Diversification of the Carbodicarbene Class by Embedding an Anionic Component in its Scaffold.

Carbodicarbene (CDC) has become an emerging ligand in many fields due to its strong σ-donating ability.

Binuclear Macrocyclic Silver(I) Complex of a Bis(carbone) Pincer Ligand: Synthesis and Application as a Carbone-Transfer Agent.

A facile synthesis of a binuclear AgI complex 2 of a bis(carbone) ligand L and its application as a carbone-transfer agent for the generation of other transition-metal complexes of AuI (3), NiII (4), and PdII (5) is presented. Complex 2 was synthesized through multiple synthetic routes under mild reaction conditions using the tetracationic [LH4][OTf·Cl]2 precursor salt, the dicationic [LH2][OTf]2 ylide salt, and the free ligand L. The first two synthesis routes require no prior isolation of the air-, moisture-, and temperature-sensitive free ligand L, thus affording complex 2 with high yield and purity. Multinuclear NMR techniques, high-resolution mass spectrometry, and single-crystal X-ray diffraction analysis confirmed the identity of complex 2 as a binuclear AgI complex of L with a molecular formula of [L2Ag2][OTf]2 and a 16-membered-ring metallomacrocyclic structure. During the transmetalation reaction with AuI, the binuclear nature of complex 2 remains intact to give analogous complex 3 ([L2Au2][OTf]2). However, the dimeric structure was disrupted upon the carbone-transfer reaction with NiII and PdII, yielding mononuclear C-N-C pincer-type complexes 4 ([LNiCl][OTf]) and 5 ([LPdCl][OTf]), respectively. These results demonstrated the versatile use of complex 2 as a carbone-transfer agent to other transition metals regardless of the type or size of the metals or the geometry they prefer.

Videofluoroscopy dysphagia severity scale is predictive of subsequent remote pneumonia in dysphagia patients.

Introduction: Dysphagia-associated pneumonia is a critical health issue especially in the elders and stroke patients which carries a poorer prognosis. Therefore, we aim to identify methods with the potentials to predict subsequent pneumonia in dysphagia patients, which will be of great value in the prevention and early management of pneumonia. Methods: One-hundred dysphagia patients were enrolled and measurements including Dysphagia Severity Scale (DSS), Functional Oral Intake Scale (FOIS), Ohkuma Questionnaire, and Eating Assessment Tool-10 (EAT-10) were assessed by either videofluoroscopy (VF), videoendoscopy (VE), or the study nurse. The patients were categorized into mild or severe groups based on each screening method. All the patients were assessed for pneumonia at 1, 3, 6, and 20 months after the examinations. Results: VF-DSS (p=0.001) is the only measurement being significantly associated with subsequent pneumonia with sensitivity and specificity of 0.857 and 0.486. The Kaplan-Meier curves revealed that significant differences between the mild/severe groups start to emerge 3 months after VF-DSS (p=0.013). Cox regression models used for adjusted hazard ratio of severe VF-DSS in association with subsequent pneumonia of different timepoints after controlling the important covariates showed the following results: 3 months, p=0.026, HR=5.341, 95%CI=1.219-23.405; 6 months, p=0.015, HR=4.557, 95%CI=1.338-15.522; 20 months, p=0.004, HR=4.832, 95%CI=1.670-13.984. Conclusions: Dysphagia severity evaluated by VE-DSS, VE-FOIS, VF-FOIS, Ohkuma Questionnaire, and EAT-10 is not associated with subsequent pneumonia. Only VF-DSS is associated with both short-term and long-term subsequent pneumonia. In patients with dysphagia, VF-DSS is predictive of subsequent pneumonia.

Consistencies among miscellaneous scales for evaluation of post-stroke dysphagia.

