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Cultural evolution is changing humanity much faster than genetic evolution, but at present we lack a way to empirically ground models of cultural evolution in a quantitative, content-agnostic way analogous to counting alleles in models of genetic evolution. A way to measure what information ends up in which minds would permit quantitative models of the many different processes that govern the flow of memes through minds. We offer a method for estimating the amount of information retained based on previous exposure to a cultural artifact. Entropy estimates that are generated based on a test set from e.g. Harry Potter will differ between a treatment group (Readers, people who have read Harry Potter), and a control group (Non-Readers). This difference is an expression, in bits, of how much information from the book stored in Readers' minds and therefore capable of influencing behavior.

Abstract Genome-wide association studies (GWAS) identify genetic variants underlying complex traits but are limited by stringent genome-wide significance thresholds. We present GRIN (Gene set Refinement through Interacting Networks), which increases confidence in the expanded gene set by retaining genes strongly connected by biological networks when GWAS thresholds are relaxed. GRIN was validated on both simulated interrelated gene sets as well as multiple GWAS traits. From multiple GWAS summary statistics of suicide attempt, a complex phenotype, GRIN identified additional genes that replicated across independent cohorts and retained biologically interrelated genes despite a relaxed significance threshold. We present a conceptual model of how these retained genes interact through neurobiological pathways that may influence suicidal behavior, and identify existing drugs associated with these pathways that would not have been identified under traditional GWAS thresholds. We demonstrate GRIN’s utility in boosting GWAS results by increasing the number of true positive genes identified from GWAS results.

Abstract A key to achieving the 17 Sustainable Development Goals is the sustainable provisioning of clean water and sanitation services. The sustainable management of water resources strengthens resilience, protects livelihoods, fosters economic growth, and contributes to poverty reduction. This paper reviews the challenges faced by Caribbean Small Island Developing States (SIDS) with a focus on water resource management. While the Caribbean region is seemingly blessed with water resources, with more than 90% of Caribbean residents having access to improved water, it faces challenges due to inefficient management and diverse geographical realities, creating spatial disparities. Furthermore, economic and physical scarcity coexist with some islands lacking proper infrastructure and others nearing the exhaustion of natural freshwater reserves. Climate change intensifies these issues through variable precipitation patterns and extreme weather events. Additionally, the region’s dependence on tourism and susceptibility to environmental pressures necessitates a focus on targets related to SDGs 1 and 8. To address increasing water stress within the region, it is becoming increasingly urgent to identify root causes and develop targeted solutions that consider socioeconomic and environmental factors. The promotion of Integrated Water Resource Management is a key strategy for encouraging increased investment in climate-resilient infrastructure and fostering sustainable financing practices.

Abstract Lassa fever virus (LASV), a member of the Arenavirus family, is the etiological agent of Lassa fever, a severe hemorrhagic disease that causes considerable morbidity and mortality in the endemic areas of West Africa. LASV is a rodent-borne CDC Tier One biological threat agent and is on the World Health Organization’s (WHO) Priority Pathogen list. Currently, no FDA-licensed vaccines or specific therapeutics are available. Here, we describe the efficacy of a deactivated rabies virus (RABV)-based vaccine encoding the glycoprotein precursor (GPC) of LASV (LASSARAB). Nonhuman primates (NHPs) were administered a two-dose regimen of LASSARAB or an irrelevant RABV-based vaccine to serve as a negative control. NHPs immunized with LASSARAB developed strong humoral responses to LASV-GPC. Upon challenge, NHPs vaccinated with LASSARAB survived to the study endpoint, whereas NHPs in the control group did not. This study demonstrates that LASSARAB is a worthy candidate for continued development.

