Through their many and varied metabolic functions, mitochondria power life. Paradoxically, mitochondria also have a central role in apoptotic cell death. Upon induction of mitochondrial apoptosis, ...mitochondrial outer membrane permeabilization (MOMP) usually commits a cell to die. Apoptotic signalling downstream of MOMP involves cytochrome c release from mitochondria and subsequent caspase activation. As such, targeting MOMP in order to manipulate cell death holds tremendous therapeutic potential across different diseases, including neurodegenerative diseases, autoimmune disorders and cancer. In this Review, we discuss new insights into how mitochondria regulate apoptotic cell death. Surprisingly, recent data demonstrate that besides eliciting caspase activation, MOMP engages various pro-inflammatory signalling functions. As we highlight, together with new findings demonstrating cell survival following MOMP, this pro-inflammatory role suggests that mitochondria-derived signalling downstream of pro-apoptotic cues may also have non-lethal functions. Finally, we discuss the importance and roles of mitochondria in other forms of regulated cell death, including necroptosis, ferroptosis and pyroptosis. Collectively, these new findings offer exciting, unexplored opportunities to target mitochondrial regulation of cell death for clinical benefit.
Klebsiella pneumoniae is an opportunistic pathogen that is often difficult to treat due to its multidrug resistance (MDR). We have previously shown that K. pneumoniae strains are able to "adapt" ...(become more resistant) to the widely used bisbiguanide antiseptic chlorhexidine. Here, we investigated the mechanisms responsible for and the phenotypic consequences of chlorhexidine adaptation, with particular reference to antibiotic cross-resistance. In five of six strains, adaptation to chlorhexidine also led to resistance to the last-resort antibiotic colistin. Here, we show that chlorhexidine adaptation is associated with mutations in the two-component regulator phoPQ and a putative Tet repressor gene (smvR) adjacent to the major facilitator superfamily (MFS) efflux pump gene, smvA Upregulation of smvA (10- to 27-fold) was confirmed in smvR mutant strains, and this effect and the associated phenotype were suppressed when a wild-type copy of smvR was introduced on plasmid pACYC. Upregulation of phoPQ (5- to 15-fold) and phoPQ-regulated genes, pmrD (6- to 19-fold) and pmrK (18- to 64-fold), was confirmed in phoPQ mutant strains. In contrast, adaptation of K. pneumoniae to colistin did not result in increased chlorhexidine resistance despite the presence of mutations in phoQ and elevated phoPQ, pmrD, and pmrK transcript levels. Insertion of a plasmid containing phoPQ from chlorhexidine-adapted strains into wild-type K. pneumoniae resulted in elevated expression levels of phoPQ, pmrD, and pmrK and increased resistance to colistin, but not chlorhexidine. The potential risk of colistin resistance emerging in K. pneumoniae as a consequence of exposure to chlorhexidine has important clinical implications for infection prevention procedures.
Poly(ADP‐ribose) polymerases (PARPs) regulate the function of target proteins by modifying them with ADP‐ribose, a large and unique post‐translational modification. Humans express 17 PARPs; however, ...historically, much of the focus has been on PARP1 and its function in DNA damage repair. Recent work has uncovered an amazing diversity of function for these enzymes including the regulation of fundamental physiological processes in the cell and at the organismal level, as well as new roles in regulating cellular stress responses. In this review, we discuss recent advancements in our understanding of this important protein family, and technological developments that have been critical for moving the field forward. Finally, we discuss new directions that we feel are important areas of further scientific exploration.
PARPs modify target proteins with a unique post‐translational modification called ADP‐ribose. Modification of target proteins plays important roles in multiple cellular pathways including differentiation, RNA regulation, protein degradation, and cellular stress responses. Recently, several new PARP functions have been identified that we summarize in this review. Given that most of the PARPs remain unexplored, additional functions are sure to come.
