Integrated metabolomic and transcriptomic analyses provide insights into regulation mechanisms during bulbous stem development in the Chinese medicinal herb plant, Stephania kwangsiensis.

BACKGROUND: Stephania kwangsiensis Lo (Menispermaceae) is a well-known Chinese herbal medicine, and its bulbous stems are used medicinally. The storage stem of S. kwangsiensis originated from the hypocotyls. To date, there are no reports on the growth and development of S. kwangsiensis storage stems. RESULTS: The bulbous stem of S. kwangsiensis, the starch diameter was larger at the stable expanding stage (S3T) than at the unexpanded stage (S1T) or the rapidly expanding stage (S2T) at the three different time points. We used ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and Illumina sequencing to identify key genes involved in bulbous stem development. A large number of differentially accumulated metabolites (DAMs) and differentially expressed genes (DEGs) were identified. Based on the differential expression profiles of the metabolites, alkaloids, lipids, and phenolic acids were the top three differentially expressed classes. Compared with S2T, significant changes in plant signal transduction and isoquinoline alkaloid biosynthesis pathways occurred at both the transcriptional and metabolic levels in S1T. In S2T compared with S3T, several metabolites involved in tyrosine metabolism were decreased. Temporal analysis of S1T to S3T indicated the downregulation of phenylpropanoid biosynthesis, including lignin biosynthesis. The annotation of key pathways showed an up-down trend for genes and metabolites involved in isoquinoline alkaloid biosynthesis, whereas phenylpropanoid biosynthesis was not completely consistent. CONCLUSIONS: Downregulation of the phenylpropanoid biosynthesis pathway may be the result of carbon flow into alkaloid synthesis and storage of lipids and starch during the development of S. kwangsiensis bulbous stems. A decrease in the number of metabolites involved in tyrosine metabolism may also lead to a decrease in the upstream substrates of phenylpropane biosynthesis. Downregulation of lignin synthesis during phenylpropanoid biosynthesis may loosen restrictions on bulbous stem expansion. This study provides the first comprehensive analysis of the metabolome and transcriptome profiles of S. kwangsiensis bulbous stems. These data provide guidance for the cultivation, breeding, and harvesting of S. kwangsiensis.

Low­dose venetoclax combined with azacitidine in older and frail patients with newly diagnosed acute myeloid leukaemia.

In the present study, the aim was to evaluate the clinical efficacy and safety of low-dose venetoclax combined with azacitidine for the treatment of older and frail patients with newly diagnosed acute myeloid leukaemia (AML). Data of 26 older patients with newly diagnosed AML admitted to Yuyao People's Hospital (Yuyao, China) between January 2021 and May 2023 were retrospectively analysed. The treatment regimens were as follows: Subcutaneous injection of 100 mg azacitidine on days 1-5 and 100 mg oral venetoclax on days 3-16 or 200 mg oral venetoclax on days 3-30. The median age of the 26 patients was 73 years. After the first course of treatment, the complete remission (CR) and CR with incomplete haematological recovery rate was 84.6%, and the objective response rate was 96.2%. The most common adverse events noted during treatment were haematological adverse events including grade 3/4 granulocytosis (57.7%), febrile neutropenia (30.8%), pulmonary infection (32.0%), thrombocytopenia (42.3%) and anaemia (42.3%). A total of 13 (50.0%) patients did not require platelet (PLT) infusion during treatment. The main non-haematological adverse reactions included gastrointestinal reactions such as nausea, vomiting and diarrhoea. Patients were followed up until December 2023, with a median follow-up time of 9.5 months (range, 1.9-26.0 months). Of the 26 patients, nine (34.6%) patients experienced relapse, with a mean recurrence time of 5.9 months. In conclusion, preliminary results indicated that low-dose venetoclax combined with azacitidine is effective and safe for the treatment of older and frail patients with newly diagnosed AML, providing a new treatment option for these patients.

[Exploration of the theory of Renying Cunkou pulse method recorded in the Yellow Emperor's Inner Canon].

