A Stimulus-Responsive Ternary Heterojunction Boosting Oxidative Stress, Cuproptosis for Melanoma Therapy.

Cuproptosis, a recently discovered copper-dependent cell death, presents significant potential for the development of copper-based nanoparticles to induce cuproptosis in cancer therapy. Herein, a unique ternary heterojunction, denoted as HACT, composed of core-shell Au@Cu2O nanocubes with surface-deposited Titanium Dioxide quantum dots and modified with hyaluronic acid is introduced. Compared to core-shell AC NCs, the TiO2/Au@Cu2O exhibits improved energy structure optimization, successfully separating electron-hole pairs for redox use. This optimization results in a more rapid generation of singlet oxygen and hydroxyl radicals triggering oxidative stress under ultrasound radiation. Furthermore, the HACT NCs initiate cuproptosis by Fenton-like reaction and acidic environment, leading to the sequential release of cupric and cuprous ions. This accumulation of copper induces the aggregation of lipoylated proteins and reduces iron-sulfur proteins, ultimately initiating cuproptosis. More importantly, HACT NCs show a tendency to selectively target cancer cells, thereby granting them a degree of biosecurity. This report introduces a ternary heterojunction capable of triggering both cuproptosis and oxidative stress-related combination therapy in a stimulus-responsive manner. It can energize efforts to develop effective melanoma treatment strategies using Cu-based nanoparticles through rational design.

Stochastic processes shape microbial community assembly in biofilters: Hidden role of rare taxa.

Stochastic and deterministic processes are the major themes governing microbial community assembly; however, their roles in bioreactors are poorly understood. Herein, the mechanisms underlying microbial assembly and the effect of rare taxa were studied in biofilters. Phylogenetic tree analysis revealed differences in microbial communities at various stages. Null model analysis showed that stochastic processes shaped the community assembly, and deterministic processes emerged only in the inoculated activated sludge after domestication. This finding indicates the dominant role of stochastic factors (biofilm formation, accumulation, and aging). The Sloan neutral model corroborated the advantages of stochastic processes and mainly attributed these advantages to rare taxa. Cooccurrence networks revealed the importance of rare taxa, which accounted for more than 85% of the keystones. Overall, these results provide good foundations for understanding community assembly, especially the role of rare taxa, and offer theoretical support for future community design and reactor regulation.

Decoding the influence of low temperature on biofilm development: The hidden roles of c-di-GMP.

Biofilms are widely used and play important roles in biological processes. Low temperature of wastewater inhibits the development of biofilms derived from wastewater activated sludge. However, the specific mechanism of temperature on biofilm development is still unclear. This study explored the mechanism of temperature on biofilm development and found a feasible method to enhance biofilm development at low temperature. The amount of biofilm development decreased by approximately 66 % and 55 % at 4 °C and 15 °C, respectively, as compared to 28 °C. The cyclic dimeric guanosine monophosphate (c-di-GMP) concentration also decreased at low temperature and was positively correlated with extracellular polymeric substance (EPS) content, formation, and adhesion strength. Microbial community results showed that low temperature inhibited the normal survival of most microorganisms, but promoted the growth of some psychrophile bacteria like Sporosarcina, Caldilineaceae, Gemmataceae, Anaerolineaceae and Acidobacteriota. Further analysis of functional genes demonstrated that the abundance of functional genes related to the synthesis of c-di-GMP (K18968, K18967 and K13590) decreased at low temperature. Subsequently, the addition of exogenous spermidine increased the level of intracellular c-di-GMP and alleviated the inhibition effect of low temperature on biofilm development. Therefore, the possible mechanism of low temperature on biofilm development could be the inhibition of the microorganism activity and reduction of the communication level between cells, which is the closely related to the EPS content, formation, and adhesion strength. The enhancement of c-di-GMP level through the exogenous addition of spermidine provides an alternative strategy to enhance biofilm development at low temperatures. The results of this study enhance the understanding of the influence of temperature on biofilm development and provide possible strategies for enhancing biofilm development at low temperatures.

Application of JAK inhibitors in paradoxical reaction through immune-related dermatoses.

