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Abstract Explore whether the axillary outcomes differ among HER2 positive subgroups receiving standard dual-targeted therapy, aiming to identify subgroups exhibiting enhanced sensitivity to NAT among HER2-positive/node-positive breast cancer patients. HER2 positive female patients with biopsy-proven node-positive disease from April 2020 to May 2023 were included. All patients underwent standard Neoadjuvant HER2-targeted dual therapy and axillary lymph node dissection (ALND) at Breast Surgery Center of Sichuan Cancer Hospital. Univariate and multivariate analyses were used to identify factors associate with axillary pathological complete response (ApCR). Statistical analysis and graphing were performed using SPSS 24.0 and GraphPad Prism 9.0 software. This study enrolled 215 HER2 positive patients with a total ApCR rate of 76.7%, which included 49 HER2 2+/FISH + and 166 HER2 3 + cases with approximate ApCR rates of 63.3% and 80.7% (P = 0.011). Univariate and multivariate analysis indicated that HER2 3 + disease (OR = 2.43, 95% CI 1.21–4.88, P = 0.012), Ki-67 ≥ 20% disease (OR = 3.00, 95% CI 1.26–7.13, P = 0.013) and NAC regimen of TCb (OR = 2.71, 95% CI 1.39–5.38, P = 0.004) were more likely to achieve ApCR. Further subgroup analysis revealed that HER2 3 + patients receiving TCb regimen showed the highest ApCR rate of 88% compared to other subgroups. HER2 3 + breast cancer had a higher ApCR rate than HER2 2+/FISH + breast cancer during Neoadjuvant HER2-targeted dual therapy. HER2 positive patients could benefit from NAC regimen of TCb in axillary response.

Abstract Granulation is an ancient and sophisticated decorative technique. The production of granules is a crucial part of this process but has rarely been studied. The present study employed three techniques—pouring method, heating method, and crucible method—to produce gold granules. The success ratio of granule formation, granule surface morphology, microstructure, and formation were analyzed to identify the techniques used in archaeological objects. The cooling medium significantly influenced small granule formation, microstructure, and grain size. Both heating and crucible methods could control the granule formation, but these methods produced distinct microstructures. Based on these experimental granules, the probable production methods of ancient gold balls were identified. The present study provided microscopic information for determining ancient gold granule production techniques.

Abstract Background Esophageal carcinoma (EC) and gastric cardiac adenocarcinoma (GCA) have high incidence rates in the Chaoshan region of South China. Multifocal esophageal and cardiac cancer (MECC) is commonly observed in this region in clinical practice. However, the genomic characteristics of MECC remains unclear. Materials and methods In this study, a total of 2123 clinical samples of EC and GCA were analyzed to determine the frequency of multifocal tumors, as well as their occurrence sites and pathological types. Cox proportional hazards regression was used to model the relationship between age, sex, and tumor state concerning survival in our analysis of the cohort of 541 patients with available follow-up data. We performed whole-genome sequencing on 20 tumor foci and 10 normal samples from 10 MECC patients to infer clonal structure on 6 MECC patients to explore genome characteristics. Result The MECC rate of EC and GCA was 5.65% (121 of 2123). Age and sex were potential factors that may influence the risk of MECC (p

Introduction: Lipid metabolism dysfunction is widely involved in the pathological process of acute ischemic stroke (AIS). The coordination of lipid metabolism between neurons and astrocytes is of great significance. However, the full scope of lipid dynamic changes and the function of key lipids during AIS remain unknown. Hence, identifying lipid alterations and characterizing their key roles in AIS is of great importance. Methods: Untargeted and targeted lipidomic analyses were applied to profile lipid changes in the ischemic penumbra and peripheral blood of transient middle cerebral artery occlusion (tMCAO) mice as well as the peripheral blood of AIS patients. Infarct volume and neurological deficits were assessed after tMCAO. The cell viability and dendritic complexity of primary neurons were evaluated by CCK8 assay and Sholl analysis. Seahorse, MitoTracker Green, tetramethyl rhodamine methyl ester (TMRM), 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) and MitoSOX were used as markers of mitochondrial health. Fluorescent and isotopic free fatty acid (FFA) pulse-chase assays were used to track FFA flux in astrocytes. Results: Long-chain acylcarnitines (LCACs) were the lipids with the most dramatic changes in the ischemic penumbra and peripheral blood of tMCAO mice. LCACs were significantly elevated on admission in AIS patients and associated with poor outcomes in AIS patients. Increasing LCACs through a bolus administration of palmitoylcarnitine amplified stroke injury, while decreasing LCACs by overexpressing carnitine palmitoyltransferase 2 (CPT2) ameliorated stroke injury. Palmitoylcarnitine aggravated astrocytic mitochondrial damage after OGD/R, while CPT2 overexpression in astrocytes ameliorated cocultured neuron viability. Further study revealed that astrocytes stimulated by OGD/R liberated FFAs from lipid droplets into mitochondria to form LCACs, resulting in mitochondrial damage and lowered astrocytic metabolic support and thereby aggravated neuronal damage. Conclusion: LCACs could accumulate and damage neurons by inducing astrocytic mitochondrial dysfunction in AIS. LCACs play a crucial role in the pathology of AIS and are novel promising diagnostic and prognostic biomarkers for AIS.

