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The CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 genome editing system has been a major technological breakthrough that has brought revolutionary changes to genome editing for therapeutic and diagnostic purposes and precision medicine. With the advent of the CRISPR/Cas9 system, one of the critical limiting factors has been the safe and efficient delivery of this system to cells or tissues of interest. Several approaches have been investigated to find delivery systems that can attain tissue-targeted delivery, lowering the chances of off-target editing. While viral vectors have shown promise for in vitro, in vivo and ex vivo delivery of CRISPR/Cas9, their further clinical applications have been restricted due to shortcomings including limited cargo packaging capacity, difficulties with large-scale production, immunogenicity and insertional mutagenesis. Rapid progress in nonviral delivery vectors, including the use of lipid, polymer, peptides, and inorganic nanoparticle-based delivery systems, has established nonviral delivery approaches as a viable alternative to viral vectors. This review will introduce the molecular mechanisms of the CRISPR/Cas9 gene editing system, current strategies for delivering CRISPR/Cas9-based tools, an overview of strategies for overcoming off-target genome editing, and approaches for improving genome targeting and tissue targeting. We will also highlight current developments and recent clinical trials for the delivery of CRISPR/Cas9. Finally, future directions for overcoming the limitations and adaptation of this technology for clinical trials will be discussed. Graphical Abstract

Hepatocellular carcinoma (HCC) is a common malignant tumor with a high recurrence rate and a poor prognosis. Long intergenic nonprotein coding RNA 942 (LINC00942) is reported to be related to ferroptosis and the immune response in HCC and serves as an oncogene in various cancers. This research aimed to explore the contribution of LINC00942 in HCC progression. Functional assays were used to evaluate the functional role of LINC00942 in vitro and in vivo. Mechanistic assays were conducted to assess the association of LINC00942 with insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) and solute carrier family 7 member 11 (SLC7A11) and the regulatory pattern of LINC00942 in HCC cells. LINC00942 was found to exhibit upregulation in HCC tissue and cells. LINC00942 facilitated HCC cell proliferation, suppressed ferroptosis, and converted naive CD4 + T cells to inducible Treg (iTreg) cells by regulating SLC7A11. Furthermore, SLC7A11 expression was positively modulated by LINC00942 in HCC cells. IGF2BP3 was a shared RNA-binding protein (RBP) for LINC00942 and SLC7A11. The binding between the SLC7A11 3′ untranslated region and IGF2BP3 was verified, and LINC00942 was found to recruit IGF2BP3 to promote SLC7A11 mRNA stability in an m6A-dependent manner. Moreover, mouse tumor growth and proliferation were inhibited, and the number of FOXP3 + CD25 + T cells was increased, while ferroptosis was enhanced after LINC00942 knockdown in vivo. LINC00942 suppresses ferroptosis and induces Treg immunosuppression in HCC by recruiting IGF2BP3 to enhance SLC7A11 mRNA stability, which may provide novel therapeutic targets for HCC.

PurposeSchisandra is a well-known traditional Chinese medicine in East Asia. As a traditional Chinese medicine derivative with Schisandra chinensis as raw material, bicyclol is well known for its significant anti-inflammatory effect. Chronic inflammation plays a significant part in obesity-induced cardiomyopathy. Our purpose was to explore the effect and mechanism of bicyclol on obesity-induced cardiomyopathy.MethodsMice fed with a high-fat diet (HFD) and cardiomyocytes stimulated by palmitic acid (PA) were used as models of obesity-related cardiomyopathy in vivo and in vitro, respectively. The therapeutic effect of bicyclol on pathological changes such as myocardial hypertrophy and fibrosis was evaluated by staining cardiac tissue sections. PCR was used to detect inflammatory factors in H9c2 cells and animal heart tissue after bicyclol treatment. Then, we used western blotting to detect the expression levels of the myocardial hypertrophy related protein, myocardial fibrosis related protein, NF-κB and MAPK pathways.ResultsOur results indicated that bicyclol treatment significantly alleviates HFD-induced myocardial inflammation, fibrosis, and hypertrophy by inhibiting the MAPK and NF-κB pathways. Similar to animal level results, bicyclol could significantly inhibit PA-induced inflammation and prevent NF-κB and MAPK pathways from being activated.ConclusionOur results showed that bicyclol has potential as a drug to treat obesity-induced cardiomyopathy.

