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This paper presents a palynological analysis of sediments from Walanjiwurru 1, a rockshelter located in the Country of the Marra Aboriginal people at Limmen National Park in the Northern Territory (Australia). Analysis seeks to test rockshelter sediments as a framework for research in an environmentally difficult location, and to explore how the palaeoecological record may capture the diversity of people-nature relationships over time in the Northern Territory. The Walanjiwurru 1 pollen record provides an approximate 500-year insight into the rockshelter’s surrounding landscape. Two plant communities demonstrate local presence across this time frame—foremost a drier eucalypt woodland, and a wetter fringing Melaleuca dominated habitat, each with an integrated series of monsoonal forest taxa. With only subtle shifts in vegetation, the Marra’s consistent maintenance of relations with their landscape is observable, and this is discussed in relation to the Walanjiwurru 1’s archaeology and regional European settler colonialism. Charcoal recovery from Walanjiwurru 1 is derived from in situ campfires, making it difficult to conclude on the response of plant types and vegetation communities to long-term landscape burning. Future palaeoecological research off-site from the rockshelter has therefore been recommended.

ObjectivesThere has been growing concern about doctors? conflicts of interests (COIs) but it is unclear what processes and tools exist to enable the consistent declaration and management of such interests. This study mapped existing policies across a variety of organisations and settings to better understand the degree of variation and identify opportunities for improvement.DesignThematic analysis.Setting and ParticipantsWe studied the COI policies of 31 UK and international organisations which set or influence professional standards or engage doctors in healthcare commissioning and provision settings.Main outcome measures:Organisational policy similarities and differences.ResultsMost policies (29/31) referred to the need for individuals to apply judgement when deciding whether an interest is a conflict, with just over half (18/31) advocating a low threshold. Policies differed on the perception of frequency of COI, the timings of declarations, the type of interests that needed to be declared, and how COI and policy breaches should be managed. Just 14/31 policies stated a duty to report concerns in relation to COI. Only 18/31 policies advised COI would be published, while three stated that any disclosures would remain confidential.ConclusionsThe analysis of organisational policies revealed wide variation in what interests should be declared, when and how. This variation suggests that the current system may not be adequate to maintain a high level of professional integrity in all settings and that there is a need for better standardisation that reduces the risk of errors while addressing the needs of doctors, organisations and the public. Publisher PDF

Accurately inferring Gene Regulatory Networks (GRNs) is a critical and challenging task in biology. GRNs model the activatory and inhibitory interactions between genes and are inherently causal in nature. To accurately identify GRNs, perturbational data is required. However, most GRN discovery methods only operate on observational data. Recent advances in neural network-based causal discovery methods have significantly improved causal discovery, including handling interventional data, improvements in performance and scalability. However, applying state-of-the-art (SOTA) causal discovery methods in biology poses challenges, such as noisy data and a large number of samples. Thus, adapting the causal discovery methods is necessary to handle these challenges. In this paper, we introduce DiscoGen, a neural network-based GRN discovery method that can denoise gene expression measurements and handle interventional data. We demonstrate that our model outperforms SOTA neural network-based causal discovery methods.

CD19-specific KIR-CAR/Dap12 shows antigen-specific cytotoxicity in vitro.

SS1-KIRS2 does not affect endogenous TCR expression.

Figure legends for supplemental data.

SS1-KIRS2/DAP12 T cells mediate robust anti-tumor activity in vivo.

Chimeric antigen receptors (CAR) bearing an antigen-binding domain linked in cis to the cytoplasmic domains of CD3ζ and costimulatory receptors have provided a potent method for engineering T-cell cytotoxicity toward B-cell leukemia and lymphoma. However, resistance to immunotherapy due to loss of T-cell effector function remains a significant barrier, especially in solid malignancies. We describe an alternative chimeric immunoreceptor design in which we have fused a single-chain variable fragment for antigen recognition to the transmembrane and cytoplasmic domains of KIR2DS2, a stimulatory killer immunoglobulin-like receptor (KIR). We show that this simple, KIR-based CAR (KIR-CAR) triggers robust antigen-specific proliferation and effector function in vitro when introduced into human T cells with DAP12, an immunotyrosine-based activation motifs-containing adaptor. T cells modified to express a KIR-CAR and DAP12 exhibit superior antitumor activity compared with standard first- and second-generation CD3ζ-based CARs in a xenograft model of mesothelioma highly resistant to immunotherapy. The enhanced antitumor activity is associated with improved retention of chimeric immunoreceptor expression and improved effector function of isolated tumor-infiltrating lymphocytes. These results support the exploration of KIR-CARs for adoptive T-cell immunotherapy, particularly in immunotherapy-resistant solid tumors. Cancer Immunol Res; 3(7); 815–26. ©2015 AACR.

