The high-altitude hypoxic environment represents one of the most extreme challenges for mammals. Previous studies of humans on the Tibetan plateau and in the Andes Mountains have identified ...statistical signatures of selection in different sets of loci. Here, we first measured the hemoglobin levels in village dogs from Tibet and those from Chinese lowlands. We found that the hemoglobin levels are very similar between the two groups, suggesting that Tibetan dogs might share similar adaptive strategies as the Tibetan people. Through a whole-genome sequencing approach, we have identified EPAS1 and HBB as candidate genes for the hypoxic adaptation on the Tibetan plateau. The population genetic analysis shows a significant convergence between humans and dogs in Tibet. The similarities in the sets of loci that exhibit putative signatures of selection and the hemoglobin levels between humans and dogs of the same environment, but not between human populations in different regions, suggests an extraordinary landscape of convergent evolution between human beings and their best friend on the Tibetan plateau.
As essential techniques, intraoperative indocyanine green video angiography (ICG-VA) and FLOW 800 have been widely used in microsurgery for arteriovenous malformations (AVMs). In the present report, ...we introduced a supplementary technical trick for judging the degree of lesion resection when there were superficial drainage veins. FLOW 800 analysis is used to verify our conjecture.
A retrospective analysis of a 33 case cohort treated surgically from June 2020 to September 2022 was conducted and their lesions were removed by superficial drainage veins as a supplementary technical trick and analyzed with FLOW800.
In our 33 AVMs, the feeding artery was visualized earlier than the draining vein. Intraoperatively, the T1/2 peak and slope of the draining vein were significantly higher than that of the lesion. However, the maximum fluorescence intensity (MFI) of the draining vein decreased as the procedure progressed (
< 0.001). After reducing the blood flow to the nidus by progressive dissection of the feeding artery, the arteriovenous transit time (AVTT) decreased from 0.64 ± 0.47 s, was prolonged to 2.38 ± 0.52 (
< 0.001), and the MFI and slope of the nidus decreased from the pre-resection 435.42 ± 43.90 AI and 139.77 ± 27.55 AI/s, and decreased to 386.70 ± 48.17 AI and 116.12 ± 17.46 AI/s (
< 0.001). After resection of the nidus, the T1/2 peak of the draining vein increased from 21.42 ± 4.70 s, prolonged to after dissection of the blood feeding artery, 23.07 ± 5.29 s (
= 0.424), and after resection of the lesion, 25.13 ± 5.46 s (
= 0.016), with a slope from 135.79 ± 28.17 AI/s increased to 210.86 ± 59.67 AI/s (
< 0.001).
ICG-VA integrated with FLOW 800 is an available method for determining the velocity of superficial drainage veins. Whether the color of the superficial drainage veins on the cortical surface returns to normal can determine whether the lesion is completely resected and can reduce the possibility of residual postoperative lesions.
This study aimed to determine the role of TAR DNA binding protein-43 (TDP-43) in intracerebral hemorrhage (ICH)-induced secondary brain injury (SBI) and its underlying mechanisms. After ICH, ...expression of TDP-43 in the nucleus was significantly decreased, and its expression in the cytoplasm increased both
and
, which indicates that TDP-43 translocates from the nucleus to the cytoplasm during SBI after ICH. In addition, mutations at S409/410 of TDP-43 could inhibit its phosphorylation, attenuate nuclear loss, and abolish the increase in neuronal apoptosis in the subcortex. Inhibition of TDP-43 phosphorylation attenuated ICH-induced downregulation of mTOR activity and dynactin1 expression, which may relieve blocking of autophagosome-lysosome fusion and the increase of autophagosomal and lysosomal biogenesis induced by ICH. However, knockdown of TDP-43 could worsen ICH-induced SBI. Furthermore, TDP-43 could be dephosphorylated by calcineurin (CN), and CN activity was increased by OxyHb treatment. In conclusion, this study demonstrated that TDP-43 loss-of-function by phosphorylation at S409/410 may block autophagosome-lysosome fusion and induce elevation of LC3II and p62 levels by inhibiting the activity of mTOR and expression of dynactin1. This mechanism may play an important role in ICH-induced SBI, and TDP-43 may be a potential therapeutic target.
