A risk variant for Barrett's esophagus and esophageal adenocarcinoma at chr8p23.1 affects enhancer activity and implicates multiple gene targets.

Nineteen genetic susceptibility loci for esophageal adenocarcinoma (EAC) and its precursor Barrett's esophagus (BE) have been identified through genome-wide association studies (GWAS). Clinical translation of such discoveries, however, has been hindered by the slow pace of discovery of functional/causal variants and gene targets at these loci. We previously developed a systematic informatics pipeline to prioritize candidate functional variants using functional potential scores, applied the pipeline to select high-scoring BE/EAC risk loci and validated a functional variant at chr19p13.11 (rs10423674). Here, we selected two additional prioritized loci for experimental interrogation: chr3p13/rs1522552 and chr8p23.1/rs55896564. Candidate enhancer regions encompassing these variants were evaluated using luciferase reporter assays in two EAC cell lines. One of the two regions tested exhibited allele-specific enhancer activity - 8p23.1/rs55896564. CRISPR-mediated deletion of the putative enhancer in EAC cell lines correlated with reduced expression of three candidate gene targets: B lymphocyte kinase (BLK), nei like DNA glycosylase 2 (NEIL2) and cathepsin B (CTSB). Expression quantitative trait locus (eQTL) mapping in normal esophagus and stomach revealed strong associations between the BE/EAC risk allele at rs55896564 (G) and lower expression of CTSB, a protease gene implicated in epithelial wound repair. These results further support the utility of functional potential scores for GWAS variant prioritization, and provide the first experimental evidence of a functional variant and risk enhancer at the 8p23.1 GWAS locus. Identification of CTSB, BLK and NEIL2 as candidate gene targets suggests that altered expression of these genes may underlie the genetic risk association at 8p23.1 with BE/EAC.

Prioritization and functional analysis of GWAS risk loci for Barrett's esophagus and esophageal adenocarcinoma.

Genome-wide association studies (GWAS) have identified ~20 genetic susceptibility loci for esophageal adenocarcinoma (EAC), and its precursor, Barrett's esophagus (BE). Despite such advances, functional/causal variants and gene targets at these loci remain undefined, hindering clinical translation. A key challenge is that most causal variants map to non-coding regulatory regions such as enhancers, and typically, numerous potential candidate variants at GWAS loci require testing. We developed a systematic informatics pipeline for prioritizing candidate functional variants via integrative functional potential scores (FPS) consolidated from multi-omics annotations, and used this pipeline to identify two high-scoring variants for experimental interrogation: chr9q22.32/rs11789015 and chr19p13.11/rs10423674. Minimal candidate enhancer regions spanning these variants were evaluated using luciferase reporter assays in two EAC cell lines. One of the two variants tested (rs10423674) exhibited allele-specific enhancer activity. CRISPR-mediated deletion of the putative enhancer region in EAC cell lines correlated with reduced expression of two genes-CREB-regulated transcription coactivator 1 (CRTC1) and Cartilage oligomeric matrix protein (COMP); expression of five other genes remained unchanged (CRLF1, KLHL26, TMEM59L, UBA52, RFXANK). Expression quantitative trait locus mapping indicated that rs10423674 genotype correlated with CRTC1 and COMP expression in normal esophagus. This study represents the first experimental effort to bridge GWAS associations to biology in BE/EAC and supports the utility of FPS to guide variant prioritization. Our findings reveal a functional variant and candidate risk enhancer at chr19p13.11 and implicate CRTC1 and COMP as putative gene targets, suggesting that altered expression of these genes may underlie the BE/EAC risk association.

Attributional styles are associated with care burden in geriatric depression: older adults and their caregivers in Taiwan.

