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BACKGROUND: Tumor necrosis factor alpha (TNF-alpha) mediates inflammation. High TNF-alpha production has adverse effects during disease. Polymorphisms in the TNF-alpha and lymphotoxin alpha genes influence TNF-alpha production. Fish oil suppresses TNF-alpha production and has variable antiinflammatory effects on disease. OBJECTIVE: We examined the relation between TNF-alpha and lymphotoxin alpha genotypes and the ability of dietary fish oil to suppress TNF-alpha production by peripheral blood mononuclear cells (PBMCs) in healthy men. DESIGN: Polymorphisms in the TNF-alpha (TNF*1 and TNF*2) and lymphotoxin alpha (TNFB*1 and TNFB*2) genes were determined in 111 healthy young men. TNF-alpha production by endotoxin-stimulated PBMCs was measured before and 12 wk after dietary supplementation with fish oil (6 g/d). RESULTS: Homozygosity for TNFB*2 was 2.5 times more frequent in the highest than in the lowest tertile of inherent TNF-alpha production. The percentage of subjects in whom fish oil suppressed TNF-alpha production was lowest (22%) in the lowest tertile and doubled with each ascending tertile. In the highest and lowest tertiles, mean TNF-alpha production decreased by 43% (P < 0.05) and increased by 160% (P < 0.05), respectively. In the lowest tertile of TNF-alpha production, only TNFB*1/TNFB*2 heterozygous subjects were responsive to the suppressive effect of fish oil. In the middle tertile, this genotype was 6 times more frequent than the other lymphotoxin alpha genotypes among responsive individuals. In the highest tertile, responsiveness to fish oil appeared unrelated to lymphotoxin alpha genotype. CONCLUSION: The ability of fish oil to decrease TNF-alpha production is influenced by inherent TNF-alpha production and by polymorphisms in the TNF-alpha and lymphotoxin alpha genes. Copyright © 2002 American Society for Clinical Nutrition [ABSTRACT FROM AUTHOR]

AIDS helplines provide an important public health service in disseminating information on HIV/AIDS, sexual risk behaviors, testing information, and situations that do not confer the risk of HIV acquisition. The Alaskan AIDS Assistance Association (AAAA) maintained a telephone helpline for the state of Alaska. This paper evaluated data collection efforts at this community-based organization. Data concerning the demographics of callers and topics and patterns of helpline utilization for the years 1991,1992,1995, and 1996 were investigated. Differences were found in topics of inquiry with respect to caller gender and time of day in which the call was logged, using correspondence analysis. Men were more likely to request information on HIV testing and safe-sex practices. Women were more likely to request information on other topics such as household transmission of HIV and information on transmission of HIV to children in settings such as childcare centers and schools. Knowledge of caller demographics and concerns has been used by AAAA to improve helpline services and volunteer training. Revelations concerning missing data have resulted in changes to data collection procedures. [ABSTRACT FROM AUTHOR]

Background: Cigarette smoke has both pro-inflammatory and immunosuppressive effects. Both active and passive cigarette smoke exposure are linked to an increased incidence and severity of respiratory virus infections, but underlying mechanisms are not well defined. We hypothesized, based on prior gene expression profiling studies, that upregulation of pro-inflammatory mediators by short term smoke exposure would be protective against a subsequent influenza infection.Methods: BALB/c mice were subjected to whole body smoke exposure with 9 cigarettes/day for 4 days. Mice were then infected with influenza A (H3N1, Mem71 strain), and analyzed 3 and 10 days later (d3, d10). These time points are the peak and resolution (respectively) of influenza infection.Results: Inflammatory cell influx into the bronchoalveolar lavage (BALF), inflammatory mediators, proteases, histopathology, viral titres and T lymphocyte profiles were analyzed. Compared to smoke or influenza alone, mice exposed to smoke and then influenza had more macrophages, neutrophils and total lymphocytes in BALF at d3, more macrophages in BALF at d10, lower net gelatinase activity and increased activity of tissue inhibitor of metalloprotease-1 in BALF at d3, altered profiles of key cytokines and CD4+ and CD8+ T lymphocytes, worse lung pathology and more virus-specific, activated CD8+ T lymphocytes in BALF. Mice smoke exposed before influenza infection had close to 10-fold higher lung virus titres at d3 than influenza alone mice, although all mice had cleared virus by d10, regardless of smoke exposure. Smoke exposure caused temporary weight loss and when smoking ceased after viral infection, smoke and influenza mice regained significantly less weight than smoke alone mice.Conclusion: Smoke induced inflammation does not protect against influenza infection.In most respects, smoke exposure worsened the host response to influenza. This animal model may be useful in studying how smoke worsens respiratory viral infections. [ABSTRACT FROM AUTHOR]

