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Eculizumab, a monoclonal antibody (mAb) directed against complement protein C5, is considered to be the current standard of care for patients with paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome. This study describes the generation and preclinical attributes of ALXN1210, a new long-acting anti-C5 mAb, obtained through select modifications to eculizumab to both largely abolish target-mediated drug disposition (TMDD) and increase recycling efficiency via the neonatal Fc receptor (FcRn). To attenuate the effect of TMDD on plasma terminal half-life (t1/2), histidine substitutions were engineered into the complementarity-determining regions of eculizumab to enhance the dissociation rate of the mAb:C5 complex in the acidic early endosome relative to the slightly basic pH of blood. Antibody variants with optimal pH-dependent binding to C5 exhibited little to no TMDD in mice in the presence of human C5. To further enhance the efficiency of FcRn-mediated recycling of the antibody, two additional substitutions were introduced to increase affinity for human FcRn. These substitutions yielded an additional doubling of the t½ of surrogate anti-mouse C5 antibodies with reduced TMDD in transgenic mice expressing the human FcRn. In conclusion, ALXN1210 is a promising new therapeutic candidate currently in clinical development for treatment of patients with PNH and atypical hemolytic uremic syndrome.

In crop plants, a high-density genetic linkage map is essential for both genetic and genomic researches. The complexity and the large size of wheat genome have hampered the acquisition of a high-resolution genetic map. In this study, we report a high-density genetic map based on an individual mapping population using the Affymetrix Wheat660K single-nucleotide polymorphism (SNP) array as a probe in hexaploid wheat. The resultant genetic map consisted of 119 566 loci spanning 4424.4 cM, and 119 001 of those loci were SNP markers. This genetic map showed good collinearity with the 90 K and 820 K consensus genetic maps and was also in accordance with the recently released wheat whole genome assembly. The high-density wheat genetic map will provide a major resource for future genetic and genomic research in wheat. Moreover, a comparative genomics analysis among gramineous plant genomes was conducted based on the high-density wheat genetic map, providing an overview of the structural relationships among theses gramineous plant genomes. A major stable quantitative trait locus (QTL) for kernel number per spike was characterized, providing a solid foundation for the future high-resolution mapping and map-based cloning of the targeted QTL.

The role of focal amplifications and extrachromosomal DNA (ecDNA) is unknown in gastric cardia adenocarcinoma (GCA). Here, we identify frequent focal amplifications and ecDNAs in Chinese GCA patient samples, and find focal amplifications in the GCA cohort are associated with the chromothripsis process and may be induced by accumulated DNA damage due to local dietary habits. We observe diverse correlations between the presence of oncogene focal amplifications and prognosis, where ERBB2 focal amplifications positively correlate with prognosis and EGFR focal amplifications negatively correlate with prognosis. Large-scale ERBB2 immunohistochemistry results from 1668 GCA patients show survival probability of ERBB2 positive patients is lower than that of ERBB2 negative patients when their surviving time is under 2 years, however, the tendency is opposite when their surviving time is longer than 2 years. Our observations indicate that the ERBB2 focal amplifications may represent a good prognostic marker in GCA patients. The role of focal amplifications and extrachromosomal DNA (ecDNA) is unknown in gastric cardia adenocarcinoma (GCA). Here, the authors identify frequent focal amplifications and ecDNAs in Chinese GCA patient samples, as well as the potential associations of these alterations with prognosis and dietary habits.

