Cartilage protective and anti-edema effects of JTF in osteoarthritis via inhibiting NCOA4-HMGB1-driven ferroptosis and aquaporin dysregulation.

BACKGROUND: Preventing joint edema is crucial in halting osteoarthritis (OA) progression. Growing clinical evidence indicate that Jianpi-Tongluo Formula (JTF) may have a promising anti-edema effect. However, the therapeutic properties of JTF and the underlying mechanisms remains unclear. MATERIALS AND METHODS: An OA rat model was established and employed to evaluate pharmacological effects of JTF in vivo based on dynamic histopathologic assessments and micro-CT observations. Then, OA-related genes and potential targets of JTF were identified through clinical transcriptomic data analysis and "disease gene-drug target" network analysis, which were verified by a series of in vivo experiments. RESULTS: JTF administration effectively reduced pain and joint edema, inhibited matrix degradation, chondrocyte apoptosis, and aquaporin expression in OA rats. Notably, JTF dose-dependently reversed damage-associated molecular patterns and inflammatory factor upregulation. Mechanically, our "disease gene-drug target" network analysis indicated that the NCOA4-HMGB1-GSK3B-AQPs axis, implicated in ferroptosis and aquaporin dysregulation, may be potentially served as a target of JTF against OA. Accordingly, JTF mitigated NCOA4, HMGB1, and GSK3B expression, oxidative stress, and iron metabolism aberrations in OA rats. Furthermore, JTF treatment significantly attenuated the aberrant upregulation of AQP1, AQP3, and AQP4 proteins observed in cartilage tissues of OA rats. CONCLUSION: Our data reveal for the first time that JTF may exert cartilage protective and anti-edema effects in osteoarthritis therapy by inhibiting NCOA4-HMGB1-driven ferroptosis and aquaporin dysregulation.

The role of vitamin D receptor in predentin mineralization and dental repair after injury.

Dentin is a permeable and complex tubular composite formed by the mineralization of predentin that mineralization and repair are of considerable clinical interest during dentin homeostasis. The role of Vdr, a receptor of vitamin D, in dentin homeostasis remains unexplored. The aim of the present study was to assess the impact of Vdr on predentin mineralization and dental repair. Vdr-knockout (Vdr-/-) mice models were constructed; histology and immunohistochemistry analyses were conducted for both WT and Vdr-/- mice. The finding revealed a thicker predentin in Vdr-/- mice, characterized by higher expression of biglycan and decorin. A dental injury model was employed to observe tertiary dentin formation in Vdr-/- mice with dental injuries. Results showed that tertiary dentin was harder to form in Vdr-/- mice with dental injury. Over time, heightened pulp invasion was observed at the injury site in Vdr-/- mice. Expression of biglycan and decorin was reduced in the predentin at the injury site in the Vdr-/- mice by immunohistochemistry. Taken together, our results imply that Vdr plays a regulatory role in predentin mineralization and tertiary dentin formation during dentin homeostasis.

High-beam-quality low-resistance vertical-cavity surface-emitting laser array with graphene electrode.

Thermal crosstalk and current crowding effects are pressing issues that significantly impact the beam quality and efficiency of vertical-cavity surface-emitting laser (VCSEL) arrays. In this paper, by taking advantage of the excellent current transmission characteristics of graphene, what we believe to be a novel VCSEL array based on graphene electrode is designed to realize vertical current injections. The series resistance and self-heating of arrays are reduced by controlling the transport direction of the current, effectively suppressing the thermal crosstalk effect. Furthermore, high array beam quality is obtained by optimizing the current density distribution in active regions. Ultimately, the high-power quasi-single mode emission of VCSEL arrays is achieved by introducing graphene electrodes (Gr-VCSEL array) designs. Compared to traditional VCSEL arrays, the 10 × 10 Gr-VCSEL array demonstrates a 41% reduction in series resistance, a side mode suppression ratio of 32 dB, and a divergence angle around 12 °. This structure simultaneously achieves quasi-single mode emission and effectively suppresses the thermal crosstalk effect, providing a new method for the development of high-beam quality VCSEL arrays.

