Odorant receptors (ORs) in olfactory sensory neurons (OSNs) mediate detection of volatile odorants. Divalent sulfur compounds, such as thiols and thioethers, are extremely potent odorants. We identify a mouse OR, MOR244-3, robustly responding to (methylthio)methanethiol (MeSCH 2 SH; MTMT) in heterologous cells. Found specifically in male mouse urine, strong-smelling MTMT [human threshold 100 parts per billion (ppb)] is a semiochemical that attracts female mice. Nonadjacent thiol and thioether groups in MTMT suggest involvement of a chelated metal complex in MOR244-3 activation. Metal ion involvement in thiol-OR interactions was previously proposed, but whether these ions change thiol-mediated OR activation remained unknown. We show that copper ion among all metal ions tested is required for robust activation of MOR244-3 toward ppb levels of MTMT, structurally related sulfur compounds, and other metal-coordinating odorants (e.g., strong-smelling transcyclooctene) among >125 compounds tested. Copper chelator (tetraethylenepentamine, TEPA) addition abolishes the response of MOR244-3 to MTMT. Histidine 105, located in the third transmembrane domain near the extracellular side, is proposed to serve as a copper-coordinating residue mediating interaction with the MTMTcopper complex. Electrophysiological recordings of the OSNs in the septal organ, abundantly expressing MOR244-3, revealed neurons responding to MTMT. Addition of copper ion and chelator TEPA respectively enhanced and reduced the response of some MTMTresponding neurons, demonstrating the physiological relevance of copper ion in olfaction. In a behavioral context, an olfactory discrimination assay showed that mice injected with TEPA failed to discriminate MTMT. This report establishes the role of metal ions in mammalian odor detection by ORs.

Primitive stromal cells can be isolated from umbilical cord Wharton's jelly (UC-PSCs). Umbilical cord can be easily obtained without causing pain to donors, and the procedure avoids ethical and technical issues. UC-PSCs are more primitive than mesenchymal stem cells (MSCs) isolated from some other tissue sources. In this study, UC-PSCs were induced to differentiate into insulin-producing cells, and compared with bone marrow-derived MSCs (BM-MSCs) for their pancreatic differentiation potential. UC-PSCs showed significantly higher proliferation than BM-MSCs. During pancreatic induction, UC-PSCs formed larger islet-like cell clusters than BM-MSCs. Immunocytochemical analysis showed that higher expression of the pancreatic-specific transcription factor PDX-1 was detected in differentiated UC-PSCs than in differentiated BM-MSCs. Flow cytometry analysis demonstrated that the percentage of differentiated UC-PSCs expressing pancreatic-specific marker C-peptide was 72% higher than differentiated BM-MSCs. Radioimmunoassay revealed that differentiated UC-PSCs secreted significantly more insulin than differentiated BM-MSCs. These results demonstrated that UC-PSCs had higher pancreatic differentiation potential than BM-MSCs. Therefore, UC-PSCs are more suitable for pancreatic tissue engineering in the treatment of type I diabetes than BM-MSCs.

Ethosomes can promote the penetration of lipophilic drugs into the skin, but the underlying mechanism is still unknown. The purpose of this study was to investigate the mechanism of transdermal permeation promotion of lipophilic drugs by ethosomes. The formulation of ethosomes was optimized using the Box–Behnken experimental design, in which Rhodamine B and 1-palmitoyl-2-{12-[(7-nitro-2-1,3-benzoxadiazol-4-yl)amino]dodecanoyl}- sn -glycero-3-phosphocholine were used to simulate a model lipophilic drug and act as a fluorescent tracer of ethosomal phospholipids, respectively. Liposomes with the same phospholipid concentration and a hydroethanolic solution with the same ethanol concentration were also prepared as controls. The percutaneous progression of the above fluorescent preparations was observed by confocal laser scanning microscopy, and the fluorescence intensity of the images was analyzed. The optimized ethosome formulation consisted of 2.45% yolk phospholipids, 30% ethanol, and 67.55% distilled water. The percutaneous permeation of Rhodamine B in the optimized ethosomes was superior to that in hydroethanolic solution ( P <0.05) and liposomes ( P <0.05). The ethosomes could penetrate the skin via the percutaneous pathway of the hair follicle and stratum corneum, while during the process of penetration, the vesicles were broken and the phospholipids were retained in the upper epidermis, with the test compounds penetrating gradually. The superior percutaneous penetration of ethosomes was linked to the synergistic effects of their ingredients. The percutaneous pathways of ethosomes included open hair follicles and stratum corneum pathways. In addition, the vesicles might break up during percutaneous penetration in the superficial layer of the skin, allowing the test compounds to keep permeating into the deeper layer alone, while the phospholipid was retained in the upper epidermis.

