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Mcm10 plays an essential role in the activation of replicative helicase CMG through the cell cycle-regulated interaction with the prototype MCM double hexamer in Saccharomyces cerevisiae. In this study, we reported that Mcm10 is phosphorylated by S-phase cyclin-dependent kinases (S-CDKs) at S66, which enhances Mcm10–-MCM association during the S phase. S66A single mutation or even deletion of whole N-terminus (a.a. 1–128) only causes mild growth defects. Nevertheless, S66 becomes indispensable in the absence of the Mcm10 C-terminus ((a.a. 463–571), the major MCM-binding domain. Using a two-degron strategy to efficiently deplete Mcm10, we show that mcm10-S66AΔC has a severe defect in proceeding into the S phase. Notably, both lethality and S-phase deficiency can be rescued by artificially tethering mcm10-S66AΔC to MCM. These findings illustrate how the Mcm10–MCM association is regulated as a crucial event in DNA replication initiation.

Abstract Psoriasis is an immune-mediated inflammatory skin disease, involving a complex interplay between genetic and environmental factors. Previous studies have demonstrated that genetic factors play a major role in the pathogenesis of psoriasis. However, non-genetic factors are also necessary to trigger the onset and recurrence of psoriasis in genetically predisposed individuals, which include infections, microbiota dysbiosis of the skin and gut, dysregulated lipid metabolism, dysregulated sex hormones, and mental illness. Psoriasis can also be induced by other environmental triggers, such as skin trauma, unhealthy lifestyles, and medications. Understanding how these triggers play a role in the onset and recurrence of psoriasis provides insights into psoriasis pathogenesis, as well as better clinical administration. In this review, we summarize the triggers for the onset and recurrence of psoriasis and update the current evidence on the underlying mechanism of how these factors elicit the disease. Video Abstract

Recently, it is been shown that cold atmospheric pressure plasmas Cold Atmospheric Plasma effectively inactivate the 2019-nCoV virus. Despite this promising finding, the precise mechanism of this inactivation remains unclear due to the limited number of studies conducted on the subject. Consequently, this paper focuses on the spike protein, a crucial part of the novel coronavirus, and the various reactive oxygen and nitrogen species (RONS) generated by the plasma. The study employs reactive molecular dynamics simulation and ReaxFF potential to explore the reactions between the spike protein molecules and different reactive oxygen nitrogen species (including H2O2, OH, O, O3, HOONO, and 1O2). The findings suggest that when a single RONS interacts with the spike protein, 1O2 and HOONO have the most potent ability to sever the spike protein. Additionally, the combined effect of long-lived and short-lived RONS presents a more potent decomposition impact.

Summary: Background: The biological aging process can be modified through lifestyle interventions to prevent age-related diseases and extend healthspan. However, evidence from population-based studies on whether tea consumption could delay the biological aging process in humans remains limited. Methods: This study included 7931 participants aged 30–79 years from the China Multi-Ethnic Cohort (CMEC) Study and 5998 participants aged 37–73 years from the UK Biobank (UKB) who participated in both the baseline and first follow-up surveys. Tea consumption information was collected through questionnaires. Biological age (BA) acceleration was calculated using clinical biomarkers and anthropometric measurements based on the Klemera Doubal method (KDM). Change-to-change analyses were performed to estimate the associations between changes in tea consumption status and changes in BA acceleration using multiple linear models. Follow-up adjusted for baseline analyses were further conducted to examine the prospective exposure-response relationship between tea consumption and BA acceleration among individuals with constant tea consumption status. Findings: During a median follow-up of 1.98 (1.78, 2.16) years in the CMEC and 4.50 (3.92, 5.00) years in the UKB, tea consumption was consistently associated with attenuated BA acceleration in both cohorts. Transitioning from nondrinking to tea-drinking was associated with decreased BA acceleration (CMEC: β = −0.319, 95% CI: −0.620 to −0.017 years; UKB: β = −0.267, 95% CI: −0.831 to 0.297 years) compared to consistent nondrinking. Even stronger associations were found in consistent tea drinkers. The exposure-response relationship suggested that consuming around 3 cups of tea or 6–8 g of tea leaves per day may offer the most evident anti-aging benefits. Interpretation: Tea consumption was associated with attenuated BA acceleration measured by KDM, especially for consistent tea drinkers with moderate consumption. Our findings highlight the potential role of tea in developing nutrition-oriented anti-aging interventions and guiding healthy aging policies. Funding: National Natural Science Foundation of China (Grant No. 82273740).