SlGolS2 influences the metabolism of chlorophyll, carotenoid, and ethylene in tomato fruits.

Galactinol synthase (GolS), which catalyzes the synthesis of galactinol, is the first critical enzyme in the biosynthesis of raffinose family oligosaccharides (RFOs) and contributes to plant growth and development, and resistance mechanisms. However, its role in fruit development remains largely unknown. In this study, we used CRISPR-Cas9 gene editing technology to create the slgols2 mutation showing uniformly green fruits without the dark green shoulder, and promoting fruit ripening. Further analysis revealed that the galactinol was undetected in slgols2 ovaries and fruits. Additionally, the mutant suppressed the accumulation of chlorophyll (Chl) and chloroplast development in tomato fruits. RNA sequencing analysis showed that genes related to chlorophyll accumulation and chloroplast development, such as SlPORB, SlGLK2, and SlCABs were downregulated in slgols2 fruits. Moreover, slgols2 lines prompted early color transformation and ethylene release by regulating the expression of genes such as SlPSY1, SlCRTISO, SlACS2, SlACS4, SlE4, SlE8, SlRIN, SlNOR and SlAP2a. Overall, our study provides evidence for the involvement of SlGolS2 in the pigment and ethylene metabolism of tomato fruits.

Feasibility of implant placement in healed mandibular molar sites: A retrospective cone beam computed tomography study.

STATEMENT OF PROBLEM: Implant placement in the mandibular molar sites plays a crucial role in the restoration of edentulous mandibles. However, the evaluation of bone quantity before implant surgery using cone beam computed tomography (CBCT) is lacking. PURPOSE: The purpose of this clinical study was to evaluate CBCT images of edentulous patients to analyze the feasibility of implant placement in healed mandibular molar sites. MATERIAL AND METHODS: The CBCT data of 138 patients were analyzed in the sagittal plane for measurements of mandibular bone height (MBH), superior bone height (SBH), inferior bone height (IBH), buccal bone width (BBW), lingual bone width (LBW), and alveolar bone widths (ABWs). The edentulous sites were categorized according to the bone quantity and complexity of the implant surgery. Multivariate analysis of variance (MANOVA) was used to analyze the site, sex, and age-related variations. An independent t test was used to compare the difference of bone dimension in different sites and between sexes. One-way ANOVA followed by post hoc tests were used to analyze the difference between different age groups. Categorical variables were presented as number of events and percentages. The chi-squared test was used to compare categorical variables (α=.05). RESULTS: A total of 534 sites of interest were recorded, including 274 hemimandibles. A significant difference in BBW was found between the first and second molar sites. Men had higher MBH, SBH, IBH, and BBW than women. The distribution of implant surgical complexity in the conventional group was 63.5%, while the buccolingual tilted implant group accounted for 17.0%, and the complicated group accounted for 19.5%. Of the 274 hemimandibles, an implant could be placed directly at molar sites in 88% of situations. CONCLUSIONS: The BBW at the mandibular second molar site was greater than that at the first molar site. The amount of available bone in the SBH and BBW was greater in men than in women at the healed molar sites. Age did not significantly affect the complexity of the implant surgery. Implants can be placed directly in healed mandibular molar sites in most patients who require a complete arch mandibular implant-supported restoration.

Ligand engineering to achieve synergistic properties in a 2D bilayer supertetrahedral chalcogenide cluster-based assembled material.

Incorporating functional organic linkers into supertetrahedral chalcogenolate cluster-based materials is an effective synthetic strategy to expand structural diversity and generate tunable optical and photoelectric properties arising from synergistic effects. Herein, a mixed ligand engineering approach was adopted to design a supertetrahedral cluster-based assembled material [(Cd6Ag4(SPh)16(TPPA)(BPE)0.5)·2DMF]n (denoted as SCCAM-3) with a 2D bilayer architecture and broader visible-light absorption. Interestingly, SCCAM-3 demonstrates a long-lived afterglow at 83 K and efficient photocatalytic activity for degrading tetracycline in water.

Advanced oxidation protein products attenuate the autophagy-lysosome pathway in ovarian granulosa cells by modulating the ROS-dependent mTOR-TFEB pathway.

