxorubicin, cardiomyocyte-specific TFEB overexpression provoked cardiac remodeling, while systemic TFEB overexpression increased growth differentiation factor 15 (GDF15) and caused heart failure and death. Cardiomyocyte TFEB knockout attenuated doxorubicin cardiotoxicity, while recombinant GDF15 was sufficient to cause cardiac atrophy. Our studies identify that both sustained alternate-day fasting and a TFEB/GDF15 pathway exacerbate doxorubicin cardiotoxicity

Steatosis drives monocyte-derived macrophage accumulation in human metabolic dysfunction-associated fatty liver disease

BACKGROUND & AIMS: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a common complication of obesity with a hallmark feature of hepatic steatosis. Recent data from animal models of MAFLD have demonstrated substantial changes in macrophage composition in the fatty liver. In humans, the relationship between liver macrophage heterogeneity and liver steatosis is less clear. METHODS: Liver tissue from 21 participants was collected at time of bariatric surgery and analysed using flow cytometry, immunofluorescence, and H&E microscopy. Single-cell RNA sequencing was also conducted on a subset of samples (n = 3). Intrahepatic triglyceride content was assessed via MRI and tissue histology. Mouse models of hepatic steatosis were used to investigate observations made from human liver tissue. RESULTS: We observed variable degrees of liver steatosis with minimal fibrosis in our participants. Single-cell RNA sequencing revealed four macrophage clusters that exist in the human fatty liver encompassing Kupffer cells and monocyte-derived macrophages (MdMs). The genes expressed in these macrophage subsets were similar to those observed in mouse models of MAFLD. Hepatic CD14 CONCLUSIONS: The human liver in MAFLD contains macrophage subsets that align well with those that appear in mouse models of fatty liver disease. Recruited myeloid cells correlate well with the degree of liver steatosis in humans. MdMs appear to participate in lipid uptake during early stages of MALFD. IMPACT AND IMPLICATIONS: Metabolic dysfunction associated fatty liver disease (MAFLD) is extremely common; however, the early inflammatory responses that occur in human disease are not well understood. In this study, we investigated macrophage heterogeneity in human livers during early MAFLD and demonstrated that similar shifts in macrophage subsets occur in human disease that are similar to those seen in preclinical models. These findings are important as they establish a translational link between mouse and human models of disease, which is important for the development and testing of new therapeutic approaches for MAFLD

Search for gravitational waves from low mass compact binary coalescence in LIGO's sixth science run and Virgo's science runs 2 and 3

We report on a search for gravitational waves from coalescing compact binaries using LIGO and Virgo observations between July 7, 2009, and October 20, 2010. We searched for signals from binaries with total mass between 2 and 25M⊙; this includes binary neutron stars, binary black holes, and binaries consisting of a black hole and neutron star. The detectors were sensitive to systems up to 40 Mpc distant for binary neutron stars, and further for higher mass systems. No gravitational-wave signals were detected. We report upper limits on the rate of compact binary coalescence as a function of total mass, including the results from previous LIGO and Virgo observations. The cumulative 90% confidence rate upper limits of the binary coalescence of binary neutron star, neutron star-black hole, and binary black hole systems are 1.3×10−4, 3.1×10−5, and 6.4×10−6  Mpc−3 yr−1, respectively. These upper limits are up to a factor 1.4 lower than previously derived limits. We also report on results from a blind injection challenge. © 2012 The American Physical Societ

Upper limits on a stochastic gravitational-wave background using LIGO and Virgo interferometers at 600-1000 Hz

A stochastic background of gravitational waves is expected to arise from a superposition of many incoherent sources of gravitational waves, of either cosmological or astrophysical origin. This background is a target for the current generation of ground-based detectors. In this article we present the first joint search for a stochastic background using data from the LIGO and Virgo interferometers. In a frequency band of 600–1000 Hz, we obtained a 95% upper limit on the amplitude of ΩGW(f)=Ω3(f/900  Hz)3, of Ω3<0.32, assuming a value of the Hubble parameter of h100=0.71. These new limits are a factor of seven better than the previous best in this frequency band. © 2012 The American Physical Societ