Land use and land cover (LULC) patterns fundamentally influence the carbon cycle of terrestrial ecosystems, and rational optimization of LULC patterns can contribute to achieving carbon neutrality goals. This study constructs a multi-objective LULC optimization coupled model by integrating the objective of carbon neutrality into the LULC optimization process, with Northwest China serving as the study case. This model integrated the Integrated Valuation of Ecosystem Services and Trade-offs (InVEST) model with the Intergovernmental Panel on Climate Change (IPCC) inventory methodology to assess the spatiotemporal variations in carbon storage and emissions in Northwest China between 2000 and 2020, which aimed to elucidate the mechanisms through which changes in LULC affect carbon neutrality. Additionally, through the amalgamation of the Non-dominated Sorting Genetic Algorithm-II (NSGA-II) and the Patch-Generating Land Use Simulation (PLUS) model, optimized the quantitative structure and spatial layout of four LULC scenarios for Northwest China in 2060: natural development (ND), low carbon emissions (CE), high carbon storage (CS), and carbon neutrality (CN), projected the evolving pathways of carbon storage and emissions within these scenarios while examining the values of different LULC scenarios and their respective contributions to carbon neutrality. The study's findings underscore that the substantial expansion of built-up land development areas and farmland from 2000 to 2020 has resulted in notable carbon storage and emissions increases. Moreover, changes in carbon emissions and carbon storage show significant spatial consistency with changes in LULC patterns. In contrast to the ND scenario, the LULC patterns within the CE, CS, and CN scenarios exhibit higher LULC values and contribute more substantially to carbon neutrality. Remarkably, among these scenarios, the CN scenario stands out for achieving the maximum contribution to carbon neutrality and LULC value, thereby establishing it as the preeminent LULC pattern for the Northwest China region. As the study concludes, it recommended that future developmental strategies in Northwest China prioritize curtailing the expansion of built-up areas while bolstering the conservation of vital ecological zones such as forests and grasslands. This study addresses the inherent tension between regional economic progress and environmental preservation, offering a foundation of scientific insights for effectively managing LULC patterns and attaining carbon neutrality goals.

Summary: Smart wearable sensors are electronic devices worn on the body that collect, process, and transmit various physiological data. Compared to traditional devices, their advantages in terms of portability and comfort have made them increasingly important in the medical field. This review takes a unique clinical physician’s standpoint, diverging from conventional sensor-type-based classifications, and provides a comprehensive overview of the diverse clinical applications of wearable sensors in recent years. In this review, we categorize these applications according to different diseases, encompassing skin diseases and injuries, cardiovascular diseases, abnormal human motion, as well as endocrine and metabolic disorders. Additionally, we discuss the challenges and perspectives hindering the development of sensors for clinical use, emphasizing the critical need for interdisciplinary collaboration between medical and engineering professionals. Overall, this review would serve as an important reference for the future direction of sensor devices in clinical use.

IntroductionPsoriasis is a common inflammatory skin disease recognized by the World Health Organization as "an incurable chronic, noninfectious, painful, disfiguring and disabling disease." The fact that metabolic syndrome (MetS) is the most common and important comorbidities of psoriasis suggests an important role of lipid metabolism in the pathogenesis of psoriasis. Narciclasine (Ncs) is an alkaloid isolated from the Amaryllidaceae plants. Its biological activities include antitumor, antibacterial, antiinflammatory, anti-angiogenic and promoting energy expenditure to improve dietinduced obesity. Here, we report that Ncs may be a potential candidate for psoriasis, acting at both the organismal and cellular levels.MethodsThe therapeutic effect of Ncs was assessed in IMQ-induced psoriasis-like mouse model. Then, through in vitro experiments, we explored the inhibitory effect of Ncs on HaCaT cell proliferation and Th17 cell polarization; Transcriptomics and lipidomics were used to analyze the major targets of Ncs; Single-cell sequencing data was used to identify the target cells of Ncs action.ResultsNcs can inhibit keratinocyte proliferation and reduce the recruitment of immune cells in the skin by inhibiting psoriasis-associated inflammatory mediators. In addition, it showed a direct repression effect on Th17 cell polarization. Transcriptomic and lipidomic data further revealed that Ncs extensively regulated lipid metabolismrelated genes, especially the Phospholipase A2 (PLA2) family, and increased antiinflammatory lipid molecules. Combined with single-cell data analysis, we confirmed that keratinocytes are the main cells in which Ncs functions.DiscussionTaken together, our findings indicate that Ncs alleviates psoriasiform skin inflammation in mice, which is associated with inhibition of PLA2 in keratinocytes and improved phospholipid metabolism. Ncs has the potential for further development as a novel anti-psoriasis drug.

Melanoma is the most lethal skin cancer with rising incidence worldwide. Despite significant advances in target therapy and immunotherapy, low response rates and the development of drug resistance remain key clinical barriers affecting patient prognosis. The complex interplay between multiple signaling molecules and pathways has brought little understanding of melanoma pathogenesis and resistance. The genetic mutation and hypermetabolic environment of melanoma cells lead to increasing demands for protein synthesis and perturb proteostasis resulting in endoplasmic reticulum (ER) stress. Subsequently, three unfolded protein response (UPR) signaling branches, represented by IRE1α, PERK and ATF6, are activated to direct cell fate towards pro-survival or pro-apoptosis depending on the intensity and duration of ER stress. In this review, we summarize ER stress and UPR in melanoma cells and tumor-infiltrating immune cells along with the crosstalk among these pathways. We provide the latest advances in understanding melanoma pathogenesis and resistance and discuss the potential of targeting the ER stress or UPR process for melanoma therapy.

