miR-24 Regulates Apoptosis by Targeting the Open Reading Frame (ORF) Region of FAF1 in Cancer Cells

BACKGROUND: microRNAs (miRNAs) are small noncoding RNAs that regulate cognate mRNAs at the post-transcriptional stage. Several studies have shown that miRNAs modulate gene expression in mammalian cells by base pairing to complementary sites in the 3'-untranslated region (3'-UTR) of the target mRNAs. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, miR-24 was found to target fas associated factor 1(FAF1) by binding to its amino acid coding sequence (CDS) region, thereby regulating apoptosis in DU-145 cells. This result supports an augmented model whereby animal miRNAs can exercise their effects through binding to the CDS region of the target mRNA. Transfection of miR-24 antisense oligonucleotide (miR-24-ASO) also induced apoptosis in HGC-27, MGC-803 and HeLa cells. CONCLUSIONS/SIGNIFICANCE: We found that miR-24 regulates apoptosis by targeting FAF1 in cancer cells. These findings suggest that miR-24 could be an effective drug target for treatment of hormone-insensitive prostate cancer or other types of cancers. Future work may further develop miR-24 for therapeutic applications in cancer biology

Serum peptidome profiling for the diagnosis of colorectal cancer: Discovery and validation in two independent cohorts

Colorectal cancer (CRC) is one of the most common malignant neoplasms worldwide. Except for the existing fecal occult blood test, colonoscopy and sigmoidoscopy, no widely accepted in vitro diagnostic methods have been available. To identify potential peptide biomarkers for CRC, serum samples from a discovery cohort (100 CRC patients and 100 healthy controls) and an independent validation cohort (91 CRC patients and 91 healthy controls) were collected. Peptides were fractionated by weak cation exchange magnetic beads (MB-WCX) and analysed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDITOF MS). Five peptides (peaks at m/z 1895.3, 2020.9, 2080.7, 2656.8 and 3238.5) were identified as candidate biomarkers for CRC. A diagnostic panel based on the five peptides can discriminate CRC patients from healthy controls, with an accuracy of 91.8%, sensitivity of 95.6%, and specificity of 87.9% in the validation cohort. Peptide peaks at m/z 1895.3, 2020.9 and 3238.5 were identified as the partial sequences of complement component 4 (C4), complement component 3 (C3) and fibrinogen a chain (FGA), respectively. This study potentiated peptidomic analysis as a promising in vitro diagnostic tool for diagnosis of CRC. The identified peptides suggest the involvement of the C3, C4 and FGA in CRC pathogenesis

Profiling Plasma Peptides for the Identification of Potential Ageing Biomarkers in Chinese Han Adults

Advancing age is associated with cardiovascular disease, diabetes mellitus and cancer, and shows significant inter-individual variability. To identify ageing-related biomarkers we performed a proteomic analysis on 1890 Chinese Han individuals, 1136 males and 754 females, aged 18 to 82 years, using weak cation exchange magnetic bead based MALDI-TOF-MS analysis. The study identified 44 peptides which varied in concentration in different age groups. In particular, apolipoprotein A-I (ApoA1) concentration gradually increased between 18 to 50 years of age, the levels of fibrinogen alpha (FGA) decreased over the same age span, while albumin (ALB) was significantly degraded in middle-aged individuals. In addition, the plasma peptide profiles of FGA and four other unidentified proteins were found to be gender-dependent. Plasma proteins such as FGA, ALB and ApoA1 are significantly correlated with age in the Chinese Han population and could be employed as indicative ageingrelated biomarkers

Profile of immunoglobulin G N-glycome in COVID-19 patients: A case-control study

Coronavirus disease 2019 (COVID-19) remains a major health challenge globally. Previous studies have suggested that changes in the glycosylation of IgG are closely associated with the severity of COVID-19. This study aimed to compare the profiles of IgG N-glycome between COVID-19 patients and healthy controls. A case-control study was conducted, in which 104 COVID-19 patients and 104 age- and sex-matched healthy individuals were recruited. Serum IgG N-glycome composition was analyzed by hydrophilic interaction liquid chromatography with the ultra-high-performance liquid chromatography (HILIC-UPLC) approach. COVID-19 patients have a decreased level of IgG fucosylation, which upregulates antibody-dependent cell cytotoxicity (ADCC) in acute immune responses. In severe cases, a low level of IgG sialylation contributes to the ADCC-regulated enhancement of inflammatory cytokines. The decreases in sialylation and galactosylation play a role in COVID-19 pathogenesis via the activation of the lectin-initiated alternative complement pathway. IgG N-glycosylation underlines the complex clinical phenotypes of SARS-CoV-2 infection