Objectives Currently, there is no consensus on the optimal timing for the initiation of peritoneal dialysis (PD) after catheter placement.Design Systematic review and meta-analysis.Exact date of data collection From inception till July 31, 2023.Main outcome measures To assess the outcomes and safety of unplanned PD initiation (

BackgroundOccupational stress and job satisfaction significantly impact the well-being and performance of healthcare professionals, including radiologists. Understanding the complex interplay between these factors through network analysis can provide valuable insights into intervention strategies to enhance workplace satisfaction and productivity.MethodIn this study, a convenience sampling method was used to recruit 312 radiologists for participation. Data on socio-demographic characteristics, job satisfaction measured by the Minnesota job satisfaction questionnaire revised short version (MJSQ-RSV), and occupational stress assessed using the occupational stress scale. Network analysis was employed to analyze the data in this study.ResultsThe network analysis revealed intricate patterns of associations between occupational stress and job satisfaction symptoms among radiologists. Organizational management and occupational interests emerged as crucial nodes in the network, indicating strong relationships within these domains. Additionally, intrinsic satisfaction was identified as a central symptom with high connectivity in the network structure. The stability analysis demonstrated robustness in the network edges and centrality metrics, supporting the reliability of the findings.ConclusionThis study sheds light on the complex relationships between occupational stress and job satisfaction in radiologists, offering valuable insights for targeted interventions and support strategies to promote well-being and job satisfaction in healthcare settings.

Our examination of RNA helicases for effects on HIV-1 protein production and particle assembly identified Rocaglamide (RocA), a known modulator of eIF4A1 function, as an inhibitor of HIV-1 replication in primary CD4+ T cells and three cell systems. HIV-1 attenuation by low-nM RocA doses was associated with reduced viral particle formation without a marked decrease in Gag production. Rather, the co-localization of Gag and HIV-1 genomic RNA (gRNA) assemblies was impaired by RocA treatment in a reversible fashion. Ribonucleoprotein (RNP) immunoprecipitation studies recapitulated the loss of Gag-gRNA assemblies upon RocA treatment. Parallel biophysical studies determined that neither RocA nor eIF4A1 independently affected the ability of Gag to interact with viral RNA, but together, they distorted the structure of the HIV-1 RNP visualized by electron microscopy. Taken together, several lines of evidence indicate that RocA induces stable binding of eIF4A1 onto the viral RNA genome in a manner that interferes with the ordered assembly of Gag along Gag-gRNA assemblies required to generate infectious virions.

The chemical industry is not only a crucial sector of national economy, but also a significant consumer of water resources and a major initiator of water pollution. The sustainable development of this sector is intricately linked to the regional water ecological carrying capacity (WECC). Based on SBM-DEA and Global Moran’s I, the green total factor productivity (GTFP) and spatial correlation characteristics of the chemical industry in 13 cities within China’s chemical agglomeration region in Jiangsu Province were estimated from 2015 to 2019. By combining the WECC results, the Tobit model was employed to reveal the driving factors of WECC in optimizing GTFP. The results indicated that the regional WECC in southern Jiangsu was increasing compared with that in northern Jiangsu, which promoted the growth of GTFP. WECC has been a positive radiation-driven effect since 2017, and the optimization of the various subsystems of WECC has had a different impact on GTFP. For the sustainable development of Jiangsu’s chemical industry, effective water resource policies should be formulated by the government, while enterprises need to pursue sustained structural adjustments.

The research on urban flood resilience will contribute to building a more resilient city and provide valuable reference for municipal decision-makers. There are many frameworks and approaches for empirical studies on what constitutes urban flood resilience and how to evaluate it. In this study, a typical region suffering from flood disaster in China-Jiangsu Province was selected as the study area, including 13 prefecture-level cities. The pressure-state-response (PSR) framework, the projection pursuit based on real-coded accelerated genetic algorithm (RAGA-PP) and the technique for order preference by similarity to an ideal solution based on the Kullback-Leibler distance (KL-TOPSIS) were combined to develop a hybrid multi-criteria approach for assessing urban flood resilience. Then the grey relational analysis obtained the important factors. The results illustrate that (1) the development of each subsystem in the city is uncoordinated, that is, the pressure-subsystem has little influence on urban flood resilience, while the state-subsystem and the response-subsystem have great influence. (2) The urban flood resilience in Jiangsu Province presents obvious polarization trend, that is, Southern Jiangsu is more resilient than Northern Jiangsu. The underlying factors are closely related to the level of economic development. Furthermore, the proposed method provides a practical evaluation approach for other fields. HIGHLIGHTS The PSR framework, RAGA-PP and KL-TOPSIS were combined to develop hybrid multi-criteria indices approach for assessing urban flood resilience.; The development of each subsystem in the city is uncoordinated.; Southern Jiangsu is more resilient than Northern Jiangsu.; The underlying factors affecting the urban flood resilience are closely related to the level of economic development.;

