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The cyanobacterium Trichodesmium fixes as much as half of the nitrogen (N2) that supports tropical open-ocean biomes, but its growth is frequently limited by iron (Fe) availability1,2. How future ocean warming may interact with this globally widespread Fe limitation of Trichodesmium N2 fixation is unclear3. Here, we show that the optimum growth temperature of Fe-limited Trichodesmium is ~5 °C higher than for Fe-replete cells, which results in large increases in growth and N2 fixation under the projected warmer Fe-deplete sea surface conditions. Concurrently, the cellular Fe content decreases as temperature rises. Together, these two trends result in thermally driven increases of ~470% in Fe-limited cellular iron use efficiencies (IUEs), defined as the molar quantity of N2 fixed by Trichodesmium per unit time per mole of cellular Fe (mol N2 fixed h–1 mol Fe–1), which enables Trichodesmium to much more efficiently leverage the scarce available Fe supplies to support N2 fixation. Modelling these results in the context of the IPCC representative concentration pathway (RCP) 8.5 global warming scenario4 predicts that IUEs of N2 fixers could increase by ~76% by 2100, and largely alleviate the prevailing Fe limitation across broad expanses of the tropical Pacific and Indian Oceans. Thermally enhanced cyanobacterial IUEs could increase future global marine N2 fixation by ~22% over the next century, and thus profoundly alter the biology and biogeochemistry of open-ocean ecosystems.

Background HIF-1α is thought to be a novel regulator which contributes to carcinogenesis. However, the mechanism underlying the effect of HIF-1α in gliomas remains largely unknown. Methods In the research, we demonstrate that HIF-lα mRNA and protein levels are elevated in glioma cells. The colony formation assays, transwell assays, and wound-healing assays showed that overexpression of HIF-1α promoted proliferation and invasion of glioma cells. Results Overexpression of HIF-lα also increased the expression of inflammatory factors related to pyrolysis (TNF-α, IL-10, and IL-1β) and protein related to pyrolysis signal pathway (NLRP3, ASC, caspase-1, GSDMD, and GSDME). Conclusions Therefore, we speculate that HIF-1α promotes the proliferation and invasion of glial cells by regulating pyrolysis pathway. These results might provide a novel strategy and target for treatment of glioma.

Background Human brucellosis has become one of the major public health problems in China, and increases atypical manifestations, such as fever of unknown origin (FUO), and misdiagnosis rates has complicated the diagnosis of brucellosis. To date, no relevant study on the relationship between brucellosis and FUO has been conducted. Methods We retrospectively reviewed the medical charts of 35 patients with confirmed human brucellosis and prospectively recorded their outcomes by telephone interview. The patients were admitted to the Second Affiliated Hospital of Nanchang University between January 01, 2013 and October 31, 2019. Patient data were collected from hospital medical records. Results The percentage of males was significantly higher than that of female in FUO (78.95% vs. 21.05%, P  < 0.05), and 80% of the patients had a clear history of exposure to cattle and sheep. Moreover, 19 (54%) cases were hospitalized with FUO, among which the patients with epidemiological histories were significantly more than those without ( P  < 0.05). The incidence of toxic hepatitis in FUO patients was higher than that in non-FUO patients (89% vs. 50%, P  < 0.05). Meanwhile, the misdiagnosis rate was considerably higher in the FUO group than in the non-FUO group (100% vs. 63%; P  < 0.05). Conclusion Brucellosis is predominantly FUO admission in a non-endemic area of China, accompanied by irregular fever and toxic hepatitis. Careful examination of the epidemiological history and timely improvement of blood and bone marrow cultures can facilitate early diagnosis and prevent misdiagnosis.

Primary liver cancer represents a major health problem. It comprises hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), which differ markedly with regards to their morphology, metastatic potential and responses to therapy. However, the regulatory molecules and tissue context that commit transformed hepatic cells towards HCC or ICC are largely unknown. Here we show that the hepatic microenvironment epigenetically shapes lineage commitment in mosaic mouse models of liver tumorigenesis. Whereas a necroptosis-associated hepatic cytokine microenvironment determines ICC outgrowth from oncogenically transformed hepatocytes, hepatocytes containing identical oncogenic drivers give rise to HCC if they are surrounded by apoptotic hepatocytes. Epigenome and transcriptome profiling of mouse HCC and ICC singled out Tbx3 and Prdm5 as major microenvironment-dependent and epigenetically regulated lineage-commitment factors, a function that is conserved in humans. Together, our results provide insight into lineage commitment in liver tumorigenesis, and explain molecularly why common liver-damaging risk factors can lead to either HCC or ICC. The tumour microenvironment determines which type of liver cancer develops, with transformed hepatocytes giving rise to intrahepatic cholangiocarcinoma or hepatocellular carcinoma depending or whether they are surrounded by cells undergoing necroptosis or apoptosis.

