Clinical features and genetic analysis of developmental and epileptic encephalopathy caused by biallelic variants of CACNA1B.

Objective: To analyze the clinical features and genetic etiology of a patient with developmental and epileptic encephalopathy. Methods: The clinical information and peripheral blood of the patient and their family members were collected before the whole exome sequencing analysis was performed and Sanger sequencing was employed to verify the potential variant. Results: The patient presented with epilepsy and cerebral palsy with his parents, brother, and sister being all healthy. Whole exome sequencing analysis revealed that the child carried the paternal c.823del (p. R275Gfs*31) heterozygous variant and the maternal c.2456del (p.V819Gfs*190) heterozygous variant of the CACNA1B gene. Pedigree verification found that the elder brother and amniotic fluid of fetus in womb carried the paternal c.823del heterozygous variant, and the elder sister carried the maternal c.2456del heterozygous variant, which conformed to the law of autosomal recessive inheritance. Neither of these two variants has been reported in the literature and has not been included in the Genomic Mutation Frequency Database (gnomAD); according to the American Academy of Medical Genetics and Genomics Variation Grading Guidelines (ACMG), both variants are classified as pathogenic variants (PVS1+PM2-Supporting + PM3). Conclusion: This study reported the first case of a child with neurodevelopmental disorder and epilepsy caused by a new compound heterozygous variant of the CACNA1B gene in China, clarified its genetic etiology, enriched the mutation spectrum and disease spectrum of CACNA1B gene, and provided a basis for prenatal diagnosis of the family.

Rab11b promotes M1-like macrophage polarization by restraining autophagic degradation of NLRP3 in alcohol-associated liver disease.

Macrophage polarization is vital to mounting a host defense or repairing tissue in various liver diseases. Excessive activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome is related to the orchestration of inflammation and alcohol-associated liver disease (ALD) pathology. Rab GTPases play critical roles in regulating vesicular transport. In this study we investigated the role of Rab11b in ALD, aiming to identify effective therapeutic targets. Here, we first demonstrated a decreased expression of Rab11b in macrophages from ALD mice. Knockdown of Rab11b by macrophage-specific adeno-associated virus can alleviate alcohol induced liver inflammation, injury and steatosis. We found that LPS and alcohol stimulation promoted Rab11b transferring from the nucleus to the cytoplasm in bone marrow-derived macrophages (BMDM) cells. Rab11b specifically activated the NLRP3 inflammasome in BMDMs and RAW264.7 cells to induce M1 macrophage polarization. Rab11b overexpression in BMDMs inhibited autophagic flux, leading to the suppression of LC3B-mediated NLRP3 degradation. We conclude that impaired Rab11b could alleviate alcohol-induced liver injury via autophagy-mediated NLRP3 degradation.

Phylogenomics, taxonomy and morphological characters of the Microdochiaceae (Xylariales, Sordariomycetes).

Species of the family Microdochiaceae (Xylariales, Sordariomycetes) have been reported from worldwide, and collected from different plant hosts. The proposed new genus and two new species, viz., Macroidriella gen. nov., M.bambusae sp. nov. and Microdochiumaustrale sp. nov., are based on multi-locus phylogenies from a combined dataset of ITS rDNA, LSU, RPB2 and TUB2 with morphological characteristics. Microdochiumsinense has been collected from diseased leaves of Phragmitesaustralis and this is the first report of the fungus on this host plant. Simultaneously, we annotated 10,372 to 11,863 genes, identified 4,909 single-copy orthologous genes, and conducted phylogenomic analysis based on genomic data. A gene family analysis was performed and it will expand the understanding of the evolutionary history and biodiversity of the Microdochiaceae. The detailed descriptions and illustrations of species are provided.

Alleviating tiling effect by random walk sliding window in high-resolution histological whole slide image synthesis.

