A Visible-Light-Driven Self-Powered Nodularin-R Biosensing Platform Controlled by an Integrated Portable Photoelectrochemical Detection Device.

The presence of nodularin-R (NOD-R) in water has gained considerable attention because of its widespread distribution and high toxicity. In this study, an accurate and rapid visible-light-driven self-powered photoelectrochemical (PEC) biosensor was developed by integrating a portable paper-based electrode with a custom-built miniaturized PEC detection device. The newly designed system successfully achieved on-site detection of NOD-R in real water samples based on PEC technology. First, target recognition triggers the initiation of the hybridization chain reaction to generate double-stranded DNA. The thus-formed double-stranded DNA entrapped methylene blue (MB), and the dye molecules were irradiated with visible light for conversion to leuco-MB in the presence of ascorbic acid. The resulting leuco-MB species significantly amplified the PEC signal output of TiO2-MXene, enabling NOD-R detection. Under optimal conditions, the proposed PEC assay strategy demonstrated NOD-R detection within a concentration range from 20 fg mL-1 to 10 ng mL-1 with a detection limit of 19.6 fg mL-1. In addition, a custom-built miniaturized PEC detection device conveniently integrates the detection component with the light source, enabling the real-time collection of results via a wireless module. This innovative self-powered PEC platform provides significant advancements in smooth and intelligent detection compared to traditional PEC detection devices.

Effects of residual feed intake on the economic traits of fast-growing meat ducks.

Feed efficiency (FE) is a crucial economic indicator of meat duck production. The objective of this study was to assess the impact of residual feed intake (RFI), defined as the difference between the actual and expected feed intake based on animal's production and maintenance requirements, on the growth performance (GP), slaughter and internal organ characteristics of fast-growing meat ducks. In total, 1,300 healthy 14-day-old male fast-growing meat ducks were housed in individual cages until slaughter at the age of 35 d. The characteristics of the carcass and internal organs of 30 ducks with the highest RFI (HRFI) and the lowest RFI (LRFI) were respectively determined. RFI, the feed conversion ratio (FCR), and average day feed intake (ADFI) were significantly lower in the LRFI group than the HRFI group (P < 0.001), while there were no significant differences in marketing BW or BW gain (BWG) (P > 0.05). The thigh muscle and lean meat yields were higher, and the abdominal fat content was lower (P < 0.001) in the LRFI group, while there were no significant differences in other carcass traits between the groups (P > 0.05). The liver and gizzard yields were significantly higher (P < 0.001) in the LRFI group, while there were no significant differences (P > 0.05) in intestinal length between the groups. RFI was highly positively correlate with FCR and ADFI (P < 0.01), but negatively correlated the yields of thigh muscle, lean meat, liver, and gizzard, and positively correlated with abdominal fat content. These results indicate that selection for low RFI could improve the FE of fast-growing meat ducks without affecting the marketing BW and BWG, while increasing yields of thigh muscle and lean meat and reducing abdominal fat content. These findings offer useful insights into the biological processes that influence FE of fast-growing meat ducks.

Bidirectional regulation of levodopa-induced dyskinesia by a specific neural ensemble in globus pallidus external segment.

Levodopa-induced dyskinesia (LID) is an intractable motor complication arising in Parkinson's disease with the progression of disease and chronic treatment of levodopa. However, the specific cell assemblies mediating dyskinesia have not been fully elucidated. Here, we utilize the activity-dependent tool to identify three brain regions (globus pallidus external segment [GPe], parafascicular thalamic nucleus, and subthalamic nucleus) that specifically contain dyskinesia-activated ensembles. An intensity-dependent hyperactivity in the dyskinesia-activated subpopulation in GPe (GPeTRAPed in LID) is observed during dyskinesia. Optogenetic inhibition of GPeTRAPed in LID significantly ameliorates LID, whereas reactivation of GPeTRAPed in LID evokes dyskinetic behavior in the levodopa-off state. Simultaneous chemogenetic reactivation of GPeTRAPed in LID and another previously reported ensemble in striatum fully reproduces the dyskinesia induced by high-dose levodopa. Finally, we characterize GPeTRAPed in LID as a subset of prototypic neurons in GPe. These findings provide theoretical foundations for precision medication and modulation of LID in the future.

Priority index for critical Covid-19 identifies clinically actionable targets and drugs.

