https://ogma.newcastle.edu.au/vital/access/ /manager/Index ${session.getAttribute("locale")} 5 https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:54520 5% O2. Through the generation of a germline-specific Epas1 knockout mouse line, and through modulation of EPAS1 levels in primary cultures of spermatogonia with the small drug molecule Daprodustat, we have demonstrated that EPAS1 is required for robust SSC function in regenerative conditions (post-transplantation and post-chemotherapy), via the regulation of key cellular processes such as metabolism. These findings shed light on the relationship between hypoxia and male fertility and will potentially facilitate optimization of in vitro culture conditions for infertility treatment pipelines using SSCs, such as those directed at pediatric cancer survivors.]]> Wed 28 Feb 2024 16:12:13 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:50942 Wed 28 Feb 2024 16:05:34 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:50960 Wed 28 Feb 2024 15:22:37 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:54995 Wed 27 Mar 2024 16:40:03 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:45285 Wed 26 Oct 2022 17:27:09 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:54882 Wed 20 Mar 2024 13:18:18 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:37510 Wed 19 Jan 2022 15:15:31 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:46366 in vivo may have disruptive therapeutic potential. Here, we demonstrate that the anti-emetic/anti-psychotic prochlorperazine can be repurposed to reversibly inhibit the in vivo endocytosis of membrane proteins targeted by therapeutic monoclonal antibodies, as directly demonstrated by our human tumor ex vivo assay. Temporary endocytosis inhibition results in enhanced target availability and improved efficiency of natural killer cell-mediated antibody-dependent cellular cytotoxicity (ADCC), a mediator of clinical responses induced by IgG1 antibodies, demonstrated here for cetuximab, trastuzumab, and avelumab. Extensive analysis of downstream signaling pathways ruled out on-target toxicities. By overcoming the heterogeneity of drug target availability that frequently characterizes poorly responsive or resistant tumors, clinical application of reversible endocytosis inhibition may considerably improve the clinical benefit of ADCC-mediating therapeutic antibodies.]]> Wed 16 Nov 2022 08:57:15 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:33813 Wed 16 Jan 2019 15:33:53 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:51041 Wed 16 Aug 2023 10:37:28 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:37079 Wed 15 Dec 2021 16:07:28 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:46821 CRKL. A total of 45 of the 62 variants were associated with increased risk for CTDs (odds ratio [OR) ranges: 1.64–4.75). Associations of four variants were replicated in a meta-analysis of three genome-wide association studies of CTDs in affected individuals without 22q11.2DS. One of the replicated variants, rs178252, is located in an open chromatin region and resides in the double-elite enhancer, GH22J020947, that is predicted to regulate CRKL (CRK-like proto-oncogene, cytoplasmic adaptor) expression. Approximately 23% of patients with nested LCR22C-D deletions have CTDs, and inactivation of Crkl in mice causes CTDs, thus implicating this gene as a modifier. Rs178252 and rs6004160 are expression quantitative trait loci (eQTLs) of CRKL. Furthermore, set-based tests identified an enhancer that is predicted to target CRKL and is significantly associated with CTD risk (GH22J020946, sequence kernal association test (SKAT) p = 7.21 × 10−5) in the 22q11.2DS cohort. These findings suggest that variance in CTD penetrance in the 22q11.2DS population can be explained in part by variants affecting CRKL expression.]]> Wed 13 Mar 2024 15:07:07 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:44101 Wed 13 Mar 2024 09:41:39 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:50257 Wed 12 Jul 2023 10:27:00 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:37064 30-billion USD, wildlife-based tourism industry. Population monitoring is an important component of wildlife conservation. Rafiq et al. demonstrate that tourist photographs can provide cost-effective, robust measures of wildlife densities that could be used toward species conservation efforts.]]