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African easterly waves (AEWs) are known precursors to Atlantic tropical cyclones (TCs), and are therefore often directly connected to extreme weather events that can be both deadly and destructive. It is well established that not all AEWs develop into TCs, and there has been substantial research that has addressed the different characteristics and environments of developing and non-developing waves. In this study, however, we specifically examine 41-years of developing AEWs to provide a better understanding of the relationship between the developing wave and the environment, and the resulting TC. To conduct this research, we identified TCs with AEW origins from the observational record between 1980 and 2020. We then used an objective tracking algorithm to identify the developing AEWs in reanalysis data. We found a statistically significant relationship between the strength of the developing AEWs, TC genesis location and landfall, and sea surface temperature (SST) during TC genesis. Weaker AEWs tend to develop into TCs closer to the Americas in a region with warmer SSTs than those of the stronger AEWs, which tend to develop into TCs closer to Africa. Consequently, the TCs that develop from weaker AEWs are more likely to make landfall due to the close proximity of their genesis locations to the Americas.

Noncoding DNA is central to our understanding of human gene regulation and complex diseases1,2, and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome3,4,5,6,7,8,9. Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA10, the relatively short timescales separating primate species11, and the previously limited availability of whole-genome sequences12. Here we construct a whole-genome alignment of 239 species, representing nearly half of all extant species in the primate order. Using this resource, we identified human regulatory elements that are under selective constraint across primates and other mammals at a 5% false discovery rate. We detected 111,318 DNase I hypersensitivity sites and 267,410 transcription factor binding sites that are constrained specifically in primates but not across other placental mammals and validate their cis-regulatory effects on gene expression. These regulatory elements are enriched for human genetic variants that affect gene expression and complex traits and diseases. Our results highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals.

BACKGROUND: In spite of infants and children aged 0-5 years experiencing mental health difficulties being estimated to be in the range of 6%-18% globally, the mental health care needs for this age group are often overlooked in the design of specialist mental health services. Although there is increasing recognition of the importance of infant mental health services and treatments for younger children, access remains a barrier. Mental health services specifically designed for children 0-5 years are vital; however, little is known about how these services ensure access for infants at risk of mental health difficulties and their families. This scoping review seeks to address this knowledge gap. METHODS: A scoping review methodology framework was used to search for relevant articles published between January 2000 and July 2021, identified using five databases: MEDLINE, CINAHL, PsycINFO, SocIndex and Web of Science. The selection of studies was based on empirical research about access to infant mental health services and models of care. A total of 28 relevant articles met the eligibility criteria for inclusion in this review. RESULTS: Findings can be summarised under five broad themes: (1) accessibility for at-risk populations (2) the importance of early detection of infants in need of mental health services and interventions; (3) the promotion of culturally responsive services and interventions; (4) ensuring the sustainability of IMH services and programs and (5) the integration of innovative interventions to improve existing practice models. CONCLUSIONS: The findings from this scoping review highlight barriers to access and provision of infant mental health services. Future infant mental health service design, informed by research, is needed to improve access for infants and young children with mental health difficulties and their families.

Extreme weather has a direct and significant impact on buildings and infrastructure, resulting in billions of dollars of damage each year. This problem continues to grow as climate patterns change and buildings are exposed to new and different hazards than what they were designed to withstand. In order to better plan for the long-range sustainment, restoration, modernization, and eventual recapitalization of these buildings, organizations with large building portfolios, such as the U.S. Department of Defense (DoD), must have an awareness of the risks that these extreme weather events present. This research aimed to develop an approach to estimate condition loss and reduction in service life for the components of a building due to extreme weather hazards, to understand the risks that may be present in certain buildings and building systems. To achieve this objective, a damage association matrix was developed that categorizes climate hazards, the damage modes that they produce, and the individual component types impacted. This damage matrix formally links state-of-the-art climate model output, which provides projections of the probability of various climate hazards with a damage effects model that quantifies the consequence on component-level condition and service life. This method is applied to an actual portfolio of buildings in a particular geographic location and with a pre-defined component inventory that comprises the building. This approach can be aggregated to the system-, facility-, and site-level thus helping support billions of dollars in recapitalization decisions related to restoration/modernization of facilities.

Vocal production learning (vocal learning) is a convergently evolved trait in vertebrates. To identify brain genomic elements associated with mammalian vocal learning, we integrated genomic, anatomical, and neurophysiological data from the Egyptian fruit bat (Rousettus aegyptiacus) with analyses of the genomes of 215 placental mammals. First, we identified a set of proteins evolving more slowly in vocal learners. Then, we discovered a vocal motor cortical region in the Egyptian fruit bat, an emergent vocal learner, and leveraged that knowledge to identify active cis-regulatory elements in the motor cortex of vocal learners. Machine learning methods applied to motor cortex open chromatin revealed 50 enhancers robustly associated with vocal learning whose activity tended to be lower in vocal learners. Our research implicates convergent losses of motor cortex regulatory elements in mammalian vocal learning evolution.

Mungbean [Vigna radiata (L.) R. Wilczek var. radiata] is an important source of plant protein for consumers and a high-value export crop for growers across Asia, Australia, and Africa. However, many commercial cultivars are highly vulnerable to biotic stresses, which rapidly reduces yield within the season. Fusarium oxysporum is a soil-borne pathogen that is a growing concern for mungbean growers globally. This pathogen causes Fusarium wilt by infecting the root system of the plant resulting in devastating yield reductions. To understand the impact of Fusarium on mungbean development and productivity and to identify tolerant genotypes, a panel of 23 diverse accessions were studied. Field trials conducted in 2016 and 2021 in Warwick, Queensland, Australia under rainfed conditions investigated the variation in phenology, canopy and yield component traits under disease and disease-free conditions. Analyses revealed a high degree of genetic variation for all traits. By comparing the performance of these traits across these two environments, we identified key traits that underpin yield under disease and disease-free conditions. Aboveground biomass components at 50% flowering were identified as significant drivers of yield development under disease-free conditions and when impacted by Fusarium resulted in up to 96% yield reduction. Additionally, eight genotypes were identified to be tolerant to Fusarium. These genotypes were found to display differing phenological and morphological behaviours, thereby demonstrating the potential to breed for tolerant lines with a range of diverse trait variations. The identification of tolerant genotypes that sustain yield under disease pressure may be exploited in crop improvement programs.

