Age-associated epigenetic changes are implicated in aging. Notably, age-associated DNA methylation changes comprise a so-called aging "clock", a robust biomarker of aging. However, while genetic, ...dietary and drug interventions can extend lifespan, their impact on the epigenome is uncharacterised. To fill this knowledge gap, we defined age-associated DNA methylation changes at the whole-genome, single-nucleotide level in mouse liver and tested the impact of longevity-promoting interventions, specifically the Ames dwarf Prop1
mutation, calorie restriction and rapamycin.
In wild-type mice fed an unsupplemented ad libitum diet, age-associated hypomethylation was enriched at super-enhancers in highly expressed genes critical for liver function. Genes harbouring hypomethylated enhancers were enriched for genes that change expression with age. Hypermethylation was enriched at CpG islands marked with bivalent activating and repressing histone modifications and resembled hypermethylation in liver cancer. Age-associated methylation changes are suppressed in Ames dwarf and calorie restricted mice and more selectively and less specifically in rapamycin treated mice.
Age-associated hypo- and hypermethylation events occur at distinct regulatory features of the genome. Distinct longevity-promoting interventions, specifically genetic, dietary and drug interventions, suppress some age-associated methylation changes, consistent with the idea that these interventions exert their beneficial effects, in part, by modulation of the epigenome. This study is a foundation to understand the epigenetic contribution to healthy aging and longevity and the molecular basis of the DNA methylation clock.
The Gram-negative bacterial genus
includes several hard-to-treat human pathogens: two biothreat species,
(causing glanders) and
(causing melioidosis), and the
complex (BCC) and
, which cause chronic ...lung infections in persons with cystic fibrosis. All
spp. possess an Ambler class A Pen β-lactamase, which confers resistance to β-lactams. The β-lactam-β-lactamase inhibitor combination sulbactam-durlobactam (SUL-DUR) is in clinical development for the treatment of
infections. In this study, we evaluated SUL-DUR for
and
activity against
clinical isolates. We measured MICs of SUL-DUR against BCC and
(
= 150),
(
= 30), and
(
= 28), studied the kinetics of inhibition of the PenA1 β-lactamase from
and the PenI β-lactamase from
by durlobactam, tested for
induction by SUL-DUR, and evaluated
efficacy in a mouse model of melioidosis. SUL-DUR inhibited growth of 87.3% of the BCC and
strains and 100% of the
and
strains at 4/4 μg/ml. Durlobactam potently inhibited PenA1 and PenI with second-order rate constant for inactivation (
) values of 3.9 × 10
M
s
and 2.6 × 10
M
s
and apparent
(
) of 15 nM and 241 nM, respectively, by forming highly stable covalent complexes. Neither sulbactam, durlobactam, nor SUL-DUR increased production of PenA1. SUL-DUR demonstrated activity
in a murine melioidosis model. Taken together, these data suggest that SUL-DUR may be useful as a treatment for
infections.
The cercal sensory system of cricket mediates the detection, localization, and identification of air current signals generated by predators, mates, and competitors. This mechanosensory system has ...been used extensively for experimental and theoretical studies of sensory coding at the cellular and system levels. It is currently thought that sensory interneurons (INs) in the terminal abdominal ganglion extract information about the direction, velocity, and acceleration of the air currents in the animal's immediate environment and project a coarse-coded representation of those parameters to higher centers. All feature detection is thought to be carried out in higher ganglia by more complex, specialized circuits. We present results that force a substantial revision of current hypotheses. Using multiple extracellular recordings and a special sensory stimulation device, we demonstrate that four well-studied interneurons in this system respond with high sensitivity and selectivity to complex dynamic multidirectional features of air currents that have a spatial scale smaller than the physical dimensions of the cerci. The INs showed much greater sensitivity for these features than for unidirectional bulk-flow stimuli used in previous studies. Thus, in addition to participating in the ensemble encoding of bulk airflow stimulus characteristics, these interneurons are capable of operating as feature detectors for naturalistic stimuli. In this sense, these interneurons are encoding and transmitting information about different aspects of their stimulus environment; they are multiplexing information. Major aspects of the stimulus-response specificity of these interneurons can be understood from the dendritic anatomy and connectivity with the sensory afferent map.
