Pickettcarstens2249

In haemoglobin the change from the low-spin (LS) hexacoordinated haem to the high spin (HS, S = 2) pentacoordinated domed deoxy-myoglobin (deoxyMb) form upon ligand detachment from the haem and the reverse process upon ligand binding are what ultimately drives the respiratory function. Here we probe them in the case of Myoglobin-NO (MbNO) using element- and spin-sensitive femtosecond Fe Kα and Kβ X-ray emission spectroscopy at an X-ray free-electron laser (FEL). We find that the change from the LS (S = 1/2) MbNO to the HS haem occurs in ~800 fs, and that it proceeds via an intermediate (S = 1) spin state. We also show that upon NO recombination, the return to the planar MbNO ground state is an electronic relaxation from HS to LS taking place in ~30 ps. Thus, the entire ligand dissociation-recombination cycle in MbNO is a spin cross-over followed by a reverse spin cross-over process.The folate-coupled metabolic enzyme MTHFD2 (the mitochondrial methylenetetrahydrofolate dehydrogenase/cyclohydrolase) confers redox homeostasis and drives cancer cell proliferation and migration. Here, we show that MTHFD2 is hyperacetylated and lysine 88 is the critical acetylated site. SIRT3, the major deacetylase in mitochondria, is responsible for MTHFD2 deacetylation. Interestingly, chemotherapeutic agent cisplatin inhibits expression of SIRT3 to induce acetylation of MTHFD2 in colorectal cancer cells. Cisplatin-induced acetylated K88 MTHFD2 is sufficient to inhibit its enzymatic activity and downregulate NADPH levels in colorectal cancer cells. Ac-K88-MTHFD2 is significantly decreased in human colorectal cancer samples and is inversely correlated with the upregulated expression of SIRT3. Our findings reveal an unknown regulation axis of cisplatin-SIRT3-MTHFD2 in redox homeostasis and suggest a potential therapeutic strategy for cancer treatments by targeting MTHFD2.Alcoholic liver disease (ALD) is a chronic alcohol-induced disorder of the liver for which there are few effective therapies for severe forms of ALD and for those who do not achieve alcohol abstinence. In this study, we used a systematic drug-repositioning bioinformatics approach querying a large compendium of gene-expression profiles to identify candidate U.S. Food and Drug Administration (FDA)-approved drugs to treat ALD. One of the top compounds predicted to be therapeutic for ALD by our approach was dimethyl fumarate (DMF), an nuclear factor erythroid 2-related factor 2 (NRF2) inducer. We experimentally validated DMF in liver cells and in vivo. Our work demonstrates that DMF is able to significantly upregulate the NRF2 protein level, increase NRF2 phosphorylation, and promote NRF2 nuclear localization in liver cells. DMF also reduced the reactive oxygen species (ROS) level, lipid peroxidation, and ferroptosis. Furthermore, DMF treatment could prevent ethanol-induced liver injury in ALD mice. Our results provide evidence that DMF might serve as a therapeutic option for ALD in humans, and support the use of computational repositioning to discover therapeutic options for ALD.Brain injury causes serious motor, sensory, and cognitive disabilities. Accumulating evidence has demonstrated that histone deacetylase (HDAC) inhibitors exert neuroprotective effects against various insults to the central nervous system (CNS). In this study, we investigated the effects of the HDAC inhibition on the expression of brain-derived neurotrophic factor (BDNF) and functional recovery after traumatic brain injury (TBI) in mice. Administration of class I HDAC inhibitor increased the number of synaptic boutons in rewiring corticospinal fibers and improved the recovery of motor functions after TBI. Immunohistochemistry results showed that HDAC2 is mainly expressed in the neurons of the mouse spinal cord under normal conditions. After TBI, HDAC2 expression was increased in the spinal cord after 35 days, whereas BDNF expression was decreased after 42 days. Administration of CI-994 increased BDNF expression after TBI. Knockdown of HDAC2 elevated H4K5ac enrichment at the BDNF promoter, which was decreased following TBI. Together, our findings suggest that HDAC inhibition increases expression of neurotrophic factors, and promote neuronal rewiring and functional recovery following TBI.Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. LncRNA small nucleolar RNA host gene 14 (SNHG14) functions as an oncogene in a variety of cancers. However, the role of SNHG14 in HCC remains elusive. The aim of this study is to unravel the functional role and regulatory mechanism of SNHG14 in HCC. A cohort of 40 HCC tumor tissues and paired adjacent normal tissues were collected. Histopathological changes were analyzed by hematoxylin and eosin and immunohistochemistry. qRT-PCR and western blotting were performed to determine the levels of SNHG14, PABPC1, and PTEN signaling molecules. CCK-8, immunofluorescence, and colony formation assays were conducted to monitor cell proliferation. Wound healing and tube formation assays were employed to determine cell migration and angiogenesis. ChIP assay was performed to investigate the enrichment of H3K27 acetylation in PABPC1 promoter. Xenograft mice model was constructed to further verify the SNHG14/PABPC1 axis in vivo. SNHG14 was highly expressed in HCC tissues and cells, which promoted cell proliferation, migration, and angiogenesis in Hep3B and HepG2 cells. PABPC1 functioned as a downstream effector of SNHG14. SNHG14 dramatically induced upregulation of PABPC1 via H3K27 acetylation. In addition, SNHG14/PABPC1 promoted cell proliferation and angiogenesis via PTEN signaling pathway in vitro and in vivo. SNHG14 promoted cell proliferation and angiogenesis via upregulating PABPC1 through H3K27 acetylation and modulating PTEN signaling in the tumorigenesis of HCC.Charge acceleration during an intense light field application to solids attracts much attention as elementary processes in high-harmonic generation and photoelectron