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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.

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.

Satellite estimation shows that, contrary to daily precipitation intensity whose heavier centers are almost all located over the moisture‐rich oceans, a large portion of the heavier hourly precipitation intensity (HPI) centers are located over the moisture‐limited mainland. However, the direct cause of this inverted land‐sea contrast (ILSC) of HPI is still unclear. We find the ERA5 data generally reproduces the above ILSC pattern, although its heavier HPI centers are generally weaker than CMORPH data. Then we find the distribution of convective precipitation (CP) plays a key role based on ERA5 data. The CP intensity centers match well with that of the hourly total precipitation over land areas, which are generally greater than those over ocean; contrarily, the large‐scale precipitation intensity centers are mainly located in ocean. This study provides important clues for establishing physical interpretations in the future, but further evaluations based on more direct observations are still needed. Plain Language Summary Previous research based on observational data set indicates that the distribution of the climatological average and extreme hourly precipitation intensity (HPI) centers is distinct from the daily or monthly precipitation. However, research on this phenomenon is limited. Here, we preliminarily investigate the direct causes of the spatial distribution feature of the global HPI centers based on the ERA5 reanalysis. Because the total precipitation is the sum of convective precipitation (CP) and large‐scale precipitation (LSP) in ERA5 data, we investigate the separate contributions of the two types of precipitation. We document that the CP intensity centers are much higher in land than in the oceans; in contrast, the LSP intensity centers are mainly distributed in the oceans. Based on zonal‐averaged global HPI on land and oceans, we confirm that variations of CP intensity across latitudes shape the land‐sea difference in the total precipitation depicted above, supporting that the land‐sea contrast of hourly total precipitation is mainly determined by hourly CP. This study provides important clues for establishing physical interpretations of the land‐sea contrast of heavy hourly precipitation centers based on ERA5 reanalysis data, but the results still need to be further evaluated according to more direct observations in the future. Key Points The observed land‐sea contrast features of global hourly precipitation intensity (HPI) based on satellite data are generally reproduced in ERA5 Convective precipitation plays a key role in shaping the land‐sea contrast of the global HPI in ERA5

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.

Hypoxia is an important feature of most solid tumors, conferring resistance to radiation and many forms of chemotherapy. However, it is possible to exploit the presence of tumor hypoxia with hypoxia-activated prodrugs (HAPs), agents that in low oxygen conditions undergo bioreduction to yield cytotoxic metabolites. Although many such agents have been developed, we will focus here on TH-302. TH-302 has been extensively studied, and we discuss its mechanism of action, as well as its efficacy in preclinical and clinical studies, with the aim of identifying future research directions.

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. Plain Language Summary Through using the NSIDC satellite and the latest ERA5‐Land reanalysis data, we explore the impacts of the Western Tibetan Vortex (WTV) on the springtime snow cover variability over the western Tibetan Plateau (TP) tail (63°E−70°E, 32°N−37°N), where is overlapping the central region of the WTV. This study reveals that WTV explains up to 40% of the spring snow cover variability over the western TP tail. The change of cyclonic WTV leads that of snow cover by about one day. We find that cyclonic (anticyclonic) WTV is generally associated with the convergence (divergence) winds and the ascending (sinking) motions near the center of the WTV over the western TP tail, which induces more (less) moisture over the western TP tail, leading to more (less) snowfall and snow cover. Among the four boundaries of the western TP tail, the water vapor transport at the southern boundary serves as the most important boundary, mainly receiving water vapor from the tropical Indian Ocean. This research provides new evidence on the influence of the atmospheric circulation on snow cover variability over the western TP, which improves our understanding of the hydrological cycle, surface radiative processes and climate change over the western TP. Key Points The snow cover variability over the western Tibetan Plateau (TP) tail is significantly influenced by the Western Tibetan Vortex (WTV) Anomalous uplift and moisture convergence near the cyclonic WTV center promoting snow cover over the western TP tail by ∼1 day later The southern boundary of the western TP tail serves as the primarily source receiving moisture from the nonboring tropical Indian Ocean

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.

Rheumatoid arthritis is a chronic systemic autoimmune disease characterized by synovial hyperplasia, inflammatory cell infiltration, and proliferation of inflammatory tissue (angiogranuloma). The destruction of joints and surrounding tissues eventually causes joint deformities and dysfunction or even loss. The S100 protein family is one of the biggest subtribes in the calcium-binding protein family and has more than 20 members. The overexpression of most S100 proteins in rheumatoid arthritis is closely related to its pathogenesis. This paper reviews the relationship between S100 proteins and the occurrence and development of rheumatoid arthritis. It will provide insights into the development of new clinical diagnostic markers and therapeutic targets for rheumatoid arthritis.

The re-emergence of Zika virus (ZIKV) in the Western Hemisphere has resulted in global public health crisis since 2015. ZIKV preferentially infects and targets human neural progenitor cells (hNPCs) and causes fetal microcephaly upon maternal infection. hNPCs not only play critical roles during fetal brain development, but also persist in adult brain throughout life. Yet the mechanism of innate antiviral immunity in hNPCs remains largely unknown. Here, we show that ZIKV infection triggers the abundant production of virus-derived small interfering RNAs in hNPCs, but not in the more differentiated progenies or somatic cells. Ablation of key RNAi machinery components significantly enhances ZIKV replication in hNPCs. Furthermore, enoxacin, a broad-spectrum antibiotic that is known as an RNAi enhancer, exerts potent anti-ZIKV activity in hNPCs and other RNAi-competent cells. Strikingly, enoxacin treatment completely prevents ZIKV infection and circumvents ZIKV-induced microcephalic phenotypes in brain organoid models that recapitulate human fetal brain development. Our findings highlight the physiological importance of RNAi-mediated antiviral immunity during the early stage of human brain development, uncovering a novel strategy to combat human congenital viral infections through enhancing RNAi.