cfOmics: a cell-free multi-Omics database for diseases.

Liquid biopsy has emerged as a promising non-invasive approach for detecting, monitoring diseases, and predicting their recurrence. However, the effective utilization of liquid biopsy data to identify reliable biomarkers for various cancers and other diseases requires further exploration. Here, we present cfOmics, a web-accessible database (https://cfomics.ncRNAlab.org/) that integrates comprehensive multi-omics liquid biopsy data, including cfDNA, cfRNA based on next-generation sequencing, and proteome, metabolome based on mass-spectrometry data. As the first multi-omics database in the field, cfOmics encompasses a total of 17 distinct data types and 13 specimen variations across 69 disease conditions, with a collection of 11345 samples. Moreover, cfOmics includes reported potential biomarkers for reference. To facilitate effective analysis and visualization of multi-omics data, cfOmics offers powerful functionalities to its users. These functionalities include browsing, profile visualization, the Integrative Genomic Viewer, and correlation analysis, all centered around genes, microbes, or end-motifs. The primary objective of cfOmics is to assist researchers in the field of liquid biopsy by providing comprehensive multi-omics data. This enables them to explore cell-free data and extract profound insights that can significantly impact disease diagnosis, treatment monitoring, and management.

Development of the fetal brain cortico-cortical structural network during the second-to-third trimester based on diffusion MRI.

During the second-to-third trimester, the neuronal pathways of the fetal brain experience rapid development, resulting in the complex architecture of the inter-wired network at birth. While diffusion MRI-based tractography has been employed to study the prenatal development of structural connectivity network (SCN) in preterm neonatal and post-mortem fetal brains, the in-utero development of SCN in the normal fetal brain remains largely unknown. In this study, we utilized in-utero dMRI data from human fetuses of both sexes between 26 to 38 gestational weeks to investigate the developmental trajectories of the fetal brain SCN, focusing on intra-hemispheric connections. Our analysis revealed significant increases in global efficiency, mean local efficiency, and clustering coefficient, along with significant decrease in shortest path length, while small-worldness persisted during the studied period, revealing balanced network integration and segregation. Widespread short-ranged connectivity strengthened significantly. The nodal strength developed in a posterior-to-anterior and medial-to-lateral order, reflecting a spatiotemporal gradient in cortical network connectivity development. Moreover, we observed distinct lateralization patterns in the fetal brain SCN. Globally, there was a leftward lateralization in network efficiency, clustering coefficient, and small-worldness. The regional lateralization patterns in most language, motor, and visual-related areas were consistent with prior knowledge, except for the Wernicke's area, indicating lateralized brain wiring is an innate property of the human brain starting from the fetal period. Our findings provided a comprehensive view of the development of the fetal brain SCN and its lateralization, as a normative template that may be used to characterize atypical development.Significance Statement We studied the normal development of intra-hemispheric cortico-cortical structural connectivity networks (SCNs) of the fetal brain from 26 to 38 gestational weeks using in-utero diffusion MRI data. Graph-theory-based analysis revealed significant enhancement in network efficiency and clustering, as well as persisted small-worldness with age, revealing balanced integration and segregation in the fetal brain SCN during the studied period, supported by regional developmental patterns. Leftward lateralization in network efficiency, clustering coefficient and small-worldness was observed. Regional lateralization patterns in most language, motor, and visual-related areas were consistent with prior knowledge. We also summarized the challenges of investigating the fetal brain SCN development, and provided suggestions for future studies.

GLABRA 2 regulates ETHYLENE OVERPRODUCER 1 accumulation during nutrient deficiency-induced root hair growth.

