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Partisan animosity has been on the rise in America. Partisan animosity involves blame, wherein political partisans blame outparty members for their beliefs and actions. Here, we examine whether a historicist thinking intervention—drawn from research on blame mitigation—can reduce partisan animosity. The intervention consisted of three components: (1) a narrative about the idiosyncratic development of one political opponent paired with (2) a message about how unique life experiences shape everyone's political beliefs and (3) a suggestion that outparty members can be changed by future formative experiences. Experiments 1 and 2 showed that the intervention reduced cold feelings—measured via Feeling Thermometer—towards the outparty for both Democrats and Republicans. Experiments 3 and 4 focused on more specific emotional changes. Experiment 3 showed that, for Democrats, the intervention increased compassion. Experiment 4 showed that, for Republicans, the intervention reduced disgust, disapproval, anger, and contempt, but had no impact on compassion. For Democrats, but not for Republicans, reductions in animosity were mediated by reduced perceptions of control of self-formation, the mediator identified in prior work on historicist thinking and blame mitigation. [ABSTRACT FROM AUTHOR]

The blameworthiness of an offender is often discussed in groups. Yet, the research literature overwhelmingly examines individuals assessing blameworthiness in isolation. To address this gap in the literature, the present study examines group deliberations about blameworthiness, with a particular focus on how group deliberations impact utilization of mitigating information about an offender's unfortunate life history. Participants from introductory psychology courses at a U.S. university were placed in groups of two or three and each group also included a confederate who followed a script. Groups were randomly assigned to one of four conditions. In one condition (deed only), groups learned only about the offender's heinous crimes. In the three remaining conditions, participants also received a historicist narrative regarding how the offender's unfortunate history deformed his moral character. These conditions differed in terms of the confederate's arguments: Neutral arguments, arguments to ignore the narrative, or arguments to give great weight to the narrative. Results showed that the historicist narrative was particularly effective at reducing outrage and increasing compassion when the confederate argued for its utilization. The reduction in outrage mediated a reduction in spiteful punitiveness toward the offender. Interestingly, the confederate who urged fellow deliberators to ignore the historicist narrative had no impact on outrage or compassion. We also examined mediation of the impact of historicist narratives on outrage and compassion. We found that when the confederate remained neutral the impact of historicist narratives on outrage and compassion was mediated via diminished perceptions of the offender's control of self-formation. This mirrors what is typically found in prior work focused on individual judgments. In contrast, when the confederate argued that great weight should be given to the narrative, reductions in outrage were mediated via diminished perceptions of offender freedom of action. This pattern of mediation is not typically found but has been found in one previous study where participants received social encouragement to mitigate blame. Results are discussed in terms of how social influence might alter the inferences draw from historicist narratives. Suggestions for future research on social influence in the context of blame are presented. [ABSTRACT FROM AUTHOR]

Some argue that it is ethically justifiable to unilaterally withdraw life‐sustaining treatment during crisis standards of care without the patient's consent in order to reallocate it to another patient with a better chance of survival. This justification has been supported by two lines of argument: the equivalence thesis and the rule of the double effect. We argue that there are theoretical issues with the first and practical ones with the second, as supported by an experiment aimed at exploring whether the Knobe effect, which affects the folk concept of intention, applies to situations of unilateral withdrawal. Fifty‐two critical care physicians from one university were asked to ascribe intention in two hypothetical scenarios A and B in which outcomes differ—the patient from whom life‐sustaining treatment is withdrawn dies in scenario A but survives in scenario B—but the intention, to save the other patient regardless of the outcome of the other, is the same. The survey was administered via a web‐based survey and all answers were anonymous. A paired proportion test was used to compare responses to both questions. All 52 surveyed individuals responded in scenario A and 30 (57.7%) ascribed intention when outcomes were unfavorable, whereas 50 responded in scenario B and 8 (16%) ascribed intention when outcomes were favorable, a difference that was statistically significant (p < 0.001). There are theoretical and practical issues with the arguments proposed to justify the unilateral withdrawal of life‐sustaining treatment based on the equivalence thesis and the rule of double effect. [ABSTRACT FROM AUTHOR]

The influence of the housing system on sperm productivity and reproductive capacity of rabbits was studied. Indicators like ejaculate volume, sperm density, activity, and concentration, as well as the percentage of fertility were measured for silver breed rabbits of three coloured lines housed in aggregates "Rabbitax-8" and in a modular rabbit house developed by Mykolayiv National Agrarian University. The highest male sperm productivity and reproductive capacity were found for rabbits housed in aggregates "Rabbitax-8". [ABSTRACT FROM AUTHOR]

Background: The co-occurrence of frailty and cognitive impairment in older (50+ years) persons with HIV (PWH) is common and increases the risk of poor outcomes. In HIV clinics, the most commonly used frailty measures are the frailty phenotype (FP), which requires measuring grip strength and gait speed to implement, and the frailty index (FI) based on comprehensive health data collected on patients. We examined construct and criterion-related validity (as it predicts cognition) of the Clinical Frailty Scale (CFS), a less resource-intensive approach for assessing frailty, in relation to these more commonly used frailty assessments (FP and FI). Setting/ Methods: A total of 143 older (age 50+) PWH (mean age 57 years; 88% male) seen at the Southern Alberta Clinic underwent both frailty screening with the FP, CFS, and FI and neuropsychological testing. Mixed-effects regressions examined the associations between frailty status and cognition. Results: Concordance with the FP was slightly superior for the CFS than the FI. The FP and CFS had similar associations with domainspecific cognitive performance with frail PWH performing worse than nonfrail individuals on tests requiring manual dexterity (Trail Making Part A and B; Symbol Digit; and Grooved Pegboard; P values ,0.05). Neither were associated with executive function, learning, or memory performance. The FI was associated with worse fluency, fine motor skills (Grooved Pegboard), and Trail Making Part A. Conclusion: The CFS is a simple screening tool with good construct and criterion-related validity. It was associated with a similar pattern of cognitive deficits as the FP. If confirmed and the associations are extended to other clinically significant characteristics and outcomes, the CFS can be considered as an alternative to the FP and FI in assessing frailty in older PWH. [ABSTRACT FROM AUTHOR]

