ORCID Profile
0000-0003-2085-9851
Current Organisation
Baylor College of Medicine
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Publisher: Cold Spring Harbor Laboratory
Date: 09-12-2018
DOI: 10.1101/490649
Abstract: Mucosal-associated invariant T (MAIT) cells are MR1-restricted innate-like T cells conserved across mammalian species, including mice and humans. By sequencing RNA from sorted MR1-5-OP-RU tetramer + cells derived from either human blood or murine lungs, we define the basic transcriptome of an activated MAIT cell in both species and demonstrate how this profile changes during resolution and reinfection phases of infection. We observe strong similarities between MAIT cells in humans and mice. Compared with previously published T cell transcriptomes, MAIT cells displayed most similarity to iNKT cells when activated, but to γδ T cells, after resolution of infection. In both species activation leads to strong expression of pro-inflammatory cytokines and chemokines, and also a strong tissue repair signature, recently described in murine commensal-specific H2-M3-restricted T cells. These data define the requirements for, and consequences of, MAIT cell activation, revealing a tissue repair phenotype expressed upon MAIT cell activation in both species.
Publisher: Public Library of Science (PLoS)
Date: 07-12-2011
Publisher: Springer Science and Business Media LLC
Date: 15-02-2018
DOI: 10.1038/S41419-018-0332-4
Abstract: Glucocorticoids (GCs) are potent anti-inflammatory drugs whose mode of action is complex and still debatable. One likely cellular target of GCs are monocytes/macrophages. The role of GCs in monocyte survival is also debated. Although both granulocyte macrophage-colony stimulating factor (GM-CSF) and macrophage-CSF (M-CSF) are important regulators of macrophage lineage functions including their survival, the former is often associated with proinflammatory functions while the latter is important in lineage homeostasis. We report here that the GC, dexamethasone, induces apoptosis in GM-CSF-treated human monocytes while having no impact on M-CSF-induced monocyte survival. To understand how GCs, GM-CSF, and M-CSF are regulating monocyte survival and other functions during inflammation, we firstly examined the transcriptomic changes elicited by these three agents in human monocytes, either acting alone or in combination. Transcriptomic and Ingenuity pathway analyses found that dexamethasone differentially modulated dendritic cell maturation and TREM1 signaling pathways in GM-CSF-treated and M-CSF-treated monocytes, two pathways known to be regulated by ERK1/2 activity. These analyses led us to provide evidence that the GC inhibits ERK1/2 activity selectively in GM-CSF-treated monocytes to induce apoptosis. It is proposed that this inhibition of ERK1/2 activity leads to inactivation of p90 ribosomal-S6 kinase and Bad dephosphorylation leading in turn to enhanced caspase-3 activity and subsequent apoptosis. Furthermore, pharmacological inhibition of GC receptor activity restored the ERK1/2 signaling and prevented the GC-induced apoptosis in GM-CSF-treated monocytes. Increased tissue macrophage numbers, possibly from enhanced survival due to mediators such as GM-CSF, can correlate with inflammatory disease severity also reduction in these numbers can correlate with the therapeutic benefit of a number of agents, including GCs. We propose that the ERK1/2 signaling pathway promotes survival of GM-CSF-treated proinflammatory monocytes, which can be selectively targeted by GCs as a novel mechanism to reduce local monocyte/macrophage numbers and hence inflammation.
Publisher: Public Library of Science (PLoS)
Date: 29-01-2016
Publisher: Cold Spring Harbor Laboratory
Date: 05-02-2020
DOI: 10.1101/2020.02.03.933218
Abstract: Naive CD8 + T cell activation results in an autonomous program of cellular proliferation and differentiation. However, the mechanisms that underpin this process are unclear. Here we profiled genome-wide changes in chromatin accessibility, gene transcription and the deposition of a key chromatin modification (H3K27me3) early after naive CD8 + T cell activation. Rapid upregulation of the histone demethylase, KDM6B, prior to first cell ision was required for initiating H3K27me3 removal at genes essential for subsequent T cell differentiation and proliferation. Inhibition of KDM6B-dependent H3K27me3 demethylation limited the magnitude of an effective primary virus-specific CD8 + T cell response and the formation of memory CD8 + T cell populations. Accordingly, we define the early spatio-temporal events underpinning early lineage-specific epigenetic reprogramming that is necessary for autonomous CD8 + T cell proliferation and differentiation.
Publisher: Rockefeller University Press
Date: 29-04-2021
DOI: 10.1084/JEM.20200940
Abstract: Tissue-resident memory T cells (TRM cells) are key elements of tissue immunity. Here, we investigated the role of the regulator of T cell receptor and cytokine signaling, Ptpn2, in the formation and function of TRM cells in skin. Ptpn2-deficient CD8+ T cells displayed a marked defect in generating CD69+ CD103+ TRM cells in response to herpes simplex virus type 1 (HSV-1) skin infection. This was accompanied by a reduction in the proportion of KLRG1− memory precursor cells and a transcriptional bias toward terminal differentiation. Of note, forced expression of KLRG1 was sufficient to impede TRM cell formation. Normalizing memory precursor frequencies by transferring equal numbers of KLRG1− cells restored TRM generation, demonstrating that Ptpn2 impacted skin seeding with precursors rather than downstream TRM cell differentiation. Importantly, Ptpn2-deficient TRM cells augmented skin autoimmunity but also afforded superior protection from HSV-1 infection. Our results emphasize that KLRG1 repression is required for optimal TRM cell formation in skin and reveal an important role of Ptpn2 in regulating TRM cell functionality.
