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Low-input proteomics identifies vWF as a negative regulator of Tet2 mutant hematopoietic stem cell expansion
Get PDFDespite rapid advances in mapping genetic drivers and gene expression changes in hematopoietic stem cells (HSCs), few studies exist at the protein level. We perform a deep, multi-omics characterization (epigenome, transcriptome, and proteome) of HSCs in a mouse model carrying a loss-of-function mutation in Tet2, a driver of increased self-renewal in blood cancers. Using state-of-the-art, multiplexed, low-input mass spectrometry (MS)-based proteomics, we profile TET2-deficient (Tet2 -/-) HSCs, revealing previously unrecognized molecular processes that define the pre-leukemic HSC molecular landscape. Specifically, we obtain more accurate stratification of wild-type and Tet2 -/- HSCs than transcriptomic approaches and identify extracellular matrix (ECM) molecules as being dysregulated upon TET2 loss. HSC expansion assays using ECM-functionalized hydrogels confirm a selective effect on the expansion of Tet2-mutant HSCs. Taken together, our study represents a comprehensive molecular characterization of Tet2-mutant HSCs and identifies a previously unanticipated role of ECM molecules in regulating self-renewal of disease-driving HSCs
Dynamic Protein Structures in Solution:Decoding the Amide I Band with 2D-IR Spectral Libraries and Machine Learning
No full textDoxorubicin induces bone loss and modifies multiple cell populations in vivo – Implications for modelling of bone metastasis
Get PDFDoxorubicin (DOX), commonly used to treat breast cancer, is associated with cardiotoxicity and has negative effects on other organ systems, including the skeleton. DOX-induced bone damage has been demonstrated in murine models; however, results are conflicting due to the use of different doses, schedules, and rat/mouse strains. As DOX is used to limit tumour progression in models of skeletal metastasis, it is paramount to determine how the agent affects the bone microenvironment in the relevant mouse strains, to enable correct interpretation of DOX effects in tumour studies. We have therefore investigated the effects of DOX on bone structure and a range of bone and bone marrow cell populations, comparing immunocompetent and immunocompromised mice.
Groups of 7-week-old female BALB/c and BALB/c Nude mice were treated with either saline (control), 4 or 6 mg/kg DOX weekly for four weeks. Effects on bone volume and structure was determined using ex vivo µCT, a panel of bone marrow cell populations were quantified by flow cytometry and osteoblast/osteoclast numbers were assessed using bone histomorphometry.
DOX caused trabecular bone loss, with immunocompetent BALB/c mice being more sensitive to DOX than the immunocompromised BALB/c nude counterparts. The 6 mg/kg dose of DOX altered the ratio of bone marrow immune and haematopoietic cell populations in both groups, increasing the numbers of hematopoietic cells and progenitors, decreasing B cells and increasing the number of neutrophils. Bone marrow macrophage and monocyte numbers were increased following DOX treatment in BALB/c nude mice only. Our data demonstrate that DOX impacts a number of cell types in the bone microenvironment, highlighting the importance of considering treatment-induced bone effects when using DOX in models of bone metastasis
What Does it Mean to be Passionate about Your Job? Three Meanings of ‘Collectively Oriented Passion’ in UK Pubs
Get PDFThis article examines how understandings of passion shape people’s agency at work, through interviews with UK publicans. It addresses calls to rethink how ‘passion’ is conceptualised in the sociology of work. While discourses around passion are often thought to legitimise individualised working practices, the article explores more collective interpretations. It analyses how publicans exercised agency in negotiating externally imposed problems including the pandemic and exploitative relationships with leading industry actors. It identifies a collective understanding of passion centralising notions of community, which shaped participants’ agency in responding to these problems in three ways: providing motivation to persist in the industry; a frame for critiquing perceived injustice and (occasionally) mobilising against it; and a resource for reinvention in pursuing business sustainability. The main contribution is thus new concepts for analysing how ‘collectively oriented passion’ shapes individuals’ agency at work
Relating tribology to astringency perception in acidic plant protein-fortified fiber-based smoothies
Get PDFWith increased need to address environmental sustainability, there has been a pronounced interest on incorporating plant proteins in health-promoting fiber-rich fruit based drinks. Often such matrices are acidic in nature posing challenges for incorporating plant proteins causing undesirable textural issues such as astringency, which is poorly understood in the literature. This study aimed to understand how tribological and rheological characterization can help to explain mouthfeel of plant proteins when incorporated in fiber-based matrices (both model and real smoothies) at pH 3.8. Ten different commercially available isolated plant proteins (5 wt% protein solutions) exhibited significant aggregation being close to their isoelectric point in the fiber-based model smoothie dispersion (0.3 wt% pectin, 0.8 wt% inulin). Particularly, the viscosity of model smoothies spanned across three orders of magnitude, with many, if not, most demonstrating shear-thinning behaviors. Plant proteins exhibited diverse frictional dissipation, with some of the tested commercial fava bean protein, pea protein and chickpea protein concentrates outperforming industry standards, such as soy protein isolate. Model smoothie’s effectively mimicked real smoothies in mouthfeel attributes (11 trained panelists), showing plant proteins governing the mouthfeel. Pearson’s correlation identified strong relationships between boundary friction, rheology, and sensory attributes, highlighting the predictive value of in vitro methods. Notably, %soluble fraction negatively correlated with all tested undesirable attributes, such as astringency offering a facile screening metric for plant protein performance. Overall, this study validates the use of in vitro tools for mouthfeel assessment in complex food matrices, streamlining protein selection for accelerating the development of sustainable plant-based foods