Oxidative stress dysfunction has recently been found to be involved in the pathogenesis of premature ovarian insufficiency (POI). Previously, we found that advanced oxidation protein products (AOPPs) in plasma were elevated in women with POI and had an adverse effect on granulosa cell proliferation. However, the mechanism underlying the effects of AOPPs on autophagy-lysosome pathway regulation in granulosa cells remains unclear. In this study, the effect of AOPPs on autophagy and lysosomal biogenesis and the underlying mechanisms were explored by a series of in vitro experiments in KGN and COV434 cell lines. AOPP-treated rat models were employed to determine the negative effect of AOPPs on the autophagy-lysosome systems in vivo. We found that increased AOPP levels activated the mammalian target of rapamycin (mTOR) pathway, and inhibited the autophagic response and lysosomal biogenesis in KGN and COV434 cells. Furthermore, scavenging of reactive oxygen species (ROS) with N-acetylcysteine and blockade of the mTOR pathway with rapamycin or via starvation alleviated the AOPP-induced inhibitory effects on autophagy and lysosomal biogenesis, suggesting that these effects of AOPPs are ROS-mTOR dependent. The protein expression and nuclear translocation of transcription factor EB (TFEB), the key regulator of lysosomal and autophagic function, were also impaired by the AOPP-activated ROS-mTOR pathway. In addition, TFEB overexpression attenuated the AOPP-induced impairment of autophagic flux and lysosomal biogenesis in KGN and COV434 cells. Chronic AOPP stimulation in vivo also impaired autophagy and lysosomal biogenesis in granulosa cells of rat ovaries. The results highlight that AOPPs lead to impairment of autophagic flux and lysosomal biogenesis via ROS-mTOR-TFEB signaling in granulosa cells and participate in the pathogenesis of POI.

Extracellular vesicles from UTX-knockout endothelial cells boost neural stem cell differentiation in spinal cord injury.

BACKGROUND: Vascular endothelial cells are pivotal in the pathophysiological progression following spinal cord injury (SCI). The UTX (Ubiquitously Transcribed Tetratripeptide Repeat on Chromosome X) serves as a significant regulator of endothelial cell phenotype. The manipulation of endogenous neural stem cells (NSCs) offers a compelling strategy for the amelioration of SCI. METHODS: Two mouse models were used to investigate SCI: NSCs lineage-traced mice and mice with conditional UTX knockout (UTX KO) in endothelial cells. To study the effects of UTX KO on neural differentiation, we harvested extracellular vesicles (EVs) from both UTX KO spinal cord microvascular endothelial cells (SCMECs) and negative control SCMECs. These EVs were then employed to modulate the differentiation trajectory of endogenous NSCs in the SCI model. RESULTS: In our NSCs lineage-traced mice model of SCI, a marked decrease in neurogenesis was observed post-injury. Notably, NSCs in UTX KO SCMECs mice showed enhanced neuronal differentiation compared to controls. RNA sequencing and western blot analyses revealed an upregulation of L1 cell adhesion molecule (L1CAM), a gene associated with neurogenesis, in UTX KO SCMECs and their secreted EVs. This aligns with the observed promotion of neurogenesis in UTX KO conditions. In vivo administration of L1CAM-rich EVs from UTX KO SCMECs (KO EVs) to the mice significantly enhanced neural differentiation. Similarly, in vitro exposure of NSCs to KO EVs resulted in increased activation of the Akt signaling pathway, further promoting neural differentiation. Conversely, inhibiting Akt phosphorylation or knocking down L1CAM negated the beneficial effects of KO EVs on NSC neuronal differentiation. CONCLUSIONS: In conclusion, our findings substantiate that EVs derived from UTX KO SCMECs can act as facilitators of neural differentiation following SCI. This study not only elucidates a novel mechanism but also opens new horizons for therapeutic interventions in the treatment of SCI. Video Abstract.

Osteoking promotes bone formation and bone defect repair through ZBP1-STAT1-PKR-MLKL-mediated necroptosis.