When one learns that current struggles or transgressions of an individual or group are rooted in an unfortunate history, one experiences compassion and reduced blame. Prior research has demonstrated this by having participants receive (or not) a concrete historicist narrative regarding the particular individual or group under consideration. Here, we take a different approach. We explore the possibility that everyday people show meaningful variation in a broad lay theory that we call lay historicism. Lay historicists believe that—as a general fact—people's psychological characteristics and life outcomes are powerfully molded by their life histories. We present eight studies linking lay historicism to broad tendencies toward compassion and non-blaming. Collectively, Studies 1–5 suggest that lay historicism affects compassion and blame, respectively, via distinct mechanisms: (1) Lay historicism is associated with compassion because it creates a sense that—as a general fact—past suffering lies behind present difficulties, and (2) lay historicism is associated with blame mitigation because historicists reject the idea that—as a general fact—people freely and autonomously create their moral character. Thus, lay historicism increases compassion and decreases blame via distinct mechanisms. The remaining studies diversify our evidence base. Study 6 examines criminal justice philosophies rather than broad moral traits (as in the earlier studies) and shows that lay historicism is associated with preference for humane criminal justice philosophies. Study 7 moves from abstract beliefs to concrete situations and shows that lay historicism predicts reduced blaming of an irresponsible peer who is encountered face-to-face. One additional study—in our Supplemental Materials—shows that lay historicism predicts lower levels of blaming on implicit measures, although only among those who also reject lay controllability theories. Overall, these studies provide consistent support for the possibility that lay historicism is broadly associated with humane responding to the struggles and transgressions of others. [ABSTRACT FROM AUTHOR]

Genetic structure of animals of several Ukrainian modern breeds analysed by genes of protein and lipid exchange CSN3 (kappa-casein), BLG (betalactaglobulin), LEP (leptin), Pit-1 (pituitery transcription factor), TG-5 (thyroglobulin) were investigated in cows of three domestic breeds (Ukrainian Red Dairy, Ukrainian Black-speckled Dairy, Ukrainian Red-speckled Dairy). Polymer-ase chain reaction, followed by restriction fragment length polymorphism was used for the molecular-genetic analysis. [ABSTRACT FROM AUTHOR]

Essentialist beliefs about social groups can contribute to prejudice and intergroup distancing. To date, little data have been gathered regarding minority group members’ essentialistic thinking about the White majority in the U.S. Do essentialist beliefs show a similar structure when minority group members are thinking about the majority as when the majority group is thinking about the minority group? Do minority group essentialist beliefs predict affective prejudice and diminished desire for intergroup contact as they do among White respondents? We sought answers to these questions in a study that included 248 African American participants. We found clear evidence that the structure of Blacks’ essentialist thinking about Whites matches the structure of Whites’ essentialist thinking about Blacks. Specifically, Black respondents made a distinction between bio-somatic and bio-behavioral essentialism, and reported stronger endorsement of the former as compared to the latter. Also replicating prior studies of Whites’ essentialist thinking, only bio-behavioral essentialist beliefs were predictive of negative attitudes. This suggests that essentialism can be linked to prejudice even in contexts that do not involve a dominant group rationalizing its social advantages. Discussion centers on implications of this work for prejudice reduction. [ABSTRACT FROM AUTHOR]

Paradoxically, the thymidine kinase (TK) encoded by Kaposi sarcoma-associated herpesvirus (KSHV) is an extremely inefficient nucleoside kinase, when compared to TKs from related herpesviruses. We now show that KSHV-TK, in contrast to HSV1-TK, associates with the actin cytoskeleton and induces extensive cell contraction followed by membrane blebbing. These dramatic changes in cell morphology depend on the auto-phosphorylation of tyrosines 65, 85 and 120 in the N-terminus of KSHV-TK. Phosphorylation of tyrosines 65/85 and 120 results in an interaction with Crk family proteins and the p85 regulatory subunit of PI3-Kinase, respectively. The interaction of Crk with KSHV-TK leads to tyrosine phoshorylation of this cellular adaptor. Auto-phosphorylation of KSHV-TK also induces a loss of FAK and paxillin from focal adhesions, resulting in activation of RhoA-ROCK signalling to myosin II and cell contraction. In the absence of FAK or paxillin, KSHV-TK has no effect on focal adhesion integrity or cell morphology. Our observations demonstrate that by acting as a tyrosine kinase, KSHV-TK modulates signalling and cell morphology. [ABSTRACT FROM AUTHOR]

Why is he poor? Why is she failing academically? Why is he so generous? Why is she so conscientious? Answers to such everyday questions—social explanations—have powerful effects on relationships at the interpersonal and societal levels. How do people select an explanation in particular cases? We suggest that, often, explanations are selected based on the individual's pre-existing general theories of social causality. More specifically, we suggest that over time individuals develop general beliefs regarding the causes of social events. We refer to these beliefs as social explanatory styles. Our goal in the present article is to offer and validate a measure of individual differences in social explanatory styles. Accordingly, we offer the Social Explanatory Styles Questionnaire (SESQ), which measures three independent dimensions of social explanatory style: Dispositionism, historicism, and controllability. Studies 1–3 examine basic psychometric properties of the SESQ and provide positive evidence regarding internal consistency, factor structure, and both convergent and divergent validity. Studies 4–6 examine predictive validity for each subscale: Does each explanatory dimension moderate an important phenomenon of social cognition? Results suggest that they do. In Study 4, we show that SESQ dispositionism moderates the tendency to make spontaneous trait inferences. In Study 5, we show that SESQ historicism moderates the tendency to commit the Fundamental Attribution Error. Finally, in Study 6 we show that SESQ controllability predicts polarization of moral blame judgments: Heightened blaming toward controllable stigmas (assimilation), and attenuated blaming toward uncontrollable stigmas (contrast). Decades of research suggest that explanatory style regarding the self is a powerful predictor of self-functioning. We think it is likely that social explanatory styles—perhaps comprising interactive combinations of the basic dimensions tapped by the SESQ—will be similarly potent predictors of social functioning. We hope the SESQ will be a useful tool for exploring that possibility. [ABSTRACT FROM AUTHOR]

Viral enzymes that process small molecules provide potential chemotherapeutic targets. A key constraint- the replicative potential of spontaneous enzyme mutants-has been hard to define with human gammaherpesviruses because of their narrow species tropisms. Here, we disrupted the murid herpesvirus 4 (MuHV-4) ORF61, which encodes its ribonucleotide reductase (RNR) large subunit. Mutant viruses showed delayed in vitro lytic replication, failed to establish infection via the upper respiratory tract, and replicated to only a very limited extent in the lower respiratory tract without reaching lymphoid tissue. RNR could therefore provide a good target for gammaherpesvirus chemotherapy. [ABSTRACT FROM AUTHOR]

In the mid-20th century, descriptive meta-ethics addressed a number of central questions, such as whether there is a necessary connection between moral judgment and motivation, whether moral reasons are absolute or relative, and whether moral judgments express attitudes or describe states of affairs. I maintain that much of this work in mid-20th century meta-ethics proceeded on an assumption that there is good reason to question. The assumption was that our ordinary discourse is uniform and determinate enough to vindicate one side or the other of these meta-ethical debates. I suggest that ordinary moral discourse may be much less uniform and determinate than 20th century meta-ethics assumed. [ABSTRACT FROM AUTHOR]

The article provides information on three perspectives in making moral judgments such as moral sentimentalism, descriptive and prescriptive moral pluralism. It cites several works which prove that emotions play a crucial role in making ordinary moral judgments to explain the moral sentimentalism. The basic rules that affect judgment, along with the details of descriptive and prescriptive moral judgment, are also discussed.