Among the various ceramic substrate materials, Si3N4 ceramics have demonstrated high thermal conductivity, good thermal shock resistance, and excellent corrosion resistance. As a result, they are well-suited for semiconductor substrates in high-power and harsh conditions encountered in automobiles, high-speed rail, aerospace, and wind power. In this work, Si3N4 ceramics with various ratios of α-Si3N4 and β-Si3N4 in raw powder form were prepared by spark plasma sintering (SPS) at 1650 °C for 30 min under 30 MPa. When the content of β-Si3N4 was lower than 20%, with the increase in β-Si3N4 content, the ceramic grain size changed gradually from 1.5 μm to 1 μm and finally resulted in 2 μm mixed grains. However, As the content of β-Si3N4 seed crystal increased from 20% to 50%, with the increase in β-Si3N4 content, the ceramic grain size changed gradually from 1 μm and 2 μm to 1.5 μm. Therefore, when the content of β-Si3N4 in the raw powder is 20%, the sintered ceramics exhibited a double-peak structure distribution and the best overall performance with a density of 97.5%, fracture toughness of 12.1 MPa·m1/2, and a Vickers hardness of 14.5 GPa. The results of this study are expected to provide a new way of studying the fracture toughness of silicon nitride ceramic substrates.

Background: As a cause of respiratory tract infections in humans, influenza remains with high morbidity and mortality, with associated significant healthcare burden and increased financial burden. Traditional Chinese medicine injections (TCMIs) combined with oseltamivir (TCMIs + oseltamivir) are the representative therapeutic strategies for influenza, which is a compliant with clinical applications in China. The aim of this study was to describe the comparative efficacy and safety of TCMIs + oseltamivir in patients with influenza, based on the current evidence.Methods: PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, VIP information resource integration service platform databases, and the Chinese biomedical literature service system were searched to find randomized controlled trials where TCMIs + oseltamivir are the representative therapeutic strategies for influenza, from inception until October 2021, without language restriction. Two investigators independently screened eligibility criteria, extracted data, and appraised the risk of bias with the same criteria. We conducted a network meta-analysis using the Bayesian random method for each outcome and performed the sensitivity analysis, meta-regression, and Egger’s and Begg’s tests for the reliability and robustness of our results.Results: Thirty-one trials including 2,893 participants proved eligible and reported on four TCMIs + oseltamivir versus oseltamivir. Network meta-analysis showed Yanhuning (YHN) +oseltamivir (MD = −1.7, 95% CrI: −2.5 to −0.88; SUCRA = 0.89; low certainty of evidence) in fever disappearance time, Tanreqing (TRQ) +oseltamivir (MD = −1.9, 95% CrI: −2.8 to −1; SUCRA = 0.97; low certainty of evidence) in cough disappearance time, and Xiyanping (XYP) +oseltamivir (OR = 5.9, 95% CrI: 3.1 to 11; SUCRA = 0.82; very low certainty of evidence) in the response rate to be more efficacious than oseltamivir alone with the best SUCRA. Based on the combined SUCRA value for primary outcomes, TRQ + oseltamivir is probably better in cough disappearance time, and XYP + oseltamivir and YHN + oseltamivir may be better in fever disappearance time than others. No significant difference in safety between the treatments.Conclusion: In patients with influenza, TCMIs + oseltamivir only partially improve flu symptoms. Overall therapeutic efficacy and safety are inconclusive, based on low to very low certainty of evidence. However, the safety remains uncertain, and TCMI treatments for influenza should be considered with caution. More high-quality studies examining the efficacy and safety of TCMIs are needed.Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42021286994