Biologics play a positive and effective role in the treatment of immune-related dermatoses. However, many other immune-related diseases have also manifested along with biologics treatment. Paradoxical reaction through immune-related dermatoses refer to the new onset or exacerbation of other immune-mediated dermatoses (mainly psoriasis and atopic dermatitis) after biologics treatment of inflammatory dermatoses (mainly psoriasis and atopic dermatitis), such as new atopic dermatitis (AD) in psoriasis (PsO) treatment and new PsO in AD treatment. A common genetic background and Inflammatory pathway are possible pathogenesis. Faced with paradoxical reactions, the choice of therapy needs to be directed toward therapies effective for both diseases, such as Janus kinase (JAK) inhibitors. The Janus kinase and signal transducer and activator of transcription (JAK-STAT) pathway plays an important role in the inflammatory pathway, and has been widely used in the treatment of AD and PsO in recent years. This article focuses on JAK inhibitors such as tofacitinib, baricitinib, ruxolitinib, Abrocitinib, upadacitinib, and deucravacitinib, to explore the possible application in treatment of paradoxical reactions. Common side effects, baseline risk factors and safety use of JAK inhibitors were discussed.

RNA modifications in cellular metabolism: implications for metabolism-targeted therapy and immunotherapy.

Cellular metabolism is an intricate network satisfying bioenergetic and biosynthesis requirements of cells. Relevant studies have been constantly making inroads in our understanding of pathophysiology, and inspiring development of therapeutics. As a crucial component of epigenetics at post-transcription level, RNA modification significantly determines RNA fates, further affecting various biological processes and cellular phenotypes. To be noted, immunometabolism defines the metabolic alterations occur on immune cells in different stages and immunological contexts. In this review, we characterize the distribution features, modifying mechanisms and biological functions of 8 RNA modifications, including N6-methyladenosine (m6A), N6,2'-O-dimethyladenosine (m6Am), N1-methyladenosine (m1A), 5-methylcytosine (m5C), N4-acetylcytosine (ac4C), N7-methylguanosine (m7G), Pseudouridine (Ψ), adenosine-to-inosine (A-to-I) editing, which are relatively the most studied types. Then regulatory roles of these RNA modification on metabolism in diverse health and disease contexts are comprehensively described, categorized as glucose, lipid, amino acid, and mitochondrial metabolism. And we highlight the regulation of RNA modifications on immunometabolism, further influencing immune responses. Above all, we provide a thorough discussion about clinical implications of RNA modification in metabolism-targeted therapy and immunotherapy, progression of RNA modification-targeted agents, and its potential in RNA-targeted therapeutics. Eventually, we give legitimate perspectives for future researches in this field from methodological requirements, mechanistic insights, to therapeutic applications.

Association of CirAEs and Efficacy in NSCLC Patients Treated with PD-1/PD-L1: A Meta-analysis of Cohort Studies.

PURPOSE: To systematically evaluate the relationship between cutaneous immunerelated adverse events (cirAEs) and the efficacy of PD-1/PD-L1 in the treatment of non-small cell lung cancer (NSCLC) and to provide an evidence-based reference for the clinical application of PD-1/PD-L1 and safety evaluation. METHODS: Electronic databases (PubMed, Embase, Medline, Web of Science, and the Cochrane Library) were screened systematically to collect prospective or retrospective cohort studies on the correlation between cirAEs and efficacy of PD-1/PD-L1 in the treatment of NSCLC. RESULTS: A total of 3514 participants were included in 13 cohort studies (enclosing an ambidirectional cohort study). Outcomes revealed that compared with those patients with non cirAEs, patients suffering cirAEs were associated with significantly higher objective response rate (ORR) [risk ratio (RR): 1.74, 95% confidence interval (CI): 1.42-2.14, P<0.00001], longer progressionfree survival (PFS) [RR: 0.52, 95% CI: 0.45-0.60, P<0.00001], and longer overall survival (OS) [RR:0.46, 95% CI: 0.38-0.56]. Sensitivity analyses through the exclusion of one study at a time did not significantly influence the outcomes, indicating that the meta-analysis results were relatively robust. Furthermore, subgroup analyses revealed consistent results in the study design (prospective or retrospective cohort studies), as well as in the endpoint results (PFS and OS) of Kaplan-Meier curves or Cox proportional hazards regression for evaluable patients. CONCLUSION: Currently, evidence reveals that cirAEs development may be associated with a good prognosis and can be an early predictor of the efficacy of PD-1/PD-L1 in the treatment of NSCLC patients.