Abstract Background Very preterm infants often require mechanical ventilation. However, objective criteria to predict the outcomes of extubation in very premature neonates remain lacking. The aim of this study was to investigate the accuracy of the spontaneous breathing trial (SBT) using a combined model of continuous positive airway pressure (CPAP) and low-level pressure support ventilation (PSV) to predict the extubation outcomes of preterm infants with gestational age

Summary: Neutrophil aggregation and clearance are important factors affecting neuroinflammatory injury during acute ischemic stroke. Emerging evidence suggests that energy metabolism is essential for microglial functions, especially microglial phagocytosis, which determines the degree of brain injury. Here, we demonstrate that Resolvin D1 (RvD1), a lipid mediator derived from docosahexaenic acid (DHA), promotes the phagocytosis of neutrophils by microglia, thereby reducing neutrophil accumulation in the brain and alleviating neuroinflammation in the ischemic brain. Further studies reveal that RvD1 reprograms energy metabolism from glycolysis to oxidative phosphorylation (OXPHOS), providing sufficient energy for microglial phagocytosis. Moreover, RvD1 enhances microglial glutamine uptake and stimulates glutaminolysis to support OXPHOS to boost ATP production depending on adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) activation. Overall, our results reveal that RvD1 reprograms energy metabolism to promote the microglial phagocytosis of neutrophils after ischemic stroke. These findings may guide perspectives for stroke therapy from modulating microglial immunometabolism.

The brain-derived neurotrophic factor (BDNF) and its high-affinity receptor tropomyosin-related kinase receptor B (TrkB) are widely expressed in the central nervous system. It is well documented that neurons express BDNF and full-length TrkB (TrkB.FL) as well as a lower level of truncated TrkB (TrkB.T). However, there are conflicting reports regarding the expression of BDNF and TrkB in glial cells, particularly microglia. In this study, we employed a sensitive and reliable genetic method to characterize the expression of BDNF and TrkB in glial cells in the mouse brain. We utilized three Cre mouse strains in which Cre recombinase is expressed in the same cells as BDNF, TrkB.FL, or all TrkB isoforms, and crossed them to Cre-dependent reporter mice to label BDNF- or TrkB-expressing cells with soma-localized EGFP. We performed immunohistochemistry with glial cell markers to examine the expression of BDNF and TrkB in microglia, astrocytes, and oligodendrocytes. Surprisingly, we found no BDNF- or TrkB-expressing microglia in examined CNS regions, including the somatomotor cortex, hippocampal CA1, and spinal cord. Consistent with previous studies, most astrocytes only express TrkB.T in the hippocampus of adult brains. Moreover, there are a small number of astrocytes and oligodendrocytes that express BDNF in the hippocampus, the function of which is to be determined. We also found that oligodendrocyte precursor cells, but not mature oligodendrocytes, express both TrkB.FL and TrkB.T in the hippocampus of adult mice. These results not only clarify the expression of BDNF and TrkB in glial cells but also open opportunities to investigate previously unidentified roles of BDNF and TrkB in astrocytes and oligodendrocytes.

Abstract Adenoid cystic carcinoma (AdCC) of the breast is a rare indolent carcinoma of salivary gland-type tumors, frequently associated with MYB genetic alteration. Solid and basaloid adenoid cystic carcinoma (SB-AdCC) is considered a sparse variant of AdCC. This study sought to search for clinicopathological and genomic features in SB-AdCC. Registered clinicopathological data on a cohort of 13 AdCC of the breast cases, including six conventional adenoid cystic carcinoma (C-AdCC) cases and seven SB-AdCC cases, were collected. MYB gene rearrangement via fluorescent in situ hybridization was investigated and MYB protein expression was evaluated by immunohistochemistry. Compared with C-AdCC, we found that the distribution of SB-AdCC cases were shifted to older age and were more frequently distant metastasis. Moreover, metastasis cases also showed a high (exceed 30%) Ki-67 index. Both groups showed MYB rearrangements and MYB protein expression, but they were less frequent in SB-AdCC than C-AdCC. To conclude, our results suggest that SB-AdCC is an aggressive variant of mammary AdCC with a higher incidence of distant metastases compared with C-AdCC, though they share common molecular features. A high Ki-67 index may be an adverse prognostic factor for metastasis.

The mechanism of sphingosine-1-phosphate (S1P)-mediated phagocytosis remains unknown. Here, we found that S1P or FTY720 (an analog of S1P) promoted microglial phagocytosis in stroke independent of S1PRs. First, we used computer simulation of molecular docking to predict that S1P might be a ligand for triggering receptor expressed on myeloid cells 2 (TREM2). Next, microscale thermophoresis (MST), surface plasmon resonance (SPR) and liquid chromatography–tandem mass spectrometry (LC–MS/MS) were performed to reveal that S1P was a novel TREM2 ligand. Then, we confirmed the pro-phagocytosis of S1P targeting in Trem2-Dap12 transfected CHO cells and TREM2 knockdown microglia. Point mutation analysis showed that D104 was the critical binding residue. Trem2−/− mice were used to demonstrate the role of S1P-induced phagocytosis targeting on TREM2 in protecting against ischemic brain injury. Finally, further studies revealed that apolipoprotein E (APOE) loaded with S1P was released by microglia and bound to apoptotic neurons via LDL receptor related protein 1B (LRP1B) and thereby induced microglia to phagocytose apoptotic neurons. Overall, the present work reveals for the first time that S1P acts as a novel endogenous ligand of TREM2 to effectively promote microglial phagocytosis. Our findings provide a new lead compound for developing immunomodulator targeting on TREM2.