Background: Psoriasis is characterized by keratinocyte proliferation and massive inflammatory leukocytes infiltration, affecting 0.14%–1.99% of the world’s population. Our aim was to identify novel potential therapeutic strategies for psoriasis.Methods: Weighted gene co-expression network analysis (WGCNA) was performed to identify gene modules that were closely related to psoriasis based on the GSE30999 dataset, which contained expression data from 85 patients with moderate-to-severe psoriasis. Then, angiopoietin-like 4 (ANGPTL4), one of the most related hub genes, was selected for in vitro and in vivo functional assays. In our experiments, imiquimod (IMQ)-induced psoriasiform dermatitis in mice and human keratinocytes (HaCaT) cells were used to study the potential roles and mechanisms of ANGPTL4 in psoriasis.Results: WGCNA analysis revealed the turquoise module was most correlated with psoriasis, and ANGPTL4 is one of the most related hub genes that significantly upregulated in psoriasis lesions compared with non-lesional skin. Consistent with the bioinformatic analysis, the expression of ANGPTL4 was significantly upregulated in IMQ-induced psoriasiform skin of mice. Exogenous recombinant ANGPLT4 protein treatment could promote the proliferation and induce the expression of inflammatory cytokines in HaCaTs, whereas silencing of ANGPTL4 effectively inhibited these effects. Then we demonstrated that recombinant ANGPTL4 protein exacerbated psoriasiform inflammation and epidermal hyperproliferation in vivo. Mechanismly, extracellular signal-regulated kinase 1/2 (ERK1/2) and signal transducer and activator of transcription 3 (STAT3) pathways were involved in ANGPTL4-mediated regulation of proliferation and inflammation.Conclusion: We found ANGPTL4 was significantly increased in IMQ-induced psoriasiform skin of mice. ANGPTL4 could promote keratinocyte proliferation and inflammatory response via ERK1/2 and STAT3 dependent signaling pathways in psoriasis.

Pemphigus is a chronic and severe autoimmune bullous disease caused by autoantibodies targeting adhesion molecules between keratinocytes. It requires 2–3 years on average to manage the disease. To date, although Rituximab combined with short-term systemic glucocorticoids was accepted as first-line therapy, systemic glucocorticoids remain the primary therapeutic option for pemphigus patients, successfully decreasing morbidity and mortality from pemphigus. However, novel therapeutic strategies are desirable due to the low efficacy in some subset of patients and the long-term severe adverse effects of traditional therapies. Recently, immunotherapy has proved to be encouraging for disease control or cure. Based on the current understanding of the immune mechanisms of pemphigus, we review the immune targets and corresponding agents applied in practice or under clinical trials. The goals of the novel treatments are to improve the quality of life of pemphigus patients by improving efficacy and safety, minimizing side effects, achieving fast disease control, or curing the disease.

Yersinia pestis, the cause of plague, is a newly evolved Gram-negative bacterium. Through the acquisition of the plasminogen activator (Pla), Y. pestis gained the means to rapidly disseminate throughout its mammalian hosts. It was suggested that Y. pestis utilizes Pla to interact with the DEC-205 (CD205) receptor on antigen-presenting cells (APCs) to initiate host dissemination and infection. However, the evolutionary origin of Pla has not been fully elucidated. The PgtE enzyme of Salmonella enterica, involved in host dissemination, shows sequence similarity with the Y. pestis Pla. In this study, we demonstrated that both Escherichia coli K-12 and Y. pestis bacteria expressing the PgtE-protein were able to interact with primary alveolar macrophages and DEC-205-transfected CHO cells. The interaction between PgtE-expressing bacteria and DEC-205-expressing transfectants could be inhibited by the application of an anti-DEC-205 antibody. Moreover, PgtE-expressing Y. pestis partially re-gained the ability to promote host dissemination and infection. In conclusion, the DEC-205-PgtE interaction plays a role in promoting the dissemination and infection of Y. pestis, suggesting that Pla and the PgtE of S. enterica might share a common evolutionary origin.

Background: Cannabinoid receptor 2 (CB2R) is a potential target for anti-inflammatory and pain therapeutics given its significant immunomodulatory and analgesic effects. However, the role of CB2R in imiquimod (IMQ)-induced psoriasiform dermatitis (PsD) and itch is poorly understood.Objective: To investigate the function and mechanism of CB2R in PsD and itch in mice.Methods: Following daily treatment with topical IMQ cream for 5-7 consecutive days in C56BL/6 wild-type (WT) and CB2R gene knockout (KO) mice, we assessed the Psoriasis Area and Severity Index (PASI) scores and the scratch bouts every day, and hematoxylin and eosin (H&E) staining, toluidine blue staining were used to observe the histological changes. mRNA levels were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Protein levels were detected by western blotting (WB), immunohistochemistry (IHC), immunofluorescence (IF) and cytometric bead array (CBA). Flow cytometry (FCM) was used to examine the proportion of Th17/Treg cells.Results: We found that CB2R expression levels were increased in mice with psoriasis. Compared with WT mice, CB2R deficiency exacerbated IMQ-induced PsD and scratching bouts and upregulated the expression of proinflammatory cytokines by increasing the infiltration of CD4+ T cells and the Th17/Treg ratio. Obvious proliferation and prolongation of nerve fibers and high expression of nerve growth factor (NGF) were observed in PsD and CB2R KO mice. Pretreatment with the CB2R agonist, JWH-133 significantly reversed inflammation and scratching bouts. CB2R didn't participate in the induction of itch in psoriasis by regulating the expression of IL-31, thymic stromal lymphopoietin (TSLP) and mast cells in mouse skins.Conclusion: Our results demonstrate that CB2R plays a pivotal role in the pathophysiology of psoriasis, providing a new potential target for anti-inflammatory and antipruritic drugs.