Strain-insensitive and multiplexed potentiometric ion sensors via printed PMMA molecular layer.

Wearable biomimetic electronics have aroused tremendous attention due to their capability to continuously detect and deliver real-time dynamic physiological signals pertaining to the wearer's environment. However, upon close contact with the human skins, a wearable sensor undergoes mechanical strain which inevitably degrades the electrical performance. To address this issue, we demonstrate a universal design approach for stretchable and multiplexed biosensors that can yield unaltered ion sensing performance under variable mechanical tensile strains, which is achieved by introducing a PMMA molecular layer between stretchable substrate and ion sensors. Such design demonstrates reliable multiplexed ion sensing capability and provides high sensitivity (>50 mV/decade), reliable selectivity, as well as wide working range (0.1-100 mM) for sodium, ammonium, potassium and calcium ions in complex sweat biomarkers. Via this introduced PMMA molecular layer, our sensor even exhibits 95 % electrical performance maintained up to 30 % tensile strain, whereas the mechanical tensile property is far superior to original sensor performance. Besides, the sensors were also utilized for real-time monitoring of ions in sweat to validate its biomedical electronics applications. This sensing platform can be easily extended to other biomimetic sensors to enable stable signal acquisition for biomedical electronics.

Effects of wearing masks during COVID-19 pandemic on the composition and diversity of skin bacteria and fungi in medical workers.

Background: Although studies have shown that wearing masks can affect the skin microbiome, more detailed and comprehensive research on wearing masks needs to be further explored. Objective: This study aimed to characterize the influence of mask wearing on the diversity and structural characteristics of the facial skin microbial community of medical staff during the COVID-19 pandemic by means of metagenomic sequencing (mNGS). Methods: A total of 40 samples were taken by swabbing the cheek in the 2 × 2 cm2 area before and after wearing the masks. DNA was extracted for metagenomic sequencing. Results: A statistically significant decrease was found in the α diversity between BN and AN groups and between B2 h and A2 h groups. BN and AN mean groups before and after 8 h of wearing the medical protective mask (N95), including 10 volunteers, respectively. B2 h and A2 h mean groups before and after 8 h of wearing masks, including 10 volunteers changing mask every 2 h, respectively. The ß diversity was found to be statistically reduced between BS and AS groups (p = 0.025), BN and AN groups (p = 0.009), and B2 h and A2 h group (p = 0.042). The fungal beta diversity was significantly decreased in every group before and after wearing masks. The main bacteria on the face before and after wearing masks were Cutibacterium (68.02 and 71.73%). Among the fungi, Malassezia predominated the facial skin surface before and after wearing masks (35.81 and 39.63%, respectively). Conclusion: Wearing different types of masks and changing masks according to different frequency will have different effects on the facial skin's microbiota.

Microplastics exposure promotes the proliferation of skin cancer cells but inhibits the growth of normal skin cells by regulating the inflammatory process.

Cutaneous squamous cell carcinoma (CSCC) is one of the most common malignant tumors of the skin, occurring primarily in the elderly population. CSCC is the second most common nonmelanoma skin malignancy in humans. The development of cutaneous squamous cell carcinoma is closely linked to environmental factors. Microplastics, as a new pollutant, are currently being intensively studied for their potential health effects. However, the effect of microplastics on skin cancer is not yet known and is an important scientific question that needs to be addressed. To this end, in the current study, two skin squamous cell carcinoma cell lines (SCL-1 and A431) were utilized to investigate the effects of microplastics on skin cancer, and cell behavior experiments showed that microplastics were internalized into the skin squamous cell carcinoma cell line in a time- and dose-dependent manner. Further experiments showed that microplastics promoted the proliferation of skin cancer cells by MTT, flow cytometry, laser confocal microscopy, Western blotting and other experimental techniques. Mechanistic studies showed that microplastics could lead to increased mitochondrial ROS in skin cancer cells, which in turn caused a change in mitochondrial membrane potential, thus opening mPTP, which in turn caused the release of mt-DNA from mitochondria into the cytoplasm, thus activating NLRP3 and ultimately causing skin cancer cell proliferation. We further evaluated the effect of microplastics on HaCaT cells in a normal skin cell model and showed that microplastics caused damage to normal skin cells through NLRP3-mediated inflammation and scorch death. The current study suggests that microplastics, as a new contaminant, may promote tumor cell proliferation while causing damage to normal skin.