All gamma-herpesviruses encode at least one homolog of the cellular enzyme formyl-glycineamide-phosphoribosylamidotransferase. Murid herpesvirus-4 (MuHV-4) encodes 3 (ORFs 75a, 75b and 75c), suggesting that at least some copies have acquired new functions. Here we show that the corresponding proteins are all present in virions and localize to infected cell nuclei. Despite these common features, ORFs 75a and 75b did not substitute functionally for a lack of ORF75c, as ORF75c virus knockouts were severely impaired for lytic replication in vitro and for host colonization in vivo. They showed 2 defects: incoming capsids failed to migrate to the nuclear margin following membrane fusion, and genomes that did reach the nucleus failed to initiate normal gene expression. The latter defect was associated with a failure of in-coming virions to disassemble PML bodies. The capsid transport deficit seemed to be functionally more important, since ORF75c- MuHV-4 infected both PML+ and PML- cells poorly. The original host enzyme has therefore evolved into a set of distinct and multi-functional viral tegument proteins. One important function is moving incoming capsids to the nuclear margin for viral genome delivery. [ABSTRACT FROM AUTHOR]

Viruses lack self-propulsion. To move in multi-cellular hosts they must therefore manipulate infected cells. Herpesviruses provide an archetype for many aspects of host manipulation, but only for alpha-herpesviruses in is there much information about they move. Other herpesviruses are not necessarily the same. Here we show that Murine gamma-herpesvirus-68 (MHV-68) induces the outgrowth of long, branched plasma membrane fronds to create an intercellular network for virion traffic. The fronds were actin-based and RhoA-dependent. Time-lapse imaging showed that the infected cell surface became highly motile and that virions moved on the fronds. This plasma membrane remodelling was driven by the cytoplasmic tail of gp48, a MHV-68 glycoprotein previously implicated in intercellular viral spread. The MHV-68 ORF58 was also required, but its role was simply transporting gp48 to the plasma membrane, since a gp48 mutant exported without ORF58 did not require ORF58 to form membrane fronds either. Together, gp48/ORF58 were sufficient to induce fronds in transfected cells, as were the homologous BDLF2/BMRF2 of Epstein-Barr virus. Gp48/ORF58 therefore represents a conserved module by which gamma-herpesviruses rearrange cellular actin to increase intercellular contacts and thereby promote their spread. [ABSTRACT FROM AUTHOR]

The nucleoside kinase encoded by Kaposi's sarcoma-associated herpesvirus (KSHV) is a relatively inefficient enzyme with substrate specificity for thymidine alone, unlike alphaherpesvirus thymidine kinases (TKs). Similar to all gammaherpesvirus TKs, KSHV TK is composed of two distinct domains, a conserved C-terminal kinase and a novel and uncharacterized N terminus. Ectopic expression of KSHV TK in adherent cells induced striking morphological changes and anchorage independence although cells survived, a property shared with the related rhadinovirus TKs of rhesus monkey rhadinovirus and herpesvirus saimiri. To determine whether KSHV TK served alternate functions relevant to the rhadinovirus life cycle and to reveal the contribution of the N terminus, an enhanced green fluorescent protein-tagged fusion protein and serial mutants were generated for investigation of intracellular localization and cell biology. Analysis of truncation mutants showed that a proline-rich region located within the N terminus cooperated with the conserved C-terminal kinase to tether KSHV TK to a reticular network in the cytoplasm and to induce morphological change. Fusion of the KSHV N terminus to herpes simplex virus type 1 TK, a nucleus-localized enzyme, similarly resulted in cytoplasmic redistribution of the chimeric protein but did not alter cell shape or adhesion. Unlike other human herpesvirus TKs, KSHV TKs and related rhadinovirus TKs are constitutively tyrosine phosphorylated; a KSHV TK mutant that was hypophosphorylated failed to detach and grow in suspension. Loss of adhesion may enhance terminal differentiation, viral replication, and egress at the cellular level and at the organism level may facilitate detachment and distant migration of KSHV-replicating cells within body fluids—promoting oropharyngeal transmission and perhaps contributing to the multifocal lesions that characterize KS. [ABSTRACT FROM AUTHOR]

Postconsumer plastic chips that cannot be processed for useful applications may end up in a landfill. This constitutes an environmental problem and is considered an additional burden on the already tight landfill space. In this research, plastic chips were used as partial replacement of coarse aggregates in concrete mixtures. The testing program was organized to study the effect of adding plastic aggregates to the concrete in order to reduce the density and gain superior deformation qualities. In this study, plastic aggregates replaced 5, 10, and 15% by mass of coarse aggregates. A total of 198 concrete cubes were made to examine the effect of plastic content and water/cement ratio on the mechanical properties of concrete. The cubes were tested in compression at 1, 7, 14, 21, and 28 days where measurements of deformation were made. The measured load and deformation were used to calculate stress, strain, and modulus of elasticity as related to different plastic content and water/cement ratio. Test results were used to optimize mix design and to establish mathematical relationships between plastic content in the mix and the strength and deformation characteristics of the hardened concrete. Furthermore, digital imaging was employed to scan cross sections of cubes with plastic aggregates to study the orientation of plastic chips in the cube, and to correlate the area of plastics to the increase in durability or the decrease in strength. Test results demonstrated that plastic aggregates are viable in providing the concrete with a high degree of deformability as compared with regular concrete. This characteristic makes the concrete useful in situations where it will be subjected to harsh weather, such as expansion or contraction, or freeze and thaw. [ABSTRACT FROM AUTHOR]

CD21 is a multifunctional receptor for Epstein-Barr virus (EBV), for C3dg and for CD23. Upon engagement of immune complexes CD21 modulates immunoreceptor signaling, linking innate and adaptive immune responses. The mechanisms enabling CD21 to independently relay information between the exterior and interior of the cell, however, remain unresolved. We show that formin homologue overexpressed in spleen (FHOS/FHOD1) binds the cytoplasmic domain of human CD21 through its C terminus. When expressed in cells, EGFP-FHOS localizes to the cytoplasm and accumulates with actin in membrane protrusions. Plasma membrane aggregation, redistribution and co-localization of both proteins are stimulated when EBV (ligand) binds CD21. Though widely expressed, FHOS RNA is most abundant in the littoral cell, a major constituent of the red pulp of human spleen believed to function in antigen filtration. Formins are molecular scaffolds that nucleate actin by a pathway distinct from Arp2/3 complex, linking signal transduction to actin reorganization and gene transcription. Thus, ligand stimulation of FHOS-CD21 interaction may transmit signals through promotion of cytoskeletal rearrangement. Moreover, formin recruitment to sites of actin assembly initiated by immunoreceptors could be a general mechanism whereby co-receptors such as CD21 modulate intracellular signaling. [ABSTRACT FROM AUTHOR]