Abstract Background An increasing number of extremely preterm (EP) infants have survived worldwide. However, few data have been reported from China. This study was designed to investigate the short-term outcomes of EP infants at discharge in Guangdong province. Methods A total of 2051 EP infants discharged from 26 neonatal intensive care units during 2008–2017 were enrolled. The data from 2008 to 2012 were collected retrospectively, and from 2013 to 2017 were collected prospectively. Their hospitalization records were reviewed. Results During 2008–2017, the mean gestational age (GA) was 26.68 ± 1.00 weeks and the mean birth weight (BW) was 935 ± 179 g. The overall survival rate at discharge was 52.5%. There were 321 infants (15.7%) died despite active treatment, and 654 infants (31.9%) died after medical care withdrawal. The survival rates increased with advancing GA and BW (p

Asymptomatic/subclinical gonococcal infections in females continue to be prevalent within the general population, thus emerging as a global health problem. However, the reasons for these clinical manifestations are unknown. Our group had previously found out that in females, asymptomatic gonococcal infections correlate with higher serum progesterone (P4) levels and lower IL-1β levels in cervical secretions. We used murine infection model and THP-1 cells to determine whether P4 exerts anti-inflammatory effects on gonococcal infections. In the murine infection model, P4 (1 mg/day) inhibited the inflammatory effects induced by gonococcal infections which led to decreased neutrophil infiltration, reduced polymorphonuclear neutrophils (PMNs) numbers, IL-1β, TNF-α, and IL-6 levels in vaginal secretions. In addition, P4 down-regulated the mRNA and protein levels of NLRP3, associated with lower mRNA levels of pro-IL-1β, repressed caspase-1 activity in genital tissues and THP-1 cells. Moreover, P4 suppressed the phosphorylation levels of NF-κB and attenuated Neisseria gonorrhoeae (N. gonorrhoeae, gonococci or GC)-induced ROS generation. This is consistent with the two signals required for activation of the NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome. In conclusion, our result shows that P4 suppresses the gonococci induced-inflammation, especially through the NLRP3 inflammasome pathway, and partially explains the pathogenesis of asymptomatic GC infection in women.

Neisseria gonorrhoeae (N. gonorrhoeae, gonococci, or GC), the etiologic agent of gonorrhea, is a human-obligate bacterial pathogen. The GC surface contains pili that mediate the adherence to host cells. Studies have shown that GC pili, coded by pilin genes, undergo remarkable changes during human experimental gonorrhea, possibly generated by DNA phase variation during infection. The question that arises is whether the changes in pilins can alter the adherence capacity of N. gonorrhoeae to host cells. In this study, six variants initially isolated from male volunteers infected with one single clone of GC were examined for their adherence patterns with human Chang conjunctiva cells. In this study, we showed that the variants showed distinct adherence patterns to this cell line under light microscopy and scanning electron microscopy. Moreover, two reisolates showed higher adherence capacities than that of the input strain. The results provide an additional example as to how the pilus variation may play a role in the pathogenesis of N. gonorrhoeae.

Melanoma is the leading cause of cancer-related death among skin tumors, with an increasing incidence worldwide. Few studies have effectively investigated the significance of an immune-related gene (IRG) signature for melanoma prognosis. Here, we constructed an IRGs prognostic signature using bioinformatics methods and evaluated and validated its predictive capability. Then, immune cell infiltration and tumor mutation burden (TMB) landscapes associated with this signature in melanoma were analyzed comprehensively. With the 10-IRG prognostic signature, melanoma patients in the low-risk group showed better survival with distinct features of high immune cell infiltration and TMB. Importantly, melanoma patients in this subgroup were significantly responsive to MAGE-A3 in the validation cohort. This immune-related prognostic signature is thus a reliable tool to predict melanoma prognosis; as the underlying mechanism of this signature is associated with immune infiltration and mutation burden, it might reflect the benefit of immunotherapy to patients.

Uropathogenic Escherichia coli (UPEC), a Gram-negative bacterial pathogen, is a major causative agent of urinary tract infections (UTIs). However, the molecular mechanisms of how UPEC causes infections have not been determined. Recent studies indicated that certain enteric Gram-negative bacteria interact with and hijack innate immune receptors DC-SIGN (CD209a) and SIGNR1 (CD209b), often expressed by antigen-presenting cells (APCs), such as macrophages, leading to dissemination and infection. It was not known whether UPEC could utilize DC-SIGN receptors to promote its infection and dissemination similarly to the enteric pathogens. The results of this study reveal that UPEC interacts with CD209-expressing macrophages and transfectants. This interaction is inhibited by anti-CD209 antibody, indicating that CD209s are receptors for UPEC. Additionally, in contrast to the results of previous studies, mice lacking SIGNR1 are more susceptible to infection of this uropathogen, leading to prolonged bacterial persistence. Overall, the results of our study indicate that the innate immune receptor CD209s participate in the clearance of UPEC during UTIs.

