Summary RNA modifications play critical roles in important biological processes. However, the functions of N6-methyladenosine (m6A) mRNA modification in cancer biology and cancer stem cells remain largely unknown. Here, we show that m6A mRNA modification is critical for glioblastoma stem cell (GSC) self-renewal and tumorigenesis. Knockdown of METTL3 or METTL14, key components of the RNA methyltransferase complex, dramatically promotes human GSC growth, self-renewal, and tumorigenesis. In contrast, overexpression of METTL3 or inhibition of the RNA demethylase FTO suppresses GSC growth and self-renewal. Moreover, inhibition of FTO suppresses tumor progression and prolongs lifespan of GSC-grafted mice substantially. m6A sequencing reveals that knockdown of METTL3 or METTL14 induced changes in mRNA m6A enrichment and altered mRNA expression of genes (e.g., ADAM19) with critical biological functions in GSCs. In summary, this study identifies the m6A mRNA methylation machinery as promising therapeutic targets for glioblastoma.

Reprogrammed glucose metabolism as a result of increased glycolysis and glucose uptake is a hallmark of cancer. Here we show that cancer cells can suppress glucose uptake by non-tumour cells in the pre-metastatic niche, by secreting vesicles that carry high levels of the miR-122 microRNA. High miR-122 levels in the circulation have been associated with metastasis in breast cancer patients and we show that cancer-cell-secreted miR-122 facilitates metastasis by increasing nutrient availability in the pre-metastatic niche. Mechanistically cancer-cell-derived miR-122 suppresses glucose uptake by niche cells in vitro and in vivo by downregulating the glycolytic enzyme pyruvate kinase (PKM). In vivo inhibition of miR-122 restores glucose uptake in distant organs, including brain and lungs, and decreases the incidence of metastasis. These results demonstrate that by modifying glucose utilization by recipient pre-metastatic niche cells, cancer-derived extracellular miR-122 is able to reprogram systemic energy metabolism to facilitate disease progression.

To the Editor: Despite the large and rapidly rising number of cases of coronavirus disease 2019 (Covid-19) and resulting deaths, 1 there are limited data about the clinical characteristics of pregnant women with the disease. 2,3 We extracted information regarding epidemiologic, clinical, laboratory, and radiologic characteristics, treatment, and outcomes of pregnant women with Covid-19 through the epidemic reporting system of the National Health Commission of China, which stores the medical records of all 50 designated hospitals in Wuhan city. From December 8, 2019, to March 20, 2020, we identified 118 pregnant women with Covid-19 in Wuhan according to the criteria of the Chinese Clinical Guidance for Covid-19 Pneumonia Diagnosis and Treatment; 84 women (71%) had positive polymerase-chain-reaction (PCR) testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the remaining 34 (29%) had suggestive findings on computed tomography (CT) of the chest. Criteria for mild, severe, and critical disease and other methodologic details are provided in the Supplementary Appendix, available with the full text of this letter at NEJM.org. The pregnant patients represented 0.24% of all reported patients with Covid-19 at these hospitals during this time. The median age of the women was 31 years (interquartile range, 28 to 34); 55 of 106 (52%) were nulliparous, and 75 of 118 (64%) had been infected with SARS-CoV-2 in the third trimester. The most common symptoms in 112 women with available data were fever (in 75%) and cough (in 73%) (Table 1). Lymphopenia was present in 51 of 116 patients (44%). A total of 88 of the 111 women (79%) who underwent chest CT had infiltrates in both lungs. Additional clinical data are provided in the Supplementary Appendix. * The denominators of patients who were included in each analysis are provided if they differed from the total numbers in the relevant study group. Percentages may not total 100 because of rounding. Covid-19 denotes coronavirus disease 2019, and IQR interquartile range. † Asymptomatic patients were screened because of exposure to persons with confirmed or suspected Covid-19. ‡ The signs and symptoms listed include those reported to occur before admission and during hospitalization. Data were extracted from the medical record and may not reflect complete accounting of symptoms. § The reason that there were 70 live births but 68 deliveries was that there were 2 sets of twins. ¶ These abortions were induced because of the patient's concern about Covid-19. ‖ The data shown are as of March 20, 2020. ** The Apgar score at 1 minute was available for 66 babies.

SummaryMicroRNAs are important players in stem cell biology. Among them, microRNA-9 (miR-9) is expressed specifically in neurogenic areas of the brain. Whether miR-9 plays a role in neural stem cell self-renewal and differentiation is unknown. We showed previously that nuclear receptor TLX is an essential regulator of neural stem cell self-renewal. Here we show that miR-9 suppresses TLX expression to negatively regulate neural stem cell proliferation and accelerate neural differentiation. Introducing a TLX expression vector lacking the miR-9 recognition site rescued miR-9-induced proliferation deficiency and inhibited precocious differentiation. In utero electroporation of miR-9 in embryonic brains led to premature differentiation and outward migration of the transfected neural stem cells. Moreover, TLX represses miR-9 pri-miRNA expression. MiR-9, by forming a negative regulatory loop with TLX, establishes a model for controlling the balance between neural stem cell proliferation and differentiation.

Samoans are a unique founder population with a high prevalence of obesity1–3, making them well suited for identifying new genetic contributors to obesity4. We conducted a genome-wide association study (GWAS) in 3,072 Samoans, discovered a variant, rs12513649, strongly associated with body mass index (BMI) (P = 5.3 × 10−14), and replicated the association in 2,102 additional Samoans (P = 1.2 × 10−9). Targeted sequencing identified a strongly associated missense variant, rs373863828 (p.Arg457Gln), in CREBRF (meta P = 1.4 × 10−20). Although this variant is extremely rare in other populations, it is common in Samoans (frequency of 0.259), with an effect size much larger than that of any other known common BMI risk variant (1.36–1.45 kg/m2 per copy of the risk-associated allele). In comparison to wild-type CREBRF, the Arg457Gln variant when overexpressed selectively decreased energy use and increased fat storage in an adipocyte cell model. These data, in combination with evidence of positive selection of the allele encoding p.Arg457Gln, support a ‘thrifty’ variant hypothesis as a factor in human obesity.