BACKGROUND: Given the rising prevalence of depression among older adults and the associated increase in caregiving responsibilities, understanding factors influencing caregiver burden is crucial. Previous research has not extensively explored the impact of caregivers' attributional styles, that is, how individuals interpret the causes of life events, on their care burden. AIM: This study examined the relationship between caregivers' attributional styles and their care burden for older patients with depression. METHODS: This cross-sectional study enrolled older adults aged ≥ 65 years diagnosed with depression and their caregivers. Depression was diagnosed according to the DSM-V criteria for Major Depressive Disorder or Persistent Depressive Disorder. Caregivers completed the Chinese Depression Caregiver Burden Scale (CDCBS) to assess care burden, the Hamilton Depression Rating Scale (HAM-D) to evaluate patient symptom severity, the Center for Epidemiological Studies Depression Scale (CES-D) for measuring caregivers' depression, and the Chinese Depression Patient Caregiver Attribution Style Scale (CDPCAS) to assess attributional styles. Hierarchical regression analysis was used to identify the factors independently associated with the caregiver's subjectively assessed care burden. RESULTS: The sample included 146 caregivers of geriatric patients with depression. Most depression patients were women (74.7%) with a mean age of 74.3 years, whereas the mean age of caregivers was 57.7 years. Hierarchical regression analysis identified that caregivers' gender (ß = - 0.14, p = .044), educational level (ß = 0.19, p = .008), caregivers' own depression assessed by the Center for Epidemiological Studies Depression Scale (ß = 0.41, p < .001), and attributional styles, particularly manipulation (ß = 0.29, p < .001) and illness/stress attributional style (ß = 0.23, p = .002) as independent factors associated with care burden. Patient symptom severity assessed using the Hamilton Depression Scale was not significantly correlated with care burden after controlling for attributional styles. CONCLUSIONS: Certain attributional styles, particularly the manipulation and illness/stress attributional styles, significantly increased self-reported care burden. These findings highlight the need for educational resources to change the attribution style, along with support systems and accessible mental health services for caregivers to potentially ease the care burden.

LC-MS/MS-Based Absolute Quantitation of Hemoglobin Subunits from Dried Blood Spots Reveals Novel Biomarkers for α-Thalassemia Silent Carriers.

Identification of α-thalassemia silent carriers is challenging with conventional phenotype-based screening methods. A liquid chromatography tandem mass spectrometry (LC-MS/MS)-based approach may offer novel biomarkers to address this conundrum. In this study, we collected dried blood spot samples from individuals with three α-thalassemia subtypes for biomarker discovery and validation. We observed differential expression patterns of hemoglobin subunits among various α-thalassemia subtypes and normal controls through proteomic profiling of 51 samples in the discovery phase. Then, we developed and optimized a multiple reaction monitoring (MRM) assay to measure all detectable hemoglobin subunits. The validation phase was conducted in a cohort of 462 samples. Among the measured hemoglobin subunits, subunit µ was significantly upregulated in all the α-thalassemia groups with distinct fold changes. The hemoglobin subunit µ exhibits great potential as a novel biomarker for α-thalassemia, especially for silent α-thalassemia. We constructed predictive models based on the concentrations of hemoglobin subunits and their ratios to classify the various subtypes of α-thalassemia. In the binary classification problems of silent α-thalassemia vs normal, non-deletional α-thalassemia vs normal, and deletional α-thalassemia vs normal, the best performance of the models achieved average ROCAUCs of 0.9505, 0.9430, and 0.9976 in the cross-validation, respectively. In the multiclass model, the best performance achieved an average ROCAUC of 0.9290 in cross-validation. The performance of our MRM assay and models demonstrated that the hemoglobin subunit µ would play a vital role in screening silent α-thalassemia in clinical practice.

Orbital-resolved photoelectron momentum distributions of F- ions in a counter-rotating bicircular field.