Pivotal Role of the α2A-Adrenoceptor in Producing Inflammation and Organ Injury in a Rat Model of Sepsis

Background: Norepinephrine (NE) modulates the responsiveness of macrophages to proinflammatory stimuli through the activation of adrenergic receptors (ARs). Being part of the stress response, early increases of NE in sepsis sustain adverse systemic inflammatory responses. The intestine is an important source of NE release in the early stage of cecal ligation and puncture (CLP)-induced sepsis in rats, which then stimulates TNF-a production in Kupffer cells (KCs) through the activation of the a2-AR. It is important to know which of the three a2-AR subtypes (i.e., a2A, a2B or a2C) is responsible for the upregulation of TNF-a production. The aim of this study was to determine the contribution of a2A-AR in this process. Methodology/Principal Findings: Adult male rats underwent CLP and KCs were isolated 2 h later. Gene expression of a2A-AR was determined. In additional experiments, cultured KCs were incubated with NE with or without BRL-44408 maleate, a specific a2A-AR antagonist, and intraportal infusion of NE for 2 h with or without BRL-44408 maleate was carried out in normal animals. Finally, the impact of a2A-AR activation by NE was investigated under inflammatory conditions (i.e., endotoxemia and CLP). Gene expression of the a2A-AR subtype was significantly upregulated after CLP. NE increased the release of TNF-a in cultured KCs, which was specifically inhibited by the a2A-AR antagonist BRL-44408. Equally, intraportal NE infusion increased TNF-a gene expression in KCs and plasma TNF-a which was also abrogated by co-administration of BRL-44408. NE also potentiated LPS-induced TNF-a release via the a2A-AR in vitro and in vivo. This potentiation of TNF-a release by NE was mediated through the a2A-AR coupled Gai protein and the activation of the p38 MAP kinase. Treatment of septic animals with BRL-44408 suppressed TNF-a, prevented multiple organ injury and significantly improved survival from 45% to 75%. Conclusions/Significance: Our novel finding is that hyperresponsiveness to a2-AR stimulation observed in sepsis is primarily due to an increase in a2A-AR expression in KCs. This appears to be in part responsible for the increased proinflammatory response and ensuing organ injury in sepsis. These findings provide important feasibility information for further developing the a2A-AR antagonist as a new therapy for sepsis

Baichuan 2: Open Large-scale Language Models

Large language models (LLMs) have demonstrated remarkable performance on a variety of natural language tasks based on just a few examples of natural language instructions, reducing the need for extensive feature engineering. However, most powerful LLMs are closed-source or limited in their capability for languages other than English. In this technical report, we present Baichuan 2, a series of large-scale multilingual language models containing 7 billion and 13 billion parameters, trained from scratch, on 2.6 trillion tokens. Baichuan 2 matches or outperforms other open-source models of similar size on public benchmarks like MMLU, CMMLU, GSM8K, and HumanEval. Furthermore, Baichuan 2 excels in vertical domains such as medicine and law. We will release all pre-training model checkpoints to benefit the research community in better understanding the training dynamics of Baichuan 2.Comment: Baichuan 2 technical report. Github: https://github.com/baichuan-inc/Baichuan

Experimental, numerical study and design of concrete-encased concrete-filled steel tube columns and beam-column joints

