Assessing interventions promoting the uptake of cancer-related genomic services within the Latino community: A scoping review using the RE-AIM framework.

Cancer genomic services (CGS) can support genetic risk-stratified cancer prevention and treatment. Racial/ethnic minority groups are less likely to access and utilize CGS compared with non-Hispanic Whites. Little research has described characteristics of interventions targeted at CGS among Latinos. This scoping review aimed to (1) describe interventions promoting uptake of CGS among Latinos in the United States and Latin America, (2) describe intervention adaptations for Latino participants, and (3) summarize intervention implementation factors suggested by reach, effectiveness, adoption, implementation, and maintenance (RE-AIM) framework. We conducted a search in English and Spanish of literature published between 2005 and 2022 across PubMed and Latin American and Caribbean Health Sciences Literature databases. Sixteen of 2344 papers met the inclusion criteria of the analysis. Efforts to promote CGS among Latino communities were limited in the US and lower in Latin America. This review highlights the need for in-depth exploration of acculturation-informed interventions and better reporting on implementation factors to enhance their scalability across diverse settings.

Spatial transcriptomics implicates impaired BMP signaling in NF1 fracture pseudarthrosis in murine and patient tissues.

The Neurofibromatosis Type 1 (NF1) RASopathy is associated with persistent fibrotic nonunions (pseudarthrosis) in human and mouse skeletal tissue. Here, we first performed spatial transcriptomics to define the molecular signatures across normal endochondral healing following fracture in mice. Within the control fracture callus, we observed spatially restricted activation of morphogenetic pathways, such as TGF-ß, WNT, and BMP. To investigate the molecular mechanisms contributing to Nf1-deficient delayed fracture healing, we performed spatial transcriptomic analysis on a Postn-cre;Nf1flox/- (Nf1Postn) fracture callus. Transcriptional analyses, subsequently confirmed through p-SMAD1/5/8 immunohistochemistry, demonstrated a lack of BMP pathway induction in Nf1Postn mice. To further inform the human disease, we performed spatial transcriptomic analysis of fracture pseudarthrosis tissue from a NF1 patient. Analyses detected increased MAPK signaling at the fibrocartilaginous-osseus junction. Similar to the Nf1Postn fracture, BMP pathway activation was absent within the pseudarthrosis tissue. Our results demonstrate the feasibility to delineate the molecular and tissue-specific heterogeneity inherent in complex regenerative processes, such as fracture healing, and to reconstruct phase transitions representing endochondral bone formation in vivo. Furthermore, our results provide in situ molecular evidence of impaired BMP signaling underlying NF1 pseudarthrosis, potentially informing the clinical relevance of off-label BMP2 as a therapeutic intervention.

miRNAs: Primary modulators of plant drought tolerance.

Drought is a principal environmental factor that affects the growth and development of plants. Accordingly, plants have evolved adaptive mechanisms to cope with adverse environmental conditions. One of the mechanisms is gene regulation mediated by microRNAs (miRNAs). miRNAs are regarded as primary modulators of gene expression at the post-transcriptional level and have been shown to participate in drought stress response, including ABA response, auxin signaling, antioxidant defense, and osmotic regulation through downregulating the corresponding targets. miRNA-based genetic reconstructions have the potential to improve the tolerance of plants to drought. However, there are few precise classification and discussion of miRNAs in specific response behaviors to drought stress and their applications. This review summarized and discussed the specific response behaviors of miRNAs under drought stress and the role of miRNAs as regulators in the response of plants to drought and highlighted that the modification of miRNAs might effectively improve the tolerance of plants to drought.

Genetic causal relationship between placental weight and autism spectrum disorder: A two-sample Mendelian randomization study.