Epigenetics plays an important role in the development and progression of many diseases. There is increasing evidence for the importance of epigenetic modifications in the progression of psoriasis. The aim of this study was to examine the role and potential mechanism of action of 5-hydroxymethylcytosine (5-hmC) and ten-eleven translocation-2 (TET2) in psoriasiform dermatitis in mice. Immunohistochemical staining was performed on psoriasis patients and healthy controls. Topical application of imiquimod cream to the dorsal skin of mice was used to induce psoriasiform dermatitis. In comparison with healthy controls, 5-hmC was more extensive and intense in the skin lesions from psoriasis patients. TET2 and 5-hmC were highly expressed in imiquimod-induced psoriasiform skin lesions. Importantly, knockdown of TET2 expression in mice attenuated the psoriasiform phenotype and the expression levels of proinflammatory cytokines (interleukin-17A and -17F and interferon-?) and the chemokine CXCL1 in the lesional skin of mice. This is the first demonstration of a critical role for TET2 in psoriasiform dermatitis in a mouse model, and indicates that 5-hmC may serve as a potential biomarker of psoriasis.

Improving the transdermal delivery efficiency of medicine is a crucial measure to improve the treatment efficiency of psoriasis. This paper developed a low-cost, highly active, and large-action-area low-temperature plasma (LTP) jet array. The two components of plasma—the high concentration of reactive oxygen and nitrogen species and the strong electric field—easily changed the structural integrity of the stratum corneum, which enhanced the transdermal delivery of the medicine. Tripterygium wilfordii Hook F (TwHF) is a medicine used to treat autoimmune and inflammatory conditions. The enhanced transdermal delivery of TwHF significantly alleviated the severed psoriasiform dermatitis induced by the imiquimod. Unlike the TwHF treatment alone, the LTP + TwHF treatment was more efficient at suppressing epidermal thickening and inhibiting systemic inflammation without noticeable side effects. LTP + TwHF treatment provides a potential new solution for psoriasis treatment.

Deep convolutional neural networks (DCNNs) have achieved breakthrough performance on bird species identification using a spectrogram of bird vocalization. Aiming at the imbalance of the bird vocalization dataset, a single feature identification model (SFIM) with residual blocks and modified, weighted, cross-entropy function was proposed. To further improve the identification accuracy, two multi-channel fusion methods were built with three SFIMs. One of these fused the outputs of the feature extraction parts of three SFIMs (feature fusion mode), the other fused the outputs of the classifiers of three SFIMs (result fusion mode). The SFIMs were trained with three different kinds of spectrograms, which were calculated through short-time Fourier transform, mel-frequency cepstrum transform and chirplet transform, respectively. To overcome the shortage of the huge number of trainable model parameters, transfer learning was used in the multi-channel models. Using our own vocalization dataset as a sample set, it is found that the result fusion mode model outperforms the other proposed models, the best mean average precision (MAP) reaches 0.914. Choosing three durations of spectrograms, 100 ms, 300 ms and 500 ms for comparison, the results reveal that the 300 ms duration is the best for our own dataset. The duration is suggested to be determined based on the duration distribution of bird syllables. As for the performance with the training dataset of BirdCLEF2019, the highest classification mean average precision (cmAP) reached 0.135, which means the proposed model has certain generalization ability.

A simple and rapid UPLC–MS/MS method to simultaneously determine gemcitabine and its L-carnitine ester derivative (2'-deoxy-2', 2'-difluoro-N-((4-amino-4-oxobutanoyl) oxy)-4-(trimethyl amm-onio) butanoate-cytidine, JDR) in rat plasma was developed and validated. The conventional plasma sample preparation method of nucleoside analogues is solid-phase extraction (SPE) which is time-consuming and cost-expensive. In this study, gradient elution with small particles size solid phase was applied to effectively separate gemcitabine and JDR, and protein precipitation pretreatment was adopted to remove plasma protein and extract the analytes with high recovery(>81%). Method validation was performed as per the FDA guidelines, and the standard curves were found to be linear in the range of 5–4000 ng/ml for JDR and 4–4000 ng/ml for gemcitabine, respectively. The lower limit of quantitation (LLOQ) of gemcitabine and JDR was 4 and 5 ng/ml, respectively. The intra-day and inter-day precision and accuracy results were within the acceptable limits. Finally, the developed method was successfully applied to investigate the pharmacokinetic studies of JDR and gemcitabine after oral administration to rats.