Abstract Aim To investigate the effect of implementing a model for continuous quality improvement in the nutritional management of patients with nasopharyngeal carcinoma (NPC) treated with radiotherapy. Design methods In the intervention group (n = 77), a model for the continuous quality improvement of efforts at nutrition management was implemented. These efforts included the development of a new process for nutrition management, a system to provide nutritional support and the use of targeted intervention plans to improve nutrition. The time from diagnosis to the administration of radiation therapy, the severity of oral mucositis and dietary factors were recorded and considered in the development of targeted nutrition intervention and nutrition education. The control group (n = 71) followed the original procedures for nutrition management. Results The study found that the CQI model can decrease the severity of oral mucositis caused by radiation and improve nutritional status in affected patients.

Abstract Background Previous studies report that lipopolysaccharide (LPS)-preconditioned mesenchymal stem cells have enhanced trophic support and improved regenerative and repair properties. Extracellular vesicles secreted by synovial mesenchymal stem cells (EVs) can reduce cartilage damage caused by osteoarthritis (OA). Previous studies show that extracellular vesicles secreted by LPS-preconditioned synovial mesenchymal stem cells (LPS-pre EVs) can improve the response to treatment of osteoarthritis (OA). This study sought to explore effects of LPS-pre EVs on chondrocyte proliferation, migration, and chondrocyte apoptosis, as well as the protective effect of LPS-pre EVs on mouse articular cartilage. Methods Chondrocytes were extracted to explore the effect of LPS-pre EVs on proliferation, migration, and apoptosis of chondrocytes. In addition, the effect of LPS-pre EVs on expression level of important proteins of chondrocytes was explored suing in vitro experiments. Further, intraarticular injection of LPS-pre EVs was performed on the destabilization of the medial meniscus (DMM)-induced mouse models of OA to explore the therapeutic effect of LPS-pre EVs on osteoarthritis in vivo. Results Analysis showed that LPS-pre EVs significantly promoted proliferation and migration of chondrocytes and inhibited the apoptosis of chondrocytes compared with PBS and EVs. Moreover, LPS-pre EVs inhibited decrease of aggrecan and COL2A1 and increase of ADAMTS5 caused by IL-1β through let-7b. Furthermore, LPS-pre EVs significantly prevented development of OA in DMM-induced mouse models of OA. Conclusions LPS pretreatment is an effective and promising method to improve therapeutic effect of extracellular vesicles secreted from SMSCs on OA.

Several direct-acting antivirals (DAAs) are available, providing interferon-free strategies for a hepatitis C cure. In contrast to DAAs, host-targeting agents (HTAs) interfere with host cellular factors that are essential in the viral replication cycle; as host genes, they are less likely to rapidly mutate under drug pressure, thus potentially exhibiting a high barrier to resistance, in addition to distinct mechanisms of action. We compared the effects of cyclosporin A (CsA), a HTA that targets cyclophilin A (CypA), to DAAs, including inhibitors of nonstructural protein 5A (NS5A), NS3/4A, and NS5B, in Huh7.5.1 cells. Our data show that CsA suppressed HCV infection as rapidly as the fastest-acting DAAs. CsA and inhibitors of NS5A and NS3/4A, but not of NS5B, suppressed the production and release of infectious HCV particles. Intriguingly, while CsA rapidly suppressed infectious extracellular virus levels, it had no significant effect on the intracellular infectious virus, suggesting that, unlike the DAAs tested here, it may block a post-assembly step in the viral replication cycle. Hence, our findings shed light on the biological processes involved in HCV replication and the role of CypA.

Abstract Extracellular vesicles (EVs), as a novel intercellular communication carrier transferring cargo microRNAs (miRNAs), could play important roles in the brain remodeling process after ischemic stroke. However, the detailed mechanisms involved in EVs derived miRNAs-mediated cellular interactions in the brain remain unclear. Several studies indicated that microRNA-98 (miR-98) might participate in the pathogenesis of ischemic stroke. Here, we showed that expression of miR-98 in penumbra field kept up on the first day but dropped sharply on the 3rd day after ischemic stroke in rats, indicating that miR-98 could function as an endogenous protective factor post-ischemia. Overexpression of miR-98 targeted inhibiting platelet activating factor receptor-mediated microglial phagocytosis to attenuate neuronal death. Furthermore, we showed that neurons transferred miR-98 to microglia via EVs secretion after ischemic stroke, to prevent the stress-but-viable neurons from microglial phagocytosis. Therefore, we reveal that EVs derived miR-98 act as an intercellular signal mediating neurons and microglia communication during the brain remodeling after ischemic stroke. The present work provides a novel insight into the roles of EVs in the stroke pathogenesis and a new EVs-miRNAs-based therapeutic strategy for stroke.

