Hypoxia pulmonary arterial hypertension (HPAH) is a disease of the small vessels characterized by sustained vasoconstriction, thickening of arterial walls, vascular remodeling, and progressive increase in pulmonary vascular resistance, thus leading to right heart failure and finally death. Recent evidence demonstrated that massive pulmonary artery smooth muscle-like cells (PASMLCs) accumulating in the intima might also be developed from the differentiation of pulmonary myofibroblast (PMF) of tunica media. And PMF appeared the phenomenon of the cytoskeleton remodeling. So, it would be important in the clarification of the pivotal factors controlling this cytoskeleton structure change.

Ischemic injury to neurons represents the underlying cause of stroke to the brain. Our previous studies identified MG53 as an essential component of the cell membrane repair machinery. Here we show that the recombinant human (rh)MG53 protein facilitates repair of ischemia-reperfusion (IR) injury to the brain. MG53 rapidly moves to acute injury sites on neuronal cells to form a membrane repair patch. IR-induced brain injury increases permeability of the blood-brain-barrier, providing access of MG53 from blood circulation to target the injured brain tissues. Exogenous rhMG53 protein can protect cultured neurons against hypoxia/reoxygenation-induced damages. Transgenic mice with increased levels of MG53 in the bloodstream are resistant to IR-induced brain injury. Intravenous administration of rhMG53, either prior to or after ischemia, can effectively alleviate brain injuries in rats. rhMG53-mediated neuroprotection involves suppression of apoptotic neuronal cell death, as well as activation of the pro-survival RISK signaling pathway. Our data indicate a physiological function for MG53 in the brain and suggest that targeting membrane repair or RISK signaling may be an effective means to treat ischemic brain injury.

Breast cancer metastasis suppressor 1 (BRMS1) is a metastasis suppressor gene. This study aimed to investigate the impact of BRMS1 on metastasis in nasopharyngeal carcinoma (NPC) and to evaluate the prognostic significance of BRMS1 in NPC patients.

Target delineation variability is a significant technical impediment in multi-institutional trials which employ intensity modulated radiotherapy (IMRT), as there is a real potential for clinically meaningful variances that can impact the outcomes in clinical trials. The goal of this study is to determine the variability of target delineation among participants from different institutions as part of Southwest Oncology Group (SWOG) Radiotherapy Committee's multi-institutional in-silico quality assurance study in patients with Pancoast tumors as a "dry run" for trial implementation.

N-acetyl group metabolites are a general class of endogenous compounds characterized by a conjugated system consisting of an acetyl group and nitrogen moiety. The aim of our exploratory pilot case-control study is to compare the levels of five N-acetyl derivatives (i.e., N-acetyl-glutamine, N-acetyl-ornithine, N6-acetyl-L-lysine, N-acetyl-putrescine, and N-acetyl-galactosamine) in serum samples between individuals with first-episode schizophrenia and healthy controls (HC). A 1:2 age- and sex- matched pilot case-control study was performed, involving 30 cases of first-episode schizophrenia and 60 HC aged between 18 and 40 years old. The serum samples containing these N-acetyl derivatives from (first-episode patients with schizophrenia and HC were measured using liquid chromatography-tandem mass spectrometry (LC-MS). Results indicated that higher levels of N-acetyl-glutamine and lower levels of N6-acetyl-L-lysine may have a significant association with schizophrenia after adjusting for age, sex and BMI. N-acetyl-putrescine was elevated among subjects with first-episode schizophrenia when compared to HC, suggesting it as a predictor for schizophrenia onset. Further exploration of the mechanisms of N-acetyl group metabolites with respect to schizophrenia is warranted and may be useful for identifying novel disease markers and/or drug target molecules in schizophrenia.