Evaluation of resting myocardial computed tomography perfusion (CTP) by coronary CT angiography (CCTA) might serve as a useful addition for determining coronary artery disease. We aimed to evaluate the incremental benefit of resting CTP over coronary stenosis for predicting ischemia using a computational algorithm trained by machine learning methods. 252 patients underwent CCTA and invasive fractional flow reserve (FFR). CT stenosis was classified as 0%, 1-30%, 31-49%, 50-70%, and >70% maximal stenosis. Significant ischemia was defined as invasive FFR < 0.80. Resting CTP analysis was performed using a gradient boosting classifier for supervised machine learning. On a per-patient basis, accuracy, sensitivity, specificity, positive predictive, and negative predictive values according to resting CTP when added to CT stenosis (>70%) for predicting ischemia were 68.3%, 52.7%, 84.6%, 78.2%, and 63.0%, respectively. Compared with CT stenosis [area under the receiver operating characteristic curve (AUC): 0.68, 95% confidence interval (CI) 0.62-0.74], the addition of resting CTP appeared to improve discrimination (AUC: 0.75, 95% CI 0.69-0.81, P value .001) and reclassification (net reclassification improvement: 0.52, P value < .001) of ischemia. The addition of resting CTP analysis acquired from machine learning techniques may improve the predictive utility of significant ischemia over coronary stenosis.

Background and aim A novel study found interferon enhanced antitumor activity of anti-PD-1-based immunotherapy and played a crucial role in improving efficacy on HCC, but the opposite results about the efficacy of interferon on HBV-related HCC were obtained from previous clinical studies and meta-analyses. Thus, this meta-analysis aimed to re-evaluate whether interferon could improve survival and reduce recurrence of patients with HBV-related HCC after curative surgery. Methods MEDLINE/PubMed, Cochrane Library, EMBASE, Web of Science and CNKI were searched for eligible studies from inception to November 2022 and a meta-analysis was done. Results 10 trials with a total of 2062 subjects were screened. Interferon significantly improved 1-, 2-, 3- and 5-year OS and 1-, 2- and 3-year DFS, and reduced 2-, 3- and 5-year recurrence rates of patients with HBV-related HCC after curative surgery. However, interferon did not improve 8-year OS and 5-year DFS, did not reduce 1-year recurrence rate. Conclusions Interferon may significantly reduce recurrence and improve DFS of patients with HBV-related HCC after curative surgery, and finally improve the OS. However, the efficacy advantage may gradually weaken as time goes on. The clinical application of interferon combined with NAs recommended in this meta-analysis is needed to be further studied.

The addition of non-pollen palynomorphs (NPPs) to pollen analytical studies has improved the interpretational frame, especially concerning the local regime in anthropogenically disturbed environments. Using advanced ordination techniques this paper explores the variation of NPP-assemblages and the indicative value of individual NPP-types by comparison to independent classical proxies. Sediment samples from a forest hollow at Tårup Lund, Denmark, covering the last 5,500 years, were prepared for NPP-analysis using a non-aggressive procedure. Correlations between non-pollen palynomorphs and sediment, pollen and macrofossil inferred environmental explanatory variables were studied based on a constant counting sum of NPPs. This approach identified main drivers influencing NPP assemblage composition and indicated that a change in these drivers occurred at the onset of the Pre-Roman Iron Age. Twelve known and 12 specific, but so far unknown, NPPs correlating with the environmental variables were identified and their possible indicator value presented. The mild preparation procedure resulted in a very large dataset allowing for sub-assemblages to be explored separately. This approach indicated the potential for identifying further environmental indicators among these groups.

