Language processing following childhood poverty: Evidence for disrupted neural networks.

Childhood poverty is related to deficits in multiple cognitive domains including adult language function. It is unknown if the brain basis of language is disrupted in adults with childhood poverty backgrounds, controlling for current functioning. Fifty-one adults (age 24) from an existing longitudinal study of childhood poverty, beginning at age 9, were examined on behavioral phonological awareness (LP) and completed an event-related fMRI speech/print processing LP task. Adults from childhood poverty backgrounds exhibited lower LP in adulthood. The middle-income group exhibited greater activation of the bilateral IFG and hippocampus during language processing. In psychophysiological interaction (PPI) analyses, the childhood poverty group exhibited greater coupling between ventral Broca's and the middle temporal gyrus (MTG) as well as coupling between Wernicke's region and bilateralization. Childhood poverty disrupts language processing neural networks in adulthood, after controlling for LP, suggesting that poverty in childhood influences the neurophysiological basis for language processing into adulthood.

Integrative Molecular Structure Elucidation and Construction of an Extended Metabolic Pathway Associated with an Ancient Innate Immune Response in COVID-19 Patients.

We present compelling evidence for the existence of an extended innate viperin-dependent pathway, which provides crucial evidence for an adaptive response to viral agents, such as SARS-CoV-2. We show the in vivo biosynthesis of a family of novel endogenous cytosine metabolites with potential antiviral activities. Two-dimensional nuclear magnetic resonance (NMR) spectroscopy revealed a characteristic spin-system motif, indicating the presence of an extended panel of urinary metabolites during the acute viral replication phase. Mass spectrometry additionally enabled the characterization and quantification of the most abundant serum metabolites, showing the potential diagnostic value of the compounds for viral infections. In total, we unveiled ten nucleoside (cytosine- and uracil-based) analogue structures, eight of which were previously unknown in humans allowing us to propose a new extended viperin pathway for the innate production of antiviral compounds. The molecular structures of the nucleoside analogues and their correlation with an array of serum cytokines, including IFN-α2, IFN-γ, and IL-10, suggest an association with the viperin enzyme contributing to an ancient endogenous innate immune defense mechanism against viral infection.

Chemoenzymatic Synthesis of 3'-Deoxy-3',4'-didehydro-cytidine triphosphate (ddhCTP).

3'-Deoxy-3',4'-didehydro-cytidine triphosphate (ddhCTP) is a novel antiviral molecule produced by the enzyme viperin during the early stages of the innate immune response. ddhCTP has been shown to act as a chain terminator of flavivirus RNA-dependent RNA polymerases. To date, synthesis of ddhCTP requires complicated synthetic protocols or isolation of the enzyme viperin to catalyze the production of ddhCTP from CTP. Recombinant viperin approaches preclude the production of highly pure ddhCTP (free of contaminants such as CTP), whereas the chemical synthesis involves techniques or equipment not readily available to most laboratories. Herein, we describe the chemoenzymatic synthesis of ddhCTP, starting from commercially available ddhC. We utilize these methods to produce milligram quantities of ddhCTP, ddhCDP, and ddhCMP. Using purified semisynthetic ddhCTP and fully synthetic ddhCTP, we also show ddhCTP does not inhibit NAD+-dependent enzymes such as glyceraldehyde 3-phosphate dehydrogenase, malate dehydrogenase, or lactate dehydrogenase, contrary to a recent report.

Designing learning environments for promoting young people's constructive coping with climate change.

This chapter first summarizes how the consequences of global climate change (GCC) can harm young people's well-being through physical health impacts and awareness of GCC. We then outline how youth may cope with GCC by denying the problem, distancing themselves from it, or taking individual actions. However, the coping strategy shown to have the best mental well-being outcomes relates to collective actions and agency. Next, an examination of school-based GCC interventions reveals that engaging, participatory approaches may be more effective in promoting positive outcomes for youth and climate action. Our main contribution is a discussion of how the evidence-based design of learning environments presents an undeveloped but potentially effective way to enhance interventions for the development of constructive GCC coping strategies among youth. Utilizing environmental affordances and design as scaffolding can guide the design of learning environments that give youth opportunities for active cognitive, emotional, and physical engagement with climate change education. Natural environments may be particularly effective in supporting active engagement and pathways to constructive coping. More research is needed to understand what design features underly these pathways to improved well-being and GCC coping strategies that may have positive implications for youth climate action.