Subjects with schizophrenia have high risks of metabolic abnormalities and bioenergetic dysfunction. Acyl-carnitines involved in bioenergetic pathways provide potential biomarker targets for identifying early changes and onset characteristics in subjects with schizophrenia. We measured 29 acyl-carnitine levels within well-characterized plasma samples of adults with schizophrenia and healthy controls using liquid chromatography-mass spectrometry (LC-MS). Subjects with schizophrenia were measured at baseline and after 8 weeks of treatment. A total of 225 subjects with schizophrenia and 175 age- and gender-matched healthy controls were enrolled and 156 subjects completed the 8-week follow-up. With respect to plasma acyl-carnitines, the individuals with schizophrenia at baseline showed significantly higher levels of C4-OH (C3-DC) and C16:1, but lower concentrations of C3, C8, C10, C10:1, C10:2, C12, C14:1-OH, C14:2, and C14:2-OH when compared with healthy controls after controlling for age, sex, body mass index (BMI), smoking, and drinking. For the comparison between pretreatment and posttreatment subjects, all detected acyl-carnitines were significantly different between the two groups. Only the concentration of C3 and C4 were increased after selection by variable importance in projection (VIP) value >1.0 and false discovery rate (FDR) q value <0.05. A panel of acyl-carnitines were selected for the ability to differentiate subjects of schizophrenia at baseline from controls, pre- from post-treatment, and posttreatment from controls. Our data implicated acyl-carnitines with abnormalities in cellular bioenergetics of schizophrenia. Therefore, acyl-carnitines can be potential targets for future investigations into their roles in the pathoetiology of schizophrenia.

Physicians and physicists are expected to contribute to patient safety and quality improvement (QI) in Radiation Oncology (RO), but prior studies suggest that training for this may be inadequate. RO and medical physics (MP) program directors (PDs) were surveyed to better understand the current patient safety/QI training in their residency programs.

Growth-regulating factor (GRF) interacting factors (GIFs) are involved in several developmental processes in Arabidopsis. We previously showed that upregulation of OsGIF1 expression improves rice grain size. However, whether OsGIF1 is involved in other developmental processes remains unclear. Here, we report pleiotropic effects of OsGIF1 on rice organ size regulation. Overexpression and functional knock-out via a CRISPR/Cas9 strategy revealed that OsGIF1 not only positively regulates the sizes of rice leaf, stem, and grain but also influences rice reproduction. Expression profiles based on both qRT-PCR and GUS (β-glucuronidase) histochemical staining suggested that OsGIF1 is differentially expressed across various rice tissues, consistent with its roles in regulating the development of multiple rice organs. Additionally, we found that OsGIF1-GFP localized preferentially in the nucleus, which supports its proposed role as a transcriptional cofactor. Further histological analysis suggested that OsGIF1 affected rice organ size possibly by regulating cell size. Our results suggest that OsGIF1 plays important roles in vegetative and reproductive developmental processes, with important implications for rice breeding.

Sorafenib (SOR) is the only systemic agent known to improve survival for hepatocellular carcinoma (HCC). However, SOR prolongs survival by less than 3 months and does not alter symptomatic progression. To improve outcomes, several phase I-II trials are currently examining SOR with radiation (RT) for HCC utilizing heterogeneous concurrent and sequential treatment regimens. Our study provides preclinical data characterizing the effects of concurrent versus sequential RT-SOR on HCC cells both in vitro and in vivo. Concurrent and sequential RT-SOR regimens were tested for efficacy among 4 HCC cell lines in vitro by assessment of clonogenic survival, apoptosis, cell cycle distribution, and γ-H2AX foci formation. Results were confirmed in vivo by evaluating tumor growth delay and performing immunofluorescence staining in a hind-flank xenograft model. In vitro, concurrent RT-SOR produced radioprotection in 3 of 4 cell lines, whereas sequential RT-SOR produced decreased colony formation among all 4. Sequential RT-SOR increased apoptosis compared to RT alone, while concurrent RT-SOR did not. Sorafenib induced reassortment into less radiosensitive phases of the cell cycle through G1-S delay and cell cycle slowing. More double-strand breaks (DSBs) persisted 24 h post-irradiation for RT alone versus concurrent RT-SOR. In vivo, sequential RT-SOR produced the greatest tumor growth delay, while concurrent RT-SOR was similar to RT alone. More persistent DSBs were observed in xenografts treated with sequential RT-SOR or RT alone versus concurrent RT-SOR. Sequential RT-SOR additionally produced a greater reduction in xenograft tumor vascularity and mitotic index than either concurrent RT-SOR or RT alone. In conclusion, sequential RT-SOR demonstrates greater efficacy against HCC than concurrent RT-SOR both in vitro and in vivo. These results may have implications for clinical decision-making and prospective trial design.