PURPOSE: Post-stroke dysphagia (PSD) is the most common type of dysphagia. Stroke patients with sustained dysphagia have poorer outcomes. The severity of PSD is assessed using miscellaneous scales with unknown consistencies. We aim to investigate the consistencies among miscellaneous scales, which could aid in the assessment of PSD. METHODS: A total of 49 PSD patients were enrolled. Functional Oral Intake Scale (FOIS), Dysphagia Severity Scale (DSS), Ohkuma Questionnaire, Eating Assessment Tool-10, and Repetitive Saliva Swallowing Test were performed. FOIS was performed by physicians, and DSS was conducted by both the physicians and nurses; the physicians used either videofluoroscopy (VF) or videoendoscopy (VE) for evaluation; while, the nurses assessed PSD by observation and subjective judgment. RESULTS: When using VF (VF-DSS and VF-FOIS) as the gold standard for the evaluation, VE-FOIS (κ = 0.625, 95% CI 0.300-0.950, p < 0.001) has a substantial agreement with VF-FOIS, and VE-DSS (κ = 0.381, 95% CI 0.127-0.636, p = 0.007) has a fair agreement with VF-DSS. The weighted kappa of FOIS to DSS in VE (weighted κ = 0.577, 95% CI 0.414-0.740, p < 0.001) is not lower than that in VF (weighted kappa = 0.249, 95% CI 0.136-0.362, p < 0.001). CONCLUSION: For both DSS and FOIS, only VE has a statistically significant agreement with VF. Though VF has been viewed as the traditional gold standard of dysphagia screening, it has the limitations of being invasive and equipment dependent. For PSD, VE could be considered as a substitution when VF is not available or suitable.

Acetylation-Mimic Mutation of TRIM28-Lys304 to Gln Attenuates the Interaction with KRAB-Zinc-Finger Proteins and Affects Gene Expression in Leukemic K562 Cells.

TRIM28/KAP1/TIF1ß is a crucial epigenetic modifier. Genetic ablation of trim28 is embryonic lethal, although RNAi-mediated knockdown in somatic cells yields viable cells. Reduction in TRIM28 abundance at the cellular or organismal level results in polyphenism. Posttranslational modifications such as phosphorylation and sumoylation have been shown to regulate TRIM28 activity. Moreover, several lysine residues of TRIM28 are subject to acetylation, but how acetylation of TRIM28 affects its functions remains poorly understood. Here, we report that, compared with wild-type TRIM28, the acetylation-mimic mutant TRIM28-K304Q has an altered interaction with Krüppel-associated box zinc-finger proteins (KRAB-ZNFs). The TRIM28-K304Q knock-in cells were created in K562 erythroleukemia cells by CRISPR-Cas9 (Clustered regularly interspaced short palindromic repeats/CRISPR-associated protein nuclease 9) gene editing method. Transcriptome analysis revealed that TRIM28-K304Q and TRIM28 knockout K562 cells had similar global gene expression profiles, yet the profiles differed considerably from wild-type K562 cells. The expression levels of embryonic-related globin gene and a platelet cell marker integrin-beta 3 were increased in TRIM28-K304Q mutant cells, indicating the induction of differentiation. In addition to the differentiation-related genes, many zinc-finger-proteins genes and imprinting genes were activated in TRIM28-K304Q cells; they were inhibited by wild-type TRIM28 via binding with KRAB-ZNFs. These results suggest that acetylation/deacetylation of K304 in TRIM28 constitutes a switch for regulating its interaction with KRAB-ZNFs and alters the gene regulation as demonstrated by the acetylation mimic TRIM28-K304Q.

Basilar Artery Fenestration Versus Hypoglycemia-Induced Vertebrobasilar Insufficiency: A Case Report.

PURPOSE: Vertebrobasilar insufficiency (VBI) is a common transient neurological condition related to posterior circulation hemodynamic insufficiency. However, it is rarely seen as an initial presentation in basilar artery (BA) fenestration or hypoglycemia. We present this case to further clarify the association between BA fenestration and hypoglycemia-induced VBI, as well as the difficulty in diagnosis, especially in acute clinical settings. CASE REPORT: Herein, we report a case with BA fenestration, in which the patient suffered from transient episodes of focal neurological deficits, including dysarthria, focal limbs weakness, and ataxia with subsequent total recovery. Apart from hypoglycemia, no other abnormal laboratory surveys were found. This concurrent finding of hypoglycemia with transient focal neurological deficit poses a difficulty in differentiating between hypoglycemia-induced VBI and true acute ischemic stroke in the clinical setting. Subsequent brain imaging studies revealed no evidence of acute infarction and no evidence of atherosclerosis changes in vessels but BA fenestration was observed. We prescribed antiplatelets for the prevention of future strokes. However, currently, no consensus exists regarding the prevention of cerebral ischemia with BA fenestration. CONCLUSION: BA fenestration-induced VBI and hypoglycemia-induced VBI are rarely reported and their mechanisms of action remain uncertain and controversial. However, BA fenestration-induced VBI may pose a risk for future cerebral ischemic events and warrants further investigations.

A Bis-(carbone) Pincer Ligand and Its Coordinative Behavior toward Multi-Metallic Configurations.