Abstract While alterations in nucleus size, shape, and color are ubiquitous in cancer, comprehensive quantification of nuclear morphology across a whole-slide histologic image remains a challenge. Here, we describe the development of a pan-tissue, deep learning-based digital pathology pipeline for exhaustive nucleus detection, segmentation, and classification and the utility of this pipeline for nuclear morphologic biomarker discovery. Manually-collected nucleus annotations were used to train an object detection and segmentation model for identifying nuclei, which was deployed to segment nuclei in H&E-stained slides from the BRCA, LUAD, and PRAD TCGA cohorts. Interpretable features describing the shape, size, color, and texture of each nucleus were extracted from segmented nuclei and compared to measurements of genomic instability, gene expression, and prognosis. The nuclear segmentation and classification model trained herein performed comparably to previously reported models. Features extracted from the model revealed differences sufficient to distinguish between BRCA, LUAD, and PRAD. Furthermore, cancer cell nuclear area was associated with increased aneuploidy score and homologous recombination deficiency. In BRCA, increased fibroblast nuclear area was indicative of poor progression-free and overall survival and was associated with gene expression signatures related to extracellular matrix remodeling and anti-tumor immunity. Thus, we developed a powerful pan-tissue approach for nucleus segmentation and featurization, enabling the construction of predictive models and the identification of features linking nuclear morphology with clinically-relevant prognostic biomarkers across multiple cancer types.

This research study focuses on preservice teachers' (n=66) inspection of pedagogical connections between geography and geometrical reasoning. The aim of this study was to empirically investigate the use of mathematical analysis to enrich the social studies topics of the distortion of country sizes on the world map. The analysis of data collected from the 66 participants generated seven specific pedagogical strategies and covered nine identified mathematics and social studies topics during their lesson concepts for introducing the world map to elementary students. Results from this study reveal that after being corrected regarding this misconception, the participating preservice teachers were successful in developing learning activities to address this topic, employing student-centered strategies including technology-based, paper-based, hands-on, and feet-on approaches.

This case study uncovers how controversial issues such as the recent influx of refugees and immigrants were being addressed in upper elementary classrooms on the United States (US) side of the US/Mexico border. Public school administrators and sixth-grade teachers from two school sites participated. Transborder pedagogy contextualized the findings of the research. With the COVID-19 pandemic, classroom discussions of border issues have been superseded with other concerns. This research underscores the immediacy of transborder pedagogy during times of uncertainty.

Abstract Viral myocarditis, an inflammatory disease of the heart, causes significant morbidity and mortality. Type I interferon (IFN)-mediated antiviral responses protect against myocarditis, but the mechanisms are poorly understood. We previously identified A Disintegrin And Metalloproteinase domain 9 (ADAM9) as an important factor in viral pathogenesis. ADAM9 is implicated in a range of human diseases, including inflammatory diseases; however, its role in viral infection is unknown. Here, we demonstrate that mice lacking ADAM9 are more susceptible to encephalomyocarditis virus (EMCV)-induced death and fail to mount a characteristic type I IFN response. This defect in type I IFN induction is specific to positive-sense, single-stranded RNA (+ ssRNA) viruses and involves melanoma differentiation-associated protein 5 (MDA5)—a key receptor for +ssRNA viruses. Mechanistically, ADAM9 binds to MDA5 and promotes its oligomerization and thereby downstream mitochondrial antiviral-signaling protein (MAVS) activation in response to EMCV RNA stimulation. Our findings identify a role for ADAM9 in the innate antiviral response, specifically MDA5-mediated IFN production, which protects against virus-induced cardiac damage, and provide a potential therapeutic target for treatment of viral myocarditis.

Lifecycle analysis was used to estimate well-to-wheel greenhouse gas (GHG) emissions associated with the production, transport, and use of oxygenated gasoline in Colombia, Japan, and France. The study evaluated fuel blends containing ethanol and/or ethyl tertiary-butyl ether (ETBE) that aligned with oxygen and octane specifications currently in place or under consideration for each country. For Colombia, fuel blends meeting a 3.7 wt.% oxygen specification were analyzed using ethanol sourced and produced in the U.S. from corn and in Colombia from sugarcane, and ETBE processed in the U.S. Gulf Coast. For Japan, blends with 1.3, 2.7 and 3.7 wt.% oxygen were analyzed using ethanol sourced and produced in the U.S. and Brazil, and ETBE processed in the U.S. Gulf Coast. For France, oxygenated gasoline blends with 3.7 to 8.0 wt.% oxygen content were analyzed with ethanol produced locally from corn, beet, and wood and imported sugarcane ethanol. Data were populated from both publicly available secondary data sources and new primary data developed for ETBE production in the U.S. and Europe. This study also accounted for distinct lifecycle emissions among gasoline components, focused on aromatic-rich reformate used to boost octane in non-oxygenated fuels. Across each country, results indicate that the replacement of reformate in ethanol-free (E0) gasoline with oxygenates up to 3.7 wt.% oxygen reduces lifecycle GHG emissions by 6–9%, with the highest GHG reduction provided when ETBE alone is used for oxygenate. For higher oxygen blends modeled for France, the highest GHG reduction (19%) was for a blend of 51 vol.% ETBE to achieve 8.0 wt.% oxygen, the equivalent of E23 (gasoline with 23 vol.% ethanol). Overall, displacing ethanol with ETBE to achieve a fixed oxygen level increased GHG benefits relative to ethanol-only blends, owing to the greater volume of the carbon-intensive reformate displaced.