Noncoding DNA is central to our understanding of human gene regulation and complex diseases1,2, and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome3,4,5,6,7,8,9. Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA10, the relatively short timescales separating primate species11, and the previously limited availability of whole-genome sequences12. Here we construct a whole-genome alignment of 239 species, representing nearly half of all extant species in the primate order. Using this resource, we identified human regulatory elements that are under selective constraint across primates and other mammals at a 5% false discovery rate. We detected 111,318 DNase I hypersensitivity sites and 267,410 transcription factor binding sites that are constrained specifically in primates but not across other placental mammals and validate their cis-regulatory effects on gene expression. These regulatory elements are enriched for human genetic variants that affect gene expression and complex traits and diseases. Our results highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals.

Noncoding DNA is central to our understanding of human gene regulation and complex diseases1,2, and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome3,4,5,6,7,8,9. Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA10, the relatively short timescales separating primate species11, and the previously limited availability of whole-genome sequences12. Here we construct a whole-genome alignment of 239 species, representing nearly half of all extant species in the primate order. Using this resource, we identified human regulatory elements that are under selective constraint across primates and other mammals at a 5% false discovery rate. We detected 111,318 DNase I hypersensitivity sites and 267,410 transcription factor binding sites that are constrained specifically in primates but not across other placental mammals and validate their cis-regulatory effects on gene expression. These regulatory elements are enriched for human genetic variants that affect gene expression and complex traits and diseases. Our results highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals.

The Australian Centre for Health, Independence, Economic participation and Value Enhanced care for adolescents and young adults with Cerebral Palsy (CP-ACHIEVE) is a Centre of Research Excellence (CRE), funded for 5-year by the National Health and Medical Research Council of Australia. The vision of CP-ACHIEVE is an Australia where people with cerebral palsy receive excellent healthcare throughout their lives and live in, and contribute to, supportive communities that welcome and enable their participation. CP-ACHIEVE began with the ethical commitment to bring together people with lived experience of cerebral palsy, researchers, and health professionals to develop and conduct research informed by, and relevant to, people with cerebral palsy and their allies. From inception, co-research and collaboration with (not 'to' or 'about') young people with cerebral palsy (10 to 30 years of age) and their families has been central to our work. In this paper, we describe the CP-ACHIEVE values, structure and strategy for this approach, and its implementation at each stage of the research process. We then provide an example of the strategy in action, using a qualitative exploration of CP-ACHIEVE's Participation Theme team's experiences of collaboration and involvement as co-researchers. Active participation in research for young people with lived experience of cerebral palsy and their families is a fundamental human right, based on their right to be active agents in decisions that affect them. In this paper we explore how our collaborative approach, and the integration of diverse views, has enhanced the relevance, quality, usefulness, and translation of our research. We also describe (i) the structural elements of our research group that have facilitated our work together, (ii) our challenges, and (iii) how the ownership of our research by people with cerebral palsy is driving future research directions and empowering involvement of people with lived experience beyond CP-ACHIEVE

Noncoding DNA is central to our understanding of human gene regulation and complex diseases1,2, and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome3,4,5,6,7,8,9. Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA10, the relatively short timescales separating primate species11, and the previously limited availability of whole-genome sequences12. Here we construct a whole-genome alignment of 239 species, representing nearly half of all extant species in the primate order. Using this resource, we identified human regulatory elements that are under selective constraint across primates and other mammals at a 5% false discovery rate. We detected 111,318 DNase I hypersensitivity sites and 267,410 transcription factor binding sites that are constrained specifically in primates but not across other placental mammals and validate their cis-regulatory effects on gene expression. These regulatory elements are enriched for human genetic variants that affect gene expression and complex traits and diseases. Our results highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals.

Tornadoes are a co-occurring extreme that can be produced by landfalling tropical cyclones (TCs). These tornadoes can exacerbate the loss of life and property damage caused by the TC from which they were spawned. It is uncertain how the severe weather environments of landfalling TCs may change in a future climate and how this could impact tornado activity from TCs. In this study, we investigated four TCs that made landfall in the U.S. and produced large tornado outbreaks. We performed four-member ensembles of convective-allowing (4-km resolution) regional climate model simulations representing each TC in the historical climate and a mid-twenty-first century future climate. To identify potentially tornadic storms, or TC-tornado (TCT) surrogates, we used thresholds for three-hourly maximum updraft helicity and radar reflectivity, as tornadoes are not resolved in the model. We found that the ensemble-mean number of TCT-surrogates increased substantially (56–299%) in the future, supported by increases in most-unstable convective available potential energy, surface-to-700-hPa bulk wind shear, and 0–1-km storm-relative helicity in the tornado-producing region of the TCs. On the other hand, future changes in most-unstable convective inhibition had minimal influence on future TCT-surrogates. This provides robust evidence that tornado activity from TCs may increase in the future. Furthermore, TCT-surrogate frequency between 00Z and 09Z increased for three of the four cases, suggesting enhanced tornado activity at night, when people are asleep and more likely to miss warnings. All of these factors indicate that TC-tornadoes may become more frequent and a greater hazard in the future, compounding impacts from future increases in TC winds and precipitation.

Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss among the elderly in Western communities, with an estimated global prevalence of 10 - 20% in people older than 65 years. AMD leads to central vision loss due to degeneration of the photoreceptors, retinal pigment epithelium and the choriocapillaris. Beckman's classification for AMD, based upon color fundus photographs, divides the disease into early, intermediate, and late forms. The late, vision-threatening stage includes both neovascular AMD and geographic atrophy. Despite its high prevalence and impact on patients' quality of life, treatment options for AMD are limited. While neovascular AMD can be medically managed with anti-VEGF intravitreal injections, until very recently there has been no approved treatment options for atrophic AMD; however, in February 2023 the first treatment for geographic atrophy - pegcetacoplan - was approved by the US FDA. We describe the current landscape of potential gene and cell therapeutic strategies for late-stage AMD, with an emphasis on the therapeutic options that might become available in the next few years.

Single-cell RNA sequencing (scRNA-Seq) has emerged as a powerful tool for understanding cellular heterogeneity and function. However the choice of sample multiplexing reagents can impact data quality and experimental outcomes. In this study, we compared various multiplexing reagents, including MULTI-Seq, Hashtag antibody, and CellPlex, across diverse sample types such as human peripheral blood mononuclear cells (PBMCs), mouse embryonic brain and patient-derived xenografts (PDXs). We found that all multiplexing reagents worked well in cell types robust to ex vivo manipulation but suffered from signal-to-noise issues in more delicate sample types. We compared multiple demultiplexing algorithms which differed in performance depending on data quality. We find that minor improvements to laboratory workflows such as titration and rapid processing are critical to optimal performance. We also compared the performance of fixed scRNA-Seq kits and highlight the advantages of the Parse Biosciences kit for fragile samples. Highly multiplexed scRNA-Seq experiments require more sequencing resources, therefore we evaluated CRISPR-based destruction of non-informative genes to enhance sequencing value. Our comprehensive analysis provides insights into the selection of appropriate sample multiplexing reagents and protocols for scRNA-Seq experiments, facilitating more accurate and cost-effective studies.