The Macleaya spp., including Macleaya cordata and Macleaya microcarpa, are traditional anti-virus, inflammation eliminating, and insecticide herb medicines for their isoquinoline alkaloids. They are also known as the basis of the popular natural animal food addictive in Europe. However, few studies especially at genomics level were conducted on them. Hence, we performed the Macleaya spp. transcriptome and integrated it with iTRAQ proteome analysis in order to identify potential genes involved in alkaloids biosynthesis.

Recent studies have shown that pulmonary angiogenesis is an important pathological process in the development of hepatopulmonary syndrome (HPS), and growing evidence has indicated that Stromal cell-derived factor 1/C-X-C chemokine receptor type 4 (SDF-1/CXCR4) axis is involved in pulmonary vascular disease by mediating the accumulation of c-kit+ cells. This study aimed to test the effect of AMD3100, an antagonist of CXCR4, in HPS pulmonary angiogenesis. Common bile duct ligation (CBDL) rats were used as experimental HPS model and were treated with AMD3100 (1.25mg/kg/day, i.p.) or 0.9% saline for 3weeks. The sham rats underwent common bile duct exposure without ligation. The c-kit+ cells accounts and its angiogenic-related functions, prosurvival signals, pulmonary angiogenesis and arterial oxygenation were analysed in these groups. Our results showed that pulmonary SDF-1/CXCR4, Akt, Erk and VEGF/VEGFR2 were significantly activated in CBDL rats, and the numbers of circulating and pulmonary c-kit+ cells were increased in CBDL rats compared with control rats. Additionally, the angiogenic-related functions of c-kit+ cells and pulmonary microvessel counts were also elevated in CBDL rats. CXCR4 inhibition reduced pulmonary c-kit+ cells and microvessel counts and improved arterial oxygenation within 3weeks in CBDL rats. The pulmonary prosurvival signals and pro-angiogenic activity of c-kit+ cells were also down-regulated in AMD3100-treated rats. In conclusion, AMD3100 treatment attenuated pulmonary angiogenesis in CBDL rats and prevented the development of HPS via reductions in pulmonary c-kit+ cells and inhibition of the prosurvival signals. Our study provides new insights in HPS treatment.

In previous research, voltage-dependent anion channel protein 2 (VDAC2) and the receptor of activated protein C kinase 1 (RACK1) in flounder (Paralichthys olivaceus) were confirmed as functional receptors for lymphocystis disease virus (LCDV) entry; however, the underlying mechanism of VDAC2- and RACK1-mediated LCDV entry remains unclear. In this study, we elucidated the endocytosis pathway of LCDV entry into flounder gill (FG) cells by treatment with specific inhibitory agents, siRNAs, and co-localization analysis. LCDV entry was significantly inhibited by the disruption of caveolae-mediated endocytosis, dynamin, and microtubules, and the knockdown of caveoline-1 and dynamin expression, but was not inhibited by the disruption of clathrin-mediated endocytosis, micropinocytosis, or low-pH conditions. The disruption of caveolae-mediated and clathrin-mediated endocytosis was verified by the internalization of cholera toxin subunit B (CTB) and transferrin, respectively. Confocal immunofluorescence assay demonstrated that LCDV was co-localized with VDAC2 and RACK1, CTB was co-localized with VDAC2 and RACK1 and partially with LCDV, but transferrin was not co-localized with LCDV, VDAC2, or RACK1, indicating that LCDV utilized the same pathway as CTB, i.e., caveolae-mediated endocytosis. This was different from the pathway of transferrin, which used clathrin-mediated endocytosis. Furthermore, caveolin-1 was co-localized with LCDV, VDAC2, and RACK1, suggesting that caveolin-1 was involved in LCDV entry. These results revealed for the first time that LCDV entered into FG cells via caveolae-mediated endocytosis facilitated by VDAC2 and RACK1 receptors, relying on dynamin and microtubules in a pH-independent manner, which provided new insight into the molecular mechanisms of LCDV entry and potential for the development of antiviral agents, expanding our understanding of iridovirus infection.

