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Hypoxia is an important feature of the tumor microenvironment, and is closely associated with cell proliferation, angiogenesis, metabolism and the tumor immune response. All these factors can further promote tumor progression, increase tumor aggressiveness, enhance tumor metastatic potential and lead to poor prognosis. In this review, these effects of hypoxia on tumor biology will be discussed, along with their significance for tumor detection and treatment.

Temperature scaling studies suggest that hourly rainfall magnitudes might increase beyond thermodynamic expectations with global warming1–3; that is, above the Clausius–Clapeyron (CC) rate of ~6.5% °C−1. However, there is limited evidence of such increases in long-term observations. Here, we calculate continental-average changes in the magnitude and frequency of extreme hourly and daily rainfall observations from Australia over the years 1990–2013 and 1966–1989. Observed changes are compared with the uncertainty from natural variability and expected changes from CC scaling as a result of global mean surface temperature change. We show that increases in daily rainfall extremes are consistent with CC scaling, but are within the range of natural variability. In contrast, changes in the magnitude of hourly rainfall extremes are close to or exceed double the expected CC scaling, and are above the range of natural variability, exceeding CC × 3 in the tropical region (north of 23° S). These continental-scale changes in extreme rainfall are not explained by changes in the El Niño–Southern Oscillation or changes in the seasonality of extremes. Our results indicate that CC scaling on temperature provides a severe underestimate of observed changes in hourly rainfall extremes in Australia, with implications for assessing the impacts of extreme rainfall.

Background and aimsLiver fibrosis is a wound-healing response that disrupts the liver architecture and function by replacing functional parenchyma with scar tissue. Recent progress has advanced our knowledge of this scarring process, but the detailed mechanism of liver fibrosis is far from clear.MethodsThe fibrotic specimens of patients and HLF (hepatic leukemia factor)PB/PB mice were used to assess the expression and role of HLF in liver fibrosis. Primary murine hepatic stellate cells (HSCs) and human HSC line Lx2 were used to investigate the impact of HLF on HSC activation and the underlying mechanism.ResultsExpression of HLF was detected in fibrotic livers of patients, but it was absent in the livers of healthy individuals. Intriguingly, HLF expression was confined to activated HSCs rather than other cell types in the liver. The loss of HLF impaired primary HSC activation and attenuated liver fibrosis in HLFPB/PB mice. Consistently, ectopic HLF expression significantly facilitated the activation of human HSCs. Mechanistic studies revealed that upregulated HLF transcriptionally enhanced interleukin 6 (IL-6) expression and intensified signal transducer and activator of transcription 3 (STAT3) phosphorylation, thus promoting HSC activation. Coincidentally, IL-6/STAT3 signalling in turn activated HLF expression in HSCs, thus completing a feedforward regulatory circuit in HSC activation. Moreover, correlation between HLF expression and alpha-smooth muscle actin, IL-6 and p-STAT3 levels was observed in patient fibrotic livers, supporting the role of HLF/IL-6/STAT3 cascade in liver fibrosis.ConclusionsIn aggregate, we delineate a paradigm of HLF/IL-6/STAT3 regulatory circuit in liver fibrosis and propose that HLF is a novel biomarker for activated HSCs and a potential target for antifibrotic therapy.

A mutation that increases the secretion of Zika virus non-structural protein 1 (NS1) in infected hosts enhances the ability of the virus to infect its mosquito vector Aedes aegypti and might have contributed to the recent Zika epidemic. Mutation enhances Zika infectivity in mosquitoes Several flaviviruses, such as dengue fever virus and Zika virus, are transmitted by mosquitos. Gong Cheng and colleagues have previously shown that the acquisition of flaviviruses by mosquitoes can be influenced by the flavivirus non-structural protein 1 (NS1), which can be secreted into the serum of an infected host and acquired by the mosquitoes together with the virus. Here, the authors show that such a mechanism also operates to enhance the acquisition of Zika virus (ZIKV) infection by its mosquito vector A. aegypti . The authors identify a mutation in NS1 that enhances its secretion and hence serves to increase mosquito acquisition of the virus. In a survey of NS1 proteins from Asian isolates of ZIKV, the authors also find that the mutation is observed in all isolates collected after 2013. The authors speculate that this mutation in NS1 may have contributed to the rapid spread of the recent epidemic. Zika virus (ZIKV) remained obscure until the recent explosive outbreaks in French Polynesia (2013–2014) and South America (2015–2016) 1 , 2 , 3 . Phylogenetic studies have shown that ZIKV has evolved into African and Asian lineages. The Asian lineage of ZIKV was responsible for the recent epidemics in the Americas 1 , 3 . However, the underlying mechanisms through which ZIKV rapidly and explosively spread from Asia to the Americas are unclear. Non-structural protein 1 (NS1) facilitates flavivirus acquisition by mosquitoes from an infected mammalian host and subsequently enhances viral prevalence in mosquitoes 4 . Here we show that NS1 antigenaemia determines ZIKV infectivity in its mosquito vector Aedes aegypti , which acquires ZIKV via a blood meal. Clinical isolates from the most recent outbreak in the Americas were much more infectious in mosquitoes than the FSS13025 strain, which was isolated in Cambodia in 2010. Further analyses showed that these epidemic strains have higher NS1 antigenaemia than the FSS13025 strain because of an alanine-to-valine amino acid substitution at residue 188 in NS1. ZIKV infectivity was enhanced by this amino acid substitution in the ZIKV FSS13025 strain in mosquitoes that acquired ZIKV from a viraemic C57BL/6 mouse deficient in type I and II interferon (IFN) receptors (AG6 mouse). Our results reveal that ZIKV evolved to acquire a spontaneous mutation in its NS1 protein, resulting in increased NS1 antigenaemia. Enhancement of NS1 antigenaemia in infected hosts promotes ZIKV infectivity and prevalence in mosquitoes, which could have facilitated transmission during recent ZIKV epidemics.

