Multidimensional analysis of cortical interneuron synaptic features reveals underlying synaptic heterogeneity.

Cortical interneurons represent a diverse set of neuronal subtypes characterized in part by their striking degree of synaptic specificity. However, little is known about the extent of synaptic diversity because of the lack of unbiased methods to extract synaptic features among interneuron subtypes. Here, we develop an approach to aggregate image features from fluorescent confocal images of interneuron synapses and their post-synaptic targets, in order to characterize the heterogeneity of synapses at fine scale. We started by training a model that recognizes pre- and post-synaptic compartments and then determines the target of each genetically-identified interneuron synapse in vitro and in vivo. Our model extracts hundreds of spatial and intensity features from each analyzed synapse, constructing a multidimensional data set, consisting of millions of synapses, which allowed us to perform an unsupervised analysis on this dataset, uncovering novel synaptic subgroups. The subgroups were spatially distributed in a highly structured manner that revealed the local underlying topology of the postsynaptic environment. Dendrite-targeting subgroups were clustered onto subdomains of the dendrite along the proximal to distal axis. Soma-targeting subgroups were enriched onto different postsynaptic cell types. We also find that the two main subclasses of interneurons, basket cells and somatostatin interneurons, utilize distinct strategies to enact inhibitory coverage. Thus, our analysis of multidimensional synaptic features establishes a conceptual framework for studying interneuron synaptic diversity.

Intermittent hypoxic pretreatment exacerbates house dust mite-induced asthma airway inflammation.

BACKGROUND: Asthma is widely recognized as an inflammatory disorder. In the context of this inflammatory microenvironment, the involvement of hypoxia and its impact on related pathways have drawn considerable attention. However, the exact role of hypoxia, a prevalent environmental factor, in the development and progression of asthma remains poorly understood. METHODS: Mice were treated with house dust mite (HDM) extracts for 23 days to induce asthma. Mice were divided into room air (RA) group and intermittent hypoxic (IH) group by exposing to different conditions and IH preconditioning (IHP) were underwent to the above groups before the hypoxic regimen. Airway inflammation in mice was evaluated by airway hyperresponsiveness, excessive mucus secretion, and recruitment of inflammatory cells. Immunohistochemistry was employed to quantify the expression levels of NF-κB. Subsequently, the dose of allergen was modified to investigate whether the impact of hypoxia on asthma is affected by different doses of allergens. RESULT: Compared to the RA and IH groups, HDM-treated mice in the IHP group exhibited aggravated inflammatory cell infiltration and airway hyperresponsiveness (p＜.05). Moreover, there was an increased release of inflammatory mediators and higher expression levels of NF-κB (p＜.05). Importantly, the impact ia on asthma was found to be influenced by high dose of allergen (p＜.05). CONCLUSION: IHP treatment potentially exacerbates HDM-induced airway inflammation in asthma, with the involvement of NF-κB, particularly under high-dose allergen stimulation.

The Understanding and Compact Modeling of Reliability in Modern Metal-Oxide-Semiconductor Field-Effect Transistors: From Single-Mode to Mixed-Mode Mechanisms.

With the technological scaling of metal-oxide-semiconductor field-effect transistors (MOSFETs) and the scarcity of circuit design margins, the characteristics of device reliability have garnered widespread attention. Traditional single-mode reliability mechanisms and modeling are less sufficient to meet the demands of resilient circuit designs. Mixed-mode reliability mechanisms and modeling have become a focal point of future designs for reliability. This paper reviews the mechanisms and compact aging models of mixed-mode reliability. The mechanism and modeling method of mixed-mode reliability are discussed, including hot carrier degradation (HCD) with self-heating effect, mixed-mode aging of HCD and Bias Temperature Instability (BTI), off-state degradation (OSD), on-state time-dependent dielectric breakdown (TDDB), and metal electromigration (EM). The impact of alternating HCD-BTI stress conditions is also discussed. The results indicate that single-mode reliability analysis is insufficient for predicting the lifetime of advanced technology and circuits and provides guidance for future mixed-mode reliability analysis and modeling.

Compact Physics Hot-Carrier Degradation Model Valid over a Wide Bias Range.