Loss of the Y chromosome (LoY) is frequently observed in somatic cells of elderly men. However, LoY is highly increased in tumor tissue and correlates with an overall worse prognosis. The underlying ...causes and downstream effects of LoY are widely unknown. Therefore, we analyzed genomic and transcriptomic data of 13 cancer types (2375 patients) and classified tumors of male patients according to loss or retain of the Y chromosome (LoY or RoY, average LoY fraction: 0.46). The frequencies of LoY ranged from almost absence (glioblastoma, glioma, thyroid carcinoma) to 77% (kidney renal papillary cell carcinoma). Genomic instability, aneuploidy, and mutation burden were enriched in LoY tumors. In addition, we found more frequently in LoY tumors the gate keeping tumor suppressor gene TP53 mutated in three cancer types (colon adenocarcinoma, head and neck squamous carcinoma, lung adenocarcinoma) and oncogenes MET, CDK6, KRAS, and EGFR amplified in multiple cancer types. On the transcriptomic level, we observed MMP13, known to be involved in invasion, to be up-regulated in LoY of three adenocarcinomas and down-regulation of the tumor suppressor gene GPC5 in LoY of three cancer types. Furthermore, we found enrichment of a smoking-related mutation signature in LoY tumors of head and neck and lung cancer. Strikingly, we observed a correlation between cancer type-specific sex bias in incidence rates and frequencies of LoY, in line with the hypothesis that LoY increases cancer risk in males. Overall, LoY is a frequent phenomenon in cancer that is enriched in genomically unstable tumors. It correlates with genomic features beyond the Y chromosome and might contribute to higher incidence rates in males.
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Background The identification of cancer driver genes from sequencing data has been crucial in deepening our understanding of tumor biology and expanding targeted therapy options. However, apart from ...the most commonly altered genes, the mechanisms underlying the contribution of other mutations to cancer acquisition remain understudied. Leveraging on our whole-exome sequencing of the largest Asian lung adenocarcinoma (LUAD) cohort (n = 302), we now functionally assess the mechanistic role of a novel driver, PARP4. Methods In vitro and in vivo tumorigenicity assays were used to study the functional effects of PARP4 loss and mutation in multiple lung cancer cell lines. Interactomics analysis by quantitative mass spectrometry was conducted to identify PARP4's interaction partners. Transcriptomic data from cell lines and patient tumors were used to investigate splicing alterations. Results PARP4 depletion or mutation (I1039T) promotes the tumorigenicity of KRAS- or EGFR-driven lung cancer cells. Disruption of the vault complex, with which PARP4 is commonly associated, did not alter tumorigenicity, indicating that PARP4's tumor suppressive activity is mediated independently. The splicing regulator hnRNPM is a potentially novel PARP4 interaction partner, the loss of which likewise promotes tumor formation. hnRNPM loss results in splicing perturbations, with a propensity for dysregulated intronic splicing that was similarly observed in PARP4 knockdown cells and in LUAD cohort patients with PARP4 copy number loss. Conclusions PARP4 is a novel modulator of lung adenocarcinoma, where its tumor suppressive activity is mediated not through the vault complex--unlike conventionally thought, but in association with its novel interaction partner hnRNPM, thus suggesting a role for splicing dysregulation in LUAD tumorigenesis. Keywords: Non-small-cell lung cancer, Functional genomics, Mechanisms of disease
We present the analysis of the evolution of tumors in a case of hepatocellular carcinoma. This case is particularly informative about cancer growth dynamics and the underlying driving mutations. We ...sampled nine different sections from three tumors and seven more sections from the adjacent nontumor tissues. Selected sections were subjected to exon as well as whole-genome sequencing. Putative somatic mutations were then individually validated across all 9 tumor and 7 nontumor sections. Among the mutations validated, 24 were amino acid changes; in addition, 22 large indels/copy number variants (>1 Mb) were detected. These somatic mutations define four evolutionary lineages among tumor cells. Separate evolution and expansion of these lineages were recent and rapid, each apparently having only one lineage-specific protein-coding mutation. Hence, by using a cell-population genetic definition, this approach identified three coding changes (CCNG1, P62, and an indel/fusion gene) as tumor driver mutations. These three mutations, affecting cell cycle control and apoptosis, are functionally distinct from mutations that accumulated earlier, many of which are involved in inflammation/immunity or cell anchoring. These distinct functions of mutations at different stages may reflect the genetic interactions underlying tumor growth.