Root hairs (RHs), extensive structures of root epidermal cells, are important for plant nutrient acquisition, soil anchorage, and environmental interactions. Excessive production of the phytohormone ethylene (ET) leads to substantial root hair growth, manifested as tolerance to plant nutrient deficiencies. However, the molecular basis of ET production during root hair growth in response to nutrient starvation remains unknown. Herein, we found that a critical transcription factor, GLABRA 2 (GL2), inhibits ET production during root hair growth in Arabidopsis (Arabidopsis thaliana). GL2 directly binds to the promoter of the gene encoding ET OVERPRODUCER 1 (ETO1), one of the most important ET-production-regulation factors, in vitro and in vivo, and then regulates the accumulation and function of ETO1 in root hair growth. The GL2-regulated-ETO1 module is required for promoting root hair growth under nitrogen, phosphorus, or potassium deficiency. Genome-wide analysis revealed numerous genes, such as ROOT HAIR DEFECTIVE 6-LIKE 4, ETHYLENE-INSENSITIVE 3-LIKE 2, ROOT HAIR SPECIFIC 13, are involved in the GL2-regulated-ETO1 module. Our work reveals a key transcription mechanism in the control of ET production during root hair growth under three major nutrient deficiencies.

TRIP6 promotes neural stem cell maintenance through YAP-mediated Sonic Hedgehog activation.

In the adult mammalian brain, new neurons are continuously generated from neural stem cells (NSCs) in the subventricular zone (SVZ)-olfactory bulb (OB) pathway. YAP, a transcriptional co-activator of the Hippo pathway, promotes cell proliferation and inhibits differentiation in embryonic neural progenitors. However, the role of YAP in postnatal NSCs remains unclear. Here, we showed that YAP was present in NSCs of the postnatal mouse SVZ. Forced expression of Yap promoted NSC maintenance and inhibited differentiation, whereas depletion of Yap by RNA interference or conditional knockout led to the decline of NSC maintenance, premature neuronal differentiation, and collapse of neurogenesis. For the molecular mechanism, thyroid hormone receptor-interacting protein 6 (TRIP6) recruited protein phosphatase PP1A to dephosphorylate LATS1/2, therefore inducing YAP nuclear localization and activation. Moreover, TRIP6 promoted NSC maintenance, cell proliferation, and inhibited differentiation through YAP. In addition, YAP regulated the expression of the Sonic Hedgehog (SHH) pathway effector Gli2 and Gli1/2 mediated the effect of YAP on NSC maintenance. Together, our findings demonstrate a novel TRIP6-YAP-SHH axis, which is critical for regulating postnatal neurogenesis in the SVZ-OB pathway.

Hemispheric lateralization of language processing: insights from network-based symptom mapping and patient subgroups.

The hemispheric laterality of language processing has become a hot topic in modern neuroscience. Although most previous studies have reported left-lateralized language processing, other studies found it to be bilateral. A previous neurocomputational model has proposed a unified framework to explain that the above discrepancy might be from healthy and patient individuals. This model posits an initial symmetry but imbalanced capacity in language processing for healthy individuals, with this imbalance contributing to language recovery disparities following different hemispheric injuries. The present study investigated this model by analyzing the lateralization patterns of language subnetworks across multiple attributes with a group of 99 patients (compared to nonlanguage processing) and examining the lateralization patterns of language subnetworks in subgroups with damage to different hemispheres. Subnetworks were identified using a whole-brain network-based lesion-symptom mapping method, and the lateralization index was quantitatively measured. We found that all the subnetworks in language processing were left-lateralized, while subnetworks in nonlanguage processing had different lateralization patterns. Moreover, diverse hemisphere-injury subgroups exhibited distinct language recovery effects. These findings provide robust support for the proposed neurocomputational model of language processing.

Actin depolymerizing factor ADF7 inhibits actin bundling protein VILLIN1 to regulate root hair formation in response to osmotic stress in Arabidopsis.

