Simultaneous single-cell three-dimensional genome and gene expression profiling uncovers dynamic enhancer connectivity underlying olfactory receptor choice.

The simultaneous measurement of three-dimensional (3D) genome structure and gene expression of individual cells is critical for understanding a genome's structure-function relationship, yet this is challenging for existing methods. Here we present 'Linking mRNA to Chromatin Architecture (LiMCA)', which jointly profiles the 3D genome and transcriptome with exceptional sensitivity and from low-input materials. Combining LiMCA and our high-resolution scATAC-seq assay, METATAC, we successfully characterized chromatin accessibility, as well as paired 3D genome structures and gene expression information, of individual developing olfactory sensory neurons. We expanded the repertoire of known olfactory receptor (OR) enhancers and discovered unexpected rules of their dynamics: OR genes and their enhancers are most accessible during early differentiation. Furthermore, we revealed the dynamic spatial relationship between ORs and enhancers behind stepwise OR expression. These findings offer valuable insights into how 3D connectivity of ORs and enhancers dynamically orchestrate the 'one neuron-one receptor' selection process.

Comprehensive analysis of annexin gene family and its expression in response to branching architecture and salt stress in crape myrtle.

BACKGROUND: Annexin (ANN) is calcium (Ca2+)-dependent and phospholipid binding protein family, which is involved in plant growth and development and response to various stresses. However, little known about ANN genes were identified from crape myrtle, an ornamental horticultural plant widely cultivated in the world. RESULTS: Here, 9 LiANN genes were identified from Lagerstroemia indica, and their characterizations and functions were investigated in L. indica for the first time. The LiANN genes were divided into 2 subfamilies. The gene structure, chromosomal location, and collinearity relationship were also explored. In addition, the GO annotation analysis of these LiANNs indicated that they are enriched in molecular functions, cellular components, and biological processes. Moreover, transcription factors (TFs) prediction analysis revealed that bHLH, MYB, NAC, and other TFs can interact with the LiANN promoters. Interestingly, the LiANN2/4/6-9 were demonstrated to play critical roles in the branching architecture of crape myrtle. Furthermore, the LiANN2/6/8/9 were differentially expressed under salt treatment, and a series of TFs regulating LiANN2/6/8/9 expression were predicted to play essential roles in salt resistance. CONCLUSIONS: These results shed light on profile and function of the LiANN gene family, and lay a foundation for further studies of the LiANN genes.

Recent advances in understanding the immune microenvironment in ovarian cancer.

The occurrence of ovarian cancer (OC) is a major factor in women's mortality rates. Despite progress in medical treatments, like new drugs targeting homologous recombination deficiency, survival rates for OC patients are still not ideal. The tumor microenvironment (TME) includes cancer cells, fibroblasts linked to cancer (CAFs), immune-inflammatory cells, and the substances these cells secrete, along with non-cellular components in the extracellular matrix (ECM). First, the TME mainly plays a role in inhibiting tumor growth and protecting normal cell survival. As tumors progress, the TME gradually becomes a place to promote tumor cell progression. Immune cells in the TME have attracted much attention as targets for immunotherapy. Immune checkpoint inhibitor (ICI) therapy has the potential to regulate the TME, suppressing factors that facilitate tumor advancement, reactivating immune cells, managing tumor growth, and extending the survival of patients with advanced cancer. This review presents an outline of current studies on the distinct cellular elements within the OC TME, detailing their main functions and possible signaling pathways. Additionally, we examine immunotherapy rechallenge in OC, with a specific emphasis on the biological reasons behind resistance to ICIs.

Registered trials on novel therapies for myasthenia gravis: a cross-sectional study on ClinicalTrials.gov.

Novel biologics in MG therapy research is on the rise. This research aimed to investigate the characteristics of registered trials on novel therapies for myasthenia gravis on ClinicalTrials.gov. This cross-sectional study used a descriptive approach to assess the features of the included trials on ClinicalTrials.gov. We found 62 registered trials from 2007 to 2023 on ClinicalTrials.gov. The results showed a yearly rise in the number of registered trials (r = 0.76, p < 0.001). Following 2017, more industry-sponsored trials were conducted (91.5% [43] vs. 60% [9], p = 0.009), fewer results were released (10.6% [5] vs. 60% [9], p = 0.001), and more trials entered phase 3 (67.4% [31] vs. 20% [2], p = 0.001). The most researched novel medications were neonatal Fc receptor inhibitors (51.2% [21]), complement inhibitors (39.0% [16]), and B cell depletors (14.6% [6]). According to the website's data, the neonatal Fc receptor inhibitors and complement inhibitors were effective in treating myasthenia gravis patients in three trials (NCT03315130, NCT03669588, and NCT00727194). This study provides valuable insights into the profile of registered trials on novel therapies for myasthenia gravis. More clinical studies are needed in the future to prove the value of its application.

