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The non-essential amino acid cysteine is used within cells for multiple processes that rely on the chemistry of its thiol group. Under physiological conditions, many non-transformed tissues rely on glutathione, circulating cysteine, and the de novo cysteine synthesis (transsulfuration) pathway as sources of intracellular cysteine to support cellular processes. In contrast, many cancers require exogeneous cystine for proliferation and viability. Herein, we review how the cystine transporter, xCT, and exogenous cystine fuel cancer cell proliferation and the mechanisms that regulate xCT expression and activity. Further, we discuss the potential contribution of additional sources of cysteine to the cysteine pool and what is known about the essentiality of these processes in cancer cells. Finally, we discuss whether cyst(e)ine dependency and associated metabolic alterations represent therapeutically targetable metabolic vulnerabilities.

Cancer cells require exogenous cysteine for proliferation and survival. In this issue of Nature Metabolism , Zhang et al. demonstrate that deletion of 5-methylthioadenosine phosphorylase promotes the synthesis of polyamines from methionine, thereby conferring sensitivity to cysteine starvation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Cysteine plays critical roles in cellular biosynthesis, enzyme catalysis, and is an essential contributor to redox metabolism. While cultured cells are highly dependent on exogenous cystine for proliferation and survival, how diverse tissues obtain and use cysteine in vivo has not been characterized. We comprehensively interrogated cysteine metabolism in normal murine tissues and the cancer that arise from them using stable isotope 13C-serine and 13C-cystine tracing. We found that de novo cysteine synthesis was highest in normal liver and pancreas and absent in lung tissue. In tumors, cysteine synthesis was either inactive or downregulated during tumorigenesis. By contrast, cystine uptake and metabolism to downstream metabolites was a universal feature of normal tissues and tumors. Differences in cysteine catabolism were evident across tumor types, including glutathione synthesis. Thus, cystine is a major contributor to the cysteine pool in tumors and cysteine catabolic pathways are differentially active across tumor types.

Focal adhesion kinase (FAK) relays integrin signaling from outside to inside cells and contributes to cell adhesion and motility. However, the spatiotemporal dynamics of FAK activity in single FAs is unclear due to the lack of a robust FAK reporter, which limits our understanding of these essential biological processes. Here we have engineered a genetically encoded FAK activity sensor, dubbed FAK–separation of phases-based activity reporter of kinase (SPARK), which visualizes endogenous FAK activity in living cells and vertebrates. Our work reveals temporal dynamics of FAK activity during FA turnover. Most importantly, our study unveils polarized FAK activity at the distal tip of newly formed single FAs in the leading edge of a migrating cell. By combining FAK–SPARK with DNA tension probes, we show that tensions applied to FAs precede FAK activation and that FAK activity is proportional to the strength of tension. These results suggest tension-induced polarized FAK activity in single FAs, advancing the mechanistic understanding of cell migration. Engineering of a focal adhesion kinase (FAK) reporter that visualizes endogenous FAK activity with dynamic spatiotemporal resolution in living cells and vertebrates reveals tension-induced polarized FAK activity in single focal adhesions during cell migration.

ObjectiveWe sought to conduct a systematic review and meta-analysis of evidence to inform policies that reduce density and proximity of tobacco retailers.Data sourcesTen databases were searched on 16 October 2020: MEDLINE via PubMed, PsycINFO, Global Health, LILACS, Embase, ABI/Inform, CINAHL, Business Source Complete, Web of Science and Scopus, plus grey literature searches using Google and the RAND Publication Database.Study selectionIncluded studies used inferential statistics about adult participants to examine associations between tobacco retailer density/proximity and tobacco use behaviours and health outcomes. Of 7373 studies reviewed by independent coders, 37 (0.5%) met inclusion criteria.Data extractionEffect sizes were converted to a relative risk reduction (RRR) metric, indicating the presumed reduction in tobacco use outcomes based on reducing tobacco retailer density and decreasing proximity.Data synthesisWe conducted a random effects meta-analysis and examined heterogeneity across 27 studies through subgroup analyses and meta-regression. Tobacco retailer density (RRR=2.55, 95% CI 1.91 to 3.19, k=155) and proximity (RRR=2.38, 95% CI 1.39 to 3.37, k=100) were associated with tobacco use behaviours. Pooled results including both density and proximity found an estimated 2.48% reduction in risk of tobacco use from reductions in tobacco retailer density and proximity (RRR=2.48, 95% CI 1.95 to 3.02, k=255). Results for health outcomes came from just two studies and were not significant. Considerable heterogeneity existed.ConclusionsAcross studies, lower levels of tobacco retailer density and decreased proximity are associated with lower tobacco use. Reducing tobacco supply by limiting retailer density and proximity may lead to reductions in tobacco use. Policy evaluations are needed.