The recent Zika virus （ZIKV） epidemic in Latin America coincided with a marked increase in microcephaly in newborns. However, the causal link between maternal ZIKV infection and malformation of the fetal brain has not been firmly established. Here we show a vertical transmission of ZIKV in mice and a marked effect on fetal brain development. We found that intraperitoneal （i.p.） injection of a contemporary ZIKV strain in pregnant mice led to the infection of radial gila cells （RGs） of dorsal ventricular zone of the fetuses, the primary neural progenitors responsi- ble for cortex development, and caused a marked reduction of these cortex founder cells in the fetuses. Interestingly, the infected fetal mice exhibited a reduced cavity of lateral ventricles and a discernable decrease in surface areas of the cortex. This study thus supports l;he conclusion that vertically transmitted ZIKV affects fetal brain development and provides a valuable animal model for the evaluation of potential therapeutic or preventative strategies.

Snow cover changes are of great importance to the hydrological cycle of the western Tibetan Plateau (TP). However, the influence of the atmospheric circulation on snow cover over the western TP is still unclear. This study finds that springtime snow cover variability over the western TP tail is significantly modulated by the Western Tibetan Vortex (WTV), which explains up to 40% variance. Cyclonic (anticyclonic) WTV variability generally causes water vapor convergence (divergence) and ascending (sinking) motions over the western TP tail, which thereby leads to more (less) snowfall and snow cover about one day later. Horizontal water vapor transport at the southern boundary of the western TP tail from the tropical Indian Ocean is key for the influence of the WTV. This study elucidates the impact of the WTV on springtime snow cover, which augments our understanding of the hydrological cycle over the western TP.

The newly identified Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has resulted in a global health emergency because of its rapid spread and high mortality. The molecular mechanism of interaction between host and viral genomic RNA is yet unclear. We demonstrate herein that SARS-CoV-2 genomic RNA, as well as the negative-sense RNA, is dynamically N6-methyladenosine (m6A)-modified in human and monkey cells. Combined RIP-seq and miCLIP analyses identified a total of 8 m6A sites at single-base resolution in the genome. Especially, epidemic strains with mutations at these identified m6A sites have emerged worldwide, and formed a unique cluster in the US as indicated by phylogenetic analysis. Further functional experiments showed that m6A methylation negatively regulates SARS-CoV-2 infection. SARS-CoV-2 infection also triggered a global increase in host m6A methylome, exhibiting altered localization and motifs of m6A methylation in mRNAs. Altogether, our results identify m6A as a dynamic epitranscriptomic mark mediating the virus–host interaction.

Identifying mechanisms driving spatially heterogeneous glacial mass-balance patterns in the Himalaya, including the ‘Karakoram anomaly’, is crucial for understanding regional water resource trajectories. Streamflows dependent on glacial meltwater are strongly positively correlated with Karakoram summer air temperatures, which show recent anomalous cooling. We explain these temperature and streamflow anomalies through a circulation system—the Karakoram vortex—identified using a regional circulation metric that quantifies the relative position and intensity of the westerly jet. Winter temperature responses to this metric are homogeneous across South Asia, but the Karakoram summer response diverges from the rest of the Himalaya. We show that this is due to seasonal contraction of the Karakoram vortex through its interaction with the South Asian monsoon. We conclude that interannual variability in the Karakoram vortex, quantified by our circulation metric, explains the variability in energy-constrained ablation manifested in river flows across the Himalaya, with important implications for Himalayan glaciers’ futures. The mass balance of glaciers will influence regional water resources in the Himalayas. Changes in atmospheric dynamics, the Karakoram vortex contraction, and interaction with the monsoon influence the glacial melt of the region.

Zika virus (ZIKV) has evolved into a global health threat because of its unexpected causal link to microcephaly. Phylogenetic analysis reveals that contemporary epidemic strains have accumulated multiple substitutions from their Asian ancestor. Here we show that a single serine-to-asparagine substitution [Ser139→Asn139 (S139N)] in the viral polyprotein substantially increased ZIKV infectivity in both human and mouse neural progenitor cells (NPCs) and led to more severe microcephaly in the mouse fetus, as well as higher mortality rates in neonatal mice. Evolutionary analysis indicates that the S139N substitution arose before the 2013 outbreak in French Polynesia and has been stably maintained during subsequent spread to the Americas. This functional adaption makes ZIKV more virulent to human NPCs, thus contributing to the increased incidence of microcephaly in recent ZIKV epidemics.