Base editors: a powerful tool for generating animal models of human diseases

Myriads of genetic mutations, including base substitutions, deletions, and insertions as well as chromosome structural variations, have been detected in many human diseases. Although current combination of genomics and bioinformatics has contributed greatly to understanding the genetics of these disorders, it remains challenging to ensure the causal functions of each mutation, and then to further investigate the underlying mechanism and to develop therapeutic strategies. Animal models generated by genome engineering are the key to address these issues. In this review, we will first revisit the limitation of conventional gene editing tools and mouse models generated in the past. We will then introduce a novel tool, base editors (BEs), which present a new promising approach to establish pathogenically relevant animal models. Finally, we will discuss the application of BEs in non-human primates and share our perspectives on future development of base-editing techniques

Computational Emotion Analysis From Images: Recent Advances and Future Directions

Emotions are usually evoked in humans by images. Recently, extensive research efforts have been dedicated to understanding the emotions of images. In this chapter, we aim to introduce image emotion analysis (IEA) from a computational perspective with the focus on summarizing recent advances and suggesting future directions. We begin with commonly used emotion representation models from psychology. We then define the key computational problems that the researchers have been trying to solve and provide supervised frameworks that are generally used for different IEA tasks. After the introduction of major challenges in IEA, we present some representative methods on emotion feature extraction, supervised classifier learning, and domain adaptation. Furthermore, we introduce available datasets for evaluation and summarize some main results. Finally, we discuss some open questions and future directions that researchers can pursue.Comment: Accepted chapter in the book "Human Perception of Visual Information Psychological and Computational Perspective

Advances in CRISPR/Cas gene therapy for inborn errors of immunity

Inborn errors of immunity (IEIs) are a group of inherited disorders caused by mutations in the protein-coding genes involved in innate and/or adaptive immunity. Hematopoietic stem cell transplantation (HSCT) is a mainstay definitive therapy for many severe IEIs. However, the lack of HLA-matched donors increases the risk of developing severe immunological complications. Gene therapy provides long-term clinical benefits and could be an attractive therapeutic strategy for IEIs. In this review, we describe the development and evolution of clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated proteins (Cas) gene-editing systems, including double-strand break (DSB)-based gene editing and DSB-free base editing or prime editing systems. Here, we discuss the advances in and issues associated with CRISPR/Cas gene editing tools and their potential as therapeutic alternatives for IEIs. We also highlight the progress of preclinical studies for the treatment of human genetic diseases, including IEIs, using CRISR/Cas and ongoing clinical trials based on this versatile technology

FATS is a transcriptional target of p53 and associated with antitumor activity

Frequent mutations of p53 in human cancers exemplify its crucial role as a tumor suppressor transcription factor, and p21, a transcriptional target of p53, plays a central role in surveillance of cell-cycle checkpoints. Our previous study has shown that FATS stabilize p21 to preserve genome integrity. In this study we identified a novel transcript variant of FATS (GenBank: GQ499374) through screening a cDNA library from mouse testis, which uncovered the promoter region of mouse FATS. Mouse FATS was highly expressed in testis. The p53-responsive elements existed in proximal region of both mouse and human FATS promoters. Functional study indicated that the transcription of FATS gene was activated by p53, whereas such effect was abolished by site-directed mutagenesis in the p53-RE of FATS promoter. Furthermore, the expression of FATS increased upon DNA damage in a p53-dependent manner. FATS expression was silent or downregulated in human cancers, and overexpression of FATS suppressed tumorigenicity in vivo independently of p53. Our results reveal FATS as a p53-regulated gene to monitor genomic stability

Multi-functional groups decorated composite nanofiber separator with excellent chemical stability in ester-based electrolyte for enhancing the lithium-ion transport

As various heat-resistant polymer separators come out, although they possess better thermal stability and superior affinity to liquid electrolyte than commercial polyolefin separator, the porous structure and chemical stability of these novel separators should be paid more attention. In this work, we prepare a thin polyacrylonitrile/cellulose acetate (PAN/CA) composite nanofiber separator and discuss the importance of chemical stability in the ester-based electrolyte. The addition of CA decreases the PAN/CA fiber diameter from 310 nm to 210 nm. However, CA containing a lot of ester groups is easy to be dissolved by liquid electrolyte for the property of similarity and compatibility. Hence, the obtained PAN/CA composite nanofiber separator is treated via alkaline hydrolysis process, and some ester groups are transformed to be hydroxyl groups. Noteworthily, hydroxyl-rich PAN/CA composite nanofiber separator not only remains stable in electrolyte, but also possesses an improved lithium-ion transport property for reducing concentration polarization effect. As a result, the LiCoO2/Li half cells employing the hydroxyl-rich composite nanofiber separator exhibits better capacity retention (118.5 mAh g -1 after 300 cycles) and superior rate performance (143.1 mAh g -1 at 3C). Therefore, this multi-functional groups decorated composite nanofiber separator with excellent chemical stability is a candidate for next-generation lithium-based battery

