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Mitochondrial matrix peptidase CLPP is crucial during cell stress. Its loss causes Perrault syndrome type 3 (PRLTS3) with infertility, neurodegeneration and growth deficit. Its target proteins are disaggregated by CLPX, which also regulates heme biosynthesis via unfolding ALAS enzyme, providing access of pyridoxal-5’-phosphate (PLP). Despite efforts in diverse organisms with multiple techniques, CLPXP substrates remain controversial. Here, avoiding recombinant overexpression, we employed complexomics in mitochondria from three mouse tissues to identify endogenous targets. CLPP absence caused accumulation and dispersion of CLPX-VWA8 as AAA+ unfoldases, and of PLPBP. Similar changes and CLPX-VWA8 comigration were evident for mitoribosomal central protuberance clusters, translation factors like GFM1-HARS2, RNA granule components LRPPRC-SLIRP, and enzymes OAT-ALDH18A1. Mitochondrially translated proteins in testis showed reductions to <30% for MTCO1-3, misassembly of complex-IV supercomplex, and accumulated metal-binding assembly factors COX15-SFXN4. Indeed, heavy metal levels were increased for iron, molybdenum, cobalt and manganese. RT-qPCR showed compensatory downregulation only for Clpx mRNA, most accumulated proteins appeared transcriptionally upregulated. Immunoblots validated VWA8, MRPL38, MRPL18, GFM1 and OAT accumulation. Coimmunoprecipitation confirmed CLPX binding to MRPL38, GFM1 and OAT, so excess CLPX and PLP may affect their activity. Our data elucidate mechanistically the mitochondrial translation fidelity deficits, which underlie progressive hearing impairment in PRLTS3.
Viruses that carry a positive-sense, single-stranded (+ssRNA) RNA translate their genomes soon after entering the host cell to produce viral proteins, with the exception of retroviruses. A distinguishing feature of retroviruses is reverse transcription, where the +ssRNA genome serves as a template to synthesize a double-stranded DNA copy that subsequently integrates into the host genome. As retroviral RNAs are produced by the host cell transcriptional machinery and are largely indistinguishable from cellular mRNAs, we investigated the potential of incoming retroviral genomes to directly express proteins. Here we show through multiple, complementary methods that retroviral genomes are translated after entry. Our findings challenge the notion that retroviruses require reverse transcription to produce viral proteins. Synthesis of retroviral proteins in the absence of productive infection has significant implications for basic retrovirology, immune responses and gene therapy applications.
Viruses that carry a positive-sense, single-stranded RNA translate their genomes after entering the host cell to produce viral proteins, with the exception of retroviruses. A distinguishing feature of retroviruses is reverse transcription, where the ssRNA genome serves as a template to synthesize a double-stranded DNA copy that subsequently integrates into the host genome. As retroviral RNAs are produced by the host transcriptional machinery and are largely indistinguishable from cellular mRNAs, we investigated the potential of incoming retroviral genomes to express proteins. Here we show through various biochemical methods that HIV-1 genomes are translated after entry, in case of minimal or full-length genomes, envelopes using different cellular entry pathways and in diverse cell types. Our findings challenge the dogma that retroviruses require reverse transcription to produce viral proteins. Synthesis of retroviral proteins in the absence of productive infection has significant implications for basic retrovirology, immune responses and gene therapy applications.
The total charm-quark production cross section per unit of rapidity dσ(cc)/dy, and the fragmentation fractions of charm quarks to different charm-hadron species f(c → hc), are measured for the first time in p–Pb collisions at √sNN = 5.02 TeV at midrapidity (−0.96 < y < 0.04 in the centre-ofmass frame) using data collected by ALICE at the CERN LHC. The results are obtained based on all the available measurements of prompt production of ground-state charm-hadron species: D0, D+,D+s, and J/ψ mesons, and Λ+cand Ξ0cbaryons. The resulting cross section is dσ(cc)/dy = 219.6±6.3 (stat.)+10.5−11.8(syst.)+7.6−2.9(extr.)±5.4 (BR)±4.6 (lumi.)±19.5 (rapidity shape) +15.0 (Ω0c) mb, which is consistent with a binary scaling of pQCD calculations from pp ollisions. The measured fragmentation fractions are compatible with those measured in pp collisions at √s = 5.02 and 13 TeV, showing an increase in the relative production rates of charm baryons with respect to charm mesons in pp and p–Pb collisions compared with e+e − and e−p collisions. The pT-integrated nuclear modification factor of charm quarks, RpPb(cc) = 0.91±0.04 (stat.) +0.08 −0.09 (syst.) +0.04 −0.03 (extr.)±0.03 (lumi.), is found to be consistent with unity and with theoretical predictions including nuclear modifications of the parton distribution functions.
