Thyroxine regulates pig Sertoli cell line proliferation and maturation through the IKK/NFκB and p38 MAPK signaling pathways.

The aim of this study was to investigate the signaling pathways involved in the proliferation and differentiation of pig Sertoli cells (SCs) mediated by thyroid hormone (T3) to provide a theoretical and practical basis for enhancing pig semen production. The effects of different concentrations of T3 on the proliferation of pig SCs were evaluated using the CCK8 assay. The impact of T3 on the proliferation and differentiation of pig SCs was further examined using RNA-seq, qPCR, and Western Blotting techniques. Additionally, the involvement of the p38 MAPK and NFκB pathways in mediating the effects of T3 on SCs proliferation and differentiation was investigated. Our findings revealed a strong correlation between the dosage of T3 and the inhibition of pig SCs proliferation and promotion of maturation. T3 regulated the activation state of the NFκB signaling pathway by upregulating IKKα, downregulating IKKß, and promoting IκB phosphorylation. Furthermore, T3 facilitated SCs maturation by upregulating AR and FSHR expression while downregulating KRT-18. In conclusion, T3 inhibits pig SCs proliferation and promote pig SCs maturation through the IKK/NFκB and p38 MAPK pathways. These findings provide valuable insights into the mechanisms by which T3 influences the proliferation and maturation of pig SCs.

Influence of urbanization on meteorological conditions and ozone pollution in the Central Plains Urban Agglomeration, China.

Changes in aerodynamic and thermal conditions caused by urbanization can impact regional meteorological conditions, subsequently affecting air quality. Updated Moderate-resolution Imaging Spectroradiometer (MODIS) land use data and coupled with the urban canopy models (UCMs) in the Weather Research and Forecasting (WRF) model. This enabled the impact of urban land expansion on meteorological conditions and ozone (O3) concentrations to be evaluated. Urban expansion increased the temperature at 2 m (T2) and the probability of precipitation in urban expansion areas, and enhanced the surface urban heat island at night. As the expansion areas became progressively larger, the increase in T2 became more pronounced. The proportions of urban surfaces in June 2016, 2018, and 2020 compared to 2001 increased by 0.69%, 0.83%, and 1.04%, respectively, while T2 increased by 0.12, 0.19, and 0.20 °C in urban areas, respectively. With urban expansion, the O3 concentration increased by 1.12, 1.37, and 0.76 µg/m3 (three-year averages) in urban, suburban, and rural areas, respectively. After coupling a multi-layer urban canopy model (building effect parameterization, BEP), or a multi-layer urban canopy model with a building energy model including anthropogenic heat due to air conditioning (BEP + BEM, abbreviated as BEM simulation), the O3 concentration changed significantly in the urban expansion area, compared to the results of a single-layer urban canopy model (UCM). O3 concentrations decreased most in the BEP simulation (-0.77 µg/m3), while O3 concentrations increased most in the BEM simulation (+1.85 µg/m3). The average observed O3 concentration was 108.35 µg/m3 (three-year average), while the simulated value was 75.65-83.72 µg/m3 (R = 0.69-0.77). The validation results in the BEM and Global Optimal Scenario (GOS) simulations were relatively good, with the GOS simulation producing slightly better results than the BEM. The simulation of O3 in urban agglomerations could be improved by integrating the results of the UCMs.

Endoscopic endonasal resection of symptomatic Rathke's cleft cysts: outcomes of the strategy to maintain the fenestration open.

PURPOSE: The study intends to clarify the optimal endoscopic endonasal surgical strategy for symptomatic Rathke's cleft cysts (RCCs). METHODS: We retrospectively analyzed patients with RCCs that underwent EEA surgery. The strategy for surgical and reconstruction method selection was presented. Patients were split into groups of fenestration open or closed. Pre- and postoperative symptoms, imaging, ophthalmologic, and endocrinologic exams were reviewed. The incidence of complications and the recurrence rates were determined. RESULTS: The 75 individuals were all received primary operations. The fenestration closed group contained 32 cases, while the fenestration open group contained 43 cases. The median follow-up period was 39 months. The three primary complaints were headache (n = 51, 68.00%), vision impairment (n = 45, 60.00%), and pituitary dysfunction (n = 16, 21.33%). Of the 51 patients with preoperative headaches, 48 (94.12%) reported improvement in their symptoms following surgery. Twenty-three out of 45 patients (51.11%) experienced an improvement in visual impairment. Pituitary dysfunction was found improved in 14 out of 16 individuals (87.50%). There was no discernible difference in the rate of symptom alleviation between both groups. There were three patients (3/75, 4.00%) had cyst reaccumulation. One of them (1/75, 1.33%), which needed reoperation, was healed using pterional approach. In term of complications, cerebral infections occurred in two patients (2/75, 2.67%). Both of them recovered after antibiotic treatment. No postoperative cerebrospinal fluid rhinorrhea occurred. One patient (1/75, 1.33%) in the open group experienced epistaxis. There was no persistent hypopituitarism or diabetes insipidus (DI). Analysis of headache related factors showed that the presence of wax like nodules was related to it. CONCLUSION: RCC was successfully treated with endoscopic endonasal surgery with few problems when the fenestration was kept as open as feasible. Preoperative identification of T2WI hypointense nodules may be a potential reference factor for surgical indication.