Ngũgĩ wa Thiong’o and the Writing of Political Freedom
Get PDFNgũgĩ wa Thiong'o's rewriting of stories in Secret Lives informs plotlines in A Grain of Wheat. I argue that while A Grain of Wheat attempts to model decolonial narrative sovereignty following Kenyan Independence, it unconsciously enters into identificatory dependency. I conclude that Ngũgĩ's literary career follows a trajectory to that tries to undo this creative bind
Alkylthienyl side groups in conjugated polymers enable localization of π electron density and facilitate efficient hole transfer
Get PDFRecent advances in molecular design have seen peripheral alkoxy groups replaced with alkylthienyl substituents in conjugated polymers for high-performing organic photovoltaics. However, little is known about the mechanistic origins behind this improvement in performance. In this work, transient absorption spectroscopy is used in conjunction with resonance Raman spectroscopy to shed light on this question. Alkoxy-substituted polymer PBDB is compared with alkylthienyl-substituted PBDB-T in blends with two different acceptors. Larger charge photogeneration yields are observed for PBDB-T:ITIC-Th compared to the PBDB:ITIC-Th blend due to more efficient hole transfer. However, an active triplet formation mechanism via charge recombination leaves the two blends with similar polaron populations on longer timescales. Importantly, resonance Raman spectroscopy demonstrates that the alkylthienyl groups in PBDB-T enable a stronger coupling of the S1 state to the benzodithiophene unit compared to the benzodithiophene-dione unit. The observation that this localization of electron density on the benzodithiophene unit only occurs for PBDB-T, and most prominently in the presence of the ITIC-Th, suggests a strong interaction between the PBDB-T and ITIC-Th. This interaction may facilitate the more efficient hole transfer and greater charge photogeneration yields observed for PBDB-T:ITIC-Th. These results demonstrate the mechanistic origin of a valuable structure-function relationship
Experimental evidence that prenatal and postnatal developmental stress affects the adult seminal fluid proteome in a precocial bird
Get PDFSeminal fluid proteins are important modulators of male fertility and reproductive success, yet little is known about how their abundance responds to early-life developmental stress. Japanese quail Coturnix japonica) males produce a unique seminal foam that enhances fertilisation success. We characterised the proteome of the seminal foam for the first time and assessed how its composition is influenced by prenatal and postnatal developmental stress. Proteomic identification using liquid chromatography–tandem mass spectrometry and subsequent gene ontology (GO) analysis of chicken (Gallus gallus domesticus) orthologs suggested roles for the foam proteome in sperm maturation and DNA protection, semen liquefaction, sperm plasma membrane homeostasis and energy production for sperm motility. Males that experienced prenatal stress exhibited increased abundance of proteins involved in lipid metabolic processes, inflammation and oxidative stress, including proteolytic enzymes, interleukin receptors and avidin-like proteins. Similarly, males that exhibited postnatal stress exhibited increased abundance of proteins involved in chromatin organisation, carbon metabolism and oxidative stress. Nine proteins involved in metabolic processes and antioxidant processes were consistently more abundant across developmentally stressed males from both experiments, suggesting convergent responses to early-life stress. These results demonstrate that early development environments can alter the seminal foam proteome of adult males, with potential implications for ejaculate quality and fertilisation ability
Measurement of the top-quark Yukawa coupling from tt production in the lepton+jets final state using pp collisions at √s = 13 TeV with the ATLAS detector
Get PDFA pilot project to evaluate the benefit of additional support in haematopoietic cell transplant (HCT) research data management on behalf of Anthony Nolan and BSBMTCT
Get PDFBackground
The participation of transplant centres in research studies that request detailed follow-up data on included patients can be challenging due to the amount of time centre Data Managers have to complete additional requests. The Research Data Manager (RDM) Pilot Project was designed to support Anthony Nolan's longitudinal Patient/Donor project and provide real-world evidence of the benefit of additional and dedicated data management resources in transplant centres.
Objectives
For Anthony Nolan to continue advancing the field of donor selection, up-to-date and accurate follow-up data is needed. This 12-month pilot project aimed to demonstrate how on-the-ground support could improve access to outcome data.
Study Design
Following RDM placements at two participating centres, we reviewed the data quality and quantity collected, thus ensuring the methods used remain effective and are likely to result in successful and continuous data improvement. The cohort covered a broad timespan and included historical patient records, posing challenges in availability of prior data and long-term follow-up of discharged patients.
Results
Following the placements, over 400 patients now have the most up-to-date and complete patient clinical outcome data available within the EBMT/BSBMTCT registry database for any group to study, reducing the burden on these centres to complete research data requests for these individuals.
Trial Registration
The authors have confirmed clinical trial registration is not needed for this submissio
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