Cancer cells exhibit several unique metabolic phenotypes that are critical for cell growth and proliferation. Specifically, they overexpress the M2 isoform of the tightly regulated enzyme pyruvate ...kinase (PKM2), which controls glycolytic flux, and are highly dependent on de novo biosynthesis of serine and glycine. Here we describe a new rheostat-like mechanistic relationship between PKM2 activity and serine biosynthesis. We show that serine can bind to and activate human PKM2, and that PKM2 activity in cells is reduced in response to serine deprivation. This reduction in PKM2 activity shifts cells to a fuel-efficient mode in which more pyruvate is diverted to the mitochondria and more glucose-derived carbon is channelled into serine biosynthesis to support cell proliferation.
Organic aerosol (OA) in the atmosphere consists of a multitude of organic species which are either directly emitted or the products of a variety of chemical reactions. This complexity challenges our ...ability to explicitly characterize the chemical composition of these particles. We find that the bulk composition of OA from a variety of environments (laboratory and field) occupies a narrow range in the space of a Van Krevelen diagram (H:C versus O:C), characterized by a slope of ∼−1. The data show that atmospheric aging, involving processes such as volatilization, oxidation, mixing of air masses or condensation of further products, is consistent with movement along this line, producing a more oxidized aerosol. This finding has implications for our understanding of the evolution of atmospheric OA and representation of these processes in models.
Diabet. Med. 29, 937–944 (2012)
Aims The Michigan Neuropathy Screening Instrument (MNSI) is used to assess distal symmetrical peripheral neuropathy in diabetes. It includes two separate assessments: ...a 15‐item self‐administered questionnaire and a lower extremity examination that includes inspection and assessment of vibratory sensation and ankle reflexes. The purpose of this study was to evaluate the performance of the MNSI in detecting distal symmetrical peripheral neuropathy in patients with Type 1 diabetes and to develop new scoring algorithms.
Methods The MNSI was performed by trained personnel at each of the 28 Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications clinical sites. Neurologic examinations and nerve conduction studies were performed during the same year. Confirmed clinical neuropathy was defined by symptoms and signs of distal symmetrical peripheral neuropathy based on the examination of a neurologist and abnormal nerve conduction findings in ≥ 2 anatomically distinct nerves among the sural, peroneal and median nerves.
Results We studied 1184 subjects with Type 1 diabetes. Mean age was 47 years and duration of diabetes was 26 years. Thirty per cent of participants had confirmed clinical neuropathy, 18% had ≥ 4 and 5% had ≥ 7 abnormal responses on the MNSI questionnaire, and 33% had abnormal scores (≥ 2.5) on the MNSI examination. New scoring algorithms were developed and cut points defined to improve the performance of the MNSI questionnaire, examination and the combination of the two.
Conclusions Altering the cut point to define an abnormal test from ≥ 7 abnormal to ≥ 4 abnormal items improves the performance of the MNSI questionnaire. The MNSI is a simple, non‐invasive and valid measure of distal symmetrical peripheral neuropathy in Type 1 diabetes.
Galaxies are thought to be fed by the continuous accretion of intergalactic gas, but direct observational evidence has been elusive. The accreted gas is expected to orbit about the galaxy's halo, ...delivering not just fuel for star formation but also angular momentum to the galaxy, leading to distinct kinematic signatures. We report observations showing these distinct signatures near a typical distant star-forming galaxy, where the gas is detected using a background quasar passing 26 kiloparsecs from the host. Our observations indicate that gas accretion plays a major role in galaxy growth because the estimated accretion rate is comparable to the star-formation rate.
Ubiquitination controls the stability of most cellular proteins, and its deregulation contributes to human diseases including cancer. Deubiquitinases remove ubiquitin from proteins, and their ...inhibition can induce the degradation of selected proteins, potentially including otherwise 'undruggable' targets. For example, the inhibition of ubiquitin-specific protease 7 (USP7) results in the degradation of the oncogenic E3 ligase MDM2, and leads to re-activation of the tumour suppressor p53 in various cancers. Here we report that two compounds, FT671 and FT827, inhibit USP7 with high affinity and specificity in vitro and within human cells. Co-crystal structures reveal that both compounds target a dynamic pocket near the catalytic centre of the auto-inhibited apo form of USP7, which differs from other USP deubiquitinases. Consistent with USP7 target engagement in cells, FT671 destabilizes USP7 substrates including MDM2, increases levels of p53, and results in the transcription of p53 target genes, induction of the tumour suppressor p21, and inhibition of tumour growth in mice.
Abstract
Background quasars are potentially sensitive probes of galactic outflows provided that one can determine the origin of the absorbing material since both gaseous discs and strong bipolar ...outflows can contribute to the absorption cross-section. Using a dozen quasars passing near spectroscopically identified galaxies at z ∼ 0.1, we find that the azimuthal orientation of the quasar sightlines with strong Mg ii absorption (with ) is bi-modal: about half the Mg ii sightlines are aligned with the major axis and the other half are within α = 30° of the minor axis, suggesting that bipolar outflows can contribute to the Mg ii cross-section. This bi-modality is also present in the instantaneous star formation rates (SFRs) of the hosts. For the sightlines aligned along the minor axis, a simple bi-conical wind model is indeed able to reproduce the observed Mg ii kinematics and the Mg ii dependence with impact parameter b, (). Using our wind model, we can directly extract key wind properties such as the de-projected outflow speed V
out of the cool material traced by Mg ii and the outflow rates . The outflow speeds V
out are found to be 150-300 km s−1, i.e. of the order of the circular velocity, and smaller than the escape velocity by a factor of ∼2. The outflow rates are typically two to three times the instantaneous SFRs. Our results demonstrate how background quasars can be used to measure wind properties with high precision.
The integration of nanophotonics and atomic physics has been a long-sought goal that would open new frontiers for optical physics, including novel quantum transport and many-body phenomena with ...photon-mediated atomic interactions. Reaching this goal requires surmounting diverse challenges in nanofabrication and atomic manipulation. Here we report the development of a novel integrated optical circuit with a photonic crystal capable of both localizing and interfacing atoms with guided photons. Optical bands of a photonic crystal waveguide are aligned with selected atomic transitions. From reflection spectra measured with average atom number N=1.1+/-0.4, we infer that atoms are localized within the waveguide by optical dipole forces. The fraction of single-atom radiative decay into the waveguide is Γ1D/Γ'≃(0.32±0.08), where Γ1D is the rate of emission into the guided mode and Γ' is the decay rate into all other channels. Γ1D/Γ' is unprecedented in all current atom-photon interfaces.
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