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Wong, S.

Publications and source records attributed to Wong, S..

63 records · Page 4Linked to original sources

Extreme niche partitioning promotes a remarkably high diversity of soil microbiomes across eastern Antarctica.

Terrestrial Antarctica, a predominantly microbial realm, encompasses some of the most unique environments on Earth where resident soil microbiota play key roles in the sustainability and evolution of the ecosystem. Yet the fundamental ecological processes that govern the assemblage of these natural communities remain unclear. Here, we combined multivariate analyses, co-occurrence networks and fitted species abundance distributions of amplicon sequencing data to disentangle community assemblage patterns of polar soil microbiomes across two ice-free deserts (Windmill Islands and Vestfold Hills) situated along the coastline of eastern Antarctica. Our findings report that communities were predominantly structured by non-neutral processes, with niche partitioning being particularly strong for bacterial communities at the Windmill Islands. In contrast, both eukaryotic and archaeal communities exhibited multimodal distributions, indicating the potential emergence of neutrality. Between the three microbial domains, polar soil bacterial communities consistently demonstrated the greatest taxonomic diversity, estimated richness, network connectivity and linear response to contemporary environmental soil parameters. We propose that reduced niche overlap promotes greater phylogenetic diversity enabling more bacterial species to co-exist and essentially thrive under adversity. However, irrespective of overall relative abundance, consistent and robust associations between co-existing community members from all three domains of life highlights the key roles that diverse taxa play in ecosystem dynamics. SignificanceIn the face of a warming Antarctica, contemporary dynamics between polar soil microbial communities will inevitably change due to the climate-induced expansion of new ice-free areas. Increasing concern about disturbance and rapid biodiversity loss has intensified the need to better understand microbial community structure and function in high-latitude soils. We have taken an integrated approach to elucidate domain-level assemblage patterns across east Antarctic soil microbiomes. These assemblage patterns will be available to feed into policy management and conservation planning frameworks to potentially mitigate future biodiversity loss.

microbiology↗

Identification of frequent activating HER2 mutations in primary canine pulmonary adenocarcinoma

Naturally occurring primary canine lung cancers are aggressive malignancies that are increasingly common in pet dogs. They share clinicopathologic features with human lung cancers in never-smokers, but their genetic underpinnings are unknown. Through multi-platform sequencing of 88 primary canine lung tumors or cell lines, we discovered somatic, coding HER2 (ERRB2) point mutations in 38% of canine pulmonary adenocarcinomas (cPAC, 28/74), but none in adenosquamous (cPASC, 0/11) or squamous cell (cPSCC, 0/3) carcinomas. In cPASC, PTEN was the most frequently mutated gene (18%) while one case each bore likely pathogenic HRAS, KRAS, EGFR, MET, TP53, or VHL somatic mutations. In cPSCC, no recurrently mutated genes were identified, but individual somatic coding mutations were found in BRAF and PTPN11. In cPAC, we also identified recurrent somatic mutation of TP53 (13.5%), SMAD4 (5.4%), PTEN (4.1%), and VHL (2.7%). cPACs assessed by exome sequencing displayed a low somatic mutation burden (median 64 point mutations, 19 focal copy number variants, and 1 translocation). The majority (93%) of HER2 mutations were hotspot V659E transmembrane domain (TMD) mutations comparable to activating mutations at this same site in human cancer. Other HER2 mutations identified in this study were located in the extracellular domain and TMD. HER2V659E was detected in the plasma of 33% (2/6) of dogs with localized HER2V659E tumors. HER2V659E correlated with constitutive phosphorylation of AKT in cPAC cell lines and HER2V659E lines displayed hypersensitivity to the HER2 inhibitors lapatinib and neratinib relative to HER2-wild-type cell lines. These findings have translational and comparative relevance for lung cancer and HER2 inhibition.