Actin cytoskeleton is essential for root hair formation. However, the underlying molecular mechanisms of actin dynamics in root hair formation in response to abiotic stress are largely undiscovered. Here, genetic analysis showed that actin-depolymerizing protein ADF7 and actin-bundling protein VILLIN1 (VLN1) were positively and negatively involved in root hair formation of Arabidopsis respectively. Moreover, RT-qPCR, GUS staining, western blotting, and genetic analysis revealed that ADF7 played an important role in inhibiting the expression and function of VLN1 during root hair formation. Filament actin (F-actin) dynamics observation and actin pharmacological experiments indicated that ADF7-inhibited-VLN1 pathway led to the decline of F-actin bundling and thick bundle formation, as well as the increase of F-actin depolymerization and turnover to promote root hair formation. Furthermore, the F-actin dynamics mediated by ADF7-inhibited-VLN1 pathway was associated with the reactive oxygen species (ROS) accumulation in root hair formation. Finally, ADF7-inhibited-VLN1 pathway was critical for osmotic stress-induced root hair formation. Our work demonstrates that ADF7 inhibits VLN1 to regulate F-actin dynamics in root hair formation in response to osmotic stress, providing the novel evidence on the F-actin dynamics and their molecular mechanisms in root hair formation and in abiotic stress.

Efficacy of a novel affitoxin targeting MOMP against Chlamydia trachomatis in vitro and in vivo.

Targeted therapy is an attractive approach for treating infectious diseases. Affibody molecules have similar capability to antibodies that facilitate molecular recognition in both diagnostic and therapeutic applications. Targeting major outer membrane protein (MOMP) for treating infection of Chlamydia trachomatis, one of the most common sexually transmitted pathogens, is a promising therapeutic approach. Previously, we have reported a MOMP-specific affibody (ZMOMP:461) from phage display library. Here, we first fused it with modified Pseudomonas Exotoxin (PE38KDEL) and a cell-penetrating peptide (CPP) to develop an affitoxin, Z461X-CPP. We then verified the addition of both toxin and CPPs that did not affect the affinitive capability of ZMOMP:461 to MOMP. Upon uptake by C.trachomatis-infected cells, Z461X-CPP induced cell apoptosis in vitro. In animal model, Z461X significantly shortened the duration of C. trachomatis infection and prevented pathological damage in mouse reproductive system. These findings provide compelling evidence that the MOMP-specific affitoxin has great potential for targeting therapy of C. trachomatis infection.

Age-dependent functional development pattern in neonatal brain: An fMRI-based brain entropy study.

The relationship between brain entropy (BEN) and early brain development has been established through animal studies. However, it remains unclear whether the BEN can be used to identify age-dependent functional changes in human neonatal brains and the genetic underpinning of the new neuroimaging marker remains to be elucidated. In this study, we analyzed resting-state fMRI data from the Developing Human Connectome Project, including 280 infants who were scanned at 37.5-43.5 weeks postmenstrual age. The BEN maps were calculated for each subject, and a voxel-wise analysis was conducted using a general linear model to examine the effects of age, sex, and preterm birth on BEN. Additionally, we evaluated the correlation between regional BEN and gene expression levels. Our results demonstrated that the BEN in the sensorimotor-auditory and association cortices, along the 'S-A' axis, was significantly positively correlated with postnatal age (PNA), and negatively correlated with gestational age (GA), respectively. Meanwhile, the BEN in the right rolandic operculum correlated significantly with both GA and PNA. Preterm-born infants exhibited increased BEN values in widespread cortical areas, particularly in the visual-motor cortex, when compared to term-born infants. Moreover, we identified five BEN-related genes (DNAJC12, FIG4, STX12, CETN2, and IRF2BP2), which were involved in protein folding, synaptic vesicle transportation and cell division. These findings suggest that the fMRI-based BEN can serve as an indicator of age-dependent brain functional development in human neonates, which may be influenced by specific genes.

Mechanisms underlying category learning in the human ventral occipito-temporal cortex.

The human ventral occipito-temporal cortex (VOTC) has evolved into specialized regions that process specific categories, such as words, tools, and animals. The formation of these areas is driven by bottom-up visual and top-down nonvisual experiences. However, the specific mechanisms through which top-down nonvisual experiences modulate category-specific regions in the VOTC are still unknown. To address this question, we conducted a study in which participants were trained for approximately 13 h to associate three sets of novel meaningless figures with different top-down nonvisual features: the wordlike category with word features, the non-wordlike category with nonword features, and the visual familiarity condition with no nonvisual features. Pre- and post-training functional MRI (fMRI) experiments were used to measure brain activity during stimulus presentation. Our results revealed that training induced a categorical preference for the two training categories within the VOTC. Moreover, the locations of two training category-specific regions exhibited a notable overlap. Remarkably, within the overlapping category-specific region, training resulted in a dissociation in activation intensity and pattern between the two training categories. These findings provide important insights into how different nonvisual categorical information is encoded in the human VOTC.