Integrated analysis identified the role of three family members of ARHGAP in pancreatic adenocarcinoma.

The Rho GTPase activating protein family (ARHGAPs) is expressed in pancreatic adenocarcinoma (PAAD) but its function is unclear. The aim of this study was to explore the role and potential clinical value of ARHGAPs in PAAD. Using TCGA and GEO databases to analyze expression of ARHGAPs in PAAD and normal tissues. Survival curve was drawn by Kaplan-Meier. ARHGAPs were integrated analyzed by GEPIA2, TIMER, UCLCAN, cBioPortal and R language. Protein level and prognostic value were evaluated via IHC staining or survival analysis. We totally identify 18 differentially expressed (DE) ARHGAPs in PAAD. Among the 18 DE genes, 8 were positively correlated with tumor grade; abnorrmal expression of 5 was positively correlated with copy number variation; expression of 4 was positively correlated with promoter hypomethylation. Multivariate Cox regression identified ARHGAP5, ARHGAP11A, and ARHGAP12 as independent prognostic factors of PAAD. The function of ARHGAPs was mainly related to GTPase activity and signaling, axon guidance, proteoglycans in cancer and focal adhesion. Expression of 7 ARHGAPs was strongly correlated with immune infiltration. Immunohistochemistry showed increased protein levels of ARHGAP5, ARHGAP11A, and ARHGAP12 in PAAD tissues. Survival analysis confirmed a negative correlation between ARHGAP5, ARHGAP11A, and ARHGAP12 expression and patient prognosis. Multivariate Cox regression proved ARHGAP5, ARHGAP11A, and ARHGAP12 could serve as independent prognostic indicators for PAAD. Finally, this study verified ARHGAP5, ARHGAP11A, and ARHGAP12 as independent prognostic factors in PAAD, suggesting their significance for the diagnosis and treatment of PAAD.

Effects of adding bile acids to dietary storage japonica brown rice on growth performance, meat quality, and intestinal microbiota of growing-finishing Min pigs.

Introduction: This study investigated the effects of storage japonica brown rice (SJBR) and bile acids (BA) on the growth performance, meat quality, and intestinal microbiota of growing-finishing Min pigs. Methods: A total of 24 healthy Min pigs with a similar body weight of 42.25 ± 2.13 kg were randomly divided into three groups with eight replicates of one pig each. The groups were as follows: CON (50% corn), SJBR (25% corn +25% SJBR), and SJBR + BA (25% corn +25% SJBR +0.025% hyodeoxycholic acid). The experimental period lasted from day 90 (the end of the nursery phase) to day 210 (the end of the finishing phase). Results: The results showed the following: (1) Compared with the CON group, there was no significant difference in the average daily gain (ADG) and average daily feed intake (ADFI) of the SJBR and SJBR + BA groups, and the feed conversion ratio (FCR) was significantly decreased (p < 0.05). (2) Compared with the CON group, the total protein (TP) content in the serum was significantly increased, and the blood urea nitrogen (BUN) content was significantly decreased (p < 0.05) in the SJBR and SJBR + BA groups; moreover, HDL-C was significantly higher by 35% (p < 0.05) in the SJBR + BA group. (3) There were no significant differences in carcass weight, carcass length, pH, drip loss, cooking loss, and shear force among the groups; the eye muscle area was significantly increased in the SJBR group compared with the CON group (p < 0.05); back fat thickness was significantly decreased in the SJBR + BA group compared with the SJBR group (p < 0.05); and the addition of SJBR significantly increased the mRNA expression of MyHC I in the longissimus dorsi (LD) muscle of growing-finishing Min pigs (p < 0.05). (4) The cecal bacteria were detected using 16S rDNA, and the proportion of Lactobacillus was increased gradually at the genus level, but there was no significant difference among the different groups. Conclusion: In conclusion, 25% SJBR can improve the growth performance and increase the abundance of intestinal beneficial bacteria, and based on this, adding bile acids can reduce the back fat thickness of growing-finishing Min pigs.

Deep Learning Bridged Bioactivity, Structure, and GC-HRMS-Readable Evidence to Decipher Nontarget Toxicants in Sediments.