> Wed 12 Aug 2020 12:52:44 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:52458 Wed 11 Oct 2023 15:01:14 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:38201 Wed 11 Aug 2021 10:05:47 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:35087 G) derived from the father introduce a premature STOP codon leading to a truncated protein. FANCM exhibits enhanced testicular expression. In control subjects, immunohistochemical staining localized FANCM to the Sertoli and spermatogenic cells of seminiferous tubules with increasing intensity through germ cell development. This is consistent with its role in maintaining genomic stability in meiosis and mitosis. In the individual with SCOS carrying bi-allelic FANCM LoF variants, none or only faint expression was detected in the Sertoli cells. As further evidence, we detected two additional NOA-affected case subjects with independent FANCM homozygous nonsense variants, one from Estonia (p.Gln1701*; rs147021911) and another from Portugal (p.Arg1931*; rs144567652). The study convincingly demonstrates that bi-allelic recessive LoF variants in FANCM cause azoospermia. FANCM pathogenic variants have also been linked with doubled risk of familial breast and ovarian cancer, providing an example mechanism for the association between infertility and cancer risk, supported by published data on Fancm mutant mouse models.]]> Wed 10 Nov 2021 15:05:36 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:53688 Wed 10 Jan 2024 10:34:54 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:33706 Wed 09 Mar 2022 16:04:33 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:30706 Wed 09 Feb 2022 15:55:57 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:50850 Wed 09 Aug 2023 09:39:07 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:51270 Wed 01 May 2024 15:33:21 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:28231 Wed 01 Aug 2018 14:52:20 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:50411 Tue 25 Jul 2023 17:30:33 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:51128 6,000 proteins, encompassing the selective loss and gain of several hundred proteins. Further, we demonstrate epididymal-driven activation of RHOA-mediated signaling pathways is an important component of sperm maturation. These data contribute molecular insights into the complexity of proteomic changes associated with epididymal sperm maturation.]]> Tue 22 Aug 2023 15:52:22 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:53306 Tue 21 Nov 2023 12:03:02 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:48554 Tue 21 Mar 2023 15:37:49 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:35953 G) as part of a common haplotype, in combination with different loss-of-function variants in trans. The intronic variant alters splicing, and together the biallelic mutations lead to cellular deficiency of Pol ε and delayed S-phase progression. In summary, we establish POLE as a second gene in which mutations cause IMAGe syndrome. These findings add to a growing list of disorders due to mutations in DNA replication genes that manifest growth restriction alongside adrenal dysfunction and/or immunodeficiency, consolidating these as replisome phenotypes and highlighting a need for future studies to understand the tissue-specific development roles of the encoded proteins.]]> Tue 21 Jan 2020 09:52:40 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:43469 Tue 20 Sep 2022 09:38:19 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:54875 Tue 19 Mar 2024 19:54:55 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:44630 Tue 18 Oct 2022 12:11:18 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:51214 Tue 14 Nov 2023 14:48:48 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:47003 Tue 13 Dec 2022 10:59:30 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:51636 Tue 12 Sep 2023 20:14:53 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:44337 Tue 11 Oct 2022 19:21:30 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:45910 Tue 08 Nov 2022 09:32:21 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:54150 Tue 06 Feb 2024 12:05:02 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:37216 Tue 01 Sep 2020 14:51:26 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:36614 Thu 28 Oct 2021 12:37:17 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:30271 Thu 28 Oct 2021 12:36:59 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:45038 Thu 27 Oct 2022 13:52:31 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:45372 Chd4 expression significantly impairs SSC regenerative capacity, causing a ∼50% reduction in colonization of recipient testes. An scRNA-seq comparison revealed reduced expression of “self-renewal” genes following Chd4 knockdown, along with increased expression of signature progenitor genes. Co-immunoprecipitation analyses demonstrated that CHD4 regulates gene expression in spermatogonia not only through its traditional association with the remodeling complex NuRD, but also via interaction with the GDNF-responsive transcription factor SALL4. Cumulatively, the results of this study depict a previously unappreciated role for CHD4 in controlling fate decisions in the spermatogonial pool.]]