Engineering Spatially Adjacent Redox Sites with Synergistic Spin Polarization Effect to Boost Photocatalytic CO2 Methanation.

The integration of oxidation and reduction half-reactions to amplify their synergy presents a considerable challenge in CO2 photoconversion. Addressing this challenge requires the construction of spatially adjacent redox sites while suppressing charge recombination at these sites. This study introduces an innovative approach that utilizes spatial synergy to enable synergistic redox reactions within atomic proximity and employs spin polarization to inhibit charge recombination. We incorporate Mn into Co3O4 as a catalyst, in which Mn sites tend to enrich holes as water activation sites, while adjacent Co sites preferentially capture electrons to activate CO2, forming a spatial synergy. The direct H transfer from H2O at Mn sites facilitates the formation of *COOH on adjacent Co sites with remarkably favorable thermodynamic energy. Notably, the incorporation of Mn induces spin polarization in the system, significantly suppressing the recombination of photogenerated charges at redox sites. This effect is further enhanced by applying an external magnetic field. By synergizing spatial synergy and spin polarization, Mn/Co3O4 exhibits a CH4 production rate of 23.4 µmol g-1 h-1 from CO2 photoreduction, showcasing a 28.8 times enhancement over Co3O4. This study first introduces spin polarization to address charge recombination issues at spatially adjacent redox sites, offering novel insights for synergistic redox photocatalytic systems.

Bulevirtide monotherapy in patients with chronic HDV: Efficacy and safety results through week 96 from a phase 3 randomized trial.

BACKGROUND & AIMS: Bulevirtide (BLV), a first-in-class entry inhibitor, is approved in Europe for the treatment of chronic hepatitis delta (CHD). BLV monotherapy was superior to delayed treatment at week (W) 48, the primary efficacy endpoint, in the MYR301 study (NCT03852719). Here, we assessed if continued BLV therapy until W96 would improve virologic and biochemical response rates, particularly among patients who did not achieve virologic response at W24. METHODS: In this ongoing, open-label, randomized phase 3 study, patients with CHD (N = 150) were randomized (1:1:1) to treatment with BLV 2 (n = 49) or 10 mg/day (n = 50), each for 144 weeks, or to delayed treatment for 48 weeks followed by BLV 10 mg/day for 96 weeks (n = 51). Combined response was defined as undetectable hepatitis delta virus (HDV) RNA or a decrease in HDV RNA by ≥2 log10 IU/mL from baseline and alanine aminotransferase (ALT) normalization. Other endpoints included virologic response, ALT normalization, and change in HDV RNA. RESULTS: Of 150 patients, 143 (95%) completed 96 weeks of the study. Efficacy responses were maintained and/or improved between W48 and W96, with similar combined, virologic, and biochemical response rates between BLV 2 and 10 mg. Of the patients with a suboptimal early virologic response at W24, 43% of non-responders and 82% of partial responders achieved virologic response at W96. Biochemical improvement often occurred independent of virologic response. Adverse events (AEs) were mostly mild, with no serious AEs related to BLV. CONCLUSIONS: Virologic and biochemical responses were maintained and/or increased with longer-term BLV therapy, including in those with suboptimal early virologic response. BLV monotherapy for CHD was safe and well tolerated through W96. IMPACT AND IMPLICATIONS: In July 2023, bulevirtide was fully approved for the treatment of chronic hepatitis delta (CHD) in Europe based on clinical study results from up to 48 weeks of treatment. Understanding the efficacy and safety of bulevirtide over the longer term is important for healthcare providers. In this analysis, we demonstrate that bulevirtide monotherapy for 96 weeks in patients with CHD was associated with continued improvements in combined, virologic, and biochemical responses as well as liver stiffness from week 48 at both the 2-mg and 10-mg doses. Patients with suboptimal virologic responses to bulevirtide at week 24 also benefited from continued therapy, with the majority achieving virologic response or biochemical improvement by week 96. GOV IDENTIFIER: NCT03852719.