Galidesivir Triphosphate Promotes Stalling of Dengue-2 Virus Polymerase Immediately Prior to Incorporation.

Millions of people are infected by the dengue and Zika viruses each year, resulting in significant morbidity and mortality. Galidesivir is an adenosine nucleoside analog that can attenuate flavivirus replication in cell-based assays and animal models of infection. Galidesivir is converted to the triphosphorylated form by host kinases and subsequently incorporated into viral RNA by viral RNA polymerases. This has been proposed to lead to the delayed termination of RNA synthesis. Here, we report direct in vitro testing of the effects of Galidesivir triphosphate on dengue-2 and Zika virus polymerase activity. Galidesivir triphosphate was chemically synthesized, and inhibition of RNA synthesis followed using a dinucleotide-primed assay with a homopolymeric poly(U) template. Galidesivir triphosphate was equipotent against dengue-2 and Zika polymerases, with IC50 values of 42 ± 12 µM and 47 ± 5 µM, respectively, at an ATP concentration of 20 µM. RNA primer extension assays show that the dengue-2 polymerase stalls while attempting to add a Galidesivir nucleotide to the nascent RNA chain, evidenced by the accumulation of RNA products truncated immediately upstream of Galidesivir incorporation sites. Nevertheless, Galidesivir is incorporated at isolated sites with low efficiency, leading to the subsequent synthesis of full-length RNA with no evidence of delayed chain termination. The incorporation of Galidesivir at consecutive sites is strongly disfavored, highlighting the potential for modulation of inhibitory effects of nucleoside analogs by the template sequence. Our results suggest that attenuation of dengue replication by Galidesivir may not derive from the early termination of RNA synthesis following Galidesivir incorporation.

Phosphoinositide and redox dysregulation by the anticancer methylthioadenosine phosphorylase transition state inhibitor.

Methylthio-DADMe-immucillin-A (MTDIA) is an 86 picomolar inhibitor of 5'-methylthioadenosine phosphorylase (MTAP) with potent and specific anti-cancer efficacy. MTAP salvages S-adenosylmethionine (SAM) from 5'-methylthioadenosine (MTA), a toxic metabolite produced during polyamine biosynthesis. Changes in MTAP expression are implicated in cancer growth and development, making MTAP an appealing target for anti-cancer therapeutics. Since SAM is involved in lipid metabolism, we hypothesised that MTDIA alters the lipidomes of MTDIA-treated cells. To identify these effects, we analysed the lipid profiles of MTDIA-treated Saccharomyces cerevisiae using ultra-high resolution accurate mass spectrometry (UHRAMS). MTAP inhibition by MTDIA, and knockout of the Meu1 gene that encodes for MTAP in yeast, caused global lipidomic changes and differential abundance of lipids involved in cell signaling. The phosphoinositide kinase/phosphatase signaling network was specifically impaired upon MTDIA treatment, and was independently validated and further characterised via altered localization of proteins integral to this network. Functional consequences of dysregulated lipid metabolism included a decrease in reactive oxygen species (ROS) levels induced by MTDIA that was contemporaneous with changes in immunological response factors (nitric oxide, tumour necrosis factor-alpha and interleukin-10) in mammalian cells. These results indicate that lipid homeostasis alterations and concomitant downstream effects may be associated with MTDIA mechanistic efficacy.

Cumulative Neurotoxicological Air Pollution Exposure Is Associated with Lower Reading Improvement and Diminished Benefits of Literacy Interventions for Urban Elementary Students of Color.