Abstract Psoriasis is a chronic inflammatory skin disease that affects 2–3% of the global population, and there is still no known possibility of a cure. Lipoxin A4 (LXA4), an endogenous lipoxygenase-derived eicosanoid mediator, has potent dual pro-resolving and anti-inflammatory properties. BML-111 (5(S)-6(R)-7-trihydroxyheptanoic acid methyl ester), a lipoxin receptor agonist, has been previously confirmed to be equivalent to LXA4 in the anti-inflammatory processes. High mobility group box 1 (HMGB1) serves as an inflammatory cytokine when secreted extracellularly in psoriatic lesions and is involved in the development of psoriasis. Therefore, we investigated the effects of LXA4 and BML-111 on the HMGB1 signaling cascade and inflammation in lipopolysaccharide (LPS)-induced keratinocytes and imiquimod (IMQ)-induced psoriasiform dermatitis in mice. In the present study, we found that treatment with BML-111 attenuated the development of IMQ-induced psoriasiform dermatitis. Furthermore, treatment with BML-111 and LXA4 inhibited HMGB1 translocation from the nucleus to cytoplasm and downregulated the expression of toll-like receptor 4 (TLR4), receptor for advanced glycation end products (RAGE), p-ERK1/2, nuclear NF-κB p65, and proinflammatory cytokines in vivo and in vitro. Our findings indicate that LXA4 and its analog may be potential therapeutic candidates for psoriasis because of their ability to modulate the translocation and expression of HMGB1.

Long non-coding RNAs (LncRNAs) can act as competing endogenous RNA (ceRNA) involving in tumor initiation and progression. Nevertheless, the prognostic roles of lncRNAs in lncRNA-related ceRNA network of melanoma remain elusive. In this study, RNA sequence profiles were downloaded from The Cancer Genome Atlas (TCGA) database, and there were 2020 differentially expressed messenger RNAs (DEmRNAs), 438 differentially expressed lncRNAs (DElncRNAs) and 65 differentially expressed microRNAs (DEmiRNAs) between primary and metastasis melanoma patients. A ceRNA regulatory network was constructed based on the DElncRNAs-DEmiRNAs and DEmiRNAs-DEmRNAs interactions, which contained 39 lncRNAs, 10 miRNAs, and 16 mRNAs. Furthermore, univariate and multivariate Cox regression analysis were carried out to establish a 7-lncRNA prognostic signature. Subsequently, the area under the curve (AUC) value of the receiver operating characteristic (ROC) curve and the Kaplan-Meier risk survival analysis revealed the significant performance of this signature. Finally, pathway enrichment analyses implied that lncRNA MIR205HG and MIAT were associated with multiple cancer-related pathways, especially epidermis development and immune response. The current study provides novel insights into the lncRNA-related ceRNA network and the potential of lncRNAs to be candidate prognostic biomarkers and therapeutic targets in melanoma.

Near-term quantum computers are noisy, and therefore must run algorithms with a low circuit depth and qubit count. Here we investigate how noise affects a quantum neural network (QNN) for state discrimination, which is applicable on near-term quantum devices as it fulfils the above criteria. We find that for the required gradient calculation on a noisy device a quantum circuit with a large number of parameters is disadvantageous. By introducing a smaller circuit ansatz we overcome this limitation, and find that the QNN performs well at noise levels of current quantum hardware. We present a model showing that the main effect of the noise is to increase the overlap between the states as circuit gates are applied, hence making discrimination more difficult. Our findings demonstrate that noisy quantum computers can be used for state discrimination and other applications, such as classifiers of the output of quantum generative adversarial networks.

We have previously shown that the expression of the minichromosome maintenance protein 3 (MCM3) gene was upregulated in lymphocytes of patients with skeletal fluorosis. We speculated that increased MCM3 expression may be contribute to osteopathy in patients with skeletal fluorosis. Here, we investigated the effect of fluoride on the proliferation of osteoclasts derived from RAW264.7 cells and the involvement of MCM3. Our MTT assays showed that 0.25 mM NaF markedly stimulated the proliferation of RAW264.7 cells. The RT-PCR and immunoblotting assays revealed that 0.25 mM NaF upregulated MCM3 expression in RAW264.7 cells. The MTT assays additionally demonstrated that stimulation with MCM3 potentiated the effect of fluorine on the proliferation of RAW264.7 cells. These results demonstrated that fluoride at clinical relevant concentration upregulates MCM3 expression in osteoclasts in vitro. We are currently conducting a series of experiments to examine whether increased MCM3 in osteoclasts indeed contributes to osteopathy in skeletal fluorosis.

Aromatic polyimide fibers (PI) are usually produced in two steps. The precursor fibers of polyamic acid (PAA) are fabricated first, and then the fabricated fibers are converted into PI fibers through thermal treatment. In the second step (thermal treatment), the mechanical properties of the obtained PI fibers are remarkably affected. Here, the PAA fibers derived from 3,3’,4,4’-biphenyltetra-carboxylic dianhydride and p-phenylenediamine are fabricated by a dry-jet wet-spinning method. Then, the PI fibers are prepared by heating PAA fibers from room temperature to 300, 350 and 400 °C under different heating rates, ranging from 1 °C/min to 80 °C/min. When the heating rate is low, the crystallization lags behind the imidization process, and begins only when the imidization degree reaches a high level. As the heating rate increases, the crystallization tends to occur simultaneously with the imidization process, and the degree of crystallinity of the PI fibers also greatly increases. Our findings suggest that a high heating rate causes the polymer chains to undergo high mobility during thermal treatment. The tensile modulus of the PI fiber further demonstrates a high dependence on the heating rate. Moreover, a short annealing process after treatment proves to be efficient in releasing residual stress and improving tensile strength.

