Formation of covalent metal-carbon contacts assisted by Ag+ for single molecule junctions.

Covalent metal-carbon (M-C) contacts have long been pursued for constructing robust and high-performance molecular devices. Existing methods for creating such contacts usually rely on direct chemical reactions between metal electrodes and designed molecular ligands. An inherent limitation of this approach is that the commonly used metal electrodes (e.g., Au) are chemically inert, making it generally difficult to form covalent M-C bonds with molecules. Intriguingly, employing the scanning tunneling microscope-break junction technique, we find that simply adding Ag+ ions to molecular solution enables direct covalent bonding of terminal alkynes to Au electrodes. The bonding process is driven by Ag+ ion coupled in situ reactions and efficiently creates covalent Au/Ag-C interfaces in single molecule junctions. This metal ion assisted method avoids the need for complex synthesis of molecular ligands and works robustly for a wide range of alkyne-terminated molecules, offering a facile and versatile approach for precisely tuning the metal-molecule interface.

Cleavage of non-polar C(sp2)‒C(sp2) bonds in cycloparaphenylenes via electric field-catalyzed electrophilic aromatic substitution.

Electrophilic aromatic substitution (EAS) is one of the most fundamental reactions in organic chemistry. Using an oriented external electric field (OEEF) instead of traditional reagents to tune the EAS reactivity can offer an environmentally friendly method to synthesize aromatic compounds and hold the promise of broadening its scope. Despite these advantages, OEEF catalysis of EAS is difficult to realize, due to the challenge of microscopically orienting OEEF along the direction of electron reorganizations. In this work, we demonstrate OEEF-catalyzed EAS reactions in a series of cycloparaphenylenes (CPPs) using the scanning tunneling microscope break junction (STM-BJ) technique. Crucially, the unique radial π-conjugation of CPPs enables a desired alignment for the OEEF to catalyze the EAS with Au STM tip (or substrate) acting as an electrophile. Under mild conditions, the OEEF-catalyzed EAS reactions can cleave the inherently inert C(sp2)-C(sp2) bond, leading to high-yield (~97%) formation of linear oligophenylenes terminated with covalent Au-C bonds. These results not only demonstrate the feasibility of OEEF catalysis of EAS, but also offer a way of exploring new mechanistic principles of classic organic reactions aided by OEEF.

RRP9 promotes gemcitabine resistance in pancreatic cancer via activating AKT signaling pathway.

BACKGROUND: Pancreatic cancer (PC) is a highly lethal malignancy regarding digestive system, which is the fourth leading factor of cancer-related mortalities in the globe. Prognosis is poor due to diagnosis at advanced disease stage, low rates of surgical resection, and resistance to traditional radiotherapy and chemotherapy. In order to develop novel therapeutic strategies, further elucidation of the molecular mechanisms underlying PC chemoresistance is required. Ribosomal RNA biogenesis has been implicated in tumorigenesis. Small nucleolar RNAs (snoRNAs) is responsible for post-transcriptional modifications of ribosomal RNAs during biogenesis, which have been identified as potential markers of various cancers. Here, we investigate the U3 snoRNA-associated protein RRP9/U3-55 K along with its role in the development of PC and gemcitabine resistance. METHODS: qRT-PCR, western blot and immunohistochemical staining assays were employed to detect RRP9 expression in human PC tissue samples and cell lines. RRP9-overexpression and siRNA-RRP9 plasmids were constructed to test the effects of RRP9 overexpression and knockdown on cell viability investigated by MTT assay, colony formation, and apoptosis measured by FACS and western blot assays. Immunoprecipitation and immunofluorescence staining were utilized to demonstrate a relationship between RRP9 and IGF2BP1. A subcutaneous xenograft tumor model was elucidated in BALB/c nude mice to examine the RRP9 role in PC in vivo. RESULTS: Significantly elevated RRP9 expression was observed in PC tissues than normal tissues, which was negatively correlated with patient prognosis. We found that RRP9 promoted gemcitabine resistance in PC in vivo and in vitro. Mechanistically, RRP9 activated AKT signaling pathway through interacting with DNA binding region of IGF2BP1 in PC cells, thereby promoting PC progression, and inducing gemcitabine resistance through a reduction in DNA damage and inhibition of apoptosis. Treatment with a combination of the AKT inhibitor MK-2206 and gemcitabine significantly inhibited tumor proliferation induced by overexpression of RRP9 in vitro and in vivo. CONCLUSIONS: Our data reveal that RRP9 has a critical function to induce gemcitabine chemoresistance in PC through the IGF2BP1/AKT signaling pathway activation, which might be a candidate to sensitize PC cells to gemcitabine. Video abstract.

Tetrathiafulvalenes as anchors for building highly conductive and mechanically tunable molecular junctions.