Renying Cunkou pulse method is one of the classical pulse methods of acupuncture-moxibustion in the Yellow Emperor's Inner Canon, which is also a classical clinical paradigm for diagnosing and treating meridian diseases in the ancient times. Based on comprehensive review of literature and clinical practice, this paper reveals that this method compares the size of the neck Renying pulse with hand Cunkou pulse to determine the change of yin-yang and excess-deficiency identifying the affected meridians. The jing-well, xing-spring, and shu-stream points of the surface and interior meridians of affected meridians are mainly selected to regulate deficiency and excess through reinforcing and reducing methods. The Renying Cunkou pulse method possesses a simple and practical medical theory, easy diagnostic procedure, and clear meridian selection for acupuncture-moxibustion treatment, warranting further exploration of its essence and diagnostic therapeutic principles.

CdSe/TiO2NTs Heterojunction-Based Nonenzymatic Photoelectrochemical Sensor for Glucose Detection.

Compared with a single semiconductor, the heterojunction formed by two different semiconductors usually has higher light utilization and better photoelectric performance. By using stable TiO2 nanotubes as the main subject, CdSe/TiO2NTs heterojunctions were synthesized by a hydrothermal method. XRD, TEM, SEM, PL, UV-vis, and EIS were used to characterize the fabricated CdSe/TiO2NTs. Under visible light irradiation, CdSe/TiO2NTs heterojunctions exhibited a higher absorption intensity and lower degree of photogenerated carrier recombination than TiO2. The electrons and holes were proven to be effectively separated in this heterojunction via theoretical calculation. Under CdSe/TiO2NTs' optimal conditions, the glucose concentrations (10-90 µM) had a linear relationship with the photocurrent value, and the detection limit was 3.1 µM. Moreover, the CdSe/TiO2NTs sensor exhibited good selectivity and stability. Based on the experimental data and theoretical calculations, its PEC sensing mechanism was also illuminated.

Inverse Design of Nanophotonic Devices Using Generative Adversarial Networks with the Sim-NN Model and Self-Attention Mechanism.

The inverse design method based on a generative adversarial network (GAN) combined with a simulation neural network (sim-NN) and the self-attention mechanism is proposed in order to improve the efficiency of GAN for designing nanophotonic devices. The sim-NN can guide the model to produce more accurate device designs via the spectrum comparison, whereas the self-attention mechanism can help to extract detailed features of the spectrum by exploring their global interconnections. The nanopatterned power splitter with a 2 µm × 2 µm interference region is designed as an example to obtain the average high transmission (>94%) and low back-reflection (<0.5%) over the broad wavelength range of 1200~1650 nm. As compared to other models, this method can produce larger proportions of high figure-of-merit devices with various desired power-splitting ratios.

Inhibition of translation termination by the antimicrobial peptide Drosocin.

The proline-rich antimicrobial peptide (PrAMP) Drosocin (Dro) from fruit flies shows sequence similarity to other PrAMPs that bind to the ribosome and inhibit protein synthesis by varying mechanisms. The target and mechanism of action of Dro, however, remain unknown. Here we show that Dro arrests ribosomes at stop codons, probably sequestering class 1 release factors associated with the ribosome. This mode of action is comparable to that of apidaecin (Api) from honeybees, making Dro the second member of the type II PrAMP class. Nonetheless, analysis of a comprehensive library of endogenously expressed Dro mutants shows that the interactions of Dro and Api with the target are markedly distinct. While only a few C-terminal amino acids of Api are critical for binding, the interaction of Dro with the ribosome relies on multiple amino acid residues distributed throughout the PrAMP. Single-residue substitutions can substantially enhance the on-target activity of Dro.

Highly Efficient and Chemoselective Tandem Hydroformylation-Hydrogenation of Alkenes to Alcohols over g-CN Supported Bimetallic Rh and Co Nanoparticles Catalysts.

The objective of the tandem hydroformylation-hydrogenation of alkenes to corresponding alcohols was to design an efficient and stable heterogeneous catalyst. To this end, a series of novel heterogeneous graphitic carbon nitride (g-CN) supported bimetallic Rh-Co nanoparticle catalysts (Rh-Co/g-CN) were prepared and subsequently studied for this one-pot two-step reaction. The lamellar structure makes Rh and Co nanoparticles with diameters of <1 nm and 20 nm, respectively, homogeneously deposited on the surface of g-CN layers, exhibit remarkable conversion of styrene (99.9 %) and chemoselectivity for alcohol (87.8 %). More importantly, Co nanoparticles are found to play an important role in the improvement of the chemoselectivity for alcohol due to the formation of catalytic active species [HCo(CO)y ]. Besides the detailed investigation of the catalytic properties of Rh-Co/g-CN under different reaction conditions, the reuse of Rh-Co/g-CN was conducted for five times and no evident decrease in the activity and chemoselectivity was observed. Therefore, we expect that this work could offer an initial insight into g-CN-based heterogeneous catalyst on the tandem hydroformylation-hydrogenation reaction.