Publisher: The American Association of Immunologists
Date: 05-2013
Abstract: The transcription factor inhibitor of DNA binding (Id)2 modulates T cell fate decisions, but the molecular mechanism underpinning this regulation is unclear. In this study we show that loss of Id2 cripples effector differentiation and instead programs CD8+ T cells to adopt a memory fate with increased Eomesodermin and Tcf7 expression. We demonstrate that Id2 restrains CD8+ T cell memory differentiation by inhibiting E2A-mediated direct activation of Tcf7 and that Id2 expression level mirrors T cell memory recall capacity. As a result of the defective effector differentiation, Id2-deficient CD8+ T cells fail to induce sufficient Tbx21 expression to generate short-lived effector CD8+ T cells. Our findings reveal that the Id2/E2A axis orchestrates T cell differentiation through the induction or repression of downstream transcription factors essential for effector and memory T cell differentiation.
Publisher: Oxford University Press (OUP)
Date: 08-09-2016
Abstract: Does the changing molecular profile of the endometrium during menstruation correlate with the histological profile of menstruation. We identified several genes not previously associated with menstruation on Day 2 of menstruation (early-menstruation), processes related to inflammation are predominantly up-regulated and on Day 4 (late-menstruation), the endometrium is predominantly repairing and regenerating. Menstruation is induced by progesterone withdrawal at the end of the menstrual cycle and involves endometrial tissue breakdown, regeneration and repair. Perturbations in the regulation of menstruation may result in menstrual disorders including abnormal uterine bleeding. Endometrial s les were collected by Pipelle biopsy on Days 2 (n = 9), 3 (n = 9) or 4 (n = 6) of menstruation. RNA was extracted from endometrial biopsies and analysed by genome wide expression Illumina Sentrix Human HT12 arrays. Data were analysed using 'Remove Unwanted Variation-inverse (RUV-inv)'. Ingenuity pathway analysis (IPA) and the Database for Annotation, Visualization and Integrated Discovery (DAVID) v6.7 were used to identify canonical pathways, upstream regulators and functional gene clusters enriched between Days 2, 3 and 4 of menstruation. Selected in idual genes were validated by quantitative PCR. Overall, 1753 genes were differentially expressed in one or more comparisons. Significant canonical pathways, gene clusters and upstream regulators enriched during menstrual bleeding included those associated with immune cell trafficking, inflammation, cell cycle regulation, extracellular remodelling and the complement and coagulation cascade. We provide the first evidence for a role for glutathione-mediated detoxification (glutathione-S-transferase mu 1 and 2 GSTM1 and GSTM2) during menstruation. The largest number of differentially expressed genes was between Days 2 and 4 of menstruation (n = 1176). We identified several genes not previously associated with menstruation including lipopolysaccharide binding protein, serpin peptidase inhibitor, clade B (ovalbumin), member 3 (SERPINB3) and -4 (SERPINB4), interleukin-17C (IL17C), V-set domain containing T-cell activation inhibitor 1 (VTCN1), proliferating cell nuclear antigen factor (KIAA0101/PAF), trefoil factor 3 (TFF3), laminin alpha 2 (LAMA2) and serine peptidase inhibitor, Kazal type 1 (SPINK1). Genes related to inflammatory processes were up-regulated on Day 2 (early-menstruation), and those associated with endometrial repair and regeneration were up-regulated on Day 4 (late-menstruation). Participants presented with a variety of endometrial pathologies related to bleeding status and other menstrual characteristics. These variations may also have influenced the menstrual process. The temporal molecular profile of menstruation presented in this study identifies a number of genes not previously associated with the menstrual process. Our findings provide valuable insight into the menstrual process and may present novel targets for therapeutic intervention in cases of endometrial dysfunction. All microarray data have been deposited in the public data repository Gene Expression Omnibus (GSE86003). Funding for this work was provided by a National Health and Medical Research Council of Australia (NHMRC) Project Grant APP1008553 to M.H., P.R. and J.G. M.H. is supported by an NHMRC Practitioner Fellowship. P.P. is supported by a NHMRC Early Career Fellowship. The authors have no conflict of interest to declare.
Publisher: Cold Spring Harbor Laboratory
Date: 30-05-2020
DOI: 10.1101/2020.05.29.124610
Abstract: The emergence of the COVID-19 pandemic has spurred a global rush to uncover basic biological mechanisms, to inform effective vaccine and drug development. Despite viral novelty, global sequencing efforts have already identified genomic variation across isolates. To enable easy exploration and spatial visualization of the potential implications of SARS-CoV-2 mutations on infection, host immunity and drug development we have developed COVID-3D ( biosig.unimelb.edu.au/covid3d/ ).