Guarding skin under PPE: Mechanistic insights and technological innovations.

In the presence of diseases transmitted through respiratory droplets and direct contact, healthcare workers (HCWs) necessitate the use of personal protective equipment (PPE). For optimal safety, PPE should securely conform to the skin during extended wear. However, conventional PPE often lacks adequate air permeability and hygroscopicity, trapping heat and moisture emitted by the body within the enclosure. Such a hot and humid internal environment can induce skin damage, such as erythema, rash, pruritus, and itching among others, leading to microbial growth on the skin surface, the production of inflammatory mediators at the wound site and an increased risk of infection. This review strives to comprehensively elucidate the fundamental mechanisms triggering adverse skin reactions and their resultant manifestations. Furthermore, we explore recent advancements aimed at inhibiting these mechanisms to effectively mitigate the occurrence of skin lesions.

Reversing Gray Hair: Inspiring the Development of New Therapies Through Research on Hair Pigmentation and Repigmentation Progress.

Hair graying is a common and visible sign of aging resulting from decreased or absence of melanogenesis. Although it has been established that gray hair greatly impacts people's mental health and social life, there is no effective countermeasure other than hair dyes. It has long been thought that reversal of gray hair on a large scale is rare. However, a recent study reported that individual gray hair darkening is a common phenomenon, suggesting the possibility of large-scale reversal of gray hair. In this article, we summarize the regulation mechanism of melanogenesis and review existing cases of hair repigmentation caused by several factors, including monoclonal antibodies drugs, tyrosine kinase inhibitors (TKIs), immunomodulators, other drugs, micro-injury, and tumors, and speculate on the mechanisms behind them. This review offers some insights for further research into the modulation of melanogenesis and presents a novel perspective on the development of clinical therapies, with emphasis on topical treatments.

Engineering a Pseudomonas putida as living quorum quencher for biofilm formation inhibition, benzenes degradation, and environmental risk evaluation.

Bacterial communication interruption based on quorum quenching (QQ) has been proven its potential in biofilm formation inhibition and biofouling control. However, it would be more satisfying if QQ could be combined with the efficient degradation of contaminants in environmental engineering. In this study, we engineered a biofilm of Pseudomonas putida through introducing a QQ synthetic gene, which achieved both biofilm formation inhibition and efficient degradation of benzene series in wastewater. The aiiO gene introduced into the P. putida by heat shock method was highly expressed to produce QQ enzyme to degrade AHL-based signal molecules. The addition of this engineered P. putida reduced the AHLs concentration, quorum sensing gene expression, and connections of the microbial community network in activated sludge and therefore inhibited the biofilm formation. Meanwhile, the sodium benzoate degradation assay indicated an enhanced benzene series removal ability of the engineering bacteria on activated sludge. Besides, we also demonstrated a controllable environmental risk of this engineered bacteria through monitoring its abundance and horizontal gene transfer test. Overall, the results of this study suggest an alternative strategy to solve multiple environmental problems through genetic engineering means and provide support for the application of engineered bacteria in environmental biotechnology.

The economic burden and quality of life of patients with psoriasis treated with biologics in China.

BACKGROUND: Although biologics improve the quality of life of psoriasis patients, they also impose a substantial economic burden. There is a lack of research addressing the economic and humanistic impact of biologics in China. OBJECTIVE: This cross-sectional investigation aims to assess the economic cost, quality of life, and patient satisfaction among individuals with psoriasis treated with biologics and non-biologics. METHODS: From July 2021 to December 2022, eligible patients with psoriasis were recruited through both on-site and online questionnaire completion. The questionnaires collected sociodemographic data, clinical characteristics of psoriasis, economic costs associated with treatment, and the Dermatological Life Quality Index (DLQI). RESULTS: 481 patients with a mean age of 40.8 ± 13.4 years old were included and classified into a non-biologic (n = 195) and biologic (n = 286) treatment group. The direct medical cost for non-biologics patients was 7,249 CNY, accounting for 70.0% of the total cost, while biologics patients incurred 15,176 CNY, making up 94.3% of the total cost. The non-biologic group had higher costs related to hospitalization, self-purchase of drugs, and indirect costs than the biologic treatment group. Additionally, DLQI scores were higher in the non-biologic group. CONCLUSION: Patients in the biologic group experienced a higher economic burden and better quality of life than those in the non-biologic group.

