A heterotypic assembly mechanism regulates CHIP E3 ligase activity.

CHIP (C-terminus of Hsc70-interacting protein) and its worm ortholog CHN-1 are E3 ubiquitin ligases that link the chaperone system with the ubiquitin-proteasome system (UPS). CHN-1 can cooperate with UFD-2, another E3 ligase, to accelerate ubiquitin chain formation; however, the basis for the high processivity of this E3s set has remained obscure. Here, we studied the molecular mechanism and function of the CHN-1-UFD-2 complex in Caenorhabditis elegans. Our data show that UFD-2 binding promotes the cooperation between CHN-1 and ubiquitin-conjugating E2 enzymes by stabilizing the CHN-1 U-box dimer. However, HSP70/HSP-1 chaperone outcompetes UFD-2 for CHN-1 binding, thereby promoting a shift to the autoinhibited CHN-1 state by acting on a conserved residue in its U-box domain. The interaction with UFD-2 enables CHN-1 to efficiently ubiquitylate and regulate S-adenosylhomocysteinase (AHCY-1), a key enzyme in the S-adenosylmethionine (SAM) regeneration cycle, which is essential for SAM-dependent methylation. Our results define the molecular mechanism underlying the synergistic cooperation of CHN-1 and UFD-2 in substrate ubiquitylation.

Dyadic contagion in cognitive function: A nationally-representative longitudinal study of older U.S. couples.

Later-life cognitive function is strongly influenced by one's environment. At this life stage, a partner's behaviors and attributes-including their own cognitive status-are a key environmental determinant. A recent "social allostasis" theory also yields specific predictions on patterns of mutual influence-or "contagion"-in cognitive function. Yet, no population representative studies have examined these coupled dynamics. Using recently developed fixed-effects cross-lagged panel modeling (FE-CLPM) methods and ten-year data from the Health and Retirement Study-nationally-representative of U.S. adults over 50-the current study filled this gap. Results supported dyadic cognitive contagion over the long- but not short-run. Short-term associations suggested intriguing "cognitive cycling" possibilities among both men and women that need further investigation. Overall, results supported a theoretical model of coupled "cognitive careers," and relational inducement of allostatic load. Especially among men, recurrent impulses also cumulatively induced substantial path-dependent cognitive improvements, supporting the added value of repeated over one-time interventions. Theoretical and substantive implications are discussed.

Task-related hemodynamic responses are modulated by reward and task engagement.

Hemodynamic recordings from visual cortex contain powerful endogenous task-related responses that may reflect task-related arousal, or "task engagement" distinct from attention. We tested this hypothesis with hemodynamic measurements (intrinsic-signal optical imaging) from monkey primary visual cortex (V1) while the animals' engagement in a periodic fixation task over several hours was varied through reward size and as animals took breaks. With higher rewards, animals appeared more task-engaged; task-related responses were more temporally precise at the task period (approximately 10-20 seconds) and modestly stronger. The 2-5 minute blocks of high-reward trials led to ramp-like decreases in mean local blood volume; these reversed with ramp-like increases during low reward. The blood volume increased even more sharply when the animal shut his eyes and disengaged completely from the task (5-10 minutes). We propose a mechanism that controls vascular tone, likely along with local neural responses in a manner that reflects task engagement over the full range of timescales tested.

Reactivity of Nitric Oxide and Nitrosonium Ion with Copper(II/I) Schiff Base Complexes: Mechanistic Aspects of Imine C═N Bond Cleavage and Oxidation of Pyridine-2-aldehyde to Pyridine-2-carboxylic Acid.