Publisher: Cold Spring Harbor Laboratory
Date: 03-10-2021
DOI: 10.1101/2021.10.03.462599
Abstract: Megabase-scale intervals of active, gene-rich and inactive, gene-poor chromatin are known to segregate, forming the A and B compartments. Fine mapping of the contents of these A and B compartments has been hitherto impossible, owing to the extraordinary sequencing depths required to distinguish between the long-range contact patterns of in idual loci, and to the computational complexity of the associated calculations. Here, we generate the largest published in situ Hi-C map to date, spanning 33 billion contacts. We also develop a computational method, dubbed PCA of Sparse, SUper Massive Matrices (POSSUMM), that is capable of efficiently calculating eigenvectors for sparse matrices with millions of rows and columns. Applying POSSUMM to our Hi-C dataset makes it possible to assign loci to the A and B compartment at 500 bp resolution. We find that loci frequently alternate between compartments as one moves along the contour of the genome, such that the median compartment interval is only 12.5 kb long. Contrary to the findings in coarse-resolution compartment profiles, we find that in idual genes are not uniformly positioned in either the A compartment or the B compartment. Instead, essentially all (95%) active gene promoters localize in the A compartment, but the likelihood of localizing in the A compartment declines along the body of active genes, such that the transcriptional termini of long genes ( kb) tend to localize in the B compartment. Similarly, nearly all active enhancers elements (95%) localize in the A compartment, even when the flanking sequences are comprised entirely of inactive chromatin and localize in the B compartment. These results are consistent with a model in which DNA-bound regulatory complexes give rise to phase separation at the scale of in idual DNA elements.
Publisher: Wiley
Date: 2021
DOI: 10.1002/CTI2.1336
Abstract: Although co‐expression of CD38 and HLA‐DR reflects T‐cell activation during viral infections, high and prolonged CD38 + HLA‐DR + expression is associated with severe disease. To date, the mechanism underpinning expression of CD38 + HLA‐DR + is poorly understood. We used mouse models of influenza A/H9N2, A/H7N9 and A/H3N2 infection to investigate mechanisms underpinning CD38 + MHC‐II + phenotype on CD8 + T cells. To further understand MHC‐II trogocytosis on murine CD8 + T cells as well as the significance behind the scenario, we used adoptively transferred transgenic OT‐I CD8 + T cells and A/H3N2‐SIINKEKL infection. Analysis of influenza‐specific immunodominant D b NP 366 + CD8 + T‐cell responses showed that CD38 + MHC‐II + co‐expression was detected on both virus‐specific and bystander CD8 + T cells, with increased numbers of both CD38 + MHC‐II + CD8 + T‐cell populations observed in immune organs including the site of infection during severe viral challenge. OT‐I cells adoptively transferred into MHC‐II −/− mice had no MHC‐II after infection, suggesting that MHC‐II was acquired via trogocytosis. The detection of CD19 on CD38 + MHC‐II + OT‐I cells supports the proposition that MHC‐II was acquired by trogocytosis sourced from B cells. Co‐expression of CD38 + MHC‐II + on CD8 + T cells was needed for optimal recall following secondary infection. Overall, our study demonstrates that both virus‐specific and bystander CD38 + MHC‐II + CD8 + T cells are recruited to the site of infection during severe disease, and that MHC‐II presence occurs via trogocytosis from antigen‐presenting cells. Our findings highlight the importance of the CD38 + MHC‐II + phenotype for CD8 + T‐cell recall.
Publisher: Springer Science and Business Media LLC
Date: 18-07-2004
DOI: 10.1038/NBT996
Publisher: Oxford University Press (OUP)
Date: 04-03-2008
DOI: 10.1093/BIOINFORMATICS/BTN084
Abstract: Motivation: Many secretory proteins are synthesized as inactive precursors that must undergo post-translational proteolysis in order to mature and become active. In the current study, we address the challenge of sequence-based discovery of proteolytic sites in secreted proteins using machine learning. Results: The results revealed that only half of the extracellular proteolytic sites are currently annotated, leaving over 3600 unannotated ones. Furthermore, we have found that only 6% of the unannotated sites are similar to known proteolytic sites, whereas the remaining 94% do not share significant similarity with any annotated proteolytic site. The computational challenges in these two cases are very different. While the precision in detecting the former group is close to perfect, only a mere 22% of the latter group were detected with a precision of 80%. The applicability of the classifier is demonstrated through members of the FGF family, in which we verified the conservation of physiologically-relevant proteolytic sites in homologous proteins. Contact: kliger@compugen.co.il yossef.kliger@gmail.com Supplementary information: Supplementary data are available at Bioinformatics online.