Efficient gene editing in adult mouse livers via adenoviral delivery of CRISPR/Cas9

AbstractWe developed an adenovirus-based CRISPR/Cas9 system for gene editing in vivo. In the liver, we demonstrated that the system could reach the level of tissue-specific gene knockout, resulting in phenotypic changes. Given the wide spectrum of cell types susceptible to adenoviral infection, and the fact that adenoviral genome rarely integrates into its host cell genome, we believe the adenovirus-based CRISPR/Cas9 system will find applications in a variety of experimental settings

Age-related decline in hippocampal tyrosine phosphatase PTPRO is a mechanistic factor in chemotherapy-related cognitive impairment

Chemotherapy-related cognitive impairment (CRCI) or “chemo brain” is a devastating neurotoxic sequela of cancer-related treatments, especially for the elderly individuals. Here we show that PTPRO, a tyrosine phosphatase, is highly enriched in the hippocampus, and its level is tightly associated with neurocognitive function but declined significantly during aging. To understand the protective role of PTPRO in CRCI, a mouse model was generated by treating Ptpro–/– female mice with doxorubicin (DOX) because Ptpro–/– female mice are more vulnerable to DOX, showing cognitive impairments and neurodegeneration. By analyzing PTPRO substrates that are neurocognition-associated tyrosine kinases, we found that SRC and EPHA4 are highly phosphorylated/activated in the hippocampi of Ptpro–/– female mice, with increased sensitivity to DOX-induced CRCI. On the other hand, restoration of PTPRO in the hippocampal CA3 region significantly ameliorate CRCI in Ptpro–/– female mice. In addition, we found that the plant alkaloid berberine (BBR) is capable of ameliorating CRCI in aged female mice by upregulating hippocampal PTPRO. Mechanistically, BBR upregulates PTPRO by downregulating miR-25-3p, which directly targeted PTPRO. These findings collectively demonstrate the protective role of hippocampal PTPRO against CRCI.</p

Age-related decline in hippocampal tyrosine phosphatase PTPRO is a mechanistic factor in chemotherapy-related cognitive impairment.

Chemotherapy-related cognitive impairment (CRCI) or chemo brain is a devastating neurotoxic sequela of cancer-related treatments, especially for the elderly individuals. Here we show that PTPRO, a tyrosine phosphatase, is highly enriched in the hippocampus, and its level is tightly associated with neurocognitive function but declined significantly during aging. To understand the protective role of PTPRO in CRCI, a mouse model was generated by treating Ptpro-/- female mice with doxorubicin (DOX) because Ptpro-/- female mice are more vulnerable to DOX, showing cognitive impairments and neurodegeneration. By analyzing PTPRO substrates that are neurocognition-associated tyrosine kinases, we found that SRC and EPHA4 are highly phosphorylated/activated in the hippocampi of Ptpro-/- female mice, with increased sensitivity to DOX-induced CRCI. On the other hand, restoration of PTPRO in the hippocampal CA3 region significantly ameliorate CRCI in Ptpro-/- female mice. In addition, we found that the plant alkaloid berberine (BBR) is capable of ameliorating CRCI in aged female mice by upregulating hippocampal PTPRO. Mechanistically, BBR upregulates PTPRO by downregulating miR-25-3p, which directly targeted PTPRO. These findings collectively demonstrate the protective role of hippocampal PTPRO against CRCI

Age-related decline in hippocampal tyrosine phosphatase PTPRO is a mechanistic factor in chemotherapy-related cognitive impairment

Chemotherapy-related cognitive impairment (CRCI) or “chemo brain” is a devastating neurotoxic sequela of cancer-related treatments, especially for the elderly individuals. Here we show that PTPRO, a tyrosine phosphatase, is highly enriched in the hippocampus, and its level is tightly associated with neurocognitive function but declined significantly during aging. To understand the protective role of PTPRO in CRCI, a mouse model was generated by treating Ptpro–/– female mice with doxorubicin (DOX) because Ptpro–/– female mice are more vulnerable to DOX, showing cognitive impairments and neurodegeneration. By analyzing PTPRO substrates that are neurocognition-associated tyrosine kinases, we found that SRC and EPHA4 are highly phosphorylated/activated in the hippocampi of Ptpro–/– female mice, with increased sensitivity to DOX-induced CRCI. On the other hand, restoration of PTPRO in the hippocampal CA3 region significantly ameliorate CRCI in Ptpro–/– female mice. In addition, we found that the plant alkaloid berberine (BBR) is capable of ameliorating CRCI in aged female mice by upregulating hippocampal PTPRO. Mechanistically, BBR upregulates PTPRO by downregulating miR-25-3p, which directly targeted PTPRO. These findings collectively demonstrate the protective role of hippocampal PTPRO against CRCI.</p