BACKGROUND: Osteoking has been used for fracture therapy with a satisfying clinical efficacy. However, its therapeutic properties and the underlying mechanisms remain elusive. METHOD: A bone defect rat model was established to evaluate the pharmacological effects of Osteoking by the dynamic observation of X-ray, micro-CT and histopathologic examination. Transcriptome profiling was performed to identify bone defect-related genes and Osteoking effective targets. Then, a "disease-related gene-drug target" interaction network was constructed and a list of key network targets were screened, which were experimentally verified. RESULTS: Osteoking effectively promoted bone defect repair in rats by accelerating the repair of cortical bone and the growth of trabeculae. Histopathologically, the bone defect rats displayed lower histopathologic scores in cortical bone, cancellous bone and bone connection than normal controls. In contrast, Osteoking exerted a favorable effect with a dose-dependent manner. The abnormal serum levels of bone turnover markers, bone growth factors and bone metabolism-related biochemical indexes in bone defect rats were also reversed by Osteoking treatment. Following the transcriptome-based network investigation, we hypothesized that osteoking might attenuate the levels of ZBP1-STAT1-PKR-MLKL-mediated necroptosis involved into bone defect. Experimentally, the expression levels of ZBP1, STAT1, PKR and the hallmark inflammatory cytokines for the end of necroptosis were distinctly elevated in bone defect rats, but were all effectively reversed by Osteoking treatment, which were also suppressed the activities of RIPK1, RIPK3 and MLKL in bone tissue supernatants. CONCLUSIONS: Osteoking may promote bone formation and bone defect repair by regulating ZBP1-STAT1-PKR axis, leading to inhibit RIPK1/RIPK3/MLKL activation-mediated necroptosis.

Fast mass spectrometry search and clustering of untargeted metabolomics data.

The throughput of mass spectrometers and the amount of publicly available metabolomics data are growing rapidly, but analysis tools such as molecular networking and Mass Spectrometry Search Tool do not scale to searching and clustering billions of mass spectral data in metabolomics repositories. To address this limitation, we designed MASST+ and Networking+, which can process datasets that are up to three orders of magnitude larger than those processed by state-of-the-art tools.

Galactinol Regulates JA Biosynthesis to Enhance Tomato Cold Tolerance.

Low temperatures can inhibit plant growth and development and reduce fruit yield. This study demonstrated that the expression of AnGolS1 from Ammopiptanthus nanus (A. nanus) encoding a galactinol synthase enhanced tomato cold tolerance. In AnGolS1-overexpressing plants, the jasmonic acid (JA) biosynthesis substrates 13-hydroperoxylinolenicacid and 12,13-epoxylinolenicacid were significantly accumulated, and the expression levels of the ethylene response factor (SlERF4-7) and serine protease inhibitor (SlSPI5) were increased. We speculated that there may be correlations among galactinol, ethylene signaling, the protease inhibitor, protease, and JA levels. The expression levels of SlERF4-7 and SlSPI5 as well as the JA content were significantly increased under exogenous galactinol treatment. Additionally, the expression of SlSPI5 was reduced in SlERF4-7-silenced plants, and SlERF4-7 was confirmed to bind to the dehydration-responsive element (DRE) of the SlSPI5 promoter. These results suggest that SlSPI5 is a target gene of the SlERF4-7 transcription factor. In addition, SlSPI5 interacted with cysteine protease (SlCPase), while SlCPase interacted with lipoxygenase (SlLOX5) and allene oxide synthase (SlAOS2). When SlCPase was silenced, JA levels increased and plant cold tolerance was enhanced. Therefore, galactinol regulates JA biosynthesis to enhance tomato cold tolerance through the SlERF4-7-SlSPI5-SlCPase-SlLOX5/SlAOS2 model. Overall, our study provides new perspectives on the role of galactinol in the JA regulatory network in plant adaptation to low-temperature stress.

The SlGRAS9-SlZHD17 transcriptional cascade regulates chlorophyll and carbohydrate metabolism contributing to fruit quality traits in tomato.