Activation of CD8 + T cells enable them to control virus infections and tumors. This process involves the differentiation of naïve CD8 + T cells into effector and memory states, driven by specific transcription factors (TFs). Previously, we have shown that Granzyme A (Gzma) induction in activated CD8 + T cells depends on Gata3 and the establishment of a permissive chromatin landscape at the Gzma locus. Interestingly, Gzma expression is independent of IL-4 signaling, which typically upregulates Gata3 in CD4 + T cells, suggesting an alternative pathway for Gata3 induction. Here we demonstrate that Notch signals during CD8 + T cell activation promote Gzma expression. Inhibition of Notch signaling or loss of the Notch transactivator Rbp-j leads to reduced Gzma expression, with transcriptionally repressive chromatin at the Gzma locus. The genome targets of Gata3 differ in effector CD8 + T cells activated with IL-4 compared with those activated with Notch signals or isolated after IAV infection. This indicates that the signals received during CD8 + T cell activation can alter the chromatin landscape, affecting Gata3 function. Furthermore, Gata3 deficiency results in reduced IAV-specific CD8 + T cell responses and decreased Gzma expression, although the Gzma locus maintains a permissive chromatin landscape. These findings suggest that Notch signals received by virus-specific CD8 + T cells prepare the chromatin landscape for Gata3 binding to CD8 + lineage-specific gene loci, promoting effective CD8 + T cell immunity., (© 2025 The Author(s). Immunology & Cell Biology published by John Wiley & Sons Australia, Ltd on behalf of the Australian and New Zealand Society for Immunology, Inc.)

Core-shell nanoparticles can exhibit strongly enhanced performances in electro-, photo- and thermal catalysis. Lattice strain plays a key role in this and is induced by the mismatch between the crystal structure of the core and the shell metal. However, investigating the impact of lattice strain has been challenging due to the lack of a material system in which lattice strain can be controlled systematically, hampering further progress in the field of core-shell catalysis. In this work, we achieve such a core-shell nanoparticle system through the colloidal synthesis of trimetallic Pt-shell Au 1- x Cu x -core nanoparticles. Our seed-mediated growth methodology yields well-defined Au 1- x Cu x -cores, tunable in composition from 0 at% Cu to 77 at% Cu, and monodisperse in size. Subsequent overgrowth results in uniform, epitaxially grown Pt-shells with a controlled thickness of ∼3 atomic layers. By employing a multi-technique characterization strategy combining X-ray diffraction, electron diffraction and aberration corrected electron microscopy, we unravel the atomic structure of the trimetallic system on a single nanoparticle-, ensemble- and bulk scale level, and we unambiguously demonstrate the controlled variation of strain in the Pt-shell from -3.62% compressive-, to +3.79% tensile strain, while retaining full control over all other structural characteristics of the system.

Unavoidable water formation during the reduction of solid catalyst precursors has long been known to influence the nanoparticle size and dispersion in the active catalyst. This in situ transmission electron microscopy study provides insight into the influence of water vapor at the nanoscale on the nucleation and growth of the nanoparticles (2-16 nm) during the reduction of a nickel phyllosilicate catalyst precursor under H 2 /Ar gas at 700 °C. Water suppresses and delays nucleation, but counterintuitively increases the rate of particle growth. After full reduction is achieved, water vapor significantly enhances Ostwald ripening which in turn increases the likelihood of particle coalescence. This study proposes that water leads to formation of mobile nickel hydroxide species, leading to faster rates of particle growth during and after reduction., (© 2024 The Authors. Small published by Wiley‐VCH GmbH.)