> Thu 27 Oct 2022 12:14:10 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:579 Thu 25 Jul 2013 09:10:30 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:48496 Thu 24 Aug 2023 13:57:43 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:51390 Thu 23 Nov 2023 14:31:06 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:32529 de novo missense variant within the C-terminal Sin3-like domain of ZSWIM6 was previously reported to cause acromelic frontonasal dysostosis (AFND), an autosomal-dominant severe frontonasal and limb malformation syndrome, associated with neurocognitive and motor delay, via a proposed gain-of-function effect. We present detailed phenotypic information on seven unrelated individuals with a recurrent de novo nonsense variant (c.2737C > T [p.Arg913Ter]) in the penultimate exon of ZSWIM6 who have severe-profound intellectual disability and additional central and peripheral nervous system symptoms but an absence of frontonasal or limb malformations. We show that the c.2737C > T variant does not trigger nonsense-mediated decay of the ZSWIM6 mRNA in affected individual-derived cells. This finding supports the existence of a truncated ZSWIM6 protein lacking the Sin3-like domain, which could have a dominant-negative effect. This study builds support for a key role for ZSWIM6 in neuronal development and function, in addition to its putative roles in limb and craniofacial development, and provides a striking example of different variants in the same gene leading to distinct phenotypes.]]> Thu 16 Aug 2018 10:03:57 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:43298 Thu 15 Sep 2022 12:51:31 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:47202 Thu 15 Dec 2022 11:18:18 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:53744 Thu 11 Jan 2024 12:15:03 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:41704 -7). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r² > .60) spanning as much as 900 kb. To identify potential genes and mechanisms through which the previously unreported association signals act to affect adiponectin levels, we assessed cross-trait associations, expression quantitative trait loci in subcutaneous adipose, and biological pathways of nearby genes. Eight of the nine loci were also associated (p < 1 x 10^-4) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels.]]> Thu 11 Aug 2022 15:21:17 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:47931 Thu 09 Feb 2023 12:55:55 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:46914 Thu 08 Dec 2022 08:47:20 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:36885 Thu 04 Nov 2021 10:39:34 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:34616 Thu 04 Nov 2021 10:39:12 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:34260 Thu 03 Feb 2022 12:20:40 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:46824 in vivo lineage tracing to show that endometrial epithelium self-renews during development, growth, and regeneration and identified Axin2, a classical Wnt reporter gene, as a marker of long-lived bipotent epithelial progenitors that reside in endometrial glands. Axin2-expressing cells are responsible for epithelial regeneration in vivo and for endometrial organoid development in vitro. Ablation of Axin2⁺ cells severely impairs endometrial homeostasis and compromises its regeneration. More important, upon oncogenic transformation, these cells can lead to endometrial cancer. These findings provide valuable insights into the cellular basis of endometrial functions and diseases.]]> Thu 01 Dec 2022 10:59:01 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:1735 Sat 24 Mar 2018 08:27:24 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:11354 Sat 24 Mar 2018 08:08:14 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:20204 Sat 24 Mar 2018 08:06:48 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:17422 Sat 24 Mar 2018 08:01:38 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:20380 g) across functional categories (while accounting for shared variance due to linkage disequilibrium). Extensive simulations showed that in contrast to current estimates from GWAS summary statistics, the variance-component approach partitions heritability accurately under a wide range of complex-disease architectures. Across the 11 diseases DNaseI hypersensitivity sites (DHSs) from 217 cell types spanned 16% of imputed SNPs (and 24% of genotyped SNPs) but explained an average of 79% (SE = 8%) of h²_g from imputed SNPs (5.1× enrichment; p = 3.7 × 10⁻¹⁷) and 38% (SE = 4%) of h²_g from genotyped SNPs (1.6× enrichment, p = 1.0 × 10⁻⁴). Further enrichment was observed at enhancer DHSs and cell-type-specific DHSs. In contrast, coding variants, which span 1% of the genome, explained <10% of h²_g despite having the highest enrichment. We replicated these findings but found no significant contribution from rare coding variants in independent schizophrenia cohorts genotyped on GWAS and exome chips. Our results highlight the value of analyzing components of heritability to unravel the functional architecture of common disease.]]