We develop a compact physics model for hot-carrier degradation (HCD) that is valid over a wide range of gate and drain voltages (Vgs and Vds, respectively). Special attention is paid to the contribution of secondary carriers (generated by impact ionization) to HCD, which was shown to be significant under stress conditions with low Vgs and relatively high Vds. Implementation of this contribution is based on refined modeling of carrier transport for both primary and secondary carriers. To validate the model, we employ foundry-quality n-channel transistors and a broad range of stress voltages {Vgs,Vds}.

Facile Route to Achieve a Hierarchical CuO/Nickel-Cobalt-Sulfide Electrode for Energy Storage.

Herein, a novel self-supporting CuO/nickel-cobalt-sulfide (NCS) electrode was designed in a two-step electrodeposition technique followed by a calcination process. Three-dimensional copper foam (CF) was exploited as the current collector and spontaneous source for the in situ preparation of the CuO nanostructures, which ensured sufficient deposition space for the subsequent NCS layer, thus forming abundant electrochemical active sites. Such a hierarchical structure is conducive to providing a smooth path for promoting electronic transmission. Therefore, the optimized CuO/NCS electrode exhibits outstanding energy storage capability with extremely superior specific capacitance (Cs) of 7.08 F cm-2 at 4 mA cm-2 and coulombic efficiency of up to 94.83%, as well as excellent cycling stability with capacitance retention of 83.33% after 5000 cycles. The results presented in this work extend our horizons to fabricate novel hierarchical structured electrodes applied to energy storage devices.

A Coupling Mechanism between Flicker Noise and Hot Carrier Degradations in FinFETs.

A coupling mechanism between flicker noise and hot carrier degradation (HCD) is revealed in this work. Predicting the flicker noise properties of fresh and aged devices is becoming essential for circuit designs, requiring an understanding of the fundamental noise behaviors. While certain models for fresh devices have been proposed, those for aged devices have not been reported yet because of the lack of a clear mechanism. The flicker noise of aged FinFETs is characterized based on the measure-stress-measure (MSM) method and analyzed from the device physics. It is found that both the mean and deviations of the noise power spectral density increase compared with the fresh counterparts. A coupling mechanism is proposed to explain the trap time constants, leading to the trap characterizations in their energy profiles. The amplitude and number of contributing traps are also changing and are dependent on the mode of HCD and determined by the position of the induced traps. A microscopic picture is developed from the perspective of trap coupling, reproducing well the measured noise of advanced nanoscale FinFETs. The finding is important for accurate flicker noise calculations and aging-aware circuit designs.

Understanding the Effect of Top Electrode on Ferroelectricity in Atomic Layer Deposited Hf0.5Zr0.5O2 Thin Films.

It is commonly believed that the impact of the top electrodes on the ferroelectricity of hafnium-based thin films is due to strain engineering. However, several anomalies have occurred that put existing theories in doubt. This work carries out a detailed study of this issue using both theoretical and experimental approaches. The 10 nm Hf0.5Zr0.5O2 (HZO) films are prepared by atomic layer deposition, and three different top capping electrodes (W/MO/ITO) are deposited by physical vapor deposition. The electrical testing finds that the strain does not completely control the ferroelectricity of the devices. The results of further piezoelectric force microscopy characterization exclude the potential interference of the top capping electrodes and interface for electrical testing. In addition, through atomic force microscopy characterization and statistical analysis, a strong correlation between the grain size of the top electrode and the grain size of the HZO film has been found, suggesting that the grain size of the top electrode can induce the formation of the grain size in HZO thin films. Finally, the first-principles calculation is carried out to understand the impact of the strain and grain size on the ferroelectric properties of HZO films. The results show that the strain is the dominant factor for ferroelectricity when the grain size is large (>10 nm). However, when the grain size becomes thinner (<10 nm), the regulation effect of grain sizes increases significantly, which could bring a series of benefits for device scaling, such as device-to-device variations, film uniformity, and domain switch consistency. This work not only completes the understanding of ferroelectricity through top electrode modulation but also provides strong support for the precise regulation of ferroelectricity of nanoscale devices and ultrathin HZO ferroelectric films.

Safety and efficacy of unilateral and bilateral pedicle screw fixation for lumbar degenerative diseases by transforaminal lumbar interbody fusion: An updated systematic review and meta-analysis.

