Zero-shot Domain Adaptation for Neural Machine Translation with Retrieved Phrase-level Prompts

Domain adaptation is an important challenge for neural machine translation. However, the traditional fine-tuning solution requires multiple extra training and yields a high cost. In this paper, we propose a non-tuning paradigm, resolving domain adaptation with a prompt-based method. Specifically, we construct a bilingual phrase-level database and retrieve relevant pairs from it as a prompt for the input sentences. By utilizing Retrieved Phrase-level Prompts (RePP), we effectively boost the translation quality. Experiments show that our method improves domain-specific machine translation for 6.2 BLEU scores and improves translation constraints for 11.5% accuracy without additional training

The influence of methotrexate-related transporter and metabolizing enzyme gene polymorphisms on peri-engraftment syndrome and graft-versus-host disease after haplo-hematopoietic stem cell transplantation in pediatric patients with malignant hematological diseases

BackgroundMethotrexate (MTX), utilized as a graft-versus-host disease (GvHD) prophylactic agent in allogeneic hematopoietic stem cell transplantation (allo-HSCT), has been proven to effectively decrease the occurrence of the peri-engraftment syndrome (Peri-ES) and acute GvHD (aGvHD). Changes in the pharmacodynamics of MTX are closely associated with gene polymorphisms in genes encoding drug-metabolizing enzymes and transporters. Nevertheless, the current studies mainly concentrate on leukemia or autoimmune diseases, and limited studies on allo-HSCT were reported.MethodsHere, we retrospectively assessed the relationship between MTX-related transporter and metabolizing enzyme gene polymorphisms, clinical characteristics, and outcomes in 57 pediatric patients who received haploid HSCT (haplo-HSCT) with malignant tumors at a single center.ResultsWe discovered all gene polymorphisms were in the Hardy–Weinberg equilibrium in our cohort. We discovered a significant correlation between platelet recovery time and ABCB1 (1236C>T) (p = 0.042). Compared with patients with SLCO1B1 (1865+4846T>C) TT, patients with SLCO1B1 (1865+4846T>C) TC/CC had an increased incidence of Peri-ES (p = 0.030). Based on the multivariate Cox analysis, we discovered that SLCO1B1 (1865+4846T>C) TT genotype was an independent protective factor for Peri-ES morbidity (hazard ratio (HR) = 0.464, p = 0.031), and the dose of mononuclear cells reinfused was significantly correlated with II–IV aGvHD (HR = 2.604, p = 0.039).ConclusionIn summary, our findings prove that the host’s genotypes might modify the risk of developing Peri-ES, contribute to a better understanding of the inter-individual difference in efficacy, and facilitate the development of individualized approaches to GvHD prophylaxis

