Whole-transcriptome profiling reveals potential biomarkers for the reversal of thymic epithelial cell senescence by umbilical cord mesenchymal stem cells.

BACKGROUND: Reduced numbers and dysfunction of thymic epithelial cells (TECs) are important factors of thymic degeneration. Previous studies have found that umbilical cord mesenchymal stem cells (UCMSCs) reverse the structure and function of the senescent thymus in vivo. However, the transcriptomic regulation mechanism is unclear. METHODS: TECs were cultured with H2O2 for 72 hours to induce senescence. UCMSCs were cocultured with senescent TECs for 48 hours to detect SA-ß-gal, P16 and Ki67. The cocultured TECs were collected for lncRNA, mRNA and miRNA sequencing to establish a competitive endogenous regulatory network (ceRNA). And RT-qPCR, immunofluorescence staining, and western blot were used to identified key genes. RESULTS: Our results showed that H2O2 induced TEC aging and that UCMSCs reversed these changes. Compared with those in aged TECs, 2260 DE mRNAs, 1033 DE lncRNAs and 67 DE miRNAs were differentially expressed, and these changes were reversed by coculturing the cells with UCMSCs. Differential mRNA enrichment analysis of ceRNA regulation revealed that the PI3K-AKT pathway was a significant signaling pathway. UCMSC coculture upregulated VEGFA, which is the upstream factor of the PI3K-AKT signaling pathway, and the expression of the key proteins PI3K and AKT. Thus, the expression of the cell cycle suppressor P27, which is downstream of the PI3K-AKT signaling pathway, was downregulated, while the expression of the cell cycle regulators CDK2 and CCNE was upregulated. CONCLUSION: UCMSC coculture upregulated the expression of VEGFA, activated the PI3K-AKT signaling pathway, increased the expression of CDK2 and CCNE, decreased the expression of P27, and promoted the proliferation of TECs.

Synthesis of narrow-spectrum anti-mycobacterial molecules without effect on the diversity of gut microbiota in mice based on the structure of rifampicin.

Rifampicin (RIF) is a broad-spectrum antimicrobial agent that is also a first-line drug for treating tuberculosis (TB). Based on the naphthyl ring structure of RIF this study synthesized 16 narrow-spectrum antimicrobial molecules that were specifically anti-Mycobacterium tuberculosis (Mtb). The most potent candidate was 2-((6-hydroxynaphthalen-2-yl) methylene) hydrazine-1-carbothioamide (compound 3c) with minimum inhibitory concentration (MIC) of 1 µg/mL against Mtb. Synergistic anti-Mtb test indicated that none of the combinations of 3c with the major anti-TB drugs are antagonistic. Consistent with RIF, compound 3c induced large amounts of reactive oxygen radicals (ROS) in the cells of Mtb. The killing kinetics of compound 3c and RIF are very similar. Furthermore, molecular docking showed that compound 3c was able to access the RIF binding pocket of the ß subunit of Mtb RNA polymerase (RNAP). Experiments in mice showed that compound 3c increased the variety of intestinal flora in mice, while RIF significantly decreased the diversity of intestinal flora in mice. In addition, compound 3c is non-toxic to animal cells with a selection index (SI) much more than 10. The evidence from this study suggests that the further development of 3c could contribute to the development of novel drug for TB treatment.

The novel TERF2::PDGFRB fusion gene enhances tumorigenesis via PDGFRB/STAT5 signalling pathways and sensitivity to TKI in ph-like ALL.

Patients with Philadelphia chromosome-like acute lymphoblastic leukaemia (Ph-like ALL) often face a grim prognosis, with PDGFRB gene fusions being commonly detected in this subgroup. Our study has unveiled a newfound fusion gene, TERF2::PDGFRB, and we have found that patients carrying this fusion gene exhibit sensitivity to dasatinib. Ba/F3 cells harbouring the TERF2::PDGFRB fusion display IL-3-independent cell proliferation through activation of the p-PDGFRB and p-STAT5 signalling pathways. These cells exhibit reduced apoptosis and demonstrate sensitivity to imatinib in vitro. When transfused into mice, Ba/F3 cells with the TERF2::PDGFRB fusion gene induce tumorigenesis and a shortened lifespan in cell-derived graft models, but this outcome can be improved with imatinib treatment. In summary, we have identified the novel TERF2::PDGFRB fusion gene, which exhibits oncogenic potential both in vitro and in vivo, making it a potential therapeutic target for tyrosine kinase inhibitors (TKIs).