Multiplex immunofluorescence (MxIF) is an advanced molecular imaging technique that can simultaneously provide biologists with multiple (i.e., more than 20) molecular markers on a single histological tissue section. Unfortunately, due to imaging restrictions, the more routinely used hematoxylin and eosin (H&E) stain is typically unavailable with MxIF on the same tissue section. As biological H&E staining is not feasible, previous efforts have been made to obtain H&E whole slide image (WSI) from MxIF via deep learning empowered virtual staining. However, the tiling effect is a long-lasting problem in high-resolution WSI-wise synthesis. The MxIF to H&E synthesis is no exception. Limited by computational resources, the cross-stain image synthesis is typically performed at the patch-level. Thus, discontinuous intensities might be visually identified along with the patch boundaries assembling all individual patches back to a WSI. In this work, we propose a deep learning based unpaired high-resolution image synthesis method to obtain virtual H&E WSIs from MxIF WSIs (each with 27 markers/stains) with reduced tiling effects. Briefly, we first extend the CycleGAN framework by adding simultaneous nuclei and mucin segmentation supervision as spatial constraints. Then, we introduce a random walk sliding window shifting strategy during the optimized inference stage, to alleviate the tiling effects. The validation results show that our spatially constrained synthesis method achieves a 56% performance gain for the downstream cell segmentation task. The proposed inference method reduces the tiling effects by using 50% fewer computation resources without compromising performance. The proposed random sliding window inference method is a plug-and-play module, which can be generalized for other high-resolution WSI image synthesis applications. The source code with our proposed model are available at https://github.com/MASILab/RandomWalkSlidingWindow.git.

Socioeconomic traits and the risk of Barrett's esophagus and gastroesophageal reflux disease: A Mendelian randomization study.

BACKGROUND: Previous observational studies have shown that the prevalence of gastroesophageal reflux disease (GERD) and Barrett's esophagus (BE) is associated with socioeconomic status. However, due to the methodological limitations of traditional observational studies, it is challenging to definitively establish causality. AIM: To explore the causal relationship between the prevalence of these conditions and socioeconomic status using Mendelian randomization (MR). METHODS: We initially screened single nucleotide polymorphisms (SNPs) to serve as proxies for eight socioeconomic status phenotypes for univariate MR analysis. The inverse variance weighted (IVW) method was used as the primary analytical method to estimate the causal relationship between the eight socioeconomic status phenotypes and the risk of GERD and BE. We then collected combinations of SNPs as composite proxies for the eight socioeconomic phenotypes to perform multivariate MR (MVMR) analyses based on the IVW MVMR model. Furthermore, a two-step MR mediation analysis was used to examine the potential mediation of the associations by body mass index, major depressive disorder (MDD), smoking, alcohol consumption, and sleep duration. RESULTS: The study identified three socioeconomic statuses that had a significant impact on GERD. These included household income [odds ratio (OR): 0.46; 95% confidence interval (95%CI): 0.31-0.70], education attainment (OR: 0.23; 95%CI: 0.18-0.29), and the Townsend Deprivation Index at recruitment (OR: 1.57; 95%CI: 1.04-2.37). These factors were found to independently and predominantly influence the genetic causal effect of GERD. Furthermore, the mediating effect of educational attainment on GERD was found to be mediated by MDD (proportion mediated: 10.83%). Similarly, the effect of educational attainment on BE was mediated by MDD (proportion mediated: 10.58%) and the number of cigarettes smoked per day (proportion mediated: 3.50%). Additionally, the mediating effect of household income on GERD was observed to be mediated by sleep duration (proportion mediated: 9.75%). CONCLUSION: This MR study shed light on the link between socioeconomic status and GERD or BE, providing insights for the prevention of esophageal cancer and precancerous lesions.

Exosomes from umbilical cord mesenchymal stromal cells promote the collagen production of fibroblasts from pelvic organ prolapse.