I argue that a policy of presumed consent for cadaveric organ procurement. which assumes that people do want to donate their organs for transplantation after their death, would be a moral improvement over the current American system. which assumes that people do not want to donate their organs. I address what I take to be the most important objection to presumed consent. The objection is that if we implement presumed consent we will end up removing organs from the bodies of people who did not want their organs removed, and that this situation is morally unacceptable because it violates the principle of respect for autonomy that underlies our concept of informed consent. I argue that while removing organs from the bodies of people who did not want them removed is unfortunate, it is morally no worse that not removing organs from the bodies of people who did want them removed, and that a policy of presumed consent will produce fewer of these unfortunate results than the current system. [ABSTRACT FROM AUTHOR]

Research suggests that people initially take their subjective experience of an object as an accurate reflection of the object's properties, and only subsequently, occasionally, and effortfully consider the possibility that their experience was influenced by extraneous factors. The two studies reported here demonstrate that this is true even when the extraneous factors are the person's own dispositions. Dispositionally happy and unhappy participants were falsely told that they had been subliminally primed with words that might have influenced their moods, and were then asked to identify those words. Dispositionally happy participants were more likely than dispositionally unhappy participants to conclude that they had been primed with positive words, but only when they made these judgments under time pressure. The results are discussed in terms of correction models of human judgment. [ABSTRACT FROM AUTHOR]

Examines why David Hume, in his philosophical works, does not attempt to justify morality as a whole and that in his non-philosophical works Hume justifies particular moral claims in a non-reflexive way. Views by other philosophers on reflexivity in Hume's work; Problems with previous interpretations of reflexivity in Hume's work; Features of Hume's moral theory.

Biodiversity conservation is a complex and transdisciplinary problem that requires engagement and cooperation among scientific, societal, economic, and political institutions. However, historical approaches have often failed to bring together and address the needs of all relevant stakeholders in decision‐making processes. The Tropical Andes, a biodiversity hotspot where conservation efforts often conflict with socioeconomic issues and policies that prioritize economic development, provides an ideal model to develop and implement more effective approaches. In this study, we present a co‐design approach that mainstreams and improves the flow of biodiversity information in the Tropical Andes, while creating tailored outputs that meet the needs of economic and societal stakeholders. We employed a consultative process that brought together biodiversity information users and producers at the local, national, and regional levels through a combination of surveys and workshops. This approach identified priority needs and limitations of the flow of biodiversity information in the region, which led to the co‐design of user‐relevant biodiversity indicators. By leveraging the existing capacities of biodiversity information users and producers, we were able to co‐design multiple biodiversity indicators and prioritize two for full implementation ensuring that the data was findable, accessible, interoperable, and reusable based on the FAIR (Findable, Accessible, Interoperable, and Reusable) principles. This approach helped address limitations that were identified in the stakeholder engagement process, including gaps in data availability and the need for more accessible biodiversity information. Additionally, capacity‐building workshops were incorporated for all producers of biodiversity information involved, which aimed to not only improve the current flow of biodiversity information in the region but also facilitate its future sustainability. Our approach can serve as a valuable blueprint for mainstreaming biodiversity information and making it more inclusive in the future, especially considering the diverse worldviews, values, and knowledge systems between science, policy, and practice. [ABSTRACT FROM AUTHOR]

Rotaviruses are a major cause of acute gastroenteritis in children worldwide. Early stages of rotavirus assembly in infected cells occur in viroplasms. Confocal microscopy demonstrated that viroplasms associate with lipids and proteins (perilipin A, ADRP) characteristic of lipid droplets (LDs). LD-associated proteins were also found to colocalize with viroplasms containing a rotaviral NSP5-enhanced green fluorescent protein (EGFP) fusion protein and with viroplasm-like structures in uninfected cells coexpressing viral NSP2 and NSP5. Close spatial proximity of NSP5-EGFP and cellular perilipin A was confirmed by fluorescence resonance energy transfer. Viroplasms appear to recruit LD components during the time course of rotavirus infection. NSP5-specific siRNA blocked association of perilipin A with NSP5 in viroplasms. Viral double-stranded RNA (dsRNA), NSP5, and perilipin A cosedimented in low-density gradient fractions of rotavirus-infected cell extracts. Chemical compounds interfering with LD formation (isoproterenol plus isobutylmethylxanthine; triacsin C) decreased the number of viroplasms and inhibited dsRNA replication and the production of infectious progeny virus; this effect correlated with significant protection of cells from virus-associated cytopathicity. Rotaviruses represent a genus of another virus family utilizing LD components for replication, pointing at novel therapeutic targets for these pathogens. [ABSTRACT FROM AUTHOR]

The thymidine kinase (TK) encoded by Epstein-Barr virus (EBV) differs not only from that of the alphaherpesviruses but also from that of the gamma-2 herpesvirus subfamily. Because cellular location is frequently a determinant of regulatory function, to gain insight into additional role(s) of EBV TK and to uncover how the lymphocryptovirus and rhadinovirus enzymes differ, the subcellular localizations of EBV TK and the related cercopithecine herpesvirus-15 TK were investigated. We show that in contrast to those of the other family members, the gamma-1 herpesvirus TKs localize to the centrosome and even more precisely to the periphery of the centriole, tightly encircling the tubulin-rich centrioles in a microtubule-independent fashion. Centrosomal localization is observed in diverse cell types and occurs whether the protein is expressed independently or in the context of lytic EBV infection. Surprisingly, analysis of mutants revealed that the unique N-terminal domain was not critical for targeting to the centrosome, but rather, peptide sequences located C terminal to this domain were key. This is the first herpesvirus protein documented to reside in the centrosome, or microtubule-organizing center, an amembranous organelle that regulates the structural biology of the cell cycle through control of chromosome separation and cytokinesis. More recently, proteasome-mediated degradation of cell cycle regulatory proteins, production and loading of antigenic peptides onto HLA molecules, and transient homing of diverse virion proteins required for entry and/or egress have been shown to be coordinated at the centrosome. Potential implications of centrosomal localization for EBV TK function are discussed. [ABSTRACT FROM AUTHOR]

