DNA surface exploration and operator bypassing during target search.

Many proteins that bind specific DNA sequences search the genome by combining three-dimensional diffusion with one-dimensional sliding on nonspecific DNA1-5. Here we combine resonance energy transfer and fluorescence correlation measurements to characterize how individual lac repressor (LacI) molecules explore the DNA surface during the one-dimensional phase of target search. To track the rotation of sliding LacI molecules on the microsecond timescale, we use real-time single-molecule confocal laser tracking combined with fluorescence correlation spectroscopy (SMCT-FCS). The fluctuations in fluorescence signal are accurately described by rotation-coupled sliding, in which LacI traverses about 40 base pairs (bp) per revolution. This distance substantially exceeds the 10.5-bp helical pitch of DNA; this suggests that the sliding protein frequently hops out of the DNA groove, which would result in the frequent bypassing of target sequences. We directly observe such bypassing using single-molecule fluorescence resonance energy transfer (smFRET). A combined analysis of the smFRET and SMCT-FCS data shows that LacI hops one or two grooves (10-20 bp) every 200-700 µs. Our data suggest a trade-off between speed and accuracy during sliding: the weak nature of nonspecific protein-DNA interactions underlies operator bypassing, but also speeds up sliding. We anticipate that SMCT-FCS, which monitors rotational diffusion on the microsecond timescale while tracking individual molecules with millisecond resolution, will be applicable to the real-time investigation of many other biological interactions and will effectively extend the accessible time regime for observing these interactions by two orders of magnitude.

Global, regional and national temporal trends in prevalence for musculoskeletal disorders in women of childbearing age, 1990-2019: an age-period-cohort analysis based on the Global Burden of Disease Study 2019.

OBJECTIVES: To provide an overview and in-depth analysis of temporal trends in prevalence of musculoskeletal (MSK) disorders in women of childbearing age (WCBA) at global, regional and national levels over the last 30 years, with a special focus on their associations with age, period and birth cohort. METHODS: Estimates and 95% uncertainty intervals (UIs) for MSK disorders prevalence in WCBA were extracted from the Global Burden of Diseases, Injuries and Risk Factors Study 2019. An age-period-cohort model was adopted to estimate the overall annual percentage change of prevalence (net drift, % per year), annual percentage change of prevalence within each age group (local drift, % per year), fitted longitudinal age-specific rates adjusted for period deviations (age effects) and period/cohort relative risks (period/cohort effects) from 1990 to 2019. RESULTS: In 2019, the global number of MSK disorders prevalence in WCBA was 354.57 million (95% UI: 322.64 to 387.68). Fifty countries had at least one million prevalence, with India, China, the USA, Indonesia and Brazil being the highest accounting for 51.03% of global prevalence. From 1990 to 2019, a global net drift of MSK disorders prevalence in WCBA was -0.06% (95% CI: -0.07% to -0.05%) per year, ranging from -0.09% (95% CI: -0.10% to -0.07%) in low-middle sociodemographic index (SDI) region to 0.10% (95% CI: 0.08% to 0.12%) in high-middle SDI region, with 138 countries presenting increasing trends, 24 presenting decreasing trends and 42 presenting relatively flat trends. As reflected by local drift, higher SDI regions had more age groups showing rising prevalence whereas lower SDI regions had more declining prevalence. Globally, an increasing occurrence of MSK disorders prevalence in WCBA beyond adolescent and towards the adult stage has been prominent. Age effects illustrated similar patterns across different SDI regions, with risk increasing with age. High SDI region showed generally lower period risks over time, whereas others showed more unfavourable period risks. High, high-middle and middle SDI regions presented unfavourable prevalence deteriorations, whereas others presented favourable prevalence improvements in successively birth cohorts. CONCLUSIONS: Although a favourable overall temporal trend (net drift) of MSK disorders prevalence in WCBA was observed over the last 30 years globally, there were 138 countries showing unfavourable rising trends, coupled with deteriorations in period/cohort risks in many countries, collectively raising concerns about timely realisation of the Targets of Sustainable Development Goal. Improvements in the MSK disorders-related prevention, management and treatment programmes in WCBA could decline the relative risk for successively younger birth cohorts and for all age groups over period progressing.

Central anterior chamber depth correlated with white-to-white distance in normal, long, and short eyes.