Influence of workplace stress and social support on humanistic caring ability in Chinese nurses.

AIM: This study aimed to examine the relationships between how workplace stress and social support affect the level of humanistic caring ability in Chinese nurses. DESIGN: A cross-sectional study. METHODS: The sample consists of 675 nurses working in major hospitals in China. Participants completed a set of self-reported measures, including the humanistic caring ability scale (HCAS), the Chinese nurse workplace stressor scale (CNWSS), the Chinese nurse stress response scale (CNSRS), and the Chinese nurse social support scale (CNSSS). Pearson's correlation analysis and structural equation modelling (SEM) were performed to investigate the relationships among studied variables. RESULTS: The result showed that HCAS was negatively correlated with CNWSS (r = -0.427, p < 0.01) and CNSRS (r = -0.480, p < 0.01), and was positively correlated with CNSSS (r = 0.363, p < 0.01). Furthermore, a final model was conducted in which CNWSS has a strong direct effect on CNSRS (ß = 0.54, p < 0.01) and an indirect effect on HCAS (ß = -0.138, p < 0.01), which was mediated by CNSRS and CNSSS.

A Laccase Gene Reporting System That Enables Genetic Manipulations in a Brown Rot Wood Decomposer Fungus Gloeophyllum trabeum.

Brown rot fungi are primary decomposers of wood and litter in northern forests. Relative to other microbes, these fungi have evolved distinct mechanisms that rapidly depolymerize and metabolize cellulose and hemicellulose without digesting the more recalcitrant lignin. Its efficient degradative system has therefore attracted considerable attention for the development of sustainable biomass conversion technologies. However, there has been a significant lack of genetic tools in brown rot species by which to manipulate genes for both mechanistic studies and engineering applications. To advance brown rot genetic studies, we provided a gene-reporting system that can facilitate genetic manipulations in a model fungus Gloeophyllum trabeum. We first optimized a transformation procedure in G. trabeum, and then transformed the fungus into a constitutive laccase producer with a well-studied white rot laccases gene (from Trametes versicolor). With this, we built a gene reporting system based on laccase gene's expression and its rapid assay using an 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) indicator dye. The laccase reporter system was validated robust enough to allow us to test the effects of donor DNA's formats, protoplast viability, and gene regulatory elements on transformation efficiencies. Going forward, we anticipate the toolset provided in this work would expedite phenotyping studies and genetic engineering of brown rot species. IMPORTANCE One of the most ubiquitous types of decomposers in nature, brown rot fungi, has lacked robust genetic tools by which to manipulate genes and understand its biology. Brown rot fungi are primary decomposers in northern forests helping recycle the encased carbons in trees back to ecosystem. Relative to other microbes, these fungi employ distinctive mechanisms to disrupt and consume the lignified polysaccharides in wood. Its decay mechanism allows fast, selective carbohydrate catabolization, but without digesting lignin-a barren component that produces least energy trade back for fungal metabolisms. Thus, its efficient degradative system provides a great platform for developing sustainable biotechnologies for biomass conversions. However, progress has been hampered by the lack genetic tools facilitating mechanistic studies and engineering applications. Here, the laccase reporter system provides a genetic toolset for genetic manipulations in brown rot species, which we expect would advance relevant genetic studies for discovering and harnessing the unique fungal degradative mechanisms.

KCNQ1OT1 mediates keratinocyte migration to promote skin wound healing through the miR-200b-3p/SERP1 axis.