Identifying causative toxicants in mixtures is critical, but this task is challenging when mixtures contain multiple chemical classes. Effect-based methods are used to complement chemical analyses to identify toxicants, yet conventional bioassays typically rely on an apical and/or single endpoint, providing limited diagnostic potential to guide chemical prioritization. We proposed an event-driven taxonomy framework for mixture risk assessment that relied on high-throughput screening bioassays and toxicant identification integrated by deep learning. In this work, the framework was evaluated using chemical mixtures in sediments eliciting aryl-hydrocarbon receptor activation and oxidative stress response. Mixture prediction using target analysis explained <10% of observed sediment bioactivity. To identify additional contaminants, two deep learning models were developed to predict fingerprints of a pool of bioactive substances (event driver fingerprint, EDFP) and convert these candidates to MS-readable information (event driver ion, EDION) for nontarget analysis. Two libraries with 121 and 118 fingerprints were established, and 247 bioactive compounds were identified at confidence level 2 or 3 in sediment extract using GC-qToF-MS. Among them, 12 toxicants were analytically confirmed using reference standards. Collectively, we present a "bioactivity-signature-toxicant" strategy to deconvolute mixtures and to connect patchy data sets and guide nontarget analysis for diverse chemicals that elicit the same bioactivity.

Effects of erythromycin on biofilm formation and resistance mutation of Escherichia coli on pristine and UV-aged polystyrene microplastics.

Microplastics (MPs) and antibiotics co-occur widely in the environment and pose combined risk to microbial communities. The present study investigated the effects of erythromycin on biofilm formation and resistance mutation of a model bacterium, E. coli, on the surface of pristine and UV-aged polystyrene (PS) MPs sized 1-2 mm. The properties of UV-aged PS were significantly altered compared to pristine PS, with notable increases in specific surface area, carbonyl index, hydrophilicity, and hydroxyl radical content. Importantly, the adsorption capacity of UV-aged PS towards erythromycin was approximately 8-fold higher than that of pristine PS. Biofilms colonizing on UV-aged PS had a greater cell count (5.6 × 108 CFU mg-1) and a higher frequency of resistance mutation (1.0 × 10-7) than those on pristine PS (1.4 × 108 CFU mg-1 and 1.4 × 10-8, respectively). Moreover, erythromycin at 0.1 and 1.0 mg L-1 significantly (p < 0.05) promoted the formation and resistance mutation of biofilm on both pristine and UV-aged PS. DNA sequencing results confirmed that the biofilm resistance was attributed to point mutations in rpoB segment of the bacterial genome. qPCR results demonstrated that both UV aging and erythromycin repressed the expression levels of a global regulator rpoS in biofilm bacteria, as well as two DNA mismatch repair genes mutS and uvrD, which was likely to contribute to increased resistance mutation frequency.

Identification of IGF2 promotes skin wound healing by co-expression analysis.

Oral mucosa is an ideal model for studying scarless wound healing. Researchers have shown that the key factors which promote scarless wound healing already exist in basal state of oral mucosa. Thus, to identify the other potential factors in basal state of oral mucosa will benefit to skin wound healing. In this study, we identified eight gene modules enriched in wound healing stages of human skin and oral mucosa through co-expression analysis, among which the module M8 was only module enriched in basal state of oral mucosa, indicating that the genes in module M8 may have key factors mediating scarless wound healing. Through bioinformatic analysis of genes in module M8, we found IGF2 may be the key factor mediating scarless wound healing of oral mucosa. Then, we purified IGF2 protein by prokaryotic expression, and we found that IGF2 could promote the proliferation and migration of HaCaT cells. Moreover, IGF2 promoted wound re-epithelialization and accelerated wound healing in a full-thickness skin wound model. Our findings identified IGF2 as a factor to promote skin wound healing which provide a potential target for wound healing therapy in clinic.

Identification of a shared gene signature and biological mechanism between diabetic foot ulcers and cutaneous lupus erythemnatosus by transcriptomic analysis.

Diabetic foot ulcers (DFU) and cutaneous lupus erythematosus (CLE) are both diseases that can seriously affect a patient's quality of life and generate economic pressure in society. Symptomatically, both DLU and CLE exhibit delayed healing and excessive inflammation; however, there is little evidence to support a molecular and cellular connection between these two diseases. In this study, we investigated potential common characteristics between DFU and CLE at the molecular level to provide new insights into skin diseases and regeneration, and identify potential targets for the development of new therapies. The gene expression profiles of DFU and CLE were obtained from the Gene Expression Omnibus (GEO) database and used for analysis. A total of 41 common differentially expressed genes (DEGs), 16 upregulated genes and 25 downregulated genes, were identified between DFU and CLE. GO and KEGG analysis showed that abnormalities in epidermal cells and the activation of inflammatory factors were both involved in the occurrence and development of DFU and CLE. Protein-protein interaction network (PPI) and sub-module analysis identified enrichment in seven common key genes which is KRT16, S100A7, KRT77, OASL, S100A9, EPGN and SAMD9. Based on these seven key genes, we further identified five miRNAs(has-mir-532-5p, has-mir-324-3p,has-mir-106a-5p,has-mir-20a-5p,has-mir-93-5p) and7 transcription factors including CEBPA, CEBPB, GLI1, EP30D, JUN,SP1, NFE2L2 as potential upstream molecules. Functional immune infiltration assays showed that these genes were related to immune cells. The CIBERSORT algorithm and Pearson method were used to determine the correlations between key genes and immune cells, and reverse key gene-immune cell correlations were found between DFU and CLE. Finally, the DGIbd database demonstrated that Paquinimod and Tasquinimod could be used to target S100A9 and Ribavirin could be used to target OASL. Our findings highlight common gene expression characteristics and signaling pathways between DFU and CLE, indicating a close association between these two diseases. This provides guidance for the development of targeted therapies and mutual interactions.