A Load-Adaptive Driving Method for a Quasi-Continuous-Wave Laser Diode.

A quasi-continuous-wave (QCW) laser diode (LD) driver is commonly used to drive diode bars and stacks designed specifically for QCW operations in solid-state lasers. Such drivers are optimized to deliver peak current and voltage pulses to LDs while maintaining low average power levels. As a result, they are widely used in laser processing devices and laser instruments. Traditional high-energy QCW LD drivers primarily use capacitors as energy storage components and pulsed constant-current sources with op-amps and power metal-oxide-semiconductor field-effect transistors (MOSFETs) as their core circuits for generating repeated constant-current pulses. The drawback of this type of driver is that the driver's output voltage needs to be manually adjusted according to the operating voltage of the load before use to maximize driver efficiency while providing a sufficient current. Another drawback is its inability to automatically adjust the output voltage to maintain high efficiency when the load changes during the driver operation. Drastic changes in the load can cause the driver to fail to function properly in extreme cases. Based on the above traditional circuit structure, this study designed a stability compensation circuit and realized a QCW LD driver for driving a GS20 diode stack with a maximum repetition rate of 100 Hz, a constant current of approximately 300 A, a load voltage of approximately 10 V, and a pulse width of approximately 300 µs. In particular, a high-efficiency, load-adaptive driving method was used with the MOSFETs in the critical saturation region (i.e., between the linear and saturated regions), controlling its power loss effectively while achieving maximum output current of the driver. The experiments demonstrated that the driver efficiency could be maintained at more than 80% when the load current varied from 50 to 300 A.

Characterization, expression pattern, and function analysis of gibberellin oxidases in Salix matsudana.

Gibberellin oxidases (GAoxs) identified from many species play indispensable roles in GA biosynthesis and GA signal transduction. However, there has been limited research conducted on the GAox family of Salix matsudana, a tetraploid ornamental tree species. Here, 54 GAox genes were identified from S. matsudana and renamed as SmGA20ox1-22, SmGA2ox1-24, SmGA3ox1-6, and SmGAox-like1/2. Gene structure and conserved motif analysis showed that SmGA3ox members possess the 1 intron and other SmGAoxs contain 2-3 introns, and motif 1/2/7 universally present in all SmGAoxs. A total of 69 gene pairs were identified from SmGAox family members, and the Ka/Ks values indicated the SmGAoxs experience the purifying selection. The intra species collinearity analysis implied S. matsudana, S. purpurea, and Populus trichocarpa have the close genetic relationship. The GO analysis suggested SmGAoxs are dominantly involved in GA metabolic process, ion binding, and oxidoreductase activity. RNA-sequencing demonstrated that some SmGAoxs may play an essential role in salt and submergence stresses. In addition, the SmGA20ox13/21 displayed the dominant vitality of GA20 oxidase, but the SmGA20ox13/21 still possessed low activities of GA2 and GA3 oxidases. This study can contribute to reveal the regulatory mechanism of salt and submergence tolerance in willow.

Crape myrtle LiGAoxs displaying activities of gibberellin oxidases respond to branching architecture.

In the realm of ornamental horticulture, crape myrtle (Lagerstroemia indica) stands out for its aesthetic appeal, attributed largely to its vibrant flowers and distinctive branching architecture. This study embarked on a comprehensive exploration of the gibberellin oxidase (GAox) gene family in crape myrtle, illuminating its pivotal role in regulating GA levels, a key determinant of plant developmental processes. We identified and characterized 36 LiGAox genes, subdivided into GA2ox, GA3ox, GA20ox, and GAox-like subgroups, through genomic analyses. These genes' evolutionary trajectories were delineated, revealing significant gene expansions attributed to segmental duplication events. Functional analyses highlighted the divergent expression patterns of LiGAox genes across different crape myrtle varieties, associating them with variations in flower color and branching architecture. Enzymatic activity assays on selected LiGA2ox enzymes exhibited pronounced GA2 oxidase activity, suggesting a potential regulatory role in GA biosynthesis. Our findings offered a novel insight into the molecular underpinnings of GA-mediated growth and development in L. indica, providing a foundational framework for future genetic enhancements aimed at optimizing ornamental traits.