BACKGROUND: Pelvic organ prolapse (POP) involves pelvic organ herniation into the vagina due to pelvic floor tissue laxity, and vaginal structure is an essential factor. In POP, the vaginal walls exhibit abnormal collagen distribution and decreased fibroblast levels and functions. The intricate etiology of POP and the prohibition of transvaginal meshes in pelvic reconstruction surgery present challenges in targeted therapy development. Human umbilical cord mesenchymal stromal cells (hucMSCs) present limitations, but their exosomes (hucMSC-Exo) are promising therapeutic tools for promoting fibroblast proliferation and extracellular matrix remodeling. AIM: To investigate the effects of hucMSC-Exo on the functions of primary vaginal fibroblasts and to elucidate the underlying mechanism involved. METHODS: Human vaginal wall collagen content was assessed by Masson's trichrome and Sirius blue staining. Gene expression differences in fibroblasts from patients with and without POP were assessed via RNA sequencing (RNA-seq). The effects of hucMSC-Exo on fibroblasts were determined via functional experiments in vitro. RNA-seq data from fibroblasts exposed to hucMSC-Exo and microRNA (miRNA) sequencing data from hucMSC-Exo were jointly analyzed to identify effective molecules. RESULTS: In POP, the vaginal wall exhibited abnormal collagen distribution and reduced fibroblast 1 quality and quantity. Treatment with 4 or 6 µg/mL hucMSC-Exo suppressed inflammation in POP group fibroblasts, stimulated primary fibroblast growth, and elevated collagen I (Col1) production in vitro. High-throughput RNA-seq of fibroblasts treated with hucMSC-Exo and miRNA sequencing of hucMSC-Exo revealed that abundant exosomal miRNAs downregulated matrix metalloproteinase 11 (MMP11) expression. CONCLUSION: HucMSC-Exo normalized the growth and function of primary fibroblasts from patients with POP by promoting cell growth and Col1 expression in vitro. Abundant miRNAs in hucMSC-Exo targeted and downregulated MMP11 expression. HucMSC-Exo-based therapy may be ideal for safely and effectively treating POP.

Evaluation of Mac-2 binding protein glycosylation isomer (M2BPGi) as a diagnostic marker for staging liver fibrosis: a meta-analysis.

Objective: This study aimed to assess the accuracy of Mac-2 binding protein glycosylation isomer (M2BPGi) in predicting the stage of liver fibrosis. Methods: Articles published until October 10, 2023, were searched in the PubMed, Embase, Web of Science, and Cochrane Library databases. Pooled sensitivity, specificity, diagnostic odds ratio (DOR), summary receiver-operator curves (SROC), and Spearman's rank correlation coefficient were used to examine the accuracy of M2BPGi in predicting the stage of liver fibrosis. A 95% confidence interval (CI) was provided for each estimate. Results: Twenty-four studies were included in this meta-analysis, including 3,839 patients with liver fibrosis, 409 of whom progressed to stage 4 or above. The pooled sensitivity, specificity, and area under the ROC (AUC) for M2BPGi predicting liver fibrosis ≥F3 were 0.74 (95% CI [0.65-0.82]), 0.84 (95% CI [0.76-0.89]), and 14.99 (95% CI [9.28-24.21]), respectively. The pooled sensitivity, specificity, and AUC for ≥F4 were 0.80 (95% CI [0.70-0.88]), 0.80 (95% CI [0.73-0.86]), and 16.43 (95% CI [0.84-0.90]), respectively. Conclusion: Among different sample partitions, M2BPGi has the best diagnostic performance for liver fibrosis stage ≥4. Furthermore, the cutoff of 1-2 is more accurate than that of 0-1 or 2-3 for fibrosis ≥ F3 and ≥ F4. Registration: CRD42023483260.

A novel bi-layered asymmetric membrane incorporating demineralized dentin matrix accelerates tissue healing and bone regeneration in a rat skull defect model.

