Operationalizing stakeholder engagement for gene drive research in malaria elimination in Africa-translating guidance into practice.

Gene drive mosquitoes are increasingly considered a potential transformational tool for vector control of malaria mosquitoes. As part of efforts to promote responsible research in this field, a number of guidance documents have been published by the World Health Organization, National Academies and expert groups. While virtually all recent guidance documents on gene drive research stress the importance of stakeholder engagement activities, no specific guidelines on implementing them have been established. Target Malaria, a not-for-profit research consortium developing a vector-control gene drive approach to eliminate malaria, has reflected on how its stakeholder engagement strategy translates engagement guidance documents into practice. The project analysed and addressed the tension between the context specificities and the international recommendations. The engagement strategy combines published recommendations for responsible gene drive research, information collected from the local context where the project operates and a set of principles guiding the choices made. This strategy was first developed during the early phases of the project's research, years ahead of any activities with gene drive mosquitoes in those countries of operations. These earlier activities, and their related engagement, allow the project to develop and adapt an engagement strategy appropriate for potential gene drive research in its field site countries. This paper offers a description of a stakeholder engagement strategy operationalization based on (1) adaptation to stakeholder preferences, (2) inclusiveness and (3) empowerment and accountability. The authors hope to offer concrete examples to support other projects with the development and implementation of their engagement strategies with particular attention to the co-development principle.

Genetic tools to study complexity of striatal function.

As the main input structure of the basal ganglia (BG), the striatum collects and integrates information from several brain areas and funnels them forward to other BG nuclei. The striatal projection neurons are medium-sized spiny neurons classified in two main subpopulations, based on their neurochemical characterization and projection targets. These subpopulations are segregated into two distinct circuits, the direct and the indirect pathway, which originate in the striatum and interconnect the BG, ultimately reaching their output nuclei. In this review, we discuss current opinions on the striatal circuit and present different strategies to decipher this circuit complexity by utilizing cell ablation, opto- and chemogenetics, tetanus toxin-induced neuronal silencing, and calcium imaging techniques. We also describe genetically encoded biosensors to monitor signaling dynamics in the striatal circuit with high spatial and temporal resolution by targeting both glutamate and dopamine transmission together with downstream signaling effectors. Recent findings revealing transcriptional, functional diversity, and regionally distinct signaling properties of spiny projection neurons argue that refined interrogation will be pertinent for a deeper understanding of this circuit. Moreover, future mapping the G-protein-coupled receptor repertoire in SPNs will potentially enable pathway-specific modulation of SPN activity and provide a novel framework for targeting BG diseases. Overall, these tools will be critical for designing next-generation treatments for BG diseases.

Description and characterization of a novel live-attenuated tri-segmented Machupo virus in Guinea pigs.

BACKGROUND: Machupo virus (MACV) is a member of the Mammarenavirus genus, Arenaviridae family and is the etiologic agent of Bolivian hemorrhagic fever, which causes small outbreaks or sporadic cases. Several other arenaviruses in South America Junín virus (JUNV) in Argentina, Guanarito in Venezuela, Sabiá in Brazil and Chapare in Bolivia, also are responsible for human hemorrhagic fevers. Among these arenaviruses, JUNV caused thousands of human cases until 1991, when the live attenuated Candid #1 vaccine, was used. Other than Candid #1 vaccine, few other therapeutic or prophylactic treatments exist. Therefore, new strategies for production of safe countermeasures with broad spectrum activity are needed. FINDINGS: We tested a tri-segmented MACV, a potential vaccine candidate with several mutations, (r3MACV). In cell culture, r3MACV showed a 2-log reduction in infectious virus particle production and the MACV inhibition of INF-1ß was removed from the construct and produced by infected cells. Furthermore, in an animal experiment, r3MACV was able to protect 50% of guinea pigs from a simultaneous lethal JUNV challenge. Protected animals didn't display clinical symptoms nor were virus particles found in peripheral blood (day 14) or in organs (day 28 post-inoculation). The r3MACV provided a higher protection than the Candid #1 vaccine. CONCLUSIONS: The r3MACV provides a potential countermeasure against two South America arenaviruses responsible of human hemorrhagic fever.

Molecular bases of anorexia nervosa, bulimia nervosa and binge eating disorder: shedding light on the darkness.

Eating-disorders (EDs) consequences to human health are devastating, involving social, mental, emotional, physical and life-threatening aspects, concluding on impairment and death in cases of extreme anorexia nervosa. It also implies that people suffering an ED need to find psychiatric and psychological help as soon as possible to achieve a fully physical and emotional recovery. Unfortunately, to date, there is a crucial lack of efficient clinical treatment to these disorders. In this review, we present an overview concerning the actual pharmacological and psychological treatments, the knowledge of cells, circuits, neuropeptides, neuromodulators and hormones in the human brain- and other organs- underlying these disorders, the studies in animal models and, finally, the genetic approaches devoted to face this challenge. We will also discuss the need for new perspectives, avenues and strategies to be developed in order to pave the way to novel and more efficient therapeutics.

