Influence of phycospheric bacterioplankton disruption or removal on algae growth and survival.

Phycospheric bacteria play a crucial role in the survival of microalgae. However, the potential of using the growth regulation and community structure modulation of phycospheric bacteria to prevent the occurrence of blooms is yet to be verified. The phycospheric bacterioplankton of Cyclotella sp. can be categorized into HNA (high nucleic acid) bacteria and LNA (low nucleic acid) bacteria. 16S rRNA sequencing showed that the HNA bacteria exhibited higher α-diversity compared to the LNA bacteria, and the microbial community composition also exhibited variations. Metagenomic sequencing further indicated the distinct ecological functions between HNA and LNA bacteria. Furthermore, the study showcased the restorative capacity of the phycospheric bacterioplankton. Biomass analysis revealed that the recovery of phycospheric bacterioplankton positively influenced the microalgae growth, thus affirming the significance of phycospheric bacterioplankton to microalgae. The community structure of phycospheric bacterioplankton demonstrated a notable decrease in the abundance of restored LNA core bacteria. Additionally, the restored phycospheric bacterioplankton exhibited a more complex co-occurrence network structure, resulting in decreased resistance and sensitivity of microalgae to adverse environments. The presence of phycospheric bacterioplankton provides a protective shield for microalgae, and thus destabilizing or removing phycospheric bacterioplankton may effectively inhibit growth of microalgae.

Site-specific crosslinking and assembly of tetrameric ß-glucuronidase improve glycyrrhizin hydrolysis.

In this study, eight nonconserved residues with exposed surfaces and flexible conformations of the homotetrameric PGUS (ß-glucuronidase from Aspergillus oryzae Li-3) were identified. Single-point mutation into cysteine enabled the thiol-maleimide reaction and site-specific protein assembly using a two-arm polyethylene glycol (PEG)-maleimide crosslinker (Mal2 ). The Mal2 (1k) (with 1 kDa PEG spacer)-crosslinked PGUS assemblies showed low crosslinking efficiency and unimproved thermostability except for G194C-Mal2 (1k). To improve the crosslinking efficiency, a lengthened crosslinker Mal2 (2k) (with 2 kDa PEG spacer) was used to produce PGUS assembly and a highly improved thermostability was achieved with a half-life of 47.2-169.2 min at 70°C, which is 1.04-3.74 times that of wild type PGUS. It is found that the thermostability of PGUS assembly was closely associated with the formation of inter-tetramer assembly and intratetramer crosslinking, rather than the PEGylation of the enzyme. Therefore, the four-arm PEG-maleimide crosslinker Mal4 (2k) (with 2 kDa PEG spacer) was employed to simultaneously increase the inter-tetramer assembly and intratetramer crosslinking, and the resulting PGUS assemblies showed further improved thermostabilities compared with Mal2 (2k)-crosslinked assemblies. Finally, the application of PGUS assemblies with significantly improved thermostability to the bioconversion of GL proved that the PGUS assembly is a strong catalyst for glycyrrhizin (GL) hydrolysis in industrial applications.

A single-cell landscape of pre- and post-menopausal high-grade serous ovarian cancer ascites.

High-grade serous ovarian cancer (HGSOC) is a hormone-related cancer with high mortality and poor prognosis. Based on the transcriptome of 57,444 cells in ascites from 10 patients with HGSOC (including 5 pre-menopausal and 5 post-menopausal patients), we identified 14 cell clusters which were further classified into 6 cell types, including T cells, B cells, NK cells, myeloid cells, epithelial cells, and stromal cells. We discovered an increased proportion of epithelial cells and a decreased proportion of T cells in pre-menopausal ascites compared with post-menopausal ascites. GO analysis revealed the pre-menopausal tumor microenvironments (TME) are closely associated with viral infection, while the post-menopausal TME are mostly related to the IL-17 immune pathway. SPP1/CD44-mediated crosstalk between myeloid cells and B cells, NK cells, and stromal cells mainly present in the pre-menopausal group, while SPP1/PTGER4 -mediated crosstalk between myeloid cells and epithelial cells mostly present in the post-menopausal group.