We present a theoretical study of the orbital-resolved photoelectron momentum distributions (PMDs) of F- ions by a two-color counter-rotating circularly polarized field. We show that the PMDs of F- ions can be modulated from an isotropic symmetric distribution into a three-lobe one by adding a weak fundamental counter-rotating field to the intense second harmonic circularly polarized field, and this modulation strongly depends on the initial atomic orbital. The PMDs simulated by the strong-field approximation method show good agreement with those obtained by solving the time-dependent Schrödinger equation. Based on the strong-field approximation method, we find that the radial momentum shift of PMDs for different orbitals is the fingerprint of orbital-dependent initial momentum at the tunnel exit. More importantly, we demonstrate that the lobes in PMDs appear in sequential order, highlighting that the scheme can be viewed as controllable rotating temporal Young's two-slit interferometer.

Association between air temperature and emergency admission for esophagogastric variceal bleeding: a case-crossover study in Beijing, China.

BACKGROUND AND AIMS: Studies concerning the impact of air temperature on esophagogastric variceal bleeding (EGVB) have yielded conflicting results. Our study aimed to evaluate the correlation between air temperature and EGVB. METHODS: A time-stratified case-crossover study design was performed. Patients received emergency gastroscopic hemostasis for upper gastrointestinal bleeding between Jan 1, 2014, and Dec 31, 2018 in the Fifth Medical Center of PLA General Hospital were enrolled. Conditional logistic regression analysis was applied to determine the association between air temperature and EGVB for different lag structures. RESULTS: A total of 4204 cirrhotic patients diagnosed with EGVB and received emergency gastroscopic hemostasis were enrolled. The mean number of daily EGVB cases peaked in October (2.65 ± 1.69) and fell to the lowest level in July (1.86 ± 1.38), and was 2.38 ± 1.58 in spring, 2.00 ± 1.46 in summer, 2.37 ± 1.58 in autumn, and 2.45 ± 1.58 in winter, respectively (P < 0.0001). In conditional logistic regression analysis, no significant correlations between air temperature and EGVB were observed and no significant difference were found when stratified by age, sex, etiology, liver cancer status, and grade of varices. CONCLUSION: Emergency admission for EGVB showed significant monthly and seasonal fluctuations, while in conditional logistic regression analysis, no association between minimum temperature and emergency admission for EGVB were observed.

Intratumoral injection of oncolytic virus (H101) in combination with concurrent chemoradiotherapy for locally advanced cervical cancer.

OBJECTIVES: To evaluate the efficacy of primary tumor bulk reduction and the safety of concurrent chemoradiotherapy in combination with H101, a type of oncolytic virus, for the treatment of locally advanced cervical cancer. METHODS: Patients diagnosed with stage IIB or III cervical cancer according to the International Federation of Gynecology and Obstetrics (FIGO 2009), with tumor length ≥6 cm, were enrolled at Zhejiang Cancer Hospital from July 2015 to April 2017. All patients received concurrent chemoradiotherapy in combination with intratumoral H101 injection before and during external beam radiotherapy. Outcomes included progression free survival, overall survival, tumor regression after external beam radiotherapy, and side effects. RESULTS: A total of 23 patients were included in the safety analysis and, of these, 20 were included in the efficacy analysis. Median follow-up time was 38 (range 10-58) months. The 3 year local, regional, and overall progression free survival rates for the 20 patients were 95%, 95%, and 65%, respectively, and the 3 year overall survival rate was 74.3%. Median tumor length was reduced from 6.6 cm (range 6-7.3) before treatment to 4.1 cm (range 2.2-5.5) after external beam radiotherapy. Median tumor volume was reduced from 88.4 cm3 (range 41.2-126) before treatment to 20.8 cm3 (range 11.1-47.4) after external beam radiotherapy. Median percentage reduction of tumor length and volume were 37.7% and 75.1%, respectively. The major adverse event related to H101 was fever (91.3%). CONCLUSION: H101 injection may enhance primary tumor regression for locally advanced cervical cancer, with an acceptable safety profile. This treatment regimen should undergo further prospective randomized controlled studies.ChiCTR-OPC-15006142.