The TrkB receptor is known to regulate obesity via appetite control, but the underlying neural circuits are not known. Here, the authors show that selective modulation of TrkB+ neurons in the paraventricular hypothalamus regulates food intake via circuits to ventromedial hypothalamus and lateral parabrachial nucleus.

The emergence of antibiotic resistance over the past several decades has given urgency to new antibacterial strategies that apply less selective pressure. A new class of anti-virulence compounds were developed that are active against methicillin-resistant Staphylococcus aureus (MRSA), by inhibiting bacterial virulence without hindering their growth to reduce the selective pressure for resistance development. One of the compounds CCG-211790 has demonstrated potent anti-biofilm activity against MRSA. This new class of anti-virulence compounds inhibited the gene expression of virulence factors involved in biofilm formation and disrupted the biofilm structures. In this study, the physicochemical properties of CCG-211790, including morphology, solubility in pure water or in water containing sodium dodecyl sulfate, solubility in organic solvents, and stability with respect to pH were investigated for the first time. Furthermore, a topical formulation was developed to enhance the therapeutic potential of the compound. The formulation demonstrated acceptable properties for drug release, viscosity, pH, cosmetic elegance and stability of over nine months.

Objective The aim of the study was to understand the experience of negative emotions and coping styles of patients with cervical cancer during the rehabilitation period. Methods A descriptive qualitative research method was used. Purposive sampling was used to recruit participants. Semi-structured interviews were conducted with 18 cervical cancer patients and the data were analysed using content analysis. Results The analysis identified three relevant themes. Theme 1: Negative emotions in convalescent cervical cancer patients mainly comprised fear of recurrence, worries about sex and feelings of inferiority. Theme 2: Patients used positive and negative coping styles to manage negative emotions. Theme 3: Patients expressed a strong need for rehabilitation information. Conclusions Patients with cervical cancer exhibited negative emotions during the rehabilitation period. To help these patients, medical staff should develop an understanding of their needs by communicating more with patients and providing them with targeted care to help them return to society more quickly.

Background: Glioblastoma (GBM) is one of the most malignant and aggressive primary brain tumors. The incurability of glioblastoma is heavily influenced by the glioma microenvironment. FTY720, a potent immunosuppressant, has been reported to exert anti-tumor effects in glioblastoma. However, the impact of FTY720 on the glioma microenvironment remains unclear.Methods: We examined the effects of FTY720 on the distribution and polarization of glioma-associated microglia and macrophages (GAMs) in glioma-bearing rats using immunofluorescence staining. qRT-PCR and Western blotting were used to detect the expressions of CXCR4 and MAPK pathway-related signal molecules on microglia in the coculture system. The levels of inflammatory factors were tested via ELISA. Wound healing assay and Matrigel invasion assay were used to determine the migration and invasion of C6 glioma cells.Results: We discovered that FTY720 could inhibit the growth, migration, and invasion of glioma by targeting GAMs to impede their effect on glioma cells. Simultaneously, FTY720 could block the chemoattraction of GAMs by inhibiting MAPK-mediated secretion of IL-6 through increased internalization of CXCR4. Moreover, microglia and macrophages are polarized from pro-glioma to an anti-tumor phenotype.Conclusion: These results provide novel insights into the inhibitory effects of FTY720 on glioma by targeting GAMs–glioma interaction in the tumor microenvironment.

Robot-assisted retinal cannulation is an eye surgical procedure which can dissolve the obstruction by using robot to inject anticoagulant into occluded vessel. The current research on the critical parameters of cannulation for human is scarce because of the immature technology. Considering the influence of microneedle, this work investigated the effects of drug concentration, injection velocity, injection position, and size of clot on cannulation by theoretical analysis and finite element analysis. For finite element analysis, the multiphysics continuum model was established to demonstrate species transport and reaction which simulates the entire lytic process of the occlusive clot, and four cell zones were established to describe the generation of plasmin (PLS) with the addition of tissue-type plasminogen activator (tPA) and fibrinolysis of clot by importing subroutines into each cell zone under the conditions of constant clot size and variable size, respectively. The results imply that the most efficient value of tPA concentration is 50 nM, injection velocity is 60 mm/s for clot length of 0.1 mm, and the best position to insert the cannula is 0.5 mm in front of the thrombus. For different clot lengths of 0.1 mm to 0.6 mm, the optimal range of tPA concentration and injection velocity is from 20 nM to 70 nM and from 40 mm/s to 60 mm/s, respectively, and explores the reasonable injection position of 0.3 mm to 0.5 mm in front of clot in a vein of 100 μm. This conclusion can be used to perform robot-assisted cannulation surgery to improve fibrinolytic efficiency.

Technical limitations in simultaneous microscopic visualization of HIV transcription from individual integration sites have curtailed progress in the field. Here the authors report a branched DNA in situ hybridization method for direct single-cell visualization of HIV DNA, RNA, and protein.