Dissecting the immune discrepancies in mouse liver allograft tolerance and heart/kidney allograft rejection.

The liver is the most tolerogenic of transplanted organs. However, the mechanisms underlying liver transplant tolerance are not well understood. The comparison between liver transplantation tolerance and heart/kidney transplantation rejection will deepen our understanding of tolerance and rejection in solid organs. Here, we built a mouse model of liver, heart and kidney allograft and performed single-cell RNA sequencing of 66,393 cells to describe the cell composition and immune cell interactions at the early stage of tolerance or rejection. We also performed bulk RNA-seq of mouse liver allografts from Day 7 to Day 60 post-transplantation to map the dynamic transcriptional variation in spontaneous tolerance. The transcriptome of lymphocytes and myeloid cells were characterized and compared in three types of organ allografts. Cell-cell interaction networks reveal the coordinated function of Kupffer cells, macrophages and their associated metabolic processes, including insulin receptor signalling and oxidative phosphorylation in tolerance induction. Cd11b+ dendritic cells (DCs) in liver allografts were found to inhibit cytotoxic T cells by secreting anti-inflammatory cytokines such as Il10. In summary, we profiled single-cell transcriptome analysis of mouse solid organ allografts. We characterized the immune microenvironment of mouse organ allografts in the acute rejection state (heart, kidney) and tolerance state (liver).

Optimizing water and nitrogen management strategies to improve their use efficiency, eggplant yield and fruit quality.

With improvement in living standards, consumer preferences for vegetables are changing from quantity- to quality-oriented. Water and nitrogen supply, as two major determinants of vegetable crop yield and quality, can be optimally managed to improve the yield and quality. To evaluate the response in yield, fruit quality, and water and nitrogen utilization of eggplant to different water and nitrogen management strategies, a 2-year (2021 and 2022) field trial under mulched drip irrigation was conducted. The growth period was divided into seedling, flowering and fruit set, fruit development, and fruit ripening stages. Three irrigation levels were applied during the flowering and fruit set stage: W0, adequate water supply (70%-80% of field water capacity, FC); W1, mild water deficit (60%-70% FC); and W2, moderate water deficit (50%-60% FC). In addition, three nitrogen application rates were applied: N1, low nitrogen level (215 kg ha-1); N2, medium nitrogen level (270 kg ha-1); and N3, high nitrogen level (325 kg ha-1). The irrigation and nitrogen rates were applied in all combinations (i.e., nine treatments in total). Adequate water supply throughout the reproductive period in combination with no nitrogen application served as the control (CK). The yield of the W1N2 treatment was significantly increased by 32.62% and 35.06% in 2021 and 2022, respectively, compared with that of the CK. Fruit soluble protein, soluble solids, and vitamin C contents were significantly higher under W1 than W2. Fruit quality was significantly higher under the N2 rate compared with the other nitrogen rates. The W1N2 treatment showed the highest water productivity, with a significant increase of 11.27%-37.84% (2021) and 14.71%-42.48% (2022) compared with that under the other treatments. Based on the average water-deficit degree and nitrogen application rate, W0 and N1 had the highest partial factor productivity of nitrogen. Assessment of the results using the TOPSIS (technique for order preference by similarity to an ideal solution) method indicated that mild water deficit in combination with the medium nitrogen application rate (W1N2) was the optimal water and nitrogen management strategy for cultivated eggplant. The present findings contribute novel insights into the sustainable cultivation of eggplant in an oasis arid environment.

Effects of Multiple High-Dose Methamphetamine Administration on Enteric Dopaminergic Neurons and Intestinal Motility in the Rat Model.