19 Schiff bases as antimycobacterial agents: synthesis, molecular docking and a plausible mechanism of action.

Aim: To discover novel anti-Mycobacterium tuberculosis (Mtb) drugs, 19 compounds were synthesized; their anti-Mtb effects were evaluated and mechanisms of action were preliminarily explored. Materials & methods: The compounds were synthesized and their anti-Mtb activity was elucidated using resazurin microtiter assays. The plausible target of the potential compound was investigated by microimaging techniques, gas chromatography-mass spectrometry analysis and molecular docking. Results: 19 compounds inhibited Mtb growth with minimum inhibitory concentrations ranging from 1 to 32 µg/ml. Compounds 1-17 showed inhibition of Mtb KatG enzyme. Compound 19, the most potent, might be an inhibitor of Pks13 polyketide synthase. Conclusion: This study suggests that 2-((6-fluoropyridin-3-yl)methylene) hydrazine-1-carbothioamide (19) is a potential anti-Mtb lead compound with a novel mechanism of action.

Globally, more than 1.6 million people die of tuberculosis (TB) and about 11 million new cases occur each year. The emergence of drug-resistant Mycobacterium tuberculosis (Mtb) has made it difficult to effectively treat TB. Therefore, 19 drugs were synthesized and assayed in the laboratory to verify whether they could inhibit the growth of Mtb. All compounds exhibit anti-Mtb effects at relatively low concentrations. Among them, compound 19 had a strong anti-Mtb effect, and its bactericidal effect on Mtb even exceeded that of isoniazid. In addition, it was preliminarily determined that compound 19 is a novel inhibitor of a key enzyme in the biosynthesis of Mtb cell walls. These findings demonstrate a potential new treatment option for TB but more research is needed to confirm the safety of these drugs.

Toward Smart, Flexible, and Omnidirectional Self-Powered Photodetection by an All-Solution-Processed In2O3/Pbl2 Heterojunction.

Amorphous In2O3 film is emerging as a promising oxide semiconductor for next-generation electronics and optoelectronics owing to high mobility and wide band gap. However, the persistent photocurrent phenomenon and high carrier concentration in amorphous In2O3 film are challenging the photodetection performances, resulting in a long response time and low Ilight/Idark ratio. In this work, the In2O3/PbI2 heterojunction is constructed by an all-solution synthesis process to inhibit the persistent photocurrent phenomenon and large dark current. Benefiting from the built-in electric field at the heterojunction interface, the In2O3/PbI2 heterojunction photodetector exhibits excellent self-powered photodetection performances with an ultralow dark current of 10-12 A, a high Ilight/Idark ratio of 104, and fast response times of 0.6/0.6 ms. Furthermore, the entire solution synthesis process and amorphous characteristics enable the fabrication of an In2O3/PbI2 heterojunction photodetector on arbitrary substrates to realize specific functions. When configured onto the polyimide substrate, the In2O3/PbI2 heterojunction photodetector shows excellent mechanical flexibility, bending endurance, and photoresponse stability. When implanted onto the transparent substrate, the In2O3/PbI2 heterojunction photodetector exhibits an outstanding omnidirectional self-powdered photodetection performance and imaging capability. All results pave the way for an all-solution-processed amorphous In2O3 film in advanced high-performance photodetectors.

Tunable Contacts of Bi2 O2 Se Nanosheets MSM Photodetectors by Metal-Assisted Transfer Approach for Self-Powered Near-Infrared Photodetection.

Owing to the Fermi pinning effect arose in the metal electrodes deposition process, metal-semiconductor contact is always independent on the work function, which challenges the next-generation optoelectronic devices. In this work, a metal-assisted transfer approach is developed to transfer Bi2 O2 Se nanosheets onto the pre-deposited metal electrodes, benefiting to the tunable metal-semiconductor contact. The success in Bi2 O2 Se nanosheets transfer is contributed to the stronger van der Waals adhesion of metal electrodes than that of growth substrates. With the pre-deposited asymmetric electrodes, the self-powered near-infrared photodetectors are realized, demonstrating low dark current of 0.04 pA, high Ilight /Idark ratio of 380, fast rise and decay times of 4 and 6 ms, respectively, under the illumination of 1310 nm laser. By pre-depositing the metal electrodes on polyimide and glass, high-performance flexible and omnidirectional self-powered near-infrared photodetectors are achieved successfully. This study opens up new opportunities for low-dimensional semiconductors in next-generation high-performance optoelectronic devices.