Background: We measured biomarkers of tumour growth and vascularity in interval and screen-detected colorectal cancers (CRCs) in the English Bowel Cancer Screening Programme in order to determine whether rapid tumour growth might contribute to interval CRC (a CRC diagnosed between a negative guaiac stool test and the next scheduled screening episode).Methods: Formalin-fixed, paraffin-embedded sections from 71 CRCs (screen-detected 43, interval 28) underwent immunohistochemistry for CD31 and Ki-67, in order to measure the microvessel density (MVD) and proliferation index (PI), respectively, as well as microsatellite instability (MSI) testing.Results: Interval CRCs were larger (P=0.02) and were more likely to exhibit venous invasion (P=0.005) than screen-detected tumours. There was no significant difference in MVD or PI between interval and screen-detected CRCs. More interval CRCs displayed MSI-high (14%) compared with screen-detected tumours (5%). A significantly (P=0.005) higher proportion (51%) of screen-detected CRC resection specimens contained at least one polyp compared with interval CRC (18%) resections.Conclusions: We found no evidence of biological differences between interval and screen-detected CRCs, consistent with the low sensitivity of guaiac stool testing as the main driver of interval CRC. The contribution of synchronous adenomas to occult blood loss for screening requires further investigation. [ABSTRACT FROM AUTHOR]

The small ribosomal subunit assembles cotranscriptionally on the nascent primary transcript. Cleavage at site A2 liberates the pre-40S subunit. We previously identified Bud23 as a conserved eukaryotic methyltransferase that is required for efficient cleavage at A2. Here, we report that Bud23 physically and functionally interacts with the DEAH-box RNA helicase Ecm16 (also known as Dhr1). Ecm16 is also required for cleavage at A2. We identified mutations in ECM16 that suppressed the growth and A2 cleavage defects of a bud23Δ mutant. RNA helicases often require protein cofactors to provide substrate specificity. We used yeast (Saccharomyces cerevisiae) two-hybrid analysis to map the binding site of Bud23 on Ecm16. Despite the physical and functional interaction between these factors, mutations that disrupted the interaction, as assayed by two-hybrid analysis, did not display a growth defect. We previously identified mutations in UTP2 and UTP14 that suppressed bud23Δ. We suggest that a network of protein interactions may mask the loss of interaction that we have defined by two-hybrid analysis. A mutation in motif I of Ecm16 that is predicted to impair its ability to hydrolyze ATP led to accumulation of Bud23 in an ~45S particle containing Ecm16. Thus, Bud23 enters the pre-40S pathway at the time of Ecm16 function. [ABSTRACT FROM AUTHOR]

The article presents the author's view concerning the structure and the constraints of common sense ethics. It mentions the continuous debate between the utilitarians and deontologists regarding the philosophical views of the common sense ethics. It also cites the common sense ethics' constraints as well as the criticism of its consequentialism.

Murid herpesvirus-4 (MuHV-4) provides a tractable model with which to define common, conserved features of gammaherpesvirus biology. The multi-membrane spanning glycoprotein M (gM) is one of only 4 glycoproteins that are essential for MuHV-4 lytic replication. gM binds to gN and is thought to function mainly secondary envelopment and virion egress, for which several predicted trafficking motifs in its C-terminal cytoplasmic tail could be important. We tested the contribution of the gM cytoplasmic tail to MuHV-4 lytic replication by making recombinant viruses with varying C-terminal deletions. Removing an acidic cluster and a distal YXXΦ motif altered the capsid distribution somewhat in infected cells but had little effect on virus replication, either in vitro or in vivo. In contrast, removing a proximal YXXΦ motif as well completely prevented productive replication. gM was still expressed, but unlike its longer forms showed only limited colocalization with co-transfected gN, and in the context of whole virus appeared to support gN expression less well. We conclude that some elements of the gM cytoplasmic tail are dispensible for MuHV-4 replication, but the tail as a whole is not. [ABSTRACT FROM AUTHOR]

The current Good Manufacturing Practice (cGMP) and effluent emission (use and disposal) regulations of the U.S. Food and Drug Administration (FDA) and manufacturing effluent discharge and emission regulations of the U.S. Environmental Protection Agency (U.S. EPA) require contained manufacture, use, and disposal of pharmaceuticals with the goal of minimizing the release of pharmaceutical chemicals into the environment. However, debate has recently arisen in several scientific forums over whether these regulations adequately protect human and environmental health from the new pharmaceutical drugs introduced each year into the marketplace and the multitude of existing products, each with many distinct biochemical modes of actions. To address this issue, it is important to understand the relevance of current cGMP regulations and emission regulations that have a direct bearing on the releases of pharmaceutical chemicals into the environment during the manufacture, use, and disposal of active pharmaceutical ingredients (drug substances) and drug products. This knowledge may help us assess the quantity of residues that may be released into the environment. Additionally, the information on physical, chemical, and degradation and sorption properties of the pharmaceutical chemicals may help determine the net residue levels that could persist in the environment to evaluate if such residues have any bearing on human and environmental health. The scientific and regulatory aspects of issues related to the manufacture, use, and disposal of pharmaceutical chemicals are discussed in this article, with special emphasis on potential environmental exposure pathways during the life cycle of an active pharmaceutical ingredient or drug product. The mechanisms of degradation (transformation or depletion) and dilution of pharmaceutical residues that may be released into aquatic or terrestrial environmental compartments are described. Such degradation and dilution of pharmaceutical... [ABSTRACT FROM AUTHOR]

Genes encoding glycosyltransferases can be under relatively high selection pressure, likely due to the involvement of the glycans synthesized in host-microbe interactions. Here, we used mice as an experimental model system to investigate whether loss of α−1,3-galactosyltransferase gene (GGTA1) function and Galα1-3Galβ1-4GlcNAcβ1-R (αGal) glycan expression affects host-microbiota interactions, as might have occurred during primate evolution. We found that Ggta1 deletion shaped the composition of the gut microbiota. This occurred via an immunoglobulin (Ig)-dependent mechanism, associated with targeting of αGal-expressing bacteria by IgA. Systemic infection with an Ig-shaped microbiota inoculum elicited a less severe form of sepsis compared to infection with non-Ig-shaped microbiota. This suggests that in the absence of host αGal, antibodies can shape the microbiota towards lower pathogenicity. Given the fitness cost imposed by bacterial sepsis, we infer that the observed reduction in microbiota pathogenicity upon Ggta1 deletion in mice may have contributed to increase the frequency of GGTA1 loss-of-function mutations in ancestral primates that gave rise to humans. [ABSTRACT FROM AUTHOR]