BACKGROUND: An estimated 1 in 350 women carry germline BRCA1/2 mutations, which confer an increased risk of developing breast and ovarian cancer, and may also contribute to subfertility. All mature, sex steroid-producing ovarian follicles are drawn from the pool of non-renewable primordial follicles, termed the 'ovarian reserve'. The clinical implications of early ovarian reserve exhaustion extend beyond infertility, to include the long-term adverse health consequences of loss of endocrine function and premature menopause. We aimed to determine whether conditional loss of Brca1 in oocytes impacts ovarian follicle numbers, oocyte quality and fertility in mice with advancing maternal age. We also aimed to determine the utility of AMH as a marker of ovarian function, by assessing circulating AMH levels in mice and women with BRCA1/2 mutations, and correlating this with ovarian follicle counts. METHODS: In this study, we addressed a longstanding question in the field regarding the functional consequences of BRCA1 inactivation in oocytes. To recapitulate loss of BRCA1 protein function in oocytes, we generated mice with conditional gene deletion of Brca1 in oocytes using Gdf9-Cre recombinase (WT: Brca1fl/flGdf9+/+; cKO: Brca1fl/flGdf9cre/+). FINDINGS: While the length of the fertile lifespan was not altered between groups after a comprehensive breeding trial, conditional loss of Brca1 in oocytes led to reduced litter size in female mice. Brca1 cKO animals had a reduced ovarian reserve and oocyte maturation was impaired with advanced maternal age at postnatal day (PN)300, compared to WT animals. Serum anti-Müllerian hormone (AMH) concentrations (the gold-standard indirect marker of the ovarian reserve used in clinical practice) were not predictive of reduced primordial follicle number in Brca1 cKO mice versus WT. Furthermore, we found no correlation between follicle number or density and serum AMH concentrations in matched samples from a small cohort of premenopausal women

Local Area Coordination (LAC) roles have been implemented in disability services in many countries, supporting people living with disability to connect with formal and informal support in the community. Embedded in the National Disability Insurance Scheme in Australia, the aspiration is that this LAC role will connect people with disability to supports and enable the generation of greater community capacity and inclusion. Yet, with only a limited evidence base that demonstrates the impact of this approach, a clear measurement framework is needed to provide evidence of the realization of this aspiration. We propose that this impact could be demonstrated by applying a Community Capitals Framework (CCF) as the theoretical base for the LAC role and other community capacity initiatives, such as service navigation within disability reform of disability services. The CCF is premised on seven ‘capitals’—social, natural, cultural, human, political, financial and built that intersect and interact with each other to create positive spirals of change in communities. In this critical literature review, we apply the CCF to map and synthesize existing research on the LAC’s role in building community capital and examine the utility of the CCF as a map for LAC and service navigation practices to enhance community inclusion. For this review, we analyzed peer-reviewed journal papers and grey literature that focused on LAC community capacity building for people with disability in a disability service context published between 2000 and August 2023. Of the 17 publications that met the inclusion criteria, there was no published evidence that comprehensively examined or measured community capacity building consistent with the tenets of the CCF. However, our analysis showed that all capitals, with the exception of natural capital, had been considered, with some indication that investment in these capitals (particularly social capital) could be connected in the positive spiraling way suggest

Spatial molecular data has transformed the study of disease microenvironments, though, larger datasets pose an analytics challenge prompting the direct adoption of single-cell RNA-sequencing tools including normalization methods. Here, we demonstrate that library size is associated with tissue structure and that normalizing these effects out using commonly applied scRNA-seq normalization methods will negatively affect spatial domain identification. Spatial data should not be specifically corrected for library size prior to analysis, and algorithms designed for scRNA-seq data should be adopted with caution.

Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.

The Australian Centre for Health, Independence, Economic participation and Value Enhanced care for adolescents and young adults with Cerebral Palsy (CP-ACHIEVE) is a Centre of Research Excellence (CRE), funded for 5-year by the National Health and Medical Research Council of Australia. The vision of CP-ACHIEVE is an Australia where people with cerebral palsy receive excellent healthcare throughout their lives and live in, and contribute to, supportive communities that welcome and enable their participation. CP-ACHIEVE began with the ethical commitment to bring together people with lived experience of cerebral palsy, researchers, and health professionals to develop and conduct research informed by, and relevant to, people with cerebral palsy and their allies. From inception, co-research and collaboration with (not ‘to’ or ‘about’) young people with cerebral palsy (10 to 30 years of age) and their families has been central to our work. In this paper, we describe the CP-ACHIEVE values, structure and strategy for this approach, and its implementation at each stage of the research process. We then provide an example of the strategy in action, using a qualitative exploration of CP-ACHIEVE’s Participation Theme team’s experiences of collaboration and involvement as co-researchers. Active participation in research for young people with lived experience of cerebral palsy and their families is a fundamental human right, based on their right to be active agents in decisions that affect them. In this paper we explore how our collaborative approach, and the integration of diverse views, has enhanced the relevance, quality, usefulness, and translation of our research. We also describe (i) the structural elements of our research group that have facilitated our work together, (ii) our challenges, and (iii) how the ownership of our research by people with cerebral palsy is driving future research directions and empowering involvement of people with lived experience beyond CP-ACHIEVE

BACKGROUND: Nurse perceptions of developmental care practices have been researched globally for almost 30 years. Yet, there is a lack of research exploring this subject in the specialised setting of the surgical neonatal intensive care unit (sNICU). This research explores the effect of developmental care education programs on sNICU nurses' perceptions of developmental care. OBJECTIVE: To determine perceptions and attitudes towards developmental care in a specialty neonatal setting. DESIGN: Cross-sectional study. SETTINGS: Two surgical neonatal intensive care units in Australia. PARTICIPANTS: Registered nurses permanently employed at the study sites between May 2021 to April 2022. METHODS: A modified electronic survey explored sNICU nurse perceptions of developmental care organised around three themes: effects of developmental care on parents and infants, application of developmental care, and unit practices. Associations between site, nurse characteristics, developmental care education and nurses' perceptions were explored using logistic regression [odds ratios (OR) and 95 % confidence intervals (CI)]. RESULTS: Of 295 sNICU nurses, 117 (40 %) participated in the survey. Seventy-five percent of respondents had attended a formal developmental care education program. High levels of agreement (>90 %) were reported regarding the benefits of developmental care for parents and infants. Exposure to developmental care education influenced perceptions of its application. Nurses without formal developmental care education were more likely to agree that it was consistently applied [OR:3.3, 95%CI:1.3-8.6], developmental care skills are valued [OR:2.7, 95%CI:1.1-6.8], and that their nursing peers offered support in its application ([OR:2.5, 95%CI:1.1-6.2]. CONCLUSIONS: The results from our research suggest sNICU nurses have a high level of awareness of developmental care and its positive impacts. Despite differences between the surveyed units' developmental care education program