Publisher: American Society for Clinical Investigation
Date: 15-08-2016
DOI: 10.1172/JCI87828
Publisher: Cold Spring Harbor Laboratory
Date: 12-08-2021
DOI: 10.1101/2021.08.11.456030
Abstract: N6 -methyladenosine (m 6 A) is the most predominant internal mRNA modification in eukaryotes, recognised by its reader proteins (so-called m 6 A-readers) for regulating subsequent mRNA fates — splicing, export, localisation, decay, stability, and translation — to control several biological processes. Although a few m 6 A-readers have been identified, yet the list is incomplete. Here, we identify a new m 6 A-reader protein, Moloney leukaemia virus 10 homologue (MOV10), in the m 6 A pathway. MOV10 recognises m 6 A-containing mRNAs with a conserved GGm 6 ACU motif. Mechanistic studies uncover that MOV10 facilitates mRNA decay of its bound m 6 A-containing mRNAs in an m 6 A-dependent manner within the cytoplasmic processing bodies (P-bodies). Furthermore, MOV10 decays the Gsk-3ß mRNA through m 6 A that stabilises the ß-CATENIN expression of a WNT/ß-CATENIN signalling pathway to regulate downstream NANOG expression for maintaining the mouse embryonic stem cells (mESCs) state. Thus, our findings reveal how a newly identified m 6 A-reader, MOV10 mediates mRNA decay via m 6 A that impact embryonic stem cell biology.
Publisher: Elsevier BV
Date: 11-2020
Publisher: Cold Spring Harbor Laboratory
Date: 09-02-2021
DOI: 10.1101/2021.02.09.430410
Abstract: Although co-expression of CD38 and HLA-DR on CD8 + T cells reflects activation during influenza, SARS-CoV-2, Dengue, Ebola and HIV-1 viral infections, high and prolonged CD38 + HLA-DR + expression can be associated with severe and fatal disease outcomes. As the expression of CD38 + HLA-DR + is poorly understood, we used mouse models of influenza A/H7N9, A/H3N2 and A/H1N1 infection to investigate the mechanisms underpinning CD38 + MHC-II + phenotype on CD8 + T-cells. Our analysis of influenza-specific immunodominant D b NP 366 +CD8 + T-cell responses showed that CD38 + MHC-II + co-expression was detected on both virus-specific and bystander CD8 + T-cells, with increased numbers of both CD38 + MHC-II + CD8 + T-cell populations observed in the respiratory tract during severe infection. To understand the mechanisms underlying CD38 and MHC-II expression, we also used adoptively-transferred transgenic OT-I CD8 + T-cells recognising the ovalbumin-derived K b SIINFEKL epitope and A/H1N1-SIINKEKL infection. Strikingly, we found that OT-I cells adoptively-transferred into MHC-II −/− mice did not display MHC-II after influenza virus infection, suggesting that MHC-II was acquired via trogocytosis in wild-type mice. Additionally, detection of CD19 on CD38 + MHC II + OT-I cells further supports that MHC-II was acquired by trogocytosis, at least partially, sourced from B-cells. Our results also revealed that co-expression of CD38 + MHC II + on CD8 + T-cells was needed for the optimal recall ability following secondary viral challenge. Overall, our study provides evidence that both virus-specific and bystander CD38 + MHC-II + CD8 + T-cells are recruited to the site of infection during severe disease, and that MHC-II expression occurs via trogocytosis from antigen-presenting cells. Our findings also highlight the importance of the CD38 + MHC II + phenotype for CD8 + T-cell memory establishment and recall. Co-expression of CD38 and MHC-II on CD8 + T cells is recognized as a classical hallmark of activation during viral infections. High and prolonged CD38 + HLA-DR + expression, however, can be associated with severe disease outcomes and the mechanisms are unclear. Using our established influenza wild-type and transgenic mouse models, we determined how disease severity affected the activation of influenza-specific CD38 + MHC-II + CD8 + T cell responses in vivo and the antigenic determinants that drive their activation and expansion. Overall, our study provides evidence that both virus-specific and bystander CD38 + MHC-II + CD8 + T-cells are recruited to the site of infection during severe disease, and that MHC-II expression occurs, at least in part, via trogocytosis from antigen-presenting cells. Our findings also highlight the importance of the CD38 + MHC II + phenotype for CD8 + T-cell memory establishment and recall.
Publisher: Cold Spring Harbor Laboratory
Date: 29-07-2021
DOI: 10.1101/2021.07.28.454182
Abstract: Developmental and epileptic encephalopathies (DEEs) are a group of epilepsies with early onset and severe symptoms that sometimes lead to death. While a number of genes have been successfully implicated, it remains challenging to identify causative mutations within these genes from the background variation present in all in iduals due to disease heterogeneity. Our ability to detect likely pathogenic variants has continued to improve as in silico predictors of deleteriousness have advanced. We investigate their use in prioritising likely pathogenic variants in epileptic encephalopathy patient whole exome sequences and show that the inclusion of structure-based predictors of intolerance improve upon previous attempts to demonstrate enrichment within epilepsy genes.