The effect of luteinizing hormone changes in GnRH antagonist protocol on the outcome of controlled ovarian hyperstimulation and embryo transfer.

BACKGROUD: To investigate the effect of Luteinizing hormone (LH) level changes on the outcomes of controlled ovarian hyperstimulation (COH) and embryo transfer (ET) in gonadotropin-releasing hormone antagonist (GnRH-ant) protocol. METHODS: A total of 721 patients undergoing GnRH-ant protocol COH for the first IVF/ICSI cycles were retrospectively analyzed. COH process were divided into 2 stages, before (stage 1) and after (stage 2) the GnRH-ant initiation, and each with 5 groups basing on LH levels: LH decreased more than 50% (groups A1, A2), decreased 25-50% (groups B1, B2), change less than 25% (groups C1, C2), increased 25-50% (groups D1, D2), and increased more than 50% (groups E1, E2). RESULTS: There were no significant differences among groups of stage1 regarding COH and ET outcomes. For stage 2, the more obvious the decrease of LH level, the more the number of oocytes retrieved, mature oocytes, fertilized oocytes, embryos cleavaged and the numbers of embryo available (P < 0.05), but without significant differences regarding ET outcomes. We also found the freeze-all rate in Group A2 was higher (P < 0.001). CONCLUSION: LH level changes before GnRH-ant addition were not related to COH and ET outcomes. LH level changes after the addition of GnRH-ant were related to the outcome of COH, and no significant differences were found relating to ET outcomes.

Tightly Coupled LiDAR-Inertial Odometry and Mapping for Underground Environments.

The demand for autonomous exploration and mapping of underground environments has significantly increased in recent years. However, accurately localizing and mapping robots in subterranean settings presents notable challenges. This paper presents a tightly coupled LiDAR-Inertial odometry system that combines the NanoGICP point cloud registration method with IMU pre-integration using incremental smoothing and mapping. Specifically, a point cloud affected by dust particles is first filtered out and separated into ground and non-ground point clouds (for ground vehicles). To maintain accuracy in environments with spatial variations, an adaptive voxel filter is employed, which reduces computation time while preserving accuracy. The estimated motion derived from IMU pre-integration is utilized to correct point cloud distortion and provide an initial estimation for LiDAR odometry. Subsequently, a scan-to-map point cloud registration is executed using NanoGICP to obtain a more refined pose estimation. The resulting LiDAR odometry is then employed to estimate the bias of the IMU. We comprehensively evaluated our system on established subterranean datasets. These datasets were collected by two separate teams using different platforms during the DARPA Subterranean (SubT) Challenge. The experimental results demonstrate that our system achieved performance enhancements as high as 50-60% in terms of root mean square error (RMSE).

Results and lessons from dual extraction of DNA and RNA from formalin-fixed paraffin-embedded breast tumor tissues for a large Cancer epidemiologic study.

BACKGROUND: The use of archived formalin-fixed paraffin-embedded (FFPE) tumor tissues has become a common practice in clinical and epidemiologic genetic research. Simultaneous extraction of DNA and RNA from FFPE tissues is appealing but can be practically challenging. Here we report our results and lessons learned from processing FFPE breast tumor tissues for a large epidemiologic study. METHODS: Qiagen AllPrep DNA/RNA FFPE kit was adapted for dual extraction using tissue punches or sections from breast tumor tissues. The yield was quantified using Qubit and fragmentation analysis by Agilent Bioanalyzer. A subset of the DNA samples were used for genome-wide DNA methylation assays and RNA samples for sequencing. The QC metrices and performance of the assays were analyzed with pre-analytical variables. RESULTS: A total of 1859 FFPE breast tumor tissues were processed. We found it critical to adjust proteinase K digestion time based on tissue volume to achieve balanced yields of DNA and RNA. Tissue punches taken from tumor-enriched regions provided the most reliable output. A median of 1475 ng DNA and 1786 ng RNA per sample was generated. The median DNA integrity number (DIN) was 3.8 and median DV200 for RNA was 33.2. Of 1294 DNA samples used in DNA methylation assays, 97% passed quality check by qPCR and 92% generated data deemed high quality. Of the 130 RNA samples with DV200 ≥ 20% used in RNA-sequencing, all but 5 generated usable transcriptomic data with a mapping rate ≥ 60%. CONCLUSIONS: Dual DNA/RNA purification using Qiagen AllPrep FFPE extraction protocol is feasible for clinical and epidemiologic studies. We recommend tissue punches as a reliable source material and fine tuning of proteinase K digestion time based on tissue volume. IMPACT: Our protocol and recommendations may be adapted by future studies for successful extraction of archived tumor tissues.