BACKGROUND: Nurse perceptions of developmental care practices have been researched globally for almost 30 years. Yet, there is a lack of research exploring this subject in the specialised setting of the surgical neonatal intensive care unit (sNICU). This research explores the effect of developmental care education programs on sNICU nurses' perceptions of developmental care. OBJECTIVE: To determine perceptions and attitudes towards developmental care in a specialty neonatal setting. DESIGN: Cross-sectional study. SETTINGS: Two surgical neonatal intensive care units in Australia. PARTICIPANTS: Registered nurses permanently employed at the study sites between May 2021 to April 2022. METHODS: A modified electronic survey explored sNICU nurse perceptions of developmental care organised around three themes: effects of developmental care on parents and infants, application of developmental care, and unit practices. Associations between site, nurse characteristics, developmental care education and nurses' perceptions were explored using logistic regression [odds ratios (OR) and 95 % confidence intervals (CI)]. RESULTS: Of 295 sNICU nurses, 117 (40 %) participated in the survey. Seventy-five percent of respondents had attended a formal developmental care education program. High levels of agreement (>90 %) were reported regarding the benefits of developmental care for parents and infants. Exposure to developmental care education influenced perceptions of its application. Nurses without formal developmental care education were more likely to agree that it was consistently applied [OR:3.3, 95%CI:1.3-8.6], developmental care skills are valued [OR:2.7, 95%CI:1.1-6.8], and that their nursing peers offered support in its application ([OR:2.5, 95%CI:1.1-6.2]. CONCLUSIONS: The results from our research suggest sNICU nurses have a high level of awareness of developmental care and its positive impacts. Despite differences between the surveyed units' developmental care education program

Noncoding DNA is central to our understanding of human gene regulation and complex diseases1,2, and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome3,4,5,6,7,8,9. Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA10, the relatively short timescales separating primate species11, and the previously limited availability of whole-genome sequences12. Here we construct a whole-genome alignment of 239 species, representing nearly half of all extant species in the primate order. Using this resource, we identified human regulatory elements that are under selective constraint across primates and other mammals at a 5% false discovery rate. We detected 111,318 DNase I hypersensitivity sites and 267,410 transcription factor binding sites that are constrained specifically in primates but not across other placental mammals and validate their cis-regulatory effects on gene expression. These regulatory elements are enriched for human genetic variants that affect gene expression and complex traits and diseases. Our results highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals.

In our initial research of third spaces and their use, we found a gap between the benefits of third spaces and how planners design those spaces. The existing literature on third spaces is fragmented across a myriad of terms, checksheets, and indexes, each with some overlap but different foci. This discord impedes a planner’s ability to design a third space that effectively accounts for the various factors academics have put forth in their research. To remedy this, we conducted an investigation into the existing understanding of third spaces and aggregated the results into one product, distilling them into a comprehensive list of criteria that is usable for planners. We then applied those criteria to Virginia Tech’s 2047 Beyond Boundaries plan to assess how well the university’s goals align with the existing third space literature. This serves as an example of our criteria in action, demonstrating their applicability. Finally, we created a list of qualitative questions based on our criteria that planners can use when designing a space. This will provide a concrete tool to fill the gap between third space benefits and how planners design third spaces, providing greater clarity and support as they design the spaces of tomorrow.

Transboundary fishery management represents a significant governance challenge that requires ongoing inter-organizational communication, collaboration, and collective action to ensure sustainability. Previous research suggests that different dimensions of perceived risk, trust, and control interact in complex ways to affect inter-organizational collaborative performance, providing an administrative ‘architecture’ that enables partners to share resources, engage in teamwork, resolve conflict, and coordinate tasks and responsibilities while also allaying their concerns about the alliance. However, the extent to which different control mechanisms influence trust and mitigate the perceived risks of collaboration between the diverse organizations involved in transboundary fisheries management remains unclear. This paper presents the quantitative results of survey research conducted in the Salish Sea of North America, an ecosystem spanning the Canada-US border between British Columbia and Washington State. The survey instrument operationalizes a multi-dimensional trust-control-risk framework considered suitable for studying inter-organizational natural resource management (NRM) networks. The findings support descriptions of the Salish Sea as having fewer nation-to-nation governing bodies resulting in a lack of effective formal controls, high perceived regulatory risk, and low procedural trust attributes that can negatively affect the collaborative performance of the fishery management network. This study represents the first quantitative analysis of the complex relationships between different inter-organizational management strategies, trust dimensions, and perceived risks in transboundary fisheries governance, and offers new directions for future research on NRM collaboration.

Genomes are typically mosaics of regions with different evolutionary histories. When speciation events are closely spaced in time, recombination makes the regions sharing the same history small, and the evolutionary history changes rapidly as we move along the genome. When examining rapid radiations such as the early diversification of Neoaves 66 Mya, typically no consistent history is observed across segments exceeding kilobases of the genome. Here, we report an exception. We found that a 21-Mb region in avian genomes, mapped to chicken chromosome 4, shows an extremely strong and discordance-free signal for a history different from that of the inferred species tree. Such a strong discordance-free signal, indicative of suppressed recombination across many millions of base pairs, is not observed elsewhere in the genome for any deep avian relationships. Although long regions with suppressed recombination have been documented in recently diverged species, our results pertain to relationships dating circa 65 Mya. We provide evidence that this strong signal may be due to an ancient rearrangement that blocked recombination and remained polymorphic for several million years prior to fixation. We show that the presence of this region has misled previous phylogenomic efforts with lower taxon sampling, showing the interplay between taxon and locus sampling. We predict that similar ancient rearrangements may confound phylogenetic analyses in other clades, pointing to a need for new analytical models that incorporate the possibility of such events.

