Advanced genetics (Hoboken, N.J.)最新文献

The 2022 report of the Intergovernmental Panel on Climate Change (IPCC) paints a dark picture of the future of life on earth, characterised by ecosystem collapse, species extinction, and climate hazards such as heatwaves and floods.^[1] These are all linked to physical and mental health problems, with direct and indirect consequences of increased morbidity and mortality. To avoid these catastrophic health effects across all regions of the globe, there is broad agreement—as 231 health journals argued together in 2021—that the rise in global temperature must be limited to less than 1.5°C compared with pre-industrial levels.

While the Paris Agreement of 2015 outlines a global action framework that incorporates providing climate finance to developing countries, this support has yet to materialise.^[2] COP27 is the fifth Conference of the Parties (COP) to be organised in Africa since its inception in 1995. Ahead of this meeting, we—as health journal editors from across the continent—call for urgent action to ensure it is the COP that finally delivers climate justice for Africa and vulnerable countries. This is essential not just for the health of those countries, but for the health of the whole world.

In the interest of transparency the authors wish to declare the following roles and relationships: J.K. is the Ex-Officio, President and Secretary of the Kenya Orthopedic Association; J.M. is an unpaid board member of the International Working Group for Health Systems Strengthening; D.O.-A. has a relationship with GLICO Healthcare Ltd.; P.Y. been paid to speak or participate at events by Novartis, bioMerieux and Pfizer; C.Z. is a paid consultant for the UK Health Alliance on Climate Change. The authors declare no further conflicts of interest beyond those inherent in the editorial roles listed above.

Liver metastasis is associated with immunotherapy resistance, although the underlying mechanisms remain incompletely understood. By applying single cell RNA-sequencing to a concurrent subcutaneous and liver tumor murine model to recapitulate liver metastases, it is identified that subsets within tumor-infiltrating exhausted CD8⁺ T (Tex) cells and immunosuppressive tumor-associated macrophages (TAMs) display opposite responses to concurrent liver tumors and anti-PD-1 treatment, suggesting a complex immune regulating network. Both angiogenic and interferon-reactive TAMs show increased frequencies in implanted liver tumors, and anti-PD-1 treatment further elevates the frequencies of angiogenic TAMs. Such TAMs frequencies negatively correlate with the proportions of cytotoxic T cell subsets. Further, expression of interferon-stimulated genes in TAMs is dramatically reduced under effective anti-PD-1 treatment, while such tendencies are diminished in mice with implanted liver tumors. Therefore, the study indicates that liver metastases could increase immunosuppressive TAMs frequencies and inhibit Tex responses to PD-1 blockade, resulting in compromised systemic antitumor immunity and limited immunotherapy efficacy.

Traditionally, the group 1 intron of the T4 td gene is used to generate a foreign circular sequence. However, the T4 system has been shown to be fairly inefficient in expressing circular RNA (circRNA). Here, a new method is developed to express circular sequences with high circularization efficiency to strengthen the confidence for future circRNA functional studies. CircRNA expression plasmids, constructed with different lengths derived from the actin intron (15-nt, 30-nt, 60-nt, 100-nt, 180-nt) and T4 intron, are introduced into human and mouse cell lines 293T and B16. Junction detection and sequencing are used to determine successful circularization of introns and their expression efficiencies. An actin intron with a medium length (60-nt–100-nt) shows significantly increased efficiency of circularization, whereas intron-100-nt shows the best efficiency in most conditions. RNA pull-down assays are designed to precipitate the splicing factors that are bound to the introns and intron/exon junction. The precipitated proteins are analyzed by mass spectrometry (MS), aiming to identify the possible underlying mechanism behind the high circularization efficiency. This expression system has been validated using different circRNAs, and such method shows potential in contributing to the expanding field of circRNA studies.

dsRNA Uptake

In article 2100064 by Kristen A. Panfilio and co-workers, the cuticle exoskeleton of flour beetle larvae reveals normal anatomy (above: head-to-tail in blue-to-red) and long-term parental RNAi knockdown (below), here showing a mirror-image duplication of the abdomen (red termini to yellow center). Strong knockdown can persist for months despite transmission of full-length double-stranded RNA (dsRNA) from the mother into the egg, depleting maternal dsRNA levels.