Background: The purpose of this study was to compare the safety and efficacy of unilateral vs. bilateral pedicle screw fixation (BPSF) for lumbar degenerative diseases. Methods: Electronic databases including PubMed, Web of science, the Cochrane Library, Scopus, MEDLINE, EMBASE, EBSCO were searched by computer. The deadline was set for June 1, 2022. This study included all high-quality randomized controlled trials (RCTs), prospective clinical controlled studies (PRO), and retrospective studies (Retro) that compared unilateral and bilateral pedicle screw fixation in the treatment of lumbar degenerative diseases. Revman5.3 software was used for meta-analysis after two researchers independently screened the literature, extracted data, and assessed the risk of bias in the study. Results: Fourteen studies with a total of 1,086 patients were included. Compared with BPSF, unilateral pedicle screw fixation (UPSF) has shorter operation time and hospital time, and less blood loss and operation cost, operation time [SMD = -1.75, 95% CI (-2.46 to -1.03), P < 0.00001], hospital time [SMD = -1.10, 95% CI (-1.97 to -0.22), P = 0.01], Blood loss [SMD = -1.62, 95% CI (-2.42 to -0.82), P < 0.0001], operation cost [SMD = -14.03, 95% CI (-20.08 to -7.98), P < 0.00001], the ODI after bilateral pedicle screw fixation was lower, and the degree of lumbar dysfunction was lighter, [SMD = 0.19, 95% CI (0.05-0.33), P = 0.007], better fusion effect, fusion rate [RR=0.95, 95% CI (0.91-1.00), P = 0.04]. VAS-Low back pain [SMD = 0.07, 95% CI (-0.07-0.20), P = 0.35], VAS-Leg pain [SMD = 0.18, 95% CI (-0.00-0.36), P = 0.05], SF-36 [SMD = 0.00, 95% CI (-0.30-0.30), P = 1.00], complications rate [RR = 0.94, 95% CI (0.9154-1.63), P = 0.82], the overall difference was not statistically significant. Conclusions: Currently limited evidence suggests that UPSF significantly reduces blood loss, significantly shortens the operative time and hospital stay, and reduces blood loss and costs. After BPSF, the ODI was lower, the degree of lumbar spine dysfunction was lower, and the fusion rate was significantly higher. The VAS, SF-36, and complications scores of the two groups were comparable, and there was no significant clinical difference.

Gout increases length of stay in patients hospitalized for heart failure exacerbation.

Background: It is unclear whether patients with a history of gout have longer hospitalizations in general, or only when suffering a flare. This study examines the effect of gout diagnosis and gout flare on the length of stay (LoS) in patients admitted for heart failure (HF) exacerbation. Methods: We conducted a matched retrospective cohort study and searched electronic medical records for patients admitted for HF with a prior diagnosis of gout from 1 July 2012 to 30 June 2017 and matched them to patients admitted for HF without gout. Cases who had a gout flare during the admission were identified. The log of the length of stay (log LoS) was utilized for normalization of the data. We used a linear mixed-effect model to compare the adjusted LoS of gout patient with flare, gout patient without flare, and controls. Results: A total of 978 admissions for HF exacerbation in 738 patients, including 246 individual with gout and 492 matched controls, were identified and included in the analysis. The log LoS was significantly longer in cases (1.86 ± 0.95) compared with controls (1.72 ± 0.94; p = 0.0278). The log LoS was significantly longer in those with gout who flared (2.41 ± 0.96) compared to those without gout (1.72 ± 0.94, p < 0.0001). After adjusting for potential confounders, the log LoS of patients who flared (p < 0.0001) remained significantly longer than controls, as well as those who did not flare (p = 0.042), but to a lesser extent. Conclusion: HF patients with gout had significantly longer hospitalizations than those without gout, a finding driven primarily by gout flare during hospitalization.

Receptor-Interacting Protein Kinase 3 Suppresses Mitophagy Activation via the Yes-Associated Protein/Transcription Factor EB Pathways in Septic Cardiomyopathy.

Mitophagy, known as the main mechanism of mitochondrial quality control, determines the pathophysiology of septic cardiomyopathy, although the precise regulatory mechanisms remain elusive. Data from the present study suggested that receptor-interacting protein kinase 3 (RIPK3) expression could be enhanced in response to lipopolysaccharide (LPS) challenge. Upregulated RIPK3 expression was accompanied by severe cardiac injury and cardiac dysfunction. Further examination revealed that elevated RIPK3 expression subsequently inhibited the Yes-associated protein (YAP) pathway, which was accompanied by reduced transcription factor EB (TFEB) expression. Inhibition of TFEB would reduce mitophagy, which ultimately induced cardiomyocyte death under LPS challenge. In contrast, loss of RIPK3 induced the YAP/TFEB/mitophagy pathway alleviated the sensitivity of cardiomyocytes to LPS-induced cytotoxicity. Collectively, the RIPK3/YAP/TFEB axis was confirmed to be responsible for the pathogenesis of septic cardiomyopathy by inhibiting mitophagy. These findings have potential significance for the progression of new approaches to the treatment of septic cardiomyopathy.

