Genetic variation in the SIM1 locus is associated with erectile dysfunction.

Erectile dysfunction affects millions of men worldwide. Twin studies support the role of genetic risk factors underlying erectile dysfunction, but no specific genetic variants have been identified. We conducted a large-scale genome-wide association study of erectile dysfunction in 36,649 men in the multiethnic Kaiser Permanente Northern California Genetic Epidemiology Research in Adult Health and Aging cohort. We also undertook replication analyses in 222,358 men from the UK Biobank. In the discovery cohort, we identified a single locus (rs17185536-T) on chromosome 6 near the single-minded family basic helix-loop-helix transcription factor 1 (SIM1) gene that was significantly associated with the risk of erectile dysfunction (odds ratio = 1.26, P = 3.4 × 10-25). The association replicated in the UK Biobank sample (odds ratio = 1.25, P = 6.8 × 10-14), and the effect is independent of known erectile dysfunction risk factors, including body mass index (BMI). The risk locus resides on the same topologically associating domain as SIM1 and interacts with the SIM1 promoter, and the rs17185536-T risk allele showed differential enhancer activity. SIM1 is part of the leptin-melanocortin system, which has an established role in body weight homeostasis and sexual function. Because the variants associated with erectile dysfunction are not associated with differences in BMI, our findings suggest a mechanism that is specific to sexual function

Exploring the Transporters Dynamics in Blood-Brain Barrier Functionality and Innovative Treatments for Non-Alcoholic Fatty Liver Disease/Steatohepatitis