Background: RTP1S facilitates the translocation of odorant receptors (ORs).Results: Different domains in RTP1S are important for different stages of OR trafficking, odorant-mediated responses, and interaction with ORs. Conclusion: RTP1S mediates the trafficking and ligand-induced response of ORs by acting through multiple steps. Significance: Probing the structure-function of RTP1S is crucial for understanding the mechanism of OR trafficking and activation.

ABSTRACTdence suggests that microRNA (miRNA, miR) are functionally involved in MSC senescence. [18][19][20] The ablation of Dicer1 (an RNAse III endonuclease essential for miRNA biogenesis) and the loss of mature miRNA in embryonic fibroblasts and endothelial cells inhibited cell proliferation and induced a premature senescence phenotype. 21,22 Although recent striking findings indicate that Dicer1 deletion can induce an MDS phenotype in mice 23 and that Dicer1 expression is reduced in MSC from MDS patients, 24 the precise mechanism by which the Dicer1 gene contributes to the pathogenesis of MDS remains elusive. We inferred that disordered expression of Dicer1 could contribute to abnormal MSC senescence and impaired stromal support in MDS.The aims of this study were, therefore, to evaluate the senescent features of BM-MSC from patients with MDS and to explore the role of Dicer1 in the senescence of MSC and the disturbed stromal function observed in patients with MDS. Methods Patients and control samplesA total of 77 patients with MDS were included in this study. Their characteristics are detailed in Online Supplementary Table S1. Patients were diagnosed with MDS according to the minimum diagnostic criteria established by the Conference on MDS. 25Patients were classified for the study as "lower-risk" (LR) [International Prognostic Scoring System (IPSS) low/int-1] and as "higher-risk" (HR) (IPSS-int-2/high).26 Twenty-two healthy volunteers were used as controls (median age 62 years; age range, 43-78 years) and were matched for gender and age. All study participants signed an informed consent form. The research was approved by the ethics committee of the Sixth Hospital affiliated with Shanghai Jiao Tong University, and all patient-relevant research strictly abided by the Declaration of Helsinki. Mesenchymal stromal cell characterizationBM-MSC were isolated and cultured; their immunophenotype, clonogenic and proliferative potential, and differentiation were studied and SA-β-Gal assay were performed. Detailed information about the experiments is provided in the Online Supplementary Material. RNA isolation and real-time polymerase chain reaction analysisTotal RNA was isolated using TRIzol (Invitrogen, Paisley, Scotland) according to the manufacturer's instructions. For mRNA detection, the RNA was reverse transcribed using the RevertAid First Strand cDNA Synthesis Kit (Fermentas, Burlington, Canada) according to the manufacturer's protocol, and real-time polymerase chain reaction (RT-PCR) was performed using RealMasterMix (Takara, Dalian, China). The process used was described in detail in our previous study. 27 The primers are listed in Online Supplementary Table S2. RT-PCR for miRNA was performed using the PrimeScript ™ miRNA qPCR Starter Kit Ver. 2.0 (Takara, Dalian, China). RNU6B was used as the housekeeping gene. Fold change was calculated using the DDCT method of relative quantification. Isolation of CD34 + cells and CD271 + cellsMononuclear cells were obtained from BM aspirates by density gradient separation and...

Supplementary data are available at Bioinformatics online.

No abstract

Many studies have reported that BRCA1 polymorphisms are associated with cancer risk, but the results remain controversial. The purpose of this meta-analysis is to evaluate the relationship between BRCA1 polymorphisms (rs799917, rs1799950, rs1799966, or rs16941) and cancer risk. Relevant studies were identified via a systematic search of the PubMed, Embase, and Web of Science databases up to July 31, 2017. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to examine the strength of the associations. Thirty-five studies published in 19 publications involving 28,094 cases and 50,657 controls were included in this meta-analysis. There was no obvious association between rs799917, rs1799966, or rs16941 polymorphisms and overall cancer risk in any genetic models. However, subgroup analyses revealed that the rs799917 polymorphism could decrease the risk of cervical cancer, esophageal squamous cell carcinoma (ESCC), gastric cancer, and non-Hodgkin lymphoma (NHL) among Asian populations in one or more genetic models and that rs16941 could increase overall cancer risk among Caucasian populations in the homozygote and recessive models. Our meta-analysis also indicated that rs1799950 could decrease the breast cancer (BC) risk among Caucasian populations in the homozygote and recessive models. In summary, our results suggest that BRCA1 polymorphisms may play an important role in the etiology of cancer. However, due to the limited number of studies, these findings should be confirmed by new studies with larger sample sizes that address various types of cancer.