Constacyclic Codes over Finite Fields

An equivalence relation called isometry is introduced to classify constacyclic codes over a finite field; the polynomial generators of constacyclic codes of length $\ell^tp^s$ are characterized, where $p$ is the characteristic of the finite field and $\ell$ is a prime different from $p$

Large genomic fragment deletion and functional gene cassette knock-in via Cas9 protein mediated genome editing in one-cell rodent embryos

The CRISPR-Cas RNA-guided system has versatile uses in many organisms and allows modification of multiple target sites simultaneously. Generating novel genetically modified mouse and rat models is one valuable application of this system. Through the injection of Cas9 protein instead of mRNA into embryos, we observed fewer off-target effects of Cas9 and increased point mutation knock-in efficiency. Large genomic DNA fragment (up to 95 kb) deletion mice were generated for in vivo study of lncRNAs and gene clusters. Site-specific insertion of a 2.7 kb CreERT2 cassette into the mouse Nfatc1 locus allowed labeling and tracing of hair follicle stem cells. In addition, we combined the Cre-Loxp system with a gene-trap strategy to insert a GFP reporter in the reverse orientation into the rat Lgr5 locus, which was later inverted by Cre-mediated recombination, yielding a conditional knockout/reporter strategy suitable for mosaic mutation analysis

CRISPR/Cas9‐mediated somatic correction of a novel coagulator factor IX gene mutation ameliorates hemophilia in mouse

The X‐linked genetic bleeding disorder caused by deficiency of coagulator factor IX, hemophilia B, is a disease ideally suited for gene therapy with genome editing technology. Here, we identify a family with hemophilia B carrying a novel mutation, Y371D, in the human F9 gene. The CRISPR/Cas9 system was used to generate distinct genetically modified mouse models and confirmed that the novel Y371D mutation resulted in a more severe hemophilia B phenotype than the previously identified Y371S mutation. To develop therapeutic strategies targeting this mutation, we subsequently compared naked DNA constructs versus adenoviral vectors to deliver Cas9 components targeting the F9 Y371D mutation in adult mice. After treatment, hemophilia B mice receiving naked DNA constructs exhibited correction of over 0.56% of F9 alleles in hepatocytes, which was sufficient to restore hemostasis. In contrast, the adenoviral delivery system resulted in a higher corrective efficiency but no therapeutic effects due to severe hepatic toxicity. Our studies suggest that CRISPR/Cas‐mediated in situ genome editing could be a feasible therapeutic strategy for human hereditary diseases, although an efficient and clinically relevant delivery system is required for further clinical studies

Allogeneic haematopoietic stem cell transplantation with decitabine-containing preconditioning regimen in TP53-mutant myelodysplastic syndromes: A case study

Myelodysplastic syndrome (MDS) with TP53 mutations has a poor prognosis after transplantation, and novel therapeutic means are urgently needed. Decitabine (Dec) monotherapy has demonstrated improved overall response rates in MDS and acute myeloid leukaemia, although these responses were not durable. This study aimed to preliminary evaluate the efficacy of a Dec-containing allogeneic haematopoietic stem cell transplantation (allo-HSCT) preconditioning regimen in TP53-mutant MDS. Nine patients with TP53-mutant myelodysplastic syndromes received the decitabine-containing preconditioning regimen and subsequent myeloablative allo-HCT between April 2013 and September 2021 in different centres. At a median follow-up of 42 months (range, 5 to 61 months), the overall survival (OS) was 89% (8/9), progression-free survival (PFS) was 89% (8/9), and relapse incidence was 11.1%. The incidence of severe acute (grade III-IV) graft-versus-host disease (GVHD) was 22.2% (2/9) and that of chronic moderate-to-severe GVHD was 11.1% (1/9). The 1-year GVHD-free/relapse-free survival (GRFS) was 56% (5/9). In conclusion, we found real-world clinical data that supports the use of a Dec-containing preconditioning regimen before allo-HSCT for possible improved outcomes in TP53-mutant MDS patients; there is therefore an urgent call for an in-depth exploration of the involved mechanism to confirm these preliminary findings

PAK1IP1, a ribosomal stress-induced nucleolar protein, regulates cell proliferation via the p53–MDM2 loop

Cell growth and proliferation are tightly controlled via the regulation of the p53–MDM2 feedback loop in response to various cellular stresses. In this study, we identified a nucleolar protein called PAK1IP1 as another regulator of this loop. PAK1IP1 was induced when cells were treated with chemicals that disturb ribosome biogenesis. Overexpression of PAK1IP1 inhibited cell proliferation by inducing p53-dependent G1 cell-cycle arrest. PAK1IP1 bound to MDM2 and inhibited its ability to ubiquitinate and to degrade p53, consequently leading to the accumulation of p53 levels. Interestingly, knockdown of PAK1IP1 in cells also inhibited cell proliferation and induced p53-dependent G1 arrest. Deficiency of PAK1IP1 increased free ribosomal protein L5 and L11 which were required for PAK1IP1 depletion-induced p53 activation. Taken together, our results reveal that PAK1IP1 is a new nucleolar protein that is crucial for rRNA processing and plays a regulatory role in cell proliferation via the p53–MDM2 loop