Dynamic expression of Schlafen 11 (SLFN11) in circulating tumour cells as a liquid biomarker in small cell lung cancer.

INTRODUCTION: Small cell lung cancer (SCLC) is an aggressive malignancy with no established biomarkers. Schlafen 11(SLFN11), a DNA/RNA helicase that sensitises cancer cells to DNA-damaging agents, has emerged as a promising predictive biomarker for several drug classes including platinum and PARP inhibitors. Detection of SLFN11 in circulating tumour cells (CTCs) may provide a valuable alternative to tissue sampling. METHODS: SLFN11 expression was evaluated in tumour samples and characterised in circulating tumour cells (CTC) longitudinally to determine its potential role as a biomarker of response. RESULTS: Among 196 SCLC tumours, 51% expressed SLFN11 by IHC. In addition, 20/29 extra-thoracic high-grade neuroendocrine tumours expressed SLFN11 expression. In 64 blood samples from 42 SCLC patients, 83% (53/64) of samples had detectable CTCs, and SLFN11-positive CTCs were detected in 55% (29/53). Patients actively receiving platinum treatment had the lowest number of CTCs and a lower percentage of SLFN11-positive CTCs (p = 0.014). Analysis from patients with longitudinal samples suggest a decrease in CTC number and in SLFN11 expression that correlates with clinical response. CONCLUSIONS: SLFN11 levels can be monitored in CTCs from SCLC patients using non-invasive liquid biopsies. The ability to detect SLFN11 in CTCs from SCLC patients adds a valuable tool for the detection and longitudinal monitoring of this promising biomarker.

Predicting Probability of Response to Tumor Necrosis Factor Inhibitors for Individual Patients With Ankylosing Spondylitis.

Importance: Tumor necrosis factor inhibitors (TNFis) have revolutionized the management of ankylosing spondylitis (AS); however, the lack of notable clinical responses in approximately one-half of patients suggests important heterogeneity in treatment response. Identifying patients likely to respond or not respond to TNFis could provide opportunities to personalize treatment strategies. Objective: To develop models of the probability of short-term response to TNFi treatment in individual patients with active AS. Design, Setting, and Participants: This is a retrospective cohort study using data of the TNFi group (ie, treatment group) from 10 randomized clinical trials (RCTs) of TNFi treatment among patients with active AS, conducted from 2002 to 2016. Participants were adult patients with active AS who failed nonsteroidal anti-inflammatory drugs. Included RCTs were phase 3 and 4 studies that assessed the efficacy of an originator TNFi at week 12 and/or week 24, either compared with placebo or an antirheumatic drug. The cohort was divided into a training and a testing set. Data analysis was conducted from July 1, 2019, to November 30, 2020. Exposures: All included patients received an originator TNFi for at least 12 weeks. Main Outcomes and Measures: Outcomes included major response and no response based on the change of AS Disease Activity Score at 12 weeks. Machine learning algorithms were applied to estimate the probability of having major response and no response for individual patients. Results: The study included 1899 participants from 10 trials. The training set included 1207 individuals (mean [SD] age, 39 [12] years; 908 [75.2%] men), of whom 407 (33.7%) had major response and 414 (34.3%) had no response. In the reduced logistic regression models, accuracy was 0.74 for major response and 0.75 for no response. The probability of major response increased with higher C-reactive protein (CRP) level, patient global assessment (PGA), and Bath AS Disease Activity Index (BASDAI) question 2 score and decreased with higher body mass index (BMI) and Bath AS Functional Index (BASFI) score. The probability of no response increased with age and BASFI score, and decreased with higher CRP level, BASDAI question 2 score, and PGA. In the testing set (692 participants; mean [SD] age, 38 [11] years; 533 [77.0%] men), models demonstrated moderate to high accuracy. Conclusions and Relevance: In this cohort study, the probability of initial response to TNFi was predicted from baseline variables, which may facilitate personalized treatment decision-making.