A set of sensory interneurons that have been studied for over 30 years by several different research groups were discovered to have previously unknown encoding characteristics. As well as encoding the direction of bulk airflow with a coarse-coding scheme as shown in previous studies, these interneurons are also responsive to very small-scale, directionally complex air current waveforms. This feature sensitivity can be understood in terms of the cells' complex dendritic branching patterns.
Hypercholesterolemia, the driving force of atherosclerosis, accelerates the expansion and mobilization of hematopoietic stem and progenitor cells (HSPCs). The molecular determinants connecting ...hypercholesterolemia with hematopoiesis are unclear. Here, we report that a somite-derived prohematopoietic cue, AIBP, orchestrates HSPC emergence from the hemogenic endothelium, a type of specialized endothelium manifesting hematopoietic potential. Mechanistically, AIBP-mediated cholesterol efflux activates endothelial Srebp2, the master transcription factor for cholesterol biosynthesis, which in turn transactivates Notch and promotes HSPC emergence. Srebp2 inhibition impairs hypercholesterolemia-induced HSPC expansion. Srebp2 activation and Notch up-regulation are associated with HSPC expansion in hypercholesterolemic human subjects. Genome-wide chromatin immunoprecipitation followed by sequencing (ChIP-seq), RNA sequencing (RNA-seq), and assay for transposase-accessible chromatin using sequencing (ATAC-seq) indicate that Srebp2 transregulates Notch pathway genes required for hematopoiesis. Our studies outline an AIBP-regulated Srebp2-dependent paradigm for HSPC emergence in development and HPSC expansion in atherosclerotic cardiovascular disease.
Despite a myriad of technical advances in medical imaging, as well as the growing need to address the global impact of pulmonary diseases, such as asthma and chronic obstructive pulmonary disease, on ...health and quality of life, it remains challenging to obtain in vivo regional depiction and quantification of the most basic physiological functions of the lung—gas delivery to the airspaces and gas uptake by the lung parenchyma and blood—in a manner suitable for routine application in humans. We report a method based on MRI of hyperpolarized xenon-129 that permits simultaneous observation of the 3D distributions of ventilation (gas delivery) and gas uptake, as well as quantification of regional gas uptake based on the associated ventilation. Subjects with lung disease showed variations in gas uptake that differed from those in ventilation in many regions, suggesting that gas uptake as measured by this technique reflects such features as underlying pathological alterations of lung tissue or of local blood flow. Furthermore, the ratio of the signal associated with gas uptake to that associated with ventilation was substantially altered in subjects with lung disease compared with healthy subjects. This MRI-based method provides a way to quantify relationships among gas delivery, exchange, and transport, and appears to have significant potential to provide more insight into lung disease.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Context:
There has been considerable concern recently in the scientific and lay media regarding the benefits vs. the risks of bisphosphonates for the treatment of osteoporosis. Risks include possible ...associations with osteonecrosis of the jaw (ONJ) and atypical femur fractures. In this perspective, we review the use of bisphosphonates for the treatment of osteoporosis, including an objective assessment of the risks vs. the benefits of these drugs.
Evidence Acquisition:
Authors' knowledge of the field and results of focused literature searches are presented.
Evidence Synthesis:
Bisphosphonates have proven efficacy in the prevention of bone loss and in the reduction of fractures in postmenopausal women and men with established osteoporosis. Although bisphosphonates, at doses used to treat osteoporosis, may be associated with an increased risk of ONJ and atypical femur fractures, many more fractures are prevented by the use of these drugs compared to the relatively low risk of these complications. Although oral bisphosphonates are associated with upper gastrointestinal side effects and iv bisphosphonates with acute phase reactions, the association of bisphosphonate use with esophageal cancer and atrial fibrillation is not well supported by current data.
Conclusions:
Bisphosphonates have been proven to prevent fractures in patients with established osteoporosis or those who are at high risk of fracture. In contrast, the incidence of major complications associated with bisphosphonate use, such as ONJ and atypical femur fractures, is very low.