Publisher: MDPI AG
Date: 07-03-2023
DOI: 10.3390/IJMS24065114
Abstract: Developmental and epileptic encephalopathies (DEEs) are a group of epilepsies with early onset and severe symptoms that sometimes lead to death. Although previous work successfully discovered several genes implicated in disease outcomes, it remains challenging to identify causative mutations within these genes from the background variation present in all in iduals due to disease heterogeneity. Nevertheless, our ability to detect possible pathogenic variants has continued to improve as in silico predictors of deleteriousness have advanced. We investigate their use in prioritising likely pathogenic variants in epileptic encephalopathy patients’ whole exome sequences. We showed that the inclusion of structure-based predictors of intolerance improved upon previous attempts to demonstrate enrichment within epilepsy genes.
Publisher: Humana Press
Date: 2013
DOI: 10.1007/978-1-62703-577-4_20
Abstract: Statistical matters form an integral part of a metabolomics experiment. In this chapter we describe several important aspects in the analysis of metabolomics data such as the removal of unwanted variation and the identification of differentially abundant metabolites, along with a number of other essential statistical considerations.
Publisher: Springer Science and Business Media LLC
Date: 2017
Abstract: Heavy menstrual bleeding (HMB) is a significant social and public health issue for menstruating women. Development of targeted treatments has been limited by poor understanding of local mechanisms underlying HMB. We aimed to determine how gene expression differs in menstrual phase endometrium from women with HMB. Menstrual phase endometrial biopsies were collected from women with (n = 7) and without (n = 10) HMB (regular menstrual cycles, no known pelvic pathology), as well as women with uterine fibroids (n = 7, n = 4 had HMB). Biopsies were analyzed using Illumina Sentrix Human HT12 arrays and data analyzed using "Remove Unwanted Variation-inverse". Ingenuity Pathway Analysis and the Database for Annotation, Visualization and Integrated Discovery v6.7 were used to identify gene pathways, functional gene clusters, and upstream regulators specific to the clinical groupings. In idual genes of interest were examined using quantitative polymerase chain reaction. In total, 829 genes were differentially expressed in one or more comparisons. Significant canonical pathways and gene clusters enriched in controls relative to both HMB and fibroid groups suggest the mechanisms responsible for HMB include modifications of the endometrial inflammatory or infection response. In contrast, differentially expressed genes in women with fibroids suggest modifications of hemoglobin, antigen processing, and the major histocompatibility complex (class II, beta chain) activity. In conclusion, HMB associated with fibroids may be regulated by different endometrial mechanisms from HMB in women without fibroids and from normal menstrual bleeding. These novel data provide numerous testable hypotheses that will advance our understanding of the mechanisms responsible for HMB.
Publisher: SAGE Publications
Date: 2012
Abstract: In this paper we use the WASP-IV model to estimate the impact of internalizing several environmental external costs on the electricity sector's development plan. The major impact of internalizing the external cost is on fuel use. In the current electricity generation system, more natural gas and less coal have been used. A Cost Benefit Analysis (CBA) of three scenarios has been performed focusing on taxing only one pollutant and looking at its overall implication. The benefit cost ratio was in the range of 4.32 – 5.57 while the net benefit was estimated to be in the range of 82–341 million USD annually. Greenhouse gases (GHG) contribute about 25% of these estimates hence ancillary benefits are large enough to justify reducing those gases by between 7–12 percents compared to the baseline projection. We also carried a multi-objective analysis among the different scenarios. The weights were on the 3 pollutants (NOx, SO 2 and PM) and CO 2 . Seven scenarios appear in the non-dominated set. Out of them, five appear in every year and hence policy makers ought to place higher weights on them. Out of those five, two are a single tax on one pollutant. Interestingly, most of the non-dominating strategies carry a 0 weight on CO 2 . This gives another justification to internalize externalities based on only local pollutants and so disregards the debate over the desirability of GHG reduction.
Publisher: Cold Spring Harbor Laboratory
Date: 08-09-2016
DOI: 10.1101/073676
Abstract: Until recently, 13 C-based flux analyses have almost exclusively relied on analysis of labelled amino acids in proteins. This approach is not directly applicable to Leishmania , as these parasites scavenge most of their amino acids from the media. Leishmania are also unusual in that they i) share little genomic similarity with other organisms ii) constitutively express their metabolic genes and iii) display minimal changes in the enzyme levels throughout their life cycle stages. The three factors have contributed to an early development of comprehensive and reproducible 13 C-based metabolomics approaches in these parasites. The work presented here contributes to the creation of new 13 C-based metabolic flux approaches based on the isotopologue analysis of free metabolite pools in Leishmania mexicana . Namely, a new approach is presented for simultaneous calculation of in vivo fractional fluxes (or flux ratios) into two or more metabolite nodes with carbon dioxide condensation, based on isotopologue analysis of free metabolite pools. This method is used to perform the first quantitative in vivo fractional flux calculation of central carbon metabolism in any human parasite.