Hypoxia and intracellular Ca2+ transients are fundamental traits of cancer, whereas the route and regulation of Ca2+ mobilization in hypoxic tumorigenesis are unknown. Here, we show that stromal-interaction molecule 1 (STIM1), an ER Ca2+ sensor, correlates with elevated hypoxia-inducible factor-1 alpha (HIF-1α) in hypoxic hepatocarcinoma cells (HCCs) and is upregulated during hepatocarcinoma growth. HIF-1 directly controls STIM1 transcription and contributes to store-operated Ca2+ entry (SOCE). STIM1-mediated SOCE is also required for HIF-1 accumulation in hypoxic HCCs via activation of Ca2+/calmodulin-dependent protein kinase II and p300. Administration of YC-1, a HIF-1 inhibitor, or knockdown of HIF1A significantly diminishes hypoxia-enhanced STIM1 and suppresses tumorigenesis. Moreover, ectopic expression of STIM1 or HIF-1α partially reverses impaired growth of tumors treated with YC-1. These results suggest a mutual dependency and regulation of STIM1 and HIF-1 in controlling Ca2+ mobilization and hypoxic tumor growth and highlight a potential target for early hypoxia-related intervention.

α-Mangostin is a natural product commonly used in Asia for cosmetic and medicinal applications including topical treatment of acne and skin cancer. Towards finding new pharmacological strategies that overcome NRAS mutant melanoma, we performed a cell proliferation-based combination screen using a collection of well-characterized small molecule kinase inhibitors and α-Mangostin. We found that α-Mangostin significantly enhances Sorafenib pharmacological efficacy against an NRAS mutant melanoma cell line. The synergistic effects of α-Mangostin and Sorafenib were associated with enhanced inhibition of activated AKT and ERK, induced ER stress, and reduced autophagy, eventually leading to apoptosis. The structure of α-Mangostin resembles several inhibitors of the Retinoid X receptor (RXR). MITF expression, which is regulated by RXR, was modulated by α-Mangostin. Molecular docking revealed that α-Mangostin can be accommodated by the ligand binding pocket of RXR and may thereby compete with RXR-mediated control of MITF expression. In summary, these data demonstrate an unanticipated synergy between α-Mangostin and sorafenib, with mechanistic actions that convert a known safe natural product to a candidate combinatorial therapeutic agent.

Background and aims: The relationship between alcohol consumption and age-related diseases is inconsistent. Biological age (BA) serves as both a precursor and a predictor of age-related diseases; however, longitudinal associations between alcohol consumption and BA in middle-aged and older people remain unclear. We measured whether there was a longitudinal association between drinking frequency and pure alcohol intake with BA among middle-aged and older people. Design and setting and participants: This study involved two prospective cohort studies, set in Southwestern China and the United Kingdom. A total of 8046 participants from the China Multi-Ethnic Cohort study (CMEC) and 5412 participants from the UK Biobank (UKB), aged 30-79 years, took part, with complete data from two waves of clinical biomarkers. Measurements: BA was calculated by the Klemera Doubal's method. Accelerated BA equalled BA minus chronological age. Drinking frequency and pure alcohol intake were obtained through self-reported questionnaires. Drinking frequency in the past year was classified as current non-drinking, occasional (monthly drinking) and regular (weekly drinking). Findings: Compared with consistent current non-drinkers, more frequent drinkers [CMEC: β = 0.46, 95% confidence interval (CI) = 0.13-0.80; UKB: β = 0.65, 95% CI = 0.01-1.29)], less frequent drinkers (CMEC: β = 0.62, 95% CI = 0.37-0.87; UKB: β = 0.54, 95% CI = -0.01-1.09), consistent occasional drinkers (CMEC: β = 0.51, 95% CI = 0.23-0.79; UKB: β = 0.63, 95% CI = 0.13-1.13) and consistent regular drinkers (CMEC: β = 0.56, 95% CI = 0.17-0.95; UKB: β = 0.46, 95% CI = 0.00-0.91) exhibited increased accelerated BA. A non-linear relationship between pure alcohol intake and accelerated BA was observed among consistent regular drinkers. Conclusions: In middle-aged and older people, any change in drinking frequency and any amount of pure alcohol intake seem to be positively associated with acceleration of biological ageing, compared with maintaining abstinence. [ABSTRACT FROM AUTHOR]