Lignin-Supported Heterogeneous Photocatalyst for the Direct Generation of H2O2 from Seawater.

The development of smart and sustainable photocatalysts is in high priority for the synthesis of H2O2 because the global demand for H2O2 is sharply rising. Currently, the global market share for H2O2 is around 4 billion US$ and is expected to grow by about 5.2 billion US$ by 2026. Traditional synthesis of H2O2 via the anthraquinone method is associated with the generation of substantial chemical waste as well as the requirement of a high energy input. In this respect, the oxidative transformation of pure water is a sustainable solution to meet the global demand. In fact, several photocatalysts have been developed to achieve this chemistry. However, 97% of the water on our planet is seawater, and it contains 3.0-5.0% of salts. The presence of salts in water deactivates the existing photocatalysts, and therefore, the existing photocatalysts have rarely shown reactivity toward seawater. Considering this, a sustainable heterogeneous photocatalyst, derived from hydrolysis lignin, has been developed, showing an excellent reactivity toward generating H2O2 directly from seawater under air. In fact, in the presence of this catalyst, we have been able to achieve 4085 µM of H2O2. Expediently, the catalyst has shown longer durability and can be recycled more than five times to generate H2O2 from seawater. Finally, full characterizations of this smart photocatalyst and a detailed mechanism have been proposed on the basis of the experimental evidence and multiscale/level calculations.

MALDI-TOF-MS for Rapid Screening and Typing of ß-Globin Variant and ß-Thalassemia through Direct Measurements of Intact Globin Chains.

BACKGROUND: Traditional phenotype-based screening for ß-globin variant and ß-thalassemia using hematological parameters is time-consuming with low-resolution detection. Development of a MALDI-TOF-MS assay using alternative markers is needed. METHODS: We constructed a MALDI-TOF-MS-based approach for identifying various ß-globin disorders and classifying thalassemia major (TM) and thalassemia intermedia (TI) patients using 901 training samples with known HBB/HBA genotypes. We then validated the accuracy of population screening and clinical classification in 2 separate cohorts consisting of 16 172 participants and 201 ß-thalassemia patients. Traditional methods were used as controls. Genetic tests were considered the gold standard for testing positive specimens. RESULTS: We established a prediction model for identifying different forms of ß-globin disorders in a single MALDI-TOF-MS test based on δ- to ß-globin, γ- to α-globin, γ- to ß-globin ratios, and/or the abnormal globin-chain patterns. Our validation study yielded comparable results of clinical specificity (99.89% vs 99.71%), and accuracy (99.78% vs 99.16%) between the new assay and traditional methods but higher clinical sensitivity for the new method (97.52% vs 88.01%). The new assay identified 22 additional abnormal hemoglobins in 69 individuals including 9 novel ones, and accurately screened for 9 carriers of deletional hereditary persistence of fetal hemoglobin or δß-thalassemia. TM and TI were well classified in 178 samples out of 201 ß-thalassemia patients. CONCLUSIONS: MALDI-TOF-MS is a highly accurate, predictive tool that could be suitable for large-scale screening and clinical classification of ß-globin disorders.