Aims: The aim of this study was to describe and compare joint-specific and generic health-related quality of life outcomes of the first versus second knee in patients undergoing staged bilateral total knee arthroplasty (BTKA) for osteoarthritis. Methods: This retrospective cohort study used Australian national arthroplasty registry data from January 2013 to January 2021 to identify participants who underwent elective staged BTKA with six to 24 months between procedures. The primary outcome was Oxford Knee Score (OKS) at six months postoperatively for the first TKA compared to the second TKA, adjusted for age and sex. Secondary outcomes compared six-month EuroQol five-dimension five-level (EQ-5D-5L) domain scores, EQ-5D index scores, and the EQ visual analogue scale (EQ-VAS) between knees at six months postoperatively. Results: The cohort included 635 participants (1,270 primary procedures). Preoperative scores were worse in the first knee compared to the second for all instruments; however, comparing the first knee at six months postoperatively with the second knee at six months postoperatively, the mean between-knee difference was minimal for OKS (-0.8 points; 95% confidence interval (CI) -1.4 to -0.2), EQ-VAS (3.3; 95% CI 1.9 to 4.7), and EQ-5D index (0.09 points; 95% CI 0.07 to 0.12). Outcomes for the EQ-5D-5L domains ‘mobility’, ‘usual activities’, and ‘pain/discomfort’ were better following the second TKA. Conclusion: At six months postoperatively, there were no clinically meaningful differences between the first and second TKA in either the joint-specific or overall generic health-related quality of life outcomes. However, individual domain scores assessing mobility, pain, and usual activities were notably higher after the second TKA, likely reflecting the cumulative improvement in quality of life after both knees have been replaced. Cite this article: Bone Jt Open 2024;5(3):202–209.

Abstract Background The ability to efficiently identify patients at higher risk of poor outcomes after joint replacement would enable limited resources for post-operative follow-up to be directed to those with the greatest clinical need. This is particularly important as joint replacement rates continue to grow internationally, stretching health system capabilities. Patient-reported outcome measures (PROMs) are routinely administered in many settings and offer an opportunity to detect suboptimal patient outcomes early. This study aimed to determine whether hip-specific and generic PROM scores are associated with early revision hip replacement within six to 24 months after the primary procedure. Methods Pre-operative and six-month post-operative PROM scores for patients undergoing primary total hip replacement (THR) were obtained from the Australian Orthopaedic Association National Joint Replacement Registry and Arthroplasty Clinical Outcomes Registry National and linked to revision surgery data. Clinically important improvement was defined using anchor-based thresholds. Associations between PROM scores (hip pain, Oxford Hip Score, HOOS-12, EQ-5D-5L, EQ VAS, patient-perceived change, satisfaction) and revision surgery were evaluated using t-tests, chi-square tests and regression models. Results Data were analysed for 21,236 primary THR procedures between 2013 and 2022. Eighty-eight revision procedures were performed at six to 24 months. Patients who were revised had more back pain and worse HOOS-12 scores pre-operatively but between-group differences were small. Worse post-operative PROM scores (hip pain, Oxford, HOOS-12, EQ-5D-5L, EQ VAS) were associated with early revision, after adjusting for age and sex (p

Abstract Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple autoantibody types, some of which are produced by long-lived plasma cells (LLPC). Active SLE generates increased circulating antibody-secreting cells (ASC). Here, we examine the phenotypic, molecular, structural, and functional features of ASC in SLE. Relative to post-vaccination ASC in healthy controls, circulating blood ASC from patients with active SLE are enriched with newly generated mature CD19−CD138+ ASC, similar to bone marrow LLPC. ASC from patients with SLE displayed morphological features of premature maturation and a transcriptome epigenetically initiated in SLE B cells. ASC from patients with SLE exhibited elevated protein levels of CXCR4, CXCR3 and CD138, along with molecular programs that promote survival. Furthermore, they demonstrate autocrine production of APRIL and IL-10, which contributed to their prolonged in vitro survival. Our work provides insight into the mechanisms of generation, expansion, maturation and survival of SLE ASC.

