Many cancer cells consume large quantities of glutamine to maintain TCA cycle anaplerosis and support cell survival. It was therefore surprising when RNAi screening revealed that suppression of ...citrate synthase (CS), the first TCA cycle enzyme, prevented glutamine-withdrawal-induced apoptosis. CS suppression reduced TCA cycle activity and diverted oxaloacetate, the substrate of CS, into production of the nonessential amino acids aspartate and asparagine. We found that asparagine was necessary and sufficient to suppress glutamine-withdrawal-induced apoptosis without restoring the levels of other nonessential amino acids or TCA cycle intermediates. In complete medium, tumor cells exhibiting high rates of glutamine consumption underwent rapid apoptosis when glutamine-dependent asparagine synthesis was suppressed, and expression of asparagine synthetase was statistically correlated with poor prognosis in human tumors. Coupled with the success of L-asparaginase as a therapy for childhood leukemia, the data suggest that intracellular asparagine is a critical suppressor of apoptosis in many human tumors.
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•Glutamine depletion-induced apoptosis results from asparagine depletion•Reducing citrate synthase levels promotes aspartate/asparagine biosynthesis•Asparagine is sufficient to suppress apoptosis in response to glutamine depletion•Asparagine promotes ATF4-dependent adaptive stress responses
Many cancer cells require glutamine for survival even though it is a nonessential amino acid. Using RNAi screening and subsequent investigation, Zhang et al. identify that asparagine is necessary and sufficient to suppress apoptosis in glutamine-deprived cells. In vivo, asparagine synthetase expression is correlated with poor prognosis in human tumors.
The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first ...meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group.
The study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11–78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10–87 years; 53% male) assessed with standardized methods at 39 centers worldwide.
Compared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen’s d = −0.530/−0.516) and smaller surface area (left/right hemisphere: Cohen’s d = −0.251/−0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset.
The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia.
The existence of massive (10
solar masses) elliptical galaxies by redshift z ≈ 4 (refs 1, 2, 3; when the Universe was 1.5 billion years old) necessitates the presence of galaxies with star-formation ...rates exceeding 100 solar masses per year at z > 6 (corresponding to an age of the Universe of less than 1 billion years). Surveys have discovered hundreds of galaxies at these early cosmic epochs, but their star-formation rates are more than an order of magnitude lower. The only known galaxies with very high star-formation rates at z > 6 are, with one exception, the host galaxies of quasars, but these galaxies also host accreting supermassive (more than 10
solar masses) black holes, which probably affect the properties of the galaxies. Here we report observations of an emission line of singly ionized carbon (C ii at a wavelength of 158 micrometres) in four galaxies at z > 6 that are companions of quasars, with velocity offsets of less than 600 kilometres per second and linear offsets of less than 100 kiloparsecs. The discovery of these four galaxies was serendipitous; they are close to their companion quasars and appear bright in the far-infrared. On the basis of the C ii measurements, we estimate star-formation rates in the companions of more than 100 solar masses per year. These sources are similar to the host galaxies of the quasars in C ii brightness, linewidth and implied dynamical mass, but do not show evidence for accreting supermassive black holes. Similar systems have previously been found at lower redshift. We find such close companions in four out of the twenty-five z > 6 quasars surveyed, a fraction that needs to be accounted for in simulations. If they are representative of the bright end of the C ii luminosity function, then they can account for the population of massive elliptical galaxies at z ≈ 4 in terms of the density of cosmic space.