Changes in self-harm- and violence-related urgent psychiatric consultation in the emergency department during the different stages of the COVID-19 pandemic.

BACKGROUND: The coronavirus disease 2019 pandemic significantly affected emergency department (ED) visits and urgent psychiatric consultation (UPC) seeking behavior in EDs. Our study explored the changes in UPCs during and after the pandemic peak. METHODS: This retrospective observational study evaluated UPCs in the ED of a referral medical center in Taiwan, where treated both physical and psychiatric complaints. We defined the COVID-19 pandemic peak period as calendar week 4-18, 2020. The corresponding baseline as calendar week 4-18, 2019, and the slack period as week 4-18, 2021. The total number of UPCs, patient demographic data such as sex and age of the patients seen, the referral system (whether police or emergency medical service [EMS] or other sources), and the chief complaint (self-harm or violence) were recorded. RESULTS: Compared with the baseline period, a significant decline in UPCs was observed in the pandemic peak period, and a rebound was observed in the slack period, with the median [IQR] Q1, Q3 values of 22 [18, 26], 12 [10, 17]), and 16 [15, 23], respectively. We observed significantly few men (34.9% vs 45.2%) and less violence (10.2% vs 17.6%) in the peak period compared with in the baseline period, but no significant difference was found compared with the slack period. Throughout the pandemic, younger patients (41.8 ± 17.4 in 2019, 39.2 ± 18.5 [p = 0.121] in 2020, and 35.6 ± 17.2 [p < 0.001] in 2021), higher proportions of police/EMS referral (38.7% in 2019, 41.9% [p = 0.473] in 2020, and 51.9% [p = 0.001] in 2021) and self-harm-related complaints (57% in 2019, 62.4% [p = 0.233] in 2020, and 64.9% [p = 0.049] in 2021) was noted among UPC seekers during the pandemic. However, the proportion of violence-related UPCs (17.6% in 2019, 10.2% [p = 0.023] in 2020, and 12.3% [p = 0.072] in 2021) declined. CONCLUSIONS: This study found that UPCs changed throughout the pandemic. This result raises the concern that mental health needs are masked during the pandemic.

Neuroprotective Effects of Tetrahydroxystilbene Glucoside against Rotenone-Induced Toxicity in PC12 Cells.

To investigate the mechanism of the protective effect of tetrahydroxystilbene glucoside (TSG) on nerve cells, an injury model induced by rotenone in PC12 cells was constructed. Cell viability was detected by using cell counting kit-8 (CCK8) assay. Apoptosis was detected by using flow cytometry. The mitochondrial membrane potential (MMP) was detected by using the fluorescent probe JC-1. Generation of reactive oxygen species (ROS) in PC12 cells was determined using the 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate acetyl ester (CM-H2DCFDA) probe. Protein expression in PC12 cells was detected using Western blotting. The results showed that TSG (20-100 µM) attenuated the cytotoxic effects of rotenone on PC12 cells. TSG pretreatment attenuated the apoptosis rate, the degradation of poly(ADP-ribose)polymerase (PARP) and the activation of cleaved caspase 3, which was induced by rotenone. TSG can significantly reduce the effect of rotenone on the reduction of MMP and the expression of cytoC in the cytosolic fraction. TSG attenuated rotenone-induced de-phosphorylation and mitochondrial translocation of cofilin, as well as rotenone-induced accumulation of ROS. The Western blot results showed that ROT could decrease the expression level of phosphorylated (p)-Glycogen synthase kinase-3ß (GSK)-3ß and p-AKT, and TSG could weaken these effects of rotenone. In addition, TSG increased the expression level of nuclear factor-E2-related factor 2 (Nrf2) in the nuclear fraction. These results suggest that TSG could protect PC12 cells against rotenone through multiple pathways. Thus, TSG has the potential to become a novel neuroprotective agent.