PURPOSE: To explore the associations between central anterior chamber depth (CACD) and other anterior segment biometric parameters and to determine the possible determinants of CACD in short, normal, and long eyes. METHODS: The biometric data of pre-operation patients aged 50-80 years with coexisting cataract and primary angle-closure disease or senile cataract were reviewed. Axial length (AL), CACD, lens thickness (LT), central corneal thickness (CCT), and white-to-white distance (WTW) were measured by Lenstar optical biometry (Lenstar 900). The data of 100 normal eyes (AL = 22 to 26 mm), 100 short eyes (AL ≤ 22 mm), and 100 long eyes (AL ≥ 26 mm) were consecutively collected for subsequent analyses. RESULTS: The mean age of the subjects was 66.60 ± 7.85 years, with 25.7% of the sample being men. Both CACD and WTW were found to be smallest in short eyes and were smaller in normal eyes than in long eyes (F = 126.524, P < 0.001; F = 28.458, P < 0.001). The mean LT was significantly thicker in short eyes than in normal and long eyes (4.66 mm versus 4.49 mm versus 4.40 mm; F = 18.099, P < 0.001). No significant differences were observed in CCT between the three AL groups (F = 2.135, P = 0.120). Stepwise regression analysis highlighted AL, LT, and WTW as three independent factors associated with CACD in the normal AL group. In the short AL group and long AL group, LT and WTW were independent factors associated with CACD. CONCLUSIONS: CACD increases as AL elongates and reaches a peak when AL exceeds 26 mm. Furthermore, CACD showed inverse correlation with LT and positive correlation with WTW. A relatively small WTW results in an anteriorly positioned lens, and thus, a decrease in CACD.

Single-center phase 2 study of PD-1 inhibitor combined with DNA hypomethylation agent + CAG regimen in patients with relapsed/refractory acute myeloid leukemia.

Anti-PD-1 monotherapy had limited clinical efficacy in relapsed/refractory (r/r) AML patients with higher PD-1 and PD-L1 expression. Hence, we investigated the efficacy and safety of PD-1 inhibitor with DNA hypomethylating agent (HMA) + CAG regimen in patients who had failed prior AML therapy. In this phase 2, single-arm study, r/r AML patients received azacitidine or decitabine plus CAG regimen with tislelizumab. Primary endpoints were efficacy (objective response rate [ORR]) and safety. Secondary endpoints included overall survival (OS), event-free survival (EFS) and duration of response (DOR). Statistical analyses were performed using Stata 14.0 and SPSS 20.0 software where P < 0.05 denoted significance. Twenty-seven patients were enrolled patients and completed 1 cycle, and 14 (51.9%) and 4 (14.8%) patients completed 2 and 3 cycles, respectively. ORR was 63% (14: complete remission [CR]/CR with incomplete hematologic recovery [CRi], 3: partial remission (PR), 10: no response [NR]). Median OS (mOS) and EFS were 9.7 and 9.2 months, respectively. With a median follow-up of 8.2 months (1.1-26.9), the mOS was not reached in responders (CR/CRi/PR) while it was 2.4 months (0.0-5.4) in nonresponders (P = 0.002). Grade 2-3 immune-related adverse events (irAEs) were observed in 4 (14.8%) patients and 3 nonresponders died of lung infection after treatment. Tislelizumab + HMA + CAG regimen showed improved outcomes in r/r AML patients with lower pretherapy leukemia burden. irAEs were mild and low-grade and higher pretherapy bone marrow CD4+ CD127+ PD-1+ T cells might serve as a predictor of treatment response.ClinicalTrials.gov identifier NCT04541277.

CiTSA: a comprehensive platform provides experimentally supported signatures of cancer immunotherapy and analysis tools based on bulk and scRNA-seq data.