Background and objective: Cisplatin is an alkylating agent that has become a first-line therapy for some tumors. However, overproduction of reactive oxygen species (ROS) by cisplatin can cause male infertility, which can affect patients’ quality of life. Melatonin, which has the ability to provide resistance against oxidation, is a potential therapy for male infertility caused by cisplatin. Material and methods: Normal human spermatozoa samples were divided into (i) control group incubated with physiological saline solution; (ii) cisplatin group incubated with cisplatin; (iii) melatonin group incubated with melatonin; and (iv) melatonin + cisplatin group incubated with melatonin and cisplatin. Spermatozoa motility was measured using a computer-aided semen analysis system. Additionally, we determined spermatozoa apoptosis through terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling. The mitochondrial membrane potential (ΔΨm) and levels of ATP, ROS, and malondialdehyde, as a metabolite of oxidative stress, were measured to study the mechanism by which melatonin can protect human spermatozoa. Results: Melatonin improved sperm motility, and decreased apoptosis and increased the ΔΨm value and level of ATP in sperm. More importantly, the overproduction of ROS induced by cisplatin was reduced by melatonin. Furthermore, western blotting revealed that melatonin increased the expression of antioxidant pathway components nuclear factor erythroid 2-related factor (Nrf2) and heme oxygenase-1 (HO-1) that was reduced by cisplatin. Conclusion: Our studies suggested that melatonin might protect human spermatozoa against the effects of cisplatin through Nrf2/HO-1.

Therapeutic hypothermia is a promising strategy for acute cerebral ischemia via physical or pharmacological methods. In this study, we pharmacologically induced hypothermia on Sprague Dawley rats by intraperitoneally injecting PD149163. We found that mild hypothermia was induced by PD149163 treatment without local cerebral blood flow (LCBF) alteration. To evaluate the neuroprotective effects of PD149163, TTC staining, HE staining and Nissl's staining were performed in our study. We found that PD149163 could prevent neuronal damage, and inhibit proliferation and activation of glial cells induced by ischemia. Simultaneously, we observed PD149163 ameliorated apoptosis characterized by down-regulated caspase-3 and Bax, but elevated Bcl-2. Moreover, PD149163 dramatically reduced JNK and AMPK/mTOR signaling pathway activation, and thereby inhibited autophagy by increased P62 expression, decreased the ratio of LC3-Ⅱ to LC3-Ⅰ and the expression of Beclin. Taken together, the present findings reveal the therapeutic effects of PD149163-induced hypothermia in brain ischemia, and provide a new strategy for stroke treatment.

Abstract Background As an important outcome measure among rheumatoid arthritis (RA) patients, functional disability may contribute to unemployment, loss of work productivity, and impaired quality of life. However, little is known about the risk factors of functional disability in Chinese RA patients. This study aimed (1) to examine the prevalence of functional disability in Chinese RA patients; (2) to explore factors associated with the health assessment questionnaire-disability index (HAQ-DI). Methods A total of 101 RA patients in this cross-sectional study underwent standardized laboratory examinations and responded to the questionnaire for demographic data, the HAQ-DI for functional disability, the Compliance Questionnaire on Rheumatology (CQR) for medication adherence, the Hospital Anxiety and Depression Scale (HADS) for psychological status, and the Short Form 36 health survey (SF-36) for quality of life. Pain, grip/pinch strength, disease activity, and large joint mobility were recorded. Independent samples t-tests, chi-square analyses, and logistic regression modeling were used to analyze the data. Results The mean ± SD age of RA patients was 54.9 ± 11.9 years. Approximately 15.8% RA patients in mainland China experience functional disability (defined as a HAQ-DI score ≥ 1). Long disease duration, pain, high disease activity, a larger number of tender and swollen joints, high C-reactive protein (CRP) level, decreased grip strength, and limitation of shoulder, elbow, wrist, knee, and ankle motion were associated with the HAQ-DI. Participants with functional disability tended to have more severe depressive symptoms and a lower quality of life compared with individuals without functional disability. Stepwise logistic regression analyses found that limitation of wrist extension (P = 0.001) and lower body pain (BP) score (P = 0.001) explained higher HAQ-DI score. Conclusions The present study reported that functional disability was common in Chinese RA patients. A low quality of life and limitation of joint mobility had great impacts on functional disability in Chinese RA patients. Targeted and culturally sensitive interventions should be strengthened to delay the onset of disabilities of this population.