Effects of folic acid supplementation on cognitive impairment: A meta-analysis of randomized controlled trials.

OBJECTIVE: With the increasing number of patients with cognitive impairment, nonpharmacological ways to delay cognitive impairment have attracted people's attention, such as lifestyle changes and nutritional supplementation. Folic acid supplementation appears to be a promising treatment option. However, it remains controversial whether folic acid supplementation is effective in delaying adult's cognitive impairment. Therefore, we conducted a meta-analysis to analyze the effects of folic acid supplementation on different cognitive impairments. METHODS: We systematically searched PubMed, Web of Science, EMbase, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure (CNKI), WanFang and VIP databases for randomized controlled trials on January 22, 2024. The included population comprised those diagnosed with cognitive impairment. We included trials that compared folic acid treatment with placebo, other dosing regimens, or other intervention controls. Conducting quality evaluation of included studies according to the Cochrane Risk of Bias tool. Statistical analyses were performed using Review Manager software. RESULTS: Twenty-two trials, including 3604 participants, met inclusion criteria. Compared with controls, the cognitive function of Alzheimer's disease (AD) patients showed improvement with folic acid supplementation: supplementation with < 3 mg (standardized mean differences (SMD) = 0.15, 95% confidence interval (CI) -0.10 to 0.41), and supplementing with ≥ 3 mg folic acid could improve cognitive function in AD patients (SMD = 1.03, 95% CI 0.18 to 1.88). Additionally, it reduced homocysteine (HCY) levels (mean differences (MD) = -4.74, 95% CI -8.08 to -1.39). In mild cognitive impairment (MCI) patients, cognitive function improved with folic acid supplementation: supplementation with > 400 µg (SMD = 0.38, 95% CI 0.13 to 0.63), and supplementation with ≤ 400 µg (SMD = 1.10, 95% CI 0.88 to 1.31). It also reduced HCY levels at intervention ≤ 6 months (MD = -3.93, 95% CI -5.05 to -2.82) and intervention > 6 months (MD = -4.38, 95% CI -5.15 to -3.61). However, supplementing with folic acid did not improve cognitive function in vascular cognitive impairment (VCI) patients, with folic acid supplements < 3 mg (SMD = -0.07, 95% CI -0.23 to -0.08), folic acid supplements ≥ 3 mg (SMD = 0.46, 95% CI -0.57 to 1.49), however, it reduced HCY levels at intervention > 6 months (MD = -5.91, 95% CI -7.13 to -4.69) and intervention ≤ 6 months (MD = -11.15, 95% CI -12.35 to -9.95). CONCLUSIONS: Supplement folic acid is beneficial to the cognitive profile of patients with MCI, supplementation with ≥ 3 mg folic acid can improve cognitive function in AD patients.

scCircle-seq unveils the diversity and complexity of extrachromosomal circular DNAs in single cells.

Extrachromosomal circular DNAs (eccDNAs) have emerged as important intra-cellular mobile genetic elements that affect gene copy number and exert in trans regulatory roles within the cell nucleus. Here, we describe scCircle-seq, a method for profiling eccDNAs and unraveling their diversity and complexity in single cells. We implement and validate scCircle-seq in normal and cancer cell lines, demonstrating that most eccDNAs vary largely between cells and are stochastically inherited during cell division, although their genomic landscape is cell type-specific and can be used to accurately cluster cells of the same origin. eccDNAs are preferentially produced from chromatin regions enriched in H3K9me3 and H3K27me3 histone marks and are induced during replication stress conditions. Concomitant sequencing of eccDNAs and RNA from the same cell uncovers the absence of correlation between eccDNA copy number and gene expression levels, except for a few oncogenes, including MYC, contained within a large eccDNA in colorectal cancer cells. Lastly, we apply scCircle-seq to one prostate cancer and two breast cancer specimens, revealing cancer-specific eccDNA landscapes and a higher propensity of eccDNAs to form in amplified genomic regions. scCircle-seq is a scalable tool that can be used to dissect the complexity of eccDNAs across different cell and tissue types, and further expands the potential of eccDNAs for cancer diagnostics.