Objective To determine the risks of stillbirth and neonatal complications by gestational age in uncomplicated monochorionic and dichorionic twin pregnancies.Design Systematic review and meta-analysis.Data sources Medline, Embase, and Cochrane databases (until December 2015). Review methods Databases were searched without language restrictions for studies of women with uncomplicated twin pregnancies that reported rates of stillbirth and neonatal outcomes at various gestational ages. Pregnancies with unclear chorionicity, monoamnionicity, and twin to twin transfusion syndrome were excluded. Meta-analyses of observational studies and cohorts nested within randomised studies were undertaken. Prospective risk of stillbirth was computed for each study at a given week of gestation and compared with the risk of neonatal death among deliveries in the same week. Gestational age specific differences in risk were estimated for stillbirths and neonatal deaths in monochorionic and dichorionic twin pregnancies after 34 weeks’ gestation.Results 32 studies (29 685 dichorionic, 5486 monochorionic pregnancies) were included. In dichorionic twin pregnancies beyond 34 weeks (15 studies, 17 830 pregnancies), the prospective weekly risk of stillbirths from expectant management and the risk of neonatal death from delivery were balanced at 37 weeks’ gestation (risk difference 1.2/1000, 95% confidence interval −1.3 to 3.6; I2=0%). Delay in delivery by a week (to 38 weeks) led to an additional 8.8 perinatal deaths per 1000 pregnancies (95% confidence interval 3.6 to 14.0/1000; I2=0%) compared with the previous week. In monochorionic pregnancies beyond 34 weeks (13 studies, 2149 pregnancies), there was a trend towards an increase in stillbirths compared with neonatal deaths after 36 weeks, with an additional 2.5 per 1000 perinatal deaths, which was not significant (−12.4 to 17.4/1000; I2=0%). The rates of neonatal morbidity showed a consistent reduction with increasing gestational age in monochorionic and dichorionic pregnancies, and admission to the neonatal intensive care unit was the commonest neonatal complication. The actual risk of stillbirth near term might be higher than reported estimates because of the policy of planned delivery in twin pregnancies.Conclusions To minimise perinatal deaths, in uncomplicated dichorionic twin pregnancies delivery should be considered at 37 weeks’ gestation; in monochorionic pregnancies delivery should be considered at 36 weeks.Systematic review registration PROSPERO CRD42014007538.

A year-long intervention trial was conducted to characterise the responses of multiple biomarkers of Se status in healthy American adults to supplemental selenomethionine (SeMet) and to identify factors affecting those responses. A total of 261 men and women were randomised to four doses of Se (0, 50, 100 or 200 μg/d as l-SeMet) for 12 months. Responses of several biomarkers of Se status (plasma Se, serum selenoprotein P (SEPP1), plasma glutathione peroxidase activity (GPX3), buccal cell Se, urinary Se) were determined relative to genotype of four selenoproteins (GPX1, GPX3, SEPP1, selenoprotein 15), dietary Se intake and parameters of single-carbon metabolism. Results showed that supplemental SeMet did not affect GPX3 activity or SEPP1 concentration, but produced significant, dose-dependent increases in the Se contents of plasma, urine and buccal cells, each of which plateaued by 9–12 months and was linearly related to effective Se dose (μg/d per kg0·75). The increase in urinary Se excretion was greater for women than men, and for individuals of the GPX1 679 T/T genotype than for those of the GPX1 679 C/C genotype. It is concluded that the most responsive Se-biomarkers in this non-deficient cohort were those related to body Se pools: plasma, buccal cell and urinary Se concentrations. Changes in plasma Se resulted from increases in its non-specific component and were affected by both sex and GPX1 genotype. In a cohort of relatively high Se status, the Se intake (as SeMet) required to support plasma Se concentration at a target level (Sepl-target) is: Se_{in} = [(Se_{pl - target} - Se_{pl})/(18.2\\hairsp ng\\,d\\,kg^{0.75}/ml\\,per\\,\\mu g)] .

