Trilobolide-6-O-isobutyrate exerts anti-tumor effects on cholangiocarcinoma cells through inhibiting JAK/STAT3 signaling pathway.

Trilobolide-6-O-isobutyrate exhibits significant antitumor effects on cholangiocarcinoma (CCA) cells by effectively inhibiting the JAK/STAT3 signaling pathway. This study aims to investigate the mechanisms underlying the antitumor properties of trilobolide-6-O-isobutyrate, and to explore its potential as a therapeutic agent for CCA. This study illustrates that trilobolide-6-O-isobutyrate efficiently suppresses CCA cell proliferation in a dose- and time-dependent manner. Furthermore, trilobolide-6-O-isobutyrate stimulates the production of reactive oxygen species, leading to oxidative stress and initiation of apoptosis via the activation of the mitochondrial pathway. Data from xenograft tumor assays in nude mice confirms that TBB inhibits tumor growth, and that there are no obvious toxic effects or side effects in vivo. Mechanistically, trilobolide-6-O-isobutyrate exerts antitumor effects by inhibiting STAT3 transcriptional activation, reducing PCNA and Bcl-2 expression, and increasing P21 expression. These findings emphasizes the potential of trilobolide-6-O-isobutyrate as a promising therapeutic candidate for the treatment of CCA.

DPY30 knockdown suppresses colorectal carcinoma progression via inducing Raf1/MST2-mediated apoptosis.

Colorectal Carcinoma (CRC) is one of the most common malignant tumors of the digestive tract, with a high mortality rate. DPY30 is one of the core subunits of the histone methyltransferase complex, which was involved in many cancer processes. However, the role of DPY30 in the occurrence and progression of CRC remains unclear. In this study, we sought to evaluate the role and mechanism of DPY30 in CRC cells apoptosis. Here, we identified that knockdown of DPY30 significantly inhibited the HT29 and HCT116 cells proliferation in vitro. Moreover, the knockdown of DPY30 significantly increased the apoptosis rate and promoted the expression of apoptosis-related proteins in CRC cells. Meanwhile, DPY30 knockdown promoted CRC cells apoptosis through endogenous programmed death and in a caspase activation-dependent manner. Furthermore, RNA-seq analysis revealed that the action of DPY30 is closely related to the apoptosis biological processes, and screened its potential effectors Raf1. Mechanistically, DPY30 downregulation promotes MST2-induced apoptosis by inhibiting Raf1 transcriptional activity through histone H3 lysine 4 trimethylation (H3K4me3). In vivo experiments showed that DPY30 was correlated with Raf1 in nude mouse subcutaneous xenografts tissues significantly. Clinical colorectal specimens further confirmed that overexpression of DPY30 in malignant tissues was significantly correlated with Raf1 level. The vital role of the DPY30/Raf1/MST2 signaling axis in the cell death and survival rate of CRC cells was disclosed, which provides potential new targets for early diagnosis and clinical treatment of CRC.

Stimulus-responsive and task-dependent activations in occipital regions during pitch perception by early blind listeners.

Although it has been established that cross-modal activations occur in the occipital cortex during auditory processing among congenitally and early blind listeners, it remains uncertain whether these activations in various occipital regions reflect sensory analysis of specific sound properties, non-perceptual cognitive operations associated with active tasks, or the interplay between sensory analysis and cognitive operations. This fMRI study aimed to investigate cross-modal responses in occipital regions, specifically V5/MT and V1, during passive and active pitch perception by early blind individuals compared to sighted individuals. The data showed that V5/MT was responsive to pitch during passive perception, and its activations increased with task complexity. By contrast, widespread occipital regions, including V1, were only recruited during two active perception tasks, and their activations were also modulated by task complexity. These fMRI results from blind individuals suggest that while V5/MT activations are both stimulus-responsive and task-modulated, activations in other occipital regions, including V1, are dependent on the task, indicating similarities and differences between various visual areas during auditory processing.