As one of few viral-positive cancers, nasopharyngeal carcinoma (NPC) is extremely rare across the world but very frequent in several regions of the world, including Southern China (known as the ...Cantonese cancer). Even though several genomic studies have been conducted for NPC, their sample sizes are relatively small and systematic comparison with other cancer types has not been explored. In this study, we collected four-hundred-thirty-one samples from six previous studies and provided the first integrative analysis of NPC genomes. Combining several statistical methods for detecting driver genes, we identified 25 novel drivers for NPC, including
and NLRC5. Many of these novel drivers are enriched in several important pathways, such as autophagy and immunity. By comparing NPC with many other cancer types, we found NPC is a unique cancer type in which a high proportion of patients (45.2%) do not have any known driver mutations (termed as "missing driver events") but have a preponderance of deletion events, including chromosome 3p deletion. Through signature analysis, we identified many known and novel signatures, including single-base signatures (
= 12), double-base signatures (
= 1), indel signatures (
= 9) and copy number signatures (
= 8). Many of these new signatures are involved in DNA repair and have unknown etiology and genome instability, implying an unprecedented dynamic mutational process possibly driven by complex interactions between viral and host genomes. By combining clinical, molecular and intra-tumor heterogeneity features, we constructed the first integrative survival model for NPC, providing a strong basis for patient prognosis and stratification. Taken together, we have performed one of the first integrative analyses of NPC genomes and brought unique genomic insights into tumorigenesis of a viral-driven cancer.
Heavy metal pollution in soils threatens food safety and human health. Calcium sulfate and ferric oxide are commonly used to immobilize heavy metals in soils. However, the spatial and temporal ...variations of the heavy metals' bioavailability in soils regulated by a combined material of calcium sulfate and ferric oxide (CSF) remain unclear. In this work, two soil column experiments were conducted to investigate the spatial and temporal variations of CSF immobilized Cd, Pb, and As. In the horizontal soil column, the results showed that CSF's immobilization range for Cd increased over time, and adding CSF in the center of the soil column decreased the concentrations of bioavailable Cd significantly, up to 8 cm away by day 100. The CSF immobilization effect on Pb and As only existed in the center of the soil column. The CSF's immobilization depths for Cd and Pb in the vertical soil column increased over time and extended to 20 cm deep by day 100. However, the CSF's immobilization depths for As only extended to between 5 and 10 cm deep after 100 days of incubation. Overall, the results from this study can serve as a guide to determine the CSF application frequency and spacing distance for the in-situ immobilization of heavy metals in soils.
Human immunodeficiency virus (HIV) actively modulates the protein stability of host cells to optimize viral replication. To systematically examine this modulation in HIV infection, we used isobaric ...tag-based mass spectrometry to quantify changes in the abundance of over 14,000 proteins during HIV-1 infection of human primary CD4
T cells. We identified P-selectin glycoprotein ligand 1 (PSGL-1) as an HIV-1 restriction factor downregulated by HIV-1 Vpu, which binds to PSGL-1 and induces its ubiquitination and degradation through the ubiquitin ligase SCF
. PSGL-1 is induced by interferon-γ in activated CD4
T cells to inhibit HIV-1 reverse transcription and potently block viral infectivity by incorporating in progeny virions. This infectivity block is antagonized by Vpu via PSGL-1 degradation. We further show that PSGL-1 knockdown can significantly abolish the anti-HIV activity of interferon-γ in primary CD4
T cells. Our study identifies an HIV restriction factor and a key mediator of interferon-γ's anti-HIV activity.
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