Carbones are divalent carbon(0) species that contain two lone pairs of electrons. Herein, we have prepared the first known stable and isolable free bis-(carbone) pincer framework with a well-defined solid-state structure. This bis-(carbone) ligand is an effective scaffold for forming monometallic (Ni and Pd) and trinuclear heterometallic complexes with Au-Pd-Au, Au-Ni-Au, and Cu-Ni-Cu configurations. Sophisticated quantum-theoretical analyses found that the metal-metal interactions are too weak to play a significant role in upholding these multi-metallic configurations; rather, the four lone pairs of electrons within the bis-(carbone) framework are the main contributors to the stability of the complexes.

Synergistic Catalysis by Brønsted Acid/Carbodicarbene Mimicking Frustrated Lewis Pair-Like Reactivity.

Carbodicarbene (CDC), unique carbenic entities bearing two lone pairs of electrons are well-known for their strong Lewis basicity. We demonstrate herein, upon introducing a weak Brønsted acid benzyl alcohol (BnOH) as a co-modulator, CDC is remolded into a Frustrated Lewis Pair (FLP)-like reactivity. DFT calculation and experimental evidence show BnOH loosely interacting with the binding pocket of CDC via H-bonding and π-π stacking. Four distinct reactions in nature were deployed to demonstrate the viability of proof-of-concept as synergistic FLP/Modulator (CDC/BnOH), demonstrating enhanced catalytic reactivity in cyclotrimerization of isocyanate, polymerization process for L-lactide (LA), methyl methacrylate (MMA) and dehydrosilylation of alcohols. Importantly, the catalytic reactivity of carbodicarbene is uniquely distinct from conventional NHC which relies on only single chemical feature of nucleophilicity. This finding also provides a new spin in diversifying FLP reactivity with co-modulator or co-catalyst.

Carbodicarbene: geminal-Bimetallic Coordination in Selective Manner.

The reaction of Pd(OAc)2 with free carbodicarbene (CDC) generates a Pd acetate trinuclear complex 1 via intramolecular C(sp3 )-H bond activation at one of the CDC methyl side arms. The solid structure of 1 reveals the capability of CDC to facilitate a double dative bond with two palladium centers in geminal fashion. This is attributed to the chelating mode of CDC, which can frustrate π-conjugation within the CDC framework. Such effect maybe also amplified by ligand-ligand interaction. The formation of other gem-bimetallic Pd-Pd, Pd-Au, and Ni-Au provides further structural evidence for this proof-of-concept in selective installation. Structural analysis is supported by computational calculations based on state-of-the-art energy decomposition analysis (EDA) in conjunction with natural orbitals for chemical valence (NOCV) method.

TRIM28 Regulates Dlk1 Expression in Adipogenesis.

The tripartite motif-containing protein 28 (TRIM28) is a transcription corepressor, interacting with histone deacetylase and methyltransferase complexes. TRIM28 is a crucial regulator in development and differentiation. We would like to investigate its function and regulation in adipogenesis. Knockdown of Trim28 by transducing lentivirus-carrying shRNAs impairs the differentiation of 3T3-L1 preadipocytes, demonstrated by morphological observation and gene expression analysis. To understand the molecular mechanism of Trim28-mediated adipogenesis, the RNA-seq was performed to find out the possible Trim28-regulated genes. Dlk1 (delta-like homolog 1) was increased in Trim28 knockdown 3T3-L1 cells both untreated and induced to differentiation. Dlk1 is an imprinted gene and known as an inhibitor of adipogenesis. Further knockdown of Dlk1 in Trim28 knockdown 3T3-L1 would rescue cell differentiation. The epigenetic analysis showed that DNA methylation of Dlk1 promoter and differentially methylated regions (DMRs) was not altered significantly in Trim28 knockdown cells. However, compared to control cells, the histone methylation on the Dlk1 promoter was increased at H3K4 and decreased at H3K27 in Trim28 knockdown cells. Finally, we found Trim28 might be recruited by transcription factor E2f1 to regulate Dlk1 expression. The results imply Trim28-Dlk1 axis is critical for adipogenesis.

Interface-Controlled Synthesis of Au-BINOL Hybrid Nanostructures and Mechanism Study.