What Factors Contribute to Reading in ADHD: Examining Reading-Related Skills in Children With ADHD Only/Comorbid Developmental Dyslexia.

BACKGROUND: ADHD and developmental dyslexia (DD) frequently co-occur. However, it is unclear why some children with ADHD acquire DD while others do not. METHODS: A total of 830 children (including typically developing controls, ADHD only, DD only, and ADHD + DD groups) of two ages (younger: first-third grade; older: fourth-sixth grade) were assessed on measures of reading ability and reading-related skills. RESULTS: The clinical groups had different degrees of impairment in each reading-related skill. Regression results found that the four groups had different skills in predicting reading ability in younger and older grades. Especially, rapid automatized naming (RAN) was the only predictor of reading ability in children with ADHD only. CONCLUSIONS: The study highlights that RAN plays an important role in the reading development of children with ADHD only, reflecting the possible protective role of RAN in reading development.

The influence of guide stabilizers and their application sequences on trueness and precision of surgical guides in free end situations: An in vitro analysis.

OBJECTIVES: To evaluate the impact of guide stabilizers and their application sequences on implant placement accuracy of guided implant surgery in multiple teeth loss at free end. MATERIALS AND METHODS: In this study, 96 implants were placed in the regions of #34, #36, and #37 of 32 identical mandibular models. The influence of using guide stabilizers or not (group A and group B) and various guide stabilizers application sequences (group B: #34 → #36 → #37; group C: #36 → #34 → #37; group D: #37 → #34 → #36) on implant placement trueness and precision was investigated. Data were analyzed using T-tests and one-way ANOVA. RESULTS: Group B showed significant benefits in enhancing implant placement precision. Compared to group A, it resulted in reducing 3D-deviation at crest and 2D deviation in vestibular-oral direction at both crest and apex. Furthermore, group D demonstrated greater improvement in global implant placement precision by reducing 2D deviation in mesial-distal direction at both crest and apex. Among the three different stabilizer application sequences, group D exhibited the highest level of implant placement precision. CONCLUSIONS: In cases of missing teeth at distal free end, the use of guide stabilizers and their application sequences does not have a significant impact on implant placement trueness. However, they do improve implant placement precision compared to methods that do not utilize guide stabilizers. Specifically, applying a guide stabilizer first at the furthest implant site to change teeth loss classification from free end to edentulous space with posterior support is the most reliable sequence.

Developmental plasticity of the structural network of the occipital cortex in congenital blindness.

The occipital cortex is the visual processing center in the mammalian brain. An unanswered scientific question pertains to the impact of congenital visual deprivation on the development of various profiles within the occipital network. To address this issue, we recruited 30 congenitally blind participants (8 children and 22 adults) as well as 31 sighted participants (10 children and 21 adults). Our investigation focused on identifying the gray matter regions and white matter connections within the occipital cortex, alongside behavioral measures, that demonstrated different developmental patterns between blind and sighted individuals. We discovered significant developmental changes in the gray matter regions and white matter connections of the occipital cortex among blind individuals from childhood to adulthood, in comparison with sighted individuals. Moreover, some of these structures exhibited cognitive functional reorganization. Specifically, in blind adults, the posterior occipital regions (left calcarine fissure and right middle occipital gyrus) showed reorganization of tactile perception, and the forceps major tracts were reorganized for braille reading. These plastic changes in blind individuals may be attributed to experience-dependent neuronal apoptosis, pruning, and myelination. These findings provide valuable insights into the longitudinal neuroanatomical and cognitive functional plasticity of the occipital network following long-term visual deprivation.

RARγ promotes the invasion and metastasis of thyroid carcinoma by activating the JAK1-STAT3-CD24/MMPs axis.