BACKGROUND: The basic functions of keratinocyte are crucial steps during skin wound healing. KCNQ1OT1 long noncoding RNA was found to accelerate the migration and proliferation of keratinocyte in psoriasis. Here, we elucidated the action and mechanism of KCNQ1OT1 in skin wound healing. METHODS: Expression levels of genes and proteins were evaluated by quantitative real-time PCR (qRT-PCR) and western blotting. Cell migration was assessed by using scratch and transwell assays. The interaction between miR-200b-3p and KCNQ1OT1 or SERP1 (Stress Associated Endoplasmic Reticulum Protein 1) was confirmed by bioinformatics analysis, dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay and pull-down assay. RESULTS: KCNQ1OT1 had increased significantly in wound edge 1 day and 7 day after injury. Functionally, overexpression of KCNQ1OT1 promoted keratinocyte migration. Mechanistically, KCNQ1OT1/miR-200b-3p/SERP1 constituted a competing endogenous RNA (ceRNA) network in keratinocytes. A series of rescue experiments showed that miR-200b-3p up-regulation in keratinocytes attenuated the pro-migration action of KCNQ1OT1 in cells. Moreover, knockdown of miR-200b-3p could promote keratinocyte migration, which was abolished by SERP1 silencing. KCNQ1OT1 competitively sponged for miR-200b-3p to elevate the expression of its target SERP1. CONCLUSION: KCNQ1OT1 could promote keratinocyte migration by miR-200b-3p/SERP1 axis, suggesting that KCNQ1OT1 might play a crucial role in skin wound healing.

Investigating the shared genetic architecture between hypothyroidism and rheumatoid arthritis.

Background: There is still controversy regarding the relationship between hypothyroidism and rheumatoid arthritis (RA), and there has been a dearth of studies on this association. The purpose of our study was to explore the shared genetic architecture between hypothyroidism and RA. Methods: Using public genome-wide association studies summary statistics of hypothyroidism and RA, we explored shared genetics between hypothyroidism and RA using linkage disequilibrium score regression, ρ-HESS, Pleiotropic analysis under a composite null hypothesis (PLACO), colocalization analysis, Multi-Trait Analysis of GWAS (MTAG), and transcriptome-wide association study (TWAS), and investigated causal associations using Mendelian randomization (MR). Results: We found a positive genetic association between hypothyroidism and RA, particularly in local genomic regions. Mendelian randomization analysis suggested a potential causal association of hypothyroidism with RA. Incorporating gene expression data, we observed that the genetic associations between hypothyroidism and RA were enriched in various tissues, including the spleen, lung, small intestine, adipose visceral, and blood. A comprehensive approach integrating PLACO, Bayesian colocalization analysis, MTAG, and TWAS, we successfully identified TYK2, IL2RA, and IRF5 as shared risk genes for both hypothyroidism and RA. Conclusions: Our investigation unveiled a shared genetic architecture between these two diseases, providing novel insights into the underlying biological mechanisms and establishing a foundation for more effective interventions.

Novel insights into aerobic duration control-based partial nitritation in source-separated blackwater treatment: Growth type, inoculation source, and comammox threat.

Aerobic duration control (ADC), whereby aeration is terminated before nitrite is extremely oxidized during the nitrification process, is an effective strategy to achieve partial nitritation (PN) for blackwater. This study evaluated the effects of microbial growth type, influent ammonia-oxidizing organisms (AOO), and comammox bacteria from seeding sludge to ADC-based PN. The long-term operation of lab-scale reactors and model simulations were implemented to select the best growth type. The biofilm formed on the inner wall of the activated sludge reactor decreased the nitrite accumulation ratio (NAR) from 99.2% to 77.2%. Meanwhile, the NAR of the pure-biofilm reactor decreased from 95.9% to 47.8%. The deteriorated PN of the biofilm-related reactors was due to the extended solid retention time and increased substrate saturation constants of AOOs compared with those of nitrite-oxidizing organisms (NOO). Periodic biofilm carrier regeneration and biofilm thickness control can recover PN performance but are difficult to implement. In contrast, the optimized activated sludge reactor exhibited high (NAR >94%) and stable (>3 months) PN performance when treating real blackwater. Nitrifiers were found in blackwater, and chemically enhanced high-rate activated sludge pretreatment removed more NOOs than AOOs (41.8% vs. 24.3%) and increased the influent AOO/NOO ratio. Interestingly, the influent AOOs supported fast PN start-up in the moving-bed biofilm reactor without the initial inoculation of activated sludge. Moreover, model simulations verified that high and stable PN could also be realized in an activated sludge reactor by the continuous inoculation of influent AOOs, which is a novel PN start-up strategy. Metagenomic analyses showed that the comammox bacteria from the seeding sludge eventually disappeared owing to their intrinsic specific growth rates and free ammonia inhibition. The findings of this study will provide insightful guidelines for PN application in decentralized and semi-centralized wastewater treatment systems.