A Report of Eruptive Pruritic Papular Porokeratosis Treated with Abrocitinib.

Eruptive pruritic papular porokeratosis (EPPP) is a subtype of porokeratosis (PK). EPPP is characterized by intense itching and challenging to treat in some cases. Herein, for the first time, a case of successful relief of EPPP treated with abrocitinib was reported. A 75-year-old male with a 60-year history of PK suddenly experienced severe itching in the past 6 months. The patient's use of antihistamines, prednisone, vitamin A derivatives, vitamin D derivatives, and tripterygium wilfordii showed poor efficacy. Abrocitinib is a highly selective JAK1 inhibitor, and JAK1 appears to play a crucial role in pruritic diseases. Abrocitinib can quickly relieve itching within 24 hours. Before abrocitinib treatment, the visual analog scale (VAS) score was 10, the 12-item pruritus severity scale (12-PSS) score was 19, and the dermatology life quality index (DLQI) score was 18. Abrocitinib (100 mg) was taken orally once a day. After 1 month of oral administration of abrocitinib, the skin lesions gradually subsided, pruritus was relieved, and no adverse side effects occurred. The VAS, 12-PSS, and DLQI scores of the patient decreased to 2, 3, and 4, respectively. This report suggests a potential therapeutic benefit of abrocitinib in managing EPPP. However further investigations with larger sample sizes and controlled studies are necessary to validate its efficacy as a clinical therapy.

Top 100 Pemphigus Papers of the Highest Citation: A Bibliometric Analysis.

Background: There have been several papers published about pemphigus. Bibliometric analysis is useful in determining the most significant research in a certain topic. By bibliometric research, we were able to determine the 100 most frequently reference articles in pemphigus. Aims and Objective: Using bibliometric tools to find and evaluate the top 100 most reference papers in pemphigus. Materials and Methods: On 19 February 2023, the Web of Science database was utilized to launch a title-specific search. Publications were listed in degrading order on the basis of their total citations. We examined the top 100 most reference pemphigus publications. Results: The years of publication varied from 1971 to 2020, with the 1990s being the most active. According to diverse study objectives, the 100 publications were separated into clinical aspects and diagnosis (20%), pathophysiology (52%), therapy (13%), epidemiology (8%), related disorders (1%) and others (6%). The 100 papers were published in 37 different publications. The top 100 reference articles included 54 first authors of 11 nations, most of whom came from North America and Europe. Stanley, J R, from Uniformed Services University of the Health Sciences, was the principal author. Conclusions: A thorough bibliometric research of the top 100 publications in pemphigus was provided by the research, which may be useful for future research.

Efficacy and safety of microneedling, fractional CO2 laser, and cryotherapy combined with 5-aminolevulinic acid photodynamic therapy in the treatment of actinic keratosis: A multicenter prospective randomized controlled study.

BACKGROUND: Photodynamic therapy (PDT) for actinic keratosis (AK) is limited by the depth of treatment. Microneedling or fractional CO2 laser can facilitate the penetration of photosensitizer, while cryotherapy can treat deeper tissues but is not suitable for field cancerization. OBJECTIVE: To investigate the efficacy of microneedling, fractional CO2 laser, and cryotherapy in combination with PDT for AK. METHODS: Patients with AK were randomized into 4 groups, including group A with microneedling + PDT, group B with fractional CO2 laser + PDT, group C with cryotherapy + PDT, and group D with PDT. After 12 weeks, the clinical, dermoscopic, and reflectance confocal microscopy (RCM) outcomes were assessed. RESULTS: A total of 129 patients were included in this study, with 31, 30, 35, and 31 patients in each group, yielding clinical response rates of 90.3%, 93.3%, 97.1%, and 74.2%, respectively (P=0.026). The RCM response rates were 71.0%, 80.0%, 85.7%, and 54.8%, respectively (P=0.030). The dermoscopic response rates were 77.4%, 83.3%, 88.6%, and 60.0%, respectively (P=0.039). Group C showed the best efficacy in terms of clinical, dermoscopic, and RCM outcomes. CONCLUSIONS: All three treatments improved the efficacy of PDT and were well tolerated, with cryotherapy + PDT showing the best efficacy.

