Explore the vast range of titles available.

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.Mitochondria are key executioners of apoptosis. However, it has recently become clear that beyond driving apoptosis, mitochondria also contribute to pro-inflammatory signalling and other types of regulated cell death. These functions are relevant to disease and could be targeted in the treatment of, for example, degenerative disorders, infection and cancer.

Mechanical strain is a powerful tuning knob for excitons, Coulomb-bound electron–hole complexes dominating optical properties of two-dimensional semiconductors. While the strain response of bright free excitons is broadly understood, the behaviour of dark free excitons (long-lived excitations that generally do not couple to light due to spin and momentum conservation) or localized excitons related to defects remains mostly unexplored. Here, we study the strain behaviour of these fragile many-body states on pristine suspended WSe 2 kept at cryogenic temperatures. We find that under the application of strain, dark and localized excitons in monolayer WSe 2 —a prototypical 2D semiconductor—are brought into energetic resonance, forming a new hybrid state that inherits the properties of the constituent species. The characteristics of the hybridized state, including an order-of-magnitude enhanced light/matter coupling, avoided-crossing energy shifts, and strain tunability of many-body interactions, are all supported by first-principles calculations. The hybridized excitons reported here may play a critical role in the operation of single quantum emitters based on WSe 2 . Furthermore, the techniques we developed may be used to fingerprint unidentified excitonic states. Mechanical strain is a powerful tuning knob for excitons in two-dimensional semiconductors. Here, the authors find that under the application of strain, dark and localized excitons in monolayer WSe 2 are brought into energetic resonance, forming a new hybrid state that inherits the properties of the constituent species.

Black hole physics: A new window on the Galactic Centre Using Very Long Baseline Interferometry (VLBI) at the relatively short radio wavelength of 1.3 mm, a new intrinsic size estimate has been obtained for Sagittarius A*, the supermassive black hole candidate at the centre of the Milky Way. The resulting lower limit on the size of Sgr A* is less than the predicted size of the event horizon of the presumed black hole, suggesting that Sgr A* emissions centre not on the black hole itself but on the surrounding accretion flow. VLBI observations of the Galactic Centre at around 1.3 mm, less influenced by interstellar scattering than those made at longer wavelengths, open a new window onto black-hole physics that will become even more sensitive as new VLBI stations are built. The cores of most large galaxies are thought to harbour super massive black holes. Sagittarius A*, the compact source of radio, infrared and x-ray emission at the centre of the Milky Way, is the closest example of this phenomenon. This paper reports observations that set a limit less than the expected apparent size of the event horizon of the presumed black hole, suggesting that the bulk of Sgr A* emission may not be centred on the black hole, but arises in the surrounding accretion flow. The cores of most galaxies are thought to harbour supermassive black holes, which power galactic nuclei by converting the gravitational energy of accreting matter into radiation 1 . Sagittarius A* (Sgr A*), the compact source of radio, infrared and X-ray emission at the centre of the Milky Way, is the closest example of this phenomenon, with an estimated black hole mass that is 4,000,000 times that of the Sun 2 , 3 . A long-standing astronomical goal is to resolve structures in the innermost accretion flow surrounding Sgr A*, where strong gravitational fields will distort the appearance of radiation emitted near the black hole. Radio observations at wavelengths of 3.5 mm and 7 mm have detected intrinsic structure in Sgr A*, but the spatial resolution of observations at these wavelengths is limited by interstellar scattering 4 , 5 , 6 , 7 . Here we report observations at a wavelength of 1.3 mm that set a size of microarcseconds on the intrinsic diameter of Sgr A*. This is less than the expected apparent size of the event horizon of the presumed black hole, suggesting that the bulk of Sgr A* emission may not be centred on the black hole, but arises in the surrounding accretion flow.

Chimeric antigen receptor-modified T cell (CAR-T) immunotherapy has revolutionised blood cancer treatment. Parsing the genetic underpinnings of T cell quality and CAR-T efficacy is challenging. Transcriptomics inform CAR-T state, but the nature of dynamic transcription during activation hinders identification of transiently or minimally expressed genes, such as transcription factors, and over-emphasises effector and metabolism genes. Here we explore whether analyses of transcriptionally repressive and permissive histone methylation marks describe CAR-T cell functional states and therapeutic potential beyond transcriptomic analyses. Histone mark analyses improve identification of differences between naïve, central memory, and effector memory CD8 + T cell subsets of human origin, and CAR-T derived from these subsets. We find important differences between CAR-T manufactured from central memory cells of healthy donors and of patients. By examining CAR-T products from a clinical trial in lymphoma (NCT01865617), we find a novel association between the activity of the transcription factor KLF7 with in vivo CAR-T accumulation in patients and demonstrate that over-expression of KLF7 increases in vitro CAR-T proliferation and IL-2 production.  In conclusion, histone marks provide a rich dataset for identification of functionally relevant genes not apparent by transcriptomics. Transcriptomics is widely used to identify functional and developmental states of T cells and their genetically engineered therapeutic counterparts, such as CAR-T cells. Here authors show that by looking at epigenetic markers in human CD8 + T cells and CAR-T cells, properties and quality of these cells, which are not obvious from gene expression analysis, could be accurately described.