MAPK4 promotes triple negative breast cancer growth and reduces tumor sensitivity to PI3K blockade.

About 15-20% of breast cancer (BCa) is triple-negative BCa (TNBC), a devastating disease with limited therapeutic options. Aberrations in the PI3K/PTEN signaling pathway are common in TNBC. However, the therapeutic impact of PI3K inhibitors in TNBC has been limited and the mechanism(s) underlying this lack of efficacy remain elusive. Here, we demonstrate that a large subset of TNBC expresses significant levels of MAPK4, and this expression is critical for driving AKT activation independent of PI3K and promoting TNBC cell and xenograft growth. The ability of MAPK4 to bypass PI3K for AKT activation potentially provides a direct mechanism regulating tumor sensitivity to PI3K inhibition. Accordingly, repressing MAPK4 greatly sensitizes TNBC cells and xenografts to PI3K blockade. Altogether, we conclude that high MAPK4 expression defines a large subset or subtype of TNBC responsive to MAPK4 blockage. Targeting MAPK4 in this subset/subtype of TNBC both represses growth and sensitizes tumors to PI3K blockade.

Defects Induced Charge Trapping/Detrapping and Hysteresis Phenomenon in MoS2 Field-Effect Transistors: Mechanism Revealed by Anharmonic Marcus Charge Transfer Theory.

One critical problem inhibiting the application of MoS2 field-effect transistors (FETs) is the hysteresis in their transfer characteristics, which is typically associated with charge trapping (CT) and charge detrapping (CDT) induced by atomic defects at the MoS2-dielectric interface. Here, we propose a novel atomistic framework to simulate electronic processes across the MoS2-SiO2 interface, demonstrating the distinct CT/CDT behavior of different types of atomic defects and further revealing the defect type(s) that most likely cause hysteresis. An anharmonic approximation of the classical Marcus theory is developed and combined with state-of-the-art density functional theory to calculate the gate bias-dependent CT/CDT rates. All the key electronic quantities are calculated with Heyd-Scuseria-Ernzerhof hybrid functionals. The results show that single Si-dangling bond defects are active electron trapping centers. Single O-dangling bond defects are active hole trapping centers, which are more likely to be responsible for the hysteresis phenomenon due to their significant CT rate and apparent threshold voltage shift. In contrast, double Si-dangling bond defects are not active trap centers. These findings provide fundamental physical insights for understanding the hysteresis behavior of MoS2 FETs and provide vital support for understanding and solving the reliability of nanoscale devices.

Ventilation status of the residential kitchens in severe cold region and improvement based on simulation: A case of Shenyang, China.

Residents tend to close the doors and windows of their residential kitchens in severe cold conditions, making insufficient outdoor air supply and aggravating indoor air pollution. In order to understand the ventilation and pollution status of the residential kitchens in a severe cold region and improve the ventilation system, this study used questionnaires, on-site tests, and Computational Fluid Dynamics (CFD) simulation to analyze a pollution and ventilation case in Shenyang, China. The method of using ceiling openings to compensate for outdoor air supply was proposed and optimized to improve air distribution in the residential kitchen. The average CO2 concentration in the breathing region, air velocity, and temperature levels in the kitchen, before and after the improvement, were compared. The results indicated that the kitchen pollution in severe cold area of Shenyang is serious, and the ventilation habit has regional characteristics. Furthermore, the overall kitchen environment including air velocity, temperature, pollutant levels, static pressure, CO2 concentration, indoor airflow fluctuation, and cooking fire were obviously improved for the ceiling make-up air cases. These findings provide a basis for improving the reasonable air distribution of residential kitchens in cold regions and for building a thermally comfortable environment.Implications: In order to understand the ventilation and pollution status of the residential kitchens in a severe cold region and improve the ventilation system, this study used questionnaires, on-site tests, and Computational Fluid Dynamics (CFD) simulation to analyze one pollution and ventilation case in Shenyang, China. The method of ceiling openings to compensate for outdoor air supply was proposed and optimized to improve air distribution in the residential kitchen. The average CO2 concentration in the breathing region, air velocity, and temperature levels in the kitchen, both before and after the improvement, were compared. The results indicated that the kitchen's air velocity, temperature, and pollutant levels are much better for the ceiling make-up air case compared with permeation and opening window cases. The static pressure, CO2 concentration, indoor airflow fluctuation, and cooking fire showed remarkable improvement in the residential kitchens. These findings provide a basis for improving the reasonable air distribution of residential kitchens in cold regions and for building a thermally comfortable environment.