The interface between molecules and electrodes has great impact on charge transport of molecular devices. Precisely manipulating the structure and electronic coupling of electrode-molecule interface at a molecular level is very challenging. Here, we develop new molecular junctions based on tetrathiafulvalene (TTF)-fused naphthalene diimide (NDI) molecules which are anchored to gold electrodes through direct TTF-Au contacts formed via Au-S bonding. These contacts enable highly efficient orbital hybridization of gold electrodes and the conducting π-channels, yielding strong electrode-molecule coupling and remarkably high conductivity in the junctions. By further introducing additional thiohexyl (SHe) anchors to the TTF units, we develop molecular wires with multiple binding sites and demonstrate reversibly switchable electrode-molecule contacts and junction conductance through mechanical control. These findings show a superb electrode-molecule interface and provide a new strategy for precisely tunning the conductance of molecular devices towards new functions.

Single cycloparaphenylene molecule devices: Achieving large conductance modulation via tuning radial π-conjugation.

Conjugated macrocycles cycloparaphenylenes (CPPs) have unusual size-dependent electronic properties because of their unique radially π-conjugated structures. Contrary to linearly π-conjugated molecules, their highest occupied molecular orbital (HOMO)­lowest unoccupied molecular orbital (LUMO) gap shrinks as the molecular size reduces, and this feature can, in principle, be leveraged to achieve unexpected size-dependent transport properties. Here, we examine charge transport characteristics of [n]CPPs (n = 5 to 12) at the single molecule level using the scanning tunneling microscope­break junction technique. We find that the [n]CPPs have a much higher conductance than their linear oligoparaphenylene counterparts at small ring size and at the same time show a large tunneling attenuation coefficient comparable to saturated alkane series. These results show that the radially π-conjugated molecular systems can offer much larger conductance modulation range than standard linear molecules and can be a new platform for building molecular devices with highly tunable transport behaviors.

AKT1/FOXP3 axis-mediated expression of CerS6 promotes p53 mutant pancreatic tumorigenesis.

Ceramide synthases (CerSs) catalyze the formation of ceramides from sphingoid bases and acyl-CoA substrates. Increasing evidence suggests that cancer cells generally exhibit altered sphingolipid metabolism in the tumorigenesis of multiple cancers. However, there is no evidence that CerSs are associated with pancreatic ductal carcinoma (PDAC). In the present study, we examined CerS expression in clinical tissue and conducted data mining to investigate the clinical significance of CerSs in the TCGA-PAAD database. We found that high CerS6 expression positively correlated with progression and predicted worse prognosis in PDAC patients, establishing CerS6 as a potential biomarker for PDAC. Furthermore, CerS6 promoted cell proliferation, colony formation and invasion by producing C16-ceramide and was required for tumor formation. Mechanistically, AKT1 interacted with and phosphorylated FOXP3 at S418, which decreased the binding of FOXP3 to the CERS6 promoter and in turn induced CerS6 expression by reconstituting an activated state on the CERS6 promoter. The AKT1/FOXP3 axis mediated the CerS6 expression and promoted p53 mutant pancreatic tumorigenesis by producing excessive C16-ceramide, which induced the accumulation of mutant p53. Thus, our study explores the relationship between PI3K/AKT signaling and sphingolipid metabolism, revealing an oncogenic role for CerS6, which may represent a potential target for PDAC treatment.

The revised Atlanta criteria 2012 altered the classification, severity assessment and management of acute pancreatitis.

BACKGROUND: The Atlanta criteria for acute pancreatitis (AP) has been revised recently. This study was to evaluate its practical value in classification of AP, the severity assessment and management. METHODS: The clinical features, severity classification, outcome and risk factors for mortality of 3212 AP patients who had been admitted in Ruijin Hospital from 2004 to 2011 were analyzed based on the revised Atlanta criteria (RAC) and the original Atlanta criteria (OAC). RESULTS: Compared to the OAC group, the incidence of severe acute pancreatitis (SAP) was decreased by approximately one half (13.9% vs 28.2%) in the RAC group. The RAC presented a lower sensitivity but higher specificity, and its predictive value for severity and poor outcome was higher than those of the OAC. The proportion of SAP diagnosis and ICU admission in the early phase in the RAC group was significantly lower than that in the OAC group (P<0.05). Based on the RAC, the risk factors for death among SAP patients were older age, high CT severity index (CTSI), renal failure, cardiovascular failure, acute necrotic collection and walled-off necrosis. Compared to the OAC, the acute physiology and chronic health evaluation II (APACHE II) score, Ranson score, idiopathic etiology, respiratory failure and laparotomy debridement were not risk factors of death in contrast to walled-off necrosis. Interestingly, hypertriglyceridemia-related SAP had good outcomes in both groups. CONCLUSIONS: The RAC showed a higher predictive value for severity and poorer outcome than the OAC. However, the RAC resulted in fewer ICU admissions in the early phase due to its lower sensitivity for diagnosis of SAP. Among SAP cases, older age, high CTSI, renal and cardiovascular failure, complications of acute necrotic collection and walled-off necrosis were independent risk factors for mortality.