Analysis of Uncertainty and Sensitivity in Tailings Dam Breach-Runout Numerical Modelling.

Tailings dam breaches (TDBs) and subsequent flows can pose significant risk to public safety, the environment, and the economy. Numerical runout models are used to simulate potential tailings flows and understand their downstream impacts. Due to the complex nature of the breach-runout processes, the mobility and downstream impacts of these types of failures are highly uncertain. We applied the first-order second-moment (FOSM) methodology to a database of 11 back-analyzed historical tailings flows to evaluate uncertainties in TDB runout modelling and conducted a sensitivity analysis to identify key factors contributing to the variability of the HEC-RAS model output, including at different locations along the runout path. The results indicate that prioritizing resources toward advancements in estimating the values of primary contributors to the sensitivity of the selected model outputs is necessary for more reliable model results. We found that the total released volume is among the top contributors to the sensitivity of modelled inundation area and maximum flow depth, while surface roughness is among the top contributors to the sensitivity of modelled maximum flow velocity and flow front arrival time. However, the primary contributors to the sensitivity of the model outputs varied depending on the case study; therefore, the selection of appropriate rheological models and consideration of site-specific conditions are crucial for accurate predictions. The study proposes and demonstrates the FOSM methodology as an approximate probabilistic approach to model-based tailings flow runout prediction, which can help improve the accuracy of risk assessments and emergency response plans. Supplementary Information: The online version contains supplementary material available at 10.1007/s10230-024-00970-w.

Las roturas de presas de relaves (TDBs) y los flujos subsiguientes pueden suponer un riesgo significativo para la seguridad pública, el medio ambiente y la economía. Los modelos numéricos de desbordamiento se utilizan para simular posibles flujos de relaves y comprender su impacto aguas abajo. Debido a la naturaleza compleja de los procesos de rotura-desbordamiento, la movilidad y los impactos aguas abajo de este tipo de fallos tienen mucha incertidumbre. Se aplicó la metodología del segundo-momento de primer-orden (FOSM) a una base de datos de 11 flujos históricos de relaves analizados retrospectivamente para evaluar las incertidumbres en la modelización del desbordamiento de TDB y se realizó un análisis de sensibilidad para identificar los factores clave que contribuyen a la variabilidad de los resultados del modelo HEC-RAS, incluso en diferentes ubicaciones a lo largo de la trayectoria de fuga. Los resultados indican que es necesario priorizar los recursos hacia avances en la estimación de los valores de los principales contribuyentes a la sensibilidad de los resultados del modelo seleccionado para obtener resultados más fiables del modelo. El volumen total liberado se encuentra entre los principales contribuyentes a la sensibilidad del área de inundación modelizada y la profundidad máxima del flujo, mientras que la rugosidad de la superficie se encuentra entre los principales contribuyentes a la sensibilidad de la velocidad máxima del flujo modelizado y el tiempo de llegada del frente de flujo. Sin embargo, los principales factores que contribuyen a la sensibilidad de los resultados del modelo varían dependiendo del caso de estudio; por lo tanto, la selección de modelos reológicos apropiados y la consideración de las condiciones específicas del emplazamiento son cruciales para obtener predicciones precisas. El estudio propone y muestra la metodología FOSM como un enfoque probabilístico aproximado para la predicción de la extensión de flujos de relaves basada en modelos, que puede ayudar a mejorar la precisión de las evaluaciones de riesgos y los planes de respuesta a emergencias.

Homologous Recombination Deficiency: Concepts, Definitions, and Assays.

BACKGROUND: Homologous recombination deficiency (HRD) is a phenotype that is characterized by the inability of a cell to effectively repair DNA double-strand breaks using the homologous recombination repair (HRR) pathway. Loss-of-function genes involved in this pathway can sensitize tumors to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapy, which target the destruction of cancer cells by working in concert with HRD through synthetic lethality. However, to identify patients with these tumors, it is vital to understand how to best measure homologous repair (HR) status and to characterize the level of alignment in these measurements across different diagnostic platforms. A key current challenge is that there is no standardized method to define, measure, and report HR status using diagnostics in the clinical setting. METHODS: Friends of Cancer Research convened a consortium of project partners from key healthcare sectors to address concerns about the lack of consistency in the way HRD is defined and methods for measuring HR status. RESULTS: This publication provides findings from the group's discussions that identified opportunities to align the definition of HRD and the parameters that contribute to the determination of HR status. The consortium proposed recommendations and best practices to benefit the broader cancer community. CONCLUSION: Overall, this publication provides additional perspectives for scientist, physician, laboratory, and patient communities to contextualize the definition of HRD and various platforms that are used to measure HRD in tumors.