Damaged or superfluous cells are typically eliminated by apoptosis. Although apoptosis is a cell-autonomous process, apoptotic cells communicate with their environment in different ways. Here we describe a mechanism whereby cells under apoptotic stress can promote survival of neighbouring cells. We find that upon apoptotic stress, cells release the growth factor FGF2, leading to MEK-ERK-dependent transcriptional upregulation of pro-survival BCL-2 proteins in a non-cell autonomous manner. This transient upregulation of pro-survival BCL-2 proteins protects neighbouring cells from apoptosis. Accordingly, we find in certain cancer types a correlation between FGF-signalling, BCL-2 expression and worse prognosis. In vivo, upregulation of MCL-1 occurs in an FGF-dependent manner during skin repair, which regulates healing dynamics. Importantly, either co-treatment with FGF-receptor inhibitors or removal of apoptotic stress restores apoptotic sensitivity to cytotoxic therapy and delays wound healing. These data reveal a pathway by which cells under apoptotic stress can increase resistance to cell death in surrounding cells. Beyond mediating cytotoxic drug resistance, this process also provides a potential link between tissue damage and repair. Apoptosis is a cellular process that eliminates damaged or superfluous cells. Here the authors show that cells undergoing apoptotic stresss secrete the growth factor FGF2, which upregulates pro-survival BCL-2 proteins in neighbouring cells, thereby promoting their survival.

Intervalley excitons with electron and hole wavefunctions residing in different valleys determine the long-range transport and dynamics observed in many semiconductors. However, these excitons with vanishing oscillator strength do not directly couple to light and, hence, remain largely unstudied. Here, we develop a simple nanomechanical technique to control the energy hierarchy of valleys via their contrasting response to mechanical strain. We use our technique to discover previously inaccessible intervalley excitons associated with K, Γ, or Q valleys in prototypical 2D semiconductors WSe 2 and WS 2 . We also demonstrate a new brightening mechanism, rendering an otherwise “dark” intervalley exciton visible via strain-controlled hybridization with an intravalley exciton. Moreover, we classify various localized excitons from their distinct strain response and achieve large tuning of their energy. Overall, our valley engineering approach establishes a new way to identify intervalley excitons and control their interactions in a diverse class of 2D systems. The authors develop a nanomechanical straining technique to reveal previously inaccessible intervalley excitons in suspended WSe 2 and WS 2 . They further unveil a mechanism that brightens the dark intervalley excitons through strain-controlled hybridization with intravalley excitons.

This work discusses sensing properties of a long-period grating (LPG) and microcavity in-line Mach–Zehnder interferometer (µIMZI) when both are induced in the same single-mode optical fiber. LPGs were either etched or nanocoated with aluminum oxide (Al2O3) to increase its refractive index (RI) sensitivity up to ≈2000 and 9000 nm/RIU, respectively. The µIMZI was machined using a femtosecond laser as a cylindrical cavity (d = 60 μm) in the center of the LPG. In transmission measurements for various RI in the cavity and around the LPG we observed two effects coming from the two independently working sensors. This dual operation had no significant impact on either of the devices in terms of their functional properties, especially in a lower RI range. Moreover, due to the properties of combined sensors two major effects can be distinguished—sensitivity to the RI of the volume and sensitivity to the RI at the surface. Considering also the negligible temperature sensitivity of the µIMZI, it makes the combination of LPG and µIMZI sensors a promising approach to limit cross-sensitivity or tackle simultaneous measurements of multiple effects with high efficiency and reliability.