Lattice-mismatch-free construction of III-V/chalcogenide core-shell heterostructure nanowires.

Growing high-quality core-shell heterostructure nanowires is still challenging due to the lattice mismatch issue at the radial interface. Herein, a versatile strategy is exploited for the lattice-mismatch-free construction of III-V/chalcogenide core-shell heterostructure nanowires by simply utilizing the surfactant and amorphous natures of chalcogenide semiconductors. Specifically, a variety of III-V/chalcogenide core-shell heterostructure nanowires are successfully constructed with controlled shell thicknesses, compositions, and smooth surfaces. Due to the conformal properties of obtained heterostructure nanowires, the wavelength-dependent bi-directional photoresponse and visible light-assisted infrared photodetection are realized in the type-I GaSb/GeS core-shell heterostructure nanowires. Also, the enhanced infrared photodetection is found in the type-II InGaAs/GeS core-shell heterostructure nanowires compared with the pristine InGaAs nanowires, in which both responsivity and detectivity are improved by more than 2 orders of magnitude. Evidently, this work paves the way for the lattice-mismatch-free construction of core-shell heterostructure nanowires by chemical vapor deposition for next-generation high-performance nanowire optoelectronics.

Fabrication of ß-Ga2O3 Nanotubes via Sacrificial GaSb-Nanowire Templates.

ß-Ga2O3 nanostructures are attractive wide-band-gap semiconductor materials as they exhibit promising photoelectric properties and potential applications. Despite the extensive efforts on ß-Ga2O3 nanowires, investigations into ß-Ga2O3 nanotubes are rare since the tubular structures are hard to synthesize. In this paper, we report a facile method for fabricating ß-Ga2O3 nanotubes using pre-synthesized GaSb nanowires as sacrificial templates. Through a two-step heating-treatment strategy, the GaSb nanowires are partially oxidized to form ß-Ga2O3 shells, and then, the residual inner parts are removed subsequently in vacuum conditions, yielding delicate hollow ß-Ga2O3 nanotubes. The length, diameter, and thickness of the nanotubes can be customized by using different GaSb nanowires and heating parameters. In situ transmission electron microscopic heating experiments are performed to reveal the transformation dynamics of the ß-Ga2O3 nanotubes, while the Kirkendall effect and the sublimation process are found to be critical. Moreover, photoelectric tests are carried out on the obtained ß-Ga2O3 nanotubes. A photoresponsivity of ~25.9 A/W and a detectivity of ~5.6 × 1011 Jones have been achieved with a single-ß-Ga2O3-nanotube device under an excitation wavelength of 254 nm.

Complete mitochondrial genomic sequence of Auricularia delicata (Auriculariaceae), an edible Chinese mushroom.

Auricularia delicata (Mont.) Henn. 1893 is an edible and medicinal jelly mushroom popular in China. Here, we report the assembly and annotation of a complete A. delicata mitochondrial genome based on data sequenced using an Illumina NovaSeq 6000 platform. The length of the complete circular A. delicata mitochondrial genome is 189,696 bp, with a GC content of 34.1%. The A. delicata mitochondrial genome contains 60 genes, including 32 protein-coding genes, 26 tRNA genes, and two rRNA genes. Phylogenetic analysis indicated that A. delicata clustered with the Auricularia group, alongside A. auricula-judae and A. heimuer. Additionally, A. delicata was found to be genetically distant from other species of Polyporales, Russulales, and Agaricales. This genome will provide an invaluable reference for the continued study and utilization of A. delicata and other Auricularia species.

Immune function, gastrointestinal hormone levels, and their clinical significance in patients with gastric ulcers complicated with depression.