Throughout spring and summer 2020, ozone stations in the northern extratropics recorded unusually low ozone in the free troposphere. From April to August, and from 1 to 8 kilometers altitude, ozone was on average 7% (≈4 nmol/mol) below the 2000–2020 climatological mean. Such low ozone, over several months, and at so many stations, has not been observed in any previous year since at least 2000. Atmospheric composition analyses from the Copernicus Atmosphere Monitoring Service and simulations from the NASA GMI model indicate that the large 2020 springtime ozone depletion in the Arctic stratosphere contributed less than one‐quarter of the observed tropospheric anomaly. The observed anomaly is consistent with recent chemistry‐climate model simulations, which assume emissions reductions similar to those caused by the COVID‐19 crisis. COVID‐19 related emissions reductions appear to be the major cause for the observed reduced free tropospheric ozone in 2020. Plain Language Summary: Worldwide actions to contain the COVID‐19 virus have closed factories, grounded airplanes, and have generally reduced travel and transportation. Less fuel was burnt, and less exhaust was emitted into the atmosphere. Due to these measures, the concentration of nitrogen oxides and volatile organic compounds (VOCs) decreased in the atmosphere. These substances are important for photochemical production and destruction of ozone in the atmosphere. In clean or mildly polluted air, reducing nitrogen oxides and/or VOCs will reduce the photochemical production of ozone and result in less ozone. In heavily polluted air, in contrast, reducing nitrogen oxides can increase ozone concentrations, because less nitrogen oxide is available to destroy ozone. In this study, we use data from three types of ozone instruments, but mostly from ozonesondes on weather balloons. The sondes fly from the ground up to 30 kilometers altitude. In the first 8 km, we find significantly reduced ozone concentrations in the northern extratropics during spring and summer of 2020, less than in any other year since at least 2000. We suggest that reduced emissions due to the COVID‐19 crisis have lowered photochemical ozone production and have caused the observed ozone reductions in the troposphere. Key Points: In spring and summer 2020, stations in the northern extratropics report on average 7% (4 nmol/mol) less tropospheric ozone than normalSuch low tropospheric ozone, over several months, and at so many sites, has not been observed in any previous year since at least 2000Most of the reduction in tropospheric ozone in 2020 is likely due to emissions reductions related to the COVID‐19 pandemic [ABSTRACT FROM AUTHOR]

We tested the proposal that the C-terminal domain (CTD) of the AMPAR subunit GluA1 is required for LTP. We found that a knock-in mouse lacking the CTD of GluA1 expresses normal LTP and spatial memory, assayed by the Morris water maze. Our results support a model in which LTP generates synaptic slots, which capture passively diffusing AMPARs. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Parent-of-origin effect and risk for attention-deficit/hyperactivity disorder: Balancing the evidence against bias and chance findings," by Ridha Joober and Sarojini Sengupta in the present issue of the journal.

Late onset Alzheimer’s disease is the most common form of dementia for which about 30 susceptibility loci have been reported. The aim of the current study is to identify novel genes associated with Alzheimer’s disease using the largest up-to-date reference single nucleotide polymorphism (SNP) panel, the most accurate imputation software and a novel gene-based analysis approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer’s Project Consortium, comprising over 7 million genotypes from 17,008 Alzheimer’s cases and 37,154 controls. In addition to earlier reported genes, we detected three novel gene-wide significant loci PPARGC1A (p = 2.2 × 10−6), RORA (p = 7.4 × 10−7) and ZNF423 (p = 2.1 × 10−6). PPARGC1A and RORA are involved in circadian rhythm; circadian disturbances are one of the earliest symptoms of Alzheimer’s disease. PPARGC1A is additionally linked to energy metabolism and the generation of amyloid beta plaques. RORA is involved in a variety of functions apart from circadian rhythm, such as cholesterol metabolism and inflammation. The ZNF423 gene resides in an Alzheimer’s disease-specific protein network and is likely involved with centrosomes and DNA damage repair. [ABSTRACT FROM AUTHOR]

Background: It is not known whether immune dysfunction is associated with increased risk of death after cancer diagnosis in persons with HIV (PWH). AIDS-defining illness (ADI) can signal significant immunosuppression. Our objective was to determine differences in cancer stage and mortality rates in PWH with and without history of ADI. Methods: PWH with anal, oropharynx, cervical, lung cancers, or Hodgkin lymphoma diagnoses from January 2000 to December 2009 in the North American AIDS Cohort Collaboration on Research and Design were included. Results: Among 81,865 PWH, 814 had diagnoses included in the study; 341 (39%) had a history of ADI at time of cancer diagnosis. For each cancer type, stage at diagnosis did not differ by ADI (P > 0.05). Mortality and survival estimates for cervical cancer were limited by n = 5 diagnoses. Adjusted mortality rate ratios showed a 30%-70% increase in mortality among those with ADI for all cancer diagnoses, although only lung cancer was statistically significant. Survival after lung cancer diagnosis was poorer in PWH with ADI vs. without (P = 0.0001); the probability of survival was also poorer in those with ADI at, or before other cancers although not statistically significant. Conclusions: PWH with a history of ADI at lung cancer diagnosis had higher mortality and poorer survival after diagnosis compared to those without. Although not statistically significant, the findings of increased mortality and decreased survival among those with ADI (vs. without) were consistent for all other cancers, suggesting the need for further investigations into the role of HIV-related immune suppression and cancer outcomes. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: In 2015, the World Health Organization recommended that all HIV‐infected individuals consider ART initiation as soon as possible after diagnosis. Sex differences in choice of initial ART regimen, indications for switching, time to switching and choice of second‐line regimens have not been well described. The aims of this study were to describe first‐line ART and CD4 count at ART initiation by sex, calendar year and region, and to analyse time to change or interruption in first‐line ART, according to sex in each region. Methods: Participating cohorts included: Southern, East and West Africa (IeDEA‐Africa), North America (NA‐ACCORD), Caribbean, Central/South America (CCASAnet) and Asia‐Pacific including Australia (IeDEA Asia‐Pacific). The primary outcomes analysed for each region and according to sex were choice of initial ART, time to switching and time to discontinuation of the first‐line regimen. Results and Discussion: The combined cohort data set comprised of 715,252 participants across seven regions from low‐ to high‐income settings. The median CD4 count at treatment initiation was lower in men compared with women in nearly all regions and time periods. Women from North America and Southern Africa were more likely to switch ART compared to men (p < 0.001) with approximately 90% of women reporting a major change after 10 years in North America. Overall, after 8 years on ART, >50% of HIV‐ positive men and women from Southern Africa, East Africa, South and Central America remained on their original regimen. Men were more likely to have a treatment interruption compared with women in low‐ and middle‐income countries from the Asia/Pacific region (p < 0.001) as were men from Southern Africa (p < 0.001). Greater than 75% of men and women did not report a treatment interruption after 10 years on ART from all regions except North America and Southern Africa. Conclusions: There are regional variations in the ART regimen commenced at baseline and rates of major change and treatment interruption according to sex. Some of this is likely to reflect changes in local and international antiretroviral guideline recommendations but other sex‐specific factors such as pregnancy may contribute to these differences. [ABSTRACT FROM AUTHOR]