Cytotoxicity induced by SS1-KIRS2, but not receptor expression at the cell surface, depends upon DAP12 co-expression.

Mesothelin-specific CD3ζ CARs and SS1-KIRS2/Dap12 show comparable antigen-specific in vitro cytotoxicity toward EM-meso cells.

FAP-specific KIR-CAR/Dap12 T cells induce bone marrow hypocellularity and loss of body weight.

Reputation-based cooperation on social networks offers a causal mechanism between graph properties and social trust. Recent papers on the `structural microfoundations` of the society used this insight to show how demographic processes, such as falling fertility, urbanisation, and migration, can alter the logic of human societies. This paper demonstrates the underlying mechanism in a way that is accessible to scientists not specialising in networks. Additionally, the paper shows that, when the size and degree of the network is fixed (i.e., all graphs have the same number of agents, who all have the same number of connections), it is the clustering coefficient that drives differences in how cooperative social networks are., 16 pages, 6 figures

Studies of introduced subject matter in rock-art assemblages typically focus on themes of cross-cultural interaction, change and continuity, power and resistance. However, the economic frameworks guiding or shaping the production of an assemblage have often been overlooked. In this paper we use a case study involving a recently recorded assemblage of introduced subject matter from Marra Country in northern Australia's southwest Gulf of Carpentaria region to explore their production using a hybrid economy framework. This framework attempts to understand the nature of the forces that shape people's engagement with country and subsequently how it is being symbolically marked as adjustments to country occur through colonization. We argue that embedding these motifs into a hybrid economy context anchored in the pastoral industry allows for a more nuanced approach to cross-cultural interaction studies and adds another layer to the story of Aboriginal place-marking in colonial contexts. This paper aims to go beyond simply identifying motifs thought to represent introduced subject matter, and the cross-cultural framework(s) guiding their interpretation, and instead to direct attention to the complex network of relations that potentially underpin the production of such motifs.

Supplemental material, sj-pdf-1-jrs-10.1177_01410768231181248 for Policies on doctors’ declaration of interests in medical organisations: a thematic analysis by Victoria Tzortziou Brown, Margaret McCartney, Patrycja Talaga, Richard Huxtable, Andrew Papanikitas and Elizabeth David-Barrett in Journal of the Royal Society of Medicine

This is the full Mathematica code of the calculations.

Background The burden of knee replacement prosthetic joint infection (KR PJI) is increasing. KR PJI is difficult to treat, outcomes can be poor and it is financially expensive and limited evidence is available to guide treatment decisions. Aim To provide guidelines for surgeons and units treating KR PJI. Methods Guideline formation by consensus process undertaken by BASK's Revision Knee Working Group, supported by outputs from UK-PJI meetings. Results Improved outcomes should be achieved through provision of care by revision centres in a network model. Treatment of KR PJI should only be undertaken at specialist units with the required infrastructure and a regular infection MDT. This document outlines practice guidelines for units providing a KR PJI service and sets out: • The necessary infrastructure required to provide a high-quality KR PJI service • The MDT composition — who and when • The KR PJI care pathway • Medical and surgical treatment strategies • The indications for referral to tertiary units (Major Revision Centres) • Outcome metrics and auditable standards Conclusions KR PJI patients treated within the NHS should be provided the best care possible. This report sets out guidance and support for surgeons and units to achieve this.