Objectives: Despite vaccination strategies, people with chronic kidney disease, particularly kidney transplant recipients (KTRs), remained at high risk of poor COVID-19 outcomes. We assessed serological responses to the three-dose COVID-19 vaccine schedule in KTRs and people on dialysis, as well as seroresponse predictors and the relationship between responses and breakthrough infection., Methods: Plasma from 30 KTRs and 17 people receiving dialysis was tested for anti-Spike receptor binding domain (RBD) IgG and neutralising antibodies (NAb) to the ancestral and Omicron BA.2 variant after Doses 2 and 3 of vaccination., Results: After three doses, KTRs achieved lower anti-Spike RBD IgG levels ( P  < 0.001) and NAb titres than people receiving dialysis ( P  = 0.002). Seropositive cross-reactive Omicron neutralisation levels were achieved in 11/27 (40.7%) KTRs and 11/14 (78.6%) dialysis recipients. ChAdOx1/viral-vector vaccine type, higher mycophenolate dose (> 1 g per day) and lower absolute B-cell counts predicted poor serological responses in KTRs. ChAdOx-1 vaccine type and higher monocyte counts were negative predictors in dialysis recipients. Among ancestral NAb seroresponders, higher NAb levels positively correlated with higher Omicron neutralisation ( R  = 0.9, P  < 0.001). More KTRs contracted SARS-CoV-2 infection (14/30; 47%) than dialysis recipients (5/17; 29%) and had more severe disease. Those with breakthrough infections had significantly lower median interdose incremental change in anti-Spike RBD IgG and ancestral NAb titres., Conclusion: Serological responses to COVID-19 vaccines in KTRs lag behind their dialysis counterparts. KTRs remained at high risk of breakthrough infection after their primary vaccination schedule underlining their need for booster doses, strict infection prevention measures and close surveillance., Competing Interests: MCvZ is an inventor on a patent related to this work. The other authors have no conflicts of interest to declare., (© 2024 The Author(s). Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)

The close bond that can exist between humans and their dogs is an important aspect of the evolutionary, economic, and social connections between the two species. There is a need for a better understanding of the place of the dog within the human-dog bond and on ways the human-dog bond affects dog welfare. We conducted a scoping review to investigate to what extent and in what ways dog welfare is addressed in the research literature on the human-dog bond. We identified 706 publications on the human-dog bond from across the globe that were published from 2012 to 2023. We found that 246 of these 706 publications had a focus on dog welfare. Our review showed that the interplay of characteristics and backgrounds of owners/handlers and their dogs was linked to dog welfare in multiple, both positive and negative, ways. Our review is limited by the fact that most of the research that we reviewed involved pet dogs and in majority came from Western, Educated, Industrialized, Rich, Democratic (WEIRD) societies. There is a need for a better understanding of how the human-dog bond affects the welfare of working, assistance, and service dogs.

A long-standing paradigm of arc geochemistry is that the trace element compositions of arc lavas arise from two compositionally distinct slab components: an aqueous dehydration fluid from the subducting igneous ocean crust that transports "fluid-mobile" elements, such as barium (Ba), and a sediment melt that supplies thorium (Th) and the light rare earth elements. This two-component framework has been widely called upon to explain global geochemical trends as well as geochemical variations within individual arcs, such as the Marianas. Here, we show that this paradigm is inconsistent with mass balance, due to the low Ba contents of igneous ocean crust, and with experimental data, which show that aqueous fluids from the igneous oceanic crust would be too dilute to substantially affect arc compositions. Observations previously attributed to the sediment melt/igneous-crust-fluid hypothesis are better explained by diverse subducting sediment compositions coupled with ambient mantle wedge heterogeneity, both globally and for the Marianas.