Objectives: The technique of guided bone regeneration (GBR) has been widely used in the field of reconstructive dentistry to address hard tissue deficiency. The objective of this research was to manufacture a novel bi-layered asymmetric membrane that incorporates demineralized dentin matrix (DDM), a bioactive bone replacement derived from dentin, in order to achieve both soft tissue isolation and hard tissue regeneration simultaneously. Methods: DDM particles were harvested from healthy, caries-free permanent teeth. The electrospinning technique was utilized to synthesize bi-layered DDM-loaded PLGA/PLA (DPP) membranes. We analyzed the DPP bilayer membranes' surface topography, physicochemical properties and degradation ability. Rat skull critical size defects (CSDs) were constructed to investigate in vivo bone regeneration. Results: The synthesized DPP bilayer membranes possessed suitable surface characteristics, acceptable mechanical properties, good hydrophilicity, favorable apatite forming ability and suitable degradability. Micro-computed tomography (CT) showed significantly more new bone formation in the rat skull defects implanted with the DPP bilayer membranes. Histological evaluation further revealed that the bone was more mature with denser bone trabeculae. In addition, the DPP bilayer membrane significantly promoted the expression of the OCN matrix protein in vivo. Conclusions: The DPP bilayer membranes exhibited remarkable biological safety and osteogenic activity in vivo and showed potential as a prospective candidate for GBR applications in the future.

LncRNAH19 acts as a ceRNA of let-7 g to facilitate endothelial-to-mesenchymal transition in hypoxic pulmonary hypertension via regulating TGF-ß signalling pathway.

BACKGROUND: Hypoxic pulmonary hypertension (HPH) is a challenging lung arterial disorder with remarkably high incidence and mortality rates, and the efficiency of current HPH treatment strategies is unsatisfactory. Endothelial-to-mesenchymal transition (EndMT) in the pulmonary artery plays a crucial role in HPH. Previous studies have shown that lncRNA-H19 (H19) is involved in many cardiovascular diseases by regulating cell proliferation and differentiation but the role of H19 in EndMT in HPH has not been defined. METHODS: In this research, the expression of H19 was investigated in PAH human patients and rat models. Then, we established a hypoxia-induced HPH rat model to evaluate H19 function in HPH by Echocardiography and hemodynamic measurements. Moreover, luciferase reporter gene detection, and western blotting were used to explore the mechanism of H19. RESULTS: Here, we first found that the expression of H19 was significantly increased in the endodermis of pulmonary arteries and that H19 deficiency obviously ameliorated pulmonary vascular remodelling and right heart failure in HPH rats, and these effects were associated with inhibition of EndMT. Moreover, an analysis of luciferase activity indicated that microRNA-let-7 g (let-7 g) was a direct target of H19. H19 deficiency or let-7 g overexpression can markedly downregulate the expression of TGFßR1, a novel target gene of let-7 g. Furthermore, inhibition of TGFßR1 induced similar effects to H19 deficiency. CONCLUSIONS: In summary, our findings demonstrate that the H19/let-7 g/TGFßR1 axis is crucial in the pathogenesis of HPH by stimulating EndMT. Our study may provide new ideas for further research on HPH therapy in the near future.

Glass-Forming Ability, Mechanical Properties, and Energetic Characteristics of ZrCuNiAlNbHfY Bulk Metallic Glasses.

The effects of partially substituting Al for Cu in Zr59.62Cu18.4-xNi12Al6+xNb3Hf0.78Y0.2 (x = 0, 2, 4, 6, 8 at.%) bulk metallic glasses (BMGs) on their glass-forming ability (GFA), quasi-static and dynamic mechanical properties, and energy characteristics were investigated. The results showed that an appropriate substitution of Al for Cu can improve GFA and reach a critical casting size up to 10 mm. Additionally, with Al replacement of Cu, the change in the distribution and content of free volume inside the BMGs was the main reason for the quasi-static compression plasticity. In contrast, the BMGs exhibited no plasticity during dynamic compression and high-speed impact, owing to the short loading time and thermal softening effect. In terms of energy characteristics, all alloys have a high combustion enthalpy. And on the surface of the fragments collected from impact, the active elements Zr, Al, and Nb reacted because of the adiabatic temperature rise. Further, x = 4 at.% Zr-based BMG with its superior overall performance could penetrate a 6 mm Q235 plate at a speed of 1038 m/s, combining excellent mechanical properties and energy characteristics. This study contributes to the development of Zr-based BMGs as novel energetic structural materials.

Gustative Roussy Immune Score is a Predictor for Major Pathological Response in Rectal Cancer: A Result from the Preoperative Intraarterial Chemoembolization Combined with Radiotherapy (PCAR) Study.