BACKGROUND: Gastric ulcer (GU) is a common digestive tract disease, and medical records of GU combined with depression are increasingly common. Currently, the risk factors and pathogenesis of GU complicated with depression remain unclear. Low immune function and gastrointestinal hormone levels may also be significant risk factors. Therefore, this study explored the immune function and gastrointestinal hormone levels in patients with GU combined with depression. AIM: To explore the immune function, gastrointestinal hormone level, and clinical significance of patients with GU combined with depression. METHODS: A retrospective analysis was conducted on 300 patients with GU combined with depression admitted to Guizhou Provincial People's Hospital from January 2021 to June 2022 as the study subjects. According to the Hamilton Depression Scale (HAMD) score, patients were divided into mild-to-moderate (n = 210) and heavy (n = 90) groups. Basic data, immune function indices [immunoglobulin A (IgA), IgM, IgG, serum CD4+ and CD8+ percentage, and CD4+/CD8+ ratio], and gastrointestinal hormone indices [serum gastrin (GAS), cholecystokinin (CCK), and motilin (MTL) levels] were collected. The basic data of the two groups were compared, and the immune function and gastrointestinal hormone indices were analyzed. Multivariate logistic regression was used to analyze the factors influencing the severity of GU complicated with depression. The receiver operating characteristic (ROC) curve and area under the ROC curve (AUC) were used to analyze the value of the immune function index, gastrointestinal hormone index, and combined index in predicting the severity of GU complicated with depression. RESULTS: There were no marked differences in sex, age, body mass index, abdominal distension, abdominal pain, belching, nausea, vomiting, or sleep disorders between the heavy and mild-to-moderate groups (P > 0.05). There was a marked difference in the family history of depression between the heavy and mild-to-moderate groups (P < 0.05). There were significant differences in serum IgA and IgM levels and serum CD4+, CD8+, and CD4+/CD8+ ratios between the heavy and mild-to-moderate groups (P < 0.05). Multivariate analysis showed that IgA, IgM, GAS, and CCK serum levels influenced the severity of GU with depression (P < 0.05). The AUC of the ROC curve for serum IgA level predicting GU with depression severity was 0.808 [95% confidence interval (CI): 0.760-0.857], the AUC of the serum IgM level was 0.757 (95%CI: 0.700-0.814), the AUC of the serum GAS level was 0.853 (95%CI: 0.810-0.897), the AUC of the serum CCK level was 0.762 (95%CI: 0.709-0.822), the AUC of immune function (IgA, IgM) and gastrointestinal hormone levels (GAS, CCK) for the prediction of GU with depression severity was 0.958 (95%CI: 0.933-0.976). CONCLUSION: Important factors influencing GU complicated with depression are serum IgA, IgM, GAS, and CCK indicators. They can be used as indicators to predict the severity of GU complicated with depression.

An Amorphous Native Oxide Shell for High Bias-Stress Stability Nanowire Synaptic Transistor.

The inhomogeneous native oxide shells on the surfaces of III-V group semiconductors typically yield inferior and unstable electrical properties metrics, challenging the development of next-generation integrated circuits. Herein, the native GaOx shells are profitably utilized by a simple in-situ thermal annealing process to achieve high-performance GaSb nanowires (NWs) field-effect-transistors (FETs) with excellent bias-stress stability and synaptic behaviors. By an optimal annealing time of 5 min, the as-constructed GaSb NW FET demonstrates excellent stability with a minimal shift of transfer curve (ΔVth ≈ 0.54 V) under a 60 min gate bias, which is far more stable than that of pristine GaSb NW FET (ΔVth ≈ 8.2 V). When the high bias-stress stability NW FET is used as the chargeable-dielectric free synaptic transistor, the typical synaptic behaviors, such as short-term plasticity, long-term plasticity, spike-time-dependent plasticity, and reliable learning stability are demonstrated successfully through the voltage tests. The mobile oxygen ion in the native GaOx shell strongly offsets the trapping states and leads to enhanced bias-stress stability and charge retention capability for synaptic behaviors. This work provides a new way of utilizing the native oxide shell to realize stable FET for chargeable-dielectric free neuromorphic computing systems.

Synthesis, antimycobacterial evaluation, and molecular docking study of 1,2,4-triazole derivatives.

