Second-generation sequencing technologies have replaced array-based technologies and become the default method for genomics and epigenomics analysis. Second-generation sequencing technologies ...sequence tens of millions of DNA/cDNA fragments in parallel. After the resulting sequences (short reads) are mapped to the genome, one gets a sequence of short read counts along the genome. Effective extraction of signals in these short read counts is the key to the success of sequencing technologies. Nonparametric methods, in particular smoothing splines, have been used extensively for modeling and processing single sequencing samples. However, nonparametric joint modeling of multiple second-generation sequencing samples is still lacking due to computational cost. In this article, we develop an adaptive basis selection method for efficient computation of exponential family smoothing splines for modeling multiple second-generation sequencing samples. Our adaptive basis selection gives a sparse approximation of smoothing splines, yielding a lower-dimensional effective model space for a more scalable computation. The asymptotic analysis shows that the effective model space is rich enough to retain essential features of the data. Moreover, exponential family smoothing spline models computed via adaptive basis selection are shown to have good statistical properties, e.g., convergence at the same rate as that of full basis exponential family smoothing splines. The empirical performance is demonstrated through simulation studies and two second-generation sequencing data examples.
Full text
Available for:
BFBNIB, NMLJ, NUK, PNG, UL, UM, UPUK
BACKGROUND: Integrin-regulated monocyte recruitment and cellular responses of monocyte-derived macrophages are critical for the pathogenesis of atherosclerosis. In the canonical model, talin1 ...controls ligand binding to integrins, a prerequisite for integrins to mediate leukocyte recruitment and induce immune responses. However, the role of talin1 in the development of atherosclerosis has not been studied. Our study investigated how talin1 in myeloid cells regulates the progression of atherosclerosis. METHODS: On an Apoe −/− background, myeloid talin1-deficient mice and the control mice were fed with a high-fat diet for 8 or 12 weeks to induce atherosclerosis. The atherosclerosis development in the aorta and monocyte recruitment into atherosclerotic lesions were analyzed. RESULTS: Myeloid talin1 deletion facilitated the formation of atherosclerotic lesions and macrophage deposition in lesions. Talin1 deletion abolished integrin β2–mediated adhesion of monocytes but did not impair integrin α4β1–dependent cell adhesion in a flow adhesion assay. Strikingly, talin1 deletion did not prevent Mn 2+ - or chemokine-induced activation of integrin α4β1 to the high-affinity state for ligands. In an in vivo competitive homing assay, monocyte infiltration into inflamed tissues was prohibited by antibodies to integrin α4β1 but was not affected by talin1 deletion or antibodies to integrin β2. Furthermore, quantitative polymerase chain reaction and ELISA (enzyme-linked immunosorbent assay) analysis showed that macrophages produced cytokines to promote inflammation and the proliferation of smooth muscle cells. Ligand binding to integrin β3 inhibited cytokine generation in macrophages, although talin1 deletion abolished the negative effects of integrin β3. CONCLUSIONS: Integrin α4β1 controls monocyte recruitment during atherosclerosis. Talin1 is dispensable for integrin α4β1 activation to the high-affinity state and integrin α4β1–mediated monocyte recruitment. Yet, talin1 is required for integrin β3 to inhibit the production of inflammatory cytokines in macrophages. Thus, intact monocyte recruitment and elevated inflammatory responses cause enhanced atherosclerosis in talin1-deficient mice. Our study provides novel insights into the roles of myeloid talin1 and integrins in the progression of atherosclerosis.
The biologic and clinical significance of
KIT overexpression that associates with
KIT gain-of-function mutations occurring in subsets of acute myeloid leukemia (AML) (i.e., core binding factor AML) ...is unknown. Here, we show that
KIT mutations lead to
MYC-dependent
miR-29b repression and increased levels of the
miR-29b target Sp1 in KIT-driven leukemia. Sp1 enhances its own expression by participating in a NFκB/HDAC complex that further represses
miR-29b transcription. Upregulated Sp1 then binds NFκB and transactivates
KIT. Therefore, activated KIT ultimately induces its own transcription. Our results provide evidence that the mechanisms of Sp1/NFκB/HDAC/
miR-29b-dependent
KIT overexpression contribute to leukemia growth and can be successfully targeted by pharmacological disruption of the Sp1/NFκB/HDAC complex or synthetic
miR-29b treatment in KIT-driven AML.
