Gag-like proteins: Novel mediators of prenatal alcohol exposure in neural development.

BACKGROUND: We previously showed that ethanol did not kill fetal neural stem cells (NSCs), but that their numbers nevertheless are decreased due to aberrant maturation and loss of self-renewal. To identify mechanisms that mediate this loss of NSCs, we focused on a family of Gag-like proteins (GLPs), derived from retroviral gene remnants within mammalian genomes. GLPs are important for fetal development, though their role in brain development is virtually unexplored. Moreover, GLPs may be transferred between cells in extracellular vesicles (EVs) and thereby transfer environmental adaptations between cells. We hypothesized that GLPs may mediate some effects of ethanol in NSCs. METHODS: Sex-segregated male and female fetal murine cortical NSCs, cultured ex vivo as nonadherent neurospheres, were exposed to a dose range of ethanol and to mitogen-withdrawal-induced differentiation. We used siRNAs to assess the effects of NSC-expressed GLP knockdown on growth, survival, and maturation and in silico GLP knockout, in an in vivo single-cell RNA-sequencing dataset, to identify GLP-mediated developmental pathways that were also ethanol-sensitive. RESULTS: PEG10 isoform-1, isoform-2, and PNMA2 were identified as dominant GLP species in both NSCs and their EVs. Ethanol-exposed NSCs exhibited significantly elevated PEG10 isoform-2 and PNMA2 protein during differentiation. Both PEG10 and PNMA2 were mediated apoptosis resistance and additionally, PEG10 promoted neuronal and astrocyte lineage maturation. Neither GLP influenced metabolism nor cell cycle in NSCs. Virtual PEG10 and PNMA2 knockout identified gene transcription regulation and ubiquitin-ligation processes as candidate mediators of GLP-linked prenatal alcohol effects. CONCLUSIONS: Collectively, GLPs present in NSCs and their EVs may confer apoptosis resistance within the NSC niche and contribute to the abnormal maturation induced by ethanol.

Nucleophile-Initiated Catalytic and Multicomponent Reactions.

A number of well-known reactions, proceed through the intermediacy of dipolar/zwitterionic species generated via the addition of a neutral nucleophile with an unsaturated electrophile. A mechanistic understanding of these reactions was made possible by seminal contributions of Huisgen. The design of novel reactions based on such dipolar species was, however, not pursued in detail for a long time. Our efforts to exploit various reactivity profiles available for the zwitterionic/dipolar intermediates have resulted in the discovery of a large number of novel, convenient protocols to access a wide variety of products. The nucleophilic initiators may participate in the reaction or play a mediating role depending upon the nature of nucleophile, its quantity and the reaction conditions. In a majority of these transformations two electrophilic components, that would normally be inert towards each other, are combined by the intermediacy of a nucelophile. A brief summary of such nucleophile-initiated novel reactions that were developed in our research group are described. Reactions involving a variety of nucleophiles such as phosphines, pyridine, quinoline, isoquinoline, isocyanides, dimethoxycarbene and N-heterocyclic carbenes (NHCs) are discussed.

Recent Advances in the Chemistry of Pentafulvenes.

Pentafulvenes are a unique class of compounds that originally attracted attention due to their propensity to display nonbenzenoid aromaticity. Subsequently, they were recognized as valuable synthons for the construction of a wide range of compounds by virtue of their ability to display multiple cycloaddition profiles. Naturally, this area of organic chemistry has experienced rapid growth over the last five decades, fueled by elegant work showcasing the unique reactivity of pentafulvenes in a plethora of cycloaddition reactions. In this Review, we have attempted to provide a systematic account of the methods for the generation of pentafulvenes, their rich and varied cycloaddition chemistry, organometallic reactions, and theoretical studies that support their versatility. Further, we have highlighted their applications in the synthesis of a variety of complex structural frameworks. It is our conviction that this Review will be useful to a wide range of chemists, and will spur further research in this promising area.

Environmental quality monitoring and impact assessment of solid waste dumpsites in high altitude sub-tropical regions.

