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.

A Thiophene-2-carboxamide-Functionalized Zr(IV) Organic Framework as a Prolific and Recyclable Heterogeneous Catalyst for Regioselective Ring Opening of Epoxides.

A new thiophene-2-carboxamide-functionalized Zr-UiO-66 MOF (1) was synthesized by employing a traditional solvothermal procedure. Compound 1 displayed high thermal (up to 340 °C under an Ar atmosphere) and chemical stability (in water, 1 M HCl, and acetic acid). A nitrogen physisorption measurement with the activated form of 1 (denoted 1') exhibited a BET surface area (781 m2/g) despite attachment of a bulky side chain with the linker molecule. Compound 1' was able to heterogeneously catalyze the ring-opening reaction of epoxides with  amines. Catalyst 1' exhibited significant yields as well as wide substrate scope in the ring opening of epoxides by means of amines. It also displayed better catalytic performance in comparison to known MOF catalysts such as Cu3(BTC)2, Fe(BTC) (BTC: 1, 3, 5-benzenetricarboxylate), and Zr-UiO-66. Control experiments were performed with free linker,  Zr(IV) salt and without catalyst 1', confirming the exclusive role of 1' in the catalytic reaction. The reusability characteristics of catalyst 1' was established for up to five consecutive catalytic cycles. The synthesis and characterization of the linker molecule, material 1, and 1' and mechanism of the catalysis reaction were studied elaborately.

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.

Rolling Circle cDNA Synthesis Uncovers Circular RNA Splice Variants.

High-throughput RNA sequencing and novel bioinformatic pipelines have identified thousands of circular (circ)RNAs containing backsplice junction sequences. However, circRNAs generated from multiple exons may contain different combinations of exons and/or introns arising from alternative splicing, while the backsplice junction sequence is the same. To be able to identify circRNA splice variants, we developed a method termed circRNA-Rolling Circle Amplification (circRNA-RCA). This method detects full-length circRNA sequences by performing reverse transcription (RT) in the absence of RNase H activity, followed by polymerase chain reaction (PCR) amplification of full-length circRNAs using a forward primer spanning the backsplice junction sequence and a reverse primer exactly upstream of the forward primer. By sequencing the PCR products, circRNA splice variants bearing the same backsplice junctions, which were otherwise only predicted computationally, could be experimentally validated. The splice variants were further predicted to associate with different subsets of target RNA-binding proteins and microRNAs, supporting the notion that different circRNA splice variants can have different biological impacts. In sum, the circRNA-RCA method allows the accurate identification of full-length circRNA sequences, offering unique insight into their individual function.

Dyadic Configurations of Sexual Problems Among Older U.S. Adults: A National Study.

Using data from the 2010-2011 National Social Life Health and Aging Project (NSHAP)-a nationally representative probability sample of older U.S. adults as well as their partners-this study provides the first comprehensive, population-based analysis of dyadic configurations of sexual problems and their correlates among those aged 60 to 90 years. Results suggest the majority of late-life partnerships (N = 854) may not have a heavy burden of sexual difficulties. However, almost a fifth (18.21%) of partnered older women do not abstain from sex despite low sexual motivation and capacity. This relational "type" seems unlinked to demographic or health attributes, and may be driven more by partnership strains. In addition, an "at risk" group with consistent sexual problems, arguably due to age-related decline, comprises 27.16% of all late-life couples.

Dexamethasone induces heat shock response and slows down disease progression in mouse and fly models of Huntington's disease.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by abnormal expansion of glutamine repeats in the protein huntingtin. In HD brain, mutant huntingtin undergoes proteolytic processing, and its N-terminal fragment containing poly-glutamine repeats accumulate as insoluble aggregates leading to the defect in cellular protein quality control system and heat shock response (HSR). Here we demonstrate that the defective HSR in the brain is due to the down-regulation of heat shock factor 1 (HSF1) in both mice and fly models of HD. Interestingly, treatment of dexamethasone (a synthetic glucocorticoid) to HD mice or flies significantly increased the expression and transactivation of HSF1 and induction of HSR and these effects are mediated through the down-regulation of HSP90. Dexamethasone treatment also significantly decreased the aggregate load and transient recovery of HD-related behavioural phenotypes in both disease models. These results suggest that dexamethasone could be a potential therapeutic molecule for the treatment of HD and related poly-glutamine disorders.

Sexual Contact in Childhood, Revictimization, and Lifetime Sexual and Psychological Outcomes.

Using data from the 2010 to 2011 wave of the National Social Life, Health, and Aging Project-a nationally representative probability sample of older U.S. adults-this study queried distinctive linkages of mild and of severe childhood sexual contact with lifetime sexual and psychological outcomes among women and men aged 60-99 years (N = 3283). In addition, we examined stratification of these associations by sexual revictimization (forced sex and/or harassment). Among women, sequelae of childhood contact seemed consistently negative for the mild rather than severe variant-but only in the co-presence of revictimization-a pattern that may have remained obscured in previous analysis of event effects. Men's results suggested lifelong eroticizing but not psychological effects of this early experience-with the co-presence of revictimization potentially enhancing rather than lowering their mental health. Overall, findings appeared to reflect gendered patterns of risk-with mild childhood contact potentially channeling women but not men into revictimization and finally to elevated sexuality and poor mental health in late life. Early sexual experiences should thus be conceptualized not as singular events, but as part of a lifelong career with regularities and rhythms that may influence their pathogenic potential.