The nuclear receptor superfamily RAR is generally considered to play a crucial role in the development of tumors by regulating the transcription of target genes. Nevertheless, whether RARγ performs tumor-promoting or tumor-suppressing functions and its specific mechanism in thyroid carcinoma (TC) remain unknown. Here, our study demonstrated that RARγ was abnormally overexpressed in TC tissues compared with normal thyroid tissues. Moreover, RARγ expression was remarkably correlated with cell phenotypes such as cell proliferation, migration and invasion. Mechanistically, RARγ knockdown effectively decreased the phosphorylation levels of JAK1 and STAT3, leading to decreased expression of the membrane protein CD24. In a coculture system, TC cells with high levels of CD24 in the membrane were more likely to escape phagocytosis by macrophages via the combination of CD24 with the inhibitory receptor Siglec-10 in the membrane of macrophages. In contrast, the ability of macrophages to engulf TC cells was notably elevated through exogenous addition of CD24 antibody. Collectively, our study revealed a previously undiscovered molecular mechanism of RARγ in promoting the development of TC, shedding light on RARγ as a promising therapeutic target for TC.

Sparse Topic Modeling: Computational Efficiency, Near-Optimal Algorithms, and Statistical Inference.

Sparse topic modeling under the probabilistic latent semantic indexing (pLSI) model is studied. Novel and computationally fast algorithms for estimation and inference of both the word-topic matrix and the topic-document matrix are proposed and their theoretical properties are investigated. Both minimax upper and lower bounds are established and the results show that the proposed algorithms are rate-optimal, up to a logarithmic factor. Moreover, a refitting algorithm is proposed to establish asymptotic normality and construct valid confidence intervals for the individual entries of the word-topic and topic-document matrices. Simulation studies are carried out to investigate the numerical performance of the proposed algorithms. The results show that the proposed algorithms perform well numerically and are more accurate in a range of simulation settings comparing to the existing literature. In addition, the methods are illustrated through an analysis of the COVID-19 Open Research Dataset (CORD-19).

Inducing the "re-development state" of periodontal ligament cells via tuning macrophage mediated immune microenvironment.

INTRODUCTION: Periodontal regeneration, specifically the restoration of the cementum-periodontal ligament (PDL)-alveolar bone complex, remains a formidable challenge in the field of regenerative dentistry. In light of periodontal development, harnessing the multi-tissue developmental capabilities of periodontal ligament cells (PDLCs) and reinitiating the periodontal developmental process hold great promise as an effective strategy to foster the regeneration of the periodontal complex. OBJECTIVES: This study aims to delve into the potential effects of the macrophage-mediated immune microenvironment on the "developmental engineering" regeneration strategy and its underlying molecular mechanisms. METHODS: In this study, we conducted a comprehensive examination of the periodontium developmental process in the rat mandibular first molar using histological staining. Through the induction of diverse immune microenvironments in macrophages, we evaluated their potential effects on periodontal re-development events using a cytokine array. Additionally, we investigated PDLC-mediated periodontal re-development events under these distinct immune microenvironments through transcriptome sequencing and relevant functional assays. Furthermore, the underlying molecular mechanism was also performed. RESULTS: The activation of development-related functions in PDLCs proved challenging due to their declined activity. However, our findings suggest that modulating the macrophage immune response can effectively regulate PDLCs-mediated periodontium development-related events. The M1 type macrophage immune microenvironment was found to promote PDLC activities associated with epithelial-mesenchymal transition, fiber degradation, osteoclastogenesis, and inflammation through the Wnt, IL-17, and TNF signaling pathways. Conversely, the M2 type macrophage immune microenvironment demonstrated superiority in inducing epithelium induction, fibers formation, and mineralization performance of PDLCs by upregulating the TGFß and PI3K-Akt signaling pathway. CONCLUSION: The results of this study could provide some favorable theoretical bases for applying periodontal development engineering strategy in resolving the difficulties in periodontal multi-tissue regeneration.

K2CO3-promoted synthesis of amides from 1-aryl-2,2,2-trifluoroethanones and amines under mild conditions.