All-sky search for gravitational-wave bursts in the second joint LIGO-Virgo run

We present results from a search for gravitational-wave bursts in the data collected by the LIGO and Virgo detectors between July 7, 2009 and October 20, 2010: data are analyzed when at least two of the three LIGO-Virgo detectors are in coincident operation, with a total observation time of 207 days. The analysis searches for transients of duration ≲1  s over the frequency band 64–5000 Hz, without other assumptions on the signal waveform, polarization, direction or occurrence time. All identified events are consistent with the expected accidental background. We set frequentist upper limits on the rate of gravitational-wave bursts by combining this search with the previous LIGO-Virgo search on the data collected between November 2005 and October 2007. The upper limit on the rate of strong gravitational-wave bursts at the Earth is 1.3 events per year at 90% confidence. We also present upper limits on source rate density per year and Mpc3 for sample populations of standard-candle sources. As in the previous joint run, typical sensitivities of the search in terms of the root-sum-squared strain amplitude for these waveforms lie in the range ∼5×10−22  Hz−1/2 to ∼1×10−20  Hz−1/2. The combination of the two joint runs entails the most sensitive all-sky search for generic gravitational-wave bursts and synthesizes the results achieved by the initial generation of interferometric detectors. © 2012 The American Physical Societ

Search for gravitational waves from compact binary coalescence in LIGO and Virgo data from S5 and VSR1

We report the results of the first search for gravitational waves from compact binary coalescence using data from the Laser Interferometer Gravitational-Wave Observatory and Virgo detectors. Five months of data were collected during the Laser Interferometer Gravitational-Wave Observatory’s S5 and Virgo’s VSR1 science runs. The search focused on signals from binary mergers with a total mass between 2 and 35M⊙. No gravitational waves are identified. The cumulative 90%-confidence upper limits on the rate of compact binary coalescence are calculated for nonspinning binary neutron stars, black hole-neutron star systems, and binary black holes to be 8.7×10−3  yr−1 L10−1, 2.2×10−3  yr−1 L10−1, and 4.4×10−4  yr−1 L10−1, respectively, where L10 is 1010 times the blue solar luminosity. These upper limits are compared with astrophysical expectations. © 2010 The American Physical Societ

Search for gravitational waves from intermediate mass binary black holes

We present the results of a weakly modeled burst search for gravitational waves from mergers of nonspinning intermediate mass black holes in the total mass range 100–450  M⊙ and with the component mass ratios between 1∶1 and 4∶1. The search was conducted on data collected by the LIGO and Virgo detectors between November of 2005 and October of 2007. No plausible signals were observed by the search which constrains the astrophysical rates of the intermediate mass black holes mergers as a function of the component masses. In the most efficiently detected bin centered on 88+88  M⊙, for nonspinning sources, the rate density upper limit is 0.13 per Mpc3 per Myr at the 90% confidence level. © 2012 The American Physical Societ

All-sky search for periodic gravitational waves in the full S5 LIGO data

We report on an all-sky search for periodic gravitational waves in the frequency band 50–800 Hz and with the frequency time derivative in the range of 0 through −6×10−9  Hz/s. Such a signal could be produced by a nearby spinning and slightly nonaxisymmetric isolated neutron star in our Galaxy. After recent improvements in the search program that yielded a 10× increase in computational efficiency, we have searched in two years of data collected during LIGO’s fifth science run and have obtained the most sensitive all-sky upper limits on gravitational-wave strain to date. Near 150 Hz our upper limit on worst-case linearly polarized strain amplitude h0 is 1×10−24, while at the high end of our frequency range we achieve a worst-case upper limit of 3.8×10−24 for all polarizations and sky locations. These results constitute a factor of 2 improvement upon previously published data. A new detection pipeline utilizing a loosely coherent algorithm was able to follow up weaker outliers, increasing the volume of space where signals can be detected by a factor of 10, but has not revealed any gravitational-wave signals. The pipeline has been tested for robustness with respect to deviations from the model of an isolated neutron star, such as caused by a low-mass or long-period binary companion. © 2012 The American Physical Societ

Modeling Neurodegeneration in Zebrafish

The zebrafish, Danio rerio, has been established as an excellent vertebrate model for the study of developmental biology and gene function. It also has proven to be a valuable model to study human diseases. Here, we reviewed recent publications using zebrafish to study the pathology of human neurodegenerative diseases including Parkinson’s, Huntington’s, and Alzheimer’s. These studies indicate that zebrafish genes and their human homologues have conserved functions with respect to the etiology of neurodegenerative diseases. The characteristics of the zebrafish and the experimental approaches to which it is amenable make this species a useful complement to other animal models for the study of pathologic mechanisms of neurodegenerative diseases and for the screening of compounds with therapeutic potential