Some essential components of fleshy fruits are dependent on photosynthetic activity and carbohydrate metabolism. Nevertheless, the regulatory mechanisms linking chlorophyll and carbohydrate metabolism remain partially understood. Here, we uncovered the role of SlGRAS9 and SlZHD17 transcription factors in controlling chlorophyll and carbohydrate accumulation in tomato fruit. Knockout or knockdown of SlGRAS9 or SlZHD17 resulted in marked increase in chlorophyll content, reprogrammed chloroplast biogenesis and enhanced accumulation of starch and soluble sugars. Combined genome-wide transcriptomic profiling and promoter-binding experiments unveiled a complex mechanism in which the SlGRAS9/SlZHD17 regulatory module modulates the expression of chloroplast and sugar metabolism either via a sequential transcriptional cascade or through binding of both TFs to the same gene promoters, or, alternatively, via parallel pathways where each of the TFs act on different target genes. For instance, the regulation of SlAGPaseS1 and SlSUS1 is mediated by SlZHD17 whereas that of SlVI and SlGLK1 occurs only through SlGRAS9 without the intervention of SlZHD17. Both SlGRAS9 and SlZHD17 can also directly bind the promoter of SlPOR-B to regulate its expression. Taken together, our findings uncover two important regulators acting synergistically to manipulate chlorophyll and carbohydrate accumulation and provide new potential breeding targets for improving fruit quality in fleshy fruits.

Recent advances on neutrophil dysregulation in the pathogenesis of rheumatic diseases.

PURPOSE OF REVIEW: The exact pathogenic mechanisms of rheumatic diseases (RMD) remain largely unknown. Increasing evidence highlights a pathogenic role of neutrophil dysregulation in the development of RMD. RECENT FINDINGS: The purpose of this review is to present a current overview of recent advancements in understanding the role of neutrophil dysfunction in the development of RMD. Additionally, this review will discuss strategies for targeting pathways associated with neutrophil dysregulation as potential treatments for RMD. One specific aspect of neutrophil dysregulation, known as neutrophil extracellular traps (NETs), will be explored. NETs have been found to contribute to chronic pulmonary inflammation and fibrosis, as well as serve as DNA scaffolds for binding autoantigens, including both citrullinated and carbamylated autoantigens. Putative therapies, such as 6-gingerol or defibrotide, have demonstrated beneficial effects in the treatment of RMD by suppressing NETs formation. SUMMARY: Recent advances have significantly reinforced the crucial role of neutrophil dysregulation in the pathogenesis of RMD. A deeper understanding of the potential mechanisms underlying this pathogenic process would aid in the development of more precise and effective targeting strategies, thus ultimately improving the outcomes of RMD.

Extensive preclinical evaluation of combined mangiferin and glycyrrhizic acid for restricting synovial neovascularization in rheumatoid arthritis.

BACKGROUND: Synovial neovascularization promotes rheumatoid arthritis (RA) progression. Baihu guizhi decoction (BHGZD) has a potential in restricting this pathological change of RA. PURPOSE: To identify bioactive compounds (BACs) of BHGZD and to elucidate the underlying mechanisms in restricting synovial neovascularization of RA. METHOD: Through transcriptomic profiling, the chemical profiling of BHGZD and its effective transcriptomic profiling against RA were identified. Then, candidate targets and the corresponding BACs against synovial neovascularization were screened by "disease gene-drug target" interaction network analysis and in silico molecular docking. The binding affinities of candidate BAC-target pairs were verified using surface plasmon resonance, and the pharmacokinetic characteristics of BACs in vivo after BHGZD administration at different time points were detected by Ultra Performance Liquid Chromatography-Mass spectrum/Mass spectrum. After that, in vivo experiments based on adjuvant-induced arthritis (AIA-M) rats, and in vitro experiments based on human umbilical vein endothelial cells (HUVEC) and arthritic synovial fibroblasts (MH7A) were carried out to evaluate the pharmacological effects of BHGZD and the two-BACs-combination, and to verify the associated mechanisms. RESULT: VEGFA/VEGFR2/SRC/PI3K/AKT signal axis was screened as one of the key network targets of BHGZD against synovial neovascularization in RA. Mangiferin (MG) and glycyrrhizic acid (GA) were identified as the representative BACs of BHGZD for their strong binding affinities with components of the VEGFA/VEGFR2/SRC/PI3K/AKT signal axis, and their high exposed quantity in vivo. Both BHGZD and the two-BAC combination of MG and GA were demonstrated to be effective in restricting disease severity, reducing synovial inflammation and decreasing the formation of vascular opacities in AIA-M rats, and also reducing the migrative and invasive activities of HUVEC and MH7A cells and attenuating the lumen formation ability of HUVEC cells significantly. Mechanically, both BHGZD and the two-BAC combination markedly reduced the expression of VEGFA in synovial tissues, the serum levels of VEGF and NO, and the enzymatic activity of eNOS, increased the content of endostatin, and also reversed the abnormal alterations in the VEGFA/VEGFR2/SRC/PI3K/AKT signal axis in vivo and in vitro. CONCLUSION: MG and GA may be the representative BACs of BHGZD for restricting excessive synovial vascularization in RA via regulating VEGFA/VEGFR2/SRC/PI3K/AKT signal axis.