Several studies have identified the effects of methamphetamine (MA) on central dopaminergic neurons, but its effects on enteric dopaminergic neurons (EDNs) are unclear. The aim of this study was to investigate the effects of MA on EDNs and intestinal motility. Male Sprague-Dawley rats were randomly divided into MA group and saline group. The MA group received the multiple high-dose MA treatment paradigm, while the controls received the same saline treatment. After enteric motility was assessed, different intestinal segments (i.e., duodenum, jejunum, ileum, and colon) were taken for histopathological, molecular biological, and immunological analysis. The EDNs were assessed by measuring the expression of two dopaminergic neuronal markers, dopamine transporter (DAT) and tyrosine hydroxylase (TH), at the transcriptional and protein levels. We also used c-Fos protein, a marker of neural activity, to detect the activation of EDNs. MA resulted in a significant reduction in TH and DAT mRNA expression as well as in the number of EDNs in the duodenum and jejunum (p < 0.05). MA caused a dramatic increase in c-Fos expression of EDNs in the ileum (p < 0.001). The positional variability of MA effects on EDNs paralleled the positional variability of its effect on intestinal motility, as evidenced by the marked inhibitory effect of MA on small intestinal motility (p < 0.0001). This study found significant effects of MA on EDNs with locational variability, which might be relevant to locational variability in the potential effects of MA on intestinal functions, such as motility.

Macroalgae culture-induced carbon sink in a large cultivation area of China.

Macroalgae culture-induced carbon sink in sediments has been little investigated. Here, total organic carbon (TOC), total nitrogen (TN), and δ13C were examined in sediments in a cultivation field of macroalgae (kelp and Gracilariopsis lemaneiformis) in Sansha Bay, Southeast China. Both proxies of C/N (TOC to TN ratio) and δ13C indicated a multisource of TOC. Based on a three-endmember model, macroalgae-derived TOC (TOCma) accounted for < 35% of the total TOC, averaging 16 ± 9% (mean ± SD). On average, terrestrial and phytoplankton-derived TOC showed much higher percentages of 24 ± 17% and 60 ± 20%, respectively (t-test, p < 0.02). A preliminary estimate suggested that TOCma represents a carbon sink of 8.2 × 103 tons per year, corresponding to about 22% of the sink associated with phytoplankton and macroalgae and 8 ± 6% of the macroalgae carbon production in Sansha Bay. Considering its production magnitude, the macroalgae-induced carbon sink seems to be insignificant, on a national or global scale, to phytoplankton, though it should be taken into account given the small cultivation area.

The parallel biosynthesis routes of hyperoside from naringenin in Hypericum monogynum.

Hyperoside is a bioactive flavonoid galactoside in both medicinal and edible plants. It plays an important physiological role in the growth of flower buds. However, the hyperoside biosynthesis pathway has not been systematically elucidated in plants, including its original source, Hypericaceae. Our group found abundant hyperoside in the flower buds of Hypericum monogynum, and we sequenced its transcriptome to study the biosynthetic mechanism of hyperoside. After gene screening and functional verification, four kinds of key enzymes were identified. Specifically, HmF3Hs (flavanone 3-hydroxylases) and HmFLSs (flavonol synthases) could catalyze flavanones into dihydroflavonols, as well as catalyzing dihydroflavonols into flavonols. HmFLSs could also convert flavanones into flavonols and flavones with varying efficiencies. HmF3'H (flavonoid 3'-hydroxylase) was found to act broadly on 4'-hydroxyl flavonoids to produce 3',4'-diydroxylated flavanones, dihydroflavonols, flavonols, and flavones. HmGAT (flavonoid 3-O-galactosyltransferase) would transform flavonols into the corresponding 3-O-galactosides, including hyperoside. The parallel hyperoside biosynthesis routes were thus depicted, one of which was successfully reconstructed in Escherichia coli BL21(DE3) by feeding naringenin, resulting in a hyperoside yield of 25 mg/l. Overall, this research not only helped us understand the interior catalytic mechanism of hyperoside in H. monogynum concerning flower development and bioactivity, but also provided valuable insights into these enzyme families.

Mitochondria-targeting nanozyme alleviating temporomandibular joint pain by inhibiting the TNFα/NF-κB/NEAT1 pathway.

