Vertebrates diverged from other chordates ~500 Myr ago and experienced successful innovations and adaptations, but the genomic basis underlying vertebrate origins are not fully understood. Here we suggest, through comparison with multiple lancelet (amphioxus) genomes, that ancient vertebrates experienced high rates of protein evolution, genome rearrangement and domain shuffling and that these rates greatly slowed down after the divergence of jawed and jawless vertebrates. Compared with lancelets, modern vertebrates retain, at least relatively, less protein diversity, fewer nucleotide polymorphisms, domain combinations and conserved non-coding elements (CNE). Modern vertebrates also lost substantial transposable element (TE) diversity, whereas lancelets preserve high TE diversity that includes even the long-sought RAG transposon. Lancelets also exhibit rapid gene turnover, pervasive transcription, fastest exon shuffling in metazoans and substantial TE methylation not observed in other invertebrates. These new lancelet genome sequences provide new insights into the chordate ancestral state and the vertebrate evolution.

We established a system to generate hiPSC-derived hepatobiliary organoids in vitro. To varying degrees, this model recapitulated several key aspects of hepatobiliary organogenesis. The hepatobiliary organoids displayed a series of hepatic and biliary functional attributes. This system does not rely on any exogenous cells or genetic manipulation.

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An alternative adaptive-immune system is present in the most basal vertebrates--lampreys and hagfish--the only surviving jawless vertebrates. These eel-like fish use leucine-rich repeat-based receptors for Ag recognition instead of the Ig-based receptors used in jawed vertebrates. We report that in Japanese lamprey (Lampetra japonica), variable lymphocyte receptor (VLR)B interacts with C1q and C3 proteins to mediate complement-dependent cytotoxicity for bacteria and tumor cells. The immune-based lysis involves deposition of VLRB and C1q-like protein complex on the surface of target cells, activation of C3, and ultimate disruption of cell wall integrity. The demonstration of functional interaction between VLRB and complement components in lamprey provides evidence for the emergence of cooperative innate and adaptive-immune responses at a pivotal point in vertebrate evolution, before or in parallel with the evolution of Ig-based Abs and the classical complement-activation pathway.

Construction of a monoclonal antibody (mAb) bank containing a vast variety of antibodies against human tissue proteins is important for proteomic research. A novel strategy of subtractive immunization using fractionated native proteins was developed for high throughput generation of mAb against human plasma proteins. By this novel approach, the bottleneck of antigen preparation can be overcome by combining repeated immunization of animals with subtracted fractions of plasma or tissue proteins and identification of target antigen by immunoprecipitation/mass spectrum strategies. Plasma freshly collected from healthy adults was pooled and three fractions were prepared by size exclusion chromatography. Mice were immunized with the fractionated plasma proteins, and 205 strains of hybridomas secreting mAb were obtained after two-round subtractive immunizations and cell fusions. In the first round, 110 strains of hybridomas were established, in which 77 strains secreting mAb were identified against 10 human plasma high-abundant proteins. In the second round, plasma fraction I was absorbed with mAb against IgM, IgG, ceruloplasmin and haptoglobin. The absorbed fraction I was used as immunogen for the second round immunization and cell fusion. Ninety-five strains of hybridomas secreting mAb were obtained. Although the target antigens of mAb from 82 strains of hybridomas were identified as IgM, IgA, alpha2-macroglobulin and fibrinogen, about 85% antibodies obtained from this round were identified as new antibodies when compared with mAb obtained in the first round immunization with plasma fraction I. The results suggest that subtractive immunization with fractionated plasma proteins followed by identification of antigens with immunoprecipitation/mass spectrum may be an effective approach for rapid preparation of mAb against high-and medium-abundant plasma or tissue proteins.

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Background and Aims. Previous studies have revealed the close relation of irisin with the occurrence and development of nonalcoholic fatty liver disease (NAFLD). A systematic review and meta-analysis were conducted to evaluate the association of circulating irisin levels and NAFLD. Methods. A systematic literature search of PubMed, Embase, Cochrane Library, Clinicaltrials.gov, WANFANG, CNKI, and CBM databases was performed for relevant articles till August 2020. The weighted mean difference (WMD) values and 95% confidence intervals (CIs) were estimated to compare the case-control studies and pooled results using meta-analysis. Results. The meta-analysis included 5 case-control studies with a total of 1087 people. The results revealed that the circulating irisin levels showed no significant difference between NAFLD and healthy groups ( WMD = 7.51 (-12.53, 27.56) ng/ml, P > 0.05 ). Subgroup analysis based on races showed that the average irisin levels were higher in the NAFLD group than in the healthy group ( WMD = 13.53 (0.71, 26.34) ng/ml, P < 0.05 ) in 4 Asian studies. Subgroup analysis based on disease severity from 3 Asian studies revealed that the average irisin levels were higher in the NAFLD group than in the healthy group ( WMD = 25.1 (22.85, 27.51) ng/ml, P < 0.05 and WMD = 13.52 (22.85, 27.51) ng/ml, P < 0.05 , respectively). Subgroup analysis including 3 studies from Asia suggested that the irisin levels were higher in mild NAFLD than in moderate-severe NAFLD ( WMD = 11.68 (9.03, 14.32) ng/ml, P < 0.05 ). Conclusion. The average irisin levels might be higher in the NAFLD group than in the healthy group in Asians. The irisin levels in the mild NAFLD group might be higher than those in the moderate-severe group in Asians. It is important to monitor the changing trend of irisin levels in predicting the course of NAFLD disease and its changes.

This network meta-analysis addresses the need for evidence-based best-practice treatment regimens for HER2-positive breast cancer. We compared the relative efficacy and tolerability of currently available HER2-positive neoadjuvant immunotherapy regimens based on systematic searches of available randomized controlled trials (RCTs) data. Based on intention-to-treat principle, pathological complete response (pCR), overall serious adverse events (SAEs), and breast-conserving surgery (BCS) rate were analyzed using random-effect, Bayesian network meta-analysis, and standard pairwise meta-analysis. 16 RCTs (3868 patients) were included. Analyzed treatment regimens were as follows: chemotherapy+trastuzumab+pertuzumab (CTP), trastuzumab emtansine+pertuzumab (MP), chemotherapy+trastuzumab (CT), chemotherapy+pertuzumab (CP), trastuzumab+pertuzumab (TP), chemotherapy+trastuzumab+lapatinib (CTL), and chemotherapy+lapatinib (CL), and chemotherapy (C) alone. We found that, for the chance of achieving pCR, CTP was ranked first (SUCRA: 97%), followed by CTL, MP, and CT (SUCRA: 80%, 75%, and 55%, resp.). MP provided the safest regimen (SUCRA: 97%), then TP, C, and TPC (SUCRA: 82%, 76%, and 47%, resp.). CTL proved the most toxic therapy (SUCRA: 7%). No significant difference between neoadjuvant regimens was identified for BCS. Hormone receptor status did not impact ORs for pCR in any regimen. In conclusion, our findings support CTP as the optimum neoadjuvant regimen for HER2-positive breast cancer, with the best pCR and acceptable toxicity compared with CT. MP provides a therapeutic option for patients with poor performance status.