Inhibition of UTX/KDM6A improves recovery of spinal cord injury by attenuating BSCB permeability and macrophage infiltration through the MLCK/p-MLC pathway.

Spinal cord injury (SCI) can prompt an immediate disruption to the blood-spinal cord barrier (BSCB). Restoring the integrity of this barrier is vital for the recovery of neurological function post-SCI. The UTX protein, a histone demethylase, has been shown in previous research to promote vascular regeneration and neurological recovery in mice with SCI. However, it is unclear whether UTX knockout could facilitate the recovery of the BSCB by reducing its permeability. In this study, we systematically studied BSCB disruption and permeability at different time points after SCI and found that conditional UTX deletion in endothelial cells (ECs) can reduce BSCB permeability, decrease inflammatory cell infiltration and ROS production, and improve neurological function recovery after SCI. Subsequently, we used RNA sequencing and ChIP-qPCR to confirm that conditional UTX knockout in ECs can down-regulate expression of myosin light chain kinase (MLCK), which specifically mediates myosin light chain (MLC) phosphorylation and is involved in actin contraction, cell retraction, and tight junctions (TJs) protein integrity. Moreover, we found that MLCK overexpression can increase the ratio of p-MLC/MLC, further break TJs, and exacerbate BSCB deterioration. Overall, our findings indicate that UTX knockout could inhibit the MLCK/p-MLC pathway, resulting in decreased BSCB permeability, and ultimately promoting neurological recovery in mice. These results suggest that UTX is a promising new target for treating SCI.

The Relationship Between Theta Power, Theta Asymmetry and the Effect of Escitalopram in the Treatment of Depression.

Objective: Only about one-third of depressed patients respond to initial antidepressant treatment. Therefore, it is crucial to find effective predictors of antidepressants. The purpose of our study was to learn the relationship between EEG theta power, theta asymmetry, and the efficacy of escitalopram. Methods: The study included 34 patients with depression. Before and after each patient's course of treatment, EEG data was gathered. Both the Hamilton Anxiety Scale (HAMA) and the 17-item Hamilton Depression Scale (HAMD-17) were evaluated simultaneously. The natural logarithm of right frontal theta power minus left frontal theta power was used to calculate inter-electrode theta asymmetry (AT). Results: First, our study found no statistically significant difference between intra-electrode theta power and inter-electrode AT before and after treatment (P ≥ 0.05). When we later looked at the data regarding treatment effects, the findings revealed that patients (n = 9) who did not respond to treatment had lower baseline theta power at C4 [6.190 (2.000, 12.990) vs 15.800 (7.255, 22.330), z = -2.166, P = 0.030]. The two groups had no difference in other electrodes (P ≥ 0.05). The AT of C3/C4 in non-responders (n = 9) was lower [0.012 (0.795) vs 0.733 (0.539), t = -3.224, P = 0.005]. However, there was no difference in inter-electrode AT between the two groups in F3/F4 and F7/F8 (P ≥ 0.05). We finally show that the theta power at C4 was negatively correlated with HAMD scores before treatment (r = -0.346, P = 0.045). Conclusion: Our findings determined that increased theta power and positive asymmetry in the right frontal-central area correlate with favourable escitalopram treatment, providing a basis for finding predictive markers for antidepressants.