Inflammatory cytokines that are secreted into the spinal trigeminal nucleus caudalis (Sp5C) may augment inflammation and cause pain associated with temporomandibular joint disorders (TMD). In a two-step process, we attached triphenylphosphonium (TPP) to the surface of a cubic liposome metal-organic framework (MOF) loaded with ruthenium (Ru) nanozyme. The design targeted mitochondria and was designated Mito-Ru MOF. This structure scavenges free radicals and reactive oxygen species (ROS) and alleviates oxidative stress. The present study aimed to investigate the effects and mechanisms by which Mito-Ru MOF ameliorates TMD pain. Intra-temporomandibular joint (TMJ) injections of complete Freund's adjuvant (CFA) induced inflammatory pain for ≥10 d in the skin areas innervated by the trigeminal nerve. Tumor necrosis factor-alpha (TNF-α), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), long non-coding RNA nuclear paraspeckle assembly transcript 1 (lncRNA NEAT1), and ROS also have been proved to be significantly upregulated in the Sp5C of TMD mice. Moreover, a single Mito-Ru MOF treatment alleviated TMD pain for 3 d and downregulated TNF-α, NF-κB, lncRNA NEAT1, and ROS. NF-κB knockdown downregulated NEAT1 in the TMD mice. Hence, Mito-Ru MOF inhibited the production of ROS and alleviated CFA-induced TMD pain via the TNF-α/NF-κB/NEAT1 pathway. Therefore, Mito-Ru MOF could effectively treat the pain related to TMD and other conditions associated with severe acute inflammatory activation.

Evaluating a WeChat-Based Health Behavioral Digital Intervention for Patients With Hypertension: Protocol for a Randomized Controlled Trial.

BACKGROUND: Hypertension is the most prevalent chronic condition and a significant risk factor for cardiovascular and kidney diseases. The efficacy of health behavioral interventions in blood pressure (BP) control has been demonstrated by a large and expanding body of literature, with "adherence" playing a crucial role. WeChat is the most common social communication mobile app in China, and it has been shown to be an acceptable delivery platform for delivering health interventions. The WeChat-based health behavioral digital intervention program (WHBDIP) showed high feasibility and efficacy. However, the results regarding BP improvement between the WHBDIP and control groups were inconsistent. OBJECTIVE: The objective of this study is to develop a WHBDIP and assess its efficacy in controlling BP and improving adherence among patients with hypertension. METHODS: A 2-arm, parallel-group, and randomized trial design was used. Patients older than 60 years and with hypertension were randomly assigned to either the control group or the experimental group, which received a 12-week intervention. The program, primarily developed based on the Behavior Change Wheel (BCW) theory, offers health education on exercise, diet, BP monitoring, and medicine adherence (MA). It also includes other behavior interventions guided by an intervention manual, incorporating behavior change techniques (BCTs). The primary outcomes encompass BP and adherence indicators, while the secondary outcomes encompass cardiovascular function indicators, body composition indicators, learning performance, satisfaction, and acceptability. The exercise and blood pressure monitoring adherence (BPMA) indicators for the WHBDIP group were assessed weekly via WeChat during the initial 3 months, while other outcome data for both groups will be collected at the baseline assessment phase, 3 months after the intervention, and 1 year after the program. RESULTS: The trial will assess the efficacy of WHBDIP for patients with hypertension (N=68). The WHBDIP seeks to enhance participants' knowledge of healthy behaviors and assist patients in developing positive health behaviors to improve their health outcomes. Patient recruitment for individuals with hypertension commenced on September 5, 2022, and concluded on September 19, 2022. The 3-month intervention and phased data collection were finalized in January 2023. Data analysis will commence in August 2023, and the final 1-year health outcome results will be collected in September 2023. CONCLUSIONS: A successful WHBDIP will establish the management mode as a feasible approach for hypertension management in the community. Additionally, it will pave the way for the development of related mobile health programs. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2200062643; https://tinyurl.com/mwyv67wk. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/46883.