Soil-bentonite vertical cutoff walls, consisting of a sandy soil mixed with Na-bentonite as backfill, are used extensively as engineered barriers for contaminant containment. However, suitable sandy ...soil and Na-bentonite may not be available at some sites. Consequently, locally available clayey soil and Ca-bentonite may be considered as an alternative backfill. The use of clayey soil/Ca-bentonite backfill may be advantageous to achieve relatively low hydraulic conductivity, which has equivalent performance as that of conventional sandy soil/Na-bentonite backfills. However, studies on the compressibility and hydraulic conductivity of these clayey soil-bentonite backfills are very limited. This paper presents a comprehensive laboratory investigation on the compressibility and hydraulic conductivity of clayey soil/Ca-bentonite backfill through a series of oedometer tests. Kaolin is used as the control clayey soil and it is amended with different contents of Ca-bentonite, 0 (kaolin alone), 5, 10, and 15% (by dry weight basis), to prepare the clayey soil/Ca-bentonite backfills. The initial water contents for the backfills are selected to be 0.75, 1.0, 1.25, and 1.50 times their corresponding liquid limits. The results reveal that the backfills exhibit a noticeable inverse 'S' shaped e-log( sigma ') compression curves attributed to the existence of the remolded yield stress ( sigma ' sub(yr)). The compressibility, in terms of sigma ' sub(yr) and the compression index (C sub(c)), is significantly affected by the initial water content and bentonite content. The void ratio at an effective vertical compression stress of 1 kPa (denoted as e sub(1)) is a useful characteristic parameter to uniquely correlate with C sub(c) for the clayey soil/Ca-bentonite backfills in this study as well as for sandy soil/Na-bentonite and sandy soil-clay backfills that are reported in previous published studies. Unique relationships are also found between the sigma ' sub(yr), initial void ratio (e sub(0)), e sub(1), and the void ratio at liquid limit (e sub(L)). The hydraulic conductivity of the clayey soil/Ca-bentonite backfills is significantly reduced by the bentonite content; generally to less than 10 super(- 9) m/s. An empirical method based on the framework of Kozeny-Carman equation is proposed to predict the hydraulic conductivity of the clayey soil/Ca-bentonite backfills, and the predicted hydraulic conductivity values using these methods are found to fall in the range of 1/3 to 3 times those obtained from the oedometer tests. The proposed method is shown to estimate the hydraulic conductivity for both the clayey soil/Ca-bentonite backfills in this study and the sandy soil-bentonite backfills from published study with reasonable accuracy. Additional research is warranted to prepare the backfills to simulate typical field practice (e.g., use of tap water) and at workable initial water contents (based on the slump testing).
Targeting the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis has demonstrated clinical benefit in recurrent/metastatic head and neck squamous cell carcinoma (R/M ...HNSCC). Combining immunotherapies targeting PD-L1 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) has shown evidence of additive activity in several tumor types. This phase III study evaluated the efficacy of durvalumab (an anti-PD-L1 monoclonal antibody) or durvalumab plus tremelimumab (an anti-CTLA-4 monoclonal antibody) versus standard of care (SoC) in R/M HNSCC patients.
Patients were randomly assigned to receive 1 : 1 : 1 durvalumab (10 mg/kg every 2 weeks q2w), durvalumab plus tremelimumab (durvalumab 20 mg/kg q4w plus tremelimumab 1 mg/kg q4w × 4, then durvalumab 10 mg/kg q2w), or SoC (cetuximab, a taxane, methotrexate, or a fluoropyrimidine). The primary end points were overall survival (OS) for durvalumab versus SoC, and OS for durvalumab plus tremelimumab versus SoC. Secondary end points included progression-free survival (PFS), objective response rate, and duration of response.
Patients were randomly assigned to receive durvalumab (n = 240), durvalumab plus tremelimumab (n = 247), or SoC (n = 249). No statistically significant improvements in OS were observed for durvalumab versus SoC hazard ratio (HR): 0.88; 95% confidence interval (CI): 0.72–1.08; P = 0.20 or durvalumab plus tremelimumab versus SoC (HR: 1.04; 95% CI: 0.85–1.26; P = 0.76). The 12-month survival rates (95% CI) were 37.0% (30.9–43.1), 30.4% (24.7–36.3), and 30.5% (24.7–36.4) for durvalumab, durvalumab plus tremelimumab, and SoC, respectively. Treatment-related adverse events (trAEs) were consistent with previous reports. The most common trAEs (any grade) were hypothyroidism for durvalumab and durvalumab plus tremelimumab (11.4% and 12.2%, respectively), and anemia (17.5%) for SoC. Grade ≥3 trAE rates were 10.1%, 16.3%, and 24.2% for durvalumab, durvalumab plus tremelimumab, and SoC, respectively.