The cognitive and behavioral deficits associated with air pollution exposure may have far-reaching negative effects on children's scholastic achievement. Moreover, air pollution may be conditioning the success of educational investments that support students who face greatest levels of societal adversity. This study examined the direct main effects of cumulative neurotoxicological exposure on annual reading improvement. We also tested the statistical interaction (i.e., moderation) of neurotoxicological exposure and academic intervention sessions on annual reading improvement for a large sample of ethnic minority (95%) elementary school children (n = 6080, k-6th grade) enrolled in a standard literacy enrichment program. These children were all behind grade level in reading and attended predominantly low-income schools (n = 85) in urban settings across the state of California. Multi-level modeling assessments accounted for random effects associated with school and neighborhood environments, and incorporated extensive individual, school, and community level covariates. Findings show individual elementary students of color to progress less in reading when exposed to greater accumulations of neurotoxin air pollution in their home and school environments, with the average deficit equivalent to 1.5 weeks of learning delay per year. Findings also show neurotoxicological exposure to diminish the efficacy of literacy intervention sessions received on reading improvement throughout the school year. Results suggest that pollution abatement can be a salient strategy to help bridge the child educational achievement gap. In addition to several methodological strengths, this study is one of the first to show that ambient pollution can undermine program efficacy of a literacy enrichment program.

An Isomer of Galidesivir That Potently Inhibits Influenza Viruses and Members of the Bunyavirales Order.

We report for the first time the antiviral activities of two iminovirs (antiviral imino-C-nucleosides) 1 and 2, structurally related to galidesivir (Immucillin A, BCX4430). An iminovir containing the 4-aminopyrrolo[2,1-f][1,2,4-triazine] nucleobase found in remdesivir exhibited submicromolar inhibition of multiple strains of influenza A and B viruses, as well as members of the Bunyavirales order. We also report the first syntheses of ProTide prodrugs of iminovir monophosphates, which unexpectedly displayed poorer viral inhibition than their parent nucleosides in vitro. An efficient synthesis of the 4-aminopyrrolo[2,1-f][1,2,4-triazine]-containing iminovir 2 was developed to enable preliminary in vivo studies, wherein it displayed significant toxicity in BALB/c mice and limited protection against influenza. Further modification of this anti-influenza iminovir will therefore be required to improve its therapeutic value.

Pessimistic cognitive biases mediate socioeconomic status and children's mental health problems.

Low socioeconomic status (SES) is associated with higher rates of emotional disorders in childhood and beyond. Here we assessed one possible contributor to this disparity, a cognitive bias in the interpretation of negative events, in a group of 341 9-year-olds (49% female, 94% White) ranging widely in SES. This cognitive bias, known as pessimism in the attributional style literature, is the tendency to interpret negative events as persistent (Stable) and pervasive (Global). It was found to be more common among lower SES children (effect sizes = 0.18-0.24 depending on SES measures: income to needs ratio, proportion of poverty from birth to age 9, and parental educational attainment). Moreover, persistent, pervasive adversity in children's lives predicted this bias and mediated the SES-pessimism link. Pessimistic attributional style, in turn, was related to childhood emotional problems and mediated the relation between SES and these problems. Finally, evidence for serial mediation of the SES-mental health problems relationship was found via persistent, pervasive adversity and pessimism, respectively.

Measuring Repositioning in Home Care for Pressure Injury Prevention and Management.

Despite the widespread agreement on the need for the regular repositioning of at-risk individuals for pressure injury prevention and management, adherence to repositioning schedules remains poor in the clinical environment. The situation in the home environment is likely even worse. Our team has developed a non-contact system that can determine an individual's position in bed (left-side lying, supine, or right-side lying) using data from a set of inexpensive load cells placed under the bed. This system was able to detect whether healthy participants were left-side lying, supine, or right-side lying with 94.2% accuracy in the lab environment. The objective of the present work was to deploy and test our system in the home environment for use with individuals who were sleeping in their own beds. Our system was able to detect the position of our nine participants with an F1 score of 0.982. Future work will include improving generalizability by training our classifier on more participants as well as using this system to evaluate adherence to two-hour repositioning schedules for pressure injury prevention or management. We plan to deploy this technology as part of a prompting system to alert a caregiver when a patient requires repositioning.

Cost of resilience: Childhood poverty, mental health, and chronic physiological stress.

Childhood poverty is associated with elevated internalizing symptoms. Nevertheless, some children exposed to poverty evince remarkable resilience, demonstrating lower than expected levels of psychological distress. However, recent work suggests that coping with adversity can lead to undesirable physical health consequences. Specifically, successful adaptation in the context of early adversity, including socioeconomic disadvantage, appears to be associated with elevated chronic physiological stress and ill health. The current study adds to this emerging literature by examining in a longitudinal context whether low levels of internalizing symptoms in the face of childhood poverty is accompanied by elevated chronic physiological stress (allostatic load) during childhood, as well as over time from childhood to adulthood. Results (n = 341; M=9.2 years, 49 % female; 94 % Caucasian) show that childhood poverty was prospectively associated with higher allostatic load during adolescence, controlling for baseline allostatic load. Furthermore, greater duration of childhood poverty led to steeper, more elevated allostatic load trajectories from childhood to adulthood, for youth with lower levels of internalizing symptoms. Efforts to manage adverse sequelae of early adversity likely yield a complex array of benefits and costs.