► Aberrant KIT activity from mutation or overexpression contributes to leukemogenesis ► KIT activation inhibits
miR-29b and unblocks expression of the
miR-29b target Sp1 ► Sp1-NFκB recruits HDAC for further
miR-29b inhibition, and transactivates
KIT ► Therapeutic modulation of
miR-29b/Sp1/NFκB/HDAC network overcomes KIT-driven leukemia
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The Beiya gold deposit is located in the central part of the Jinshajiang–Honghe strike–slip belt, at the junction zone of the Tethys-Himalaya orogenic belt and the Yangtze plate in SW China. This ...large-scale (125.6millionmetrictonnes with a mean grade of 2.42g/t) Au-rich polymetallic deposit is related to alkaline porphyry intrusions. Previous studies show that the Beiya alkaline porphyry intrusions are the fractionation product of a mantle-derived magma emplaced in an extension environment at the post-collision stage of the India–Eurasian plate collision; the Beiya deposit is considered to be skarn-related. Based on detailed field studies and previous work, we propose that the Beiya porphyry and associated Au-rich polymetallic ores were formed by the emplacement of magmas within the Jinshajiang–Honghe strike–slip fault during the late stage of the India–Eurasian plate collision at 45–25Ma.
At Beiya, the mineralized zones in the Cu–Au-rich porphyries are surrounded by Au–Cu–Fe skarns and Au (Cu) veins. Pb–Zn–Ag-rich mineralization was derived from the inner porphyry, and is widely developed outside the central alkaline-rich porphyry.
The sulfur isotope signature of the sulfide mineralization in the Beiya and Qinhe deposits is −2.40‰–4.50‰ and 1.25–2.75‰, respectively. These values are close to 0‰, indicating that the sulfur may be mantle-derived. The δ18O compositions of the ore-forming fluids responsible for the formation of calcites at Qinhe are 8.10‰–9.61‰, which is lower than that of Beiya (δ18O=10.5‰) where the ores contain a larger contribution of oxygen from the mantle. The Beiya porphyry magmas provided fluids and the heat that drove the transport of the metals to the site of deposition.
Alkaline porphyries are widely distributed throughout the Jinshajiang–Honghe strike–slip fault belt, and they are potential hosts to future discoveries of Beiya-style mineralization.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Aim
Aggravated neuronal loss, caused mainly by neuronal apoptosis, is observed in the brain of patients with Alzheimer's disease (AD) and animal models of AD. A truncated form of Dual‐specific and ...tyrosine phosphorylation‐regulated protein kinase 1A (Dyrk1A) plays a vital role in AD pathogenesis. Downregulation of anti‐apoptotic Bcl‐xL is tightly correlated with neuronal loss in AD. However, the molecular regulation of neuronal apoptosis and Bcl‐x expression by Dyrk1A in AD remains largely elusive. Here, we aimed to explore the role and molecular mechanism of Dyrk1A in apoptosis.
Methods
Cell Counting Kit‐8 (CCK8), flow cytometry, and TdT‐mediated dUTP Nick‐End Labeling (TUNEL) were used to check apoptosis. The cells, transfected with Dyrk1A or/and ASF with Bcl‐x minigene, were used to assay Bcl‐x expression by RT‐PCR and Western blots. Co‐immunoprecipitation, autoradiography, and immunofluorescence were conducted to check the interaction of ASF and Dyrk1A. Gene set enrichment analysis (GSEA) of apoptosis‐related genes was performed in mice overexpressing Dyrk1A (TgDyrk1A) and AD model 5xFAD mice.
Results
Dyrk1A promoted Bcl‐xS expression and apoptosis. Splicing factor ASF promoted Bcl‐x exon 2b inclusion, leading to increased Bcl‐xL expression. Dyrk1A suppressed ASF‐mediated Bcl‐x exon 2b inclusion via phosphorylation. The C‐terminus deletion of Dyrk1A facilitated its binding and kinase activity to ASF. Moreover, Dyrk1a1–483 further suppressed the ASF‐mediated Bcl‐x exon 2b inclusion and aggravated apoptosis. The truncated Dyrk1A, increased Bcl‐xS, and enrichment of apoptosis‐related genes was observed in the brain of 5xFAD mice.