Clinical characteristics of axial spondyloarthritis patients in China: results from ChinaSpA, the Chinese Spondyloarthritis Registry.

OBJECTIVES: The objective of this study is to describe the clinical features of patients with axial spondyloarthritis (axial SpA) in the ChinaSpA registry. METHODS: Patients with clinical diagnosis of ankylosing spondylitis (AS) or axial SpA were enrolled into the registry. Patients with a complete set of pelvis radiograph, pelvis MRI and HLA-B27 (Complete Set group, CS group) were further categorised based on classification criteria into AS, radiographic axial SpA (r-axSpA) and non-radiographic axial SpA (nr-axSpA). Early axial SpA was defined as symptom duration of less than three years. Descriptive statistics were used to describe clinical characteristics of enrolled patients. ANOVA analyses were used to compare patients in different groups. RESULTS: A total of 5270 patients were enrolled in the study, and 3223 patients had complete sets of pelvis radiographs, MRIs and HLA-B27 status. Among them, more than 80% patients met both the ASAS criteria for r-axSpA and the modified New York criteria for AS. Among those with early axial SpA, 92% of patients had sacroiliitis on pelvis radiograph, 3.8% had sacroiliitis only on pelvis MRI, and 3.8% were in the clinical arm without any sacroiliitis on imaging studies. Patients in nr-axSpA clinical arm had less diagnosis delay, lower inflammatory markers and ASDAS, compared topatients in the r-axSpA, nr-axSpA MRI arm. CONCLUSIONS: In the ChinaSpA registry, patients in nr-axSpA clinical arm had the shortest diagnostic delay, lower inflammatory markers and ASDAS, but no difference in extra-articular manifestation, compared to patients in the r-axSpA and nr-axSpA MRI arm.

Cytokine release syndrome in COVID-19: a major mechanism of morbidity and mortality.

The coronavirus disease 2019 (COVID-19) triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) erupted in Hubei Province of China in December 2019 and has become a pandemic. Severe COVID-19 patients who suffer from acute respiratory distress syndrome (ARDS) and multi-organ dysfunction have high mortality. Several studies have shown that this is closely related to the cytokine release syndrome (CRS), often loosely referred to as cytokine storm. IL-6 is one of the key factors and its level is positively correlated with the severity of the disease. The molecular mechanisms for CRS in COVID-19 are related to the effects of the S-protein and N-protein of the virus and its ability to trigger NF-κB activation by disabling the inhibitory component IκB. This leads to activation of immune cells and the secretion of proinflammatory cytokines such as IL-6 and TNF-α. Other mechanisms related to IL-6 include its interaction with GM-CSF and interferon responses. The pivotal role of IL-6 makes it a target for therapeutic agents and studies on tocilizumab are already ongoing. Other possible targets of treating CRS in COVID-19 include IL-1ß and TNF-α. Recently, reports of a CRS like illness called multisystem inflammatory syndrome in children (MIS-C) in children have surfaced, with a variable presentation which in some cases resembles Kawasaki disease. It is likely that the immunological derangement and cytokine release occurring in COVID-19 cases is variable, or on a spectrum, that can potentially be governed by genetic factors. Currently, there are no approved biological modulators for the treatment of COVID-19, but the urgency of the pandemic has led to numerous clinical trials worldwide. Ultimately, there is great promise that an anti-inflammatory modulator targeting a cytokine storm effect may prove to be very beneficial in reducing morbidity and mortality in COVID-19 patients.

Cyclophosphamide inhibits Pax5 methylation to regulate the growth of retinoblastoma via the Notch1 pathway.