This dissertation presents a multifaceted study exploring critical aspects of drug development, focusing on the transporters on Blood-Brain Barrier (BBB) and a novel approach for Non-Alcoholic Fatty Liver Disease/Steatohepatitis (NAFLD/NASH).The first segment of this research offers an in-depth analysis of the BBB transporters, focusing on age-related changes in protein expression and the functional impact of polymorphisms. The Blood-Brain Barrier (BBB) serves as a selective barrier for a variety of small molecules, including chemical carcinogens, environmental toxins, and therapeutic drugs. This barrier is constructed from brain capillary endothelial cells, pericytes, and astrocytic end-feet, working in unison to protect neurons and maintain brain homeostasis throughout life. The selective nature of the BBB is attributed to the tight junctions within the capillaries, which prevent the free passage of small molecules, and also to an array of transporters that regulate the influx of essential nutrients and the exclusion of many xenobiotics. The goal of this part of the dissertation is to elucidate the effect of aging from neonates to elderly on the human BBB, with an emphasis on transporters. A secondary goal is to examine in detail the determinants of function of a key transporter in the human BBB, ATP-binding cassette transporter, ABCG2 (BCRP). This part of the dissertation begins with an overview of the current understanding of elements that influence the operation of the BBB, particularly transporters. It starts with a review of the BBB's structural components and their joint function in sustaining barrier integrity. It then summarizes how the BBB controls the movement of nutrients and medicines into the brain through various transport methods. The discussion includes the development of the BBB, how it changes as we age, and how diseases may affect it, emphasizing the dynamics of BBB and the challenges it creates for creating brain-targeted drugs. The chapter then shifts to how genetic variants in transporters influence BBB function and drug disposition, focusing particularly on the prominently expressed ATP-binding cassette transporters ABCB1 and ABCG2. After the overview, this dissertation provides a rich set of comprehensive analyses how age and genetic variations in transporters impact the functionality of BBB to advance our understanding of the multifaceted regulatory framework that controls BBB in physiological and pathological contexts. Major gaps in our understanding of the BBB, which are addressed by this dissertation research, are highlighted.Chapter 2 examines changes in the human BBB proteome throughout a human lifespan, noting the significant shifts in protein expression that influence barrier permeability and the transport of nutrients and drugs. It is acknowledged that the BBB matures after birth, adjusting its transport mechanisms to align with each stage of development, and later alters due to aging and neurodegenerative disorders. Yet, fully grasping these modifications in the human BBB is an ongoing challenge. This chapter introduces a comprehensive proteomic analysis of the evolution and senescence of proteins in brain microvessels (BMVs). Samples from healthy individuals across a wide age spectrum and Alzheimer’s disease patients were analyzed using LC-MS/MS. A plethora of proteins, including numerous SLC and ABC transporters, were identified. Network analysis of the BMV proteome suggested potential alterations in BBB permeability over time and pinpointed transporters crucial for nutrient supply and drug penetration that exhibit age-dependent expression patterns. This investigation sheds light on the dynamic regulation of BBB proteins, emphasizing how transporter variations with age can affect drug permeability. These findings are crucial for refining pharmacokinetic modeling and therapeutic approaches across different stages of life.The dissertation (Part A) then pivots to explore how genetic factors may alter the functionality of transporters, potentially causing variances in drug distribution within the brain. It focuses particularly on ABCG2, a transporter highly expressed at the BBB, noting that genetic variations leading to functional changes can result in differing drug responses. Utilizing deep mutational scanning (DMS), an innovative technique that combines next-generation sequencing (NGS) with functional outcomes of numerous variants, this study evaluated 12,724 variants of the ABCG2 gene. Our experimental setup was crafted to assess over ten thousand of missense, synonymous, and deletion variants of ABCG2 in a high-throughput manner. The abundance of ABCG2 was quantified, its surface expression was measured, and the functional effects of each variant were examined using the anti-cancer drug, mitoxantrone. The resulting detailed functional map, visualized through heatmaps and integrated with the structural data of ABCG2, helped identify crucial residues essential for ABCG2's function and poly-specificity. This study enhances our understanding of ABCG2 and lays the groundwork for future investigations into other ABC transporters. It underscores the value of DMS in dissecting the intricacies of pharmacogenetics and the mechanisms underlying drug resistance.In summary, this part of the dissertation presents a comprehensive examination of the factors important for the functionality of BBB, shedding new light on transporters. Importantly, we unveil the BBB's dynamic protein regulation across the human lifespan, demonstrating how age-related changes affect drug permeability through a detailed proteomic analysis. Furthermore, the dissertation explores how mutations influence transporter functionality, ABCG2 as an example for developing the platform. The innovative use of Deep Mutational Scanning (DMS) to assess thousands of ABCG2 variants provides a rich functional map, revealing key insights into the transporter's operation and offering a valuable resource for future pharmacogenetic and drug resistance research. Overall, these studies highlight the necessity of understanding the BBB's complex mechanisms to enhance drug delivery strategies and overcome barriers in treating neurological disorders including neurodegenerative diseases.The second part of the dissertation (Part B) shifts focus to the global health issue of NAFLD and its more severe form, NASH. It investigates Cis-Regulation Therapy (CRT) as a novel treatment approach, utilizing nuclease-deficient gene-editing technologies to modify gene regulatory elements for therapeutic ends. Approximately 30% of people worldwide are affected by NAFLD, and about 25% of these cases may advance to NASH. NASH represents a more serious stage of NAFLD, marked by liver inflammation and damage due to fat accumulation in the liver. About 25% of those with NAFLD progress to NASH, characterized by significant liver inflammation and damage due to fat accumulation. Currently, the pharmacological treatment options for NAFLD/NASH are severely limited. Our study investigates the potential of CRT as an innovative treatment strategy. In our research, we explored the effectiveness of CRT as a promising new treatment strategy. CRT employs nuclease-deficient gene-editing technologies, such as dead Cas9 (dCas9) combined with transcriptional modulators, to alter the activity of gene regulatory elements for therapeutic purposes. The goal of this part of the dissertation research specifically focuses on the nuclear receptor-like protein 1 (NURR1, NR4A2), a transcription factor critical in regulating inflammation which is a hallmark of NASH.This part of the dissertation initiates with an overview of existing treatment options for NAFLD/NASH, pinpointing their limitations and the urgent need for more effective interventions. It further explores contemporary strategies in drug and therapeutic development targeting NAFLD/NASH, with a particular emphasis on animal models. After the overview, we present our findings that activating Nurr1 through CRISPR activation (CRISPRa) offers a promising therapeutic strategy for NAFLD/NASH within FATZO mouse models. This technique has shown efficacy in improving glucose metabolism abnormalities and reducing the CCL2-CCR2 axis, a critical inflammatory pathway, both before and after the onset of the disease. Our findings introduce a promising new therapeutic avenue for NAFLD/NASH, highlighting the capability of Nurr1 activation to control and possibly reverse the disease's progression.In summary, this dissertation delivers a comprehensive analysis of the variables impacting the functionality of BBB transporters and presents a promising therapeutic approach for NAFLD/NASH. Through this research, we aim to pave new pathways for the advancement of treatments for neurological and hepatic disorders

Comparison of Performance and Power Consumption Between GPS and Sigfox Positioning Using Pycom Modules