OBJECT: Previous research has suggested an association between placental tissue abnormalities and the diagnosis of autism spectrum disorder. This study aims to explore the causal relationship between placental weight and autism spectrum disorder. METHODS: This study employed Mendelian randomization analysis to investigate the potential causal relationship between placental weight and autism spectrum disorder. The study design involved two sample populations, with data for the exposed population sourced from previous studies focusing on PW, and data for the outcome population obtained from the Integrative Psychiatric Research and the Psychiatric Genomics Consortium study. To ensure the robustness of the results, three sensitivity analyses were performed, including heterogeneity testing, pleiotropy testing, and a leave-one-out analysis. The inverse variance weighted method served as the gold standard for the Mendelian randomization analysis. RESULTS: The results of the first analysis revealed a significant correlation between an increase in placental weight and an elevated risk of autism spectrum disorder (p = 0.02). Sensitivity analysis detected heterogeneity and outliers. After removing two outlier SNPs in the second round of analysis, the results still supported a genetic causal relationship between placental weight and autism spectrum disorder (p = 0.01). The second-round sensitivity analysis did not reveal any heterogeneity or outliers. CONCLUSION: Our study provides compelling evidence supporting a causal relationship between elevated placental weight and increased risk of autism spectrum disorder. These findings underscore the significance of placental development in the etiology of autism spectrum disorder and propose a potential early predictive indicator for autism spectrum disorder.

Antenatal reproductive screening for pregnant people including preconception: Provides the best reproductive opportunity for informed consent, quality, and safety.

INTRODUCTION: This antenatal screening review will include reproductive screening evidence and approaches for pre-conception and post-conception, using first to third trimester screening opportunities. METHODS: Focused antenatal screening peer-reviewed publications were evaluated and summarized. RESULTS: Evidenced-based reproductive antenatal screening elements should be offered and discussed, with the pregnancy planning or pregnant person, during Preconception (genetic carrier screening for reproductive partners, personal and family (including reproductive partner) history review for increased genetic and pregnancy morbidity risks); First Trimester (fetal dating with ultrasound; fetal aneuploidy screening plus consideration for expanded fetal morbidity criteria, if appropriate; pregnant person preeclampsia screening; early fetal anatomy screening; early fetal cardiac screening); Second Trimester for standard fetal anatomy screening (18-22 weeks) including cardiac; pregnant person placental and cord pathology screening; pregnant person preterm birth screening with cervical length measurement); Third Trimester (fetal growth surveillance; continued preterm birth risk surveillance). CONCLUSION: Antenatal reproductive screening has multiple elements, is complex, is time-consuming, and requires the use of pre- and post-testing counselling for most screening elements. The use of preconception and trimesters 'one to three' requires clear patient understanding and buy-in. Informed consent and knowledge transfer is a main goal for antenatal reproductive screening approaches.

Effect of meddling ARBs on ARGs dynamics in fungal infested soil and their selective dispersal along spatially distant mycelial networks.

During the recent times, environmental antibiotic resistance genes (ARGs) and their potential transfer to other bacterial hosts of pathogenic importance are of serious concern. However, the dissemination strategies of such ARGs are largely unknown. We tested that saprotrophic soil fungi differentially enriched antibiotic resistant bacteria (ARBs) and subsequently contributed in spatial distribution of selective ARGs. Wafergen qPCR analysis of 295 different ARGs was conducted for manure treated pre-sterilized soil incubated or not with selected bacterial-fungal consortia. The qPCR assay detected unique ARGs specifically found in the mycosphere of ascomycetous and basidiomycetous fungi. Both fungi exerted potentially different selection pressures on ARBs, resulting in different patterns of ARGs dissemination (to distant places) along their respective growing fungal highways. The relative abundance of mobile genetic elements (MGEs) was significantly decreased along fungal highways compared to the respective inoculation points. Moreover, the decrease in MGEs and ARGs (along fungal highways) was more prominent over time which depicts the continuous selection pressure of growing fungi on ARBs for enrichment of particular ARGs in mycosphere. Such data also indicate the potential role of saprotrophic soil fungi to facilitate horizontal gene transfer within mycospheric environmental settings. Our study, therefore, advocates to emphasize the future investigations for such (bacteria-fungal) interactive microbial consortia for potential (spatial) dissemination of resistance determinants which may ultimately increase the exposure risks of ARGs.