We describe the procedure used to flux calibrate the three-band submillimetre photometer in the Spectral and Photometric Imaging Receiver instrument on the Herschel Space Observatory. This includes ...the equations describing the calibration scheme, a justification for using Neptune as the primary calibration source, a description of the observations and data processing procedures used to derive flux calibration parameters (for converting from voltage to flux density) for every bolometer in each array, an analysis of the error budget in the flux calibration for the individual bolometers and tests of the flux calibration on observations of primary and secondary calibrators. The procedure for deriving the flux calibration parameters is divided into two parts. In the first part, we use observations of astronomical sources in conjunction with the operation of the photometer internal calibration source to derive the unscaled derivatives of the flux calibration curves. To scale the calibration curves in Jy beam−1 V−1, we then use observations of Neptune in which the beam of each bolometer is mapped using a very fine scan pattern. The total instrumental uncertainties in the flux calibration for most individual bolometers is ∼0.5 per cent, although a few bolometers have uncertainties of ∼1-5 per cent because of issues with the Neptune observations. Based on application of the flux calibration parameters to Neptune observations performed using typical scan map observing modes, we determined that measurements from each array as a whole have instrumental uncertainties of 1.5 per cent. This is considerably less than the absolute calibration uncertainty associated with the model of Neptune, which is estimated at 4 per cent.
We present results from an analysis of all data taken by the BICEP2, Keck Array, and BICEP3 CMB polarization experiments up to and including the 2018 observing season. We add additional Keck Array ...observations at 220 GHz and BICEP3 observations at 95 GHz to the previous 95 / 150 / 220 GHz dataset. The Q / U maps now reach depths of 2.8, 2.8, and 8.8 μ KCMB arcmin at 95, 150, and 220 GHz, respectively, over an effective area of ≈ 600 square degrees at 95 GHz and ≈ 400 square degrees at 150 and 220 GHz. The 220 GHz maps now achieve a signal-to-noise ratio on polarized dust emission exceeding that of Planck at 353 GHz. We take auto- and cross-spectra between these maps and publicly available WMAP and Planck maps at frequencies from 23 to 353 GHz and evaluate the joint likelihood of the spectra versus a multicomponent model of lensed Λ CDM + r + dust + synchrotron + noise . The foreground model has seven parameters, and no longer requires a prior on the frequency spectral index of the dust emission taken from measurements on other regions of the sky. This model is an adequate description of the data at the current noise levels. The likelihood analysis yields the constraint r0.05 < 0.036 at 95% confidence. Running maximum likelihood search on simulations we obtain unbiased results and find that σ ( r ) = 0.009 . These are the strongest constraints to date on primordial gravitational waves.
Posttranscriptional regulation of RNA facilitates the fine-tuning of gene expression. It occurs through multiple pathways that include the nuclear processing of mRNA and its precursors, mRNA ...silencing, regulation of mRNA decay, and regulation of translation. Poly(ADP-ribose) polymerases (PARPs), enzymes that modify target proteins with ADP-ribose, play important roles in many of the RNA regulatory pathways through multiple mechanisms. For example, RNA-binding PARPs can target specific transcripts for regulation; ADP-ribosylation of RNA-regulatory proteins can alter their localization, activity, or RNA binding; and noncovalent interactions of RNA-binding proteins with poly(ADP-ribose) can affect their function. In addition to regulating RNA during non-stress conditions, PARPs regulate RNA function during cellular stress conditions that are critical for the proper execution of a stress response. In this review, we summarize the current knowledge regarding PARP-dependent regulation of RNAs, and describe how by modulating RNA processing, translation, and decay PARPs impact multiple processes in the cell.
We report the detection of an ultra-bright fast radio burst (FRB) from a modest, 3.4-day pilot survey with the Australian Square Kilometre Array Pathfinder. The survey was conducted in a wide-field ...fly's-eye configuration using the phased-array-feed technology deployed on the array to instantaneously observe an effective area of 160 deg2, and achieve an exposure totaling 13200 deg2 hr . We constrain the position of FRB 170107 to a region in size (90% containment) and its fluence to be 58 6 Jy ms. The spectrum of the burst shows a sharp cutoff above 1400 MHz, which could be due to either scintillation or an intrinsic feature of the burst. This confirms the existence of an ultra-bright ( Jy ms) population of FRBs.
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