Data collected during well-observed eruptions can lead to dramatic increases in our understanding of volcanic processes. However, the necessary prioritization of public safety and hazard mitigation during a crisis means that scientific opportunities may be sacrificed. Thus, maximizing the scientific gains from eruptions requires improved planning and coordinating science activities among governmental organizations and academia before and during volcanic eruptions. One tool to facilitate this coordination is a Scientific Advisory Committee (SAC). In the USA, the Community Network for Volcanic Eruption Response (CONVERSE) has been developing and testing this concept during workshops and scenario-based activities. The December 2020 eruption of Kīlauea volcano, Hawaii, provided an opportunity to test and refine this model in real-time and in a real-world setting. We present here the working model of a SAC developed during this eruption. Successes of the Kīlauea SAC (K-SAC) included broadening the pool of scientists involved in eruption response and developing and codifying procedures that may form the basis of operation for future SACs. Challenges encountered by the K-SAC included a process of review and facilitation of research proposals that was too slow to include outside participation in the early parts of the eruption and a decision process that fell on a small number of individuals at the responding volcano observatory. Possible ways to address these challenges include (1) supporting community-building activities between eruptions that make connections among scientists within and outside formal observatories, (2) identifying key science questions and pre-planning science activities, which would facilitate more rapid implementation across a broader scientific group, and (3) continued dialog among observatory scientists, emergency responders, and non-observatory scientists about the role of SACs. The SAC model holds promise to become an integral part of future efforts, leading in the short and longer term to more effective hazard response and greater scientific discovery and understanding.

Epithelial adenocarcinoma of the ovary and colon are associated with the highest rates of cancer-related deaths in women in the U.S. The literature supports the role of HDL-associated apolipoproteins in the treatment of cancer and other pro-inflammatory diseases. Previously, we developed a novel 20-amino acid mimetic peptide, HM-10/10, which potently inhibits tumor development and growth in colon and ovarian cancer. Here, we report the properties of HM-10/10 relative to its stability in vitro. The results demonstrated that HM-10/10 had the highest half-life in human plasma compared to plasma from other species tested. HM-10/10 demonstrated stability in human plasma and simulated gastric environment, increasing its promise as an oral pharmaceutical. However, under conditions modeling the small intestine, HM-10/10 demonstrated significant degradation, likely due to the peptidases encountered therein. Furthermore, HM-10/10 demonstrated no evidence of time-dependent drug-drug interactions, although it demonstrated CYP450 induction slightly above cutoff. As proteolytic degradation is a common limitation of peptide-based therapeutics, we are pursuing strategies to improve the stability properties of HM-10/10 by extending its bioavailability while retaining its low toxicity profile. HM-10/10 holds promise as a new agent to address the international women's health crisis of epithelial carcinomas of the ovary and colon.

Mutations in the protein superoxide dismutase-1 (SOD1) promote its misfolding and aggregation, ultimately causing familial forms of the debilitating neurodegenerative disease amyotrophic lateral sclerosis (ALS). Currently, over 220 (mostly missense) ALS-causing mutations in the SOD1 protein have been identified, indicating that common structural features are responsible for aggregation and toxicity. Using in silico tools, we predicted amyloidogenic regions in the ALS-associated SOD1-G85R mutant, finding seven regions throughout the structure. Introduction of proline residues into β-strands II (I18P) or III (I35P) reduced the aggregation propensity and toxicity of SOD1-G85R in cells, significantly more so than proline mutations in other amyloidogenic regions. The I18P and I35P mutations also reduced the capability of SOD1-G85R to template onto previously formed non-proline mutant SOD1 aggregates as measured by fluorescence recovery after photobleaching. Finally, we found that, while the I18P and I35P mutants are less structurally stable than SOD1-G85R, the proline mutants are less aggregation-prone during proteasome inhibition, and less toxic to cells overall. Our research highlights the importance of a previously underappreciated SOD1 amyloidogenic region in β-strand II (15QGIINF20) to the aggregation and toxicity of SOD1 in ALS mutants, and suggests that β-strands II and III may be good targets for the development of SOD1-associated ALS therapies