Palaeoenvironmental conditions during the last 10,500 years cal bp are reconstructed for the vicinity of the Polistovo-Lovatskaya mire system in Pskov Oblast (administrative division), Russia, using the latest data from pollen and plant macrofossil records, ash content, radiocarbon dating and the moisture index of samples obtained from the Kokorevskoe peat core in the central part of that mire system. Comparing the results of this study with earlier data obtained from neighbouring sites in southern Estonia, northern Belarus and central Russia indicates a great similarity of the main patterns of vegetation changes throughout the Holocene. Certain distinctions were also observed along this longitude associated with changing climate and local post-glacial processes. The vegetation dynamics of the Polistovo-Lovatskaya mire system during the Holocene have specific features, such as a late increase in the pollen records of broadleaved trees (Quercus, Tilia, Fraxinus and Ulmus) at ca. 7,500 cal bp, with a maximum at ca. 3,500–2,500 cal bp. Four crucial time periods for the appearance and development of early agriculture were identified: the first cultivation signs (ca. 4,200 cal bp), an increase during the Iron Age (2,500–2,300 cal bp), an increase during the Slav colonization (ca. 1,000 cal BP) and further expansion after 400 cal BP. Corresponding changes in forest composition in the region were also observed. The climatic reconstruction revealed several features which are known all over northern Europe in the Holocene, for example the “event of 9,400 years bp”, “event of 8,200 years BP” and a sharp increase of temperature at 7,700 cal BP.

The analysis of organic residues in pottery can provide abundant information on the lives of ancient people, including the natural resources consumed, the techniques applied, the functions of pottery, and so on. In this paper, a variety of methods, including FT-IR (Fourier transform infrared spectroscopy), GC–MS (gas chromatography-mass spectrometry), SEM (scanning electron microscopy) and SR-µCT (synchrotron radiation micro-computed tomography), have been employed to characterize the carbonized residues from an amphora, unearthed from the Changning site, Qinghai Province, Northwest China. The pottery residues were identified as birch bark tar, so ancient people in China could have used the particular local plant resources, birch bark, to produce tar as early as the Qijia cultural period (c. 4,000–3,500 BP). The birch bark tar could have been used to make composite tools discovered at the Changning site, and the amphora has probably been used for tar production. This, to our knowledge so far, is the earliest evidence for the use of birch bark tar in China. Due to the special geographical location of the Gansu-Qinghai Region, and the transition of subsistence strategy during the Qijia cultural period, the production and utilization of birch bark tar could not rule out the possibility of western influence, which needs further evidence.

The reconstruction of fruit collection and cultivation based on plant remains plays an important role in understanding the subsistence strategies of ancient societies. Here, we report the identification of fossil charcoal from eight sites in the Hexi Corridor to give a clue to the early exploitation of fruit resources in the period 2300–400 BC. Charcoal assemblages show that millet farmers may have collected some tree fruits including bird cherry (Padus sp.), pear (Pyrus sp.) and whitebeam (Sorbus sp.) in the period 2300–2000 BC. From 2000 to 1500 BC there was continuing utilization of Padus sp., Sorbus sp. and cotoneaster (Cotoneaster sp.), at a time when cereal agriculture of wheat and barley had been introduced from outside. Based on analysis of ecological distribution, reproductive biology and the history of utilization, we infer that these fruits were gathered from the wild rather than cultivated. Later, the cultivation of non-native mulberry (Morus alba) began around 1500 BC in the context of an established high-yield wheat agriculture, probably indicating the earliest sign of horticulture in the Hexi Corridor. As with the beginning of agriculture, the horticulture is associated with cultivation of non-native species. In short, the variations in the presence of charred wood of fruit trees indicate that people might have collected wild fruits over a period of time, and that horticulture occurred much later than the spread of a variety of cereal and other crops in the Hexi Corridor.

Cylindrospermopsis raciborskii is a toxic cyanobacterium with an invasive nature. The species is found in all the main continents but its origin and dispersal routes on a worldwide perspective remain yet mostly unknown. In this study, 27 isolates of C. raciborskii gathered worldwide have been used for an in-deep phylogenetic analyses with a concatenated system of three genetic markers (16 rRNA, 16S–23S ITS larger subunit, and RNA polymerase rpoC1) comprehending 3,188 bp. Our results provide support for an origin of C. raciborskii in the American continent. Dispersal routes included afterward a spread into the African continent and then Asia and Australia, being Europe the last continent to be colonized by this species. Our phylogenetic inferences suggest that C. raciborskii seem to have a well-defined dispersal behavior with a well-established population structure around the world.