In a novel animal model Octodon degus we tested the hypothesis that, in addition to genetic predisposition, early life stress (ELS) contributes to the etiology of attention-deficit hyperactivity disorder-like behavioral symptoms and the associated brain functional deficits. Since previous neurochemical observations revealed that early life stress impairs dopaminergic functions, we predicted that these symptoms can be normalized by treatment with methylphenidate. In line with our hypothesis, the behavioral analysis revealed that repeated ELS induced locomotor hyperactivity and reduced attention towards an emotionally relevant acoustic stimulus. Functional imaging using ( 14 C)-2-fluoro-deoxyglucose-autoradiography revealed that the behavioral symptoms are paralleled by metabolic hypoactivity of prefrontal, mesolimbic and subcortical brain areas. Finally, the pharmacological intervention provided further evidence that the behavioral and metabolic dysfunctions are due to impaired dopaminergic neurotransmission. Elevating dopamine in ELS animals by methylphenidate normalized locomotor hyperactivity and attention-deficit and ameliorated brain metabolic hypoactivity in a dose-dependent manner.

Characteristics and radiative forcing of the aerosol and ozone fields of two configurations of the Centre National de Recherches Météoroglogiques (CNRM) and Cerfacs climate model are analyzed over the historical period (1850–2014), using several Coupled Model Intercomparison Project 6 (CMIP6) simulations. CNRM‐CM6‐1 is the atmosphere‐ocean general circulation model including prescribed aerosols and a linear stratospheric ozone scheme, while the Earth System Model CNRM‐ESM2‐1 has interactive tropospheric aerosols and chemistry of the midtroposphere aloft. The representations of aerosols and ozone in CNRM‐CM6‐1 are issued from simulations of CNRM‐ESM2‐1, and this ensures some comparability of both representations. In particular, present‐day anthropogenic aerosol optical depths are similar (0.018), and their spatial patterns correspond to those of reference data sets such as MACv2 and MACv2‐SP despite a negative bias. Effective radiative forcings (ERFs) have been estimated using 30‐year fixed sea surface temperature simulations (piClim) and several calls to the radiative scheme. Present‐day anthropogenic aerosol ERF, aerosol‐radiation ERF, and aerosol cloud ERF are fully within CMIP5 estimates and, respectively, equal to −1.10, −0.36, and −0.81 W m −2 for CNRM‐CM6‐1 and −0.21, −0.61, and −0.74 W m −2 for CNRM‐ESM2‐1. Additional CMIP6‐type piClim simulations show that these differences are mainly due to the interactivity of the aerosol scheme whose impact is confirmed when assessing the response of both climate model configurations to rising CO 2. Present‐day stratospheric ozone ERF, equal to −0.04 W m −2, is in agreement with that of the CMIP6 ozone. No trend appears in the ozone ERF over the historical period although the evolution of the total column ozone is correctly simulated. Plain Language Summary The manuscript documents the Météo‐France Centre National de Recherches Météorologiques aerosol‐chemistry modeling contributions to the sixth Coupled Model Intercomparison Project that supports the sixth IPCC Assessment Report of climate change. It establishes that their results are suitable for use by the scientific community in the analysis of the sixth Coupled Model Intercomparison Project experiments. The authors provide an evaluation of the model performance in both present‐day and historical (1850–2014) contexts, as well as a detailed analysis of the model calculated effective radiative forcing due to ozone and aerosols. Key Points The representations of aerosol and ozone in the CMIP6 CNRM‐CM6‐1 and CNRM‐ESM2‐1 models is described Present‐day and historical aerosol and ozone distributions are assessed, as well as their effective radiative forcing (ERF) The present‐day anthropogenic aerosol ERF (‐1.10 W m −2 for CNRM‐CM6‐1) is sensitive to the interactivity of aerosols

The multidrug resistant (MDR) opportunistic pathogen Klebsiella pneumoniae has previously been shown to adapt to chlorhexidine by increasing expression of the MFS efflux pump smvA . Here we show that loss of the regulator SmvR, through adaptation to chlorhexidine, results in increased resistance to a number of cationic biocides in K. pneumoniae and other members of the Enterobacteriaceae. Clinical Enterobacteriaceae isolates which lack smvA and smvR also have an increased susceptibility to chlorhexidine. When smvA from Salmonella and K. pneumoniae are expressed in Escherichia coli , which lacks a homologue to SmvAR, resistance to chlorhexidine increased (4-fold) but plasmid carriage of smvA alone was detrimental to the cell. Challenge of K. pneumoniae with chlorhexidine and another cationic biocide, octenidine, resulted in increased expression of smvA (approx. 70 fold). Adaptation to octenidine was achieved through mutating key residues in SmvA (A363V; Y391N) rather than abolishing the function of SmvR, as with chlorhexidine adaptation. Molecular modelling was able to predict that octenidine interacted more strongly with these mutated SmvA forms. These results show that SmvA is a major efflux pump for cationic biocides in several bacterial species and that increased efflux through SmvA can lead to increased chlorhexidine and octenidine tolerance.