Viperin triggers ribosome collision-dependent translation inhibition to restrict viral replication.

Innate immune responses induce hundreds of interferon-stimulated genes (ISGs). Viperin, a member of the radical S-adenosyl methionine (SAM) superfamily of enzymes, is the product of one such ISG that restricts the replication of a broad spectrum of viruses. Here, we report a previously unknown antiviral mechanism in which viperin activates a ribosome collision-dependent pathway that inhibits both cellular and viral RNA translation. We found that the radical SAM activity of viperin is required for translation inhibition and that this is mediated by viperin's enzymatic product, 3'-deoxy-3',4'-didehydro-CTP (ddhCTP). Viperin triggers ribosome collisions and activates the MAPKKK ZAK pathway that in turn activates the GCN2 arm of the integrated stress response pathway to inhibit translation. The study illustrates the importance of translational repression in the antiviral response and identifies viperin as a translation regulator in innate immunity.

Persistence on challenging tasks mediates the relationship between childhood poverty and mental health problems.

Childhood disadvantage is associated with psychological distress throughout the lifespan. Poor children are alleged to give up more often than their more privileged peers when facing challenges. Yet little research has examined the role of task persistence in poverty and mental health. We test whether poverty-related deficits in persistence contribute to the well-documented link between childhood disadvantage and mental health. We used growth curve modeling to analyze three waves (age 9, 13, and 17) of data assessing the trajectories of persistence on challenging tasks and mental health. Childhood poverty is the proportion of time participants lived in poverty from birth to age 9. We found that individuals experiencing more poverty in early childhood demonstrate less persistence and deteriorated mental health from ages 9 to 17. As expected, task persistence accounts for a portion of the robust childhood poverty - worsening mental health association. Clinical research on childhood disadvantage is in the early stages of unpacking underlying reasons why childhood poverty is bad for psychological well-being throughout life, revealing potential points of intervention.

Childhood poverty and psychological well-being: The mediating role of cumulative risk exposure.

The current study assessed whether the proportion of childhood (age 0-9 years) in poverty altered the developmental trajectories (ages 9-24) of multimethodological indicators of psychological well-being. In addition, we tested whether exposure to cumulative risk over time mediated the association between poverty exposure and psychological well-being. Measures of psychological well-being included internalizing and externalizing symptoms, a behavioral index of learned helplessness (task persistence), and chronic physiological stress (allostatic load). Exposure to poverty during childhood predicted the trajectory of each development outcome: individuals with more poverty exposure during childhood showed (a) relatively high levels of internalizing symptoms that diminished more slowly with maturation, (b) relatively high levels of externalizing symptoms that increased faster over time, (c) less task persistence indicative of greater learned helplessness, and (d) higher levels of chronic physiological stress which increased faster over time relative to persons with less childhood poverty exposure. Trajectories of cumulative risk exposure from physical and psychosocial surroundings from 9-24 years accounted for the association between childhood poverty and the growth curves of internalizing and externalizing symptoms but not for learned helplessness or chronic physiological stress. Additional sensitivity analyses indicate that early childhood disadvantage is particularly problematic for each outcome, except for internalizing symptoms which seem sensitive to the combination of early and lifetime poverty exposure. We also explored whether domains of cumulative risk as well as two alternatives, maternal sensitivity or family cohesion, functioned as mediators. Little evidence emerged for any of these alternative mediating constructs.

Discovery of AL-GDa62 as a Potential Synthetic Lethal Lead for the Treatment of Gastric Cancer.