While genome-wide studies have identified genomic loci in hosts associated with life-threatening Covid-19 (critical Covid-19), the challenge of resolving these loci hinders further identification of clinically actionable targets and drugs. Building upon our previous success, we here present a priority index solution designed to address this challenge, generating the target and drug resource that consists of two indexes: the target index and the drug index. The primary purpose of the target index is to identify clinically actionable targets by prioritising genes associated with Covid-19. We illustrate the validity of the target index by demonstrating its ability to identify pre-existing Covid-19 phase-III drug targets, with the majority of these targets being found at the leading prioritisation (leading targets). These leading targets have their evolutionary origins in Amniota ('four-leg vertebrates') and are predominantly involved in cytokine-cytokine receptor interactions and JAK-STAT signaling. The drug index highlights opportunities for repurposing clinically approved JAK-STAT inhibitors, either individually or in combination. This proposed strategic focus on the JAK-STAT pathway is supported by the active pursuit of therapeutic agents targeting this pathway in ongoing phase-II/III clinical trials for Covid-19.

Regulation of PDGFRα+ cells and ICC in progesterone-mediated slow colon transit in pregnant mice.

Background: Progesterone can inhibit intestinal smooth muscle contraction; however, the specific mechanism remains unclear. Besides smooth muscle cells, smooth muscle has two important mesenchymal cells, namely interstitial cells of Cajal (ICC) and PDGFRα+ cells, which induce the contraction and relaxation of smooth muscles. We aimed to explore the regulation of PDGFRα+ cells and ICC in progesterone-mediated colon slow transit in pregnant mice. Methods: Colon transit experiments were performed in vivo and in vitro to observe slow colon transit. The expression of PDGFRα and c-KIT was detected by Western blot, RT-PCR, and immunofluorescence. An isometric tension experiment was performed to investigate smooth muscle contractions. Results: The colon transit time in pregnant mice was longer than that in non-pregnant mice. Progesterone significantly blocks colonic smooth muscle contractions. However, when the relaxation and contraction of PDGFRα+ cells and ICC are blocked, progesterone cannot inhibit smooth muscle contraction. When the function of only PDGFRα+ cells are blocked, progesterone has a more obvious inhibitory effect on smooth muscle in the non-pregnant group than that in the pregnant group. However, when ICC alone was blocked, progesterone inhibited smooth muscle contractions more clearly in pregnant mice. The protein and mRNA expression of PDGFRα was higher and c-KIT was lower in pregnant mice. PDGFRα+ cells and ICC from smooth muscle all co-localize progesterone receptors. Conclusions: Under the regulation of progesterone, the relaxation function of PDGFRα+ cells is enhanced and the contraction function of ICC is weakened, leading to the slow colon transit of pregnant mice.

Optimized CRISPR/Cas9 system for gene knockout in chicken DF1 cells.

The editing efficiency primarily hinders the utility of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technology in poultry. For a better understanding of the factors that influence the efficiency of gene knockout mediated by CRISPR/Cas9 in chicken DF1 cells, the single or dual single guide RNA (sgRNA) targeted exon regions of genes (taking anti-Müllerian hormone, TGF-beta receptor type-2 and Peroxisome proliferator-activated receptor gamma as examples) were designed. The sgRNA-CRISPR/Cas9 vectors with corresponding reporter vectors were transfected into DF1 cells. T7 endonuclease 1 (T7E1) and amplicon sequencing assay were compared for evaluating genome editing efficiency and the indel profiles were analyzed based on the data of amplicon sequencing. Meanwhile, to evaluate the precision of Cas9 cleavage, we also analyzed the homology of small insertion with the nucleotides of upstream and downstream of cleave sties. The surrogate reporter systems showed strong enrichment function, and the indel percentages were increased after puromycin selection. The indel ratios of T7E1 assay were lower than amplicon sequencing assay, which indicated T7E1 isn't fit to be used as the sole evaluation criterion for the targeting efficiency of CRISPR/Cas9. Based on the amplicon sequencing analysis, the editing efficiency showed noticeable differences among cells treated with different sgRNAs. However, the variety of indel efficiencies was not related to the GC content of sgRNA or chromosome types of targeted genes. The results showed that the dual sgRNA might not raise the indel ratios compared with individual sgRNA, but they could increase the ratios of the fragment deletions. The present study suggested that the surrogate reporter was an effective method to promote the editing efficiencies of CRISPR/Cas9 in chicken cells. The dual sgRNA could increase the fragment deletions, and the sensitivity of amplicon sequencing to detect cleavage was higher than the T7 endonuclease 1 assay. These results are essential to improve the application of CRISPR/Cas9 technology in chicken cells.

Priority index for asthma (PIA): In silico discovery of shared and distinct drug targets for adult- and childhood-onset disease.