Preclinical efficacy of TZG in myofascial pain syndrome by impairing PI3K-RAC2 signaling-mediated neutrophil extracellular traps.

Tianhe Zhuifeng Gao (TZG) shows a satisfying therapeutic efficacy in treating arthromyodynia, which shares similar etiology to myofascial pain syndrome (MPS). We herein aim to explore whether TZG could be a potential prescription for MPS therapy. An MPS rat model was successfully established presenting with reduced pain thresholds, abnormal local switch responses, etc., which was effectively reversed by TZG treatment externally. A transcriptome sequencing based on the active MTrPs samples of rats, combined with network analysis revealed that TZG might ameliorate the progression of MPS by impairing neutrophil extracellular traps (NETs) release through inhibiting PI3K-RAC2 signaling to reduce NADPH oxidase-originated ROS. Experimentally, the expression levels of inducers, biomarkers of NETs formation and vessel injury, and p-PI3K, p-P47, and RAC2 proteins were all significantly up-regulated in affected tissues, which were markedly reversed by TZG. Our results not only shed light into broadening the clinical indications of TZG, but benefit MPS therapy.

Successful pregnancy and delivery in a female with pituitary stalk interruption syndrome following in vitro fertilization and embryo transfer: A case report and literature review.

Pituitary stalk interruption syndrome (PSIS) in female patients is mainly characterized by short stature, primary amenorrhea, absent or incomplete sexual maturation, and infertility. Successful pregnancies among these patients are rare. In this report, we describe a successful pregnancy and delivery in a 28-year-old Chinese woman with PSIS following in vitro fertilization and embryo transfer. The patient exhibited typical symptoms, including multiple pituitary hormone deficiency, typical triad signs in magnetic resonance imaging (MRI), undetectable serum gonadotropins and estradiol levels, and invisible antral follicles in both ovaries. During the first attempted controlled ovarian hyperstimulation cycle, 14 oocytes were retrieved and six embryos were acquired. Artificial endometrial preparation and frozen-thawed embryo transfer were performed, resulting in a clinical pregnancy after the transfer of a day 5 blastocyst. The patient was closely monitored throughout the pregnancy and multiple hormone dosages were modulated accordingly. She delivered a healthy boy by elective cesarean section, and the newborn developed normally during a 1-year follow-up period. This is the first report of a successful live birth in a woman with PSIS achieved through in vitro fertilization and frozen-thawed embryo transfer. A literature review on this topic is also presented.

Integration of multi-omics analyses highlights the secondary metabolism response of tomato fruit to low temperature storage.

Inappropriate low temperature storage usually leads to quality deterioration of harvested tomato fruits. In this study, we performed comparative metabolome, transcriptome, and proteome analyses to comprehensively understand the effects of low temperature on metabolic changes in tomato fruit (fresh fruit, C0d; 4 °C 8 days, C8d; 4 °C 7 days and then 25 °C 1 day, C7dS1). Large amounts of secondary metabolites (including flavonoids and phenolic acids) increased after low temperature treatment. The overlap differentially accumulated metabolites in three comparative groups (C0d vs. C8d, C0d vs. C7dS1, C8d vs. C7dS1) were mainly flavonoid metabolites. A total of 1438 differentially expressed genes identified in these three comparative groups were primarily enriched in metabolic pathways and secondary metabolites biosynthesis pathways. Similarly, proteomic analysis showed that the differentially expressed proteins were enriched in the secondary metabolites biosynthesis and phenylpropanoid biosynthesis pathways. There was a strong correlation between changes in flavonoid metabolites and the expression of chalcone synthase (SlCHS), chalcone isomerase-like (SlCHIL), and coumarate 3-hydroxylase (SlC3H), which are involved in the phenylpropanoid and flavonoid biosynthesis. Additionally, seven differentially expressed MYB transcription factors were identified; SlMYB91, SlMYB106, and SlMYB70 strongly correlated with flavonoid biosynthesis structural genes after low temperature treatment. Other genes involved in fruit ripening and quality were also affected by low temperature. The data generated in this study may unravel the transcriptional regulatory network of secondary metabolism associated with low-temperature storage and provide a solid foundation for future studies.