Immunotherapy has greatly changed the status of cancer treatment, and many patients do not respond or develop acquired resistance. The related research is blocked by lacking of comprehensive resources for researchers to discovery and analysis signatures, then further exploring the mechanisms. Here, we first offered a benchmarking dataset of experimentally supported signatures of cancer immunotherapy by manually curated from published literature works and provided an overview. We then developed CiTSA ( http://bio-bigdata.hrbmu.edu.cn/CiTSA/ ) which stores 878 entries of experimentally supported associations between 412 signatures such as genes, cells, and immunotherapy across 30 cancer types. CiTSA also provides flexible online tools to identify and visualize molecular/cell feature and interaction, to perform function, correlation, and survival analysis, and to execute cell clustering, cluster activity, and cell-cell communication analysis based on single cell and bulk datasets of cancer immunotherapy. In summary, we provided an overview of experimentally supported cancer immunotherapy signatures and developed CiTSA which is a comprehensive and high-quality resource and is helpful for understanding the mechanism of cancer immunity and immunotherapy, developing novel therapeutic targets and promoting precision immunotherapy for cancer.

Therapeutic effects of a novel venom abstract (ZK002) solution in an alkali-burned corneal wound-healing model.

Purpose: Corneal alkali burns can progress to corneal epithelial defects, inflammation, scarring, and angiogenesis, potentially leading to blindness. Therefore, we examined the therapeutic effects of a novel ophthalmic solution (ZK002) on wound healing in alkali-burned rat corneas. Methods: In this study, we attempted to treat alkali-exposed rat corneas using topical application of either an ophthalmic solution with ZK002 or an anti-vascular endothelial growth factor agent for 14 days. We evaluated corneal edema, corneal neovascularization area, and histological changes. We also assessed the inflammatory (MMP-9, MMP-2, and interleukin-1ß) and angiogenic (vascular endothelial growth factor receptor 2, VEGFR2) markers. Levels of inflammatory (matrix metalloproteinase (MMP)-9, MMP-2, and interleukin-1ß), profibrotic (α-smooth muscle actin, α-SMA; transforming growth factor-ß2,TGF-ß2), and angiogenic (vascular endothelial growth factor-receptor 2, VEGFR2) factors, as well as peroxisome proliferator-activated receptor γ (PPARγ) mRNA expression, were measured. Results: The analyses showed that alkali exposure caused an increase in corneal edema and fibrosis with corneal neovascularization. The accumulation of α-smooth muscle actin-positive myofibroblasts and the deposition of transforming growth factor-ß2 on the alkali-exposed corneas were noted on day 14. The mRNA expression levels of interleukin-1ß, MMP-9, MMP-2, VEGFR2, and profibrotic factors were decreased in the ZK002 group compared with the control group during the early period of corneal alkali burns on day 14. However, the expression level of PPARγ mRNA was increased in the ZK002 group. Conclusions: ZK002 decreased the fibrotic reaction and prevented neovascularization in the cornea after an alkali burn. Therefore, the novel ophthalmic solution ZK002 could be a potentially promising therapeutic clinical treatment for corneal wound healing.

Phagocyte extracellular traps formation contributes to host defense against Clostridium perfringens infection.

Clostridium perfringens (C. perfringens) is an important Gram-positive anaerobic spore-forming pathogen that provokes life-threatening gas gangrene and acute enterotoxaemia, although it colonizes as a component of the symbiotic bacteria in humans and animals. However, the mechanisms by which C. perfringens is cleared from the host remains poorly understood, thereby impeding the development of novel strategies for control this infection. Here, we uncover a beneficial effect of extracellular traps (ETs) formation on bacterial killing and clearance by phagocytes. C. perfringens strain ATCC13124, and wild-type isolates CP1 and CP3 markedly trigger ETs formation in macrophages and neutrophils. As expected, visualization of DNA decorated with histone, myeloperoxidase (MPO) and neutrophils elastase (NE) in C. perfringens-triggered classical ETs structures. Notably, the bacteria-induced ETs formation is an ERK1/2-, P38 MAPK-, store-operated calcium entry (SOCE)-, NADPH oxidase-, histone-, NE-, and MPO-dependent process, and is independent of LDH activity. Meanwhile, the defect of bactericidal activity is mediated by impairing ETs formation in phagocytes. Moreover, In vivo studies indicated that degradation of ETs by DNase I administration leads to a defect in the protection against experimental gas gangrene, with higher mortality rates, exacerbated tissue damage, and more bacterial colonization. Together, these results suggest that phagocyte ETs formation is essential for the host defense against C. perfringens infection.

Targeting aging with the healthy skeletal system: The endocrine role of bone.