Despite the emergence of various treatment strategies for rectal cancer based on neoadjuvant chemoradiotherapy, there is currently a lack of reliable biomarkers to determine which patients will respond well to neoadjuvant chemoradiotherapy. Through collecting hematological and biochemical parameters data of patients prior to receiving neoadjuvant chemoradiotherapy, we evaluated the predictive value of systemic inflammatory indices for pathological response and prognosis in rectal cancer patients. We found that baseline GRIm-Score was an independent predictor for MPR in rectal cancer patients. However, no association was observed between several commonly systemic inflammation indices and long-term outcome.

Artificial Intelligence Application in Skull Bone Fracture with Segmentation Approach.

This study aims to evaluate an AI model designed to automatically classify skull fractures and visualize segmentation on emergent CT scans. The model's goal is to boost diagnostic accuracy, alleviate radiologists' workload, and hasten diagnosis, thereby enhancing patient outcomes. Unique to this research, both pediatric and post-operative patients were not excluded, and diagnostic durations were analyzed. Our testing dataset for the observer studies involved 671 patients, with a mean age of 58.88 years and fairly balanced gender representation. Model 1 of our AI algorithm, trained with 1499 fracture-positive cases, showed a sensitivity of 0.94 and specificity of 0.87, with a DICE score of 0.65. Implementing post-processing rules (specifically Rule B) improved the model's performance, resulting in a sensitivity of 0.94, specificity of 0.99, and a DICE score of 0.63. AI-assisted diagnosis resulted in significantly enhanced performance for all participants, with sensitivity almost doubling for junior radiology residents and other specialists. Additionally, diagnostic durations were significantly reduced (p < 0.01) with AI assistance across all participant categories. Our skull fracture detection model, employing a segmentation approach, demonstrated high performance, enhancing diagnostic accuracy and efficiency for radiologists and clinical physicians. This underlines the potential of AI integration in medical imaging analysis to improve patient care.

Introducing Virtual Shared Medical Appointments as a Novel Treatment Platform for Functional Movement Disorders.

The landscape of medical care has rapidly evolved with technological advancements, particularly through the widespread adoption of virtual appointments catalyzed by the COVID-19 pandemic. This shift has transcended geographical barriers, enhancing access for underserved populations and those with disabilities to specialized healthcare providers. A notable development stemming from this trend is the emergence of virtual shared medical appointments (VSMAs), which integrate group-based education with telemedicine technology. While VSMAs have demonstrated efficacy in conditions such as obesity, diabetes, and neurological disorders, their effectiveness in managing Functional Movement Disorders (FMD) is currently under investigation. FMDs pose unique challenges in diagnosis and acceptance, with high rates of misdiagnosis and treatment delays. VSMAs offer a promising solution by providing educational modules and fostering peer support among patients with similar diagnoses. At the Cleveland Clinic Center for Neurological Restoration, VSMAs have been embraced to enhance care standards for FMD patients. The program facilitates educational sessions and follow-up meetings to improve treatment adherence and psychological well-being. Early outcomes indicate increased patient acceptance and engagement, with significant program growth observed. Ongoing research aims to evaluate stakeholder perspectives and refine session content to further reduce stigma and the healthcare burden associated with FMDs.

Viable but non-culturable state formation and resuscitation of different antibiotic-resistant Escherichia coli induced by UV/chlorine.