> Sat 24 Mar 2018 07:58:12 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:20886 Sat 24 Mar 2018 07:57:56 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:6570 Sat 24 Mar 2018 07:49:16 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:29063 Sat 24 Mar 2018 07:40:08 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:28096 Sat 24 Mar 2018 07:25:00 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:22244 Sus gene in cotton where Sus expression has been previously shown to be critical for normal seed and fiber development. Segregation analyses at T1 generation followed by studies in homozygous progeny lines revealed that increased Sus activity in cotton (1) enhanced leaf expansion with the effect evident from young leaves emerging from shoot apex; (2) improved early seed development, which reduced seed abortion, hence enhanced seed set, and (3) promoted fiber elongation. In young leaves of Sus overexpressing lines, fructose concentrations were significantly increased whereas, in elongating fibers, both fructose and glucose levels were increased. Since hexoses contribute little to osmolality in leaves, in contrast to developing fibers, it is concluded that high Sus activity promotes leaf development independently of osmotic regulation, probably through sugar signaling. The analyses also showed that doubling the Sus activity in 0-d cotton seeds increased their fresh weight by about 30%. However, further increase in Sus activity did not lead to any further increase in seed weight, indicating an upper limit for the Sus overexpression effect. Finally, based on the observed additive effect on fiber yield from increased fiber length and seed number, a new strategy is proposed to increase cotton fiber yield by improving seed development as a whole, rather than solely focusing on manipulating fiber growth.]]> Sat 24 Mar 2018 07:17:34 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:23379 2 increased from 20.1% to 25.3% in a large schizophrenia dataset and from 9.8% to 12.0% in a large multiple sclerosis dataset. A similar relative improvement in accuracy was observed for three additional large disease datasets and for non-European schizophrenia samples. The advantage of LDpred over existing methods will grow as sample sizes increase.]]> Sat 24 Mar 2018 07:16:29 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:24835 −21), implicating GNB1 as a genome-wide-significant disease-associated gene. The majority of these 13 mutations affect known Gβ binding sites, which suggests that a likely disease mechanism is through the disruption of the protein interface required for Gα-Gβγ interaction (resulting in a constitutively active Gβγ) or through the disruption of residues relevant for interaction between Gβγ and certain downstream effectors (resulting in reduced interaction with the effectors). Strikingly, 8 of the 13 individuals recruited here for a neurodevelopmental disorder have a germline de novo GNB1 mutation that overlaps a set of five recurrent somatic tumor mutations for which recent functional studies demonstrated a gain-of-function effect due to constitutive activation of G protein downstream signaling cascades for some of the affected residues.]]> Sat 24 Mar 2018 07:15:11 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:22162 Immunity, Griseri et al. (2015) identify a new GM-CSF-dependent role for eosinophils in the pathogenesis of IL-23-Th17 cell-induced colitis.]]> Sat 24 Mar 2018 07:14:59 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:23879 Sat 24 Mar 2018 07:13:41 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:52857 Mon 30 Oct 2023 10:00:44 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:53408 Mon 27 Nov 2023 09:33:54 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:36658 exp] in the gene encoding Replication Factor C1 (RFC1). This motif, not reported in the reference sequence, localized to an Alu element and replaced the reference (AAAAG)11 short tandem repeat. Genetic analyses confirmed the pathogenic expansion in 18 of 22 CANVAS-affected families and identified a core ancestral haplotype, estimated to have arisen in Europe more than twenty-five thousand years ago. WGS of the four RFC1-negative CANVAS-affected families identified plausible variants in three, with genomic re-diagnosis of SCA₃, spastic ataxia of the Charlevoix-Saguenay type, and SCA₄₅. This study identified the genetic basis of CANVAS and demonstrated that these improved bioinformatics tools increase the diagnostic utility of WGS to determine the genetic basis of a heterogeneous group of clinically overlapping neurogenetic disorders.]]