Conclusions
We speculate that increased Dyrk1A and truncated Dyrk1A may aggravate neuronal apoptosis by decreasing the ratio of Bcl‐xL/Bcl‐xS via phosphorylating ASF in AD.
The full length Dyrk1A phosphorylated ASF and inhibited ASF‐mediated Bcl‐xL exon 2b inclusion leading to cell apoptosis. Moreover, the truncated Dyrk1A deleting the C‐terminus exhibited equidistribution in the nucleoplasm and stronger interaction with ASF, leading to decreased ratio of Bcl‐xL/Bcl‐xS and neuronal apoptosis in AD.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Micro-scale laser shock punching is a high strain rate micro-forming method which uses the high-amplitude shock wave pressure induced by pulsed laser irradiation. The response of brass and pure ...titanium foils under the different ratio of laser beam diameter (d) to die hole diameter (D) in micro-scale laser shock punching was investigated experimentally and numerically. The typical fracture surface morphologies were observed using scanning electron microscope. Numerical simulations were conducted to predict the stress state of the workpiece before and after fracture. The influence of the ratio d/D on dynamic deformation and fracture of metal foils was characterized. The results demonstrate that both the crack locations and fracture surface morphologies of metal foils are strongly related to the ratio d/D. The fracture mode varies from a shear fracture mode to a mixed fracture mode, then to a tensile fracture mode as the ratio decreases. The stress state under the different ratio is discussed in detail and believed to be responsible for the variation.
•Effect of the ratio of beam diameter (d) to die hole diameter (D) is studied.•The fracture mode of metal foils varies as the ratio d/D changes.•The crack location of metal foils is strongly related to the ratio d/D.•The stress state under the different ratios is simulated and discussed.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
e13110 Background: Breast cancer with ipsilateral supraclavicular lymph node (SCLN) metastasis is defined as Ⅲc stage according to the 8th AJCC system. It is still pending whether to exert SCLN ...dissection except for regional radiotherapy to such patients. Methods: Breast cancer patients with ipsilateral SCLN metastasis from 2019.02 to 2024.01 in multiple centers in Hubei China, were enrolled. Patients received either SCLN radiotherapy alone or combined with SCLN dissection. All patients received standard therapy recommended by the NCCN guidelines. The primary endpoint was 5-year disease free survival (DFS), and secondary endpoints were complication rates, overall survival (OS), and quality of life scores. Results: As of 2024.01, a total of 181 patients with a median age of 51 years (28-78 years) were enrolled. 177 patients received neoadjuvant therapy and 4 patients underwent surgery followed by adjuvant therapy. The molecular subtyping composition was Luminal (HR+, HER2-, 38%), TNBC (triple negative breast cancer, HR-, HER2-, 23%), HER2+ (HR-, HER2+, 20%) and TPBC (triple positive breast cancer, HR+, HER2+, 19%). Of the 177 neoadjuvant treated-patients, 71.2% did not achieve pathological complete response (pCR). The percentage of molecular subtyping in non-pCR neoadjuvant patients was Luminal 45%, TNBC 26%, HER2+ 15%, and TPBC 14%, while those who got pCR were HER2+ 35%, TPBC 31%, Luminal 18%, and TNBC 16%. A total of 27 recurrent and/or metastatic events occurred, with 14.5% (8/55) in the experimental group (with SCLN dissection) and 15.1% (19/126) in the control group; while Luminal accounted for 13.4% (9/67), TPBC 13.9% (5/36), HER2+ 16.2% (6/37) and TNBC 17.1% (7/41). Using questionnaires, we found that both groups resulted in comparable complication rates, and quality of life scores were better in the group that did not undergo SCLN dissection. Conclusions: According to the preliminary results, we found several interesting phenomena. First, patients with SCLN metastasis had a higher percentage of HER2 overexpression, including HER2+ and TPBC, up to 39%. Second, receiving neoadjuvant therapy, TPBC and HER2+ subtypes were more likely to achieve pCR, possibly due to the use of dual-targeted agents. Third, even the median follow-up time has not yet been reached, preliminary data suggested that the recurrent and metastatic rates were comparable in both groups and four subtypes. These data seem to suggest that in patients with ipsilateral SCLN metastasis, SCLN dissection is not mandatory with effective systematic therapy and radiotherapy. In addition, for Luminal subtype, adjuvant therapy should not be taken lightly, while for HER2 overexpressing and TNBC subtypes, the necessity of intensive therapy is no longer purposely highlighted. Of course, we also look forward to the final statistical analysis of the differences in the primary endpoints to bring us a better answer. Clinical trial information: NCT03716245 .