Aging is an inevitable biological process, and longevity may be related to bone health. Maintaining strong bone health can extend one's lifespan, but the exact mechanism is unclear. Bone and extraosseous organs, including the heart and brain, have complex and precise communication mechanisms. In addition to its load bearing capacity, the skeletal system secretes cytokines, which play a role in bone regulation of extraosseous organs. FGF23, OCN, and LCN2 are three representative bone-derived cytokines involved in energy metabolism, endocrine homeostasis and systemic chronic inflammation levels. Today, advanced research methods provide new understandings of bone as a crucial endocrine organ. For example, gene editing technology enables bone-specific conditional gene knockout models, which allows the study of bone-derived cytokines to be more precise. We systematically evaluated the various effects of bone-derived cytokines on extraosseous organs and their possible antiaging mechanism. Targeting aging with the current knowledge of the healthy skeletal system is a potential therapeutic strategy. Therefore, we present a comprehensive review that summarizes the current knowledge and provides insights for futures studies.

Dimension-Dependent Phase Transitions, Ferroelasticity, and Photoluminescence in Hybrid Organic-Inorganic Materials.

[(CH3)3P(CH2)2OH]2Cd3(SCN)8 (1) and [(CH3)3P(CH2)2OH]Cd(SCN)3 (2) were obtained with completely different structures and properties under the same synthesis conditions. Compound 1, showing green fluorescence, has a rare three-dimensional 4,6-connected fsh topology having (43.63)2(46.66.83) Schläfli notation, while compound 2 with blue-violet phosphorescence displays a one-dimensional perovskite structure with an infinite {[Cd(SCN)3]-}∞ chain and exhibits both ferroelastic and dielectric switching characteristics.

A Maximization of the Proton Conductivity of Sulfonated Poly(Ether Ether Ketone) with Grafted Segments Containing Multiple, Flexible Propanesulfonic Acid Groups.

To enhance the proton conductivity of sulfonated poly(ether ether ketone) (SPEEK), proton-conducting groups are required to be covalently connected to SPEEK and form proton-conducting channels. Herein, SPEEK fully grafted with segments containing multiple, flexible propanesulfonic acid groups (MS-SPEEK-102) is successfully prepared. Compared with SPEEK, MS-SPEEK-102 exhibits a higher proton conductivity of 8.3 × 10-2  S cm-1 at 80 °C with 98% relative humidity, and consequently a greater power density of 0.530 W cm-2 at 60 °C. These can be ascribed to the increased number of sulfonic acid groups, and ample, uninterrupted proton-conducting channels constructed by the movement of the maximum content, flexible side-chain segments. This approach offers an idea for obtaining a proton exchange membrane with good proton conductivity based on SPEEK.

Emerging roles of air pollution and meteorological factors in autoimmune eye diseases.

Autoimmune eye diseases (AEDs), a collection of autoimmune inflammatory ocular conditions resulting from the dysregulation of immune system at the ocular level, can target both intraocular and periorbital structures leading to severe visual deficit and blindness globally. The roles of air pollution and meteorological factors in the initiation and progression of AEDs have been increasingly attractive, among which the systemic and local mechanisms are both involved in. Exposure to excessive air pollution and extreme meteorological conditions including PM2.5/PM0.1, environmental tobacco smoke, insufficient sunshine, and high temperature, etc., can disturb Th17/Treg balance, regulate macrophage polarization, activate neutrophils, induce systemic inflammation and oxidative stress, decrease retinal blood flow, promote tissue fibrosis, activate sympathetic nervous system, adversely affect nutrients synthetization, as well as induce heat stress, therefore may together deteriorate AEDs. The crosstalk among inflammation, oxidative stress and dysregulated immune system appeared to be prominent. In the present review, we will concern and summarize the potential mechanisms underlying linkages of air pollution and meteorological factors to ocular autoimmune and inflammatory responses. Moreover, we concentrate on the specific roles of air pollutants and meteorological factors in several major AEDs including uveitis, Graves' ophthalmopathy (GO), ocular allergic disease (OAD), glaucoma, diabetic retinopathy (DR), etc.

Relationship between myopia control and amount of corneal refractive change after orthokeratology lens treatment.