Applications of adenine base editors (ABEs) have been constrained by the limited compatibility of the deoxyadenosine deaminase component with Cas homologs other than SpCas9. We evolved the deaminase component of ABE7.10 using phage-assisted non-continuous and continuous evolution (PANCE and PACE), which resulted in ABE8e. ABE8e contains eight additional mutations that increase activity (kapp) 590-fold compared with that of ABE7.10. ABE8e offers substantially improved editing efficiencies when paired with a variety of Cas9 or Cas12 homologs. ABE8e is more processive than ABE7.10, which could benefit screening, disruption of regulatory regions and multiplex base editing applications. A modest increase in Cas9-dependent and -independent DNA off-target editing, and in transcriptome-wide RNA off-target editing can be ameliorated by the introduction of an additional mutation in the TadA-8e domain. Finally, we show that ABE8e can efficiently install natural mutations that upregulate fetal hemoglobin expression in the BCL11A enhancer or in the the HBG promoter in human cells, targets that were poorly edited with ABE7.10. ABE8e augments the effectiveness and applicability of adenine base editing.

The emergence and spread of mobilized colistin resistance (mcr) genes have triggered extensive concerns worldwide. Here, we characterized the global distribution of mcr-9, a newly-identified variant of mcr, by assembling the data set of mcr-9-positive isolates from GenBank database and the literature available. Genetic features of all the mcr-9-harboring plasmids were determined by bioinformatic analysis. We showed that mcr-9 is globally distributed in 21 countries across six continents, with a wide dissemination among various species of Enterobacteriaceae strains from human, animal, food and environment. IncHI2-ST1 plasmids were found to be the predominant replicon type carrying mcr-9. Comparative genomics highlighted that IncHI2-type plasmids may also serve as a critical reservoir of mcr-9, from which different types of circulating plasmids acquired the mcr-9. Results revealed that the rcnR-rcnA-pcoE-pcoS-IS903-mcr-9-wbuC structure was consistent in most mcr-9 cassettes, suggesting a relatively unitary model involved in the mobilization of mcr-9. It is most likely that the spread of mcr-9 was mainly attributed to the conjugation and recombination events of mcr-9-carrying plasmids. In summary, our results provide a comprehensive picture of the distribution and genetic environment of mcr-9, and demonstrate the central roles played by IncHI2 plasmids in the worldwide dissemination of mcr-9.

Sanguisorba officinalis L. (SO), a well-known herbal medicine, has been proven to show effect against thrombocytopenia. However, metabolites of SO in vivo are still unclear, and the underlying mechanism of SO against thrombocytopenia from the aspect of metabolites have not been well elucidated. In this study, an improved analytical method combined with UHPLC-QTOF MS and a molecular network was developed for the rapid characterization of metabolites in vivo based on fragmentation patterns. Then, network pharmacology (NP) was used to elucidate the potential mechanism of SO against thrombocytopenia. As a result, a total of 1678 exogenous metabolites were detected in urine, feces, plasma, and bone marrow, in which 104 metabolites were tentatively characterized. These characterized metabolites that originated from plasma, urine, and feces were then imported to the NP analysis. The results showed that the metabolites from plasma, urine, and feces could be responsible for the pharmacological activity against thrombocytopenia by regulating the PI3K-Akt, MAPK, JAK-STAT, VEGF, chemokine, actin cytoskeleton, HIF-1, and pluripotency of stem cells. This study provides a rapid method for metabolite characterization and a new perspective of underlying mechanism study from the aspect of active metabolites in vivo.

Filamin A, encoded by the X-linked gene FLNA, links the cell membrane with the cytoskeleton and acts as a regulator of the actin cytoskeleton. Mutations in FLNA cause a large spectrum of congenital malformations during embryonic development, including Melnick-Needles syndrome (MNS). However, reports of MNS, especially in males, are rare, and the pathogenesis molecular mechanisms are not well understood.

Twitter has become an important promotional tool for scholarly work, but individual academic publications have varied degrees of visibility on the platform. We explain this variation through the concept of Twitter-worthiness: factors making certain academic publications more likely to be visible on Twitter. Using publications from communication studies as our analytical case, we conduct statistical analyses of 32187 articles spanning 82 journals. Findings show that publications from G12 countries, covering social media topics and published open access tend to be mentioned more on Twitter. Similar to prior studies, this study demonstrates that Twitter mentions are associated with peer citations. Nevertheless, Twitter also has the potential to reinforce pre-existing disparities between communication research communities, especially between researchers from developed and less-developed regions. Open access, however, does not reinforce such disparities.