Retinoblastoma (Rb) is the most common intraocular malignant tumor in infants. Here, we investigated the function and mechanism of cyclophosphamide (CTX) in the development of Rb. Real-time quantitative polymerase chain reaction (RT-qPCR) results showed that paired box protein 5 (Pax5) expression was down-regulated in Rb tissues and cell lines. Methylation-specific PCR (MSP) results showed that the methylation level of Pax5 was up-regulated in Rb. After treatment with CTX, the Pax5 expression in Rb cell lines was increased significantly. The methylation of Pax5 and the expression of DNA methyltransferases (DNMTs) were down-regulated in the CTX group. Cyclophosphamide inhibited cell proliferation, migration, and invasion, promoted cell apoptosis via the Notch1 pathway. DNA methyltransferase inhibitor SGI-1027 had synergistic effects with CTX. Paired box protein 5 siRNA was transfected into Y79 cells treated with CTX. The expression of DNMTs, Pax5, the Notch1 pathway and apoptosis marker protein was detected by Western blotting, and changes in cell behavior were detected, respectively. Results showed that knockdown of Pax5 reversed the effects of CTX. Moreover, the Notch1 activator Valproic acid (VPA) abolished the inhibitory effects of CTX on Rb development. Moreover, CTX inhibited tumor growth in nude mice. These findings demonstrated that CTX up-regulated Pax5 expression by down-regulating DNMTs expression, and then inhibited the Notch1 signaling pathway activation and Rb growth.

Targeting the Interleukin-23/Interleukin-17 Inflammatory Pathway: Successes and Failures in the Treatment of Axial Spondyloarthritis.

The IL-23/IL-17 pathway has been implicated in the etiopathogenesis of axial spondyloarthritis through studies of genetic polymorphisms associated with disease, an animal model with over-expression of IL-23 that resembles human disease, and observations that cytokines in this pathway can be found at the site of disease in both humans and animal models. However, the most direct evidence has emerged from clinical trials of agents targeting cytokines in this pathway. Monoclonal antibodies targeting IL-17A have been shown to ameliorate signs and symptoms, as well as MRI inflammation in the spine and sacroiliac joints, in patients with radiographic and non-radiographic axial spondyloarthritis. This was evident in patients refractory to non-steroidal anti-inflammatory agents as well as patients failing treatment with tumor necrosis factor inhibitor therapies. Treatment with a bispecific antibody targeting both IL-17A and IL-17F was also effective in a phase II study. Post-hoc analyses have even suggested a potential disease-modifying effect in reducing development of spinal ankylosis. However, benefits for extra-articular manifestations were limited to psoriasis and did not extend to colitis and uveitis. Conversely, trials of therapies targeting IL-23 did not demonstrate any significant impact on signs, symptoms, and MRI inflammation in axial spondyloarthritis. These developments coincide with recent observations that expression of these cytokines is evident in many different cell types with roles in innate as well as adaptive immunity. Moreover, evidence has emerged for the existence of both IL-23-dependent and IL-23-independent pathways regulating expression of IL-17, potentially associated with different roles in intestinal and axial skeletal inflammation.

Regional Differences in Epidemiological and Clinical Characteristics, Treatment, and Clinical Outcomes of COVID-19 in Wuhan and Remote Areas of Hubei Province.

Background: The Coronavirus disease 2019 (COVID-19) pandemic has been a major threat to global health. Regional differences in epidemiological and clinical characteristics, treatment and outcomes of patients have not yet been investigated. This study was conducted to investigate these differences amongCOVID-19 patients in Hubei Province, China. Methods: This retrospective cross-sectional study analyzed data on 289 COVID-19 patients from designated hospitals in three regions:Urban (Wuhan Union West Hospital), Suburban areas of Wuhan (Hannan Hospital) and Enshi city, between February 8 and 20, 2020. The final date of follow-up was December 14th, 2020. The outcomes were case fatality rate and epidemiological and clinical data. Results: Urban Wuhan experienced a significantly higher case fatality rate (21.5%) than suburban Wuhan (5.23%) and rural area of Enshi (3.51%). Urban Wuhan had a higher proportion of patients on mechanical ventilation (24.05%) than suburban Wuhan (0%) and rural Enshi (3.57%). Treatment with glucocorticoids was equivalent in urban and suburban Wuhan (46.84 and 45.75%, respectively) and higher than Enshi (25.00%). Urban Wuhan had a higher proportion of patients with abnormal tests including liver function and serum electrolytes and a higher rate of pneumonia (p < 0.01 for all). Urban Wuhan also had a higher incidence of respiratory failure, heart disease, liver disease and shock, compared with the other two regions (all p < 0.05). Conclusions: Our findings revealed that there are regional differences in COVID-19. These findings provide novel insights into the distribution of appropriate resources for the prevention, control and treatment of COVID-19 for the global community.