Context. The Kilo-Degree Survey (KiDS) is an ongoing optical wide-field imaging survey with the OmegaCAM camera at the VLT Survey Telescope. It aims to image 1500 square degrees in four filters ...(ugri). The core science driver is mapping the large-scale matter distribution in the Universe, using weak lensing shear and photometric redshift measurements. Further science cases include galaxy evolution, Milky Way structure, detection of high-redshift clusters, and finding rare sources such as strong lenses and quasars. Aims. Here we present the third public data release and several associated data products, adding further area, homogenized photometric calibration, photometric redshifts and weak lensing shear measurements to the first two releases. Methods. A dedicated pipeline embedded in the Astro-WISE information system is used for the production of the main release. Modifications with respect to earlier releases are described in detail. Photometric redshifts have been derived using both Bayesian template fitting, and machine-learning techniques. For the weak lensing measurements, optimized procedures based on the THELI data reduction and lensfit shear measurement packages are used. Results. In this third data release an additional 292 new survey tiles (≈300 deg2) stacked ugri images are made available, accompanied by weight maps, masks, and source lists. The multi-band catalogue, including homogenized photometry and photometric redshifts, covers the combined DR1, DR2 and DR3 footprint of 440 survey tiles (44 deg2). Limiting magnitudes are typically 24.3, 25.1, 24.9, 23.8 (5σ in a 2′′ aperture) in ugri, respectively, and the typical r-band PSF size is less than 0.7′′. The photometric homogenization scheme ensures accurate colours and an absolute calibration stable to ≈2% for gri and ≈3% in u. Separately released for the combined area of all KiDS releases to date are a weak lensing shear catalogue and photometric redshifts based on two different machine-learning techniques.
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FMFMET, NUK, UL, UM, UPUK
The biological reduction of dinitrogen (N2) to ammonia (NH3) by nitrogenase is an energetically demanding reaction that requires low-potential electrons and ATP; however, pathways used to deliver the ...electrons from central metabolism to the reductants of nitrogenase, ferredoxin or flavodoxin, remain unknown for many diazotrophic microbes. The FixABCX protein complex has been proposed to reduce flavodoxin or ferredoxin using NADH as the electron donor in a process known as electron bifurcation. Herein, the FixABCX complex from Azotobacter vinelandii was purified and demonstrated to catalyze an electron bifurcation reaction: oxidation of NADH (E m = −320 mV) coupled to reduction of flavodoxin semiquinone (E m = −460 mV) and reduction of coenzyme Q (E m = 10 mV). Knocking out fix genes rendered Δrnf A. vinelandii cells unable to fix dinitrogen, confirming that the FixABCX system provides another route for delivery of electrons to nitrogenase. Characterization of the purified FixABCX complex revealed the presence of flavin and iron–sulfur cofactors confirmed by native mass spectrometry, electron paramagnetic resonance spectroscopy, and transient absorption spectroscopy. Transient absorption spectroscopy further established the presence of a short-lived flavin semiquinone radical, suggesting that a thermodynamically unstable flavin semiquinone may participate as an intermediate in the transfer of an electron to flavodoxin. A structural model of FixABCX, generated using chemical cross-linking in conjunction with homology modeling, revealed plausible electron transfer pathways to both high- and low-potential acceptors. Overall, this study informs a mechanism for electron bifurcation, offering insight into a unique method for delivery of low-potential electrons required for energy-intensive biochemical conversions.
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IJS, KILJ, NUK, PNG, UL, UM
Immune checkpoint blockade produces clinical benefit in many patients. However, better biomarkers of response are still needed, and mechanisms of resistance remain incompletely understood. To address ...this, we recently studied a cohort of melanoma patients treated with sequential checkpoint blockade against cytotoxic T lymphocyte antigen-4 (CTLA-4) followed by programmed death receptor-1 (PD-1) and identified immune markers of response and resistance. Building on these studies, we performed deep molecular profiling including T cell receptor sequencing and whole-exome sequencing within the same cohort and demonstrated that a more clonal T cell repertoire was predictive of response to PD-1 but not CTLA-4 blockade. Analysis of CNAs identified a higher burden of copy number loss in nonresponders to CTLA-4 and PD-1 blockade and found that it was associated with decreased expression of genes in immune-related pathways. The effect of mutational load and burden of copy number loss on response was nonredundant, suggesting the potential utility of a combinatorial biomarker to optimize patient care with checkpoint blockade therapy.
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