Identification and characterization of colorectal-cancer-associated SNPs on the SMAD7 locus.

PURPOSE: Genome-wide association studies have identified SMAD7 as a colorectal cancer (CRC) susceptibility gene. However, its underlying mechanism has not yet been characterized. This study screened functional SNPs (fSNPs) related to colorectal cancer through Reel-seq and obtained regulatory proteins on functional SNPs. METHODS: The candidate fSNPs on the SMAD7 locus were screened by Reel-seq method. Eight SNPs such as rs8085824 were identified as functional SNPs by luciferase reporter assay and EMSA, SDCP-MS and AIDP-WB revealed that HNRNPK can specifically bind to the rs8085824-C allele. The knockdown of HNRNPK by RNAi proved that HNRNPK could affect cell function by regulating SMAD7. RESULTS: Eight functional SNPs was found on the SMAD7 locus in linkage disequilibrium (LD) with R2 > 0.8, i.e., rs12953717, rs7227023, rs34007497, rs58920878, rs8085824, rs4991143, rs4939826, and rs7227023. We also identified allele-imbalanced binding of HNRNPK to rs8085824, H1-3 to rs12953717, THOC6 to rs7227023, and DDX21 to rs58920878. Further functional analysis revealed that these proteins are the regulatory proteins that modulate the expression of SMAD7 in the human colorectal cancer cell line DLD1. In particular, we discovered that siRNA knockdown of HNRNPK inhibits cell proliferation and cell clonal formation by downregulating SMAD7, as the decreased cell proliferation and cell clonal formation in the siRNA HNRNPK knockdown cells was restored by SMAD7 overexpression. CONCLUSION: Our findings reveal a mechanism which underlies the contribution of the fSNP rs8085824 on the SMD7 locus to CRC susceptibility.

Solution Self-Assembly of Amphiphilic Tadpole-like Giant Molecules Constructed by Monotethering Diblock Copolymer Chain onto a Nanoparticle.

The self-assembly behavior of a tadpole-like giant molecule (TGM) constructed from a hydrophobic nanoparticle (NP) monotethered by a single amphiphilic AB diblock copolymer chain was investigated by combining self-consistent field theory and density functional theory in solution. The effects of the hydrophobicities of the B blocks and NPs (i.e., solvent properties) on the self-assembly behavior of the TGMs were investigated in the cases of weak and strong intramolecular interactions (i.e., incompatibilities) between the components of giant molecules, respectively. Besides conventional ordered aggregates (such as spheres, rings, and vesicles) with hydrophobic B-cores covered by NP shells, several aggregates with novel hierarchical structures, including vesicles with NP-inserted hydrophobic walls, bead-string-like micelles, and long cylindrical micelles with NP bumps, were obtained by tuning the solvent properties under different intramolecular interactions. Noteworthy that the simulation results show that the arrangement of the NP bumps on the long cylindrical micelles may have a certain degree of helicity, which means that these micelles may have some unique electromagnetic features such as circular dichroism. Phase diagrams as a function of the hydrophobicities of the B blocks and NPs were constructed to show the formation conditions of these novel structures. These findings can not only offer new insights into understanding of the self-assembly behavior of the TGM in solution but also provide useful guidance for simple and efficient regulation of the morphology, as well as the NP distribution and arrangement of the ordered aggregates in experiments.

RVE2, a new regulatory factor in jasmonic acid pathway, orchestrates resistance to Verticillium wilt.