A base-promoted amidation of 1-aryl-2,2,2-trifluoroethanones with amines via Haller-Bauer reaction has been developed. In this reaction, the direct transformation of 1-aryl-2,2,2-trifluoroethanones into amides via C(O)-C bond cleavage occurs without the use of any stoichiometric chemical oxidants or transition-metal catalysts. A series of primary and secondary amines are shown to be compatible with this transformation, and several pharmaceutical molecules were synthesized.

DPY30 Promotes Proliferation and Cell Cycle Progression of Colorectal Cancer Cells via Mediating H3K4 Trimethylation.

DPY30, a core subunit of the SET1/MLL histone H3K4 methyltransferase complexes, plays an important role in diverse biological functions through the epigenetic regulation of gene transcription, especially in cancer development. However, its involvement in human colorectal carcinoma (CRC) has not been elucidated yet. Here we demonstrated that DPY30 was overexpressed in CRC tissues, and significantly associated with pathological grading, tumor size, TNM stage, and tumor location. Furthermore, DPY30 knockdown remarkably suppressed the CRC cell proliferation through downregulation of PCNA and Ki67 in vitro and in vivo, simultaneously induced cell cycle arrest at S phase by downregulating Cyclin A2. In the mechanistic study, RNA-Seq analysis revealed that enriched gene ontology of cell proliferation and cell growth was significantly affected. And ChIP result indicated that DPY30 knockdown inhibited H3 lysine 4 trimethylation (H3K4me3) and attenuated interactions between H3K4me3 with PCNA, Ki67 and cyclin A2 respectively, which led to the decrease of H3K4me3 establishment on their promoter regions. Taken together, our results demonstrate overexpression of DPY30 promotes CRC cell proliferation and cell cycle progression by facilitating the transcription of PCNA, Ki67 and cyclin A2 via mediating H3K4me3. It suggests that DPY30 may serve as a potential therapeutic molecular target for CRC.

Visual Deprivation Alters Functional Connectivity of Neural Networks for Voice Recognition: A Resting-State fMRI Study.

Humans recognize one another by identifying their voices and faces. For sighted people, the integration of voice and face signals in corresponding brain networks plays an important role in facilitating the process. However, individuals with vision loss primarily resort to voice cues to recognize a person's identity. It remains unclear how the neural systems for voice recognition reorganize in the blind. In the present study, we collected behavioral and resting-state fMRI data from 20 early blind (5 females; mean age = 22.6 years) and 22 sighted control (7 females; mean age = 23.7 years) individuals. We aimed to investigate the alterations in the resting-state functional connectivity (FC) among the voice- and face-sensitive areas in blind subjects in comparison with controls. We found that the intranetwork connections among voice-sensitive areas, including amygdala-posterior "temporal voice areas" (TVAp), amygdala-anterior "temporal voice areas" (TVAa), and amygdala-inferior frontal gyrus (IFG) were enhanced in the early blind. The blind group also showed increased FCs of "fusiform face area" (FFA)-IFG and "occipital face area" (OFA)-IFG but decreased FCs between the face-sensitive areas (i.e., FFA and OFA) and TVAa. Moreover, the voice-recognition accuracy was positively related to the strength of TVAp-FFA in the sighted, and the strength of amygdala-FFA in the blind. These findings indicate that visual deprivation shapes functional connectivity by increasing the intranetwork connections among voice-sensitive areas while decreasing the internetwork connections between the voice- and face-sensitive areas. Moreover, the face-sensitive areas are still involved in the voice-recognition process in blind individuals through pathways such as the subcortical-occipital or occipitofrontal connections, which may benefit the visually impaired greatly during voice processing.

Initialization of Nanowire or Cluster Growth Critically Controlled by the Effective V/III Ratio at the Early Nucleation Stage.