Publisher: SAGE Publications
Date: 10-11-2012
Abstract: Supporting the family-as-a-whole presents challenges in palliative care, although family meetings are increasingly used in routine practice. The Family Focused Grief Therapy (FFGT) Model guides clinicians in using a range of intervention strategies. To examine the therapists’ techniques used in assessing ‘at risk’ families in palliative care to better illuminate what helps and what remains challenging. Recorded sessions 1 and 2 were coded using the FFGT fidelity coding measure, with its glossary of definitions. Inter-rater reliability between three coders was satisfactory at 88%. Frequencies of strategy utilization were computed, with extraction of ex les of both successful and problematic approaches. From within a larger study of family therapy during palliative care at a comprehensive cancer center, the first two sessions ( n = 144) delivered to 74 families (299 in iduals) by 32 therapists were coded and analyzed. Therapists readily explored the story of illness and families’ ways of coping (97%) and assessed communication and cohesiveness in the majority. Exploration of relational patterns occurred in 89% of sessions, use of a genogram in 80%, understanding members’ roles in 65% and family values and beliefs in 62%. Less use was made of summaries (39%), family mottos (34%), exploration of family conflict (35%) and the formalization of a comprehensive family treatment plan (20%). Challenges exist in therapy with difficult families. Therapy in the home brings special issues. Therapists can apply most of the interventions prescribed by the FFGT model.
Publisher: Proceedings of the National Academy of Sciences
Date: 20-02-2019
Abstract: Promoting effective CD8 + T cell memory is a primary goal of T cell-based vaccination and immunotherapy strategies. While it is well established that CD4 + T cell help is required for enduring CD8 + T cell memory, how such help contributes to establishing optimal CD8 + T cell memory generation and persistence remains unclear. In this study, we demonstrate that CD4 + help at the time of priming ensures that memory CD8 + T cells are programmed to engage metabolic biological pathways essential for effective recall responses. Such understanding has clear implications for the augmentation of vaccine therapies designed to promote protective T cell immunity.
Publisher: Cold Spring Harbor Laboratory
Date: 04-03-2020
DOI: 10.1101/2020.03.02.973958
Abstract: Influenza virus is a major human health threat. Neutralizing antibodies elicited through prior infection or vaccination play an irreplaceable role in protection from subsequent infection. The efficacy of antibody-dependent vaccines relies on both virus replication and neutralization, but their quantitative relationship was unknown. Here we use mathematical models to quantitatively investigate viral survivability determined by antibody concentration and inocula size. We performed focus reduction assays for 49 seasonal influenza A/H3N2 viruses circulating during 2017–2019 against influenza antisera raised in ferrets, and find that the antibody consumption rates of in idual reactions were either small or large, and this was strongly positively correlated with virus saturation. Regardless of antibody consumption rate, virus-antibody interactions always lead to antibody-induced bistable viral kinetics. As a result, at a specific interval of antibody concentration, small viral inocula are eliminated but not large virus inocula, which is triggered by saturated virus neutralization or antibody consumption. Our finding highlights virus-antibody interaction with different antigenic properties, thereby explaining commonly observed influenza re-infection and enhancing vaccine efficiency.
Publisher: Elsevier BV
Date: 07-2011
Publisher: American Society for Microbiology
Date: 15-03-2019
DOI: 10.1128/JVI.01986-18
Abstract: Airway epithelial cells (AEC) and airway macrophages (AM) represent major targets of influenza A virus (IAV) infection in the lung, yet the two cell types respond very differently to IAV infection. We have used RNA sequencing to define the host transcriptional responses in each cell type under steady-state conditions as well as following IAV infection. To do this, different cell subsets isolated from the lungs of mock- and IAV-infected mice were subjected to RNA sequencing. Under steady-state conditions, AM and AEC express distinct transcriptional activities, consistent with distinct physiological roles in the airways. Not surprisingly, these cells also exhibited major differences in transcriptional responses following IAV infection. These studies shed light on how the different transcriptional architectures of airway cells from two different lineages drive transcriptional responses to IAV infection.
Publisher: Georg Thieme Verlag KG
Date: 2012
Abstract: Estrogens are frequently used in reproductive medicine. The Women's Health Initiative trial found that the risks of menopausal hormone therapy (MHT) exceed the benefits. The estrogens in MHT, however, were introduced prior to our understanding of the mechanism of action of estrogens. Estrogen signaling is highly complex, involving various DNA regulatory elements to which estrogen receptors bind. Numerous transcription factors and co-regulatory proteins modify chromatin structure to further regulate gene transcription. With a greater understanding of estrogen action, the major problem with the current estrogens in MHT appears to be that they are nonselective. This produces beneficial effects in bone, brain, and adipose tissue but increases the risk of breast and endometrial cancer and thromboembolism. Resurrecting MHT for long-term therapy will require the development of more selective estrogens, such as estrogen receptor (ER)β-selective estrogens and tissue-selective ERα agonists. These compounds will offer the best prospects to expand the indications of MHT and thus prevent the chronic conditions associated with menopause.