Diffuse gastric cancer and lobular breast cancer are aggressive malignancies that are frequently associated with inactivating mutations in the tumor suppressor gene CDH1. Synthetic lethal (SL) vulnerabilities arising from CDH1 dysfunction represent attractive targets for drug development. Recently, SLEC-11 (1) emerged as a SL lead in E-cadherin-deficient cells. Here, we describe our efforts to optimize 1. Overall, 63 analogues were synthesized and tested for their SL activity toward isogenic mammary epithelial CDH1-deficient cells (MCF10A-CDH1-/-). Among the 26 compounds with greater cytotoxicity, AL-GDa62 (3) was four-times more potent and more selective than 1 with an EC50 ratio of 1.6. Furthermore, 3 preferentially induced apoptosis in CDH1-/- cells, and Cdh1-/- mammary and gastric organoids were significantly more sensitive to 3 at low micromolar concentrations. Thermal proteome profiling of treated MCF10A-CDH1-/- cell protein lysates revealed that 3 specifically inhibits TCOF1, ARPC5, and UBC9. In vitro, 3 inhibited SUMOylation at low micromolar concentrations.

Neural Responses During Emotion Transitions and Emotion Regulation.

Why are some people more susceptible to interference from previous emotional stimuli? Neural mechanisms underlying emotion regulation are typically studied with one-off positive or negative stimuli. Less is known about how they operate during dynamic emotional experiences, which more closely resemble how emotions occur in real life. Therefore, we investigated the interaction among temporal context, stimulus content, and regulatory strategy. Image sequences included either neutral to negative emotion or negative to neutral emotion. Participants were instructed to either passively watch the emotional stimuli or apply cognitive reappraisal during the image sequences presentation. Participants also reported their habitual use of cognitive reappraisal in their daily lives on a standard scale. We measured functional connectivity (FC) with electroencephalography (EEG) source localization. A three-way interaction suggested that, in addition to momentary emotional content and regulatory effort, the temporal context of stimuli impacts the FC between the ventromedial prefrontal cortex (vmPFC) and the ventral anterior cingulate cortex (ACC) in both alpha and beta frequency bands. In the reappraisal condition-but not the passive watch conditions-, individual differences in habitual reappraisal were manifested in the FC of vmPFC-ACC in alpha band. Emotion transitions may be more demanding because prefrontal-posterior FC in the beta band decreased during emotion transitions regardless of emotional content or regulation efforts. Flexible emotion regulation enables the recruiting of neural activities in response to the content of dynamic, ever-changing experiences encountered in daily life. Studying brain responses to dynamic emotional stimuli may shed light on individual differences in adaptation and psychological health. It also provides a more ecologically valid assessment of emotion regulation.

Chemical Synthesis of the Antiviral Nucleotide Analogue ddhCTP.

3'-Deoxy-3',4'-didehydro-cytidine triphosphate (ddhCTP) is a novel antiviral molecule produced by the enzyme viperin as part of the innate immune response. ddhCTP has been shown to act as an obligate chain terminator of flavivirus and SARS-CoV-2 RNA-dependent RNA polymerases; however, further biophysical studies have been precluded by limited access to this promising antiviral. Herein, we report a robust and scalable synthesis of ddhCTP as well as the mono- and diphosphates ddhCMP and ddhCDP, respectively. Identification of a 2'-silyl ether protection strategy enabled selective synthesis and facile purification of the 5'-triphosphate, culminating in the preparation of ddhCTP on a gram scale.

A single point mutation converts a glutaryl-7-aminocephalosporanic acid acylase into an N-acyl-homoserine lactone acylase.

OBJECTIVE: To change the specificity of a glutaryl-7-aminocephalosporanic acid acylase (GCA) towards N-acyl homoserine lactones (AHLs; quorum sensing signalling molecules) by site-directed mutagenesis. RESULTS: Seven residues were identified by analysis of existing crystal structures as potential determinants of substrate specificity. Site-saturation mutagenesis libraries were created for each of the seven selected positions. High-throughput activity screening of each library identified two variants-Arg255Ala, Arg255Gly-with new activities towards N-acyl homoserine lactone substrates. Structural modelling of the Arg255Gly mutation suggests that the smaller side-chain of glycine (as compared to arginine in the wild-type enzyme) avoids a key clash with the acyl group of the N-acyl homoserine lactone substrate. CONCLUSIONS: Mutation of a single amino acid residue successfully converted a GCA (with no detectable activity against AHLs) into an AHL acylase. This approach may be useful for further engineering of 'quorum quenching' enzymes.