Histologically confirmed HT is associated with a significantly higher risk of PTC, due primarily to the higher serum TSH concentrations resulting from the tendency to hypothyroidism in HT. Autoimmunity is another independent risk factor for PTC but may be associated with a better prognosis.

Gaucher disease (GD) is an autosomal recessive disorder caused by mutations in the acid beta-glucocerebrosidase (GBA) gene. The hallmark of GD is the presence of lipid-laden Gaucher macrophages, which infiltrate bone marrow and other organs. These pathological macrophages are believed to be the source of elevated levels of inflammatory mediators present in the serum of GD patients. The alteration in the immune environment caused by GD is believed to play a role in the increased risk of developing multiple myeloma and other malignancies in GD patients. To determine directly whether Gaucher macrophages are abnormally activated and if their functional defects can be reversed by pharmacological intervention, we generated GD macrophages by directed differentiation of human iPS cells (hiPSC) derived from patients with types 1, 2, and 3 GD. GD hiPSC-derived macrophages expressed higher levels of TNF alpha, IL-6, and IL-1beta than control cells, and this phenotype was exacerbated by treatment with LPS. In addition, GD hiPSC macrophages exhibited a striking delay in clearance of phagocytosed red blood cells, recapitulating the presence of RBC remnants in Gaucher macrophages from bone marrow aspirates. Incubation of GD hiPSC macrophages with recombinant glucocerebrosidase, or with the chaperones isofagomine and ambroxol, corrected the abnormal phenotypes of GD macrophages to an extent that reflected their known clinical efficacies. We conclude that Gaucher macrophages are the likely source of the elevated levels of inflammatory mediators in the serum of GD patients, and that GD hiPSC are valuable new tools for studying disease mechanisms and drug discovery.

Background: Papillary thyroid cancer has been associated with chronic inflammation. A systematic understanding of immune cell infiltration in PTC is essential for subsequent immune research and new diagnostic and therapeutic strategies.Methods: Three different algorithms, single-sample gene set enrichment analysis (ssGSEA), immune cell marker and CIBERSORT, were used to evaluate immune cell infiltration levels (abundance and proportion) in 10 data sets (The Cancer Genome Atlas [TCGA], GSE3467, GSE3678, GSE5364, GSE27155, GSE33630, GSE50901, GSE53157, GSE58545, and GSE60542; a total of 799 PTC and 194 normal thyroid samples). Consensus unsupervised clustering divided PTC patients into low-immunity and high-immunity groups. Weighted gene coexpression network analysis (WGCNA) and gene set enrichment analysis (GSEA) were used to analyze the potential mechanisms causing differences in the immune response.Results: Compared with normal tissues, PTC tissues had a higher overall immune level and higher abundance levels and proportions of M2 macrophages, Tregs, monocytes, neutrophils, dendritic cells (DCs), mast cells (MCs), and M0 macrophages. Compared with early PTC, advanced PTC showed higher immune infiltration and higher abundance levels and proportions of M2 macrophages, Tregs, monocytes, neutrophils, DCs, MCs, and M0 macrophages. Compared to the low-immunity group, the high-immunity group exhibited more advanced stages, larger tumor sizes, greater lymph node metastases, higher tall-cell PTCs, lower follicular PTC proportions, more BRAF mutations, and fewer RAS mutations. Epstein-Barr virus (EBV) infection was the most significantly enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway for key module genes. Conclusions:In human PTC, M2 macrophages, Tregs, monocytes, neutrophils, DCs, MCs, and M0 macrophages appear to play a tumor-promoting role, while M1 macrophages, CD8+ T cells, B cells, NK cells, and T follicular helper (T FH ) cells (including eosinophils, gd T cells, and Th17 cells with weak supporting evidence) appear to play an antitumor role. During the occurrence and development of PTC, the overall immune level was increased, and the abundance and proportion of tumorpromoting immune cells were significantly increased, indicating that immune escape

The correlation between thyroglobulin antibodies (TgAb) or thyroid peroxidase antibodies (TPOAb) and papillary thyroid cancer (PTC) remains controversial. This histological study aimed to explore the correlation between thyroid autoantibodies (TAb), thyroid-stimulating hormone (TSH), and PTC in patients with thyroid nodules (TN). This was a retrospective study. 2,132 non-autoimmune thyroid diseases (AITD) patients who underwent thyroidectomy were subdivided into: TgAb or TPOAb single positive (TgAb+ or TPOAb+) TN group; TgAb and TPOAb double positive or negative (TAb+ or TAb-) TN group. PTC patients showed a higher rate of TAb+ TN (10.24 vs. 4.89 %; P = 0.000) and a higher TSH level (1.83 ± 0.07 vs. 1.39 ± 0.03 mIU/L; P = 0.000) than patients with benign nodules. TAb+ TN patients showed a higher TSH level and PTC frequency than those with TAb- TN (1.91 ± 0.17 vs. 1.47 ± 0.03 mIU/L; P = 0.011) (41.35 vs. 22.08 %; P = 0.000). In PTC, TAb+ TN patients showed a higher TSH level (2.57 ± 0.35 vs. 1.79 ± 0.07 mIU/L; P = 0.032), a greater frequency of lymph node metastasis (52.73 vs. 36.51 %, P = 0.026), and a lower micro-PTC frequency (16.36 vs. 39.51 %; P = 0.001) than TAb- TN patients. PTC was correlated with TgAb+ TN (OR = 1.921, CI 1.431-2.580; P = 0.000), TPOAb+ TN (OR = 1.945, CI 1.195-3.165; P = 0.007), TAb+ TN (OR = 2.393, CI 1.635-3.501; P = 0.000), and serum TSH >1.35 mIU/L (OR = 1.742, CI 1.089-2.786; P = 0.021). Serum positive TgAb or TPOAb is an independent predictor for PTC regardless of AITD. The coexistence of TgAb and TPOAb confers a greater risk for PTC than isolated positive TgAb or TPOAb, and is correlated with elevated TSH level and advanced PTC stage.

