Evolution of Human Brain Left-Right Asymmetry: Old Genes with New Functions.

The human brain is generally anatomically symmetrical, boasting mirror-like brain regions in the left and right hemispheres. Despite this symmetry, fine-scale structural asymmetries are prevalent and are believed to be responsible for distinct functional divisions within the brain. Prior studies propose that these asymmetric structures are predominantly primate specific or even unique to humans, suggesting that the genes contributing to the structural asymmetry of the human brain might have evolved recently. In our study, we identified approximately 1,500 traits associated with human brain asymmetry by collecting paired brain magnetic resonance imaging features from the UK Biobank. Each trait is measured in a specific region of one hemisphere and mirrored in the corresponding region of the other hemisphere. Conducting genome-wide association studies on these traits, we identified over 1,000 quantitative trait loci. Around these index single nucleotide polymorphisms, we found approximately 200 genes that are enriched in brain-related Gene Ontology terms and are predominantly upregulated in brain tissues. Interestingly, most of these genes are evolutionarily old, originating just prior to the emergence of Bilateria (bilaterally symmetrical animals) and Euteleostomi (bony vertebrates with a brain), at a significantly higher ratio than expected. Further analyses of these genes reveal a brain-specific upregulation in humans relative to other mammalian species. This suggests that the structural asymmetry of the human brain has been shaped by evolutionarily ancient genes that have assumed new functions over time.

N6-methyladenine demethylase ALKBH1 inhibits the differentiation of skeletal muscle.

DNA N6-methyladenine (N6-mA) was recently recognized as a new epigenetic modification in mammalian genome, and ALKBH1 was discovered as its demethylase. Knock-out mice studies revealed that ALKBH1 was indispensable for normal embryonic development. However, the function of ALKBH1 in myogenesis is largely unknown. In this study, we found that N6-mA showed a steady increase, going along with a strong decrease of ALKBH1 during skeletal muscle development. Our results also showed that ALKBH1 enhanced proliferation and inhibited differentiation of C2C12 cells. Genome-wide transcriptome analysis and reporter assays further revealed that ALKBH1 accomplished the differentiation inhibiting function by regulating a core set of genes and multiple signaling pathways, including increasing chemokine (C-X-C motif) ligand 14 (CXCL14) and activating ERK signaling. Taken together, our results demonstrated that ALKBH1 is critical for the myogenic differentiation of C2C12 cells, and suggested that N6-mA might be a new epigenetic mechanism for the regulation of myogenesis.

Senescent T Cells in Age-Related Diseases.

Age-induced alterations in human immunity are often considered deleterious and are referred to as immunosenescence. The immune system monitors the number of senescent cells in the body, while immunosenescence may represent the initiation of systemic aging. Immune cells, particularly T cells, are the most impacted and involved in age-related immune function deterioration, making older individuals more prone to different age-related diseases. T-cell senescence can impact the effectiveness of immunotherapies that rely on the immune system's function, including vaccines and adoptive T-cell therapies. The research and practice of using senescent T cells as therapeutic targets to intervene in age-related diseases are in their nascent stages. Therefore, in this review, we summarize recent related literature to investigate the characteristics of senescent T cells as well as their formation mechanisms, relationship with various aging-related diseases, and means of intervention. The primary objective of this article is to explore the prospects and possibilities of therapeutically targeting senescent T cells, serving as a valuable resource for the development of immunotherapy and treatment of age-related diseases.

Macrophage CARD9 mediates cardiac injury following myocardial infarction through regulation of lipocalin 2 expression.

Immune cell infiltration in response to myocyte death regulates extracellular matrix remodeling and scar formation after myocardial infarction (MI). Caspase-recruitment domain family member 9 (CARD9) acts as an adapter that mediates the transduction of pro-inflammatory signaling cascades in innate immunity; however, its role in cardiac injury and repair post-MI remains unclear. We found that Card9 was one of the most upregulated Card genes in the ischemic myocardium of mice. CARD9 expression increased considerably 1 day post-MI and declined by day 7 post-MI. Moreover, CARD9 was mainly expressed in F4/80-positive macrophages. Card9 knockout (KO) led to left ventricular function improvement and infarct scar size reduction in mice 28 days post-MI. Additionally, Card9 KO suppressed cardiomyocyte apoptosis in the border region and attenuated matrix metalloproteinase (MMP) expression. RNA sequencing revealed that Card9 KO significantly suppressed lipocalin 2 (Lcn2) expression post-MI. Both LCN2 and the receptor solute carrier family 22 member 17 (SL22A17) were detected in macrophages. Subsequently, we demonstrated that Card9 overexpression increased LCN2 expression, while Card9 KO inhibited necrotic cell-induced LCN2 upregulation in macrophages, likely through NF-κB. Lcn2 KO showed beneficial effects post-MI, and recombinant LCN2 diminished the protective effects of Card9 KO in vivo. Lcn2 KO reduced MMP9 post-MI, and Lcn2 overexpression increased Mmp9 expression in macrophages. Slc22a17 knockdown in macrophages reduced MMP9 release with recombinant LCN2 treatment. In conclusion, our results demonstrate that macrophage CARD9 mediates the deterioration of cardiac function and adverse remodeling post-MI via LCN2.

Integrated Analysis Reveals the Characteristics and Effects of SARS-CoV-2 Maternal-Fetal Transmission.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has caused a pandemic of coronavirus disease 2019 (COVID-19) and is threatening global health. SARS-CoV-2 spreads by air with a transmission rate of up to 15%, but the probability of its maternal-fetal transmission through the placenta is reported to be low at around 3.28%. However, it is still unclear that which tissues and developmental periods hold higher risks and what the underlying molecular mechanisms are. We conducted an integrated analysis of large-scale transcriptome and single-cell sequencing data to investigate the key factors that affect SARS-CoV-2 maternal-fetal transmission as well as the characteristics and effects of them. Our results showed that the abundance of cytomegalovirus (CMV) and Zika virus (ZIKV) infection-associated factors in the placenta were higher than their primarily infected tissues, while the expression levels of SARS-CoV-2 binding receptor angiotensin-converting enzyme II (ACE2) were similar between lung and placenta. By contrast, an important SARS-CoV-2 infection-associated factor, type II transmembrane serine protease (TMPRSS2), was poorly expressed in placenta. Further scRNA-Seq analysis revealed that ACE2 and TMPRSS2 were co-expressed in very few trophoblastic cells. Interestingly, during the embryonic development stages, the abundance of ACE2 and TMPRSS2 was much higher in multiple embryonic tissues than in the placenta. Based on our present analysis, the intestine in 20th week of embryonic development was at a high risk of SARS-CoV-2 infection. Additionally, we found that during the fetal development, ACE2 and TMPRSS2 were enriched in pathogen infection-associated pathways and may involve in the biological processes related to T-cell activation. In conclusion, our present study suggests that though the placenta provides a good physical barrier against SARS-CoV-2 infection for healthy fetal development, multiple embryonic tissues are under risks of the virus infection, which may be adversely affected once infected prenatally. Therefore, it is necessary to enhance maternal care to prevent the potential impact and harm of SARS-CoV-2 maternal-fetal transmission.