Aluminum (Al) is the most abundant metal in the Earth's crust and is not an essential element for plant growth. In contrast, nitrogen (N) is the most important mineral element for plant growth, but this non-metal is often present at low levels in soils, and plants are often N deficient. Aluminum toxicity is dominant in acid soils, and so plants growing in acid soils have to overcome both Al toxicity and N limitation. Because of low N-use efficiency, large amounts of N fertilizers are applied to crop fields to achieve high yields, leading to soil acidification and potential Al toxicity. Aluminum lowers plant N uptake and N-use efficiency because Al inhibits root growth. Although numerous studies have investigated the interactions between Al and N, a complete review of these studies was lacking. This review describes: (1) the link between plant Al tolerance and ammonium/nitrate (NH /NO ) preference; (2) the effects of NH /NO and pH on Al toxicity; (3) the effects of Al on soil N transformations; and (4) the effects of Al on NH /NO uptake and assimilation by plants. Acid soils are characterized chemically by a relatively high ratio of NH to NO and high concentrations of toxic Al. Aluminum-tolerant plants generally prefer NH as an N source, while Al-sensitive plants prefer NO . Compared with NO , NH increases the solubilization of toxic Al into soil solutions, but NH generally alleviates Al phytotoxicity under solution culture because the protons from NH compete with Al for adsorption sites on the root surface. Plant NO uptake and nitrate reductase activity are both inhibited by Al, while plant NH uptake is inhibited to a smaller degree than NO . Together, the results of numerous studies indicate that there is a synergistic interaction between plant Al tolerance and NH nutrition. This has important implications for the adaptation of plants to acid soils that are dominated chemically by toxic Al as well as NH . Finally, we discuss how this knowledge can be used to increase plant Al tolerance and N-use efficiency in acid soils.

Urbanization had a huge impact on the regional ecosystem net primary productivity (NPP). Although the urban heat island (UHI) caused by urbanization has been found to have a certain promoting effect on urban vegetation NPP, the factors on the impact still are not identified. In this study, the impact of urbanization on NPP was divided into direct impact (NPP dir ) and indirect impact (NPP ind ), taking Kunming city as a case study area. Then, the spatial heterogeneity impact of land surface temperature (LST) on NPP ind was analyzed based on the geographically weighted regression (GWR) model. The results indicated that NPP, LST, NPP dir and NPP ind in 2001, 2009 and 2018 had significant spatial autocorrelation in Kunming based on spatial analytical model. LST had a positive impact on NPP ind in the central area of Kunming. The positively correlation areas of LST on NPP ind increased by 4.56%, and the NPP ind caused by the UHI effect increased by an average of 4.423 gC m −2 from 2009 to 2018. GWR model can reveal significant spatial heterogeneity in the impacts of LST on NPP ind . Overall, our findings indicated that LST has a certain role in promoting urban NPP.

Background Emerging research has reported that circular RNAs (circRNAs) play important roles in cardiac cell death after myocardial ischemia and reperfusion (I/R). Ferroptosis, a new form of cell death discovered in recent years, has been proven to participate in the regulation of myocardial I/R. This study used circRNA sequencing to explore the key circRNA in the regulation of cardiac ferroptosis after I/R and study the mechanisms of potential circRNA function. Methods We performed circRNA sequencing to explore circRNAs differentially expressed after myocardial I/R. We used quantitative polymerase chain reactions to determine the circRNA expression in different tissues and detect the circRNA subcellular localization in the cardiomyocyte. Gain- and loss-of-function experiments were aimed to examine the function of circRNAs in cardiomyocyte ferroptosis and cardiac tissue damage after myocardial I/R. RNA pull-down was applied to explore proteins interacting with circRNA. Results Here, we identified a ferroptosis-associated circRNA (FEACR) that has an underlying regulatory role in cardiomyocyte ferroptosis. FEACR overexpression suppressed I/R-induced myocardial infarction and ameliorated cardiac function. FEACR inhibition induces ferroptosis in cardiomyocytes and FEACR overexpression inhibits hypoxia and reoxygenation-induced ferroptosis. Mechanistically, FEACR directly bound to nicotinamide phosphoribosyltransferase (NAMPT) and enhanced the protein stability of NAMPT, which increased NAMPT-dependent Sirtuin1 (Sirt1) expression, which promoted the transcriptional activity of forkhead box protein O1 (FOXO1) by reducing FOXO1 acetylation levels. FOXO1 further upregulated the transcription of ferritin heavy chain 1 ( Fth1 ), a ferroptosis suppressor, which resulted in the inhibition of cardiomyocyte ferroptosis. Conclusions Our finding reveals that the circRNA FEACR-mediated NAMPT-Sirt1-FOXO1-FTH1 signaling axis participates in the regulation of cardiomyocyte ferroptosis and protects the heart function against I/R injury. Thus, FEACR and its downstream factors could be novel targets for alleviating ferroptosis-related myocardial injury in ischemic heart diseases.