For self-catalyzed nanowires (NWs), reports on how the catalytic droplet initiates successful NW growth are still lacking, making it difficult to control the yield and often accompanying a high density of clusters. Here, we have performed a systematic study on this issue, which reveals that the effective V/III ratio at the initial growth stage is a critical factor that governs the NW growth yield. To initiate NW growth, the ratio should be high enough to allow the nucleation to extend to the entire contact area between the droplet and substrate, which can elevate the droplet off of the substrate, but it should not be too high in order to keep the droplet. This study also reveals that the cluster growth between NWs is also initiated from large droplets. This study provides a new angle from the growth condition to explain the cluster formation mechanism, which can guide high-yield NW growth.

A Metal-Polyphenol-Based Oxygen Economizer and Fenton Reaction Amplifier for Self-Enhanced Synergistic Photothermal/Chemodynamic/Chemotherapy.

To overcome the limitations of doxorubicin (DOX) chemotherapy, nanomedicines that integrate additional photothermal therapy (PTT) and chemodynamic therapy (CDT) strategies are highlighted as promising alternatives for the treatment of malignant tumors. However, time-consuming preparation processes, biosafety concerns, and the bottlenecks of individual therapeutic modalities often limit the practical applications of this strategy. To address these issues, this work designs an oxygen economizer that additionally serves as a Fenton reaction amplifier through the simple assembly of epigallocatechin gallate (EGCG), pluronic F-127 (PF127), iron (III) ions, and doxorubicin (DOX) for the enhancement of synergistic PTT/CDT/chemotherapy. The resulting nanoformulation, EFPD, can target mitochondria and inhibit cell respiration to reduce O2 consumption, thus boosting DOX-mediated H2 O2 generation for enhanced CDT and simultaneously improving hypoxia-limited DOX chemotherapy efficacy. Moreover, the coordination between EGCG and Fe3+ provides EFPD with excellent photothermal conversion efficiencies (η = 34.7%) for PTT and photothermal-accelerated drug release. Experimental results indicate that EFPD-mediated synergistic enhancement of PTT/CDT/chemotherapy can achieve excellent therapeutic outcomes, including enhanced ablation of solid tumors, reduced metastasis and cardiotoxicity, and extended life spans.

Light-Triggered Nitric Oxide Nanogenerator with High l-Arginine Loading for Synergistic Photodynamic/Gas/Photothermal Therapy.

The development of nanomedicines that combine photothermal therapy (PTT) with photodynamic therapy (PDT) is considered promising for cancer treatment, but still faces the challenge of enhancing tumoricidal efficiency. Fortunately, apart from the well-acknowledged effect on direct tumor cell-killing, nitric oxide (NO) is also considered to be effective for the enhancement of both PTT and PDT. However, both the low loading efficiency of NO precursor and the short half-life time and diffusion distance of NO hamper the synergistic therapeutic efficacy of NO. Taking the aforementioned factors into account, a mitochondria-targeted nitric oxide nanogenerator, EArgFe@Ce6, is constructed to achieve high loading of the NO donor l-Arginine (l-Arg) for synergistic photodynamic/gas/photothermal therapy upon single 660 nm light irradiation. The coordination of epigallocatechin gallate (EGCG) and ferric ions (Fe3+ ) provides EArgFe@Ce6 supreme photothermal capability to perform low-temperature PTT (mPTT). EGCG endows EArgFe@Ce6 with mitochondria-targeting capability and meanwhile favors hypoxia alleviation for enhanced PDT. The PDT-produced massive reactive oxygen species (ROS) further catalyzes l-Arg to generate a considerable amount of NO to perform gas therapy and sensitize both mPTT and PDT. In vitro and in vivo studies demonstrate that the synergistic photodynamic/gas/photothermal therapy triggered by single 660 nm light irradiation is highly effective for tumor treatments.

Self-healing bottlebrush polymer networks enabled via a side-chain interlocking design.