This work aims to differentiate strangeness produced from hard processes (jet-like) and softer processes (underlying event) by measuring the angular correlation between a high-momentum trigger hadron (h) acting as a jet-proxy and a produced strange hadron (φ(1020) meson). Measuring h–φ correlations at midrapidity in p–Pb collisions at √sNN = 5.02 TeV as a function of event multiplicity provides insight into the microscopic origin of strangeness enhancement in small collision systems. The jet-like and the underlying-event-like strangeness production are investigated as a function of event multiplicity. They are also compared between a lower and higher momentum region. The evolution of the per-trigger yields within the near-side (aligned with the trigger hadron) and away-side (in the opposite direction of the trigger hadron) jet is studied separately, allowing for the characterization of two distinct jet-like production regimes. Furthermore, the h–φ correlations within the underlying event give access to a production regime dominated by soft production processes, which can be compared directly to the in-jet production. Comparisons between h–φ and dihadron correlations show that the observed strangeness enhancement is largely driven by the underlying event, where the φ/h ratio is significantly larger than within the jet regions. As multiplicity increases, the fraction of the total φ(1020) yield coming from jets decreases compared to the underlying event production, leading to high-multiplicity events being dominated by the increased strangeness production from the underlying event
After myocardial infarction in the adult heart the remaining, non-infarcted tissue adapts to compensate the loss of functional tissue. This adaptation requires changes in gene expression networks, which are mostly controlled by transcription regulating proteins. Long non-coding transcripts (lncRNAs) are now recognized for taking part in fine-tuning such gene programs. We identified and characterized the cardiomyocyte specific lncRNA Sweetheart RNA (Swhtr), an approximately 10 kb long transcript divergently expressed from the cardiac core transcription factor coding gene Nkx2-5. We show that Swhtr is dispensable for normal heart development and function, but becomes essential for the tissue adaptation process after myocardial infarction. Re-expressing Swhtr from an exogenous locus rescues the Swhtr null phenotype. Genes depending on Swhtr after cardiac stress are significantly occupied, and therefore most likely regulated by NKX2-5. Our results indicate a synergistic role for Swhtr and the developmentally essential transcription factor NKX2-5 in tissue adaptation after myocardial injury.
Long non-coding RNAs are a very versatile class of molecules that can have important roles in regulating a cells function, including regulating other genes on the transcriptional level. One of these mechanisms is that RNA can directly interact with DNA thereby recruiting additional components such as proteins to these sites via a RNA:dsDNA triplex formation. We genetically deleted the triplex forming sequence (FendrrBox) from the lncRNA Fendrr in mice and find that this FendrrBox is partially required for Fendrr function in vivo. We find that the loss of the triplex forming site in developing lungs causes a dysregulation of gene programs, associated with lung fibrosis. A set of these genes contain a triplex site directly at their promoter and are expressed in fibroblasts. We confirm the formation of RNA:dsDNA formation with target promoters. We find that Fendrr with the Wnt signalling pathway regulates these genes, implicating that Fendrr synergizes with Wnt signalling in lung fibrosis.
Fendrr synergizes with Wnt signalling to regulate fibrosis related genes during lung development
(2021)
Long non-coding RNAs are a very versatile class of molecules that can have important roles in regulating a cells function, including regulating other genes on the transcriptional level. One of these mechanisms is that RNA can directly interact with DNA thereby recruiting additional components such as proteins to these sites via a RNA:dsDNA triplex formation. We genetically deleted the triplex forming sequence (FendrrBox) from the lncRNA Fendrr in mice and find that this FendrrBox is partially required for Fendrr function in vivo. We find that the loss of the triplex forming site in developing lungs causes a dysregulation of gene programs, associated with lung fibrosis. A set of these genes contain a triplex site directly at their promoter and are expressed in fibroblasts. We find that Fendrr with the Wnt signaling pathway regulates these genes, implicating that Fendrr synergizes with Wnt signaling in lung fibrosis.
Cannabis is the most commonly used illicit drug in the world. However due to a changing legal landscape, and rising interest in therapeutic utility, there is an increasing trend in (long-term) use and possibly, cannabis impairment. Importantly, a growing body of evidence suggests regular cannabis users develop tolerance to the impairing, as well as the rewarding, effects of the drug. However, the neuroadaptations that may underlie cannabis tolerance remain unclear. Therefore, this double-blind, randomized, placebo controlled, cross-over study assessed the acute influence of cannabis on brain and behavioral outcomes in two distinct cannabis user groups. Twelve occasional (OUs) and 12 chronic (CUs) cannabis users received acute doses of cannabis (300 μg/kg THC) and placebo, and underwent ultra-high field functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (MRS). In OUs, cannabis induced significant neurometabolic alterations in reward circuitry, namely decrements in functional connectivity and increments in striatal glutamate concentrations, which were associated with increases in subjective high and decreases in performance on a sustained attention task. Such changes were absent in CUs. The finding that cannabis altered circuitry and distorted behavior in OUs, but not CUs, suggests reduced responsiveness of the reward circuitry to cannabis intoxication in chronic users Taken together, the results suggest a pharmacodynamic mechanism for the development of tolerance to cannabis impairment.
The production of K∗(892)± meson resonance is measured at midrapidity (|y|<0.5) in Pb-Pb collisions at sNN−−−√=5.02 TeV using the ALICE detector at the LHC. The resonance is reconstructed via its hadronic decay channel K∗(892)±→K0Sπ±. The transverse momentum distributions are obtained for various centrality intervals in the pT range of 0.4-16 GeV/c. The reported measurements of integrated yields, mean transverse momenta, and particle yield ratios are consistent with previous ALICE measurements for K∗(892)0. The pT-integrated yield ratio 2K∗(892)±/(K++K−) in central Pb-Pb collisions shows a significant suppression (9.3σ) relative to pp collisions. Thermal model calculations overpredict the particle yield ratio. Although both simulations consider the hadronic phase, only HRG-PCE accurately represents the measurements, whereas MUSIC+SMASH tends to overpredict them. These observations, along with the kinetic freeze-out temperatures extracted from the yields of light-flavored hadrons using the HRG-PCE model, indicate a finite hadronic phase lifetime, which increases towards central collisions. The pT-differential yield ratios 2K∗(892)±/(K++K−) and 2K∗(892)±/(π++π−) are suppressed by up to a factor of five at pT<2 GeV/c in central Pb-Pb collisions compared to pp collisions at s√= 5.02 TeV. Both particle ratios and are qualitatively consistent with expectations for rescattering effects in the hadronic phase. The nuclear modification factor shows a smooth evolution with centrality and is below unity at pT>8 GeV/c, consistent with measurements for other light-flavored hadrons. The smallest values are observed in most central collisions, indicating larger energy loss of partons traversing the dense medium.