A Mendelian analysis of the relationships between immune cells and breast cancer.

Background: Emerging evidence showed immune cells were associated with the development of breast cancer. Nonetheless, the causal link between them remains uncertain. Consequently, the objective of this study was to investigate the causal connection between immune traits and the likelihood of developing breast cancer. Methods: A two-sample Mendelian randomization (MR) analysis was conducted to establish the causal relationship between immune cells and breast cancer in this study. Utilizing publicly accessible genetic data, we investigated causal connections between 731 immune cells and the occurrence of breast cancer. The primary approach for exploring this relationship was the application of the inverse-variance-weighted (IVW) method. Furthermore, sensitivity analyses, encompassing the leave-one-out analysis, Cochran Q test, and Egger intercept test were performed to validate the reliability of the Mendelian randomization results. Finally, we used Bayesian Weighted Mendelian Randomization (BWMR) approach to test the results of MR study. Results: According to the Bonferroni correction, no immune trait was identified with a decreased or increased risk of overall breast cancer risk. As for the ER+ breast cancer, 6 immune trait was identified after the Bonferroni method. the IVW method results showed that CD45RA- CD4+ %CD4+ (p-value:1.37×10-6), CD8dim %T cell (p-value:4.62×10-43), BAFF-R on IgD+ CD38- unsw mem (p-value:6.93×10-5), CD27 on PB/PC (p-value:2.72×10-18) lowered the risk of breast cancer. However, CD19 on IgD- CD38br (p-value:1.64×10-6), CD25 on IgD+ CD38dim (p-value: - ∞) were associated with a higher risk of developing breast cancer. As for the CX3CR1 on CD14+ CD16- monocyte (p-value: 1.15×10-166), the IVW method clearly demonstrated a protective effect against ER- breast cancer. For the above positive results, BAFF-R on IgD+ CD38- unsw mem was the sole association linked to reduced breast cancer risk using the BWMR method. The intercept terms' p-values in MR-Egger regression all exceeded 0.05, indicating the absence of potential horizontal pleiotropy. Conclusion: Through genetic approaches, our study has illustrated the distinct correlation between immune cells and breast cancer, potentially paving the way for earlier diagnosis and more efficient treatment alternatives.

Identifying therapeutic targets for breast cancer: insights from systematic Mendelian randomization analysis.

Background: Breast cancer (BC) exhibits a high incidence rate, imposing a substantial burden on healthcare systems. Novel drug targets are urgently needed for BC. Mendelian randomization (MR) has gained widespread application for identifying fresh therapeutic targets. Our endeavor was to pinpoint circulatory proteins causally linked to BC risk and proffer potential treatment targets for BC. Methods: Through amalgamating protein quantitative trait loci from 2,004 circulating proteins and comprehensive genome-wide association study data from the Breast Cancer Association Consortium, we conducted MR analyses. Employing Steiger filtering, bidirectional MR, Bayesian colocalization, phenotype scanning, and replication analyses, we further solidified MR study outcomes. Additionally, protein-protein interaction (PPI) network was harnessed to unveil latent associations between proteins and prevailing breast cancer medications. The phenome-wide MR (Phe-MR) was employed to assess potential side effects and indications for the druggable proteins of BC. Finally, we further affirmed the drugability of potential drug targets through mRNA expression analysis and molecular docking. Results: Through comprehensive analysis, we identified five potential drug targets, comprising four (TLR1, A4GALT, SNUPN, and CTSF) for BC and one (TLR1) for BC_estrogen receptor positive. None of these five potential drug targets displayed reverse causation. Bayesian colocalization suggested that these five latent drug targets shared variability with breast cancer. All drug targets were replicated within the deCODE cohort. TLR1 exhibited PPI with current breast cancer therapeutic targets. Furthermore, Phe-MR unveiled certain adverse effects solely for TLR1 and SNUPN. Conclusion: Our study uncovers five prospective drug targets for BC and its subtypes, warranting further clinical exploration.

Regulation of photosynthesis under salt stress and associated tolerance mechanisms.

Photosynthesis is crucial for the survival of all living biota, playing a key role in plant productivity by generating the carbon skeleton that is the primary component of all biomolecules. Salinity stress is a major threat to agricultural productivity and sustainability as it can cause irreversible damage to photosynthetic apparatus at any developmental stage. However, the capacity of plants to become photosynthetically active under adverse saline conditions remains largely untapped. This study addresses this discrepancy by exploring the current knowledge on the impact of salinity on chloroplast operation, metabolism, chloroplast ultrastructure, and leaf anatomy, and highlights the dire consequences for photosynthetic machinery and stomatal conductance. We also discuss enhancing photosynthetic capacity by modifying and redistributing electron transport between photosystems and improving photosystem stability using genetic approaches, beneficial microbial inoculations, and root architecture changes to improve salt stress tolerance under field conditions. Understanding chloroplast operations and molecular engineering of photosynthetic genes under salinity stress will pave the way for developing salt-tolerant germplasm to ensure future sustainability by rehabilitating saline areas.