Background: Optoacoustic tomography (OT) of breast tumour oxygenation is a promising new technique, currently in clinical trials, which may help to determine disease stage and therapeutic response. However, the ability of OT to distinguish breast tumours displaying different vascular characteristics has yet to be established. The aim of the study is to prove OT as a sensitive technique for differentiating breast tumour models with manifestly different vasculatures.Methods: Multispectral OT (MSOT) was performed in oestrogen-dependent (MCF-7) and oestrogen-independent (MDA-MB-231) orthotopic breast cancer xenografts. Total haemoglobin (THb) and oxygen saturation (SO2MSOT) were calculated. Pathological and biochemical evaluation of the tumour vascular phenotype was performed for validation.Results: MCF-7 tumours show SO2MSOT similar to healthy tissue in both rim and core, despite significantly lower THb in the core. MDA-MB-231 tumours show markedly lower SO2MSOT with a significant rim-core disparity. Ex vivo analysis revealed that MCF-7 tumours contain fewer blood vessels (CD31+) that are more mature (CD31+/aSMA+) than MDA-MB-231. MCF-7 presented higher levels of stromal VEGF and iNOS, with increased NO serum levels. The vasculogenic process observed in MCF-7 was consistent with angiogenesis, while MDA-MB-231 appeared to rely more on vascular mimicry.Conclusions: OT is sensitive to differences in the vascular phenotypes of our breast cancer models. [ABSTRACT FROM AUTHOR]

INTRODUCTION: HIV-1 infection leads to chronic inflammation and to an increased risk of non-AIDS mortality. Our objective was to determine whether AIDS-defining events (ADEs) were associated with increased overall and cause-specific non-AIDS related mortality after antiretroviral therapy (ART) initiation. METHODS: We included HIV treatment-naïve adults from the Antiretroviral Therapy Cohort Collaboration (ART-CC) who initiated ART from 1996 to 2014. Causes of death were assigned using the Coding Causes of Death in HIV (CoDe) protocol. The adjusted hazard ratio (aHR) for overall and cause-specific non-AIDS mortality among those with an ADE (all ADEs, tuberculosis (TB), Pneumocystis jiroveci pneumonia (PJP), and non-Hodgkin's lymphoma (NHL)) compared to those without an ADE was estimated using a marginal structural model. RESULTS: The adjusted hazard of overall non-AIDS mortality was higher among those with any ADE compared to those without any ADE (aHR 2.21, 95% confidence interval (CI) 2.00 to 2.43). The adjusted hazard of each of the cause-specific non-AIDS related deaths were higher among those with any ADE compared to those without, except metabolic deaths (malignancy aHR 2.59 (95% CI 2.13 to 3.14), accident/suicide/overdose aHR 1.37 (95% CI 1.05 to 1.79), cardiovascular aHR 1.95 (95% CI 1.54 to 2.48), infection aHR (95% CI 1.68 to 2.81), hepatic aHR 2.09 (95% CI 1.61 to 2.72), respiratory aHR 4.28 (95% CI 2.67 to 6.88), renal aHR 5.81 (95% CI 2.69 to 12.56) and central nervous aHR 1.53 (95% CI 1.18 to 5.44)). The risk of overall and cause-specific non-AIDS mortality differed depending on the specific ADE of interest (TB, PJP, NHL). CONCLUSIONS: In this large multi-centre cohort collaboration with standardized assignment of causes of death, non-AIDS mortality was twice as high among patients with an ADE compared to without an ADE. However, non-AIDS related mortality after an ADE depended on the ADE of interest. Although there may be unmeasured confounders, these findings suggest that a common pathway may be independently driving both ADEs and NADE mortality. While prevention of ADEs may reduce subsequent death due to NADEs following ART initiation, modification of risk factors for NADE mortality remains important after ADE survival. [ABSTRACT FROM AUTHOR]

Background: Understanding the flow of patients through the continuum of HIV care is critical to determine how best to intervene so that the proportion of HIV-infected persons who are on antiretroviral treatment and virally suppressed is as large as possible. Methods: Using immunological and virological data from the Centers for Disease Control and Prevention and the North American AIDS Cohort Collaboration on Research and Design from 2009 to 2012, we estimated the distribution of time spent in and dropout probability from each stage in the continuum of HIV care. We used these estimates to develop a queueing model for the expected number of patients found in each stage of the cascade. Results: HIV-infected individuals spend an average of about 3.1 months after HIV diagnosis before being linked to care, or dropping out of that stage of the continuum with a probability of 8%. Those who link to care wait an additional 3.7 months on average before getting their second set of laboratory results (indicating engagement in care) or dropping out of care with probability of almost 6%. Those engaged in care spent an average of almost 1 year before achieving viral suppression on antiretroviral therapy or dropping out with average probability 13%. For patients who achieved viral suppression, the average time suppressed on antiretroviral therapy was an average of 4.5 years. Conclusions: Interventions should be targeted to more rapidly identifying newly infected individuals, and increasing the fraction of those engaged in care that achieves viral suppression. [ABSTRACT FROM AUTHOR]

Objectives: To estimate mortality rates and prognostic factors in HIV-positive patients who started combination antiretroviral therapy between 1996–1999 and survived for more than ten years. Methods: We used data from 18 European and North American HIV cohort studies contributing to the Antiretroviral Therapy Cohort Collaboration. We followed up patients from ten years after start of combination antiretroviral therapy. We estimated overall and cause-specific mortality rate ratios for age, sex, transmission through injection drug use, AIDS, CD4 count and HIV-1 RNA. Results: During 50,593 person years 656/13,011 (5%) patients died. Older age, male sex, injecting drug use transmission, AIDS, and low CD4 count and detectable viral replication ten years after starting combination antiretroviral therapy were associated with higher subsequent mortality. CD4 count at ART start did not predict mortality in models adjusted for patient characteristics ten years after start of antiretroviral therapy. The most frequent causes of death (among 340 classified) were non-AIDS cancer, AIDS, cardiovascular, and liver-related disease. Older age was strongly associated with cardiovascular mortality, injecting drug use transmission with non-AIDS infection and liver-related mortality, and low CD4 and detectable viral replication ten years after starting antiretroviral therapy with AIDS mortality. Five-year mortality risk was <5% in 60% of all patients, and in 30% of those aged over 60 years. Conclusions: Viral replication, lower CD4 count, prior AIDS, and transmission via injecting drug use continue to predict higher all-cause and AIDS-related mortality in patients treated with combination antiretroviral therapy for over a decade. Deaths from AIDS and non-AIDS infection are less frequent than deaths from other non-AIDS causes. [ABSTRACT FROM AUTHOR]

A letter to the editor and a response from the authors of the article "Prenatal Screening and Perinatal HIV Transmission in Northern Alberta" in a 2009 issue is presented.