> Mon 22 Jun 2020 15:22:42 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:53265 Mon 20 Nov 2023 12:20:50 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:40758 Mon 18 Jul 2022 13:54:17 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:50980 Mon 14 Aug 2023 15:24:38 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:50946 Mon 14 Aug 2023 14:01:12 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:52367 Mon 13 Nov 2023 08:52:16 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:54744 Mon 11 Mar 2024 14:26:10 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:52297 Mon 09 Oct 2023 10:11:10 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:53000 Mon 06 Nov 2023 08:36:10 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:40281 Fri 29 Jul 2022 13:23:12 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:46603 Fri 25 Nov 2022 16:41:41 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:54928 Fri 22 Mar 2024 14:33:38 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:35158 in vitro and in vivo. Exit from pluripotency and priming for differentiation into somatic lineages is associated with genome-wide de novo DNA methylation. We show that during this phase, co-expression of enzymes required for DNA methylation turnover, DNMT3s and TETs, promotes cell-to-cell variability in this epigenetic mark. Using a combination of single-cell sequencing and quantitative biophysical modeling, we show that this variability is associated with coherent, genome-scale oscillations in DNA methylation with an amplitude dependent on CpG density. Analysis of parallel single-cell transcriptional and epigenetic profiling provides evidence for oscillatory dynamics both in vitro and in vivo. These observations provide insights into the emergence of epigenetic heterogeneity during early embryo development, indicating that dynamic changes in DNA methylation might influence early cell fate decisions.]]> Fri 21 Jun 2019 15:13:02 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:53880 Fri 19 Jan 2024 12:44:57 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:53864 Fri 19 Jan 2024 12:32:49 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:53200 Fri 17 Nov 2023 12:04:28 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:47238 Fri 16 Dec 2022 12:16:02 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:41710 HNF4A and GATA6, switch metabolic profiles from classical (pancreatic) to predominantly squamous, with glycogen synthase kinase 3 beta (GSK3β) a key regulator of glycolysis. Pharmacological inhibition of GSK3β results in selective sensitivity in the squamous subtype; however, a subset of these squamous patient-derived cell lines (PDCLs) acquires rapid drug tolerance. Using chromatin accessibility maps, we demonstrate that the squamous subtype can be further classified using chromatin accessibility to predict responsiveness and tolerance to GSK3β inhibitors. Our findings demonstrate that distinct patterns of chromatin accessibility can be used to identify patient subgroups that are indistinguishable by gene expression profiles, highlighting the utility of chromatin-based biomarkers for patient selection in the treatment of PDAC.]]> Fri 12 Aug 2022 08:35:16 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:33772 Fri 11 Jan 2019 13:41:08 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:39078 de novo CNOT1 variants, including missense, splice site, and nonsense variants, who present with a clinical spectrum of intellectual disability, motor delay, speech delay, seizures, hypotonia, and behavioral problems. To link CNOT1 dysfunction to the neurodevelopmental phenotype observed, we generated variant-specific Drosophila models, which showed learning and memory defects upon CNOT1 knockdown. Introduction of human wild-type CNOT1 was able to rescue this phenotype, whereas mutants could not or only partially, supporting our hypothesis that CNOT1 impairment results in neurodevelopmental delay. Furthermore, the genetic interaction with autism-spectrum genes, such as ASH1L, DYRK1A, MED13, and SHANK3, was impaired in our Drosophila models. Molecular characterization of CNOT1 variants revealed normal CNOT1 expression levels, with both mutant and wild-type alleles expressed at similar levels. Analysis of protein-protein interactions with other members indicated that the CCR4-NOT complex remained intact. An integrated omics approach of patient-derived genomics and transcriptomics data suggested only minimal effects on endonucleolytic nonsense-mediated mRNA decay components, suggesting that de novo CNOT1 variants are likely haploinsufficient hypomorph or neomorph, rather than dominant negative. In summary, we provide strong evidence that de novo CNOT1 variants cause neurodevelopmental delay with a wide range of additional co-morbidities. Whereas the underlying pathophysiological mechanism warrants further analysis, our data demonstrate an essential and central role of the CCR4-NOT complex in human brain development.]]> Fri 06 May 2022 12:37:33 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:49114 Fri 05 May 2023 11:38:54 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:49834 Fri 02 Jun 2023 15:50:44 AEST ]]>