Speciation is often driven by selective processes like those associated with viability, mate choice, or local adaptation, and "speciation genes" have been identified in many eukaryotic lineages. In contrast, neutral processes are rarely considered as the primary drivers of speciation, especially over short evolutionary timeframes. Here, we describe a rapid vertebrate speciation event driven primarily by genetic drift. The White Sands pupfish ( Cyprinodon tularosa ) is endemic to New Mexico's Tularosa Basin where the species is currently managed as two Evolutionarily significant units (ESUs) and is of international conservation concern (Endangered). Whole-genome resequencing data from each ESU showed remarkably high and uniform levels of differentiation across the entire genome (global F ST ≈ 0.40). Despite inhabiting ecologically dissimilar springs and streams, our whole-genome analysis revealed no discrete islands of divergence indicative of strong selection, even when we focused on an array of candidate genes. Demographic modeling of the joint allele frequency spectrum indicates the two ESUs split only ~4 to 5 kya and that both ESUs have undergone major bottlenecks within the last 2.5 millennia. Our results indicate the genome-wide disparities between the two ESUs are not driven by divergent selection but by neutral drift due to small population sizes, geographic isolation, and repeated bottlenecks. While rapid speciation is often driven by natural or sexual selection, here we show that isolation and drift have led to speciation within a few thousand generations. We discuss these evolutionary insights in light of the conservation management challenges they pose., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background and Objectives: Pathogenic variants in GRIN2A are associated with a spectrum of epilepsy-aphasia syndromes (EASs). Seizures as well as speech and language disorders occur frequently but vary widely in severity, both between individuals and across the life span. The link between this phenotypic spectrum and brain characteristics is unknown. Specifically, altered brain networks at the root of speech and language deficits remain to be identified. Patients with pathogenic variants in GRIN2A offer an opportunity to interrogate the impact of glutamate receptor dysfunction on brain development., Methods: We characterized brain anomalies in individuals with pathogenic GRIN2A variants and EASs, hypothesizing alterations in perisylvian speech-language regions and the striatum. We compared structural MRI data from 10 individuals (3 children and 7 adults, 3 female) with pathogenic GRIN2A variants with data from age-matched controls (N = 51 and N = 203 in a secondary analysis). We examined cortical thickness and volume in 4 a priori hypothesized speech and language regions (inferior frontal, precentral, supramarginal, and superior temporal) and across the whole brain. Subcortical structures (hippocampus, basal ganglia, thalamus) and the corpus callosum were also compared., Results: Individuals with pathogenic GRIN2A variants showed increased thickness and volume in the posterior part of Broca's area (inferior frontal gyrus, pars opercularis). For thickness, the effects were bilateral but more pronounced in the left (large effect size, η 2 = 0.37) than the right (η 2 = 0.12) hemisphere. Both volume and thickness were also higher in the bilateral superior temporal region while the supramarginal region showed increased thickness only. Whole-brain analyses confirmed left-sided thickness increases in Broca's area, with additional increases in the occipital and superior frontal cortices bilaterally. Hippocampal volume was reduced in the left hemisphere. There were no age-dependent effects or corpus callosum group differences., Discussion: Anomalies in perisylvian regions, with largest differences in Broca's area, suggest an altered development of classical speech-language networks in GRIN2A -related EAS. Left hippocampal reduction suggests a role for this structure in early speech and language development and is consistent with GRIN2A gene expression in that region. Overall, elucidating the neural correlates of EAS provides insights into the impact of GRIN2A dysfunction, opening avenues for targeted intervention in developmental syndromes with compromised speech-language development., Competing Interests: The authors report no relevant disclosures. Go to Neurology.org/NG for full disclosures., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Point mutations in histone variant H3.3 (H3.3K27M, H3.3G34R) and the H3.3-specific ATRX/DAXX chaperone complex are frequent events in pediatric gliomas. These H3.3 point mutations affect many chromatin modifications but the exact oncogenic mechanisms are currently unclear. Histone H3.3 is known to localize to nuclear compartments known as promyelocytic leukemia (PML) nuclear bodies, which are frequently mutated and confirmed as oncogenic drivers in acute promyelocytic leukemia., Results: We find that the pediatric glioma-associated H3.3 point mutations disrupt the formation of PML nuclear bodies and this prevents differentiation down glial lineages. Similar to leukemias driven by PML mutations, H3.3-mutated glioma cells are sensitive to drugs that target PML bodies. We also find that point mutations in IDH1/2-which are common events in adult gliomas and myeloid leukemias-also disrupt the formation of PML bodies., Conclusions: We identify PML as a contributor to oncogenesis in a subset of gliomas and show that targeting PML bodies is effective in treating these H3.3-mutated pediatric gliomas., (© 2023. The Author(s).)