PRRX1/FOXM1 reduces gemcitabin-induced cytotoxicity by regulating autophagy in bladder cancer.

Background: Bladder cancer (BC) is a common urological malignancy with high mortality worldwide. Many proteins can influence tumorigenesis by participating in cellular processes. Recently, abundant evidence has illustrated that paired related homeobox 1 (PRRX1) is closely related to the progression and development of human cancers. However, the function of PRRX1 in BC remains poorly understood. The aim of our study is to explore the role of PRRX1 in BC progression. Methods: The expression of genes (PRRX1, FOXM1, LC3B, and Beclin-1) was examined through real-time quantitative polymerase chain reaction (RT-qPCR) and western blot. The expression of proteins (PRRX1, FOXM1, LC3B, and Beclin-1) was measured through immunohistochemistry. Cell viability and the half-maximal inhibitory concentration were detected using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay. Cell apoptosis was assessed through flow cytometry. Autophagy was tested by GFP-LC3 immunofluorescence assay. Tumors were grown in nude mice in vivo, and the tumor size, volume, and weight were evaluated. Results: In our study, PRRX1 was highly expressed in BC tissues and cells, and high PRRX1 expression resulted in poor overall survival in patients with BC. PRRX1 accelerated the viability and hindered the apoptosis of BC cells. It also weakened gemcitabine-induced cytotoxicity and strengthened gemcitabine-induced autophagy. PRRX1 was found to cooperate with forkhead box protein M1 (FOXM1) to influence downstream genes, and FOXM1 was found to regulate Beclin-1 and microtubule-associated protein 1 light chain 3 (LC3) genes to influence autophagy. PRRX1 up-regulated the expression of LC3 and Beclin-1 by cooperating with FOXM1. In rescue assays, FOXM1 reversed the effects of PRRX1 on gemcitabine-induced cytotoxicity and autophagy. Knockdown of PRRX1 enhanced the inhibitive effects of gemcitabine on tumor growth in vivo. Conclusions: PRRX1 reduces gemcitabine-induced cytotoxicity in BC cells by regulating the expression of the autophagy proteins LC3 and Beclin-1. This discovery suggests that PRRX1 may be a useful therapeutic biomarker for BC.

Sall4 Guides p53-Mediated Enhancer Interference upon DNA Damage in Mouse Embryonic Stem Cells.

p53 plays a pivotal role in maintaining the genomic stability of mouse embryonic stem cells (mESCs) through transcriptionally activating and repressing target genes. However, how p53 recognizes its repressed targets remains largely unknown. Herein, we demonstrate that Sall4 negatively regulates DNA damage induced apoptosis (DIA) of mESCs through mediating p53 recruitment to enhancers of ESC-associated genes repressed by p53 from promoters of p53-activated genes. Upon DNA damage, Sall4 is transcriptionally repressed by p53 and plays an anti-apoptotic role without altering p53 activation. Moreover, Sall4 is identified as a novel p53-interacting partner. Consistently, Sall4 exerts its anti-apoptotic function in a p53-dependent manner. Intriguingly, Sall4 depletion not only promotes the transcriptional activation of several p53-regulated pro-apoptotic genes but also compromises p53-mediated repression of ESC master transcription factors in response to DNA damage. Mechanistically, Sall4 balances p53-binding affinity between p53-activated and -repressed genes through tethering p53 to ESC enhancers. In light of our study, Sall4 may contribute to tumorigenesis by antagonizing p53-mediated apoptosis.

Job-related stress associated with work-related upper extremity musculoskeletal disorders (UEMDs) in municipal waste collectors: the moderation and mediation effect of job support.