Sphingosine 1-phosphate (S1P) is involved in a variety of cellular responses including microglial activation and polarization. However, the impacts of S1P on ischemia-induced microglial activation and polarization remain unclear. In the present study, Sprague-Dawley rats were selected for middle cerebral artery occlusion (MCAO) establishment and treated with S1P analog FTY720 (0.5, 1, 2 mg/kg) for 24 h. The impacts of FTY720 on oxygen-glucose deprivation (OGD)-induced microglial polarization were examined in the primary cultured microglia. FTY720 treatment could prevent ischemia-induced brain injury and neurological dysfunction, also decrease the levels of IL-1β and TNF-α and promote M2 microglial polarization in rats. Further, we found that FTY720 inhibited the expressions of M1 markers, but increased the expressions of M2 markers in the OGD-insulted microglia. And FTY720 could enhance the phagocytic function of microglia. The sphingosine kinase 1/2 (SphK1/2) or the Sphk2 inhibitor could prevent the M1 to M2 phenotype shift improved by FTY720, but the Sphk1 inhibitor failed to affect the roles of FTY720. Furthermore, the Sphk1/2 or Sphk2 inhibitor promoted the activities of histone deacetylase (HDAC1) and inhibited the histone acetylation of the Krüppel-like factor 4 (KLF4) promoter regions, indicating that intra-nuclear pFTY720 inhibited HDAC1 activations and prevented KLF4 to interact with HDAC1, and thereby suppresses KLF4 deacetylation. Therefore, our data reveals that intra-nuclear SphK2-S1P axis might facilitate the transformation of microglial polarization from M1 to M2 phenotype, which might be intra-nuclear regulatory mechanisms of FTY720-prevented neuroinflammation.

The leading cause of death in systemic lupus erythematosus (SLE) patients is infection. The objective of this study was to evaluate the distribution of lymphocyte subsets in untreated SLE patients with infections. This was a cross-sectional study. Data from January 2017 to May 2018 were collected. Flow cytometry was used to measure the peripheral lymphocyte subsets including CD3+T cells, CD4+T cells, CD8+T cells, CD19+B cells, CD3-CD16+CD56NK cells, and CD3+CD16+CD56NKT cells in 25 healthy controls and 52 treatment-naive SLE patients, among whom 13 were complicated with infections. Association between the lymphocyte subsets and infections was further analyzed. SLE patients with infections (n=13) showed a significantly higher incidence rate of fever (84.6 vs 28.2%) and serositis (84.6 vs 23.1%), increased level of erythrocyte sedimentation rate (60.5±30.1 vs 37.4±27.1 mm/h), serum C-reactive protein (CRP) (102.7±94.9 vs 9.4±14.9 mg/L), procalcitonin (PCT) (1.07±0.08 vs 0.16±0.13 μg/L), and lower blood hemoglobin (Hb) (93.0±20.5 vs 110.4±16.0 g/L) level compared with non-infection patients (n=39) (all P

Ag3PO4/g-C3N4 heterojunctions, with different g-C3N4 dosages, were synthesized using an in situ deposition method, and the photocatalytic performance of g-C3N4/Ag3PO4 heterojunctions was studied under simulated sunlight conditions. The results revealed that Ag3PO4/g-C3N4 exhibited excellent photocatalytic degradation activity for rhodamine B (Rh B) and phenol under the same light conditions. When the dosage of g-C3N4 was 30%, the degradation rate of Rh B at 9 min and phenol at 30 min was found to be 99.4% and 97.3%, respectively. After five cycles of the degradation experiment for Rh B, g-C3N4/Ag3PO4 still demonstrated stable photodegradation characteristics. The significant improvement in the photocatalytic activity and stability of g-C3N4/Ag3PO4 was attributed to the rapid charge separation between g-C3N4 and Ag3PO4 during the Z-scheme charge transfer and recombination process.

ABSTRACT Heteroaryldihydropyrimidines (HAPs) are compounds that inhibit hepatitis B virus (HBV) replication by modulating viral capsid assembly. While their biophysical effects on capsid assembly in vitro have been previously studied, the effect of HAP treatment on capsid protein (Cp) in individual HBV-infected cells remains unknown. We report here that the HAP Bay 38-7690 promotes aggregation of recombinant Cp in vitro and causes a time- and dose-dependent decrease of Cp in infected cells, consistent with previously studied HAPs. Interestingly, immunofluorescence analysis showed Cp aggregating in nuclear foci of Bay 38-7690-treated infected cells in a time- and dose-dependent manner. We found these foci to be associated with promyelocytic leukemia (PML) nuclear bodies (NBs), which are structures that affect many cellular functions, including DNA damage response, transcription, apoptosis, and antiviral responses. Cp aggregation is not an artifact of the cell system used, as it is observed in HBV-expressing HepAD38 cells, in HepG2 cells transfected with an HBV-expressing plasmid, and in HepG2-NTCP cells infected with HBV. Use of a Cp overexpression vector without HBV sequences shows that aggregation is independent of viral replication, and use of an HBV-expressing plasmid harboring a HAP resistance mutation in Cp abrogated the aggregation, demonstrating that the effect is due to direct compound-Cp interactions. These studies provide novel insight into the effects of HAP-based treatment at a single-cell level. IMPORTANCE Despite the availability of effective vaccines and treatments, HBV remains a significant global health concern, with more than 240 million individuals chronically infected. Current treatments are highly effective at controlling viral replication and disease progression but rarely cure infections. Therefore, much emphasis is being placed on finding therapeutics with new drug targets, such as viral gene expression, covalently closed circular DNA formation and stability, capsid formation, and host immune modulators, with the ultimate goal of an HBV cure. Understanding the mechanisms by which novel antiviral agents act will be imperative for the development of curative HBV therapies.