cancer biology↗

Letrozole increases hippocampal neurogenesis in middle-aged female mice

Letrozole, a third-generation aromatase inhibitor, prevents the production of estrogens in the final step in conversion from androgens. Due to its efficacy at suppressing estrogens, letrozole has recently taken favor as a first-line adjuvant treatment for hormone-responsive breast cancer in middle-aged women. Though patient response to letrozole has generally been positive, there is conflicting evidence surrounding its impact on the development of depression. It is possible that letrozoles potential adverse effects on mood are a result of the impact of hormonal fluctuations on neurogenesis in the hippocampus. Thus, to clarify the effects of letrozole on the hippocampus and behavior, we examined how chronic administration affects hippocampal neurogenesis and depressive-like behaviour in middle-aged, intact female mice. Mice were given either letrozole (1mg/kg) or vehicle by injection (ip) daily for 3 weeks. Depressive-like behaviour was assessed during the last 3 days of treatment using the forced swim test, tail suspension test, and sucrose preference test, and the production of new neurons was quantified using the immature neuronal marker, doublecortin (DCX). We found that letrozole increased DCX expression and maturation in the dentate gyrus, but had no significant effect on depressive-like behaviour. Our findings suggest that a reduction in circulating estrogens in middle-aged females increases hippocampal neurogenesis without any adverse impact on behavior; as such, this furthers our understanding of how estrogens modulate neurogenesis, and to the rationale for the utilization of letrozole in the clinical management of breast cancer.

neuroscience↗

Phage Mediate Bacterial Self Recognition

Cells are social, and self-recognition is an important and conserved aspect of group behavior where cells assist kin and antagonize non-kin to conduct group behavior such as foraging for food and biofilm formation. However, the role of the common bacterial cohabitant, phage, in kin recognition, has not been explored. Here we find that a boundary (demarcation line) is formed between different swimming Escherichia coli strains but not between identical clones; hence, motile bacterial cells discriminate between self and non-self. The basis for this self-recognition is a novel, 49 kb, T1-type, lytic phage of the family siphoviridae (named here SW1) that controls formation of the demarcation line by utilizing one of the hosts cryptic prophage proteins, YfdM, to propagate. Critically, SW1 increases the fitness of E. coli K-12 compared to the identical strain that lacks the phage. Therefore, bacteria use phage to recognize kin.

molecular biology↗

In vivo clonal analysis reveals spatiotemporal regulation of thalamic nucleogenesis

The thalamus, a crucial regulator of cortical functions, is composed of many nuclei arranged in a spatially complex pattern. Thalamic neurogenesis occurs over a short period during mammalian embryonic development. These features have hampered the effort to understand how regionalization, cell divisions and fate specification are coordinated and produce a wide array of nuclei that exhibit distinct patterns of gene expression and functions. Here, we performed in vivo clonal analysis to track the divisions of individual progenitor cells and spatial allocation of their progeny in the developing mouse thalamus. Quantitative analysis of clone compositions revealed evidence for sequential generation of distinct sets of thalamic nuclei based on the location of the founder progenitor cells. Furthermore, we identified intermediate progenitor cells that produced neurons populating more than one thalamic nuclei, indicating a prolonged specification of nuclear fate. Our study reveals an organizational principle that governs the spatial and temporal progression of cell divisions and fate specification, and provides a framework for studying cellular heterogeneity and connectivity in the mammalian thalamus.

neuroscience↗

Signatures of the evolution of parthenogenesis and cryptobiosis in the genomes of panagrolaimid nematodes

Most animal species reproduce sexually, but parthenogenesis, asexual reproduction of various forms, has arisen repeatedly. Parthenogenetic lineages are usually short lived in evolution; though in some environments parthenogenesis may be advantageous, avoiding the cost of sex. Panagrolaimus nematodes have colonised environments ranging from arid deserts to arctic and antarctic biomes. Many are parthenogenetic, and most have cryptobiotic abilities, being able to survive repeated complete desiccation and freezing. It is not clear which genomic and molecular mechanisms led to the successful establishment of parthenogenesis and the evolution of cryptobiosis in animals in general. At the same time, model systems to study these traits in the laboratory are missing.\n\nWe compared the genomes and transcriptomes of parthenogenetic and sexual Panagrolaimus able to survive crybtobiosis, as well as a non-cryptobiotic Propanogrolaimus species, to identify systems that contribute to these striking abilities. The parthenogens are most probably tripoids originating from hybridisation (allopolyploids). We identified genomic singularities like expansion of gene families, and selection on genes that could be linked to the adaptation to cryptobiosis. All Panagrolaimus have acquired genes through horizontal transfer, some of which are likely to contribute to cryptobiosis. Many genes acting in C. elegans reproduction and development were absent in distant nematode species (including the Panagrolaimids), suggesting molecular pathways cannot directly be transferred from the model system.\n\nThe easily cultured Panagrolaimus nematodes offer a system to study developmental diversity in Nematoda, the molecular evolution of parthenogens, the effects of triploidy on genomes stability, and the origin and biology of cryptobiosis.

evolutionary biology↗

Repurposing Tofacitinib As An Anti-Myeloma Therapeutic To Reverse Growth-Promoting Effects Of The Bone Marrow Microenvironment

