Synaptic architecture of a memory engram in the mouse hippocampus.

Memory engrams are formed through experience-dependent remodeling of neural circuits, but their detailed architectures have remained unresolved. Using 3D electron microscopy, we performed nanoscale reconstructions of the hippocampal CA3-CA1 pathway following chemogenetic labeling of cellular ensembles with a remote history of correlated excitation during associative learning. Projection neurons involved in memory acquisition expanded their connectomes via multi-synaptic boutons without altering the numbers and spatial arrangements of individual axonal terminals and dendritic spines. This expansion was driven by presynaptic activity elicited by specific negative valence stimuli, regardless of the co-activation state of postsynaptic partners. The rewiring of initial ensembles representing an engram coincided with local, input-specific changes in the shapes and organelle composition of glutamatergic synapses, reflecting their weights and potential for further modifications. Our findings challenge the view that the connectivity among neuronal substrates of memory traces is governed by Hebbian mechanisms, and offer a structural basis for representational drifts.

Intentional wedge resection versus segmentectomy for ≤2 cm Ground-Glass-Opacity-Dominant Non-Small cell lung cancer: a Real-World study using inverse probability of treatment weighting.

BACKGROUND: Whether wedge resection is oncological suitable for ground glass opacity (GGO)-dominant non-small cell lung cancer (NSCLC) ≤2 cm is still debatable. The aim of this study is to investigate the short-term and long-term outcomes of intentional wedge resection and segmentectomy for those patients. MATERIALS AND METHODS: This was a real-world study from one of the largest thoracic surgery centers in XX. Patients who underwent intentional wedge resection or segmentectomy for ≤2 cm CTR(consolidation-to-tumor)≤0.5 NSCLC were consecutively included between December 2009 and December 2018. Data were prospectively collected and retrospectively reviewed. Inverse probability of treatment weighting (IPTW) was used to balance baseline characteristics. Long-term outcomes, including overall survival (OS), recurrence-free survival (RFS) and lung cancer-specific survival (LCSS), were analyzed using Cox proportional model. RESULTS: A total of 1209 patients were included (497 in the wedge resection group, 712 in the segmentectomy group). Compared to segmentectomy, wedge resection had a significantly lower rate of complications (3.8% vs. 7.7%, P=0.008), a shorter operating time (65min vs. 114min, P<0.001), and a shorter postoperative stay (3d vs. 4d, P<0.001). The median follow-up was 70.1 months. The multivariate Cox model indicated that wedge resection had survival outcomes that were similar to segmentectomy in terms of 5-year OS (98.8% vs. 99.6%, HR=1.98, 95%CI: 0.59-6.68, P=0.270), 5-year RFS (98.8% vs. 99.5%, HR=1.88, 95%CI: 0.56-6.31, P=0.307) and 5-year LCSS (99.9% vs. 99.6%, HR=1.76, 95%CI: 0.24-13.15, P=0.581). CONCLUSION: Intentional wedge resection is an appropriate choice for ≤2 cm GGO-dominant NSCLC.

Long-Term Treatment with Gadopentetic Acid or Gadodiamide Increases TRPC5 Expression and Decreases Adriamycin Nuclear Accumulation in Breast Cancer Cells.

Gadopentetic acid and gadodiamide are paramagnetic gadolinium-based contrast agents (GBCAs) that are routinely used for dynamic contrast-enhanced magnetic resonance imaging (MRI) to monitor disease progression in cancer patients. However, growing evidence indicates that repeated administration of GBCAs may lead to gadolinium (III) cation accumulation in the cortical bone tissue, skin, basal ganglia, and cerebellum, potentially leading to a subsequent slow long-term discharge of Gd3+. Gd3+ is a known activator of the TRPC5 channel that is implicated in breast cancer's resistance to chemotherapy. Herein, we found that gadopentetic acid (Gd-DTPA, 1 mM) potentiated the inward and outward currents through TRPC5 channels, which were exogenously expressed in HEK293 cells. Gd-DTPA (1 mM) also activated the Gd3+-sensitive R593A mutant of TRPC5, which exhibits a reduced sensitivity to GPCR-Gq/11-PLC dependent gating. Conversely, Gd-DTPA had no effect on TRPC5-E543Q, a Gd3+ insensitive TRPC5 mutant. Long-term treatment (28 days) of human breast cancer cells (MCF-7 and SK-BR-3) and adriamycin-resistant MCF-7 cells (MCF-7/ADM) with Gd-DTPA (1 mM) or gadodiamide (GDD, 1 mM) did not affect the IC50 values of ADM. However, treatment with Gd-DTPA or GDD significantly increased TRPC5 expression and decreased the accumulation of ADM in the nuclei of MCF-7 and SK-BR-3 cells, promoting the survival of these two breast cancer cells in the presence of ADM. The antagonist of TRPC5, AC1903 (1 µM), increased ADM nuclear accumulation induced by Gd-DTPA-treatment. These data indicate that prolonged GBCA treatment may lead to increased breast cancer cell survival owing to the upregulation of TRPC5 expression and the increased ADM resistance. We propose that while focusing on providing medical care of the best personalized quality in the clinic, excessive administration of GBCAs should be avoided in patients with metastatic breast cancer to reduce the risk of promoting breast cancer cell drug resistance.