The presence of "viable but nonculturable" (VBNC) state and bacterial antibiotic resistance (BAR) both pose significant threats to the safety of drinking water. However, limited data was available that explicitly addressed the contribution of bacterial VBNC state in the maintenance and propagation of BAR. Here, the VBNC state induction and resuscitation of two antibiotic-resistant Escherichia coli K12 strains, one carrying multidrug-resistant plasmid (RP4 E. coli) and the other with chromosomal mutation (RIF E. coli) were characterized by subjecting them to different doses of UV/chlorine. The results illustrated that the induction, resuscitation, and associated mechanisms of VBNC ARB exhibit variations based on resistance determinants. RP4 E. coli exhibited a higher susceptibility to enter VBNC state compared to the RIF E. coli., and most VBNC state and resuscitated RP4 E. coli retained original antibiotic resistance. While, reverse mutation in the rpoB gene was observed in VBNC state and recovered RIF E. coli strains induced by high doses of UV/chlorine treatment, leading to the loss of rifampicin resistance. According to RT-qPCR results, ARGs conferring efflux pumps appeared to play a more significant role in the VBNC state formation of RP4 E. coli and the down-regulation of rpoS gene enhanced the speed at which this plasmid-carrying ARB entered into the dormant state. As to RIF E. coli, the induction of VBNC state was supposed to be regulated by the combination of general stress response, SOS response, stringent response, and TA system. Above all, this study highlights that ARB could become VBNC state during UV/chlorine treatments and retain, in some cases, their ability to spread ARGs. Importantly, compared with chromosomal mutation-mediated ARB, both VBNC and resuscitated state ARB that carries multidrug-resistant plasmids poses more serious health risks. Our study provides insights into the relationship between the VBNC state and the propagation of BAR in drinking water systems.

Exploring the ecological security evaluation of water resources in the Yangtze River Basin under the background of ecological sustainable development.

The Yangtze River (hereafter referred to as the YZR), the largest river in China, is of paramount importance for ensuring water resource security. The Yangtze River Basin (hereafter referred to as the YRB) is one of the most densely populated areas in China, and complex human activities have a significant impact on the ecological security of water resources. Therefore, this paper employs theories related to ecological population evolution and the Driving Force-Pressure-State-Impact-Response (DPSIR) model to construct an indicator system for the ecological security of water resources in the YRB. The report evaluates the ecological security status of water resources in each province of the YRB from 2010 to 2019, clarifies the development trend of its water resource ecological security, and proposes corresponding strategies for regional ecological security and coordinated economic development. According to the results of the ecological population evolution competition model, the overall indicator of the ecological security of water resources in the YRB continues to improve, with the safety level increasing annually. Maintaining sound management of water resources in the YRB is crucial for sustainable socioeconomic development. To further promote the ecological security of water resources in the YRB and the coordinated development of the regional economy, this paper proposes policy suggestions such as promoting the continuous advancement of sustainable development projects, actively adjusting industrial structure, continuously enhancing public environmental awareness, and actively participating in international ecological construction and seeking cooperation among multiple departments.

The potential benefits of PGC-1α in treating Alzheimer's disease are dependent on the integrity of the LLKYL L3 motif: Effect of regulating mitochondrial axonal transportation.

Mitochondrial dysfunction is a prominent hallmark of Alzheimer's disease (AD). The transcriptional coactivator PPARγ coactivator 1 (PGC-1a) has been identified as a key regulator of mitochondrial biogenesis and function. However, the precise structure/function relationship between PGC-1a and mitochondrial quality control remains incompletely understood. In this study, we investigated the impact of PGC-1a on AD pathology and its underlying mechanisms with a specific focus on mitochondrial axonal transport. Additionally, we generated two PGC-1α mutants by substituting leucine residues at positions 148 and 149 within the LKKLL motif or at positions 209 and 210 within the LLKYL motif with alanine. Subsequently, we examined the effects of these mutants on mutAPP-induced abnormalities in anterograde and retrograde axonal transport, disrupted mitochondrial distribution, and impaired mitophagy. Mutagenesis studies revealed that the LLKYL motif at amino acid position 209-210 within PGC-1α plays an essential role in its interaction with estrogen-related receptors (ERRα), which is necessary for restoring normal mitochondrial anterograde axonal transport, maintaining proper mitochondrial distribution, and ultimately preventing neuronal apoptosis. Furthermore, it was found that the Leu-rich motif at amino acids 209-210 within PGC-1α is crucial for rescuing mutAPP-induced impairment in mitophagy and loss of membrane potential by restoring normal mitochondrial retrograde axonal transport. Conversely, mutation of residues 148 and 149 in the LKKLL motif does not compromise the effectiveness of PGC-1α. These findings provide valuable insights into the molecular determinants governing specificity of action for PGC-1α involved in regulating mutAPP-induced deficits in mitochondrial axonal trafficking. Moreover, they suggest a potential therapeutic target for addressing Alzheimer's disease.