Stuttering is a common speech disorder that interrupts speech fluency and tends to cluster in families. Typically, stuttering is characterized by speech sounds, words or syllables which may be repeated or prolonged and speech that may be further interrupted by hesitations or 'blocks'. Rare variants in a small number of genes encoding lysosomal pathway proteins have been linked to stuttering. We studied a large four-generation family in which persistent stuttering was inherited in an autosomal dominant manner with disruption of the cortico-basal-ganglia-thalamo-cortical network found on imaging. Exome sequencing of three affected family members revealed the PPID c.808C>T (p.Pro270Ser) variant that segregated with stuttering in the family. We generated a Ppid p.Pro270Ser knock-in mouse model and performed ex vivo imaging to assess for brain changes. Diffusion-weighted MRI in the mouse revealed significant microstructural changes in the left corticospinal tract, as previously implicated in stuttering. Quantitative susceptibility mapping also detected changes in cortico-striatal-thalamo-cortical loop tissue composition, consistent with findings in affected family members. This is the first report to implicate a chaperone protein in the pathogenesis of stuttering. The humanized Ppid murine model recapitulates network findings observed in affected family members., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The differentiation of naive CD8 + T lymphocytes into cytotoxic effector and memory CTL results in large-scale changes in transcriptional and phenotypic profiles. Little is known about how large-scale changes in genome organization underpin these transcriptional programs. We use Hi-C to map changes in the spatial organization of long-range genome contacts within naive, effector, and memory virus-specific CD8 + T cells. We observe that the architecture of the naive CD8 + T cell genome is distinct from effector and memory genome configurations, with extensive changes within discrete functional chromatin domains associated with effector/memory differentiation. Deletion of BACH2, or to a lesser extent, reducing SATB1 DNA binding, within naive CD8 + T cells results in a chromatin architecture more reminiscent of effector/memory states. This suggests that key transcription factors within naive CD8 + T cells act to restrain T cell differentiation by actively enforcing a unique naive chromatin state., Competing Interests: Declaration of interests A.W.G. is a member of the scientific advisory board of ArsenalBio. No funding from ArsenalBio was provided for this work., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Glucocorticoids (GCs) are potent anti-inflammatory agents and are broadly used in treating rheumatoid arthritis (RA) patients, albeit with adverse side effects associated with long-term usage. The negative consequences of GC therapy provide an impetus for research into gaining insights into the molecular mechanisms of GC action. We have previously reported that granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced CCL17 has a non-redundant role in inflammatory arthritis. Here, we provide molecular evidence that GCs can suppress GM-CSF-mediated upregulation of IRF4 and CCL17 expression via downregulating JMJD3 expression and activity. In mouse models of inflammatory arthritis, GC treatment inhibited CCL17 expression and ameliorated arthritic pain-like behavior and disease. Significantly, GC treatment of RA patient peripheral blood mononuclear cells ex vivo resulted in decreased CCL17 production. This delineated pathway potentially provides new therapeutic options for the treatment of many inflammatory conditions, where GCs are used as an anti-inflammatory drug but without the associated adverse side effects., Competing Interests: JAH had a consulting role with GlaxoSmithKline., (© 2023 The Author(s).)

Understanding nanoparticle growth is crucial to increase the lifetime of supported metal catalysts. In this study, we employ in situ gas-phase transmission electron microscopy to visualize the movement and growth of ensembles of tens of nickel nanoparticles supported on carbon for CO 2 hydrogenation at atmospheric pressure (H 2 :CO 2 = 4:1) and relevant temperature (450 °C) in real time. We observe two modes of particle movement with an order of magnitude difference in velocity: fast, intermittent movement ( v max = 0.7 nm s -1 ) and slow, gradual movement ( v average = 0.05 nm s -1 ). We visualize the two distinct particle growth mechanisms: diffusion and coalescence, and Ostwald ripening. The diffusion and coalescence mechanism dominates at small interparticle distances, whereas Ostwald ripening is driven by differences in particle size. Strikingly, we demonstrate an interplay between the two mechanisms, where first coalescence takes place, followed by fast Ostwald ripening due to the increased difference in particle size. Our direct visualization of the complex nanoparticle growth mechanisms highlights the relevance of studying nanoparticle growth in supported nanoparticle ensembles under reaction conditions and contributes to the fundamental understanding of the stability in supported metal catalysts.

Cytokines that signal via STAT1 and STAT3 transcription factors instruct decisions affecting tissue homeostasis, antimicrobial host defense, and inflammation-induced tissue injury. To understand the coordination of these activities, we applied RNA sequencing, chromatin immunoprecipitation sequencing, and assay for transposase-accessible chromatin with high-throughput sequencing to identify the transcriptional output of STAT1 and STAT3 in peritoneal tissues from mice during acute resolving inflammation and inflammation primed to drive fibrosis. Bioinformatics focused on the transcriptional signature of the immunomodulatory cytokine IL-6 in both settings and examined how profibrotic IFN-γ-secreting CD4+ T cells altered the interpretation of STAT1 and STAT3 cytokine cues. In resolving inflammation, STAT1 and STAT3 cooperated to drive stromal gene expression affecting antimicrobial immunity and tissue homeostasis. The introduction of IFN-γ-secreting CD4+ T cells altered this transcriptional program and channeled STAT1 and STAT3 to a previously latent IFN-γ activation site motif in Alu-like elements. STAT1 and STAT3 binding to this conserved sequence revealed evidence of reciprocal cross-regulation and gene signatures relevant to pathophysiology. Thus, we propose that effector T cells retune the transcriptional output of IL-6 by shaping a regulatory interplay between STAT1 and STAT3 in inflammation., (Copyright © 2023 The Authors.)