Mungbean [Vigna radiata (L.) R. Wilczek var. radiata] is an important source of plant protein for consumers and a high-value export crop for growers across Asia, Australia, and Africa. However, many commercial cultivars are highly vulnerable to biotic stresses, which rapidly reduces yield within the season. Fusarium oxysporum is a soil-borne pathogen that is a growing concern for mungbean growers globally. This pathogen causes Fusarium wilt by infecting the root system of the plant resulting in devastating yield reductions. To understand the impact of Fusarium on mungbean development and productivity and to identify tolerant genotypes, a panel of 23 diverse accessions were studied. Field trials conducted in 2016 and 2021 in Warwick, Queensland, Australia under rainfed conditions investigated the variation in phenology, canopy and yield component traits under disease and disease-free conditions. Analyses revealed a high degree of genetic variation for all traits. By comparing the performance of these traits across these two environments, we identified key traits that underpin yield under disease and disease-free conditions. Aboveground biomass components at 50% flowering were identified as significant drivers of yield development under disease-free conditions and when impacted by Fusarium resulted in up to 96% yield reduction. Additionally, eight genotypes were identified to be tolerant to Fusarium. These genotypes were found to display differing phenological and morphological behaviours, thereby demonstrating the potential to breed for tolerant lines with a range of diverse trait variations. The identification of tolerant genotypes that sustain yield under disease pressure may be exploited in crop improvement programs.

Noncoding DNA is central to our understanding of human gene regulation and complex diseases1,2, and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome3,4,5,6,7,8,9. Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA10, the relatively short timescales separating primate species11, and the previously limited availability of whole-genome sequences12. Here we construct a whole-genome alignment of 239 species, representing nearly half of all extant species in the primate order. Using this resource, we identified human regulatory elements that are under selective constraint across primates and other mammals at a 5% false discovery rate. We detected 111,318 DNase I hypersensitivity sites and 267,410 transcription factor binding sites that are constrained specifically in primates but not across other placental mammals and validate their cis-regulatory effects on gene expression. These regulatory elements are enriched for human genetic variants that affect gene expression and complex traits and diseases. Our results highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals., Noncoding DNA is central to our understanding of human gene regulation and complex diseases1,2, and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome3–9. Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA10, the relatively short timescales separating primate species11, and the previously limited availability of whole-genome sequences12. Here we construct a whole-genome alignment of 239 species, representing nearly half of all extant species in the primate order. Using this resource, we identified human regulatory elements that are under selective constraint across primates and other mammals at a 5% false discovery rate. We detected 111,318 DNase I hypersensitivity sites and 267,410 transcription factor binding sites that are constrained specifically in primates but not across other placental mammals and validate their cis-regulatory effects on gene expression. These regulatory elements are enriched for human genetic variants that affect gene expression and complex traits and diseases. Our results highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals.

Genomes are typically mosaics of regions with different evolutionary histories. When speciation events are closely spaced in time, recombination makes the regions sharing the same history small, and the evolutionary history changes rapidly as we move along the genome. When examining rapid radiations such as the early diversification of Neoaves 66 Mya, typically no consistent history is observed across segments exceeding kilobases of the genome. Here, we report an exception. We found that a 21-Mb region in avian genomes, mapped to chicken chromosome 4, shows an extremely strong and discordance-free signal for a history different from that of the inferred species tree. Such a strong discordance-free signal, indicative of suppressed recombination across many millions of base pairs, is not observed elsewhere in the genome for any deep avian relationships. Although long regions with suppressed recombination have been documented in recently diverged species, our results pertain to relationships dating circa 65 Mya. We provide evidence that this strong signal may be due to an ancient rearrangement that blocked recombination and remained polymorphic for several million years prior to fixation. We show that the presence of this region has misled previous phylogenomic efforts with lower taxon sampling, showing the interplay between taxon and locus sampling. We predict that similar ancient rearrangements may confound phylogenetic analyses in other clades, pointing to a need for new analytical models that incorporate the possibility of such events.

Noncoding DNA is central to our understanding of human gene regulation and complex diseases1,2, and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome3,4,5,6,7,8,9. Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA10, the relatively short timescales separating primate species11, and the previously limited availability of whole-genome sequences12. Here we construct a whole-genome alignment of 239 species, representing nearly half of all extant species in the primate order. Using this resource, we identified human regulatory elements that are under selective constraint across primates and other mammals at a 5% false discovery rate. We detected 111,318 DNase I hypersensitivity sites and 267,410 transcription factor binding sites that are constrained specifically in primates but not across other placental mammals and validate their cis-regulatory effects on gene expression. These regulatory elements are enriched for human genetic variants that affect gene expression and complex traits and diseases. Our results highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals.

Noncoding DNA is central to our understanding of human gene regulation and complex diseases1,2, and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome3,4,5,6,7,8,9. Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA10, the relatively short timescales separating primate species11, and the previously limited availability of whole-genome sequences12. Here we construct a whole-genome alignment of 239 species, representing nearly half of all extant species in the primate order. Using this resource, we identified human regulatory elements that are under selective constraint across primates and other mammals at a 5% false discovery rate. We detected 111,318 DNase I hypersensitivity sites and 267,410 transcription factor binding sites that are constrained specifically in primates but not across other placental mammals and validate their cis-regulatory effects on gene expression. These regulatory elements are enriched for human genetic variants that affect gene expression and complex traits and diseases. Our results highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals., Noncoding DNA is central to our understanding of human gene regulation and complex diseases1,2, and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome3–9. Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA10, the relatively short timescales separating primate species11, and the previously limited availability of whole-genome sequences12. Here we construct a whole-genome alignment of 239 species, representing nearly half of all extant species in the primate order. Using this resource, we identified human regulatory elements that are under selective constraint across primates and other mammals at a 5% false discovery rate. We detected 111,318 DNase I hypersensitivity sites and 267,410 transcription factor binding sites that are constrained specifically in primates but not across other placental mammals and validate their cis-regulatory effects on gene expression. These regulatory elements are enriched for human genetic variants that affect gene expression and complex traits and diseases. Our results highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals.