BACKGROUND: To evaluate the relationship between amount of corneal refractive change (CRC) after wearing orthokeratology (Ortho-K) lenses and axial length (AL) growth. METHODS: We retrospectively enrolled 77 patients (77 eyes) aged 8-14 years who wore Ortho-K lenses more than 12 months. We divided the patients into 2 subgroups: spherical equivalent (SE) ≤ -3.0 D and SE > -3.0 D subgroup. The sagittal and tangential curvature maps and corneal topographic data within the 8-mm diameter ring at the baseline and during follow-up visits after wearing Ortho-K lens were recorded in addition to the area, height, and volume of the CRC region. The AL data were recorded at the baseline and during follow-up visits. Multivariate linear regression was conducted to analyze associations between the area, height, and volume of the CRC region, AL elongation, and SE. RESULTS: The average change in the CRC region was 9.77 ± 0.60 D in height, 16.66 ± 3.61 mm2 in area, and 87.47 ± 8.96 D*mm2 in volume on the tangential diagram after wearing Ortho-K lenses for 3 months. The AL showed a change of 0.19 ± 0.14 mm after 1 year of Ortho-K lens wear (P < 0.05). At 1 year, AL elongation was negatively correlated with the area (P = 0.019) and volume (P < 0.001) of the CRC region. At 1 year, for every 1-mm2 increase in the area and every 1-D*mm2 increase in the volume of the CRC region, the average AL elongation decreased by 0.01 mm and 0.002 mm, respectively, in the multivariate analysis. In patients with SE ≤ -3.0 D, AL elongation was negatively correlated with the CRC-region volume (ß = -0.002, P = 0.018), and in patients with SE > -3.0 D, AL elongation was negatively correlated with the CRC-region area (ß = -0.017, P = 0.016). CONCLUSIONS: The AL elongation-control efficacy of Ortho-K lenses may be related to the area and volume of the CRC region.

Factors for incidence risk and prognosis of synchronous brain metastases in pulmonary large cell carcinoma patients: a population-based study.

BACKGROUND: Patients with pulmonary large cell carcinoma (LCC) have a high incidence of synchronous brain metastases (SBM) and a poor prognosis. Our study was to evaluate the predictive and prognostic value of the clinical characteristics of pulmonary LCC patients with SBM at initial diagnosis by utilizing the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: LCC patients, diagnosed from 2010 to 2019, were identified from the latest SEER database which was released in April 2022. Logistic regression and Cox regression were used to identify the predictive and prognostic factors for LCC patients with SBM. Propensity score matching (PSM) and Kaplan-Meier analyses were applied to assess different therapy modalities. RESULTS: A total of 1375 LCC patients were enrolled in this study and 216 (15.7%) of them had SBM at the initial diagnosis. The median overall survival (OS) of LCC patients with SBM was 4 months. Multivariate Cox regression identified age 60-79 (OR 0.57; 95% CI 0.41-0.78; p < 0.001), age ≥ 80 (OR 0.23; 95% CI 0.12-0.45; p < 0.001) and bone metastases (OR 1.75; 95% CI 1.22-2.51; p < 0.001) as significant independent predictors for developing SBM. Multivariable Cox regression revealed that age 60-79, T stage, bone metastases and chemotherapy were independent prognostic factor for OS. The surgery combined with chemotherapy and radiotherapy group, in which all patients were N0 stage and had no other site-specific metastases, exhibited the best median OS of 15 months. CONCLUSIONS: LCC patients with age < 60 or bone metastases were more likely to have SBM at initial diagnosis. Age, T stage, bone metastases and chemotherapy were independent prognostic factors for OS of LCC patients with SBM. Highly selected patients might achieve the best survival benefit from surgery combined with chemotherapy and radiotherapy.

Machine learning models for orthokeratology lens fitting and axial length prediction.

PURPOSE: In order to improve the efficiency of orthokeratology (OK) lens fitting and predict the axial length after 1 year of OK lens wear, machine learning models were proposed. METHODS: Clinical data from 1302 myopic subjects were collected retrospectively, and two machine learning models were implemented. Demographic and corneal topographic data were collected as input variables. The output variables were the parameters of the OK lens and the axial length after 1 year. Eighty percent of input variables was used as the training set and the remaining 20% was used as the validation set. The first alignment curve (AC1) of the OK lenses, deduced using machine learning models and formula calculation, were compared. Multiple regression models (support vector machine, Gaussian process, decision tree and random forest) were used to predict the axial length after 1 year. In addition, we classified data based on lens brand, and carried out more detailed parameter fitting and analysis for spherical and toric OK lenses. RESULTS: The OK lens fitting model showed higher (R2 = 0.93) and lower errors (mean absolute error [MAE] = 0.19, mean square error [MSE] = 0.09) when predicting AC1, compared with the formula calculation (R2 = 0.66, MAE = 0.44, MSE = 0.25). The machine learning model still had high R2 values ranging from 0.91 to 0.96 when considering the brand and design of the OK lenses. Further, the R2 value for the axial length prediction model was 0.94, which indicated that the machine learning model had high accuracy and good robustness. CONCLUSION: The OK lens fitting model and the axial length prediction model played an important role in guiding OK lens fitting, with high accuracy and robustness in prediction performance.