The clinical efficacy and safety of berberine in the treatment of non-alcoholic fatty liver disease: a meta-analysis and systematic review.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is becoming increasingly prevalent worldwide, emerging as a significant health issue on a global scale. Berberine exhibits potential for treating NAFLD, but clinical evidence remains inconclusive. This meta-analysis was conducted to assess the efficacy and safety of berberine for treating NAFLD. METHODS: This study was registered with PROSPERO (No. CRD42023462338). Identification of randomized controlled trials (RCTs) involved searching 6 databases covering the period from their initiation to 9 September 2023. The primary outcomes comprised liver function markers such as glutamyl transpeptidase (GGT), alanine transaminase (ALT), aspartate transaminase (AST), lipid indices including total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C), homeostasis model assessment for insulin resistance (HOMA-IR) and body mass index (BMI). Review Manager 5.4 and STATA 17.0 were applied for analysis. RESULTS: Among 10 RCTs involving 811 patients, berberine demonstrated significant reductions in various parameters: ALT (standardized mean difference (SMD) = - 0.72), 95% confidence interval (Cl) [- 1.01, - 0.44], P < 0.00001), AST (SMD = - 0.79, 95% CI [- 1.17, - 0.40], P < 0.0001), GGT (SMD = - 0.62, 95% CI [- 0.95, - 0.29], P = 0.0002), TG (SMD = - 0.59, 95% CI [- 0.86, - 0.31], P < 0.0001), TC(SMD = - 0.74, 95% CI [- 1.00, - 0.49], P < 0.00001), LDL-C (SMD = - 0.53, 95% CI [- 0.88, - 0.18], P = 0.003), HDL-C (SMD = - 0.51, 95% CI [- 0.12, 1.15], P = 0.11), HOMA-IR (SMD = - 1.56, 95% CI [- 2.54, - 0.58], P = 0.002), and BMI (SMD = - 0.58, 95% CI [- 0.77, - 0.38], P < 0.00001). Importantly, Berberine exhibited a favorable safety profile, with only mild gastrointestinal adverse events reported. CONCLUSION: This meta-analysis demonstrates berberine's efficacy in improving liver enzymes, lipid profile, and insulin sensitivity in NAFLD patients. These results indicate that berberine shows promise as an adjunct therapy for NAFLD. Trial registration The protocol was registered with PROSPERO (No. CRD42023462338). Registered on September 27, 2023.

Double-negative T cells ameliorate psoriasis by selectively inhibiting IL-17A-producing γδlow T cells.

BACKGROUND: Psoriasis is a chronic immune-mediated skin condition. Although biologic treatments are effective in controlling psoriasis, some patients do not respond or lose response to these therapies. Thus, new strategies for psoriasis treatment are still urgently needed. Double-negative T cells (DNT) play a significant immunoregulatory role in autoimmune diseases. In this study, we aimed to evaluate the protective effect of DNT in psoriasis and explore the underlying mechanism. METHODS: We conducted a single adoptive transfer of DNT into an imiquimod (IMQ)-induced psoriasis mouse model through tail vein injection. The skin inflammation and IL-17A producing γδ T cells were evaluated. RESULTS: DNT administration significantly reduced the inflammatory response in mouse skin, characterized by decreased skin folds, scales, and red patches. After DNT treatment, the secretion of IL-17A by RORc+ γδlow T cells in the skin was selectively suppressed, resulting in an amelioration of skin inflammation. Transcriptomic data suggested heightened expression of NKG2D ligands in γδlow T cells within the mouse model of psoriasis induced by IMQ. When blocking the NKG2D ligand and NKG2D (expressed by DNT) interaction, the cytotoxic efficacy of DNT against RORc+IL17A+ γδlow T cells was attenuated. Using Ccr5-/- DNT for treatment yielded evidence that DNT migrates into inflamed skin tissue and fails to protect IMQ-induced skin lesions. CONCLUSIONS: DNT could migrate to inflamed skin tissue through CCR5, selectively inhibit IL-17-producing γδlow T cells and finally ameliorate mouse psoriasis. Our study provides feasibility for using immune cell therapy for the prevention and treatment of psoriasis in the clinic.