Decreased Na(+) /K(+) -ATPase activity, and both sirtuin 1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK) have been reported to be involved in the development of diabetic cardiomyopathy (DCM). The present study aimed to investigate the advanced glycation end-products (AGE) that impair Na(+) /K(+) -ATPase stability by regulating the AMPK/SIRT1 pathway during progression of DCM. To study type 1 diabetic mellitus (T1DM), a disease model in rats was established by a single intraperitoneal injection of streptozotocin (STZ; 65 mg/kg), and neonatal rat cardiomyocytes were also cultured. Heart function was detected by Doppler, and SIRT1 and AMPK protein expression were detected by immunohistochemistry and western blotting. Na(+) /K(+) -ATPase activity was also monitored. Using in vivo rat models of DCM, we showed that Na(+) /K(+) -ATPase activity decreased when both AMPK and SIRT1 expression were downregulated. In vitro, AGE impaired Na(+) /K(+) -ATPase activity and decreased the AMPK and SIRT1 expression. Sirtuin 1 overexpression increased Na(+) /K(+) -ATPase activity. 5-aminoimidazole-4-carboxamide-3-ribonucleoside (AICAR) upregulated SIRT1 expression and increased Na(+) /K(+) -ATPase activity, which could be partially abolished by splitomicin. Our results suggest that the dysfunction of DCM is related to AGE-induced Na(+) /K(+) -ATPase activity impairment through a mechanism involving the AMPK/SIRT1 pathway.

No abstract

To assess how flow affects school structure and threat detection, startle response rates of solitary and small groups of giant danio Devario aequipinnatus were compared to visual looming stimuli in flow and no-flow conditions. The instantaneous position and heading of each D. aequipinnatus were extracted from high-speed videos. Behavioural results indicate that (1) school structure is altered in flow such that D. aequipinnatus orient upstream while spanning out in a crosswise direction, (2) the probability of at least one D. aequipinnatus detecting the visual looming stimulus is higher in flow than no flow for both solitary D. aequipinnatus and groups of eight D. aequipinnatus, however, (3) the probability of three or more individuals responding is higher in no flow than flow. Taken together, these results indicate a higher probability of stimulus detection in flow but a higher probability of internal transmission of information in no flow. Finally, results were well predicted by a computational model of collective fright response that included the probability of direct detection (based on signal detection theory) and indirect detection (i.e. via interactions between group members) of threatening stimuli. This model provides a new theoretical framework for analysing the collective transfer of information among groups of fishes and other organisms.

Gaucher disease (GD) is the most common lysosomal storage disease resulting from mutations in the lysosomal enzyme glucocerebrosidase (GCase). The hematopoietic abnormalities in GD include the presence of characteristic Gaucher macrophages that infiltrate patient tissues and cytopenias. At present, it is not clear whether these cytopenias are secondary to the pathological activity of Gaucher cells or a direct effect of GCase deficiency on hematopoietic development. To address this question, we differentiated induced pluripotent stem cells (iPSCs) derived from patients with types 1, 2, and 3 GD to CD34(+)/CD45(+)/CD43(+)/CD143(+) hematopoietic progenitor cells (HPCs) and examined their developmental potential. The formation of GD-HPCs was unaffected. However, these progenitors demonstrated a skewed lineage commitment, with increased myeloid differentiation and decreased erythroid differentiation and maturation. Interestingly, myeloid colony-formation assays revealed that GD-HPCs, but not control-HPCs, gave rise to adherent, macrophage-like cells, another indication of abnormal myelopoiesis. The extent of these hematologic abnormalities correlated with the severity of the GCase mutations. All the phenotypic abnormalities of GD-HPCs observed were reversed by incubation with recombinant GCase, indicating that these developmental defects were caused by the mutated GCase. Our results show that GCase deficiency directly impairs hematopoietic development. Additionally, our results suggest that aberrant myelopoiesis might contribute to the pathological properties of Gaucher macrophages, which are central to GD manifestations. The hematopoietic developmental defects we observed reflect hematologic abnormalities in patients with GD, demonstrating the utility of GD-iPSCs for modeling this disease.