Gene targeting to study a novel testis-specific gene Vad1.2 in spermatogenesis

Spermatogenesis is regulated by steroid hormones which induce expression of various genes responsible for the growth, proliferation and differentiation of spermatogonia to form mature haploid spermatozoa. The surrounding somatic cells including Leydig and Sertoli cells support the whole process in vivo. Previously, we used the post-vitamin A treated vitamin-A-deficient (PVA-VAD) rat model to study spermatogenesis, and identified 24 genes that are differentially up-regulated after retinol treatment. Vad1.2 is one of the up-regulated transcripts expressed in the rat testis from postnatal day 25. Vad1.2 transcript is localized to the round and elongating spermatids in the adult mouse testis. In silico analyses showed that Vad1.2 transcript is down-regulated in patients with teratozoospermia and non-obstructive azoospermia, suggesting that Vad1.2 may have important roles in spermatogenesis. However, how Vad1.2 affects spermatogenesis remains unclear. Therefore, the present study was designed to study the functional roles of Vad1.2 protein in mice using gene targeting approach and investigate the molecular changes in mice with Vad1.2 deficiency. Vad1.2 polyclonal antibody was raised against the full-length mouse Vad1.2 recombination protein and affinity purified. Vad1.2 protein was localized to the cytoplasm and flagellum of condensing spermatids, specifically to the fibrous sheath (FS) in cauda epididymal spermatozoa. Vad1.2 conditional knockout vector was constructed and used to generate Vad1.2 null mice. Vad1.2-/- male mice developed normally but were subfertile with reduced sperm count and motility. Vad1.2-/- male mice had smaller testis and higher incident of sloughing of immature germ cells into the seminiferous lumens when compared to the wild-type. Yet, the rates of germ cell proliferation and apoptosis were similar between the wild-type and the mutant testis. Interestingly approximately 50% of the mutant cauda epididymal spermatozoa showed deformed flagella and demonstrated structural defects typically associated with bending of flagellum at the principal piece or at the midpiece/principal piece junctions. The acrosome, nucleus and mitochondrial sheath of these spermatozoa appeared normal, while the flagellum displayed structural abnormalities including deformation of the two longitudinal columns of the FS and disruption of a portion of FS, suggesting that Vad1.2 might be involved in the biogenesis of FS in spermatogenesis. Furthermore, Vad1.2 interacted with Akap4 in vivo, and the two proteins were co-immunoprecipitated from the testis or cauda epididymal spermatozoa lysates. Akap4 and Vad1.2 were localized to the tail region of the testicular spermatids and cauda epididymal spermatozoa. The expression levels of pro- and mature Akap4 in Vad1.2-/- testes were markedly increased when compared with the wild-type mice. However, a significant decrease of Akap4 was found in the mutant cauda epididymal spermatozoa, suggesting that most of the mature Akap4 failed to incorporate into the FS. Taken together, Vad1.2 plays an important role in spermatogenesis and Vad1.2 deficiency leads to subfertility in mice with the deformed flagella in mature spermatozoa. Further studies on the regulation of FS formation may uncover the underlying molecular changes associated with Vad1.2 deficiency, and may provide fundamental information for treatment of infertile patients with FS defect in the spermatozoa.published_or_final_versionObstetrics and GynaecologyDoctoralDoctor of Philosoph

DNA damage response alterations in clear cell renal cell carcinoma: clinical, molecular, and prognostic implications

Abstract Background DNA damage repair (DDR) pathways modulate cancer risk, progression, and therapeutic responses. Nonetheless, the characteristics and significance of DDR alterations in clear cell renal cell carcinoma (ccRCC) remain undefined. This study aimed to explore the predictive role, molecular mechanism, and tumor immune profile of DDR genes in ccRCC. Methods We prospectively sequenced 757 tumors and matched blood DNA samples from Chinese patients with ccRCC using next-generation sequencing (NGS) and analyzed data from 537 patients from The Cancer Genome Atlas (TCGA). A comprehensive analysis was performed. Results Fifty-two percent of Chinese patients with ccRCC harbored DDR gene mutations and 57% of TCGA patients. The immunotherapy treatment prognosis of patients with DDR gene mutations was superior to that of patients without DDR gene mutations (p = 0.047). DDR gene mutations were associated with more gene mutations and a higher tumor mutation load (TMB, p < 0.001). Moreover, patients with DDR gene mutations have a distinct mutational signature compared with those with wild-type DDR. Furthermore, the DDR-mut group had elevated neoantigen load (including single-nucleotide variants (SNV) and indel neoantigen load, p = 0.037 and p = 0.002, respectively), TCR Shannon (p = 0.025), and neutrophils (p = 0.010). DDR gene mutations exhibited a distinct immune profile with significantly higher expression levels of TNFSF9, CD70, ICAM1, and indoleamine-2,3-dioxygenase (IDO) and lower expression levels of VTCN1 and IL12A. Conclusions Our data suggest that the detection of somatic mutations in DDR genes can predict the efficacy of immunotherapy in patients with ccRCC. Furthermore, we revealed the unique molecular and immune mechanisms underlying ccRCC with DDR gene mutations

Parental genetic material and oxygen concentration affect hatch dynamics of mouse embryo in vitro