Four Schiff base ligands of the general formulas [6-(R)-2-pyridyl-N-(2'-methylthiophenyl)methylenimine] (RL1) and 6-p-chlorophenyl-2-pyridyl-N-(2'-phenylthiophenyl)methylenimine (RL2), where R = H, Me, p-ClPh, and their bis-ligand copper(II) and copper(I) complexes, 1-4 and 1'-4', respectively, were synthesized and characterized. The reactivities of 1-4 with nitric oxide (NO) gas and of 1'-4' with solid NOBF4 (NO+) were examined in dry acetonitrile in the presence and absence of water (H2O). The results revealed that, in the absence of H2O, complexes 1-4 (or 1'-4') reacts with NO (or NOBF4), leading to imine C═N bond cleavage of both (or one) Schiff base(s) that generates 2 (or 1) equiv of 2-(methyl/phenyl)thiobenzenediazonium perchlorates (5/6) and the corresponding picolaldehyde (RPial) via a copper nitrosyl of a {CuNO}10-type intermediate. In the presence of H2O, the in situ formed RPial get oxidized to the corresponding picolinic acid (RPicH) via an in situ formed LCuIOH intermediate (LCuI + HO-NO → LCuIOH + NO+; L = RL1/RL2/RPic- and νO-H of CuIOH = 3650 cm-1) and subsequently produces, with the aid of NO+ oxidant, the picolinate-ligated copper(II) complexes (i) [(HPic)2Cu] (7), [(MePic)4Cu3(NO3)2]n·H2O (8·H2O), or [(ClPhPic)2Cu] (9) when NO reacts with 1-4 or (ii) [(RPic)CuII(RL1/RL2)]+ when NO+ reacts with 1'-4'. The CuII to CuI reduction of [(RPic)CuII(RL1/RL2)]+ is essential for C═N cleavage of the remaining RL1/RL2 Schiff base; excess NO can do it. The X-ray structures (1, 1', 3', 5, 7, and 8) and spectroscopic results revealed the role of CuII/I, NO, NO+, and H2O, shedding light on the mechanism of C═N bond cleavage and the oxidation of pyridine-2-aldehyde to pyridine-2-carboxylic acid. The reaction of 1 with 15NO revealed that the terminal N of the N2+ group of 5 originates from 15NO [ν14N14N- = 2248 cm-1 and ν15N14N- = 2212 cm-1].

Secularism, family ties and loneliness: A multilevel longitudinal study of ten European societies.

OBJECTIVES: Mass media suggest rising political and religious concern about secularism-induced decline of the family. Implications for loneliness remain unexamined. The current study filled this gap. METHODS: Data were from 10 national probability samples in the Survey of Health, Ageing and Retirement in Europe. Multilevel longitudinal models tested linkages of societal secularism with loneliness, their mediation by specific family relationships, and the role of this cultural dimension in weakening associations of family ties with loneliness. Both weighted Maximum Likelihood and unweighted Bayesian analyses were conducted, separately for each gender. RESULTS: Societal secularism was not positively linked to either gender's loneliness. Associations with family ties were inconsistent, with only men's average partnered status lower in more secular settings. Nor did any positive indirect effects emerge. Moderation results were also inconsistent, with secularism only weakening linkages of some family dimensions with loneliness. Bayesian estimates were generally nonsignificant. DISCUSSION: Societal secularism may not be a risk factor for loneliness or for weak family ties. Results stand at odds with religious and political rhetoric on secularism-induced decline of the family, and its individual and societal consequences.

Iron-catalyzed carboarylation of alkynes via activation of π-activated alcohols: rapid synthesis of substituted benzofused six-membered heterocycles.

An Fe(OTf)3-catalysed carboarylation of alkynes is reported for the straightforward synthesis of densely substituted 1,2-dihydroquinolines from N-propargyl anilides and π-activated alcohols. The reaction provides a new method for the synthesis of highly substituted benzofused six-membered heterocycles by the formation of two carbon-carbon bonds and one ring in a single step. The power of the methodology was further extended to the synthesis of substituted chromene and thiochromene derivatives in high yields. In addition, substituted quinoline derivatives were also achieved in a single step in the presence of FeCl3 through detosylation/aromatisation. A number of control experiments have been performed and a plausible mechanism has also been proposed to explain the formation of the products.

RPAD (RNase R treatment, polyadenylation, and poly(A)+ RNA depletion) method to isolate highly pure circular RNA.