Shigellosis in chickens was first reported in 2004. This study aimed to determine the pathogenicity of Shigella in chickens and the possibility of cross-infection between humans and chickens. The pathogenicity of Shigella in chickens was examined via infection of three-day-old SPF chickens with Shigella strain ZD02 isolated from a human patient. The virulence and invasiveness were examined by infection of the chicken intestines and primary chicken intestinal epithelial cells. The results showed Shigella can cause death via intraperitoneal injection in SPF chickens, but only induce depression via crop injection. Immunohistochemistry and transmission electron microscopy revealed the Shigella can invade the intestinal epithelia. Immunohistochemistry of the primary chicken intestinal epithelial cells infected with Shigella showed the bacteria were internalized into the epithelial cells. Electron microscopy also confirmed that Shigella invaded primary chicken intestinal epithelia and was encapsulated by phagosome-like membranes. Our data demonstrate that Shigella can invade primary chicken intestinal epithelial cells in vitro and chicken intestinal mucosa in vivo, resulting in pathogenicity and even death. The findings suggest Shigella isolated from human or chicken share similar pathogenicity as well as the possibility of human-poultry cross-infection, which is of public health significance.

Camellia nitidissima Chi (CNC), belonging to Camellia genus (Theaceae family), is a medicinal and edible plant in China. Among the whole plant, the CNC flowers are especially precious, but the biological activities and the compositions of the CNC flowers are unknown. In this study, inhibiting effects on the formation of advanced glycation end-products (AGEs) of five CNC flowers fractions and three isolated compounds were investigated, these three compounds are two flavonoid glycosides and one flavanol, namely kaempferol 3-O-[2,3,4-Tri-O-acetyl-α-L-rhamnopyranosyl-(1→3)-2,4-di-O-acetyl-α-L-rhamnopyranosyl-(1→6)]-β-D-glucopyranoside, kaempferol 3-O-[2,3,4-Tri-O-acetyl-α-L-rhamnopyranosyl-(1→3)-4-O-acetyl-α-L-rhamnopyranosyl-(1→6)]-β-D-glucopyranoside and catechin. Among these five fractions, the ethyl acetate fraction showed the highest total phenolic contents and inhibiting effects on AGE formation. Bovine serum albumin (BSA)-glucose and BSA-methylglyoxal assay showed that the ethyl acetate fraction inhibited AGE formation by 74.49% and 34.3% at 1 mg/mL, respectively. As the main components, these three compounds also showed remarkable inhibiting effects on AGE formation by scavenging methylglyoxal, next two catechin-carbonyl adducts were identified using HPLC-ESI-MS/MS. The results showed that the CNC flowers had remarkable inhibiting effects on the formation of AGEs. The primary structure-activity relationship showed (1) the glycosides could reduce the inhibiting effects compared to kaempferol and (2) the acetyl at position 2‴ in compound 1 had no remarkable influence of the inhibiting effects on AGE formation compared to compound 2. [Display omitted] •C. nitidissima Chi (CNC) is one medicinal and edible plant in China.•CNC flowers had effects on inhibiting AGE formation by scavenging methylglyoxal.•Two flavonoid glycosides and one flavanol had effects on inhibiting AGE formation.•Two catechin-carbonyl adducts were identified by HPLC-ESI-MS/MS.

Chicken infectious anemia (CIA) is an immunosuppressive disease caused by the chicken infectious anemia virus (CIAV) resulting in heavy economic losses once an outbreak is established. This study conducted a systematic analysis of the epidemiology and pathology of CIA in Henan province, China. A total of 437 clinical tissue samples and 120 poultry disease-related live attenuated vaccines were collected during 2017–2020; of which 45 were positive for CIAV nucleic acid, with a positive rate of 8.08%. Our results showed that genome sequence similarity among a total of 12 CIAV isolates was high, and ranged from 97.1 to 99.3%, and their similarity to the vaccine strains Cux-1 and Del-Ros ranged from 97.8 to 98.6%. However, There were mutations in the locus of the major capsid proteins VP1, VP2, and VP3 among all isolates. The subsequent sequence analysis indicated that the isolates of HN-4 and HN-8 showed genetic recombination and follow up animal experiments revealed that HN-4 might be a pathogenic strain. Our results reveal that both field infection and non-CIAV vaccines contamination promote the epidemiology of CIAV in China and some dominant epidemic viruses have undergone recombination and evolution. This study provides important information to help with the prevention and control of CIAV in the poultry industry.