Assessing mental fatigue (MF) by using neurophysiological signals is prospective for predicting instantaneous degradation of operator performance in safety-critical human-machine systems. Reliable MF ...classifier modeled and tested by the physiological data collected from different subjects is quite practical since such cross-subject paradigm avoids preparing comprehensive subject-specific training sets. This paper proposes a novel EEG-based cross-subject MF classifier, ensemble deep belief networks (EDBN), by exploiting advantages of the deep leaning principle for abstraction higher-level EEG representations. The EDBN framework builds two different DBNs for each training subject as the static feature abstractor and the adaptive estimator to track the novel physiological property in EEG abstractions of the testing subject. The temporal OFS is predicted by switching the ensembles of the two DBNs at each time step via a Gaussian-kernel based criterion. The competence of the EDBN is validated by examining the OFS classes defmed by the mental workload, mental fatigue, and the coupling effect of the two variables stimulated by the AutoCAMS platform. The comparison of the cross-subject OFS classification accuracy demonstrates the EDBN significantly outperforms several state-of-the-art classifiers.
•The sensor can perform blood typing and erythrocyte counting simultaneously, which has been rarely reported previously.•The assay is more sensitive, needs less sample volume and requires less time, ...compared to common gel microcolumn assay.•The optical sensing chip is quite promising to achieve full automatization, as therefore to save time and avoid human error.
ABO blood group typing and erythrocyte counting are essential for blood transfusion especially in the vital lifesaving procedures. Here, we developed a simple, rapid and reliable assay for ABO blood group typing and erythrocyte counting based on localized surface plasmon resonance biosensor. The optical biosensors were constructed by the deposition of gold nanoprisms (GNPs) on glass substrates, and the immobilization of antibodies on the GNPs surface. The sensors were further integrated into a microfluidic chip containing two independent sample cells with anti-isoagglutinins A and anti-B antibodies modified at the bottoms, respectively. The sensing chips coupled with ultraviolet-visible (UV–vis) spectrometer were applied for the identification of blood type A, B, AB and O, respectively; meanwhile, a simple proof-of-principle strategy for quantifying red blood cells (RBCs) through the optical biosensors were demonstrated with series of RBCs dilution, and observed by UV–vis spectra. The limit of detection for erythrocyte counting was as low as ∼104 cells/mL (R2 = 0.99). Additionally, we compared our sensing results with those from conventional gel column assay on 7 different blood samples, in which the accuracy of blood typing was 100%. The RBC concentrations estimated by our sensor chips were between 3.9–5.0 × 109 cells/mL, which locates in the normal range of RBCs concentration of human. The LSPR biosensors that we developed are capable of qualitative ABO blood typing and quantitative erythrocyte counting simultaneously, which have great potential to develop a preliminary and lab-training-free biomedical device for rapid clinical diagnosis.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Combustible gases often lead to fire and explosion accidents due to their unsafe characteristics. Furthermore, their explosion limits are influenced by various factors. In the industrial production ...process, the operating unit is often in a high-temperature environment, and the multi-component gas explosion limits under this condition are difficult to determine. Therefore, it is urgent to have a universal theoretical prediction model to rapidly predict the multi-component gas explosion limits at high temperatures. This paper proposes a theoretical prediction model for the lower explosion limit of multi-combustible gases containing inert gases at different temperatures based on the heat balance equation and radiation heat loss, which can be used to solve the lower explosion limit of the “multiple combustible gases + multiple inert gases” mixture at different temperatures. It solves the explosion limits of methane, ethylene, propane, and propylene mixed with nitrogen with relative errors of 2.66%, 5.98%, 6.82%, and 5.88%, respectively, compared with experimental data. It also obtained theoretically predicted gas explosion limits for methane, ethylene, propane, and propylene mixed with carbon dioxide, with relative errors of 3.24%, 5.13%, 6.19%, and 5.58%, respectively. Although the reference experimental data made the model validation somewhat limited, validation with data for multiple single gases and temperatures still gave the model considerable reliability.
PDF
