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BackgroundCopper (Cu) is essential for the functioning of various enzymes involved in important cellular and physiological processes. Although critical for normal cardiac function, excessive accumulation, or deficiency of Cu in the myocardium is detrimental to the heart. Fluctuations in cardiac Cu content have been shown to cause cardiac pathologies and imbalance in systemic Cu metabolism. However, the genetic basis underlying cardiac Cu levels and their effects on heart traits remain to be understood. Representing the largest murine genetic reference population, BXD strains have been widely used to explore genotype-phenotype associations and identify quantitative trait loci (QTL) and candidate genes.MethodsCardiac Cu concentration and heart function in BXD strains were measured, followed by QTL mapping. The candidate genes modulating Cu homeostasis in mice hearts were identified using a multi-criteria scoring/filtering approach.ResultsSignificant correlations were identified between cardiac Cu concentration and left ventricular (LV) internal diameter and volumes at end-diastole and end-systole, demonstrating that the BXDs with higher cardiac Cu levels have larger LV chamber. Conversely, cardiac Cu levels negatively correlated with LV posterior wall thickness, suggesting that lower Cu concentration in the heart is associated with LV hypertrophy. Genetic mapping identified six QTLs containing a total of 217 genes, which were further narrowed down to 21 genes that showed a significant association with cardiac Cu content in mice. Among those, Prex1 and Irx3 are the strongest candidates involved in cardiac Cu modulation.ConclusionCardiac Cu level is significantly correlated with heart chamber size and hypertrophy phenotypes in BXD mice, while being regulated by multiple genes in several QTLs. Prex1 and Irx3 may be involved in modulating Cu metabolism and its downstream effects and warrant further experimental and functional validations.

BackgroundCombination therapy with immune checkpoint inhibitors (ICIs) may benefit approximately 10-20% of microsatellite-stable colorectal cancer (MSS-CRC) patients. However, there is a lack of optimal biomarkers. This study aims to understand the predictive value of epigenetic-related gene mutations in ICIs therapy in MSS-CRC patients.MethodsWe analyzed DNA sequences and gene expression profiles from The Cancer Genome Atlas (TCGA) to examine their immunological features. The Harbin Medical University Cancer Hospital (HMUCH) clinical cohort of MSS-CRC patients was used to validate the efficacy of ICIs in patients with epigenetic-related gene mutations (Epigenetic_Mut).ResultsIn TCGA, 18.35% of MSS-CRC patients (78/425) had epigenetic-related gene mutations. The Epigenetic_Mut group had a higher tumor mutation burden (TMB) and frameshift mutation (FS_mut) rates. In all MSS-CRC samples, Epigenetic_Mut was elevated in the immune subtype (CMS1) and had a strong correlation with immunological features. Epigenetic_Mut was also associated with favorable clinical outcomes in MSS-CRC patients receiving anti-PD-1-based therapy from the HMUCH cohort. Using immunohistochemistry and flow cytometry, we demonstrated that Epigenetic_Mut samples were associated with increased anti-tumor immune cells both in tumor tissues and peripheral blood.ConclusionMSS-CRC patients with epigenetic regulation impairment exhibit an immunologically active environment and may be more susceptible to treatment strategies based on ICIs.

Lysosomal-associated transmembrane protein 5 (LAPTM5) has been demonstrated to be involved in regulating immunity, inflammation, cell death, and autophagy in the pathophysiological processes of many diseases. However, the function of LAPTM5 in cerebral ischemia-reperfusion (I/R) injury has not yet been reported. In this study, we found that LAPTM5 expression was dramatically decreased during cerebral I/R injury both in vivo and in vitro. LAPTM5 knockout (KO) mice were compared with a control, and they showed a larger infarct size and more serious neurological dysfunction after transient middle cerebral artery occlusion (tMCAO) treatment. In addition, inflammatory response and apoptosis were exacerbated in these processes. Furthermore, gain- and loss-of-function investigations in an in vitro model revealed that neuronal inflammation and apoptosis were aggravated by LAPTM5 knockdown but mitigated by its overexpression. Mechanistically, combined RNA sequencing and experimental verification showed that the apoptosis signal-regulating kinase 1 (ASK1)-c-Jun N-terminal kinase (JNK)/p38 pathway was mainly involved in the detrimental effects of LAPTM5 deficiency following I/R injury. Specifically, LAPTM5 directly interacts with ASK1, leading to decreased ASK1 N-terminal dimerization and the subsequent reduced activation of downstream JNK/p38 signaling. In conclusion, LAPTM5 was demonstrated to be a novel modulator in the pathophysiology of brain I/R injury, and targeting LAPTM5 may be feasible as a stroke treatment.