Noncoding DNA is central to our understanding of human gene regulation and complex diseases 1,2 ,and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome 3–9 .Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA 10 ,the relatively short timescales separating primate species 11 ,and the previously limited availability of whole-genome sequences 12 .Here we construct a whole-genome alignment of 239 species, representing nearly half of all extant species in the primate order. Using this resource, we identified human regulatory elements that are under selective constraint across primates and other mammals at a 5% false discovery rate. We detected 111,318 DNase I hypersensitivity sites and 267,410 transcription factor binding sites that are constrained specifically in primates but not across other placental mammals and validate their cis -regulatory effects on gene expression. These regulatory elements are enriched for human genetic variants that affect gene expression and complex traits and diseases. Our results highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals., SCOPUS: ar.j, info:eu-repo/semantics/published

This paper introduces a user-friendly platform developed by the University of Kentucky Center for Applied AI, designed to make large, customized language models (LLMs) more accessible. By capitalizing on recent advancements in multi-LoRA inference, the system efficiently accommodates custom adapters for a diverse range of users and projects. The paper outlines the system's architecture and key features, encompassing dataset curation, model training, secure inference, and text-based feature extraction. We illustrate the establishment of a tenant-aware computational network using agent-based methods, securely utilizing islands of isolated resources as a unified system. The platform strives to deliver secure LLM services, emphasizing process and data isolation, end-to-end encryption, and role-based resource authentication. This contribution aligns with the overarching goal of enabling simplified access to cutting-edge AI models and technology in support of scientific discovery., Comment: 10 pages 11 figures, 5 listings, 4 tables

This paper investigates the 1946 Great Campaign translation of the Epic of Manas and the characterization of its criticism and the justification of the translation project in the context of its 1952 condemnations. This paper explores the 1926 transcription of the Great Campaign by Sagimbay Uulu Orozbaq, his background, and political context. By examining the conditions of publication of the 1946 Great Campaign, this paper shows how these conditions contributed to the creation of an ideologically vulnerable text. This analysis is contextualize within the 1952 conference and Soviet Wide anti-epic trend, providing insight into the reasons for pulling the book from circulation. Methodologically, archival research conducted at the Central State Archives, Toktogul Museum, and Manas Ordo Museum, coupled with the examination of newspapers from the Eastview digital archive, form the backbone of this study. Personal experiences with nineteen interviews and recordings with two Manaschi in Kyrgyzstan provide invaluable insights. In conclusion, this paper underscores how the response to criticism regarding the ideological content of the book was primarily centered on justifying the role and intent of the translation project while deflecting accountability towards both the Manaschi and the 1922-26 transcription project.

Counterspeech -- speech that opposes hate speech -- has gained significant attention recently as a strategy to reduce hate on social media. While previous studies suggest that counterspeech can somewhat reduce hate speech, little is known about its effects on participation in online hate communities, nor which counterspeech tactics reduce harmful behavior. We begin to address these gaps by identifying 25 large hate communities ("subreddits") within Reddit and analyzing the effect of counterspeech on newcomers within these communities. We first construct a new public dataset of carefully annotated counterspeech and non-counterspeech comments within these subreddits. We use this dataset to train a state-of-the-art counterspeech detection model. Next, we use matching to evaluate the causal effects of hostile and non-hostile counterspeech on the engagement of newcomers in hate subreddits. We find that, while non-hostile counterspeech is ineffective at keeping users from fully disengaging from these hate subreddits, a single hostile counterspeech comment substantially reduces both future likelihood of engagement. While offering nuance to the understanding of counterspeech efficacy, these results a) leave unanswered the question of whether hostile counterspeech dissuades newcomers from participation in online hate writ large, or merely drives them into less-moderated and more extreme hate communities, and b) raises ethical considerations about hostile counterspeech, which is both comparatively common and might exacerbate rather than mitigate the net level of antagonism in society. These findings underscore the importance of future work to improve counterspeech tactics and minimize unintended harm., Comment: 19 pages, 11 figures. arXiv admin note: text overlap with arXiv:2303.13641

Many online hate groups exist to disparage others based on race, gender identity, sex, or other characteristics. The accessibility of these communities allows users to join multiple types of hate groups (e.g., a racist community and misogynistic community), which calls into question whether these peripatetic users could be further radicalized compared to users that stay in one type of hate group. However, little is known about the dynamics of joining multiple types of hate groups, nor the effect of these groups on peripatetic users. In this paper, we develop a new method to classify hate subreddits, and the identities they disparage, which we use to better understand how users become peripatetic (join different types of hate subreddits). The hate classification technique utilizes human-validated LLMs to extract the protected identities attacked, if any, across 168 subreddits. We then cluster identity-attacking subreddits to discover three broad categories of hate: racist, anti-LGBTQ, and misogynistic. We show that becoming active in a user's first hate subreddit can cause them to become active in additional hate subreddits of a different category. We also find that users who join additional hate subreddits, especially of a different category, become more active in hate subreddits as a whole and develop a wider hate group lexicon. We are therefore motivated to train an AI model that we find usefully predicts the hate categories users will become active in based on post text read and written. The accuracy of this model may be partly driven by peripatetic users often using the language of hate subreddits they eventually join. Overall, these results highlight the unique risks associated with hate communities on a social media platform, as discussion of alternative targets of hate may lead users to target more protected identities., Comment: 11 pages, 6 figures

It is well established that African easterly waves (AEWs) can serve as seedling disturbances for Atlantic tropical cyclones (TCs). However, research has shown that AEWs are not necessary to maintain specifically basin-wide TC frequency. Here, we for the first time investigate the effects of AEW suppression by wave track on Atlantic TC activity. Regional model simulations were performed, where AEWs were either prescribed or suppressed from the eastern lateral boundary condition. We found that without AEWs, there was an increase in TC frequency and strength, with the most pronounced increases occurring when the waves were suppressed in the south track. These changes coincided with more favorable environmental conditions and disturbances associated with increased convective activity over the Atlantic. Our results indicate that AEWs are not a limiting factor for TCs, and that AEW suppression, specifically in the south track, can affect the large-scale environment to enhance favorability for TC genesis.

IntroductionSwitch to dolutegravir (DTG) in treatment-experienced people living with HIV (PLH) is associated with excess weight gain in some settings; data are limited from rural low-income settings with low obesity prevalence.MethodsIn rural Kenya, we conducted a retrospective cohort study at 8 HIV clinics and a single-site prospective cohort study including adults switching to DTG during countrywide transition to DTG/tenofovir DF(TDF)/emtricitabine as first-line HIV treatment. In the retrospective analysis, we used preswitch data to model postswitch weight trajectory had each participant not switched to DTG and contrasted observed vs. predicted postswitch weight. In the prospective analysis, we measured weight post-DTG switch and evaluated predictors of 6-month weight change.ResultsOur retrospective cohort included 4445 PLH who switched to DTG between 2018 and 2020. Mean 12-month weight change was 0.6 kg preswitch and 0.8 kg postswitch. Among those on TDF throughout (n = 3374; 83% on efavirenz preswitch), 12-month postswitch weight was 0.7 kg more than predicted for women (95% CI: 0.4, 1.0) and similar among men (0.04 kg; 95% CI -0.3, 0.4). In our prospective cohort (n = 135, 100% female), mean 6-month weight change was +0.4 kg (IQR -1.1, 2.0 kg). Predicted gain varied by baseline food insecurity: +1.1 kg (95% CI: 0.34, 1.87) among food secure, -0.09 kg (95% CI -0.71, 0.54) among moderate insecure, and +0.27 kg (95% CI -0.82, 1.36) among severe insecurity.ConclusionIn contrast to some reports of large weight gain following switch to DTG, we observed small weight increases in women and no weight change in men following DTG switch when on TDF throughout. Weight gain may be attenuated by food insecurity, though was modest even among food secure.