FOXA1 functions as a pioneer transcription factor by facilitating the access to chromatin for steroid hormone receptors, such as androgen receptor and estrogen receptor1-4, but mechanisms regulating its binding to chromatin remain elusive. LSD1 (KDM1A) acts as a transcriptional repressor by demethylating mono/dimethylated histone H3 lysine 4 (H3K4me1/2)5,6, but also acts as a steroid hormone receptor coactivator through mechanisms that are unclear. Here we show, in prostate cancer cells, that LSD1 associates with FOXA1 and active enhancer markers, and that LSD1 inhibition globally disrupts FOXA1 chromatin binding. Mechanistically, we demonstrate that LSD1 positively regulates FOXA1 binding by demethylating lysine 270, adjacent to the wing2 region of the FOXA1 DNA-binding domain. Acting through FOXA1, LSD1 inhibition broadly disrupted androgen-receptor binding and its transcriptional output, and dramatically decreased prostate cancer growth alone and in synergy with androgen-receptor antagonist treatment in vivo. These mechanistic insights suggest new therapeutic strategies in steroid-driven cancers.

Crucial transitions in cancer-including tumor initiation, local expansion, metastasis, and therapeutic resistance-involve complex interactions between cells within the dynamic tumor ecosystem. Transformative single-cell genomics technologies and spatial multiplex in situ methods now provide an opportunity to interrogate this complexity at unprecedented resolution. The Human Tumor Atlas Network (HTAN), part of the National Cancer Institute (NCI) Cancer Moonshot Initiative, will establish a clinical, experimental, computational, and organizational framework to generate informative and accessible three-dimensional atlases of cancer transitions for a diverse set of tumor types. This effort complements both ongoing efforts to map healthy organs and previous large-scale cancer genomics approaches focused on bulk sequencing at a single point in time. Generating single-cell, multiparametric, longitudinal atlases and integrating them with clinical outcomes should help identify novel predictive biomarkers and features as well as therapeutically relevant cell types, cell states, and cellular interactions across transitions. The resulting tumor atlases should have a profound impact on our understanding of cancer biology and have the potential to improve cancer detection, prevention, and therapeutic discovery for better precision-medicine treatments of cancer patients and those at risk for cancer.

During the COVID-19 pandemic, the use of the labels 'heroes' and 'angels' to describe nurses (and especially critical care nurses) became prevalent. While often well intentioned, the use of these labels may not be the most positive image of nurses and the nursing profession. Critical care nurses have not previously been given the opportunity to provide their perceptions of the angel/hero narrative and the impact this may have on their practice and working environments.The objectives of this study were to explore the perspectives of critical care nurses and discover their perceptions about the angel/hero narrative and its impact on their clinical practice, safe working environments, and professional development during the COVID-19 pandemic.A semistructured qualitative virtual interview study was conducted with critical care nurses from the United Kingdom, Australia, and North America. Digital audio data were transcribed verbatim. Thematic analysis of the transcribed data was performed. The COREQ guidelines were used to report the study.Twenty-three critical care nurses located in the United Kingdom, Australia, and North America participated. Four themes were synthesised: history repeating, gender stereotypes, political pawns, and forgotten heroes.Critical care nurses did not perceive the hero and angel labels positively. Participants were concerned about unrealistic expectations, potential safety workplace risks, and poor remuneration related to these narratives. Participants perceived that context and intention were important in the interpretation of these narratives; they spoke with pride about their work and called for improved representations of their role, recognition, and work conditions.

In 2021, the UK system for regulating the conduct of parliamentarians was briefly plunged into crisis. The government responded to a proposal to sanction one of its MPs – who had been found to have egregiously breached the Code of Conduct and accompanying rules - by threatening to change the whole system. This highly unusual interference by the executive branch, though withdrawn within 24 hours, violated the axiom that the executive should not have a say in disciplining members of the legislature because this might compromise parliament’s ability to hold the government to account. Yet the ensuing debate has prompted calls to move the UK system yet further away from self-regulation and grant more powers of oversight to ‘external’ roles and bodies. This article draws on interviews with MPs to analyse whether this longstanding trajectory of reform is in line with how these “rule makers” perceive the system’s flaws. It concludes that, over the years, MPs have to a large extent forfeited the right to regulate their own conduct by repeatedly shirking their responsibilities to regulate themselves effectively. Moreover, the constant focus on ‘fixing’ the procedures for investigating and sanctioning misconduct has crowded out a more constructive discussion about how to promote ethical behaviour.