The combined functionality of components in organic-inorganic hybrid nanomaterials render them efficient nanoreactors. However, the development in this field is limited due to a lack of synthetic avenues and systematic control of the growth kinetics of hybrid structures. In this work, we take advantage of an ionic switch for regio-control of Au-BINOL(1,1'-Bi-2-naphthol) hybrid nanostructures. Aromatic BINOL molecules assemble into nanospheres, concomitant with the growth of the Au nanocrystals. The morphological evolution of Au nanocrystals is solely controlled by the presence of halides in the synthetic system. Here we show that quaternary ammonium surfactants (CTAB or CTAC), not only bridging Au and BINOL, but also contributing to the formation of concentric or eccentric structures when their concentrations are tuned to the range of 10-5 to 10-3 M. This facile strategy offers the potential advantage of scalable production, with diverse functional organic-inorganic hybrid nanocomposites being produced based on the specific archetype of Au-BINOL hybrid nanocomposites.

Salinomycin acts through reducing AKT-dependent thymidylate synthase expression to enhance erlotinib-induced cytotoxicity in human lung cancer cells.

Erlotinib (TarcevaR) is a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor in the treatment of human non-small cell lung cancer (NSCLC). Salinomycin, a polyether antibiotic, has been promising a novel therapeutic agent for lung cancer, and down-regulated the expression of thymidylate synthase (TS) in NSCLC cell lines. Previous study showed that against EGFR and TS was strongly synergistic cytotoxicity in NSCLC cells. In this study, we showed that erlotinib (1.25-10µM) treatment down-regulating of TS expression in an AKT inactivation manner in two NSCLC cell lines, human lung squamous cell carcinoma H1703 and adenocarcinoma H1975 cells. Knockdown of TS using small interfering RNA (siRNA) or inhibiting AKT activity with PI3K inhibitor LY294002 enhanced the cytotoxicity and cell growth inhibition of erlotinib. A combination of erlotinib and salinomycin resulted in synergistic enhancement of cytotoxicity and cell growth inhibition in NSCLC cells, accompanied with reduced protein levels of phospho-AKT(Ser473), phospho-AKT(Thr308), and TS. Overexpression of a constitutive active AKT (AKT-CA) or Flag-TS expression vector reversed the salinomycin and erlotinib-induced synergistic cytotoxicity. Our findings suggested that the down-regulation of AKT-mediated TS expression by salinomycin enhanced the erlotinib-induced cytotoxicity in NSCLC cells. These results may provide a rationale to combine salinomycin with erlotinib for lung cancer treatment.

Effect of green manure amendment on herbicide pendimethalin on soil.

Manure amendment in agricultural practice can have a large effect on herbicide dissipation because the period of manure plowing is close to the period of herbicide application. In addition, manure amendment is among the frequently encountered options in ameliorating pesticide pollution. In this research, the dissipation of the herbicide pendimethalin was examined after amendment with two common green manures, Lupinus luteus (L) or Cosmos bipinnatus (C), for 110 days in pH 5.2 and 7.7 soils (Sankengtzu [Sk] and Erhlin [Eh] soil, respectively). The microbial activity and ecology changes were examined by using Biolog EcoPlate and denaturing gradient gel electrophoresis (DGGE). In Sk soil, the half-lives of pendimethalin with L, C, and blank treatment were 49.0, 54.9, and 62.2 days, respectively, whereas that in Eh soil they were 46.3, 52.6, and 34.8 days, respectively. Pendimethalin dissipated quickly in more neutral soil (Eh soil), but the addition of manure can only increase the dissipation rate in acidic soil (Sk soil), indicating that the amendment of manures exerted different effect in pendimethalin dissipation rates in different pH soils. The application of pendimethalin and/or manure altered the microbial community activity after 24 h of incubation. After 110 days, the microbial community activities in green manure-amended soil were more similar to that with blank than pendimethalin treatment in both types of soils. In comparison with treatment C, microbial communities were more similar between treatment L and blank, indicating the superior effect over pendimethalin on microbial communities when applying Lupinus luteus. The research showed that the application of herbicide pendimethalin changed soil microbial community, and the amendment of manures exerted different effect in pendimethalin dissipation rates in different pH soils. It is assumed that the change in dissipation rates was originated from the microbial community change after different manure amendment.

Carbodicarbenes: Unexpected π-Accepting Ability during Reactivity with Small Molecules.

An investigation of carbodicarbenes, the less explored member of the carbenic complex/ligand family has yielded unexpected electronic features and concomitant reactivity. Observed 1,2-addition of E-H bonds (E = B, C, Si) across the carbone central carbon and that of the flanking N-heterocyclic carbene (NHC) fragment, combined with single-crystal X-ray studies of a model Pd complex strongly suggests a significant level of π-accepting ability at the central carbon of the NHC moiety. This feature is atypical of classic NHCs, which are strong σ-donors, with only nominal π-accepting ability. The unanticipated π-acidity is critical for engendering carbodicarbenes with reactivity more commonly observed with frustrated Lewis pairs (FLPs) rather than the more closely related NHCs and cyclic (alkyl)(amino)carbenes (CAACs).