IntroductionThe COVID-19 pandemic has required a shift of many routine primary care visits to telemedicine, potentially widening disparities in care access among vulnerable populations. In a publicly-funded HIV clinic, we aimed to evaluate a pre-visit phone-based planning intervention to address anticipated barriers to telemedicine.MethodsWe conducted a pragmatic randomized controlled trial of patients scheduled for a phone-based HIV primary care visit at the Ward 86 HIV clinic in San Francisco from 15 April to 15 May 2020. Once reached by phone, patients were randomized to either have a structured pre-visit planning intervention to address barriers to an upcoming telemedicine visit versus a standard reminder call. The primary outcome was telemedicine visit attendance.ResultsOf 476 scheduled telemedicine visits, 280 patients were reached by a pre-visit call to offer enrollment. Patients were less likely to be reached if virally unsuppressed (odds ratio (OR) 0.11, 95% confidence intervals (CI) 0.03-0.48), CD4 < 200 (OR 0.24, 95% CI 0.07-0.85), or were homeless (OR 0.24, 95% CI 0.07-0.87). There was no difference between intervention and control in scheduled visit attendance (83% v. 78%, OR 1.38, 95% CI 0.67-2.81).ConclusionsA structured phone-based planning call to address barriers to telemedicine in a public HIV clinic was less likely to reach patients with poorly-controlled HIV and patients experiencing homelessness, suggesting additional interventions may be needed in this population to ensure access to telemedicine-based care. Among patients reachable by phone, telemedicine visit attendance was high and not improved with a structured pre-visit intervention, suggesting that standard reminders may be adequate in this population.

Pangenome references address biases of reference genomes by storing a representative set of diverse haplotypes and their alignment, usually as a graph. Alternate alleles determined by variant callers can be used to construct pangenome graphs, but advances in long-read sequencing are leading to widely available, high-quality phased assemblies. Constructing a pangenome graph directly from assemblies, as opposed to variant calls, leverages the graph's ability to represent variation at different scales. Here we present the Minigraph-Cactus pangenome pipeline, which creates pangenomes directly from whole-genome alignments, and demonstrate its ability to scale to 90 human haplotypes from the Human Pangenome Reference Consortium. The method builds graphs containing all forms of genetic variation while allowing use of current mapping and genotyping tools. We measure the effect of the quality and completeness of reference genomes used for analysis within the pangenomes and show that using the CHM13 reference from the Telomere-to-Telomere Consortium improves the accuracy of our methods. We also demonstrate construction of a Drosophila melanogaster pangenome.

Following the end of the American Civil War in 1865, the U.S. War Department discharged an unprecedented 1.6 million personnel. While scholarship on soldiers’ lives is vast and varied, the historiography on soldiers’ lives as veterans is much less developed. Over the past thirty years, a subfield of scholarship on Civil War veterans has emerged. This dissertation, the first modern history of Union veterans in California, contributes to that scholarship by investigating how the state’s Union veterans marshaled their service to form fraternal organizations, memorialize the dead, lobby for pensions, and play prominent roles in popular and political culture. This dissertation contributes to the ongoing Western turn in Civil War-era scholarship by investigating the powerful, if protean, ideology of unionism in Reconstruction-era California. Although California has until recently been treated as marginal to the central problems of Reconstruction, uncovering how the state’s Union veterans adapted unionism to fashion communities and reshaped state politics enriches our understanding of the national struggles of the Civil War’s legacies. This research revealed that Union veterans in California employed unionism as the basis of their fellowship to promote nationalism, attack (and defend) Chinese immigration, justify imperialism, memorialize the war in public spaces, and provide medical and financial support to veterans and their dependents.

The field of molecular recognition illustrates the ability of synthetic receptors to act as hosts for important target molecules. These hosts are capable of binding guests in a manner akin to larger biological systems. Synthetic receptors are ideal molecules for observing host:guest interactions as they possess tunable structures that can be tailored to the desired target. As the differences in many biological targets are relatively small, the use of an array-based system allows for greater discrimination of these slight variations. This approach uses multiple variably functionalized receptors that act as a “chemical nose” for target molecules in a variety of optical sensing applications. This array-based system enables the receptors to sense a broader range of relevant biomacromolecules. The differential sensing of these small molecules can be measured via fluorescence outputs which are deconvoluted using Principal Component Analysis and other statistical methods. The use of water soluble deep cavitands allows for greater scope and tunability of their recognition abilities compared to other macrocyclic receptors. Much previous work has investigated deep cavitands with a negatively charged upper rim, so new structures that incorporate a positive charge were synthesized as a direct comparison of functionality. The diversification of functional groups at the upper rim broadens the scope of target molecules that the cavitands can sense, while the derivatization of the lower rim allows for increased solubility as well as secondary effects of the binding interactions. Deep cavitand hosts exhibit this selective target recognition by utilizing a self-folding deep pocket that provides a defined cavity for binding. This work has highlighted the importance of the synthetic variation of the receptors for sensing specific targets. The novel cationic cavitands remain neutral at the upper rim and only experience charge interactions at the lower rim of the structure. These positiv

We report the development of GPT-4, a large-scale, multimodal model which can accept image and text inputs and produce text outputs. While less capable than humans in many real-world scenarios, GPT-4 exhibits human-level performance on various professional and academic benchmarks, including passing a simulated bar exam with a score around the top 10% of test takers. GPT-4 is a Transformer-based model pre-trained to predict the next token in a document. The post-training alignment process results in improved performance on measures of factuality and adherence to desired behavior. A core component of this project was developing infrastructure and optimization methods that behave predictably across a wide range of scales. This allowed us to accurately predict some aspects of GPT-4's performance based on models trained with no more than 1/1,000th the compute of GPT-4., Comment: 100 pages; updated authors list; fixed author names and added citation

Tissues and organs are composed of distinct cell types that must operate in concert to perform physiological functions. Efforts to create high-dimensional biomarker catalogs of these cells have been largely based on single-cell sequencing approaches, which lack the spatial context required to understand critical cellular communication and correlated structural organization. To probe in situ biology with sufficient depth, several multiplexed protein imaging methods have been recently developed. Though these technologies differ in strategy and mode of immunolabeling and detection tags, they commonly utilize antibodies directed against protein biomarkers to provide detailed spatial and functional maps of complex tissues. As these promising antibody-based multiplexing approaches become more widely adopted, new frameworks and considerations are critical for training future users, generating molecular tools, validating antibody panels, and harmonizing datasets. In this Perspective, we provide essential resources, key considerations for obtaining robust and reproducible imaging data, and specialized knowledge from domain experts and technology developers.