One-dimensional coordinated polymers of tetraphenylethene pyridine and copper-iodide for fluorescence detection of nitroaromatic explosives.

The spatial arrangement of molecules plays a crucial role in determining the macroscopic properties of functional materials. Coordinated polymers (CPs) formed by self-assembly of organic isomeric ligands and metals offer unique performance characteristics. In this study, we present the investigation of a one-dimensional CP, named CIT-E, composed of tetraphenylethene pyridine derivative (TPE-2by-2-E) ligands and copper iodide. The resulting CP exhibits a one-dimensional bead chain structure with exceptional thermal and chemical stability. By leveraging the competitive absorption between CIT-E and the explosive analog 2,4-dinitroaniline, we achieve detection of the explosive through changes in the absorption intensity of the excitation light source and subsequent fluorescence response. The CP demonstrates high selectivity and anti-interference ability in detecting 2,4-dinitroaniline in aqueous solution, with a detection linear range of 0.1 to 300 µM and a detection limit of 0.05 µM, surpassing the national third-level emission standard. These findings highlight the potential of CP CIT-E as a promising material for the detection of explosive nitroaromatic compounds.

[Clinical and molecular genetic analysis of a child with Schmid type metaphyseal chondrodysplasia].

OBJECTIVE: To analyze the clinical features and genotype of a child with Schmid type metaphyseal chondrodysplasia. METHODS: Clinical data of the child and her parents was collected. The child was subjected to high-throughput sequencing, and candidate variant was verified by Sanger sequencing of her family members. RESULTS: Whole exome sequencing revealed that the child has harbored a heterozygous c.1772G>A (p.C591Y) variant of the COL10A1 gene, which was not found in either of her parents. The variant was not found in the HGMD and ClinVar databases, and was rated as likely pathogenic based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). CONCLUSION: The heterozygous c.1772G>A (p.C591Y) variant of the COL10A1 gene probably underlay the Schmid type metaphyseal chondrodysplasia in this child. Genetic testing has facilitated the diagnosis and provided a basis for genetic counselling and prenatal diagnosis for this family. Above finding has also enriched the mutational spectrum of the COL10A1 gene.

Microfluidic Platform for Time-Resolved Characterization of Protein Higher-Order Structures and Dynamics Using Top-Down Mass Spectrometry.

Characterization of protein higher-order structures and dynamics is essential for understanding the biological functions of proteins and revealing the underlying mechanisms. Top-down mass spectrometry (MS) accesses structural information at both the intact protein level and the peptide fragment level. Native top-down MS allows analysis of a protein complex's architecture and subunits' identity and modifications. Top-down hydrogen/deuterium exchange (HDX) MS offers high spatial resolution for conformational or binding interface analysis and enables conformer-specific characterization. A microfluidic chip can provide superior performance for front-end reactions useful for these MS workflows, such as flexibility in manipulating multiple reactant flows, integrating various functional modules, and automation. However, most microchip-MS devices are designed for bottom-up approaches or top-down proteomics. Here, we demonstrate a strategy for designing a microchip for top-down MS analysis of protein higher-order structures and dynamics. It is suitable for time-resolved native MS and HDX MS, with designs aiming for efficient ionization of intact protein complexes, flexible manipulation of multiple reactant flows, and precise control of reaction times over a broad range of flow rates on the submicroliter per minute scale. The performance of the prototype device is demonstrated by measurements of systems including monoclonal antibodies, antibody-antigen complexes, and coexisting protein conformers. This strategy may benefit elaborate structural analysis of biomacromolecules and inspire method development using the microchip-MS approach.