Abstract Background Hatching is crucial for mammalian embryo implantation, since difficulties during this process can lead to implantation failure, ectopic pregnancy and consequent infertility. Despite years of intensive researches, how internal and external factors affecting embryo hatch are still largely unclear. Methods The effects of parental genetic material and oxygen concentration on hatch process were examined. Fertilized and parthenogenetic mouse preimplantation embryos were cultured in vitro under 5 and 20% oxygen for 120 h. Zona pellucida drilling by Peizo micromanipulation were performed to resemble the breach by sperm penetration. Results Firstly, parthenogenetic embryos had similarly high blastocyst developmental efficiency as fertilized embryos, but significantly higher hatch ratio than fertilized embryos in both O2 concentrations. 5% O2 reduced the hatch rate of fertilized embryos from 58.2 to 23.8%, but increased that of parthenogenetic embryos from 81.2 to 90.8% significantly. Analogously, 5% O2 decreased the ratio of Oct4-positive cells in fertilized blastocysts, whereas increased that in parthenogenetic blastocysts. Additionally, 5% O2 increased the total embryonic cell number in both fertilized and parthegenetic embryos, when compared to 20% O2, and the total cell number of fertilized embryos was also higher than that of parthegenetic embryos, despite O2 concentration. Real-time PCR revealed that the expression of key genes involving in MAPK pathway and superoxide dismutase family might contribute to preimplantation development and consequent blastocyst hatch in vitro. Finally, we showed that fertilized and parthenogenetic embryos have diverse hatch dynamics in vitro, although the zona pellucida integrity is not the main reason for their mechanistic differences. Conclusion Both parental genetic material and O2 concentration, as the representative of intrinsic and extrinsic factors respectively, have significant impacts on mouse preimplantation development and subsequent hatch dynamics, probably by regulating the gene expression involving in MAPK pathway and superoxide dismutase family to control embryonic cell proliferation and allocation of ICM cells

CRISPR/Cas9 Promotes Functional Study of Testis Specific X-Linked Gene In Vivo.

Mammalian spermatogenesis is a highly regulated multistage process of sperm generation. It is hard to uncover the real function of a testis specific gene in vitro since the in vitro model is not yet mature. With the development of the CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated 9) system, we can now rapidly generate knockout mouse models of testis specific genes to study the process of spermatogenesis in vivo. SYCP3-like X-linked 2 (SLX2) is a germ cell specific component, which contains a Cor1 domain and belongs to the XLR (X-linked, lymphocyte regulated) family. Previous studies suggested that SLX2 might play an important role in mouse spermatogenesis based on its subcellular localization and interacting proteins. However, the function of SLX2 in vivo is still elusive. Here, to investigate the functions of SLX2 in spermatogenesis, we disrupted the Slx2 gene by using the CRISPR/Cas9 system. Since Slx2 is a testis specific X-linked gene, we obtained knockout male mice in the first generation and accelerated the study process. Compared with wild-type mice, Slx2 knockout mice have normal testis and epididymis. Histological observation of testes sections showed that Slx2 knockout affected none of the three main stages of spermatogenesis: mitosis, meiosis and spermiogenesis. In addition, we further confirmed that disruption of Slx2 did not affect the number of spermatogonial stem cells, meiosis progression or XY body formation by immunofluorescence analysis. As spermatogenesis was normal in Slx2 knockout mice, these mice were fertile. Taken together, we showed that Slx2 itself is not an essential gene for mouse spermatogenesis and CRISPR/Cas9 technique could speed up the functional study of testis specific X-linked gene in vivo

Additional file 1 of DNA damage response alterations in clear cell renal cell carcinoma: clinical, molecular, and prognostic implications

Additional file 1: Figure S1. The relationship between DDR mutation and clinical outcome in the TCGA cohort. (A) Overall survival of patients stratified by DDR-mut/wt status in all patients. (B) Progression-free survival of patients stratified by DDR-mut/wt status in all patients. (C) Progression-free survival of patients stratified by DDR-mut/wt status in the immunotherapy cohort

Additional file 1: of Parental genetic material and oxygen concentration affect hatch dynamics of mouse embryo in vitro

Real time PCR primers for genes expression analysis of 96 h blastocysts. (DOC 41 kb