Solid Waste Management (SWM) in high altitude regions is critically phased because of the non-availability of suitable facilities for the treatment and handling of large quantities of Municipal Solid Waste (MSW). Open burning practices at hill slopes were noticed which affect the surrounding environment. Hence, it became essential to measure the environmental components around the dumpsites to examine the impacts and suggest new technological solutions. The pollution parameters were monitored in and around the dumpsites, and the data was analysed using statistical tools. The assessment of air quality indicated maximum fine suspended particulate matter (PM2.5) concentration of 206.66 µg/m3 followed by respairable particulate matter (PM10), oxides of nitrogen (NOx) and sulphur dioxide (SO2). Among the gaseous emissions, methane (CH4) concentration was very high (38.53 mg/L) followed by carbon monoxide (CO) concentration (0.96 mg/L). Volatile organic compounds (VOCs) were also detected at few dumpsites with highest observed benzene (C6H6) concentration of 157.53 µg/m3. The soil sample analysis indicated that iron (Fe) concentration dominates followed by manganese (Mn), zinc (Zn), chromium (Cr), copper (Cu), and nickel (Ni). For evaluation of different alternatives for the SWM system, Rapid Impact Assessment Matrix (RIAM) was applied.

The Interplay between Stigma, Collective Efficacy, and Advocacy Communication among Men Who Have Sex with Men and Transgender Females.

Stigma and discrimination are primary drivers of health disparities among marginalized communities. Drawing on stigma management, minority stress model, and social cognitive theories, this article tests the interplay between dimensions of stigma, collective efficacy, and advocacy communication among men who have sex with men (MSM) and transgender females. Using data from a cross-sectional survey conducted in south India (N = 225), five distinct dimensions of stigma were identified using factor analysis: experienced stigma, self-stigma, felt normative stigma, and two new dimensions-HIV-related vicarious stigma and media stigma. Respondents reported highest levels of media stigma. While most of the dimensions of stigma were negatively associated with both collective efficacy and advocacy communication, collective efficacy mediated the relationship between stigma and advocacy. Implications for public health campaigns among MSM groups are discussed.

Recent advances in employing homoenolates generated by N-heterocyclic carbene (NHC) catalysis in carbon-carbon bond-forming reactions.

The use of NHCs for generating homoenolate species has gained widespread popularity in recent years. A number of highly stereoselective processes of NHC-homoenolates have emerged. Homoenolate reactions have also been employed as key steps in the total synthesis of a number of natural products. The use of compatible co-catalysts, improved NHC-catalyst design and the use of novel precursors for homoenolate generation are among the major developments in this area that were disclosed recently. This tutorial review organises and presents the advancements in this rapidly growing area of catalysis and in the process updates a previous account published in 2011 in this journal.

Correction: Recent advances in N-heterocyclic carbene (NHC)-catalysed benzoin reactions.

[This corrects the article DOI: 10.3762/bjoc.12.47.].

Recent advances in N-heterocyclic carbene (NHC)-catalysed benzoin reactions.

N-Heterocyclic carbenes (NHCs) have emerged as a powerful class of organocatalysts that mediate a variety of organic transformations. The Benzoin reaction constitutes one of the earliest known carbon-carbon bond-forming reactions catalysed by NHCs. The rapid growth of NHC catalysis in general has resulted in the development of a variety of benzoin and benzoin-type reactions. An overview of such NHC-catalysed benzoin reactions is presented.

Phosphine-mediated reaction of 3-methyl allenoate and isatins: a protocol for the synthesis of spirofuran oxindoles.

A facile synthesis of spirofuran oxindoles via phosphine-mediated reaction of 3-alkyl allenoate with isatins is presented.

Discovering functional neuronal connectivity from serial patterns in spike train data.

Repeating patterns of precisely timed activity across a group of neurons (called frequent episodes) are indicative of networks in the underlying neural tissue. This letter develops statistical methods to determine functional connectivity among neurons based on nonoverlapping occurrences of episodes. We study the distribution of episode counts and develop a two-phase strategy for identifying functional connections. For the first phase, we develop statistical procedures that are used to screen all two-node episodes and identify possible functional connections (edges). For the second phase, we develop additional statistical procedures to prune the two-node episodes and remove false edges that can be attributed to chains or fan-out structures. The restriction to nonoverlapping occurrences makes the counting of all two-node episodes in phase 1 computationally efficient. The second (pruning) phase is critical since phase 1 can yield a large number of false connections. The scalability of the two-phase approach is examined through simulation. The method is then used to reconstruct the graph structure of observed neuronal networks, first from simulated data and then from recordings of cultured cortical neurons.