emission. For manipulating such attosecond dynamics of charge, carrier-envelope-phase (CEP relative phase between carrier oscillation of light field and its envelope function) control has been employed in insulators, nanometal and graphene. In superconducting materials, collective control of charge motion is expected because of its strongly coherent nature of quasi-particles. Here we report that, in a layered organic superconductor, a non-linear petahertz current driven by a single-cycle 6 femtosecond near infrared field shows up as second harmonic generation (SHG), which is in contrast to the common belief that even harmonics are forbidden in the centrosymmetric system. The SHG represents a CEP sensitive nature and an enhancement near the superconducting temperature. The result and its quantum many-body analysis indicate that a polarized current is induced by non-linear acceleration of charge, which is amplified by superconducting fluctuations. This will lead to petahertz functions of superconductors and of strongly correlated systems.The systemic decline in autophagic activity with age impairs homeostasis in several tissues, leading to age-related diseases. Chloroquine A mechanistic understanding of adipocyte dysfunction with age could help to prevent age-related metabolic disorders, but the role of autophagy in aged adipocytes remains unclear. Here we show that, in contrast to other tissues, aged adipocytes upregulate autophagy due to a decline in the levels of Rubicon, a negative regulator of autophagy. Rubicon knockout in adipocytes causes fat atrophy and hepatic lipid accumulation due to reductions in the expression of adipogenic genes, which can be recovered by activation of PPARγ. SRC-1 and TIF2, coactivators of PPARγ, are degraded by autophagy in a manner that depends on their binding to GABARAP family proteins, and are significantly downregulated in Rubicon-ablated or aged adipocytes. Hence, we propose that age-dependent decline in adipose Rubicon exacerbates metabolic disorders by promoting excess autophagic degradation of SRC-1 and TIF2.Semiconductor spin qubits have recently seen major advances in coherence time and control fidelities, leading to a single-qubit performance that is on par with other leading qubit platforms. Most of this progress is based on microwave control of single spins in devices made of isotopically purified silicon. For controlling spins, the exchange interaction is an additional key ingredient which poses new challenges for high-fidelity control. Here, we demonstrate exchange-based single-qubit gates of two-electron spin qubits in GaAs double quantum dots. Using careful pulse optimization and closed-loop tuning, we achieve a randomized benchmarking fidelity of (99.50±0.04)% and a leakage rate of 0.13% out of the computational subspace. These results open new perspectives for microwave-free control of singlet-triplet qubits in GaAs and other materials.Complex I is the first and the largest enzyme of respiratory chains in bacteria and mitochondria. The mechanism which couples spatially separated transfer of electrons to proton translocation in complex I is not known. Here we report five crystal structures of T. thermophilus enzyme in complex with NADH or quinone-like compounds. We also determined cryo-EM structures of major and minor native states of the complex, differing in the position of the peripheral arm. Crystal structures show that binding of quinone-like compounds (but not of NADH) leads to a related global conformational change, accompanied by local re-arrangements propagating from the quinone site to the nearest proton channel. Normal mode and molecular dynamics analyses indicate that these are likely to represent the first steps in the proton translocation mechanism. Our results suggest that quinone binding and chemistry play a key role in the coupling mechanism of complex I.During cellular reprogramming, the pioneer transcription factor GATA3 binds chromatin, and in a context-dependent manner directs local chromatin remodeling and enhancer formation. Here, we use high-resolution nucleosome mapping in human cells to explore the impact of the position of GATA motifs on the surface of nucleosomes on productive enhancer formation, finding productivity correlates with binding sites located near the nucleosomal dyad axis. Biochemical experiments with model nucleosomes demonstrate sufficiently stable transcription factor-nucleosome interaction to empower cryo-electron microscopy structure determination of the complex at 3.15 Å resolution. The GATA3 zinc fingers efficiently bind their target 5'-GAT-3' sequences in the nucleosome when they are located in solvent accessible, consecutive major grooves without significant changes in nucleosome structure. Analysis of genomic loci bound by GATA3 during reprogramming suggests a correlation of recognition motif sequence and spacing that may distinguish productivity of new enhancer formation.Radiation therapy is an important modality in the treatment of lung cancer, but it can lead to radiation pneumonitis, and eventually radiation fibrosis. To date, only few available drugs can effectively manage radiation-induced pulmonary fibrosis. Lipoxins are endogenous molecules exhibit anti-inflammatory and pro-resolving effects. These molecules play a vital role in reducing excessive tissue injury and chronic inflammation; however, their effects on radiation-induced lung injury (RILI) are unknown. In this study, we investigated the effects of lipoxin A4 (LXA4) on RILI using our specialized small-animal model of RILI following focal-ablative lung irradiation (IR). LXA4 significantly inhibited immune-cell recruitment and reduced IR-induced expression of pro-inflammatory cytokines and fibrotic proteins in the lung lesion sites. In addition, micro-CT revealed that LXA4 reduced IR-induced increases in lung consolidation volume. The flexiVentTM assays showed that LXA4 significantly reversed IR-induced lung function damage.