Dorsoventrally asymmetric expression of miR319/TCP generates dorsal-specific venation patterning in petunia corolla tube.

Vein-associated pigmentation (venation) is a type of floral coloration adopted by plants to attract pollinators. Several petunia (Petunia hybrida) lines generate dorsoventrally asymmetric venation patterning of the corolla tube, in which venation is only present in the dorsal tube. The molecular mechanism underlying this trait is unknown. Here, we demonstrate that miR319 is preferentially expressed in the dorsal corolla tube, leading to dorsoventrally asymmetric expression of its target genes. Transgenic lines overexpressing phy-miR319a generated uniform venation patterning of the corolla tube. Knockout of TCP genes targeted by miR319 promoted venation patterning in the ventral and dorsal tube, while overexpression of the miR319 target gene, PhTCP6, completely inhibited corolla tube venation patterning. In addition, miR319-targeted TCPs negatively regulated venation patterning, probably by repressing the regulator of venation patterning, AN4. Together, our data demonstrate that asymmetric expression of miR319 promotes venation patterning in the petunia dorsal tube alone by repressing the expression of its target TCP genes, which negatively regulate corolla tube venation patterning. These findings provide novel insights into how the dorsoventrally asymmetric distribution of venation patterning is established in zygomorphic flowers.

System-wide identification of novel de-ubiquitination targets for USP10 in gastric cancer metastasis through multi-omics screening.

OBJECTIVE: Ubiquitin-specific peptidase 10 (USP10), a typical de-ubiquitinase, has been found to play a double-edged role in human cancers. Previously, we reported that the expression of USP10 was negatively correlated with the depth of gastric wall invasion, lymph node metastasis, and prognosis in gastric cancer (GC) patients. However, it remains unclear whether USP10 can regulate the metastasis of GC cells through its de-ubiquitination function. METHODS: In this study, proteome, ubiquitinome, and transcriptome analyses were conducted to comprehensively identify novel de-ubiquitination targets for USP10 in GC cells. Subsequently, a series of validation experiments, including in vitro cell culture studies, in vivo metastatic tumor models, and clinical sample analyses, were performed to elucidate the regulatory mechanism of USP10 and its de-ubiquitination targets in GC metastasis. RESULTS: After overexpression of USP10 in GC cells, 146 proteins, 489 ubiquitin sites, and 61 mRNAs exhibited differential expression. By integrating the results of multi-omics, we ultimately screened 9 potential substrates of USP10, including TNFRSF10B, SLC2A3, CD44, CSTF2, RPS27, TPD52, GPS1, RNF185, and MED16. Among them, TNFRSF10B was further verified as a direct de-ubiquitination target for USP10 by Co-IP and protein stabilization assays. The dysregulation of USP10 or TNFRSF10B affected the migration and invasion of GC cells in vitro and in vivo models. Molecular mechanism studies showed that USP10 inhibited the epithelial-mesenchymal transition (EMT) process by increasing the stability of TNFRSF10B protein, thereby regulating the migration and invasion of GC cells. Finally, the retrospective clinical sample studies demonstrated that the downregulation of TNFRSF10B expression was associated with poor survival among 4 of 7 GC cohorts, and the expression of TNFRSF10B protein was significantly negatively correlated with the incidence of distant metastasis, diffuse type, and poorly cohesive carcinoma. CONCLUSIONS: Our study established a high-throughput strategy for screening de-ubiquitination targets for USP10 and further confirmed that inhibiting the ubiquitination of TNFRSF10B might be a promising therapeutic strategy for GC metastasis.

Cartilage-Inspired, High-Strength, and Heat-Tolerant Lubricating Hydrogels by Macrophase Separation.