There were no statistically significant differences in OS for durvalumab or durvalumab plus tremelimumab versus SoC. However, higher survival rates at 12 to 24 months and response rates demonstrate clinical activity for durvalumab.
ClinicalTrials.gov: NCT02369874.
•OS was not significantly different for durvalumab or for durvalumab plus tremelimumab compared with SoC.•The study was not designed to assess OS between immunotherapies, but adding tremelimumab did not appear to enhance durvalumab activity.•Failure to meet the primary end point may have been impacted by factors resulting in an unexpectedly long OS for the SoC arm.
Antimicrobial resistance is a global health crisis and few novel antimicrobials have been discovered in recent decades. Natural products, particularly from Streptomyces, are the source of most ...antimicrobials, yet discovery campaigns focusing on Streptomyces from the soil largely rediscover known compounds. Investigation of understudied and symbiotic sources has seen some success, yet no studies have systematically explored microbiomes for antimicrobials. Here we assess the distinct evolutionary lineages of Streptomyces from insect microbiomes as a source of new antimicrobials through large-scale isolations, bioactivity assays, genomics, metabolomics, and in vivo infection models. Insect-associated Streptomyces inhibit antimicrobial-resistant pathogens more than soil Streptomyces. Genomics and metabolomics reveal their diverse biosynthetic capabilities. Further, we describe cyphomycin, a new molecule active against multidrug resistant fungal pathogens. The evolutionary trajectories of Streptomyces from the insect microbiome influence their biosynthetic potential and ability to inhibit resistant pathogens, supporting the promise of this source in augmenting future antimicrobial discovery.
Menthol and other counterstimuli relieve itch, resulting in an antipruritic state that persists for minutes to hours. However, the neural basis for this effect is unclear, and the underlying ...neuromodulatory mechanisms are unknown. Previous studies revealed that Bhlhb5−/− mice, which lack a specific population of spinal inhibitory interneurons (B5-I neurons), develop pathological itch. Here we characterize B5-I neurons and show that they belong to a neurochemically distinct subset. We provide cause-and-effect evidence that B5-I neurons inhibit itch and show that dynorphin, which is released from B5-I neurons, is a key neuromodulator of pruritus. Finally, we show that B5-I neurons are innervated by menthol-, capsaicin-, and mustard oil-responsive sensory neurons and are required for the inhibition of itch by menthol. These findings provide a cellular basis for the inhibition of itch by chemical counterstimuli and suggest that kappa opioids may be a broadly effective therapy for pathological itch.
•Spinal B5-I interneurons function to inhibit itch•B5-I neurons release the kappa opioid dynorphin•Kappa opioid signaling bidirectionally modulates itch within the spinal cord•Spinal B5-I interneurons mediate the inhibition of itch by menthol
Kardon et al. identify a population of spinal interneurons that function to inhibit itch. Release of the kappa opioid dynorphin from these neurons mediates the inhibition of itch by chemical counterstimuli such as menthol, suggesting that kappa opioids may be a broadly effective therapy for pathological itch.
A
bstract
We study tree-level celestial amplitudes in Yang-Mills theory — Mellin transforms of multi-gluon scattering amplitudes that convert them into the correlators of conformal primary fields on ...two-dimensional celestial sphere. By using purely field-theoretical methods, we show that the soft conformal limit of celestial amplitudes, in which one of the primary field operators associated to gauge bosons becomes a dimension one current, is dominated by the contributions of low-energy soft particles. This result confirms conclusions reached by using Yang-Mills theory formulated in curvilinear coordinates, as pioneered by Strominger. By using well-known collinear limits of Yang-Mills amplitudes, we derive the OPE rules for the primary fields and the holomorphic currents arising in the conformally soft limit. The Ward identities following from OPE have the same form as the identities derived by using soft theorems.
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