BackgroundHemodynamic changes caused by hybrid surgery for brain arteriovenous malformations (bAVM) are usually related to long-term lesions from “blood stealing”. There are currently no viable low-cost, noninvasive procedures for assessing cerebral perfusion in the operating room. This study aims to investigate the use of intraoperative laser speckle contrast image (LSCI) software in AVM surgery.MethodsIn Zhongnan Hospital of Wuhan University, 14 patients who underwent surgery with LSCI were collected. To analyze the hemodynamic features of AVM and the influence on the peripheral cortex of AVM embolization and resection, we assessed the transit time between feeding arteries and drainage veins by intraoperative digital subtraction angiography (DSA). Meanwhile, LSCI was performed at pre-embolization, post-embolization, and after complete resection of bAVM.ResultsIn this study, the transit time of bAVM before and after embolization was compared, the transit time before embolization was significantly shorter than that after embolization (p < 0.05). We also got good visualization of relative CBF, in addition, to flow imaging in the cortical vasculature round bAVM with LSCI. The flux of post-surgery was significantly higher than pre-embolization (p < 0.01).ConclusionHemodynamic variable assessment plays an important role in the resection of AVM in the hybrid operative room and LSCI can be used to visualize and evaluate cortical cerebral blood flow to detect pathological hyperperfusion in real-time with a good spatial-temporal resolution in a sensitive and continuous, non-invasive mode.

Additional file 1: Supplementary data for StemSC.

Objective: The aim of this study was to explore the effect of endothelial progenitor cells (EPCs)-collagen sponge complex on the neovascularization of chronic cerebral ischemia following multiple burr hole (MBH) surgery. Methods: Bone marrow-derived EPCs from 5 Fisher 344 (F344) inbred rats were cultured and amplified in vitro, then co-cultured to become the EPCs-collagen sponge complex. Chronic cerebral hypo-perfusion was induced in 30 inbred male F344 rats by permanent bilateral internal carotid artery occlusion (BICAO). The MBH operation was performed three days after BICAO surgery. Rats were then randomly divided into 3 groups (n=10 each group); EPCs-collagen sponge complex + MBH; collagen sponge + MBH and MBH group. Either EPCs-collagen sponge complex or collagen sponge was implanted at the burr hole site in the EPCs-collagen sponge complex + MBH and the collagen sponge + MBH group, respectively. Regional cerebral blood flow (rCBF) was measured by Laser Doppler Flowmetry (LDF), EPCs were tracked by fluorescein, and immune-histochemical analysis for the neovascularization was performed 21 days after MBH surgery. Results: Before the MBH surgery, no differences of rCBF between the EPCs-collagen sponge complex + MBH group, the collagen sponge + MBH group and the MBH alone group (P>0.05) were found. The increase of rCBF in the EPCs-collagen sponge complex + MBH group (20.29 ± 10.21%) was significantly higher when compared with the other two groups 21 days after MBH surgery (7.39 ± 6.85% and 10.32 ± 6.27%, respectively; P

To compare the prevalence of chronic atrophic gastritis (CAG) in Japan, China, Tanzania, and the Dominican Republic and to assess the usefulness of Helicobacter pylori infection and serum gastrin level as markers of CAG.The subjects were volunteers from local communities in Japan (n=859), China (n=1741), Tanzania (n=573), and the Dominican Republic (n=1215). Each individual underwent a health checkup and blood sampling for measurement of serum pepsinogen I and II, pepsinogen I /II ratio, serum gastrin, and H. pylori antibodies, and responded to a questionnaire on upper digestive tract diseases.The prevalences of H. pylori infection (23.5-96.1%), CAG (5.6-60.4%), and serum gastrin (62.0-136.5 pg/ml) varied by age, sex, and country. Serum gastrin level for men differed in each country according to age. In Tanzanian men, the median gastrin level (101.0 pg/ml) was the highest in the 40 to 49 years age group (p0.01) while there was no significant difference among different age groups in Tanzanian women. Serum gastrin level in subjectsor = 70 years was higher than in other age groups in both sexes in the Dominican Republic (males, 92.5, females, 136.5 pg/ml). The prevalence of H. pylori infection increased (p0.01) with advancing age in Japan (only for women) and the Dominican Republic but was high in all age groups of both sexes in China and Tanzania. The prevalence of CAG increased (p0.01) with age in both sexes in Japan, China (women only), and the Dominican Republic, but not in Tanzania. The odds ratio of CAG in H. pylori infected subjects was 5.3 times that in H. pylori-negative subjects. The odds ratio of CAG increased by 0.6%/1 pg/ml increase in serum gastrin.Our results indicated that H. pylori infection, serum gastrin, and advancing age are good markers of CAG and that the prevalence of CAG is the highest in Japan.

A new room temperature fluorescence enhancement system based on complex formation between europium and sparfloxacin in the presence of yttrium in sodium dodecyl sulfate micelle solution has been discovered. The characteristic fluorescence spectra and the effect factors of the fluorescence intensity of the system have been studied in detail. The study results show that the binary complex formed by europium with sparfloxacin in sodium dodecyl sulfate micelle solution can emit intrinsic fluorescence of the lanthanide ion. In the presence of yttrium, the fluorescence intensity of this system was enhanced about 5-fold compared with that of the system without Y3+. Under the optimum conditions selected, the fluorescence intensity is a linear function of the concentration of europium in the range of 5.0 × 10−11 −5.0 × 10−7 mol L−1, and the detection limit of europium is 1.0×10−13 mol L−1. The system was used for the determination of trace amounts of europium in rare earth samples with satisfactory results.