Despite a long history of colonial, military, and extractive industry imposition on the land, waters, and people of Inuit Nunangat, resistance to such efforts is thriving. Through highlighting the work of The Place Names Program and Arnait Video Productions, I show how Nunavummiut (the people living in Nunavut) employ visual media to publicly wage their place-based knowledge as a mode of creative intervention against military and extractive forces, and the ways in which such forces have permeated Inuit bodies, lands, and waters. So successful are these visual acts of resistance that they compel southerners to reevaluate their approaches to northern development so drastically that projects are abandoned or no longer seen as viable. In putting these strategies into practice, Inuit engage with state-sanctioned systems of law and governance, but ultimately reshape these structures to better suit their own needs and the needs of the Arctic land and sea. The maps produced by the Place Names Program and films produced by Arnait Video Productions resist visions of the Arctic as a wasteland and of Inuit bodies as pollutable, instead putting forward visions of consent and reciprocity. Ultimately, I argue that seeing the Arctic in ways that challenge military and extractive representations and center Inuit epistemologies and voices, plays a significant role in halting the continued molecular and chemical colonization of Inuit lands and bodies. In other words, visual media is a tool for resisting unwanted extractive and military bodily intimacies, and insisting on consent before entry of these toxic presences.

Despite a long history of colonial, military, and extractive industry imposition on the land, waters, and people of Inuit Nunangat, resistance to such efforts is thriving. Through highlighting the work of The Place Names Program and Arnait Video Productions, I show how Nunavummiut (the people living in Nunavut) employ visual media to publicly wage their place-based knowledge as a mode of creative intervention against military and extractive forces, and the ways in which such forces have permeated Inuit bodies, lands, and waters. So successful are these visual acts of resistance that they compel southerners to reevaluate their approaches to northern development so drastically that projects are abandoned or no longer seen as viable. In putting these strategies into practice, Inuit engage with state-sanctioned systems of law and governance, but ultimately reshape these structures to better suit their own needs and the needs of the Arctic land and sea. The maps produced by the Place Names Program and films produced by Arnait Video Productions resist visions of the Arctic as a wasteland and of Inuit bodies as pollutable, instead putting forward visions of consent and reciprocity. Ultimately, I argue that seeing the Arctic in ways that challenge military and extractive representations and center Inuit epistemologies and voices, plays a significant role in halting the continued molecular and chemical colonization of Inuit lands and bodies. In other words, visual media is a tool for resisting unwanted extractive and military bodily intimacies, and insisting on consent before entry of these toxic presences.

As a result of the COVID-19 pandemic, mRNA-based therapeutics have rapidly changed from being the “therapeutics of the future” to tangible FDA-approved medicines available for people of all ages and medical backgrounds. One advance that allowed these therapies to be so effective are lipid nanoparticle-based delivery vehicles. However, despite the tremendous advances in lipid nanoparticle technologies, there are some inherent disadvantages in using lipid nanoparticles in therapeutic designs. To circumvent these limitations, new biodegradable and biocompatible mRNA delivery vehicles are being pursued as tools that can accommodate roles where lipid nanoparticles prove insufficient, particularly in the field of RNA therapeutics and gene therapy. Chapter 1 of this thesis provides an extensive introduction on the background of gene therapy, RNA-based therapeutics, and current mRNA therapy delivery vehicles/ approaches along with relevant limitations. CRISPR-Cas9 gene editing will also be briefly explored, along with the different viral and synthetic vectors that are currently being explored for relevant CRISPR-Cas therapies. Chapter 2 explores a novel approach of generating multifunctional polydisulfide polymers using a post-polymerization functionalization scheme. The mRNA-delivery capability of these polymers is also detailed using two model mRNAs. Chapter 3 explores using multifunctional dendronized linear polymers to generate polymeric-RNA nanoparticles containing Cas9-encoding mRNA and gene-targeting sgRNA. CRISPR-Cas9 gene editing using these polymeric nanoparticles is discussed, and relevant nanoparticle in vivo distribution is examined. Chapter 4 discusses exploration into a facile cryopolymerization methodology to generate anionic and cationic polydisulfides for the purpose of mRNA delivery. With the works explored in Chapters 2 and 4, two new synthetic methodologies are outlined that greatly expand the use of lipoic acid-derived polydisulfides for mRNA delivery.

Daily maximum temperatures during the 2021 heatwave in the Pacific Northwest United States and Canada shattered century old records. Multiple causal factors, including anthropogenic climate change, contributed to these high temperatures, challenging traditional methods of attributing human influence. We demonstrate that the observed 2021 daily maximum temperatures are far above the bounds of Generalized Extreme Value distributions fitted from historical data. Hence, confidence in Granger causal inference statements about the human influence on this heatwave is low. Alternatively, we present a more conditional hindcast attribution study using two regional models. We performed ensembles of simulations of the heatwave to investigate how the event would have changed if it had occurred without anthropogenic climate change and with future warming. We found that global warming caused a ∼0.8°C–1°C increase in heatwave temperatures. Future warming would lead to a ∼5°C increase in heatwave temperature by the end of the 21st century.

BackgroundPeople with HIV experiencing homelessness have low rates of viral suppression, driven by sociostructural barriers and traditional care system limitations. Informed by the capability-opportunity-motivation-behavior (COM-B) model and patient preference research, we developed POP-UP, an integrated drop-in (nonappointment-based) HIV clinic with wrap-around services for persons with housing instability and viral nonsuppression in San Francisco.MethodsWe report HIV viral suppression (VS; <200 copies/mL), care engagement, and mortality at 12 months postenrollment. We used logistic regression to determine participant characteristics associated with VS.ResultsWe enrolled 112 patients with viral nonsuppression and housing instability: 52% experiencing street-homelessness, 100% with a substance use disorder, and 70% with mental health diagnoses. At 12 months postenrollment, 70% had ≥1 visit each 4-month period, although 59% had a 90-day care gap; 44% had VS, 24% had viral nonsuppression, 23% missing, and 9% died (6 overdose, 2 AIDS-associated, 2 other). No baseline characteristics were associated with VS.ConclusionsThe POP-UP low-barrier HIV care model successfully reached and retained some of our clinic's highest-risk patients. It was associated with VS improvement from 0% at baseline to 44% at 12 months among people with housing instability. Care gaps and high mortality from overdose remain major challenges to achieving optimal HIV treatment outcomes in this population.