The positive feedback loop of NHE1-ERK phosphorylation mediated by BRAFV600E mutation contributes to tumorigenesis and development of glioblastoma.

The v-raf murine sarcoma viral oncogene homolog B1 (BRAF) activating mutation V600E (BRAFV600E) is involved in glioblastoma multiforme (GBM). Na/H exchanger 1 (NHE1), a main pH regulator affecting cell microenvironment, is hyper-expressed in GBM. However, the relationship between BRAFV600E signal pathway and NHE1 in GMB cells remains unclear. This study found that NHE1 was a downstream target of BRAFV600E and an upstream factor of extracellular signal-regulated kinase (ERK). In addition, there was a positive feedback loop between NHE1-ERK phosphorylation under regulation of BRAFV600E mutation contributing to the proliferation and invasion of GBM cells. Moreover, the proliferation and invasion abilities of BRAFV600E-mutant and BRAF wild type GBM cells were all suppressed by the NHE1 inhibitor, BRAFV600E inhibitor and combination of them. The inhibitory effect of combination of the two inhibitors was better than each single drug both in vitro and in vivo. Combination of BRAFV600E and NHE1 inhibitors could be considered as a new therapeutic regimen for GBM, especially for GBM with BRAFV600E.

Identification and comprehensive characterization of lncRNAs with copy number variations and their driving transcriptional perturbed subpathways reveal functional significance for cancer.

Numerous studies have shown that copy number variation (CNV) in lncRNA regions play critical roles in the initiation and progression of cancer. However, our knowledge about their functionalities is still limited. Here, we firstly provided a computational method to identify lncRNAs with copy number variation (lncRNAs-CNV) and their driving transcriptional perturbed subpathways by integrating multidimensional omics data of cancer. The high reliability and accuracy of our method have been demonstrated. Then, the method was applied to 14 cancer types, and a comprehensive characterization and analysis was performed. LncRNAs-CNV had high specificity in cancers, and those with high CNV level may perturb broad biological functions. Some core subpathways and cancer hallmarks widely perturbed by lncRNAs-CNV were revealed. Moreover, subpathways highlighted the functional diversity of lncRNAs-CNV in various cancers. Survival analysis indicated that functional lncRNAs-CNV could be candidate prognostic biomarkers for clinical applications, such as ST7-AS1, CDKN2B-AS1 and EGFR-AS1. In addition, cascade responses and a functional crosstalk model among lncRNAs-CNV, impacted genes, driving subpathways and cancer hallmarks were proposed for understanding the driving mechanism of lncRNAs-CNV. Finally, we developed a user-friendly web interface-LncCASE (http://bio-bigdata.hrbmu.edu.cn/LncCASE/) for exploring lncRNAs-CNV and their driving subpathways in various cancer types. Our study identified and systematically characterized lncRNAs-CNV and their driving subpathways and presented valuable resources for investigating the functionalities of non-coding variations and the mechanisms of tumorigenesis.

The role of small extracellular vesicles in cerebral and myocardial ischemia-Molecular signals, treatment targets, and future clinical translation.

The heart and the brain mutually interact with each other, forming a functional axis that is disturbed under conditions of ischemia. Stem cell-derived extracellular vesicles (EVs) show great potential for the treatment of ischemic stroke and myocardial infarction. Due to heart-brain interactions, therapeutic actions of EVs in the brain and the heart cannot be regarded in an isolated way. Effects in each of the two organs reciprocally influence the outcome of the other. Stem cell-derived EVs modulate a large number of signaling pathways in both tissues. Upon ischemia, EVs prevent delayed injury, promote angiogenesis, enhance parenchymal remodeling, and enable functional tissue recovery. The therapeutic effects greatly depend on EV cargos, among which are noncoding RNAs like microRNAs (miRNAs) and proteins, which modulate cell signaling in a differential way that not always corresponds to each other in the two tissues. Interestingly, the same miRNA or protein localized in EVs can modulate different signaling pathways in the ischemic heart and brain, which may have diverse consequences for disease outcomes. Paying careful attention to unveiling these underlying mechanisms may provide new insights into tissue remodeling processes and identify targets for ischemic stroke and myocardial infarction therapies. Some of these mechanisms are discussed in this concise review, and consequences for the clinical translation of EVs are presented.