The catalytic subunit of the SWR1 remodeler is a histone chaperone for the H2A.Z-H2B dimer.

Histone variant H2A.Z-containing nucleosomes exist at most eukaryotic promoters and play important roles in gene transcription and genome stability. The multisubunit nucleosome-remodeling enzyme complex SWR1, conserved from yeast to mammals, catalyzes the ATP-dependent replacement of histone H2A in canonical nucleosomes with H2A.Z. How SWR1 catalyzes the replacement reaction is largely unknown. Here, we determined the crystal structure of the N-terminal region (599-627) of the catalytic subunit Swr1, termed Swr1-Z domain, in complex with the H2A.Z-H2B dimer at 1.78 Å resolution. The Swr1-Z domain forms a 310 helix and an irregular chain. A conserved LxxLF motif in the Swr1-Z 310 helix specifically recognizes the αC helix of H2A.Z. Our results show that the Swr1-Z domain can deliver the H2A.Z-H2B dimer to the DNA-(H3-H4)2 tetrasome to form the nucleosome by a histone chaperone mechanism.

Proteomic comparison between physiological degeneration and needle puncture model of disc generation disease.

BACKGROUND: The completeness of the intervertebral disc proteome is fundamental to the integrity and functionality of the intervertebral disc. METHODS: The 20 experimental rats were placed into two groups randomly, normal group (NG) and acupuncture pathological degeneration group-2 weeks (APDG-2w). The ten 24-month-old rats were grouped into physiological degeneration group (PDG). Magnetic resonance imaging, X-ray examination, histological staining (hematoxylin & eosin, safranin-O cartilage, and alcian blue staining), and immunohistochemical examination were carried out for assessing the degree of disc degradation. Intervertebral disc was collected, and protein composition was determined by LC- MS, followed by bioinformatic analysis including significance analysis, subcellular localization prediction, protein domain prediction, GO function and KEGG pathway analysis, and protein interaction network construction. LC-PRM was done for protein quantification. RESULTS: Physiological degeneration and especially needle puncture decreased T2 signal intensity and intervertebral disc height. Results from hematoxylin & eosin, safranin-O, and alcian blue staining revealed that the annulus fibrosus apparently showed the wavy and collapsed fibrocartilage lamellas in APDG-2w and PDG groups. The contents of the nucleus pulposus were decreased in physiological degeneration group and APDG-2w group compared with NG. Results from immunohistochemical analysis suggested the degeneration of intervertebral disc and inflammation in APDG-2w and PDG groups. The protein composition and expression between needle puncture rat models and the physiological degeneration group showed significant difference. CONCLUSIONS: Our studies produced point-reference datasets of normal rats, physiological degeneration rats, and needle puncture rat models, which is beneficial to subsequent pathological studies. There is differential expression of protein expression in degenerative discs with aging and acupuncture, which may be used as a potential discriminating index for different intervertebral degenerations.

Resveratrol inhibits the progression of premature senescence partially by regulating v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA) and sirtuin 1 (SIRT1).

OBJECTIVE: To explore the effect of resveratrol in premature senescence and reveal its anti-premature senescence mechanisms through network pharmacology. METHODS: In this study, the H2O2-induced bone marrow mesenchymal stem cells (BMMSCs) premature senescence model is applied. Cell counting kit-8 assay, ß-galactosidase staining and flow cytometry are conducted to detect the proliferation, senescence and apoptosis of BMMSCs. Bioinformatics analyses are used to screen and validate molecular targets of resveratrol acting on premature senescence. Dual-luciferase reporter assay is conducted to verify the interaction between v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA) and sirtuin 1 (SIRT1). RT-qPCR and western blot are adopted to detect mRNA and protein levels of RELA, SIRT1, senescence-related genes and apoptosis-related genes. RESULTS: First, we proved that resveratrol alleviated the H2O2-induced senescence of BMMSCs. Then, bioinformatics analysis revealed that RELA was the downstream target of resveratrol and SIRT1 was the downstream target of RELA, respectively, involved in premature aging. RELA/SIRT1 may be the potential target of resveratrol for premature senescence. Notably, rescue experiments indicated that resveratrol inhibited premature senescence partially through targeting regulation RELA/SIRT1. CONCLUSION: In our study, we confirm the functional role of the resveratrol-RELA- SIRT1 axis in the progression of premature senescence, which provides a latent target for premature senescence treatment.