Verticillium dahliae, one of the most destructive fungal pathogens of several crops, challenges the sustainability of cotton productivity worldwide because very few widely-cultivated Upland cotton varieties are resistant to Verticillium wilt (VW). Here, we report that REVEILLE2 (RVE2), the Myb-like transcription factor, confers the novel function in resistance to VW by regulating the jasmonic acid (JA) pathway in cotton. RVE2 expression was essentially required for the activation of JA-mediated disease-resistance response. RVE2 physically interacted with TPL/TPRs and disturbed JAZ proteins to recruit TPL and TPR1 in NINJA-dependent manner, which regulated JA response by relieving inhibited-MYC2 activity. The MYC2 then bound to RVE2 promoter for the activation of its transcription, forming feedback loop. Interestingly, a unique truncated RVE2 widely existing in D-subgenome (GhRVE2D) of natural Upland cotton represses the ability of the MYC2 to activate GhRVE2A promoter but not GausRVE2 or GbRVE2. The result could partially explain why Gossypium barbadense popularly shows higher resistance than Gossypium hirsutum. Furthermore, disturbing the JA-signalling pathway resulted into the loss of RVE2-mediated disease-resistance in various plants (Arabidopsis, tobacco and cotton). RVE2 overexpression significantly enhanced the resistance to VW. Collectively, we conclude that RVE2, a new regulatory factor, plays a pivotal role in fine-tuning JA-signalling, which would improve our understanding the mechanisms underlying the resistance to VW.

Invisible social grouping facilitates the recognition of individual faces.

Emerging evidence suggests a specialized mechanism supporting perceptual grouping of social entities. However, the stage at which social grouping is processed is unclear. Through four experiments, here we showed that participants' recognition of a visible face was facilitated by the presence of a second facing (thus forming a social grouping) relative to a nonfacing face, even when the second face was invisible. Using a monocular/dichoptic paradigm, we further found that the social grouping facilitation effect occurred when the two faces were presented dichoptically to different eyes rather than monocularly to the same eye, suggesting that social grouping relies on binocular rather than monocular neural channels. The above effects were not found for inverted face dyads, thereby ruling out the contribution of nonsocial factors. Taken together, these findings support the unconscious influence of social grouping on visual perception and suggest an early origin of social grouping processing in the visual pathway.

Anthropogenic original DOM is a critical factor affecting LNA bacterial community assembly.

We investigated the geographical and environmental distance-decay relationships for both of the two bacteria in the Haihe River, Tianjin, China. HNA bacteria exhibited a stronger geographical variation-dependent pattern while LNA bacteria exhibited a stronger environmental variation-dependent pattern. Variance partition analysis (VPA), Mantel test, and partial mantel test validated the discrepant impacts of geographical distance and environmental factors on their two communities. The heterogeneous selection dominated community assembly of LNA bacteria demonstrates their greater sensitivity to environmental conditions. As the deterministic environmental factor, anthropogenic original dissolved organic matter (DOM) functions exclusively on LNA bacteria, and it is the critical factor leading to the discrepant biogeographical patterns of LNA and HNA bacteria. LNA bacteria interact with HNA bacteria and mediate the DOM driving total bacteria assembly. The LNA keystone taxa, Pseudomonas, Rheinheimera, Candidatus Aquiluna, and hgcl clade are capable to compete with HNA bacteria for anthropogenic original DOM, and are potential indicators of anthropogenic pollution. Our research reveals the non-negligible effect of the LNA bacteria in regulating the ecological response of total bacteria.

Transcranial magnetic stimulation effects on cognitive enhancement in mild cognitive impairment and Alzheimer's disease: a systematic review and meta-analysis.