Publisher: Wiley
Date: 13-07-2022
DOI: 10.1111/IMCB.12566
Abstract: Special AT‐binding protein 1 (SATB1) is a chromatin‐binding protein that has been shown to be a key regulator of T‐cell development and CD4 + T‐cell fate decisions and function. The underlying function for SATB1 in peripheral CD8 + T‐cell differentiation processes is largely unknown. To address this, we examined SATB1‐binding patterns in naïve and effector CD8 + T cells demonstrating that SATB1 binds to noncoding regulatory elements linked to T‐cell lineage–specific gene programs, particularly in naïve CD8 + T cells. We then assessed SATB1 function using N ‐ethyl‐ N ‐nitrosourea‐mutant mice that exhibit a point mutation in the SATB1 DNA‐binding domain (termed Satb1 m1Anu/m1Anu ). Satb1 m1Anu/m1Anu mice exhibit diminished SATB1‐binding, naïve, Satb1 m1Anu/m1Anu CD8 + T cells exhibiting transcriptional and phenotypic characteristics reminiscent of effector T cells. Upon activation, the transcriptional signatures of Satb1 m1Anu/m1Anu and wild‐type effector CD8 + T cells converged. While there were no overt differences, primary respiratory infection of Satb1 m1Anu/m1Anu mice with influenza A virus (IAV) resulted in a decreased proportion and number of IAV‐specific CD8 + effector T cells recruited to the infected lung when compared with wild‐type mice. Together, these data suggest that SATB1 has a major role in an appropriate transcriptional state within naïve CD8 + T cells and ensures appropriate CD8 + T‐cell effector gene expression upon activation.
Publisher: The American Association of Immunologists
Date: 15-08-2019
Abstract: Virus infection triggers large-scale changes in the phenotype and function of naive CD8+ T cells, resulting in the generation of effector and memory T cells that are then critical for immune clearance. The T-BOX family of transcription factors (TFs) are known to play a key role in T cell differentiation, with mice deficient for the TF T-BET (encoded by Tbx21) unable to generate optimal virus-specific effector responses. Although the importance of T-BET in directing optimal virus-specific T cell responses is accepted, the precise timing and molecular mechanism of action remains unclear. Using a mouse model of influenza A virus infection, we demonstrate that although T-BET is not required for early CD8+ T cell activation and cellular ision, it is essential for early acquisition of virus-specific CD8+ T cell function and sustained differentiation and expansion. Whole transcriptome analysis at this early time point showed that Tbx21 deficiency resulted in global dysregulation in early programming events with inappropriate lineage-specific signatures apparent with alterations in the potential TF binding landscape. Assessment of histone posttranslational modifications within the Ifng locus demonstrated that Tbx21−/− CD8+ T cells were unable to activate “poised” enhancer elements compared with wild-type CD8+ T cells, correlating with diminished Ifng transcription. In all, these data support a model whereby T-BET serves to promote appropriate chromatin remodeling at specific gene loci that underpins appropriate CD8+ T cell lineage–specific commitment and differentiation.
Publisher: Elsevier BV
Date: 03-2021
DOI: 10.1016/J.CELREP.2021.108839
Abstract: Naive CD8
Publisher: Elsevier BV
Date: 12-2017
DOI: 10.1016/J.CELREP.2017.11.097
Abstract: Infection triggers large-scale changes in the phenotype and function of T cells that are critical for immune clearance, yet the gene regulatory mechanisms that control these changes are largely unknown. Using ChIP-seq for specific histone post-translational modifications (PTMs), we mapped the dynamics of ∼25,000 putative CD8
Publisher: Frontiers Media SA
Date: 28-04-2022
DOI: 10.3389/FCIMB.2022.855290
Abstract: Latent HIV-1 provirus in infected in iduals on suppressive therapy does not always remain transcriptionally silent. Both HIV-1 LTR and human gene promoter derived transcriptional events can contribute HIV-1 sequences to the mRNA produced in the cell. In addition, chimeric cellular:HIV mRNA can arise through readthrough transcription and aberrant splicing. Using target enrichment coupled to the Illumina Mi-Seq and PacBio RS II platforms, we show that 3’ LTR activation is frequent in latently infected cells from both the CCL19-induced primary cell model of HIV-1 latency as well as ex vivo s les. In both systems of latent HIV-1 infection, we detected several chimeric species that were generated via activation of a cryptic splice donor site in the 5’ LTR of HIV-1. Aberrant splicing involving the major HIV-1 splice donor sites, SD1 and SD4 disrupts post-transcriptional processing of the gene in which HIV-1 is integrated. In the primary cell model of HIV-1 latency, Tat-encoding sequences are incorporated into the chimeric mRNA transcripts through the use of SD4. Our study unravels clues to the characteristics of HIV-1 integrants that promote formation of chimeric cellular:HIV mRNA and improves the understanding of the HIV-1 RNA footprint in latently infected cells.