Hydrogels are considered as a potential cartilage replacement material based on their structure being similar to natural cartilage, which are of great significance in repairing cartilage defects. However, it is difficult for the existing hydrogels to combine the high load bearing and low friction properties (37 °C) of cartilage through sample methods. Herein, we report a facile and new fabrication strategy to construct the PNIPAm/EYL hydrogel by using the macrophase separation of supersaturated N-isopropylacrylamide (NIPAm) monomer solution to promote the formation of liposomes from egg yolk lecithin (EYL) and asymmetric template method. The PNIPAm/EYL hydrogels possess a relatively high compressive strength (more than 12 MPa), fracture energy (9820 J/m2), good fatigue resistance, lubricating properties, and excellent biocompatibility. Compared with the PNIPAm hydrogel, the friction coefficient (COF 0.046) of PNIPAm/EYL hydrogel is reduced by 50%. More importantly, the COF (0.056) of PNIPAm/EYL hydrogel above lower critical solution temperature (LCST) does not increase significantly, exhibiting heat-tolerant lubricity. The finite element analysis further proves that PNIPAm/EYL hydrogel can effectively disperse the applied stress and dissipate energy under load conditions. This work not only provides new insights for the design of high-strength lubricating hydrogels but also lays a foundation for the treatment of cartilage injury as a substitute material.

OTUB1 Catalytic-Independently Deubiquitinates TGFBI and Mediates the Angiogenesis in Infantile Hemangioma by Regulating Glycolysis.

BACKGROUND: Infantile hemangioma (IH) arises as a result of dysregulation of both angiogenesis and vasculogenesis. The deubiquitylase OTUB1 (OTU domain, ubiquitin aldehyde binding 1) has been reported to play an essential role in multiple cancers; however, its function in the progression of IH and the underlying mechanisms regulating angiogenesis remain unclear. METHODS: Transwell assays, EdU assays, and tube formation assays were performed to investigate the biological behavior of IH in vitro. IH animal models were established to estimate the progression of IH in vivo. Mass spectrometric analysis were conducted to detect the downstream of OTUB1 and ubiquitination sites of transforming growth factor beta induced (TGFBI). Half-life assays and ubiquitination test were performed to investigate the interaction between TGFBI and OTUB1. Extracellular acidification rate assays were employed to estimate the glycolysis level in IH. RESULTS: The expression of OTUB1 was obviously increased in proliferating IH as compared to the involuting and involuted IH tissues. Through in vitro experiments, the knockdown of OTUB1 inhibited the proliferation, migration and tube formation of human hemangioma endothelial cells, while the overexpression of OTUB1 promoted the proliferation, migration and angiogenic abilities of human hemangioma endothelial cells. The knockdown of OTUB1 significantly suppressed IH progression in vivo. Furthermore, TGFBI was predicted as a functional downstream target of OTUB1 in IH by mass spectrometry. Mechanistically, OTUB1 interacted with and deubiquitylated TGFBI on the K22 and K25 residues, which was demonstrated to be independent of the catalytic activity of OTUB1. The inhibitory effects of OTUB1 knockdown on cell proliferation, migration and tube formation ability of human hemangioma endothelial cells were reversed by TGFBI overexpression. Further, we found that OTUB1 mediated glycolysis by regulating TGFBI in infantile hemangioma. CONCLUSIONS: OTUB1 deubiquitinates TGFBI in a catalytic-independent manner and promotes angiogenesis in infantile hemangioma by regulating glycolysis. Targeting OTUB1 might be an effective therapeutic strategy for inhibiting IH progression and tumor angiogenesis.

KREP2S6 (RE = Sm, Gd, Tb, Dy): A Series of Polar Rare-Earth Thiophosphates with High Laser-Induced Damage Thresholds and Moderate Nonlinear-Optical Responses Synergistically Contributed by Isolated P2S6 Units and {[RE2S15]24-}∞ Layers.