Genetic constraint at single amino acid resolution in protein domains improves missense variant prioritisation and gene discovery.

BACKGROUND: One of the major hurdles in clinical genetics is interpreting the clinical consequences associated with germline missense variants in humans. Recent significant advances have leveraged natural variation observed in large-scale human populations to uncover genes or genomic regions that show a depletion of natural variation, indicative of selection pressure. We refer to this as "genetic constraint". Although existing genetic constraint metrics have been demonstrated to be successful in prioritising genes or genomic regions associated with diseases, their spatial resolution is limited in distinguishing pathogenic variants from benign variants within genes. METHODS: We aim to identify missense variants that are significantly depleted in the general human population. Given the size of currently available human populations with exome or genome sequencing data, it is not possible to directly detect depletion of individual missense variants, since the average expected number of observations of a variant at most positions is less than one. We instead focus on protein domains, grouping homologous variants with similar functional impacts to examine the depletion of natural variations within these comparable sets. To accomplish this, we develop the Homologous Missense Constraint (HMC) score. We utilise the Genome Aggregation Database (gnomAD) 125 K exome sequencing data and evaluate genetic constraint at quasi amino-acid resolution by combining signals across protein homologues. RESULTS: We identify one million possible missense variants under strong negative selection within protein domains. Though our approach annotates only protein domains, it nonetheless allows us to assess 22% of the exome confidently. It precisely distinguishes pathogenic variants from benign variants for both early-onset and adult-onset disorders. It outperforms existing constraint metrics and pathogenicity meta-predictors in prioritising de novo mutations from probands with developmental disorders (DD). It is also methodologically independent of these, adding power to predict variant pathogenicity when used in combination. We demonstrate utility for gene discovery by identifying seven genes newly significantly associated with DD that could act through an altered-function mechanism. CONCLUSIONS: Grouping variants of comparable functional impacts is effective in evaluating their genetic constraint. HMC is a novel and accurate predictor of missense consequence for improved variant interpretation.

Rapid discrimination of African swine fever virus nucleic acid and virions using BenzoNuclease.

African swine fever (ASF) is an acute and severe infectious disease caused by the African Swine Fever Virus (ASFV). ASFV exhibits significant resistance and stability in the environment, which, coupled with its double-stranded DNA and large genome, predisposes it to contaminate laboratory samples. This characteristic can lead to false-positive results in swine farm settings even days after disinfection, as detectable through polymerase chain reaction (PCR) or real-time fluorescent quantitative PCR (qPCR) assays. To meet the demand for efficient clinical methods capable of discriminating between ASFV nucleic acid and ASFV virions, this study aims to ascertain the efficacy of the nuclease "BenzoNuclease" in distinguishing ASFV nucleic acid (ASFV-DNA) from ASFV virions. BenzoNuclease is a versatile nucleic acid enzyme with the capacity to degrade nearly all forms of DNA and RNA. Initially, this research established a highly sensitive general PCR detection method for ASFV. Subsequently, a positive control was constructed using the M13 bacteriophage to substitute for active ASFV, facilitating the development of an improved qPCR method. It is important to note that common disinfectants have the potential to deactivate BenzoNuclease. However, in an environment simulating actual production applications, residual disinfectants do not interfere with the enzymatic efficacy of BenzoNuclease, thus not affecting the detection capabilities of this method. Positive clinical samples from pig farms, upon testing with the improved method, revealed that three samples were positive, indicating the presence of viral particles, while the remaining samples were negative, indicating the presence of nucleic acids. This provides an additional new option for sample testing in pig farms.

Preference and regulation mechanism mediated via mobile genetic elements for antibiotic and metal resistomes during composting amended with nano ZVI loaded on biochar.