High-performance stretchable conductive fibers are desired for the development of stretchable electronic devices. Here we show a simple spinning method to prepare conductive hydrogel fibers with ordered polymer chain alignment that mimics the hierarchically organized structure of spider silk. The as-prepared sodium polyacrylate hydrogel fiber is further coated with a thin layer of polymethyl acrylate to form a core–shell water-resistant MAPAH fiber. Owing to the coexistence and reversible transformation of crystalline and amorphous domains in the fibers, MAPAH fibers exhibit high tensile strength, large stretchability and fast resilience from large strain. MAPAH fiber can serve as a highly stretchable wire with a conductive hydrogel core and an insulating cover. The stretchability and conductivity of the MAPAH fiber are retained at −35 °C, indicating its anti-freezing property. As a prime example of stretchable conductive fibers, MAPAH fibers will shed light on the design of next generation textile-based stretchable electronic devices. High-performance stretchable conductive fibers are desired for the development of stretchable electronic devices but preparation of conductive hydrogel fibers is challenging. Inspired by spider silk the authors demonstrate here a spinning method to prepare stretchable conductive hydrogel fibers with ordered polymer chain alignment.

The human papillomavirus (HPV) vaccine is the first vaccine developed specifically targeting the prevention of cervical cancer. For more than 15 years, China has expedited a series of efforts on research and development of the domestically manufactured HPV vaccines, producing local population-based evidence, promoting free HPV vaccination from pilots, and launching action plans to tackle barriers in the scale-up of HPV vaccination. To further roll out the HPV vaccination program in China, several challenges should be addressed to support the steps forward. The availability of more locally manufactured HPV vaccines, pricing negotiation and local evidence supporting the efficacy of one-dose schedule would greatly alleviate the continued supply and financial constraints in China. Meanwhile, more attention should be paid to girls living in low-resource areas and males to ensure equal access to the HPV vaccination. Furthermore, linkage to secondary prevention and further real-world monitoring and evaluation are warranted to inform effective cervical cancer prevention strategies in the post-vaccine era. Graphical Abstract

Fitness cost is a common phenomenon in rice blast disease-resistance breeding. MiR396 is a highly conserved microRNA (miRNA) family targeting Growth Regulating Factor ( OsGRF ) genes. Mutation at the target site of miR396 in certain OsGRF gene or blocking miR396 expression leads to increased grain yield. Here we demonstrated that fitness cost can be trade-off in miR396- OsGRF s module via balancing growth and immunity against the blast fungus. The accumulation of miR396 isoforms was significantly increased in a susceptible accession, but fluctuated in a resistant accession upon infection of Magnaporthe oryzae . The transgenic lines over-expressing different miR396 isoforms were highly susceptible to M. oryzae . In contrast, overexpressing target mimicry of miR396 to block its function led to enhanced resistance to M. oryzae in addition to improved yield traits. Moreover, transgenic plants overexpressing OsGRF6 , OsGRF7 , OsGRF8 , and OsGRF9 exhibited enhanced resistance to M. oryzae , but showed different alteration of growth. While overexpression of OsGRF7 led to defects in growth, overexpression of OsGRF6 , OsGRF8 , and OsGRF9 resulted in better or no significant change of yield traits. Collectively, our results indicate that miR396 negatively regulates rice blast disease- resistance via suppressing multiple OsGRF s, which in turn differentially control growth and yield. Therefore, miR396- OsGRFs could be a potential module to demolish fitness cost in rice blast disease-resistance breeding.