Exploring the "active ingredients" of an online smoking intervention: a randomized factorial trial.

INTRODUCTION: Research needs to systematically identify which components increase online intervention effectiveness (i.e., active ingredients). This study explores the effects of 4 potentially important design features in an Internet-based, population-level smoking intervention. METHODS: Smokers (n = 1,865) were recruited from a large health care organization, regardless of readiness to quit. Using a full factorial design, participants were randomized to 1 of the 2 levels of each experimental factor (message tone [prescriptive vs. motivational], navigation autonomy [dictated vs. not], e-mail reminders [yes vs. no], and receipt of personally tailored testimonials [yes vs. no]) and provided access to the online intervention. Primary outcomes were self-reported 7-day point-prevalent smoking abstinence and confirmed utilization of adjunct treatment (pharmacotherapy or phone counseling) available through the health plan at 1 year. Outcomes were also assessed at 2 and 6 months and were examined among all enrolled participants (intent-to-treat [ITT]) and all who viewed the intervention (modified ITT). RESULTS: At 1 year, 13.7% were abstinent and 26.0% utilized adjunct treatment. None of the contrasting factor levels differentially influenced abstinence or treatment utilization at 12 months. In the modified ITT sample, smokers receiving testimonials were less likely to use adjunct treatment at 6 months (odds ratio = 0.54, 95% confidence interval = 0.30-0.98, p = .04). CONCLUSIONS: None of the design features enhanced treatment outcome. The negative effect observed for testimonials is provocative, but it should be viewed with caution. This study offers a model for future research testing the "active ingredients" of online interventions.

The effect of program design on engagement with an internet-based smoking intervention: randomized factorial trial.

BACKGROUND: Participant engagement influences treatment effectiveness, but it is unknown which intervention design features increase treatment engagement for online smoking cessation programs. OBJECTIVE: We explored the effects of 4 design features (ie, factors) on early engagement with an Internet-based, motivational smoking cessation program. METHODS: Smokers (N=1865) were recruited from a large health care organization to participate in an online intervention study, regardless of their interest in quitting smoking. The program was intended to answer smokers' questions about quitting in an effort to motivate and support cessation. Consistent with the screening phase in the multiphase optimization strategy (MOST), we used a 2-level, full-factorial design. Each person was randomized to 1 of 2 levels of each factor, including message tone (prescriptive vs motivational), navigation autonomy (dictated vs not), proactive email reminders (yes vs no), and inclusion of personally tailored testimonials (yes vs no). The effects of each factor level on program engagement during the first 2 months of enrollment were compared, including number of visits to the website resulting in intervention content views (as opposed to supplemental content views), number of intervention content areas viewed, number of intervention content pages viewed, and duration of time spent viewing this content, as applicable to each factor. RESULTS: Adjusting for baseline readiness to quit, persons who received content written in a prescriptive tone made the same number of visits to the website as persons receiving content in a motivational tone, but viewed 1.17 times as many content areas (95% CI 1.08-1.28; P<.001) and 1.15 times as many pages (95% CI 1.04-1.28; P=.009). Time spent viewing materials did not differ among groups (P=.06). Persons required to view content in a dictated order based on their initial readiness to quit made the same number of visits as people able to freely navigate the site, but viewed fewer content areas (ratio of means 0.80, 95% CI 0.74-0.87; P<.001), 1.17 times as many pages (95% CI 1.06-1.31; P=.003), and spent 1.37 times more minutes online (95% CI 1.17-1.59; P<.001). Persons receiving proactive email reminders made 1.20 times as many visits (95% CI 1.09-1.33; P<.001), viewed a similar number of content areas as persons receiving no reminders, viewed 1.58 times as many pages (95% CI 1.48-1.68; P<.001), and spent 1.51 times as many minutes online (95% CI 1.29-1.77; P<.001) as those who did not receive proactive emails. Tailored testimonials did not significantly affect engagement. CONCLUSIONS: Using a prescriptive message tone, dictating content viewing order, and sending reminder emails each resulted in greater program engagement relative to the contrasting level of each experimental factor. The results require replication, but suggest that a more directive interaction style may be preferable for online cessation programs. TRIAL REGISTRATION: clinicaltrials.gov NCT00992264; http://clinicaltrials.gov/ct2/show/NCT00992264 (Archived by WebCite at http://www.webcitation.org/6F7H7lr3P).