Feminized behavior and brain gene expression in a novel mouse model of Klinefelter Syndrome.

Klinefelter Syndrome (KS) is the most common sex chromosome aneuploidy in men and is characterized by the presence of an additional X chromosome (XXY). In some Klinefelter males, certain traits may be feminized or shifted from the male-typical pattern towards a more female-typical one. Among them might be partner choice, one of the most sexually dimorphic traits in the animal kingdom. We investigated the extent of feminization in XXY male mice (XXYM) in partner preference and gene expression in the bed nucleus of the stria terminalis/preoptic area and the striatum in mice from the Sex Chromosome Trisomy model. We tested for partner preference using a three-chambered apparatus in which the test mouse was free to choose between stimulus animals of either sex. We found that partner preference in XXYM was feminized. These differences were likely due to interactions of the additional X chromosome with the Y. We also discovered genes that differed in expression in XXYM versus XYM. Some of these genes are feminized in their expression pattern. Lastly, we also identified genes that differed only between XXYM versus XYM and not XXM versus XYM. Genes that are both feminized and unique to XXYM versus XYM represent strong candidates for dissecting the molecular pathways responsible for phenotypes present in KS/XXYM but not XXM. In sum, our results demonstrated that investigating behavioral and molecular feminization in XXY males can provide crucial information about the pathophysiology of KS and may aid our understanding of sex differences in brain and behavior.

Membrane ß-catenin and adherens junctions in early gonadal patterning.

BACKGROUND: Mechanisms involved in early patterning of the mammalian gonad as it develops from a bipotential state into a testis or an ovary are as yet not well understood. Sex-specific vascularization is essential in this process, but more specific mechanisms required to, for example, establish interstitial vs. cord compartments in the testis or ovigerous cords in the ovary have not been reported. Adherens junctions (AJs) are known for their roles in morphogenesis; we, therefore, examined expression of AJ components including ß-catenin, p120 catenin, and cadherins for possible involvement in sex-specific patterning of the gonad. RESULTS: We show that, at the time of early gonadal sex differentiation, membrane-associated ß-catenin and p120 catenin colocalize with cell-specific cadherins in both sex-nonspecific and sex-specific patterns. These expression patterns are consistent with an influence of AJs in overall patterning of the testis vs. ovary through known AJ mechanisms of cell-cell adhesion, cell sorting, and boundary formation. CONCLUSIONS: Together these complex and dynamic patterns of AJ component expression precisely mirror patterning of tissues during gonadogenesis and raise the possibility that AJs are essential effectors of patterning within the developing testis and ovary.

The genetics of sex differences in brain and behavior.

Biological differences between men and women contribute to many sex-specific illnesses and disorders. Historically, it was argued that such differences were largely, if not exclusively, due to gonadal hormone secretions. However, emerging research has shown that some differences are mediated by mechanisms other than the action of these hormone secretions and in particular by products of genes located on the X and Y chromosomes, which we refer to as direct genetic effects. This paper reviews the evidence for direct genetic effects in behavioral and brain sex differences. We highlight the 'four core genotypes' model and sex differences in the midbrain dopaminergic system, specifically focusing on the role of Sry. We also discuss novel research being done on unique populations including people attracted to the same sex and people with a cross-gender identity. As science continues to advance our understanding of biological sex differences, a new field is emerging that is aimed at better addressing the needs of both sexes: gender-based biology and medicine. Ultimately, the study of the biological basis for sex differences will improve healthcare for both men and women.

Epitope-specific immune tolerization ameliorates experimental autoimmune encephalomyelitis.

The availability of glatiramer acetate (GA) for inducing immune tolerance is a significant advancement in the treatment of multiple sclerosis (MS). However, a sizable proportion of patients maintain active disease, regardless of treatment. Another approach to induce T-cell tolerance is therefore still an unmet medical need. We hypothesized that induction of mucosal tolerance toward a pro-inflammatory T-cell epitope derived from a heat shock protein (HSP) (RatP2) could translate into clinical benefit. We found that treatment of experimental autoimmune encephalomyelitis (EAE, a model of MS) with the peptide RatP2 determined a significant clinical improvement, which was comparable to the standard tolerization treatment (an MBP-derived peptide pool) and superior to GA. Histological analysis demonstrated a reduction of brain and spinal cord inflammatory lesions in treated animals. Moreover, with immunological analysis we identified biomarkers associated with clinical response. This work provides proof-of-concept to support the further testing of this approach as a possible complement to currently available therapies for MS.