METTL16 promotes glycolytic metabolism reprogramming and colorectal cancer progression.

BACKGROUND: Glycolysis is the key hallmark of cancer and maintains malignant tumor initiation and progression. The role of N6-methyladenosine (m6A) modification in glycolysis is largely unknown. This study explored the biological function of m6A methyltransferase METTL16 in glycolytic metabolism and revealed a new mechanism for the progression of Colorectal cancer (CRC). METHODS: The expression and prognostic value of METTL16 was evaluated using bioinformatics and immunohistochemistry (IHC) assays. The biological functions of METTL16 in CRC progression was analyzed in vivo and in vitro. Glycolytic metabolism assays were used to verify the biological function of METTL16 and Suppressor of glucose by autophagy (SOGA1). The protein/RNA stability, RNA immunoprecipitation (RIP), Co-immunoprecipitation (Co-IP) and RNA pull-down assays were used to explore the potential molecular mechanisms. RESULTS: SOGA1 is a direct downstream target of METTL16 and involved in METTL16 mediated glycolysis and CRC progression. METTL16 significantly enhances SOGA1 expression and mRNA stability via binding the "reader" protein insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1). Subsequently, SOGA1 promotes AMP-activated protein kinase (AMPK) complex ubiquitination, inhibits its expression and phosphorylation, thus upregulates pyruvate dehydrogenase kinase 4 (PDK4), a crucial protein controlling glucose metabolism. Moreover, Yin Yang 1 (YY1) can transcriptionally inhibit the expression of METTL16 in CRC cells by directly binding to its promoter. Clinical data showed that METTL16 expression is positively correlated to SOGA1 and PDK4, and is associated with poor prognosis of CRC patients. CONCLUSIONS: Our findings suggest that METTL16/SOGA1/PDK4 axis might be promising therapeutic targets for CRC.

A spatiotemporal barrier formed by Follistatin is required for left-right patterning.

How left-right (LR) asymmetry emerges in a patterning field along the anterior-posterior axis remains an unresolved problem in developmental biology. Left-biased Nodal emanating from the LR organizer propagates from posterior to anterior (PA) and establishes the LR pattern of the whole embryo. However, little is known about the regulatory mechanism of the PA spread of Nodal and its asymmetric activation in the forebrain. Here, we identify bilaterally expressed Follistatin (Fst) as a regulator blocking the propagation of the zebrafish Nodal ortholog Southpaw (Spaw) in the right lateral plate mesoderm (LPM), and restricting Spaw transmission in the left LPM to facilitate the establishment of a robust LR asymmetric Nodal patterning. In addition, Fst inhibits the Activin-Nodal signaling pathway in the forebrain thus preventing Nodal activation prior to the arrival, at a later time, of Spaw emanating from the left LPM. This contributes to the orderly propagation of asymmetric Nodal activation along the PA axis. The LR regulation function of Fst is further confirmed in chick and frog embryos. Overall, our results suggest that a robust LR patterning emerges by counteracting a Fst barrier formed along the PA axis.

Smart nanostructures for targeted oxygen-producing photodynamic therapy of skin photoaging and potential mechanism.

Background: Photodynamic therapy increases collagen and decreases solar fibrosis in photoaged skin; however, the efficacy of photodynamic therapy is limited in tissues with a hypoxic microenvironment. Methods: A novel autogenous oxygen-targeted nanoparticle, named MCZT, was synthesized based on the zeolitic imidazole framework material ZIF-8, methyl aminolevulinate, catalase and an anti-TRPV1 monoclonal antibody, and its effects on skin photoaging were investigated. Results: MCZT was successfully synthesized and showed uniform particle size, good dispersion, and excellent biocompatibility and safety. Moreover, MCZT effectively alleviated UV-induced inflammation, cellular senescence and apoptosis in HFF-1 cells. In in vivo models, MCZT ameliorated UV-evoked erythema and wrinkling, inflammation and oxidative stress, as well as the loss of collagen fibers and water, in the skin of mice. Conclusion: These findings suggest that MCZT holds promising potential for the treatment of skin photoaging.