Social Modulation or Hormonal Causation? Linkages of Testosterone with Sexual Activity and Relationship Quality in a Nationally Representative Longitudinal Sample of Older Adults.

This study used population-representative longitudinal data from the 2005-2006 and 2010-2011 waves of the National Social Life, Health and Aging Project-a probability sample of US adults aged 57-85 at baseline (N = 650 women and 620 men)-to examine the causal direction in linkages of endogenous testosterone (T) with sexual activity and relationship quality. For both genders, our autoregressive effects indicated a large amount of temporal stability, not just in individual-level attributes (T, masturbation) but also dyadic ones (partnered sex, relationship quality)-indicating that a need for more nuanced theories of relational processes. Cross-lagged results suggested gender-specific effects-generally more consistent with sexual or relational modulation of T than with hormonal causation. Specifically, men's findings indicated their T might be elevated by their sexual (masturbatory) activity but not vice versa, although androgen levels did lower men's subsequent relationship quality. Women's T, in contrast, was negatively influenced not just by their higher relationship quality but also by their more frequent partnered sex-perhaps reflecting a changing function of sexual activity in late life.

Stimulus-related neuroimaging in task-engaged subjects is best predicted by concurrent spiking.

The implicit goal of functional magnetic resonance imaging is to infer local neural activity. There is considerable debate, however, as to whether imaging correlates most linearly with local spiking or some local field potential (LFP) measurement. Through simultaneous neuroimaging (intrinsic-signal optical imaging) and electrode recordings from alert, task-engaged macaque monkeys, we showed previously that local electrophysiology correlates with only a specific stimulus-related imaging component. Here we show that this stimulus-related component--obtained by subtracting a substantial task-related component--is particularly linear with local spiking over a comprehensive range of response strengths. Matches to concurrent LFP measurements are, to varying degrees, poorer. As a control, we also tried matching the full imaging signal to local electrophysiology without subtracting task-related components. These control matches were consistently worse; they were, however, slightly better for gamma LFP than spiking, potentially resolving discrepancies between our findings and earlier reports favoring LFP.

The E3 ligase ube3a is required for learning in Drosophila melanogaster.

Angelman syndrome and autism are neurodevelopmental disorders linked to mutations and duplications of an E3 ligase called ube3a respectively. Since cognitive deficits and learning disabilities are hallmark symptoms of both these disorders, we investigated a role for dube3a in the learning ability of flies using the aversive phototaxis suppression assay. We show that down and up-regulation of dube3a are both detrimental to learning in larvae and adults. Using conditional gene expression we found that dube3a is required for normal brain development and during adulthood. Furthermore, we suggest that dube3a could be interacting with other learning and memory genes such as derailed. Along with firmly establishing dube3a as a gene that is required for learning, our work also opens avenues for further understanding the role played by this gene in brain development and behavior.

Anticipatory haemodynamic signals in sensory cortex not predicted by local neuronal activity.

Haemodynamic signals underlying functional brain imaging (for example, functional magnetic resonance imaging (fMRI)) are assumed to reflect metabolic demand generated by local neuronal activity, with equal increases in haemodynamic signal implying equal increases in the underlying neuronal activity. Few studies have compared neuronal and haemodynamic signals in alert animals to test for this assumed correspondence. Here we present evidence that brings this assumption into question. Using a dual-wavelength optical imaging technique that independently measures cerebral blood volume and oxygenation, continuously, in alert behaving monkeys, we find two distinct components to the haemodynamic signal in the alert animals' primary visual cortex (V1). One component is reliably predictable from neuronal responses generated by visual input. The other component-of almost comparable strength-is a hitherto unknown signal that entrains to task structure independently of visual input or of standard neural predictors of haemodynamics. This latter component shows predictive timing, with increases of cerebral blood volume in anticipation of trial onsets even in darkness. This trial-locked haemodynamic signal could be due to an accompanying V1 arterial pumping mechanism, closely matched in time, with peaks of arterial dilation entrained to predicted trial onsets. These findings (tested in two animals) challenge the current understanding of the link between brain haemodynamics and local neuronal activity. They also suggest the existence of a novel preparatory mechanism in the brain that brings additional arterial blood to cortex in anticipation of expected tasks.

Conservative Christianity, partnership, hormones, and sex in late life.

Using nationally representative data from the 2005-2006 U.S. National Social Life, Health, and Aging Project, this study queried relationship, sexual, and sex hormone patterns among married evangelical women and men aged 57-85, relative to those in other religions. Results suggested that despite potentially more unequal gender roles, evangelical older women may have better marital quality, perhaps due to the recent transformation of their male counterparts into authoritative, yet-supportive, "soft patriarchs." Correspondingly, these women, especially those with greater subjective religiosity or more support from a spouse, reported consistently better sexual outcomes than their counterparts in other religions. In addition, they also had lower estradiol, whether due to psychobiological effects of their better relationships or self-selection of those with differential hormone levels into particular partnership patterns. While older men in these communities also experienced more satisfactory marriages, and had lower androgens (testosterone, DHEA), their relational assets were less uniformly matched by better sexual outcomes, perhaps reflecting a gender disparity in the linkage between these factors.