There is increasing interest in the association between depression and the development of metabolic diseases. Rosiglitazone, a therapeutic drug used to treat type 2 diabetes mellitus, has shown neuroprotective effects in patients with stroke and Alzheimer’s disease. The present study was performed to evaluate the possible roles of rosiglitazone in in vivo (unpredictable chronic mild stress-induced depressive mouse model) and in vitro (corticosterone-induced cellular model) depressive models. The results showed that rosiglitazone reversed depressive behaviors in mice, as indicated by the forced swimming test and open field test. Rosiglitazone was also found to inhibit the inflammatory response, decrease corticosterone levels, and promote astrocyte proliferation and neuronal axon plasticity in the prefrontal cortex of mice. This series of in vivo and in vitro experiments showed that autophagy among neurons was inhibited in depressive models and that rosiglitazone promoted autophagy by upregulating LKB1, which exerted neuroprotective effects. Rosiglitazone was also found to activate the Akt/CREB pathway by increasing IGF-1R expression and IGF-1 protein levels, thereby playing an anti-apoptotic role in astrocytes. Rosiglitazone’s autophagy promotion and neuroprotective effects were found to be reversed by the PPARγ antagonist T0070907 in primary neurons and by PPARγ knockdown in an N2a cell line. In conclusion, we found that rosiglitazone protects both neurons and astrocytes in in vivo and in vitro depressive models, thereby playing an anti-depressive role. These findings suggest that PPARγ could be a new target in the development of anti-depressive drugs.

This study aimed to explore an evidence-based nursing practice model of CRF management in hospitalized adult patients using the PARIHS evidence-implementation framework as the theoretical structure to provide guidance for similar nursing practices. The implementation of guideline evidence into clinical practice was conducted on the oncology and radiotherapy wards of a university-affiliated hospital. The process of integrating the guideline into the symptom management system of cancer patients was described. The impact of the evidence implementation was evaluated from three aspects: organizational innovations and outcome measures associated with nurses and with patients pre- and post-evidence implementation. During the implementation of evidence into practice on the wards, a nursing process, health education, a quality control sheet and CRF training courses were established. Through this implementation, compliance with evidence related to CRF increased significantly on the two wards, with that of ward B being higher than that of ward A. Regarding nursing outcomes, nursing knowledge, attitude and behavior scores with respect to CRF nursing care increased substantially after its application on the two wards, and the ward B nurses' scoring was higher than that of the ward A nurses. Qualitative analysis concerning the nurses suggested that leadership, patient concern about CRF management, and the need for professional development were the main motivators of the application, whereas the shortage and mobility of nursing human resources and insufficient communication between doctors and nurses were the main barriers. Additionally, most nurses felt more professional and confident about their work. Regarding patient outcomes, patient knowledge, attitude and behavior scores regarding CRF self-management increased significantly. Patients' post-implementation CRF was alleviated compared with the pre-implementation treatment cycle. The PARIHS framework may provide instructive guidance for the incorporation of evidence into practice, and the process-oriented framework might provide greater operational utility of the application.

Huntington's disease (HD) is a neurodegenerative disorder caused by CAG repeat expansion within exon1 of the HTT gene. The gene generates two mRNA variants that carry either a short or long 3' untranslated region (3'UTR) while encoding the same protein. It remains unknown whether the two mRNA variants play distinct roles in HD pathogenesis. We found that the long HTT 3'UTR was capable of guiding mRNA to neuronal dendrites, suggesting that some long-form HTT mRNA is transported to dendrites for local protein synthesis. To assay roles of two HTT mRNA variants in cell bodies, we expressed mRNA harboring HTT exon1 containing 23x or 145x CAGs with the short or long 3'UTR. We found that mutant mRNA containing the short 3'UTR produced more protein aggregates and caused more apoptosis in both cultured neurons and HEK293 cells, compared with mutant mRNA containing the long 3'UTR. Although the two 3'UTRs did not affect mRNA stability, we detected higher levels of protein synthesis from mRNA containing the short 3'UTR than from mRNA containing the long 3'UTR. These results indicate that the long HTT 3'UTR suppresses translation. Thus, short-form mutant HTT mRNA will be more efficient in producing toxic protein than its long-form counterpart.

RNA viruses are highly successful pathogens and are the causative agents for many important diseases. To fully understand the replication of these viruses it is necessary to address the roles of both positive-strand RNA ((+)RNA) and negative-strand RNA ((−)RNA), and their interplay with viral and host proteins. Here we used branched DNA (bDNA) fluorescence in situ hybridization (FISH) to stain both the abundant (+)RNA and the far less abundant (−)RNA in both hepatitis C virus (HCV)- and Zika virus-infected cells, and combined these analyses with visualization of viral proteins through confocal imaging. We were able to phenotypically examine HCV-infected cells in the presence of uninfected cells and revealed the effect of direct-acting antivirals on HCV (+)RNA, (−)RNA, and protein, within hours of commencing treatment. Herein, we demonstrate that bDNA FISH is a powerful tool for the study of RNA viruses that can provide insights into drug efficacy and mechanism of action.