1,2-Benzoquinones in Diels-Alder reactions, dipolar cycloadditions, nucleophilic additions, multicomponent reactions and more.

A brief account of the recent developments in the chemistry of 1,2-benzoquinones is presented in this tutorial review. The title compounds exhibit commendable versatility in both Diels-Alder and dipolar cycloaddition reactions. They have also been employed as electrophilic reaction partners in nucleophile-triggered catalytic processes and related multicomponent reactions. These, along with other reactions described here, lead to the synthesis of densely functionalised carbocyclic and heterocyclic frameworks that are otherwise difficult to access.

A facile four component protocol for the synthesis of dihydropyridine derivatives.

An efficient one pot synthesis of dihydropyridine derivatives employing the transient zwitterions generated from aniline and allenoates is described.

Employing homoenolates generated by NHC catalysis in carbon-carbon bond-forming reactions: state of the art.

Homoenolate is a reactive intermediate that possesses an anionic or nucleophilic carbon ß to a carbonyl group or its synthetic equivalent. The recent discovery that homoenolates can be generated from α,ß-unsaturated aldehydes via N-Heterocyclic Carbene (NHC) catalysis has led to the development of a number of new reactions. A majority of such reactions include the use of carbon-based electrophiles, such as aldehydes, imines, enones, dienones etc. resulting in the formation of a variety of annulated as well as acyclic products. The easy availability of chiral NHCs has allowed the development of very efficient enantioselective variants of these reactions also. The tolerance showed by NHCs towards magnesium and titanium based Lewis acids has been exploited in the invention of cooperative catalytic processes. This tutorial review focuses on these and other types of homoenolate reactions reported recently, and in the process, updates the previous account published in 2008 in this journal.

The distinct role of comparative risk perceptions in a breast cancer prevention program.

BACKGROUND: Comparative risk perceptions may rival other types of information in terms of effects on health behavior decisions. PURPOSE: We examined associations between comparative risk perceptions, affect, and behavior while controlling for absolute risk perceptions and actual risk. METHODS: Women at an increased risk of breast cancer participated in a program to learn about tamoxifen which can reduce the risk of breast cancer. They reported comparative risk perceptions of breast cancer and completed measures of anxiety, knowledge, and tamoxifen-related behavior intentions. Three months later, the women reported their behavior. RESULTS: Comparative risk perceptions were positively correlated with anxiety, knowledge, intentions, and behavior 3 months later. After controlling for participants' actual risk of breast cancer and absolute risk perceptions, comparative risk perceptions predicted anxiety and knowledge, but not intentions or behavior. CONCLUSIONS: Comparative risk perceptions can affect patient outcomes like anxiety and knowledge independently of absolute risk perceptions and actual risk information.

A novel NHC-catalyzed transformation of 2H-chromene-3-carboxaldehydes to 3-methyl-2H-chromen-2-ones.

An unexpected transformation of 2H-chromene-3-carboxaldehydes to coumarin derivatives, mediated by NHC, is reported.

Nucleophilic heterocyclic carbene as a novel catalyst for cyclopropanation of cyano acrylates.

Nucleophilic heterocyclic carbenes (NHCs) have been used for the first time as catalysts in the cyclopropanation of ethyl cyanocinnamates with phenacyl bromide by Michael-initiated ring-closure (MIRC).

NHC-catalysed annulation of enals to tethered dienones: efficient synthesis of bicyclic dienes.

Homoenolates generated from α,ß-unsaturated aldehydes using NHC catalysis underwent facile addition to dibenzylidene cyclohexanone to afford bicyclic cyclopentenes as single diastereomers.

A novel pseudo four component reaction involving homoenolate for the synthesis of gamma-aminobutyric acid (GABA) derivatives.

Homoenolate generated from alpha,beta-unsaturated aldehydes by NHC catalysis underwent facile addition to conjugated sulfonimines, generated in situ, and subsequent methanolysis to afford protected GABA derivatives stereoselectively and in high yields, thus constituting a novel pseudo four component reaction.