This study assessed the effectiveness of nano zero-valent iron loaded on biochar (BC-nZVI) during swine manure composting. BC-nZVI significantly reduced the abundance of antibiotic resistance genes (ARGs), metal resistance genes (MRGs), and mobile genetic elements (MGEs). BC-nZVI modified the preference of MGEs to carry ARGs and MRGs, and the corrosion products of BC-nZVI could destroy cell structure, hinder electron transfer between cells, and weaken the association between ARGs, MRGs, and host bacteria. Functional genes analysis revealed that BC-nZVI down-regulated the abundance of genes affecting the transmission and metabolism of ARGs and MRGs, including type IV secretion systems, transporter systems, two-component systems, and multidrug efflux pumps. Furthermore, the BC-nZVI decreased genes related to flagella and pili production and cell membrane permeability, thereby hindering the transfer of ARGs, MRGs, and MGEs in the environment. Redundancy analysis demonstrated that changes in the microbial community induced by BC-nZVI were pivotal factors impacting the abundance of ARGs, MRGs, and MGEs. Overall, this study confirmed the efficacy of BC-nZVI in reducing resistance genes during swine manure composting, offering a promising environmental strategy to mitigate the dissemination of these contaminants.

Evidence for human-caused founder effect in populations of Solanum jamesii at archaeological sites: II. Genetic sequencing establishes ancient transport across the Southwest USA.

PREMISE: The domestication of wild plant species can begin with gathering and transport of propagules by Indigenous peoples. The effect on genomic composition, especially in clonal, self-incompatible perennials would be instantaneous and drastic with respect to new, anthropogenic populations subsequently established. Reductions in genetic diversity and mating capability would be symptomatic and the presence of unique alleles and genetic sequences would reveal the origins and ancestry of populations associated with archaeological sites. The current distribution of the Four Corners potato, Solanum jamesii Torr. in the Southwestern USA, may thus reflect the early stages of a domestication process that began with tuber transport. METHODS: Herein genetic sequencing (GBS) data are used to further examine the hypothesis of domestication in this culturally significant species by sampling 25 archaeological and non-archaeological populations. RESULTS: Archaeological populations from Utah, Colorado and northern Arizona have lower levels of polymorphic loci, unique alleles, and heterozygosity than non-archaeological populations from the Mogollon region of central Arizona and New Mexico. Principle components analysis, Fst values, and structure analysis revealed that genetic relationships among archaeological populations did not correspond to geographic proximity. Populations in Escalante, Utah were related to those on the Mogollon Rim (400 km south) and had multiple origins and significant disjunctions with those populations in Bears Ears, Chaco Canyon, and Mesa Verde sites. CONCLUSIONS: Movement of tubers from the Mogollon region may have occurred many times and in multiple directions during the past, resulting in the complex genetic patterns seen in populations from across the Four Corners region.

Isolation by environment and its consequences for range shifts with global change: Landscape genomics of the invasive plant common tansy.

Invasive species are a growing global economic and ecological problem. However, it is not well understood how environmental factors mediate invasive range expansion. In this study, we investigated the recent and rapid range expansion of common tansy across environmental gradients in Minnesota, USA. We densely sampled individuals across the expanding range and performed reduced representation sequencing to generate a dataset of 3071 polymorphic loci for 176 individuals. We used non-spatial and spatially explicit analyses to determine the relative influences of geographic distance and environmental variation on patterns of genomic variation. We found no evidence for isolation by distance but strong evidence for isolation by environment, indicating that environmental factors may have modulated patterns of range expansion. Land use classification and soils were particularly important variables related to population structure although they operated on different spatial scales; land use classification was related to broad-scale patterns and soils were related to fine-scale patterns. All analyses indicated a distinctive genetic cluster in the most recently invaded portion of the range. Individuals from the far northwestern range margin were separated from the remainder of the range by reduced migration, which was associated with environmental resistance. This portion of the range was invaded primarily in the last 15 years. Ecological niche models also indicated that this cluster was associated with the expansion of the niche. While invasion is often assumed to be primarily influenced by dispersal limitation, our results suggest that ongoing invasion and range shifts with climate change may be strongly affected by environmental heterogeneity.