BACKGROUND: Since the policy of "keeping trash off of the ground" in Taiwan, long-term exposure to repetitive motion in waste collection process results in high risk of upper extremity musculoskeletal disorders (UEMDs). Thus, we assessed the moderation and mediation effects of job-related stress and job support on work-related UEMDs among municipal waste collectors. METHODS: A cross-sectional study was conducted in two cities located at northern Taiwan during 2018-2019. 626 municipal waste collectors voluntarily participated and anonymously filled out a structured questionnaire. The moderation and mediation effects of effort-reward imbalance (ERI) and social support on UEMDs were analyzed by Haye's Process Macro Model. RESULTS: Prevalence of UEMDs in municipal waste collectors were 43.4% for neck, 56.0% for shoulder, 24.1% for upper back, and 33.1% for hand/wrist. There was high prevalence of shoulder (72.2%), neck (48%), and upper back (30%) in female workers compared to male, most significantly in shoulders. In univariate and multivariate analysis, high ERI and low job support were significantly associated with ORs of 3.11 (95% CI:1.58-6.13) for elbow, 2.79 (95% CI:1.39-5.56) for shoulder, 3.39 (95% CI:1.64-7.00) for upper back and 3.83 (95% CI:1.98-7.41) for hand/wrist. Prevalent UEMDs were positively associated with high ERI in municipal waste collectors but negatively with job support. The moderation effects of ERI and job support on UEMDs, of which the measured synergy index exceeded one, were 18.24 for shoulder, 3.32 for elbow, and 2.45 for hand/wrist, but mediation effects were not significant. CONCLUSIONS: This study found municipal waste collectors with work-related upper extremity disorders were significantly associated with work-related psychological risk factors. Therefore, waste collection cannot only to be improved by semi-automatic and automatic processes but immediate intervention programs for the reduction of psychological risk factors is needed promptly.

Amine-Functionalized Natural Halloysite Nanotubes Supported Metallic (Pd, Au, Ag) Nanoparticles and Their Catalytic Performance for Dehydrogenation of Formic Acid.

In today's age of resource scarcity, the low-cost development and utilization of renewable energy, e.g., hydrogen energy, have attracted much attention in the world. In this work, cheap natural halloysite nanotubes (HNTs) were modified with γ-aminopropyltriethoxysilane (APTES), and the functionalized HNTs were used as to support metal (Pd, Au, Ag) catalysts for dehydrogenation of formic acid (DFA). The supports and fabricated catalysts were characterized with ICP, FT-IR, XRD, XPS and TEM. The functional groups facilitate the anchoring of metal particles to the supports, which brings about the high dispersion of metallic particles in catalysts. The catalysts show high activity against DFA and exhibit selectivity of 100% toward H2 at room temperature or less. The interactions between active centers and supports were investigated by evaluation and comparison of the catalytic performances of Pd/NH2-HNTs, PdAg/NH2-HNTs and PdAu/NH2-HNTs for DFA.

Surface Plasmon-Enhanced Photoelectrochemical Sensor Based on Au Modified TiO2 Nanotubes.

Based on the enhanced charge separation efficiency of the one-dimensional structure and strong surface plasmon resonance (SPR) of gold, a gold modified TiO2 nanotube (Au/TiO2NTs) glucose photoelectrochemical (PEC) sensor was prepared. It could be activated by visible red light (625 nm). Under optimal conditions, the Au/TiO2NTs sensor exhibited a good sensitivity of 170.37 µA·mM-1·cm-2 in the range of 1-90 µM (R2 = 0.9993), and a detection limit of 1.3 µM (S/N = 3). Due to its high selectivity, good anti-interference ability, and long-term stability, the fabricated Au/TiO2NTs sensor provides practical detection of glucose. It is expected to be used in the construction of non-invasive PEC biosensors.

hUC-MSC-mediated recovery of subacute spinal cord injury through enhancing the pivotal subunits ß3 and γ2 of the GABAA receptor.