Exploring novel healing mechanisms is a constant impetus for the development of self-healing materials. Herein, we find that side-chain interlocking of bottlebrush polymers can form a dynamic network and thereby serve as a driving force for the self-healing process of the materials. Molecular dynamics simulation indicates that the interlocking is formed by the interpenetration between the long side chains of adjacent molecules and stabilized by van der Waals interactions and molecular entanglements of side chains. The interlocking can be tailored by changing the length and density of the side chains through atom transfer radical polymerization. As a result, the optimized bottlebrush polymer shows a healing efficiency of up to 100%. Unlike chemical interactions, side-chain interlocking eliminates the introduction of specific chemical groups. Therefore, bottlebrush polymers can even self-heal under harsh aqueous conditions, including acid and alkali solutions. Moreover, the highly dynamic side-chain interlocking enables bottlebrush polymers to efficiently dissipate vibration energy, and thus they can be used as damping materials. Collectively, side-chain interlocking expands the scope of physical interactions in self-healing materials and hews out a versatile way for polymers to accomplish self-healing capability in various environments.

How Different Types of Linguistic Information Impact Voice Perception: Evidence From the Language-Familiarity Effect.

Previous studies have suggested the effect of linguistic information on voice perception (e.g., the language-familiarity effect [LFE]). However, it remains unclear which type of specific information in speech contributes to voice perception, including acoustic, phonological, lexical, and semantic information. It is also underexamined whether the roles of these different types of information are modulated by the experimental paradigm (speaker discrimination vs. speaker identification). In this study, we conducted two experiments to investigate these issues regarding LFEs. Experiment 1 examined the roles of acoustic and phonological information in speaker discrimination and identification with forward and time-reversed Mandarin and Indonesian sentences. Experiment 2 further identified the roles of phonological, lexical, and semantic information with forward, word-scrambled, and reconstructed (consisting of pseudo-Mandarin words) Mandarin and forward Indonesian sentences. For Mandarin-only participants, in Experiment 1, speaker discrimination was more accurate for forward than reversed sentences, but there was no LFE in either sentence. Speaker identification was also more accurate for forward than reversed sentences, whereas there was an LFE for forward sentences. In Experiment 2, speaker discrimination was better for word-scrambled than reconstructed Mandarin sentences. Speaker identification was more accurate for forward and word-scrambled Mandarin sentences but less accurate for Mandarin reconstructed and forward Indonesian sentences. In general, the pattern of the results for Indonesian learners was the same as that for Mandarin-only speakers. These results suggest that different kinds of information support speaker discrimination and identification in native and unfamiliar languages. The LFE in speaker identification depends on both phonological and lexical information.

High rodent abundance increases seed removal but decreases scatter-hoarding and seedling recruitment along an elevational gradient.

The distributions of small rodents in mountainous environments across different elevations can provide important information regarding the effects of climate change on the dispersal of plant species. However, few studies of oak forest ecosystems have compared the elevational patterns of sympatric rodent diversity, seed dispersal, seed bank, and seedling abundance. Thus, we tested the differences in the seed disperser composition and abundance, seed dispersal, seed bank abundance, and seedling recruitment for Quercus wutaishanica along 10 elevation levels in the Taihang Mountains, China. Our results provide strong evidence that complex asymmetric seed dispersal and seedling regeneration exist along an elevational gradient. The abundance of rodents had a significant negative correlation with the elevation and the seed removal rates peaked and then declined with increasing elevation. The seed removal rates were higher at middle and lower elevations than higher elevations but acorns were predated by 5 species of seed predators at middle and lower elevations, and thus, there was a lower likelihood of recruitment compared with those dropped beneath mother oaks at higher elevations. More importantly, the number of individual seeds in the seed bank and seedlings increased with the elevation, although dispersal services were reduced at sites lacking rodents. As conditional mutualists, the rodents could possibly act as antagonistic seed predators rather than mutualistic seed dispersers at low and middle elevations, thereby resulting in the asymmetric pattern of rodent and seedling abundance with increasing elevation to affect the community assembly and ecosystem functions on a large spatial scale.