Combined Minimally Invasive Treatment of Delayed Aortoesophageal Fistula Caused by Fishbone.

Aortoesophageal fistula caused by esophageal foreign body is a rare, catastrophic condition. We report a case of delayed aortoesophageal fistula caused by fishbone and associated with severe hematemesis, mediastinal abscess, and esophageal tear. We performed thoracic endovascular aortic repair to control the bleeding and video-assisted thoracoscopic surgery to drain the mediastinal abscess and to repair the esophageal tear. The patient recovered with limited physical and physiologic impairment after systematic treatment. This case highlights the feasibility of combined thoracic endovascular aortic repair and video-assisted thoracoscopic surgery as an optimum management strategy in cases of aortoesophageal fistula associated with severe bleeding and mediastinal abscess.

mTBI-Induced Systemic Vascular Dysfunction in a Mouse mTBI Model.

Mild traumatic brain injury (mTBI) without skull fracturing is the most common occurrence of all TBIs and is considered as a serious public health concern. Animal models of mTBI are essential to investigation of TBI and its effects. In the current study, we developed and characterized a reproducible mouse model of mild TBI, meanwhile, the effects of this mTBI model, as well as repetitive mTBIs (rmTBIs), on the endothelial function of mouse aortas were also studied. In variety of closed-head models of mTBI, impact velocity, weight, and dwell time are the main parameters that affect the severities of injury. Here, we used a device, converting parameters of velocity, tip weight, and dwell time into impact force, to develop a mouse model of close-head mTBI. Mice were subjected to a mild TBI induced by the impact forces of 500, 600, 700 and 800 kdyn, respectively. Later, brain injuries were assessed histologically and molecularly. Systemic and brain inflammation were measured by plasma cytokine assay and glial fibrillary acidic protein (GFAP) staining. The composite neurobehavioral test revealed significant acute functional deficits in mice after mTBI, corresponding to the degree of injury. Mice brain undergoing mTBI had significant elevated GFAP staining. Plasma cytokines interleukin-1ß (IL-1ß) and superoxide dismutase (SOD) were significantly increased within 2 h after mTBI. Taken together, these data suggest that the mTBI mouse model introduce within our study exhibits good repeatability and comparable pathological characters. Moreover, we used this mTBI mouse model to determine the effect of single or rmTBIs on systemic vasoconstriction and relaxation. The isometric-tension results indicate that rmTBIs induce a pronounced and long-lasting endothelial dysfunction in mouse aorta.

Nanoscale 3D EM reconstructions reveal intrinsic mechanisms of structural diversity of chemical synapses.

Chemical synapses of shared cellular origins have remarkably heterogeneous structures, but how this diversity is generated is unclear. Here, we use three-dimensional (3D) electron microscopy and artificial intelligence algorithms for image processing to reconstruct functional excitatory microcircuits in the mouse hippocampus and microcircuits in which neurotransmitter signaling is permanently suppressed with genetic tools throughout the lifespan. These nanoscale analyses reveal that experience is dispensable for morphogenesis of synapses with different geometric shapes and contents of membrane organelles and that arrangement of morphologically distinct connections in local networks is stochastic. Moreover, loss of activity increases the variability in sizes of opposed pre- and postsynaptic structures without disrupting their alignments, suggesting that inherently variable weights of naive connections become progressively matched with repetitive use. These results demonstrate that mechanisms for the structural diversity of neuronal synapses are intrinsic and provide insights into how circuits essential for memory storage assemble and integrate information.

HCA587 Protein Vaccine Induces Specific Antitumor Immunity Mediated by CD4+ T-cells Expressing Granzyme B in a Mouse Model of Melanoma.