CHI3L2 (Chitinase-3-Like Protein 2) is a member of chitinase-like proteins (CLPs), which belong to the glycoside hydrolase 18 family. Its homologous gene, CHI3L1, has been extensively studied in various tumors and has been shown to be related to immune infiltration in breast cancer and glioblastoma. High CHI3L2 expression was reported to be associated with poor prognosis in breast cancer and renal cell carcinoma. However, the prognostic significance of CHI3L2 in glioma and its correlation between immune infiltration remains unclear. In this study, we examined 288 glioma samples by immunohistochemistry to find that CHI3L2 is expressed in tumor cells and macrophages in glioma tissues and highly expressed in glioblastoma and IDH wild-type gliomas. Relationships between CHI3L2 expression and clinical features (grade, age, Ki67 index, P53, PHH3 (mitotic figures), ATRX, TERTp, MGMTp, IDH, and 1p/19q co-deleted status) were evaluated. Kaplan-Meier survival was conducted to show high CHI3L2 expression in tumor cells (TC) and macrophage cells (MC) indicated poor prognosis in diffusely infiltrating glioma (DIG), lower-grade glioma (LGG), and IDH wild-type gliomas (IDH-wt). The overall survival time was higher in patients with dual-low CHI3L2 expression in TC and MC compared to those in patients with non-dual CHI3L2 expression and dual high expression in DIG and IDH wild-type gliomas. By univariate and multivariate analysis, we found that high CHI3L2 expression in tumor cells was an independent unfavorable prognostic factor in glioma patients. Moreover, we used two datasets (TCGA and CGGA) to verify the results of our study and explore the potential functional role of CHI3L2 by GO and KEGG analyses in gliomas. TIMER platform analysis indicated CHI3L2 expression was closely related to diverse marker genes of tumor immune infiltrating cells, including monocytes, TAMs, M1 macrophages, M2 macrophages, TGFβ1+ Treg and T cell exhaustion in GBM and LGG. Western Blot validated CHI3L2 is expressed in glioma cells and microglia cells. The results of flow cytometry showed that CHI3L2 induces the apoptosis of CD8+ T cells. In conclusion, these results demonstrate CHI3L2 is related to poor prognosis and immune infiltrates in gliomas, suggesting it may serve as a promising prognostic biomarker and represent a new target for glioma patients.

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Hydroxysteroid dehydrogenase like 2 (HSDL2) can regulate lipid metabolism and take part in cell proliferation. The purpose of the present study was to explore functional role of HSDL2 gene in PTC. The expression of HSDL2 protein in PTC tissues was estimated using immunohistochemistry analysis (IHC). HSDL2 mRNA level was detected through quantitative real-time polymerase chain reaction (qRT-PCR). Effects of HSDL2 gene on cell proliferation and apoptosis were assessed using the shRNA method for both in vitro and in vivo experiments. Potential target genes of HSDL2 were determined via bioinformatics analyses and Western blotting. HSDL2 was up-regulated in PTC tissues and cell lines compared with the controls (all P<0.05). Inhibiting HSDL expression could suppress PTC cell proliferation and cycle, and promote apoptosis in vitro. In vivo, the knockdown of HSDL2 gene could significantly suppress tumor growth (all P<0.05). Furthermore, AKT3, NFATc2 and PPP3CA genes might be potential targets of HSDL2 in PTC. HSDL2 expression was increased in PTC tissues and cells, which could promote tumor progression in vitro and in vivo.

Aberrant expression of microRNAs (miRNAs) has been reported to play a role in tumorigenesis. Dysfunction of miR-1296 was found in a variety of cancers, however, the function of miR-1296 in the progression of glioma remains largely understood. Here, our results showed that miR-1296 was significantly down-regulated in glioma tissues and cell lines. Decreased expression of miR-1296 was associated with the tumor size, WHO grade and karnofsky performance scale (KPS) of glioma patients. Low expression of miR-1296 was significantly correlated with the shorter 5-year overall survival of glioma patients. Overexpression of miR-1296 inhibited the proliferation, colony formation, migration and induced apoptosis of glioma cells. MiR-1296 was found to bind the 3'-untranslated region (UTR) of ABL proto-oncogene 2 (ABL2) and subsequently repressed both the mRNA and protein expression of ABL2. ABL2 was overexpressed in glioma tissues and inversely correlated with that of miR-1296. Ectopic expressed ABL2 could reverse the inhibitory effects of miR-1296 on glioma cell proliferation. Our results illustrated the novel tumor-suppressive function of miR-1296 in glioma via repressing ABL2, suggesting a potential application of miR-1296 in the treatment of glioma.