Publisher: Informa UK Limited
Date: 04-1990
DOI: 10.1057/ORI.1990.14
Publisher: Cold Spring Harbor Laboratory
Date: 22-11-2019
DOI: 10.1101/851683
Abstract: Regulatory elements (REs) consist of enhancers and promoters that occupy a significant portion of the non-coding genome and control gene expression programs either in –cis or in – trans . Putative REs have been identified largely based on their regulatory features (co-occupancy of ESC-specific transcription factors, enhancer histone marks and DNase hypersensitivity) in mouse embryonic stem cells (mESCs). However, less has been established regarding their regulatory functions in their native context. We deployed cis- and trans- regulatory elements scanning through saturating mutagenesis and sequencing (ctSCAN-SMS) to target elements within the ∼12kb cis -region ( Cis- REs CREs) of the Oct4 gene locus, as well as genome-wide 2,613 high-confidence trans- REs (TREs), in mESCs. ctSCAN-SMS identified 10 CREs and 12 TREs, as novel candidate REs of the Oct4 gene in mESCs. Furthermore, deletions of these candidate REs confirmed that the majority of the REs are functionally active, and CREs are more active than TREs in controlling Oct4 gene expression. A subset of active CREs and TREs physically interact with the Oct4 promoter to varying degrees specifically, a greater number of active CREs compared to active TREs, physically interact with the Oct4 promoter. Moreover, comparative genomics analysis reveals that more number of active CREs than active TREs are evolutionary conserved between mouse and primates, including human. Taken together, our study demonstrates the reliability and robustness of ctSCAN-SMS screening to identify critical REs, and investigate their roles in the regulation of transcriptional output of a target gene (in this case Oct4) in their native context.
Publisher: Elsevier BV
Date: 08-2021
Publisher: Springer Science and Business Media LLC
Date: 04-01-2021
Publisher: Wiley
Date: 24-11-2015
Abstract: Numerous studies have focused on the molecular regulation of perforin (PFP) and granzyme B (GZMB) expression by activated cytotoxic T lymphocytes (CTLs), but little is known about the molecular factors that underpin granzyme A (GZMA) expression. In vitro activation of naïve CD8(+) T cells, in the presence of IL-4, enhanced STAT6-dependent GZMA expression and was associated with GATA3 binding and enrichment of transcriptionally permissive histone posttranslational modifications (PTMs) across the Gzma gene locus. While GZMA expression by effector influenza A virus specific CTLs was also associated with a similar permissive epigenetic signature, memory CTL lacked enrichment of permissive histone PTMs at the Gzma locus, although this was restored within recalled secondary effector CTLs. Importantly, GZMA expression by virus-specific CTLs was associated with GATA3 binding at the Gzma locus, and independent of STAT6-mediated signaling. This suggests regulation of GZMA expression is underpinned by differentiation-dependent regulation of chromatin composition at the Gzma locus and that, given GATA3 is key for CTL differentiation in response to infection, GATA3 expression is regulated by a distinct, IL-4 independent, signaling pathway. Overall, this study provides insights into the molecular mechanisms that control transcription of Gzma during virus-induced CD8(+) T-cell differentiation.
Publisher: Cold Spring Harbor Laboratory
Date: 06-04-2023
DOI: 10.1101/2023.04.04.535623
Abstract: The Encyclopedia of DNA elements (ENCODE) project is a collaborative effort to create a comprehensive catalog of functional elements in the human genome. The current database comprises more than 19000 functional genomics experiments across more than 1000 cell lines and tissues using a wide array of experimental techniques to study the chromatin structure, regulatory and transcriptional landscape of the Homo sapiens and Mus musculus genomes. All experimental data, metadata, and associated computational analyses created by the ENCODE consortium are submitted to the Data Coordination Center (DCC) for validation, tracking, storage, and distribution to community resources and the scientific community. The ENCODE project has engineered and distributed uniform processing pipelines in order to promote data provenance and reproducibility as well as allow interoperability between genomic resources and other consortia. All data files, reference genome versions, software versions, and parameters used by the pipelines are captured and available via the ENCODE Portal. The pipeline code, developed using Docker and Workflow Description Language (WDL openwdl.org/ ) is publicly available in GitHub, with images available on Dockerhub ( hub.docker.com ), enabling access to a erse range of biomedical researchers. ENCODE pipelines maintained and used by the DCC can be installed to run on personal computers, local HPC clusters, or in cloud computing environments via Cromwell. Access to the pipelines and data via the cloud allows small labs the ability to use the data or software without access to institutional compute clusters. Standardization of the computational methodologies for analysis and quality control leads to comparable results from different ENCODE collections - a prerequisite for successful integrative analyses. Database URL: www.encodeproject.org/
Publisher: Springer Science and Business Media LLC
Date: 07-03-2016
DOI: 10.1038/NI.3410
Publisher: Springer Science and Business Media LLC
Date: 09-09-2020
Publisher: Springer Science and Business Media LLC
Date: 04-2013
No related grants have been discovered for Moshe Olshansky.