Abstract Background We conducted a phase II study of the combination of pembrolizumab with capecitabine and oxaliplatin (CAPOX) in patients with advanced biliary tract carcinoma (BTC) to assess response rate and clinical efficacy. Exploratory objectives included correlative studies of immune marker expression, tumor evolution, and immune infiltration in response to treatment. Patients and Methods Adult patients with histologically confirmed BTC were enrolled and received oxaliplatin and pembrolizumab on day 1 of cycles 1-6. Capecitabine was administered orally twice daily as intermittent treatment, with the first dose on day 1 and the last dose on day 14 of cycles 1-6. Starting on cycle 7, pembrolizumab monotherapy was continued until disease progression. The primary endpoint was progression-free survival (PFS). Secondary endpoints were safety, tolerability, feasibility, and response rate. Immunohistochemistry (IHC) for PD-L1 and immune infiltrates was analyzed in paired tumor biopsies, as well as bulk transcriptome and exome profiling for five patients and single-cell RNA sequencing for one partial responder. Results Eleven patients enrolled, three of whom had received no prior systemic therapy. Treatment was well tolerated, and the most common treatment-related grade 3 or 4 adverse events were lymphocytopenia, anemia, and decreased platelet count. Three patients (27.3%) achieved a partial response, and six (54%) had stable disease. The disease control rate was 81.8%. The median PFS was 4.1 months with a 6-month PFS rate of 45.5%. Molecular profiling suggests qualitative differences in immune infiltration and clonal evolution based on response. Conclusion Capecitabine and oxaliplatin in combination with pembrolizumab is tolerable and a potentially effective treatment for refractory advanced BTC. This study highlights a design framework for the precise characterization of individual BTC tumors. Trial Registration This study was registered in ClinicalTrials.gov (NCT03111732). This article reports results of a phase II study of the combination of pembrolizumab with capecitabine and oxaliplatin in patients with advanced biliary tract carcinoma to assess response rate and clinical efficacy.

Otitis media (OM) is a major cause of morbidity in pediatric and adult patients. This inflammatory condition is characterized by mucous cell hyperplasia that is thought to produce mucins from the middle ear mucosa. We are interested in the role of Notch signalling pathway in this inflammatory process. Using an acute otitis media (AOM) mouse model through injection of Streptococcus Pneumoniae into the middle ear, histopathologic examination and quantitative RT-PCR, acute inflammation with the thickness of mucosa, Goblet cell hyperplasia, and cilia loss were determined and gene expression related to the Notch signaling pathway were evaluated. Upregulation of the mucous cell markers, Argr2 and Muc5AC, and downregulation of the cilia cell marker, Foxj1 and Dnai2, were observed in AOM. In addition, genes encoding Notch receptors and ligands (Notch1, Notch2, Notch3, Notch4 and Dll1) and the Notch target genes (Hes1, Hes5, Hey1, NRARP) in AOM decreased significantly. The expression of the Notch1 and Jagged1 also showed down-regulation throughout the mouse middle ear epithelium. Taken together, this study suggests that downregulation of the Notch signaling pathway is involved in the mucosa hyperplasia during AOM.

Sirtuin 1 (SIRT1) is involved in both aging and circadian-clock regulation, yet the link between the two processes in relation to SIRT1 function is not clear. Using Sirt1 -deficient mice, we found that Sirt1 and Period 2 ( Per2 ) constitute a reciprocal negative regulation loop that plays important roles in modulating hepatic circadian rhythmicity and aging. Sirt1 -deficient mice exhibited profound premature aging and enhanced acetylation of histone H4 on lysine16 (H4K16) in the promoter of Per2 , the latter of which leads to its overexpression; in turn, Per2 suppresses Sirt1 transcription through binding to the Sirt1 promoter at the Clock/Bmal1 site. This negative reciprocal relationship between SIRT1 and PER2 was also observed in human hepatocytes. We further demonstrated that the absence of Sirt1 or the ectopic overexpression of Per2 in the liver resulted in a dysregulated pace of the circadian rhythm. The similar circadian rhythm was also observed in aged wild type mice. The interplay between Sirt1 and Per2 modulates aging gene expression and circadian-clock maintenance.