Objectives: Influenza causes significant morbidity and mortality, especially in high-risk populations. Although current vaccination regimens are the best method to combat annual influenza disease, vaccine efficacy can be low in high-risk groups, such as haematopoietic stem cell transplant (HSCT) recipients., Methods: We comprehensively assessed humoral immunity, antibody landscapes, systems serology and influenza-specific B-cell responses, together with their phenotypes and isotypes, to the inactivated influenza vaccine (IIV) in HSCT recipients in comparison to healthy controls., Results: Inactivated influenza vaccine significantly increased haemagglutination inhibition (HAI) titres in HSCT recipients, similar to healthy controls. Systems serology revealed increased IgG1 and IgG3 antibody levels towards the haemagglutinin (HA) head, but not to neuraminidase, nucleoprotein or HA stem. IIV also increased frequencies of total, IgG class-switched and CD21 lo CD27 + influenza-specific B cells, determined by HA probes and flow cytometry. Strikingly, 40% of HSCT recipients had markedly higher antibody responses towards A/H3N2 vaccine strain than healthy controls and showed cross-reactivity to antigenically drifted A/H3N2 strains by antibody landscape analysis. These superior humoral responses were associated with a greater time interval after HSCT, while multivariant analyses revealed the importance of pre-existing immune memory. Conversely, in HSCT recipients who did not respond to the first dose, the second IIV dose did not greatly improve their humoral response, although 50% of second-dose patients reached a seroprotective HAI titre for at least one of vaccine strains., Conclusions: Our study demonstrates efficient, although time-dependent, immune responses to IIV in HSCT recipients, and provides insights into influenza vaccination strategies targeted to immunocompromised high-risk groups., Competing Interests: MK has acted as a consultant for Sanofi group of companies but not at the time the research was conducted. All other authors have declared that no conflict of interest exists., (© 2023 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)

Although the importance of genome organization for transcriptional regulation of cell-fate decisions and function is clear, the changes in chromatin architecture and how these impact effector and memory CD8 + T cell differentiation remain unknown. Using Hi-C, we studied how genome configuration is integrated with CD8 + T cell differentiation during infection and investigated the role of CTCF, a key chromatin remodeler, in modulating CD8 + T cell fates through CTCF knockdown approaches and perturbation of specific CTCF-binding sites. We observed subset-specific changes in chromatin organization and CTCF binding and revealed that weak-affinity CTCF binding promotes terminal differentiation of CD8 + T cells through the regulation of transcriptional programs. Further, patients with de novo CTCF mutations had reduced expression of the terminal-effector genes in peripheral blood lymphocytes. Therefore, in addition to establishing genome architecture, CTCF regulates effector CD8 + T cell heterogeneity through altering interactions that regulate the transcription factor landscape and transcriptome., Competing Interests: Declaration of interests A.W.G. is a member of the scientific advisory board of ArsenalBio. S.J.T. is a member of the scientific advisory board for Medicago, Inc., QC, Canada. No funding from Medicago or ArsenalBio was provided for this work., (Copyright © 2023 Elsevier Inc. All rights reserved.)

More than half the world's population is infected with human cytomegalovirus (HCMV), causing congenital birth defects and impacting the immuno-compromised. Many of the >170 HCMV genes remain uncharacterized, and this gap in knowledge limits the development of novel antivirals. In this study, we investigated the essential viral protein UL49 and found it displayed leaky late expression kinetics, and localized to nuclear replication compartments. Cells infected with mutant UL49 virus were unable to produce infectious virions and phenocopied other beta-gamma viral pre-initiation complex (vPIC) subunit (UL79, UL87, UL91, UL92, and UL95) mutant infections. RNA-seq analysis of vPIC mutant infections revealed a consistent diminution of genes encoding capsid subunits, including TRX2/UL85 and MCP/UL86, envelope glycoproteins gM, gL and gO, and egress-associated tegument proteins UL99 and UL103. Therefore, as a member of the vPIC, UL49 serves as a fundamental HCMV effector that governs viral gene transcription required to complete the replication cycle., Competing Interests: The authors have declared that no competing interests exist., (© 2022 The Authors.)