Introduction: Transcranial magnetic stimulation (TMS) is a non-invasive intervention that holds promise for improving cognitive function in individuals with Alzheimer's disease (AD). However, the effectiveness of this therapy and the optimal TMS parameters has not reached a consensus. The purpose of the meta-analysis was to systematically discern the effectiveness of different components of TMS protocols on cognitive improvement in patients with mild cognitive impairment (MCI) and AD. Methods: The meta-analysis was preregistered on Prospero (registration number: CRD42022345482). PubMed, Web of Science, Science Direct, and Cochrane Library databases were used to search, screen and identify eligible studies with the following keywords: Transcranial Magnetic Stimulation OR TMS OR theta burst stimulation AND Alzheimer OR Alzheimers OR Alzheimer's OR mild cognitive impairment OR MCI. Randomized controlled trials (RCTs) of participants with accepted standardized diagnostic criteria were searched by two authors independently. The risk of bias was assessed using an adapted Cochrane Risk of Bias tool. Standardized mean difference (SMD) and 95% confidence interval (CI) were calculated using the random-effects models. Subgroup analyses were performed to investigate the influential factors. Results: A total of 21 studies and 25 trials were included in this meta-analysis. The findings revealed a significant overall cognition improvement of real stimulation compared with sham stimulation (short-term effects: SMD, 0.91; 95% CI 0.44-1.38; P < 0.01; long-lasting effects: SMD, 0.91; 95% CI 0.27-1.55; P < 0.01). Subgroup analysis demonstrated that stimulation of the left dorsolateral prefrontal cortex and bilateral cerebellums, as well as moderate frequency stimulation (5 Hz and 10 Hz) on mild and moderate cognitive impairment patients, were more effective than other TMS protocols. However, the additional application of cognitive training showed no significant improvement. Conclusion: Cognitive improvement effect of TMS was demonstrated in MCI and AD patients in both short-term assessment and long-lasting outcomes, and the efficiency of TMS is affected by the stimulation frequency, stimulation site, and participant characteristics. Further RCTs are needed to validate the findings of our subgroup analysis. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022345482, identifier: CRD42022345482.

Anlotinib exerts an anti-T-cell acute lymphoblastic leukemia effect in vitro and in vivo.

BACKGROUND: Despite some progress having been made regarding the treatment of T-cell acute lymphoblastic leukemia (T-ALL), the prognosis of T-ALL, particularly adult T-ALL, is still poor. Identifying novel, effective anti-T-ALL drugs is of great significance. Anlotinib, an oral tyrosine kinase inhibitor currently utilized in the treatment of lung cancer, exhibited a promising anti-T-ALL effect. A comprehensive study should therefore be conducted to explore both the in vitro as well as in vivo mechanisms of the anti-T-ALL effects of anlotinib. METHODS: CCK8 assays and flow cytometry were employed to investigate the viability, cell cycle distribution, and apoptosis of T-ALL cell lines when treated with anlotinib. T-ALL xenograft mouse models were established to examine the in vivo antileukemic effects of anlotinib. Cellular and molecular analysis of T-ALL were conducted to define the underlying mechanisms. RESULTS: In vitro, anlotinib significantly inhibited the viability, induced G2/M phase arrest and apoptosis in T-ALL cell lines in a concentration-dependent pattern. In vivo, anlotinib also demonstrated a strong anti-tumor effect at doses that are well-tolerated. Interestingly, anlotinib could decrease the protein levels of the intracellular domains of NOTCH1 (ICN1) and c-Myc, two important targets for T-ALL. Mechanistically, anlotinib-induced c-Myc reduction was associated with proteasome-mediated degradation, while the ICN1 reduction was not due to protein degradation or transcriptional repression. CONCLUSIONS: The present study showed that anlotinib may be a promising anti-T-ALL candidate drug, and simultaneous reduction of the protein levels of both ICN1 and c-Myc may contribute to the anti-T-ALL efficacy of anlotinib.

A pan-cancer analysis of potassium channel tetramerization domain containing 12 in human cancer.

Abnormal expression of the potassium channel tetramerization domain containing 12 (KCTD12) is closely related to the occurrence and development of various tumors, but a pan-cancer analysis of KCTD12 has not yet been conducted. We explored the association between KCTD12 and more than 30 human malignancies using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. First, the mRNA and protein levels of KCTD12 were examined and their correlations with tumor stage and survival were explored. Second, we analyzed the infiltration of CD8+ and CD4+ T cells and cancer-associated fibroblasts in tumors and explored the correlation between KCTD12 expression and tumor cell stemness, genomic heterogeneity, and diagnostic specificity. Finally, we explored the molecular mechanisms associated with KCTD12 using KEGG/GO analysis. The results showed that KCTD12 mRNA and protein expression levels decreased in most tumors was significantly associated with the prognosis of tumor patients, and the phosphorylation level of KCTD12 decreased in several tumors, such as S200 and T196, pancreatic adenocarcinoma (PAAD), lung adenocarcinoma (LUAD), and breast invasive cancer (BRCA). The expression of KCTD12 was positively correlated with the degree of cancer-associated fibroblasts infiltration in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), head and neck squamous cell carcinoma (HNSC), PAAD, and stomach adenocarcinoma (STAD). The relationship between KCTD12 expression and CD8+ and CD4+ T cell infiltration was also clarified. KCTD12 showed high diagnostic sensitivity for various types of tumors and may be involved in tumor cell biology by affecting tumor cell stemness, tumor burden, and other characteristics. Finally, we analyzed the molecular functions of KCTD12 and possible KEGG/GO signaling pathways. In this study, we developed a biological marker for diagnosis, prognosis, and immune infiltration of the pan-cancers.