Steel-concrete composite construction has been widely used for many years in medium to high rise buildings in Singapore, China, America and Japan. The structural and economic advantages of both steel and concrete materials are effectively combined in composite construction. Several structural types have been developed in the steel-concrete composite system, for example, steel beam-to-reinforced concrete (RCS) column frame, steel and concrete beam-to-concrete-filled steel tube (CFST) column frame. Recently, a new type of composite columns formed by encasing the conventional CFST column with the reinforced concrete encasement, known as concrete-encased concrete-filled steel tube (CECFST) column, is developed. Steel and concrete are combined and used more efficiently in CECFST columns. The steel tube of CECFST columns provides confinement effect to the inner concrete core. In return, the concrete encasement can enhance the buckling, fire and corrosion resistance of the inner steel tube. After a comprehensive review of previous research works, the author found that there were limited studies on effects of load eccentricity and biaxial loading for CECFST columns and the seismic performance of concrete beam-to-CECFST column joints. Moreover, there has not been any codes of practice that includes the design of CECFST columns under combined loading (both uniaxial and biaxial) and concrete beam-to-CECFST column joints under seismic loading. In addition, the widely used European code EN 1993-1-8 for joint design mainly address the design of steel structure and cannot be applied to the design of RCS joints. To address these research gaps, comprehensive experimental studies, including two series of tests, were undertaken to study the structural behaviour of CECFST columns and seismic performance of concrete beam-to-CECFST column joints (both cast-in-place and precast), respectively. Design approaches were developed for the cross-section strength prediction of CECFST columns and concrete beam-to-CECFST column joints. Mechanical models were developed for capturing the behaviour of both the concrete beam-to-CECFST column joint and the RCS joint. To gain a deep insight into the performance of CECFST columns and concrete beam-to-CECFST column joints, two series of tests consisting of 15 column specimens and 6 joint specimens were conducted. The first test series including 15 CECFST columns was aimed to investigate the effects of uniaxial and biaxial load eccentricities on the behaviour of CECFST columns. The test programme for CECFST columns provided new experimental data on the structural behaviour of CECFST columns under uniaxial and biaxial eccentric compression including load versus mid-height deflection curves, moment versus curvature curves, failure modes and cross-section strengths. A finite element (FE) model was then established to capture the structural behaviour of CECFST columns under combined loading and generate mode data. Traditional cross-section design methods for composite columns were evaluated based on the obtained test and FE results. After comprehensive experimental and numerical investigations on the structural behaviour of CECFST columns, a unified design method was proposed to calculate the cross-section strength of CECFST columns under combined loading. A normalised interaction surface of CECFST columns under combined loading could be generated based on the proposed unified method, which considered the confinement effects from both inner steel tubes and stirrups. The proposed design method was applicable to a broad spectrum of material strength, steel tube diameter-to-thickness ratio, spacing of stirrups, aspect ratio between the steel tube and column cross-section for CECFST columns. The seismic performance of concrete beam-to-CECFST column joints was experimentally studied through the second test series. The effects from the construction method, axial load ratio and connection detail to the joint specimens were investigated in the second test series. Two specimens were designed as benchmarks, which were cast-in-place (CIP) concrete beam-to-CECFST column joints. The remaining four specimens were designed as precast concrete (PC) beam-to-CECFST column joints with two proposed connection details. Arising from this test programme, there were new experimental results on the structural behaviour of concrete beam-to-CECFST column joints under lateral cyclic loading including storey shear force versus horizontal displacement curves, energy dissipation, ductility, strength and stiffness degradations. The experimental results showed that PC beam-to-CECFST column joints with the proposed connection details could satisfy the ductility requirement specified in the codes of practice. In addition, the proposed connection details for the PC specimens could work effectively and reliably in comparison with the CIP specimens. According to the test results, a design formula was then proposed for concrete beam-to-CECFST column joints under seismic loading. After a comprehensive assessment of the seismic performance of concrete beam-to-CECFST column joints, a simplified model was then proposed to capture the shear behaviour of such joints. In addition, a new design approach was proposed for RCS joints which enable structural engineers to design composite joints based on a simplified and rational approach. A new calculation method was first developed for predicting the strength of RCS joints. The proposed design method for RCS joints was applicable for all the possible details and could capture two different failure modes of RCS joints. The proposed design was validated against a large set of experimental data including 54 RCS joint specimens from the literature and showed better accuracy and consistency compared to the previous design method. After that, a component-based model (CBM) was developed for capturing the nonlinear RCS joint moment–rotation response.Doctor of Philosoph

From “separation” to “Integration”: Analyzing the functional transformation of the urban greenbelt in Beijing from the perspective of “parkization”

The Urban greenbelt (UGB), vital for curbing urban expansion, experiences shifts in function across diverse development stages. Unfortunately, UGB functional transformation process, especially its social utilization of ecological functions, often receives insufficient attention, impacting urban ecosystem health enhancement and residents' well-being. The UGB park, combining ecology and social benefits, holds significance in studying varied UGB functions and their transformation. Thus, tracking park development trends (“parkization”) aids in analyzing UGB functional evolution. We employed high-precision land use/land cover (LULC) data (less than1m) from Beijing to explore UGB functional transformation law, focusing on UGB park dynamics and their ecological benefits (Park Ecological Land Use/Land Cover (PLULC) percentage (PPELULC), mean patch size (MPS), edge density (ED), area-weighted mean shape index (AWMSI), patch size standard deviation (PSSD)), and social benefits (per capita park area (PCP), per capita PLULC area (PCPELULC), accessible park service scope). Results revealed that as UGB park construction slowed, park ecological space displayed an “increasing and dispersing” trend, signifying weakened UGB park ecological benefits. Simultaneously, park social services collectively exhibited improvement, suggesting the UGB functional transformation from solely ecological protection to holistic environmental and social safeguarding. This transformation was more notable within the first greenbelt (UGB1), predominantly driven by comprehensive and natural amusement parks. The “parkization”-based UGB function evaluation method not only illuminated the functional transformation mechanism but also underscored the integrated needs of ecology and society, which is essential to the subsequent scientific formulation and implementation of ecological management strategies that meet the needs of urban environmental protectio