Sigfox is one of the newly-emerging LPWAN (Low Power Wide Area Network) technologies aiming to provide power-efficient solutions to the world of IoT. This study presents a comparison between Sigfox Geolocation and GPS (Global Positioning System) in terms of power consumption and performance which includes three metrics: accuracy and precision, response rate and response time. This study includes for the first part a series of lab tests where Sigfox Geolocation and GPS were studied in a single Sleep, Wake up, Idle, Tx/Rx cycle. For the second part, field tests with different geographical parameters (altitude, population, mobility) were conducted. Results of lab tests show that power consumption difference between Sigfox and GPS is a linear function of Idle time. In field tests, GPS presents a far superior performance than Sigfox in all metrics and marginally better power efficiency for relatively short Idle interval. For both GPS and Sigfox, a correlation between power efficiency and performance was observed. Results show that GPS operates best in rural environments while Sigfox stands out in urban ones. Payload size was observed to affect Sigfox in both power consumption and performance while different transmission rates only affect power consumption but do not seem to impact the other metrics. A solution based on the outcome of this study is suggested for a freight-monitoring system where geolocation is handled by GPS and the coordinates transmitted via Sigfox. As an emerging technology under constant development, Sigfox Geolocation is expected to have improved performance in the near future

Eelgrass detritus as a food source for the sea cucumber Apostichopus japonicus Selenka (Echinidermata: Holothuroidea) in coastal waters of North China: an experimental study in flow-through systems.

Eelgrass ecosystems have a wide variety of ecological functions in which living tissues and detritus may be a food source for many marine animals. In this study, we conducted a laboratory simulating experiment to understand the trophic relationship between the eelgrass Zostera marina L and the sea cucumber Apostichopus japonicus. A mixture of decaying eelgrass debris and seafloor surface muddy sediments was used as food to feed A. japonicus, and then specific growth rates (SGR) and fecal production rates (FPR) were measured. According to the proportion of eelgrass debris, we designed five treatment diets, i.e., ES0, ES10, ES20, ES40, and ES100, with eelgrass debris accounting for 0%, 10%, 20%, 40%, and 100% in dry weight, respectively. Results showed that diet composition had a great influence on the growth of A. japonicus. Sea cucumbers could use decaying eelgrass debris as their food source; and when the organic content of a mixture of eelgrass debris and sediment was 19.6% (ES40), a relatively high SGR (1.54%·d(-1)) and FPR (1.31 g·ind.(-1) d(-1)) of A. japonicus were obtained. It is suggested that eelgrass beds can not only provide habitat for the sea cucumber A. japonicus but can also provide an indirect food source for the deposit feeder. This means that the restoration and reconstruction of eelgrass beds, especially in coastal waters of China, would be a potential and effective measure for sea-cucumber fisheries, in respect to both resource restoration and aquaculture of this valuable species

Sensor Placement Optimization of Visual Sensor Networks for Target Tracking Based on Multi-Objective Constraints

With the advancement of sensor technology, distributed processing technology, and wireless communication, Visual Sensor Networks (VSNs) are widely used. However, VSNs also have flaws such as poor data synchronization, limited node resources, and complicated node management. Thus, this paper proposes a sensor placement optimization method to save network resources and facilitate management. First, some necessary models are established, including the sensor model, the space model, the coverage model, and the reconstruction error model, and a dimensionality reduction search method is proposed. Next, following the creation of a multi-objective optimization function to balance reconstruction error and coverage, a clever optimization algorithm that combines the benefits of Genetic Algorithms (GA) and Particle Swarm Optimization (PSO) is applied. Finally, comparison studies validate the methodology presented in this paper, and the combined algorithm can enhance optimization effect while relatively reducing running time. In addition, a sensor coverage method for large-range target space with obstacles is discussed

Assimilation efficiency (AE) of <i>Apostichopus japonicus</i>.

<p>Bars represent standard deviations of the means.</p

Mean fecal production rates (FPR; g·ind.

<p>^−<b>1</b><b> d</b>^−<b>1</b><b>) of </b><b><i>Apostichopus japonicus</i></b><b> during the experimental period.</b> Means (n = 4) with different letters denoting significant differences (<i>p</i><0.05), and bars representing standard deviations of the means.</p

Initial and final wet weight (g·ind.⁻¹) of <i>A. japonicus</i> for five diet treatments.

<p>Note: values with different letters in the same row were significantly different from each other (n = 4, <i>p</i><0.05).</p

Specific growth rates (SGR; %·d⁻¹) of <i>Apostichopus japonicus</i>.

<p>Means (n = 4) with different letters denoting significant differences (<i>p</i><0.05), and bars representing standard deviations of the means.</p