CRISPR-array-mediated imaging of non-repetitive and multiplex genomic loci in living cells.

Dynamic imaging of genomic loci is key for understanding gene regulation, but methods for imaging genomes, in particular non-repetitive DNAs, are limited. We developed CRISPRdelight, a DNA-labeling system based on endonuclease-deficient CRISPR-Cas12a (dCas12a), with an engineered CRISPR array to track DNA location and motion. CRISPRdelight enables robust imaging of all examined 12 non-repetitive genomic loci in different cell lines. We revealed the confined movement of the CCAT1 locus (chr8q24) at the nuclear periphery for repressed expression and active motion in the interior nucleus for transcription. We uncovered the selective repositioning of HSP gene loci to nuclear speckles, including a remarkable relocation of HSPH1 (chr13q12) for elevated transcription during stresses. Combining CRISPR-dCas12a and RNA aptamers allowed multiplex imaging of four types of satellite DNA loci with a single array, revealing their spatial proximity to the nucleolus-associated domain. CRISPRdelight is a user-friendly and robust system for imaging and tracking genomic dynamics and regulation.

Human CD56+CD39+ dNK cells support fetal survival through controlling trophoblastic cell fate: immune mechanisms of recurrent early pregnancy loss.

Decidual natural killer (dNK) cells are the most abundant immune cells at the maternal-fetal interface during early pregnancy in both mice and humans, and emerging single-cell transcriptomic studies have uncovered various human dNK subsets that are disrupted in patients experiencing recurrent early pregnancy loss (RPL) at early gestational stage, suggesting a connection between abnormal proportions or characteristics of dNK subsets and RPL pathogenesis. However, the functional mechanisms underlying this association remain unclear. Here, we established a mouse model by adoptively transferring human dNK cells into pregnant NOG (NOD/Shi-scid/IL-2Rγnull) mice, where human dNK cells predominantly homed into the uteri of recipients. Using this model, we observed a strong correlation between the properties of human dNK cells and pregnancy outcome. The transfer of dNK cells from RPL patients (dNK-RPL) remarkably worsened early pregnancy loss and impaired placental trophoblast cell differentiation in the recipients. These adverse effects were effectively reversed by transferring CD56+CD39+ dNK cells. Mechanistic studies revealed that CD56+CD39+ dNK subset facilitates early differentiation of mouse trophoblast stem cells (mTSCs) towards both invasive and syncytial pathways through secreting macrophage colony-stimulating factor (M-CSF). Administration of recombinant M-CSF to NOG mice transferred with dNK-RPL efficiently rescued the exacerbated pregnancy outcomes and fetal/placental development. Collectively, this study established a novel humanized mouse model featuring functional human dNK cells homing into the uteri of recipients and uncovered the pivotal role of M-CSF in fetal-supporting function of CD56+CD39+ dNK cells during early pregnancy, highlighting that M-CSF may be a previously unappreciated therapeutic target for intervening RPL.

Regulation of anthocyanin synthesis in red lettuce in plant factory conditions: A review.

Anthocyanins, natural pigments known for their vibrant hues and beneficial properties, undergo intricate genetic control. However, red vegetables grown in plant factories frequently exhibit reduced anthocyanin synthesis compared to those in open fields due to factors like inadequate light, temperature, humidity, and nutrient availability. Comprehending these factors is essential for optimizing plant factory environments to enhance anthocyanin synthesis. This review insights the impact of physiological and genetic factors on the production of anthocyanins in red lettuce grown under controlled conditions. Further, we aim to gain a better understanding of the mechanisms involved in both synthesis and degradation of anthocyanins. Moreover, this review summarizes the identified regulators of anthocyanin synthesis in lettuce, addressing the gap in knowledge on controlling anthocyanin production in plant factories, with potential implications for various crops beyond red lettuce.