Astaxanthin enhances pemetrexed-induced cytotoxicity by downregulation of thymidylate synthase expression in human lung cancer cells.

Pemetrexed, a multitargeted antifolate agent, has demonstrated clinical activity in non-small cell lung cancer (NSCLC) cells. Increased expression of thymidylate synthase (TS) is thought to be associated with resistance to pemetrexed. Astaxanthin exhibits a wide range of beneficial effects including anti-cancer and anti-inflammatory properties. In this study, we showed that down-regulating of TS expression in two NSCLC cell lines, human lung adenocarcinoma H1650 and squamous cell carcinoma H1703 cells, with astaxanthin were associated with decreased MKK1/2-ERK1/2 activity. Enforced expression of constitutively active MKK1 (MKK1-CA) vector significantly rescued the decreased TS mRNA and protein levels in astaxanthin-treated NSCLC cells. Combined treatment with a MKK1/2 inhibitor (U0126 or PD98059) further decreased the TS expression in astaxanthin-exposed NSCLC cells. Knockdown of TS using small interfering RNA (siRNA) or inhibiting ERK1/2 activity enhanced the cytotoxicity and cell growth inhibition of astaxanthin. Combination of pemetrexed and astaxanthin resulted in synergistic enhancing cytotoxicity and cell growth inhibition in NSCLC cells, accompanied with reduced activation of phospho-MKK1/2, phopho-ERK1/2, and TS expression. Overexpression of MKK1/2-CA reversed the astaxanthin and pemetrexed-induced synergistic cytotoxicity. Our findings suggested that the down-regulation of MKK1/2-ERK1/2-mediated TS expression by astaxanthin is an important regulator of enhancing the pemetrexed-induced cytotoxicity in NSCLC cells.

A Wireless and Batteryless Intelligent Carbon Monoxide Sensor.

Carbon monoxide (CO) poisoning from natural gas water heaters is a common household accident in Taiwan. We propose a wireless and batteryless intelligent CO sensor for improving the safety of operating natural gas water heaters. A micro-hydropower generator supplies power to a CO sensor without battery (COSWOB) (2.5 W at a flow rate of 4.2 L/min), and the power consumption of the COSWOB is only ~13 mW. The COSWOB monitors the CO concentration in ambient conditions around natural gas water heaters and transmits it to an intelligent gateway. When the CO level reaches a dangerous level, the COSWOB alarm sounds loudly. Meanwhile, the intelligent gateway also sends a trigger to activate Wi-Fi alarms and sends notifications to the mobile device through the Internet. Our strategy can warn people indoors and outdoors, thereby reducing CO poisoning accidents. We also believe that our technique not only can be used for home security but also can be used in industrial applications (for example, to monitor leak occurrence in a pipeline).

Expanding the Ligand Framework Diversity of Carbodicarbenes and Direct Detection of Boron Activation in the Methylation of Amines with CO2.

A simple and convergent synthetic strategy used to increase the diversity of the carbodicarbene ligand framework through incorporation of unsymmetrical pendant groups is reported. Structural analysis and spectroscopic studies of ligands and their Rh complexes are reported. Reactivity studies reveal carbodicarbenes as competent organocatalysts for amine methylation using CO2 as a synthon. A unique BH-activated boron-carbodicarbene complex was isolated as a reaction intermediate, providing mechanistic insight into the CO2 functionalization process.

Synthesis and isolation of an acyclic tridentate bis(pyridine)carbodicarbene and studies on its structural implications and reactivities.

The simple synthetic development of acyclic pincer bis(pyridine)carbodicarbene is depicted herein. Presented is the first isolated structural pincer carbodicarbene with a C-C-C angle of 143°, larger than the monodentate framework. More importantly, theoretical analysis showed that this carbodicarbene embodies a more allene-like character. Palladium complexes supported by this pincer ligand are active catalysts for Heck-Mizoroki and Suzuki-Miyaura coupling reactions.

The elusive three-coordinate dicationic hydrido boron complex.

The formation of a hitherto unknown three-coordinate dicationic hydrido boron complex is described. Interestingly, supporting ligand carbodicarbene gave unprecedented reaction with BH3 without using more highly electrophilic Lewis acid precursors. Spectroscopic, crystallographic, and computational analysis was performed to understand the electronic features of these species.