BACKGROUND: The antigen HCA587 (also known as MAGE-C2), which is considered a cancer-testis antigen, exhibits upregulated expression in a wide range of malignant tumors with unique immunological properties, and may thus serve as a promising target for tumor immunotherapy. OBJECTIVE: The study aimed to explore the antitumor effect of the HCA587 protein vaccine and the response of humoral and cell-mediated immunity. METHODS: The HCA587 protein vaccine was formulated with adjuvants CpG and ISCOM. B16 melanoma cells were subcutaneously inoculated to C57BL/6 mice, followed by treatment with HCA587 protein vaccine subcutaneously. Mouse survival was monitored daily, and tumor volume was measured every 2 to 3 days. The tumor sizes, survival time and immune cells in tumor tissues were detected. And the vital immune cell subset and effector molecules were explored. RESULTS: After treatment with HCA587 protein vaccine, the vaccination elicited significant immune responses, which delayed tumor growth and improved animal survival. The vaccination increased the proportion of CD4+ T cells expressing IFN-γ and granzyme B in tumor tissues. The depletion of CD4+T cells resulted in an almost complete abrogation of the antitumor effect of the vaccination, suggesting that the antitumor efficacy was mediated by CD4+ T cells. In addition, knockout of IFN-γ resulted in a decrease in granzyme B levels, which were secreted by CD4+ T cells, and the antitumor effect was also significantly attenuated. CONCLUSION: The HCA587 protein vaccine may increase the levels of granzyme B expressed by CD4+ T cells, and this increase is dependent on IFN-γ, and the vaccine resulted in a specific tumor immune response and subsequent eradication of the tumor.

Two new inflammatory markers associated with disease activity score-28 in patients with rheumatoid arthritis: Albumin to fibrinogen ratio and C-reactive protein to albumin ratio.

BACKGROUND: The albumin to fibrinogen ratio (AFR) and C-reactive protein to albumin ratio (CAR) have emerged as useful biomarkers to predict systemic inflammation. The aim here is to investigate the relation between AFR/CAR and Disease Activity Score of 28 joints (DAS 28) in rheumatoid arthritis (RA). METHODS: This retrospective study included 160 patients with RA and 159 healthy controls. We divided the RA patients into two groups according to the DAS 28-ESR score. Group 1 included 40 patients with a score of lower than 2.6 (patients in remission) and Group 2 included 120 patients with a score of 2.6 or higher (patients with active disease). The correlations between AFR, CAR and the disease activity were analyzed. RESULTS: For RA patients, the AFR was lower than those in the control group (P < 0.001). Patients in group 2 had higher CAR than those in group 1 (P < 0.001). The AFR was lower in group 2 than that in group 1. A positively correlation was observed between DAS 28-ESR score and CAR (r = 0.645, P < 0.001), while the correlation between DAS 28-ESR and AFR (r = -0.836, P < 0.001) was negative. AFR was related with decreased risk of RA disease activity (EXP (B) = 0.33, 95% CI (0.21-0.53), P < 0.001). CONCLUSIONS: AFR and CAR are two novel inflammatory markers for monitoring disease activity in patients with RA.

Neutrophil-lymphocyte ratio and platelet-lymphocyte ratio are 2 new inflammatory markers associated with pulmonary involvement and disease activity in patients with dermatomyositis.

BACKGROUND: The neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) have emerged as useful biomarkers to predict systemic inflammation. However, there is no study to investigate the relationship between the biomarkers and dermatomyositis (DM). METHODS: Seventy-three newly diagnosed patients with DM and 147 healthy subjects were selected in this retrospective study. We divided the 73 DM patients into 2 groups: 55 without interstitial lung disease (ILD) and 18 with ILD. Complete clinical characteristics were extracted from the medical records of DM patients. The correlations between NLR, PLR, the clinical characteristics and the disease activity were analyzed. RESULTS: For DM patients without ILD, the NLR and PLR were significantly higher than those in the control group (both P<0.001). For DM patients with ILD, the NLR and PLR were higher than in DM patients without ILD (P=0.004 and P=0.026, respectively). The NLR was positively correlated with C-reactive protein (CRP) (r=0.543, P<0.001) and the erythrocyte sedimentation rate (ESR) (r=0.513, P=0.001). The global activity scores correlated positively and significantly with NLR, PLR, and CRP (r=0.486, P<0.001; r=0.240, P=0.041; and r=0.343, P=0.003, respectively). Based on the ROC curve, to predict DM patients with ILD, the best cut-off value of the NLR was 3.98 (sensitivity 88.9%, specificity 52.7%, AUC=0.727), and the best cutoff value of PLR was 221.69 (sensitivity 77.8%, specificity 69.1%, AUC=0.722). CONCLUSIONS: Both NLR and PLR exhibit favorable diagnostic performance in predicting pulmonary involvement and disease activity in patients with DM. We provide the optimal cut-off values for DM patients with ILD that would maximize the diagnostic efficiency.