Recent developments in high-throughput RNA sequencing methods coupled with innovative bioinformatic tools have uncovered thousands of circular (circ)RNAs. CircRNAs have emerged as a vast and novel class of regulatory RNAs with potential to modulate gene expression by acting as sponges for microRNAs (miRNAs) and RNA-binding proteins (RBPs). The biochemical enrichment of circRNAs by exoribonuclease treatment or by depletion of polyadenylated RNAs coupled with deep-sequencing is widely used for the systematic identification of circRNAs. Although these methods enrich circRNAs substantially, they do not eliminate efficiently non-polyadenylated and highly-structured RNAs. Here, we describe a method we termed RPAD, based on initial RNase R treatment followed by Polyadenylation and poly(A)+ RNA Depletion. These joint interventions drastically depleted linear RNAs leading to isolation of highly pure circRNAs from total RNA pools. By facilitating the isolation of highly pure circRNAs, RPAD enables the elucidation of circRNA biogenesis, sequence, and function.

Identification and Characterization of Circular Intronic RNAs Derived from Insulin Gene.

Circular RNAs (circRNAs) are a large family of noncoding RNAs that have emerged as novel regulators of gene expression. However, little is known about the function of circRNAs in pancreatic ß-cells. Here, transcriptomic analysis of mice pancreatic islet RNA-sequencing data identified 77 differentially expressed circRNAs between mice fed with a normal diet and a high-fat diet. Surprisingly, multiple circRNAs were derived from the intron 2 of the preproinsulin 2 (Ins2) gene and are termed as circular intronic (ci)-Ins2. The expression of ci-Ins2 transcripts in mouse pancreatic islets, and ßTC6 cells were confirmed by reverse transcription PCR, DNA sequencing, and RNase R treatment experiments. The level of ci-Ins2 was altered in ßTC6 cells upon exposure to elevated levels of palmitate and glucose. Computational analysis predicted the interaction of several RNA-binding proteins with ci-Ins2 and their flanking region, suggesting their role in the ci-Ins2 function or biogenesis. Additionally, bioinformatics analysis predicted the association of several microRNAs with ci-Ins2. Gene ontology and pathway analysis of genes targeted by miRNAs associated with ci-Ins2 suggested the regulation of several key biological processes. Together, our findings indicate that differential expression of circRNAs, especially ci-Ins2 transcripts, may regulate ß-cell function and may play a critical role in the development of diabetes.

Highly Active Urea-Functionalized Zr(IV)-UiO-67 Metal-Organic Framework as Hydrogen Bonding Heterogeneous Catalyst for Friedel-Crafts Alkylation.

A new Zr(IV)-based UiO-67 metal-organic framework (1) was prepared with urea-functionalized biphenyl-4,4'-dicarboxylic acid (BPDC-urea) as the linker using conventional solvothermal technique and thoroughly characterized using X-ray powder diffraction (XRPD), Fourier transform infrared (FT-IR) spectroscopy, thermogravimetric (TG), and N2 sorption analyses. The activated form of 1 (called 1') exhibited excellent BET surface area in spite of having a large functional moiety (urea) in the linker side. The activated form of this material (1') was successfully employed for the Friedel-Crafts alkylation of indole with ß-nitrostyrene to achieve 97% yield in toluene at 70 °C for 24 h. Furthermore, the catalyst was used for four cycles, with no significant loss in its activity, and the reaction was heterogeneous in nature. The activity of 1' was comparable to UiO-67-(NH2)2, whereas the activity was 2-fold higher compared to the parent UiO-67. Further, the activity of the BPDC-urea linker was nearly 2-fold higher than that of ZrCl4, suggesting the crucial role played by the urea moiety than the metal node. In addition, the catalyst (1') exhibited a wide substrate scope, allowing the preparation of a series of compounds with moderate to high yields under the optimized reaction conditions. The roles of metal salt and linker in the catalysis have also been studied separately, and the mechanism for the catalysis has been clarified.