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Cancer immunotherapy has rapidly become the fourth mainstream treatment alternative after surgery, radiotherapy, and chemotherapy, with some promising results. It aims to kill tumor cells by mobilizing or stimulating cytotoxic immune cells. However, the clinical applications of tumor immunotherapies are limited owing to a lack of adequate delivery pathways and high toxicity. Recently, nanomaterials and genetic engineering have shown great potential in overcoming these limitations by protecting the delivery of antigens, activating targeted T cells, modulating the immunosuppressive tumor microenvironment, and improving the treatment efficacy. Bacillus Calmette-Guérin (BCG) is a live attenuated Mycobacterium bovis vaccine used to prevent tuberculosis, which was first reported to have antitumor activity in 1927. BCG therapy can activate the immune system by inducing various cytokines and chemokines, and its specific immune and inflammatory responses exert antitumor effects. BCG was first used during the 1970s as an intravesical treatment agent for bladder cancer, which effectively improved immune antitumor activity and prevented tumor recurrence. More recently, nano-BCG and genetically engineered BCG have been proposed as treatment alternatives for bladder cancer due to their ability to induce stronger and more stable immune responses. In this study, we outline the development of nano-BCG and genetically engineered BCG for bladder cancer immunotherapy and review their potential and associated challenges.

Microarray Images Contrast Enhancement and Gridding Using Genetic Algorithm.

Background: Microarray is a sophisticated tool that concurrently analyzes the expression levels of thousands of genes, giving scientists an overview of DNA and RNA study. This procedure is divided into three stages: contact with biological samples, data extraction, and data analysis. Because expression levels are disclosed by the interplay of light with fluorescent markers, the data extraction stage relies on image processing methods. To extract quantitative information from the microarray image (MAI), four steps of preprocessing, gridding, segmentation, and intensity quantification are required. During the generation of MAIs, a large number of error-prone processes occur, leading to structural problems and reduced quality in the resulting data, affecting the identification of expressed genes. Methods: In this article, the first stage has been examined. In the preprocessing stage, the contrast of the images is first enhanced using the genetic algorithm, then the source noises that appear as small artifacts are removed using morphology, and finally, to confirm the effect of the contrast enhancement (CE) on the main stages of microarray data processing, gridding is checked on complementary deoxyribonucleic acid MAIs. Results: The comparison of the obtained results with an adaptive histogram equalization (AHE) and multi-decomposition histogram equalization (M-DHE) methods shows the superiority and efficiency of the proposed method. For example, the image contrast of the Genomic Medicine Research Center Laboratory dataset is 3.24, which is 42.91 with the proposed method and 13.48 and 32.40 with the AHE and M-DHE methods, respectively. Conclusions: The performance of the proposed methods for CE is evaluated on 3 databases and a general conclusion is obtained as to which CE method is more suitable for each dataset.

[Carrier screening for 223 monogenic diseases in Chinese population: a multi-center study in 33 104 individuals].

OBJECTIVE: To investigate the epidemiological characteristics and mutation spectrum of monogenic diseases in Chinese population through a large-scale, multicenter carrier screening. METHODS: This study was conducted among a total of 33 104 participants (16 610 females) from 12 clinical centers across China.Carrier status for 223 genes was analyzed using high-throughput sequencing and different PCR methods. RESULTS: The overall combined carrier frequency was 55.58% for 197 autosomal genes and 1.84% for 26 X-linked genes in these participants.Among the 16 669 families, 874 at-risk couples (5.24%) were identified.Specifically, 584 couples (3.50%) were at risk for autosomal genes, 306(1.84%) for X-linked genes, and 16 for both autosomal and X-linked genes.The most frequently detected autosomal at-risk genes included GJB2(autosomal recessive deafness type 1A, 393 couples), HBA1/HBA2(α-thalassemia, 36 couples), PAH (phenylketonuria, 14 couples), and SMN1(spinal muscular atrophy, 14 couples).The most frequently detected X-linked at-risk genes were G6PD (G6PD deficiency, 236 couples), DMD (Duchenne muscular dystrophy, 23 couples), and FMR1(fragile X syndrome, 17 couples).After excluding GJB2 c.109G>A, the detection rate of at-risk couples was 3.91%(651/16 669), which was lowered to 1.72%(287/16 669) after further excluding G6PD.The theoretical incidence rate of severe monogenic birth defects was approximately 4.35‰(72.5/16 669).Screening for a battery of the top 22 most frequent genes in the at-risk couples could detect over 95% of at-risk couples, while screening for the top 54 genes further increased the detection rate to over 99%. CONCLUSION: This study reveals the carrier frequencies of 223 monogenic genetic disorders in the Chinese population and provides evidence for carrier screening strategy development and panel design tailored to the Chinese population.In carrier testing, genetic counseling for specific genes or gene variants can be challenging, and the couples need to be informed of these difficulties before testing and provided with options for not screening these genes or gene variants.