Rationale: Spinal cord injury (SCI) remains an incurable neurological disorder leading to permanent and profound neurologic deficits and disabilities. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) are particularly appealing in SCI treatment to curtail damage, restore homeostasis and possible neural relay. However, the detailed mechanisms underlying hUC-MSC-mediated functional recovery of SCI have not been fully elucidated. The purpose of our current study is to identify novel therapeutic targets and depict the molecular mechanisms underlying the hUC-MSC-mediated recovery of subacute SCI. Methods: Adult female rats suffering from subacute incomplete thoracic SCI were treated with intrathecal transplantation of hUC-MSCs. The beneficial effects of hUC-MSCs on SCI repair were evaluated by a series of behavioral analyses, motor evoked potentials (MEPs) recording of hindlimb and immunohistochemistry. We carried out extensive transcriptome comparative analyses of spinal cord tissues at the lesion site from the subacute phase of SCI (sub-SCI) either treated without (+PBS) or with hUC-MSCs (+MSC) at 0 (sub-SCI), 1, 2, and 4 weeks post-transplantation (wpt), as well as normal spinal cord segments of intact/sham rats (Intact). Adeno-associated virus (AAV)-mediated neuron-specific expression system was employed to functionally screen specific γ-aminobutyric acid type A receptor (GABAAR) subunits promoting the functional recovery of SCI in vivo. The mature cortical axon scrape assay and transplantation of genetically modified MSCs with either overexpression or knockdown of brain-derived neurotrophic factor (BDNF) were employed to demonstrate that hUC-MSCs ameliorated the reduction of GABAAR subunits in the injured spinal cord via BDNF secretion in vitro and in vivo, respectively. Results: Comparative transcriptome analysis revealed the GABAergic synapse pathway is significantly enriched as a main target of hUC-MSC-activated genes in the injured spinal cord. Functional screening of the primary GABAAR subunits uncovered that Gabrb3 and Garbg2 harbored the motor and electrophysiological recovery-promoting competence. Moreover, targeting either of the two pivotal subunits ß3 or γ2 in combination with/without the K+/Cl- cotransporter 2 (KCC2) reinforced the therapeutic effects. Mechanistically, BDNF secreted by hUC-MSCs contributed to the upregulation of GABAAR subunits (ß3 & γ2) and KCC2 in the injured neurons. Conclusions: Our study identifies a novel mode for hUC-MSC-mediated locomotor recovery of SCI through synergistic upregulation of GABAAR ß3 and γ2 along with KCC2 by BDNF secretion, indicating the significance of restoring the excitation/inhibition balance in the injured neurons for the reestablishment of neuronal circuits. This study also provides a potential combinatorial approach by targeting the pivotal subunit ß3 or γ2 and KCC2, opening up possibilities for efficacious drug design.

Mapping and Ablation of Isolated Frequent Symptomatic Premature Atrial Contractions in Patients With Structurally Normal Heart.

Background: The present study investigated the safety and efficacy of mapping and ablating isolated premature atrial contractions (PACs) in patients with a structurally normal heart, as well as whether the elimination of PACs by radiofrequency catheter ablation (RFCA) improved symptoms and the quality of life. Methods: Forty-three consecutive patients with frequent, symptomatic, and drug-refractory PACs, but without atrial tachyarrhythmias (≥5 beats), were enrolled. In all patients, we performed physical, laboratory, and imaging examinations to exclude structural heart disease. The quality of life questionnaire SF-36 before and 3 months after RFCA was performed in each patient. Results: Twenty-three men and 20 women with an average age of 52.6 ± 17.6 years were finally enrolled. The mean number of PACs was 21,685 ± 9,596 per 24 h, and the mean PACs' burden was 28.9 ± 13.7%. Short runs of tachycardia (<5 atrial beats) were observed in 32 patients (74.4%). All patients underwent successful RFCA without complications. The activation time at the successful ablation sites preceded the onset of the P-wave by 36 ± 7.6 ms. During 15 ± 8 months of follow-up, the recurrence of PACs was observed in 2 patients. The 24-h PAC burden was significantly reduced 3 months after RFCA (mean 0.5%, p < 0.05). The quality of life scores were significantly increased 3 months after RFCA (all p < 0.05). Conclusions: RFCA was feasible, safe, and effective to eliminate isolated frequent, symptomatic, and drug-refractory PACs in patients with a structurally normal heart. The elimination of PACs by RFCA significantly improved symptoms and the quality of life.

Modeling and analysis of narrow-linewidth distributed feedback lasers based on apodized laterally coupled gratings.

A physical model is demonstrated to optimize narrow-linewidth distributed feedback lasers based on apodized laterally coupled gratings (AG-DFB). The structure can effectively suppress the longitudinal spatial hole burning as well as remove the regrowth process during fabrication by using the apodized grating geometry. The studies include numerical simulations of the AG-DFB laser for its static and dynamic behaviors at different cavity lengths and facet coating conditions. The results show that the proposed device can achieve narrow linewidth, high slope efficiency, and broad modulation bandwidth, as compared to λ/4 phase-shifted DFB lasers.