Abstract TAR DNA-binding protein 43 (TDP-43) and Fused in Sarcoma/Translocated in Sarcoma (FUS) are ribonucleoproteins associated with pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Under physiological conditions, TDP-43 and FUS are predominantly localized in the nucleus, where they participate in transcriptional regulation, RNA splicing and metabolism. In disease, however, they are typically mislocalized to the cytoplasm where they form aggregated inclusions. A number of shared cellular pathways have been identified that contribute to TDP-43 and FUS toxicity in neurodegeneration. In the present study, we report a novel pathogenic mechanism shared by these two proteins. We found that pathological FUS co-aggregates with a ribosomal protein, the Receptor for Activated C-Kinase 1 (RACK1), in the cytoplasm of spinal cord motor neurons of ALS, as previously reported for pathological TDP-43. In HEK293T cells transiently transfected with TDP-43 or FUS mutant lacking a functional nuclear localization signal (NLS; TDP-43ΔNLS and FUSΔNLS), cytoplasmic TDP-43 and FUS induced co-aggregation with endogenous RACK1. These co-aggregates sequestered the translational machinery through interaction with the polyribosome, accompanied by a significant reduction of global protein translation. RACK1 knockdown decreased cytoplasmic aggregation of TDP-43ΔNLS or FUSΔNLS and alleviated associated global translational suppression. Surprisingly, RACK1 knockdown also led to partial nuclear localization of TDP-43ΔNLS and FUSΔNLS in some transfected cells, despite the absence of NLS. In vivo, RACK1 knockdown alleviated retinal neuronal degeneration in transgenic Drosophila melanogaster expressing hTDP-43WT or hTDP-43Q331K and improved motor function of hTDP-43WT flies, with no observed adverse effects on neuronal health in control knockdown flies. In conclusion, our results revealed a novel shared mechanism of pathogenesis for misfolded aggregates of TDP-43 and FUS mediated by interference with protein translation in a RACK1-dependent manner. We provide proof-of-concept evidence for targeting RACK1 as a potential therapeutic approach for TDP-43 or FUS proteinopathy associated with ALS and FTLD.

In the last decade the world has experienced a number of global crises which triggered economic downturns. Impacts from the global financial crisis, the global COVID pandemic, and Russia’s invasion of Ukraine trigger instability in financial markets. This paper explores similarities and differences between these crises based on inflation and its energy-related components. A Vector Autoregressive (VAR) model is used to analyze both EU-level trends, as well as data for Romania. The findings indicate idiosyncratic shifts in the relationships between variables. The changes are often specific to individual shocks and the policy context. How policy makers respond to these shocks will also impact the fiscal space, the borrowing costs of countries, and the cost of servicing debt, which risks a return to the type of austerity policies that slowed down the post-financial crisis recovery. There is a need for more detailed research and investigations in policy responses designed to respond to ongoing events.

Integrating Wastewater Reuse (WWRU) into national Water Management Schemes (WMS) is crucial as Small Island Developing States (SIDS) attempt to cope with water resource constraints in a changing climate. In 2022, the Global Environment Facility Caribbean Regional Fund (GEF CReW+) on Wastewater Management, the Ministry of Public Utilities (MPU), Trinidad and Tobago and the Trinidad and Tobago Bureau of Standards (TTBS) spearheaded the development of a national voluntary standard for treated wastewater reuse focused on agricultural and landscaping uses. During the process, the MPU conducted a Knowledge, Attitudes and Practices (KAP) and Willingness to Pay (WTP) assessment to inform the standard and subsequent implementation. Results indicated `good' knowledge on wastewater and WWRU (59.3%), however attitudes and practices were considered `poor'. Inferential Statistics performed on numerically coded survey response data revealed no statistically significant relation with the demographic factors assessed; 84.1% of respondents were willing to use treated wastewater with health concerns identified as the main barrier; 27.3% of respondents were willing to pay the same price as conventional water, while 31.2% were willing to pay 25 -50% less. This assessment can inform the implementation and pricing process and provide valuable insights to increase the uptake of WWRU in the region. HIGHLIGHTS Explains the regional dynamics associated with WWRU.; Examines knowledge, attitudes, practices and Willingness to Pay (WTP) in the context of WWRU in Trinidad and Tobago.; Outlines the key barrier in terms of public perception related to WWRU.;