Free electrons in the interstellar medium refract and diffract radio waves along multiple paths, resulting in angular and temporal broadening of radio pulses that limits pulsar timing precision. We determine multifrequency, multiepoch scattering times for the large dispersion measure millisecond PSR J1903+0327 by developing a three-component model for the emitted pulse shape that is convolved with a best-fit pulse broadening function (PBF) identified from a family of thin-screen and extended-media PBFs. We show that the scattering time, τ, at a fiducial frequency of 1500 MHz changes by approximately 10% over a 5.5 yr span with a characteristic timescale of approximately 100 days. We also constrain the spectral index and inner scale of the wavenumber spectrum of electron density variations along this line of sight. We find that the scaling law for τ versus radio frequency is strongly affected by any mismatch between the true and assumed PBF or between the true and assumed intrinsic pulse shape. We show using simulations that refraction is a plausible cause of the epoch dependence of τ, manifesting as changes in the PBF shape and 1/e timescale. Finally, we discuss the implications of our scattering results on pulsar timing including time of arrival delays and dispersion measure misestimation.

National rates of COVID-19 infection and fatality have varied dramatically since the onset of the pandemic. Understanding the conditions associated with this cross-country variation is essential to guiding investment in more effective preparedness and response for future pandemics. Daily SARS-CoV-2 infections and COVID-19 deaths for 177 countries and territories and 181 subnational locations were extracted from the Institute for Health Metrics and Evaluation's modelling database. Cumulative infection rate and infection-fatality ratio (IFR) were estimated and standardised for environmental, demographic, biological, and economic factors. For infections, we included factors associated with environmental seasonality (measured as the relative risk of pneumonia), population density, gross domestic product (GDP) per capita, proportion of the population living below 100 m, and a proxy for previous exposure to other betacoronaviruses. For IFR, factors were age distribution of the population, mean body-mass index (BMI), exposure to air pollution, smoking rates, the proxy for previous exposure to other betacoronaviruses, population density, age-standardised prevalence of chronic obstructive pulmonary disease and cancer, and GDP per capita. These were standardised using indirect age standardisation and multivariate linear models. Standardised national cumulative infection rates and IFRs were tested for associations with 12 pandemic preparedness indices, seven health-care capacity indicators, and ten other demographic, social, and political conditions using linear regression. To investigate pathways by which important factors might affect infections with SARS-CoV-2, we also assessed the relationship between interpersonal and governmental trust and corruption and changes in mobility patterns and COVID-19 vaccination rates. The factors that explained the most variation in cumulative rates of SARS-CoV-2 infection between Jan 1, 2020, and Sept 30, 2021, included the proportion of the population living below 100 m (5·4% [4·0–7·9] of variation), GDP per capita (4·2% [1·8–6·6] of variation), and the proportion of infections attributable to seasonality (2·1% [95% uncertainty interval 1·7–2·7] of variation). Most cross-country variation in cumulative infection rates could not be explained. The factors that explained the most variation in COVID-19 IFR over the same period were the age profile of the country (46·7% [18·4–67·6] of variation), GDP per capita (3·1% [0·3–8·6] of variation), and national mean BMI (1·1% [0·2–2·6] of variation). 44·4% (29·2–61·7) of cross-national variation in IFR could not be explained. Pandemic-preparedness indices, which aim to measure health security capacity, were not meaningfully associated with standardised infection rates or IFRs. Measures of trust in the government and interpersonal trust, as well as less government corruption, had larger, statistically significant associations with lower standardised infection rates. High levels of government and interpersonal trust, as well as less government corruption, were also associated with higher COVID-19 vaccine coverage among middle-income and high-income countries where vaccine availability was more widespread, and lower corruption was associated with greater reductions in mobility. If these modelled associations were to be causal, an increase in trust of governments such that all countries had societies that attained at least the amount of trust in government or interpersonal trust measured in Denmark, which is in the 75th percentile across these spectrums, might have reduced global infections by 12·9% (5·7–17·8) for government trust and 40·3% (24·3–51·4) for interpersonal trust. Similarly, if all countries had a national BMI equal to or less than that of the 25th percentile, our analysis suggests global standardised IFR would be reduced by 11·1%. Efforts to improve pandemic preparedness and response for the next pandemic might benefit from greater investment in risk communication and community engagement strategies to boost the confidence that individuals have in public health guidance. Our results suggest that increasing health promotion for key modifiable risks is associated with a reduction of fatalities in such a scenario. Bill & Melinda Gates Foundation, J Stanton, T Gillespie, J and E Nordstrom, and Bloomberg Philanthropies.