Role of extracellular signal-regulated kinase 1/2 signaling underlying cardiac hypertrophy.

Cardiac hypertrophy is the result of increased myocardial cell size responding to an increased workload and developmental signals. These extrinsic and intrinsic stimuli as key drivers of cardiac hypertrophy have spurred efforts to target their associated signaling pathways. The extracellular signal-regulated kinases 1/2 (ERK1/2), as an essential member of mitogen-activated protein kinases (MAPKs), has been widely recognized for promoting cardiac growth. Several modified transgenic mouse models have been generated through either affecting the upstream kinase to change ERK1/2 activity, manipulating the direct role of ERK1/2 in the heart, or targeting phosphatases or MAPK scaffold proteins to alter total ERK1/2 activity in response to an increased workload. Using these models, both regulation of the upstream events and modulation of each isoform and indirect effector could provide important insights into how ERK1/2 modulates cardiomyocyte biology. Furthermore, a plethora of compounds, inhibitors, and regulators have emerged in consideration of ERK, or its MAPK kinases, are possible therapeutic targets against cardiac hypertrophic diseases. Herein, is a review of the available evidence regarding the exact role of ERK1/2 in regulating cardiac hypertrophy and a discussion of pharmacological strategy for treatment of cardiac hypertrophy.

A Dual Strategy of Breeding for Drought Tolerance and Introducing Drought-Tolerant, Underutilized Crops into Production Systems to Enhance Their Resilience to Water Deficiency.

Water scarcity is the primary constraint on crop productivity in arid and semiarid tropical areas suffering from climate alterations; in accordance, agricultural systems have to be optimized. Several concepts and strategies should be considered to improve crop yield and quality, particularly in vulnerable regions where such environmental changes cause a risk of food insecurity. In this work, we review two strategies aiming to increase drought stress tolerance: (i) the use of natural genes that have evolved over time and are preserved in crop wild relatives and landraces for drought tolerance breeding using conventional and molecular methods and (ii) exploiting the reservoir of neglected and underutilized species to identify those that are known to be more drought-tolerant than conventional staple crops while possessing other desired agronomic and nutritive characteristics, as well as introducing them into existing cropping systems to make them more resilient to water deficiency conditions. In the past, the existence of drought tolerance genes in crop wild relatives and landraces was either unknown or difficult to exploit using traditional breeding techniques to secure potential long-term solutions. Today, with the advances in genomics and phenomics, there are a number of new tools available that facilitate the discovery of drought resistance genes in crop wild relatives and landraces and their relatively easy transfer into advanced breeding lines, thus accelerating breeding progress and creating resilient varieties that can withstand prolonged drought periods. Among those tools are marker-assisted selection (MAS), genomic selection (GS), and targeted gene editing (clustered regularly interspaced short palindromic repeat (CRISPR) technology). The integration of these two major strategies, the advances in conventional and molecular breeding for the drought tolerance of conventional staple crops, and the introduction of drought-tolerant neglected and underutilized species into existing production systems has the potential to enhance the resilience of agricultural production under conditions of water scarcity.

Genetic Approaches in Preeclampsia.

Preeclampsia (PE) is a serious hypertensive disorder that affects up to 8% of all pregnancies annually. An established risk factor for PE is family history, clearly demonstrating an underlying genetic component to the disorder. To date, numerous genetic studies, using both the candidate gene and genome-wide approach, have been undertaken to tease out the genetic basis of PE and understand its origins. Such studies have identified some promising candidate genes such as STOX1 and ACVR2A. Nevertheless, researchers face ongoing challenges of replicating these genetic associations in different populations and performing the functional validation of identified genetic variants to determine their causality in the disorder. This chapter will review the genetic approaches used in the study of PE, discuss their limitations and possible confounders, and describe current strategies.

Haploid Strategies for Functional Validation of Plant Genes.

Increasing knowledge of plant genome sequences requires the development of more reliable and efficient genetic approaches for genotype-phenotype validation. Functional identification of plant genes is generally achieved by a combination of creating genetic modifications and observing the according phenotype, which begins with forward-genetic methods represented by random physical and chemical mutagenesis and move towards reverse-genetic tools as targeted genome editing. A major bottleneck is time need to produce modified homozygous genotypes that can actually be used for phenotypic validation. Herein, we comprehensively address and compare available experimental approaches for functional validation of plant genes, and propose haploid strategies to reduce the time needed and cost consumed for establishing gene function.