As one of the potential candidates of nonlinear-optical (NLO) materials, rare-earth chalcophosphates have demonstrated promising properties. Here, KREP2S6 (RE = Sm, Gd, Tb, Dy) were synthesized using the facile RE2O3-B-S solid-state method. They crystallize with a monoclinic chiral P21 structure, and their layer structures are built by isolated ethane-like P2S6 dimers and RES8 bicapped trigonal prisms built {[RE2S15]24-}∞ layers. By comparing the structures with related ones, the change of the alkali metal or RE3+ ions can cause structural transformation. Their band gaps are tunable between 2.58 and 3.79 eV, and their powder samples exhibit good NLO properties. Theoretical calculations suggest that the NLO properties are mainly contributed by P2S6 units and {[RE2S15]24-}∞ layers synergistically, in which {[RE2S15]24-}∞ layers and P2S6 units dominate the contribution to the band gap and second-harmonic-generation response, respectively. This work enriches the application of rare-earth chalcophosphates as NLO materials.

Design of Pentanary Mixed-Chalcogenides Ag2In2SiS6-xSex (x = 1, 2) Based on the Bucket Effect: Local Structural Difference and High-Performance Nonlinear-Optical Properties Realized by Partial Congener Substitution.

Noncentrosymmetric chalcogenides are promising candidates for infrared nonlinear-optical (NLO) crystals, and exploring high-performance ones is a hot topic and challengeable. Herein, the combination of AgQ4, InQ4, and SiQ4 (Q = S, Se) units with different S/Se ratios resulted in the discovery of the tetrahedral chalcogenides Ag2In2SiS4Se2 (1) and Ag2In2SiS5Se (2). They both crystallize in the monoclinic Cc space group with different local structures. Co-occupied S/Se sites only exist in 2, and the arrangement of [In2SiQ3] six-membered rings builds different helical chains and 3D [(In2SiQ6)2-]n polyanionic frameworks in 1 and 2. They show balanced NLO performances, including phase-matchable moderate NLO responses (0.7 and 0.5 × AGS) and enhanced laser-induced damage thresholds (4.5 and 5.1 × AGS). Theoretical calculations reveal that their NLO responses are predominantly contributed by the AgQ4 and InQ4 units.

Potential Added Value of 18F-FDG PET Metabolic Parameters in Predicting Disease Relapse in Type 1 Autoimmune Pancreatitis.

BACKGROUND: The predictive value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) metabolic parameters for predicting AIP relapse is currently unknown. This study firstly explored the value of 18F-FDG PET/CT parameters as predictors of type 1 AIP relapse. METHODS: This multicenter retrospective cohort study analyzed 51 patients who received 18F-FDG PET/CT prior to treatment and did not receive maintenance therapy after remission. The study collected baseline characteristics and clinical data and conducted qualitative and semi-quantitative analysis of pancreatic lesions and extrapancreatic organs. The study used three thresholds to select the boundaries of pancreatic lesions to evaluate metabolic parameters, including the maximum standard uptake value (SUVmax), mean standard uptake value (SUVmean), total lesion glycolysis (TLG), metabolic tumor volume (MTV), and tumor-to-normal liver standard uptake value ratio (SUVR). Univariate and multivariate analyses were performed to identify independent predictors and build a recurrence prediction model. The model was internally validated using the bootstrap method and a nomogram was created for clinical application. RESULTS: In the univariable analysis, the relapsed group showed higher levels of SUVmax (6.0 ± 1.6 vs. 5.2 ± 1.1; P = 0.047), SUVR (2.3 [2.0-3.0] vs. 2.0 [1.6-2.4]; P = 0.026), and TLG2.5 (234.5 ± 149.1 vs. 139.6 ± 102.5; P = 0.020) among the 18F-FDG PET metabolic parameters compared to the non-relapsed group. In the multivariable analysis, serum IgG4 (OR, 1.001; 95% CI, 1.000-1.002; P = 0.014) and TLG2.5 (OR, 1.007; 95% CI, 1.002-1.013; P = 0.012) were independent predictors associated with relapse of type 1 AIP. A receiver-operating characteristic curve of the predictive model with these two predictors demonstrated an area under the curve of 0.806. CONCLUSION: 18F-FDG PET/CT metabolic parameters, particularly TLG2.5, are potential predictors for relapse in patients with type 1 AIP. A multiparameter model that includes IgG4 and TLG2.5 can enhance the ability to predict AIP relapse.