Trauma is ubiquitous, but only a subset of those who experience trauma will develop posttraumatic stress disorder (PTSD). In this review, it is argued that to determine who is at risk of developing PTSD, it is critical to examine the genetic etiology of the disorder and individual trauma profiles of those who are susceptible. First, the state of current PTSD genetic research is described, with a particular focus on studies that present evidence for trauma type specificity, or for differential genetic etiology according to gender or race. Next, approaches that leverage non-traditional phenotyping approaches are reviewed to identify PTSD-associated variants and biology, and the relative advantages and limitations inherent in these studies are reflected on. Finally, it is discussed how trauma might influence the heritability of PTSD, through type, risk factors, genetics, and associations with PTSD symptomology.

The Global Alliance for Genomics and Health (GA4GH) is developing a suite of coordinated standards for genomics for healthcare. The Phenopacket is a new GA4GH standard for sharing disease and phenotype information that characterizes an individual person, linking that individual to detailed phenotypic descriptions, genetic information, diagnoses, and treatments. A detailed example is presented that illustrates how to use the schema to represent the clinical course of a patient with retinoblastoma, including demographic information, the clinical diagnosis, phenotypic features and clinical measurements, an examination of the extirpated tumor, therapies, and the results of genomic analysis. The Phenopacket Schema, together with other GA4GH data and technical standards, will enable data exchange and provide a foundation for the computational analysis of disease and phenotype information to improve our ability to diagnose and conduct research on all types of disorders, including cancer and rare diseases.

The theories of sympatric speciation (SS) and coding and noncoding (cd and ncd =repeatome)  genome function are still contentious. Studies on SS in our two new models, “Evolution Canyon” and “Evolution Plateau”, in Israel, divergent microclimatically and geologically-edaphically, respectively, indicated that in ecologically divergent microsites SS is a common speciation model across life from bacteria to mammals. Genomically, the intergenic ncd repeatome was and is still regarded by many biologists as “selfish,” “junk,” and non-functional. In contrast, it is considered by the encyclopedia of DNA elements discovery as biochemically functional and regulatory, and the transposable elements were considered earlier by Barbara McClintock as “controlling elements” of genes. Remarkably, it is found that repeated elements can statistically identify significantly, the five species of subterranean mole rats of Spalax ehrenbergi superspecies adapted to increasingly arid climatic trend southward in Israel. Moreover, it is first discovered in the SS studies in two distant taxa, subterranean mole rats and wild barley, and later also in spiny mice in Israel and subterranean zokors in China, that the noncoding repeatome is genomically mirroring the image of the protein-coding genome in divergent ecologies. It is shown that this mirroring image is statistically significant both within and between the ecologically divergent taxa supporting the hypothesis that much of the repeatome might be regulatory and selected as the protein-coding genome by the same ecological stresses.

In this article, a caveat for advancing the genetics of Lewy body disorders is raised, given the nosological controversy about whether to consider dementia with Lewy bodies (DLB) and Parkinson's disease (PD) as one entity or two separate entities. Using the framework of the sufficient and component causes model of causation, as further developed into an evolution-based model of causation, it is proposed that a disease of complex etiology is defined as having a relatively high degree of sharing of the component causes (a genetic or environmental factor), that is, a low degree of heterogeneity of the sufficient causes. Based on this definition, only if the sharing of component causes within each of two diseases is similar to their combined sharing can lumping be warranted. However, it is not known whether the separate and combined sharing are similar before conducting the etiologic studies. This means that lumping DLB and PD can be counterproductive as it can decrease the ability to detect component causes despite the potential benefit of conducting studies with larger sample sizes. In turn, this is relevant to the development of disease-modifying treatments, because non-overlapping causal genetic factors may result in distinct pathogenetic pathways providing promising targets for interventions.