Using microneedle array electrodes for non-invasive electrophysiological signal acquisition and sensory feedback evoking.

Introduction: Bidirectional transmission of information is needed to realize a closed-loop human-machine interaction (HMI), where electrophysiological signals are recorded for man-machine control and electrical stimulations are used for machine-man feedback. As a neural interface (NI) connecting man and machine, electrodes play an important role in HMI and their characteristics are critical for information transmission. Methods: In this work, we fabricated a kind of microneedle array electrodes (MAEs) by using a magnetization-induced self-assembly method, where microneedles with a length of 500-600 µm and a tip diameter of ∼20 µm were constructed on flexible substrates. Part of the needle length could penetrate through the subjects' stratum corneum and reach the epidermis, but not touch the dermis, establishing a safe and direct communication pathway between external electrical circuit and internal peripheral nervous system. Results: The MAEs showed significantly lower and more stable electrode-skin interface impedance than the metal-based flat array electrodes (FAEs) in various testing scenarios, demonstrating their promising impedance characteristics. With the stable microneedle structure, MAEs exhibited an average SNR of EMG that is more than 30% higher than FAEs, and a motion-intention classification accuracy that is 10% higher than FAEs. The successful sensation evoking demonstrated the feasibility of the MAE-based electrical stimulation for sensory feedback, where a variety of natural and intuitive feelings were generated in the subjects and thereafter objectively verified through EEG analysis. Discussion: This work confirms the application potential of MAEs working as an effective NI, in both electrophysiological recording and electrical stimulation, which may provide a technique support for the development of HMI.

Initial Development of an Immediate Implantation Model in Rats and Assessing the Prognostic Impact of Periodontitis on Immediate Implantation.

BACKGROUND: To establish an immediate implantation rat model and to evaluate the effects of pre-existing periodontitis and two different socket rinse solutions on immediate implantation prognosis. METHODS: Sprague-Dawley (SD) rats were randomly divided into three groups before immediate implantation, including the control group, the group with experimentally induced periodontitis (EP), in which rats have been experimentally induced periodontitis before implantation, and the group with induced periodontitis and with extraction sockets rinsed with three percent H2O2 (EP-H2O2), in which rats have been induced periodontitis before implantation, and extraction sockets were rinsed with three percent H2O2. Periodontitis was induced by ligating the thread around the molars for four weeks. Six weeks after titanium alloy implants were self-tapped and left to heal transmucosally, maxillae were dissected after the clinical examination to perform micro-CT and histological analysis. RESULTS: An immediate implantation model was successfully built in rats. There was no significant difference in implant survival rates between the EP and control groups. However, the clinical examination results, micro-CT analysis, and histological analysis in EP and EP-H2O2 groups showed a significantly worse prognosis than in the control group. Three percent H2O2 showed a similar effect with saline. CONCLUSION: This study presented a protocol for establishing a rat immediate implantation model and showed that periodontitis history might negatively affect the prognosis of immediate implantation. These findings urge caution and alternative strategies for patients with periodontal disease history, enhancing the long-term success of immediate implantation in dental practice. Additionally, the comparable outcomes between 3% H2O2 and saline suggest the use of saline as a cost-effective and safer alternative for implant site preparation in dental practice.