Free-Docking and Template-Based Docking: Physics Versus Knowledge-Based Docking.

Docking methods can be used to predict the orientations of two or more molecules with respect of each other using a plethora of various algorithms, which can be based on the physics of interactions or can use information from databases and templates. The usability of these approaches depends on the type and size of the molecules, whose relative orientation will be estimated. The two most important limitations are (i) the computational cost of the prediction and (ii) the availability of the structural information for similar complexes. In general, if there is enough information about similar systems, knowledge-based and template-based methods can significantly reduce the computational cost while providing high accuracy of the prediction. However, if the information about the system topology and interactions between its partners is scarce, physics-based methods are more reliable or even the only choice. In this chapter, knowledge-, template-, and physics-based methods will be compared and briefly discussed providing examples of their usability with a special emphasis on physics-based protein-protein, protein-peptide, and protein-fullerene docking in the UNRES coarse-grained model.

Increased prevalence of the null allele of the p.Arg577Ter variant in the ACTN3 gene in Brazilian long-distance athletes: A retrospective study.

INTRODUCTION: The phenotypic consequences of the p.Arg577Ter variant in the α-actinin-3 (ACTN3) gene are suggestive of a trade-off between performance traits for speed and endurance sports. Although there is a consistent association of the c.1729C allele (aka R allele) with strength/power traits, there is still a debate on whether the null allele (c.1729T allele; aka X allele) influences endurance performance. The present study aimed to test the association of the ACTN3 p.Arg577Ter variant with long-distance endurance athlete status, using previously published data with the Brazilian population. METHODS: Genotypic data from 203 long-distance athletes and 1724 controls were analysed in a case-control approach. RESULTS: The frequency of the X allele was significantly higher in long-distance athletes than in the control group (51.5% vs. 41.4%; p = 0.000095). The R/X and X/X genotypes were overrepresented in the athlete group. Individuals with the R/X genotype instead of the R/R genotype had a 1.6 increase in the odds of being a long-distance athlete (p = 0.012), whereas individuals with the X/X genotype instead of the R/R genotype had a 2.2 increase in the odds of being a long-distance athlete (p = 0.00017). CONCLUSION: The X allele, mainly the X/X genotype, was associated with long-distance athlete status in Brazilians.

Leveraging human-mouse studies to advance the genetics of hearing impairment in Africa.

Mouse models are used extensively to understand human pathobiology and mechanistic functions of disease-associated loci. However, in this review, we investigate the potential of using genetic mouse models to identify genetic markers that can disrupt hearing thresholds in mice and then target the hearing-enriched orthologues and loci in humans. Currently, little is known about the real prevalence of genes that cause hearing impairment (HI) in Africa. Pre-screening mouse cell lines to identify orthologues of interest has the potential to improve the genetic diagnosis for HI in Africa to a significant percentage, for example, 10-20%. Furthermore, the functionality of a candidate gene derived from mouse screening with heterogeneous genetic backgrounds and multi-omic approaches can shed light on the molecular, genetic heterogeneity and plausible mode of inheritance of a gene in hearing-impaired individuals especially in the absence of large families to investigate.