A Case of Misdiagnosis Caused by the Coinheritance of Hb G-Siriraj [ß7(A4)Glu→Lys; HBB: c.22G>A] and Hb H Disease.

Despite the fact that most hemoglobin (Hb) variants are clinically and hematologically silent, they can interact with thalassemias, which could sometimes give rise to complicated routine thalassemia diagnostics. Hb G-Siriraj [ß7(A4)Glu→Lys; HBB: c.22G>A] alone is a benign condition, but its coinheritance with α-thalassemia (α-thal) may lead to misdiagnosis. We describe the case of a Chinese woman with an elevated Hb A2 level who was assumed to carry heterozygous ß-thalassemia (ß-thal), but was later shown to be a double heterozygote for Hb G-Siriraj and Hb H disease. This study for the first time described hematological characteristics of a patient with a double heterozygosity for Hb G-Siriraj and Hb H disease. It is of great significance for technicians and clinicians to expand their knowledge as well as to help guide clinical diagnosis, population screening and genetic counseling.

Germline variation in the insulin-like growth factor pathway and risk of Barrett's esophagus and esophageal adenocarcinoma.

Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal component analysis was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 single-nucleotide polymorphisms (SNPs) in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases and 3207 controls in the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17 159 controls). Global variation in the IGF pathway was associated with risk of BE (P = 0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor; P = 0.00046, false discovery rate q = 0.0056) and IGF1R (IGF1 receptor; P = 0.0090, q = 0.0542). These gene-level signals remained significant at q < 0.1 when assessed using data from the largest available BE/EAC GWAS meta-analysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R, may influence risk of BE.

Identification of MYH6 as the potential gene for human ischaemic cardiomyopathy.

The present study aimed to explore the potential hub genes and pathways of ischaemic cardiomyopathy (ICM) and to investigate the possible associated mechanisms. Two microarray data sets (GSE5406 and GSE57338) were downloaded from the Gene Expression Omnibus (GEO) database. The limma package was used to analyse the differentially expressed genes (DEGs). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, Disease Ontology (DO) and Gene Ontology (GO) annotation analyses were performed. A protein-protein interaction (PPI) network was set up using Cytoscape software. Significant modules and hub genes were identified by the Molecular Complex Detection (MCODE) app. Then, further functional validation of hub genes in other microarrays and survival analysis were performed to judge the prognosis. A total of 1065 genes were matched, with an adjusted p < 0.05, and 17 were upregulated and 25 were downregulated with|log2 (fold change)|≥1.2. After removing the lengthy entries, GO identified 12 items, and 8 pathways were enriched at adjusted p < 0.05 (false discovery rate, FDR set at <0.05). Three modules with a score >8 after MCODE analysis and MYH6 were ultimately identified. When validated in GSE23561, MYH6 expression was lower in patients with CAD than in healthy controls (p < 0.05). GSE60993 data suggested that MYH6 expression was also lower in AMI patients (p < 0.05). In the GSE59867 data set, MYH6 expression was lower in CAD patients than in AMI patients and lower in heart failure (HF) patients than in non-HF patients. However, there was no difference at different periods within half a year, and HF was increased when MYH6 expression was low (p < 0.05-0.01). We performed an integrated analysis and validation and found that MYH6 expression was closely related to ICM and HF. However, whether this marker can be used as a predictor in blood samples needs further experimental verification.