Introduction Preclinical assessment for alterations in cardiac ventricular function for drug candidates has not been a focus of ICH S7b guidelines for cardiovascular safety studies, but there is growing interest given that the cardiovascular risk is associated with positive and negative inotropes. Methods From 2003 through 2013, 163 telemetry studies with left-ventricular function analyses were conducted in dogs and monkeys at Bristol Myers Squibb (BMS) in support for drug development programs. The ability of the telemetry system to detect changes in cardiac contractility was verified with positive control agents pimobendan and atenolol. Control data from a subset of studies were analyzed to determine dP/dt reference range values, and minimum detectable mean differences (control vs. treated) for statistical significance. Results Median minimum detectable differences for dogs ranged from 14 to 21% for positive dP/dt and 11 to 21% for negative dP/dt. For monkeys, median minimum detectable differences were 25 and 14% for positive and negative dP/dt, respectively. For BMS programs, 15 drug candidates were identified that produced primary effects on contractility. Changes in contractility that were associated with, and potentially secondary to, drug-related effects on heart rate or systemic blood pressure were observed with an additional 29 drug candidates. Discussion Changes in contractility have been observed in large animals during drug development studies at BMS over the past 10 years. Model sensitivity has been demonstrated and a dP/dt beat-to-beat cloud analysis tool has been developed to help distinguish primary effects from those potentially secondary to systemic hemodynamic changes. [ABSTRACT FROM AUTHOR]

Rett Syndrome (RTT) is a severe neurodevelopmental disorder characterized by an apparently normal development followed by an arrest and subsequent regression of cognitive and psychomotor abilities. At present, RTT has no definitive cure and the treatment of RTT represents a largely unmet clinical need. Following partial elucidation of the underlying neurobiology of RTT, a new treatment has been proposed, Mecasermin (recombinant human Insulin-Like Growth Factor 1), which, in addition to impressive evidence from preclinical murine models of RTT, has demonstrated safety in human studies of patients with RTT. The present clinical study examines the disease severity as assessed by clinicians (International Scoring System: ISS), social and cognitive ability assessed by two blinded, independent observers (RSS: Rett Severity Score), and changes in brain activity (EEG) parameters of ten patients with classic RTT and ten untreated patients matched for age and clinical severity. Significant improvement in both the ISS (p=0.0106) and RSS (p=0.0274) was found in patients treated with IGF1 in comparison to untreated patients. Analysis of the novel RSS also suggests that patients treated with IGF1 have a greater endurance to social and cognitive testing. The present clinical study adds significant preliminary evidence for the use of IGF-1 in the treatment of RTT and other disorders of the autism spectrum. [ABSTRACT FROM AUTHOR]

The identification of subjects at high risk for Alzheimer's disease is important for prognosis and early intervention. We investigated the polygenic architecture of Alzheimer's disease and the accuracy of Alzheimer's disease prediction models, including and excluding the polygenic component in the model. This study used genotype data from the powerful dataset comprising 17 008 cases and 37 154 controls obtained from the International Genomics of Alzheimer's Project (IGAP). Polygenic score analysis tested whether the alleles identified to associate with disease in one sample set were significantly enriched in the cases relative to the controls in an independent sample. The disease prediction accuracy was investigated in a subset of the IGAP data, a sample of 3049 cases and 1554 controls (for whom APOE genotype data were available) by means of sensitivity, specificity, area under the receiver operating characteristic curve (AUC) and positive and negative predictive values. We observed significant evidence for a polygenic component enriched in Alzheimer's disease (P = 4.9 × 10(-26)). This enrichment remained significant after APOE and other genome-wide associated regions were excluded (P = 3.4 × 10(-19)). The best prediction accuracy AUC = 78.2% (95% confidence interval 77-80%) was achieved by a logistic regression model with APOE, the polygenic score, sex and age as predictors. In conclusion, Alzheimer's disease has a significant polygenic component, which has predictive utility for Alzheimer's disease risk and could be a valuable research tool complementing experimental designs, including preventative clinical trials, stem cell selection and high/low risk clinical studies. In modelling a range of sample disease prevalences, we found that polygenic scores almost doubles case prediction from chance with increased prediction at polygenic extremes. [ABSTRACT FROM AUTHOR]

Symptoms of attention deficit hyperactivity disorder (ADHD) in children often persist into adulthood and can lead to severe antisocial behavior. However, to-date it remains unclear whether neuro-functional abnormalities cause ADHD, which in turn can then provide a marker of persistent ADHD. Using event-related functional magnetic resonance imaging (fMRI), we measured blood oxygenation level dependent (BOLD) signal changes in subjects during a reversal learning task in which choice of the correct stimulus led to a probabilistically determined 'monetary' reward or punishment. Participants were diagnosed with ADHD during their childhood ( N = 32) and were paired with age, gender, and education matched healthy controls ( N = 32). Reassessment of the ADHD group as adults resulted in a split between either persistent (persisters, N = 17) or remitted ADHDs (remitters, N = 15). All three groups showed significantly decreased activation in the medial prefrontal cortex (PFC) and the left striatum during punished correct responses, however only remitters and controls presented significant psycho-physiological interaction between these fronto-striatal reward and outcome valence networks. Comparing persisters to remitters and controls showed significantly inverted responses to punishment ( P < 0.05, family-wise error corrected) in left PFC region. Interestingly, the decreased activation shown after punishment was located in different areas of the PFC for remitters compared with controls, suggesting that remitters might have learned compensation strategies to overcome their ADHD symptoms. Thus, fMRI helps understanding the neuro-functional basis of ADHD related behavior differences and differentiates between persistent and remittent ADHD. Hum Brain Mapp 36:4648-4663, 2015. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article related to the treatment of telaprevir-based therapy for HIV/hepatitis C coinfected patients.

Background: The aim of the present study was to investigate the association of fMRI blood oxygen--level dependent (BOLD) reactivity with the level of epigenetic methylation of SLC6A4 in blood DNA from a sample of healthy participants and patients with major depressive disorder (MDD). Methods: We investigated patients with MDD and healthy controls using fMRI and an emotional attention-shifting task. We assessed site-specific DNA methylation of a previously characterized SLC6A4 region in peripheral blood DNA using pyro-sequencing. Results: Our study involved 25 patients with MDD and 35 healthy controls. Activation in the anterior insula elicited by negative emotional content was significantly positively associated with the degree of SLC6A4 methylation. Significantly negative associations were observed between activation in the posterior insula and the degree of SLC6A4 methylation when judging the geometry of pictures after seeing negative in contrast to positive emotional stimuli. Healthy controls with a high degree of SLC6A4 methylation depicted significantly more activity elicited by positive stimuli in limbic regions and more activity elicited by negative stimuli in limbic as well as cognitive control regions than those with a low degree of SLC6A4 methylation. Limitations: It is impossible to measure methylation directly in the brain and thus we assessed peripheral methylation of SLC6A4. Since the association was cross-sectional, no conclusion about cause and effect can be drawn. Conclusion: Our study provides further support to the hypothesis that particular DNA methylation states that are associated with brain function during emotion processing are detectable in the periphery. [ABSTRACT FROM AUTHOR]