A benchmarking study of four numerical runout models for the simulation of tailings flows.

Numerical runout models are important tools for predicting the potential downstream impacts of tailings dam breaches that generate tailings flows, which is a crucial step in emergency preparedness and planning, and risk management. Most existing runout models were originally developed for the analysis of water floods or flow-like landslides (e.g. debris flows). In this study, we back-analyze two well-documented historical tailings dam breaches (1985 Stava, Italy and 1994 Merriespruit, South Africa) using four numerical models (DAN3D, MADflow, FLO-2D and FLOW-3D). The main objective of this multi-case, multi-model benchmarking exercise is to identify collective opportunities to adapt these types of models and associated modelling methods to tailings dam breach runout applications. Comparing best-fit simulation results, we find that all four models are capable of reproducing the bulk behaviour of the real events; however, (i) multiple sets of rheological parameters may produce very similar output results, (ii) the best-fit input parameter combinations are non-transferable between models and inconsistent with independently measured rheological properties of stored tailings, and (iii) choosing an appropriate set requires sufficient understanding of material rheological properties and expert judgment. Using a systematic sensitivity analysis with the First-Order Second-Moment (FOSM) approach, we also find that each model is sensitive to different input parameters, although the total released volume is among the main high-influence parameters in every scenario. We conclude that more case study back-analyses are needed to enhance our understanding of these sensitivities and develop better guidance on the use of these types of numerical models for tailings flow runout prediction.

Comprehensive Paired Tumor/Germline Testing for Lynch Syndrome: Bringing Resolution to the Diagnostic Process.

PURPOSE: The current diagnostic testing algorithm for Lynch syndrome (LS) is complex and often involves multiple follow-up germline and somatic tests. We aimed to describe the results of paired tumor/germline testing performed on a large cohort of patients with colorectal cancer (CRC) and endometrial cancer (EC) to better determine the utility of this novel testing methodology. MATERIALS AND METHODS: We retrospectively reviewed a consecutive series of patients with CRC and EC undergoing paired tumor/germline analysis of the LS genes at a clinical diagnostic laboratory (N = 702). Microsatellite instability, MLH1 promoter hypermethylation, and germline testing of additional genes were performed if ordered. Patients were assigned to one of five groups on the basis of prior tumor screening and germline testing outcomes. Results for each group are described. RESULTS: Overall results were informative regarding an LS diagnosis for 76.1% and 60.8% of patients with mismatch-repair-deficient (MMRd) CRC and EC without and with prior germline testing, respectively. LS germline mutations were identified in 24.8% of patients in the group without prior germline testing, and interestingly, in 9.5% of patients with previous germline testing; four of these were discordant with prior tumor screening. Upon excluding patients with MLH1 promoter hypermethylation and germline mutations, biallelic somatic inactivation was seen in approximately 50% of patients with MMRd tumors across groups. CONCLUSION: Paired testing identified a cause for MMRd tumors in 76% and 61% of patients without and with prior LS germline testing, respectively. Findings support inclusion of tumor sequencing as well as comprehensive LS germline testing in the LS testing algorithm. Paired testing offers a complete, convenient evaluation for LS with high diagnostic resolution.

The importance of having two X chromosomes.

Historically, it was thought that the number of X chromosomes plays little role in causing sex differences in traits. Recently, selected mouse models have been used increasingly to compare mice with the same type of gonad but with one versus two copies of the X chromosome. Study of these models demonstrates that mice with one X chromosome can be strikingly different from those with two X chromosomes, when the differences are not attributable to confounding group differences in gonadal hormones. The number of X chromosomes affects adiposity and metabolic disease, cardiovascular ischaemia/reperfusion injury and behaviour. The effects of X chromosome number are likely the result of inherent differences in expression of X genes that escape inactivation, and are therefore expressed from both X chromosomes in XX mice, resulting in a higher level of expression when two X chromosomes are present. The effects of X chromosome number contribute to sex differences in disease phenotypes, and may explain some features of X chromosome aneuploidies such as in Turner and Klinefelter syndromes.

The effects of perinatal testosterone exposure on the DNA methylome of the mouse brain are late-emerging.