Fifteen 1,2,4-triazole derivatives were synthesised in this study and their MIC values against Mycobacterium tuberculosis (Mtb) ranged from 2 to 32 µg/mL. Furthermore, their antimycobacterial activity was positively correlated with the KatG enzyme docking score. Among the 15 compounds, compound 4 showed the strongest bactericidal activity with an MIC of 2 µg/mL. The selectivity index of compound 4 is more than 10, indicating that the compound has low toxicity to animal cells and has the potential to become a drug. Molecular docking indicates that compound 4 can bind firmly to the Mtb KatG active site. The experimental results showed that compound 4 inhibited Mtb KatG and caused the accumulation of ROS in Mtb cells. We speculate that compound 4 causes the accumulation of ROS by inhibiting KatG, and ROS produces oxidative destruction, leading to the death of Mtb. This study provides a new idea for the development of novel anti-Mtb drugs.

Performance-enhanced regenerated cellulose film by adding grape seed extract.

Eco-friendly packaging material with intelligent colorimetric performance has been a requirement for food safety and quality. This work focused on a food packaging material from regenerated cellulose films that added the grape seed extract (GSE) and polyethylene glycol 200 (PEG). FTIR and SEM techniques were employed to prove the compatibility of GSE with cellulose matrix. The composite film showed an enhanced elongation at break (16.61 %) and tensile strength (33.09 MPa). The addition of PEG and GSE also improved the water contact angle of regenerated-cellulose film from 53.8° to 83.8°. Moreover, the composite films exhibited UV-blocking properties while maintaining adequate transparency. The GSE induced the regenerated films with a macroscopic change in color under different pH conditions. Furthermore, the loading of GSE slowed down the decomposition of strawberries and delayed the self-biodegradation compared with the control for more than 3 days and 18 days. The present study showed a regenerated cellulose film with acceptable mechanical and hydrophilia properties, pH-responsiveness, anti-decomposition, and delayed biodegradation performances, indicating a potential color sensor in food packaging.

Antimycobacterial Compound of Cynoglossum lanceolatum Forsk.: Bioassay Guided Isolation, Molecular Docking, Synthesis of Analogs, and a Plausible Mechanism of Action.

Tuberculosis (TB) remains a major threat to human health. Due to the prevalence of drug-resistant Mycobacterium tuberculosis (Mtb), it is urgent to discover drugs with new mechanisms of action (MOA) to ensure effectiveness against strains that are resistant to existing TB drugs. Cynoglossum lanceolatum Forsk was used to treat TB in Traditional Chinese Medicine. In this article, shikonin, the anti-Mtb active component, was obtained from the whole herb extract of C. lanceolatum by bioassay-guided isolation. Using the microplate alamar blue assay (MABA), the minimum inhibitory concentration (MIC) of shikonin against Mtb was determined to be 128 µg/mL. In order to obtain a more efficient anti-Mtb molecule, (E)-1-(6-bromo-2,3-dihydrochromen-4-ylidene)thiosemicarbazide was synthesized based on the scaffold of shikonin, which exhibited potent activity against Mtb (MIC=4 µg/mL). These results highlight that both naphthalene-1,4-dione and chroman-4-one are pharmacophores with activities against Mtb. To investigate a plausible mechanism of action, the molecular docking was firstly performed against catalase-peroxidase enzyme (KatG) of Mtb using AutoDock 4 software. The results demonstrated that both shikonin and (E)-1-(6-bromo-2,3-dihydrochromen-4-ylidene)thiosemicarbazide could bind to the active site of Mtb KatG. KatG enzyme activity and intracellular reactive oxygen species (ROS) levels in Mtb cells were then measured by ultraviolet spectrophotometric method and fluorescence microplate reader assay, respectively. The experiments confirmed that above compounds could inhibit the catalytic activity of Mtb KatG, and cause the ROS accumulation in Mtb cells. Therefore, inhibition of KatG may be a novel mechanism of action for these two compounds to fight against Mtb.

Bacteriophages allow selective depletion of gut bacteria to produce a targeted-bacterium-depleted mouse model.

The gut microbiome is essential for human health. Mouse microbiota models, including gnotobiotic mice, are the most prominent tools to elucidate the functions of gut bacteria. Here, we propose a targeted-bacterium-depleted (TBD) model using lytic bacteriophage to selectively deplete gut bacterium of healthy or otherwise defined mice. These phage-treated animals should have a near-complete spectrum of gut bacteria except for the depleted bacterium. To prove the concept, we employed Escherichia coli-specific phage T7 to repress E. coli in the healthy mice. Our results showed that the E. coli-depleted mice exhibited bravery-like behaviors, correlated to the presence of E. coli rather than the equilibrium among gut bacteria. Thus, we demonstrate that the TBD model is a powerful tool to elucidate the function of a specific bacterial species within a near-intact gut microbiota environment and complements gnotobiotic mice models.