Asthma is a chronic disease that is caused by a combination of genetic risks and environmental triggers and can affect both adults and children. Genome-wide association studies have revealed partly distinct genetic architectures for its two age-of-onset subtypes (namely, adult-onset and childhood-onset). We reason that identifying shared and distinct drug targets between these subtypes may inform the development of subtype-specific therapeutic strategies. In attempting this, we here introduce Priority Index for Asthma or PIA, a genetics-led and network-driven drug target prioritisation tool for asthma. We demonstrate the validity of the tool in improving drug target prioritisation for asthma compared to the status quo methods, as well as in capturing the underlying etiology and existing therapeutics for the disease. We also illustrate how PIA can be used to prioritise drug targets for adult- and childhood-onset asthma, as well as to identify shared and distinct pathway crosstalk genes. Shared crosstalk genes are mostly involved in JAK-STAT signaling, with clinical evidence supporting that targeting this pathway may be a promising drug repurposing opportunity for both subtypes. Crosstalk genes specific to childhood-onset asthma are enriched for PI3K-AKT-mTOR signaling, and we identify genes that are already targeted by licensed medications as repurposed drug candidates for this subtype. We make all our results accessible and reproducible at http://www.genetictargets.com/PIA. Collectively, our study has significant implications for asthma computational medicine research and can guide the future development of subtype-specific therapeutic strategies for the disease.

OpenXGR: a web-server update for genomic summary data interpretation.

How to effectively convert genomic summary data into downstream knowledge discovery represents a major challenge in human genomics research. To address this challenge, we have developed efficient and effective approaches and tools. Extending our previously established software tools, we here introduce OpenXGR (http://www.openxgr.com), a newly designed web server that offers almost real-time enrichment and subnetwork analyses for a user-input list of genes, SNPs or genomic regions. It achieves so through leveraging ontologies, networks, and functional genomic datasets (such as promoter capture Hi-C, e/pQTL and enhancer-gene maps for linking SNPs or genomic regions to candidate genes). Six analysers are provided, each doing specific interpretations tailored to genomic summary data at various levels. Three enrichment analysers are designed to identify ontology terms enriched for input genes, as well as genes linked from input SNPs or genomic regions. Three subnetwork analysers allow users to identify gene subnetworks from input gene-, SNP- or genomic region-level summary data. With a step-by-step user manual, OpenXGR provides a user-friendly and all-in-one platform for interpreting summary data on the human genome, enabling more integrated and effective knowledge discovery.

The Secondary Motor Cortex-striatum Circuit Contributes to Suppressing Inappropriate Responses in Perceptual Decision Behavior.

The secondary motor cortex (M2) encodes choice-related information and plays an important role in cue-guided actions. M2 neurons innervate the dorsal striatum (DS), which also contributes to decision-making behavior, yet how M2 modulates signals in the DS to influence perceptual decision-making is unclear. Using mice performing a visual Go/No-Go task, we showed that inactivating M2 projections to the DS impaired performance by increasing the false alarm (FA) rate to the reward-irrelevant No-Go stimulus. The choice signal of M2 neurons correlated with behavioral performance, and the inactivation of M2 neurons projecting to the DS reduced the choice signal in the DS. By measuring and manipulating the responses of direct or indirect pathway striatal neurons defined by M2 inputs, we found that the indirect pathway neurons exhibited a shorter response latency to the No-Go stimulus, and inactivating their early responses increased the FA rate. These results demonstrate that the M2-to-DS pathway is crucial for suppressing inappropriate responses in perceptual decision behavior.

Insulin-like growth factor-1 regulates follicle selection of hens by promoting proliferation and inhibiting apoptosis of granulosa cells in prehierarchical follicles in vitro.

During the reproduction stage of poultry, a single follicle is selected from a cohort of 6-8 mm small yellow follicles to initiate rapid growth and final ovulation almost daily. In the process, follicle-stimulating hormone (FSH) plays a pivotal role by interacting with intraovarian factors, including insulin-like growth Factor 1 (IGF1). The objective of this study was to analyze whether IGF1 coordinates with FSH to affect the characteristics of granulosa cells from prehierarchical follicles. After treating granulosa cells with 50 ng/mL FSH and 200 ng/mL IGF1, we detected the proliferation and apoptosis of granulosa cells using flow cytometry. The percentage of G1 phase granulosa cells was increased, and the percentage of mitotic cells and apoptotic cells was reduced under IGF1 treatment. The expression levels of the steroidogenic acute regulatory protein gene, cytochrome P450 side-chain cleavage gene and 3ß-hydroxysteroid dehydrogenase gene, which are related to steroidogenic synthesis, were reduced by cotreatment with FSH and IGF1. The expression of the cell proliferation- or apoptosis-related genes cyclin dependent kinase 2, cyclin D2, B-cell leukemia/lymphoma 2, and BCL2 like 1 and the ratio of B-cell leukemia/lymphoma 2/BCL2-associated X were increased by treatment with IGF1. There was a decrease in the expression of caspase3 after treatment with FSH and IGF1. All these results showed that IGF1 reduced the expression of genes involved in progesterone synthesis, stimulated proliferation and inhibited apoptosis in granulosa cells. Thus, IGF1 may be one of the factors involved in affecting FSH responsiveness and maintaining the undifferentiated state of prehierarchical follicles before follicle selection.