The myeloma bone marrow microenvironment promotes proliferation of malignant plasma cells and resistance to therapy. Interleukin-6 (IL-6) and downstream JAK/STAT signaling are thought to be central components of these microenvironment-induced phenotypes. In a prior drug repurposing screen, we identified tofacitinib, a pan-JAK inhibitor FDA-approved for rheumatoid arthritis, as an agent that may reverse the tumor-stimulating effects of bone marrow mesenchymal stromal cells. Here, we validated both in vitro, in stromal-responsive human myeloma cell lines, and in vivo, in orthotopic disseminated murine xenograft models of myeloma, that tofacitinib showed both single-agent and combination therapeutic efficacy in myeloma models. Surprisingly, we found that ruxolitinib, an FDA-approved agent targeting JAK1 and JAK2, did not lead to the same anti-myeloma effects. Combination with a novel irreversible JAK3-selective inhibitor also did not enhance ruxolitinib effects. RNA-seq and unbiased phosphoproteomics revealed that marrow stromal cells stimulate a JAK/STAT-mediated proliferative program in myeloma plasma cells, and tofacitinib reversed the large majority of these pro-growth signals. Taken together, our results suggest that tofacitinib specifically reverses the growth-promoting effects of the tumor microenvironment through blocking an IL-6-mediated signaling axis. As tofacitinib is already FDA-approved, these results can be rapidly translated into potential clinical benefits for myeloma patients.

cancer biology↗

Oscillatory Default Mode Network Coupling In Concussion

BackgroundConcussion is a common form of mild traumatic brain injury (mTBI). Despite the descriptor mild, a single injury can leave long-lasting and sustained alterations to brain function, including changes to localised activity and large-scale interregional communication. Cognitive complaints are thought to arise from such functional deficits. We investigated the impact of injury on neurophysiological and functionally-specialised resting networks, known as intrinsic connectivity networks (ICNs), using MEG.\n\nMethodsWe assessed neurophysiological connectivity in 40 males, 20 with concussion, 20 without, using MEG. Regions-of-interest that comprise nodes of ICNs were defined, and their time courses derived using a beamformer approach. Pairwise fluctuations and covariations in band-limited amplitude envelopes were computed reflecting measures of functional connectivity. Intra-network connectivity was compared between groups using permutation testing, and correlated with symptoms.\n\nResultsWe observed increased resting spectral connectivity in the default mode and motor networks in our concussion group when compared with controls, across alpha through gamma ranges. Moreover, these differences were not explained by power spectrum density (absolute changes in the spectral profiles within the ICNs). Furthermore, this increased coupling was significantly associated with symptoms in the DMN and MOT networks - but once accounting for comorbid symptoms (including, depression, anxiety, and ADHD) only the DMN continued to be associated with symptoms.\n\nConclusionThe DMN network plays a critical role in shifting between cognitive tasks. These data suggest even a single concussion can perturb the intrinsic coupling of functionally-specialised networks in the brain and may explain persistent and wide-ranging symptomatology.

neuroscience↗

Multiplexing droplet-based single cell RNA-sequencing using natural genetic barcodes

Droplet-based single-cell RNA-sequencing (dscRNA-seq) has enabled rapid, massively parallel profiling of transcriptomes from tens of thousands of cells. Multiplexing samples for single cell capture and library preparation in dscRNA-seq would enable cost-effective designs of differential expression and genetic studies while avoiding technical batch effects, but its implementation remains challenging. Here, we introduce an in-silico algorithm demuxlet that harnesses natural genetic variation to discover the sample identity of each cell and identify droplets containing two cells. These capabilities enable multiplexed dscRNA-seq experiments where cells from unrelated individuals are pooled and captured at higher throughput than standard workflows. To demonstrate the performance of demuxlet, we sequenced 3 pools of peripheral blood mononuclear cells (PBMCs) from 8 lupus patients. Given genotyping data for each individual, demuxlet correctly recovered the sample identity of > 99% of singlets, and identified doublets at rates consistent with previous estimates. In PBMCs, we demonstrate the utility of multiplexed dscRNA-seq in two applications: characterizing cell type specificity and inter-individual variability of cytokine response from 8 lupus patients and mapping genetic variants associated with cell type specific gene expression from 23 donors. Demuxlet is fast, accurate, scalable and could be extended to other single cell datasets that incorporate natural or synthetic DNA barcodes.

bioinformatics↗