New Approach to Low-Power-Consumption, High-Performance Photodetectors Enabled by Nanowire Source-Gated Transistors.

Power consumption makes next-generation large-scale photodetection challenging. In this work, the source-gated transistor (SGT) is adopted first as a photodetector, demonstrating the expected low power consumption and high photodetection performance. The SGT is constructed by the functional sulfur-rich shelled GeS nanowire (NW) and low-function metal, displaying a low saturated voltage of 0.61 V ± 0.29 V and an extremely low power consumption of 7.06 pW. When the as-constructed NW SGT is used as a photodetector, the maximum value of the power consumption is as low as 11.96 nW, which is far below that of the reported phototransistors working in the saturated region. Furthermore, benefiting from the adopted SGT device, the photodetector shows a high photovoltage of 6.6 × 10-1 V, a responsivity of 7.86 × 1012 V W-1, and a detectivity of 5.87 × 1013 Jones. Obviously, the low power consumption and excellent responsivity and detectivity enabled by NW SGT promise a new approach to next-generation, high-performance photodetection technology.

Flexible Omnidirectional Self-Powered Photodetectors Enabled by Solution-Processed Two-Dimensional Layered PbI2 Nanoplates.

Realizing omnidirectional self-powered photodetectors is central to advancing next-generation portable and smart photodetector systems. However, the traditional omnidirectional photodetector is typically achieved by integrating complex hemispherical microlens on multiple photodetectors, which makes the detection system cumbersome and restricts its application in the portable field. Here, facile and high-performance flexible omnidirectional self-powered photodetectors are achieved by solution-processed two-dimensional (2D) layered PbI2 nanoplates on transparent conducting substrates. Characterization of PbI2 nanoplates microstructural/compositional and their photodetection properties have been systematically characterized. Under the irradiation of a 405 nm laser, the photodetectors exhibit an impressively low dark current of 10-13 A, a high light on/off ratio up to 106, and a fast rise/decay response time of 2/3 ms. Importantly, when light irradiates the photodetector at 5°, it can still maintain high photodetection properties, realizing almost 360° omnidirectional self-powered photodetection. What is more, these self-powered photodetectors exhibit robust omnidirectional photoresponse stability of flexibility even after bending for 1200 cycles. Thus, this work broadens the applicability of 2D layered nanoplates for further extending its applications in advanced optoelectronic devices.

Increased Rapid Eye Movement Sleep Is Associated With a Reduced Risk of Heart Failure in Middle-Aged and Older Adults.

Objectives: Rapid eye movement (REM) sleep is closely related to all-cause mortality. The aim of this study is to explore the role of REM sleep on the incident heart failure (HF). Methods: We selected 4490 participants (2480 women and 2010 men; mean age, 63.2 ± 11.0 years) from the Sleep Heart Health Study. HF was identified as the first occurrence during a mean follow-up period of 10.9 years. REM sleep including percentage of REM sleep and total REM sleep time were monitored using in-home polysomnography at baseline. Multivariable Cox regression analysis was utilized to explore the relationship between REM sleep and HF. Results: In total, 436 (9.7%) cases of HF were observed during the entire follow-up period. After adjusting for potential covariates, an increased percentage of REM sleep (per 5%) was independently associated with a reduced incidence of HF [hazard ratio (HR) 0.88, 95% confidence interval (CI) 0.82-0.94, P < 0.001]. A similar result was also found between total REM sleep time (increased per 5 min) and incident HF (HR 0.97, 95% CI 0.95-0.99, P < 0.001). Moreover, the fourth quartile of both percentage of REM sleep (HR 0.65, 95% CI 0.48-0.88, P = 0.005) and total REM sleep time (HR 0.64, 95% CI 0.45-0.90, P = 0.010) had lower risk of incident HF when compared with the first quartile. Conclusion: An increased percentage of REM sleep and total REM sleep time were associated with a reduced risk of HF. REM sleep may be a predictor of the incident HF. Clinical Trial Registration: [ClinicalTrials.gov], identifier [NCT00005275].