BACKGROUND: The biological basis for sex differences in brain function and disease susceptibility is poorly understood. Examining the role of gonadal hormones in brain sexual differentiation may provide important information about sex differences in neural health and development. Permanent masculinization of brain structure, function, and disease is induced by testosterone prenatally in males, but the possible mediation of these effects by long-term changes in the epigenome is poorly understood. METHODS: We investigated the organizational effects of testosterone on the DNA methylome and transcriptome in two sexually dimorphic forebrain regions-the bed nucleus of the stria terminalis/preoptic area and the striatum. To study the contribution of testosterone to both the establishment and persistence of sex differences in DNA methylation, we performed genome-wide surveys in male, female, and female mice given testosterone on the day of birth. Methylation was assessed during the perinatal window for testosterone's organizational effects and in adulthood. RESULTS: The short-term effect of testosterone exposure was relatively modest. However, in adult animals the number of genes whose methylation was altered had increased by 20-fold. Furthermore, we found that in adulthood, methylation at a substantial number of sexually dimorphic CpG sites was masculinized in response to neonatal testosterone exposure. Consistent with this, testosterone's effect on gene expression in the striatum was more apparent in adulthood. CONCLUSION: Taken together, our data imply that the organizational effects of testosterone on the brain methylome and transcriptome are dramatic and late-emerging. Our findings offer important insights into the long-term molecular effects of early-life hormonal exposure.

The Sex Chromosome Trisomy mouse model of XXY and XYY: metabolism and motor performance.

BACKGROUND: Klinefelter syndrome (KS), caused by XXY karyotype, is characterized by low testosterone, infertility, cognitive deficits, and increased prevalence of health problems including obesity and diabetes. It has been difficult to separate direct genetic effects from hormonal effects in human studies or in mouse models of KS because low testosterone levels are confounded with sex chromosome complement. METHODS: In this study, we present the Sex Chromosome Trisomy (SCT) mouse model that produces XXY, XYY, XY, and XX mice in the same litters, each genotype with either testes or ovaries. The independence of sex chromosome complement and gonadal type allows for improved recognition of sex chromosome effects that are not dependent on levels of gonadal hormones. All mice were gonadectomized and treated with testosterone for 3 weeks. Body weight, body composition, and motor function were measured. RESULTS: Before hormonal manipulation, XXY mice of both sexes had significantly greater body weight and relative fat mass compared to XY mice. After gonadectomy and testosterone replacement, XXY mice (both sexes) still had significantly greater body weight and relative fat mass, but less relative lean mass compared to XY mice. Liver, gonadal fat pad, and inguinal fat pad weights were also higher in XXY mice, independent of gonadal sex. In several of these measures, XX mice also differed from XY mice, and gonadal males and females differed significantly on almost every metabolic measure. The sex chromosome effects (except for testis size) were also seen in gonadally female mice before and after ovariectomy and testosterone treatment, indicating that they do not reflect group differences in levels of testicular secretions. XYY mice were similar to XY mice on body weight and metabolic variables but performed worse on motor tasks compared to other groups. CONCLUSIONS: We find that the new SCT mouse model for XXY and XYY recapitulates features found in humans with these aneuploidies. We illustrate that this model has significant promise for unveiling the role of genetic effects compared to hormonal effects in these syndromes, because many phenotypes are different in XXY vs. XY gonadal female mice which have never been exposed to testicular secretions.

Modulation of T cell function by combination of epitope specific and low dose anticytokine therapy controls autoimmune arthritis.

Innate and adaptive immunity contribute to the pathogenesis of autoimmune arthritis by generating and maintaining inflammation, which leads to tissue damage. Current biological therapies target innate immunity, eminently by interfering with single pro-inflammatory cytokine pathways. This approach has shown excellent efficacy in a good proportion of patients with Rheumatoid Arthritis (RA), but is limited by cost and side effects. Adaptive immunity, particularly T cells with a regulatory function, plays a fundamental role in controlling inflammation in physiologic conditions. A growing body of evidence suggests that modulation of T cell function is impaired in autoimmunity. Restoration of such function could be of significant therapeutic value. We have recently demonstrated that epitope-specific therapy can restore modulation of T cell function in RA patients. Here, we tested the hypothesis that a combination of anti-cytokine and epitope-specific immunotherapy may facilitate the control of autoimmune inflammation by generating active T cell regulation. This novel combination of mucosal tolerization to a pathogenic T cell epitope and single low dose anti-TNFalpha was as therapeutically effective as full dose anti-TNFalpha treatment. Analysis of the underlying immunological mechanisms showed induction of T cell immune deviation.