Antibiotic bone cement accelerates diabetic foot wound healing: Elucidating the role of ROCK1 protein expression.

Clinical studies indicate antibiotic bone cement with propeller flaps improves diabetic foot wound repair and reduces amputation rates, but the molecular mechanisms, particularly key proteins' role remain largely unexplored. This study assessed the efficacy of antibiotic bone cement for treating diabetic foot wounds, focusing on molecular impact on ROCK1. Sixty patients were randomized into experimental (EXP, n = 40) and control (CON, n = 20) groups, treated with antibiotic bone cement and negative pressure. Wound healing rate, amputation rate, wound secretion culture and C-reactive protein (CRP) changes, were monitored. Comprehensive molecular investigations were conducted and animal experiments were performed to further validate the findings. Statistical methods were employed to verify significant differences between the groups and treatment outcomes. The EXP group showed significant improvements in wound healing ( χ 2 $$ {\chi}^2 $$ = 11.265, p = 0.004) and reduced amputation rates. Elevated levels of ROCK1, fibroblasts and VGF were observed in the trauma tissue post-treatment in the experimental group compared to pre-treatment and the control group (all p < 0.05). Improved trauma secretion culture and CRP were also noted in the EXP group (all p < 0.05). The study suggests that antibiotic bone cement enhances diabetic foot wound healing, possibly via upregulation of ROCK1. Further research is needed to elucidate the underlying molecular mechanisms and broader clinical implications.

Effects of Erythromycin on Nereis succinea and the Intestinal Microbiome across Different Salinity Levels.

The exposure of aquatic organisms to pollutants often occurs concomitantly with salinity fluctuations. Here, we reported the effects of erythromycin (0.250, 7.21, and 1030 µg/L) on marine invertebrate N. succinea and its intestinal microbiome under varying salinity levels (5‰, 15‰, and 30‰). The salinity elicited significant effects on the growth and intestinal microbiome of N. succinea. The susceptibility of the intestinal microbiome to erythromycin increased by 8.7- and 6.2-fold at salinities of 15‰ and 30‰, respectively, compared with that at 5‰ salinity. Erythromycin caused oxidative stress and histological changes in N. succinea intestines, and inhibited N. succinea growth in a concentration-dependent manner under 30‰ salinity with a maximum inhibition of 25%. At the intestinal microbial level, erythromycin enhanced the total cell counts at 5‰ salinity but reduced them at 15‰ salinity. Under all tested salinities, erythromycin diminished the antibiotic susceptibility of the intestinal microbiome. Two-way ANOVA revealed significant interactive effects (p < 0.05) between salinity and erythromycin on various parameters, including antibiotic susceptibility and intestinal microbial diversity. The present findings demonstrated the significant role of salinity in modulating the impacts of erythromycin, emphasizing the necessity to incorporate salinity fluctuations into environmental risk assessments.

METTL3/YTHDF2 m6A axis mediates the progression of diabetic nephropathy through epigenetically suppressing PINK1 and mitophagy.

AIMS: This research aimed to investigate the specific mechanism of methyltransferase like 3 (METTL3) in the progression of diabetic kidney disease (DKD). MATERIALS AND METHODS: The model of diabetic kidney disease was established with HK-2 cells and mice in vitro and in vivo. The N6 methyladenosine (m6A) contents in the cells and tissues were detected with a commercial kit and the m6A levels of PTEN induced putative kinase 1 (PINK2) were detected with a MeRIP kit. The mRNA and protein levels were determined with RT-qPCR and western blot. The ROS, TNF-α, and IL-6 levels were assessed with ELISA. The cell proliferative ability was measured by a CCK-8 assay and cell apoptosis was determined with TUNEL staining. The HE and Masson staining was performed to observe the renal morphology. The RIP assay was conducted to detect the interaction between METTL3/YTHDF2 and PINK1. RESULTS: The m6A content and METTL3 levels were prominently elevated in diabetic kidney disease. METTL3 silencing promoted the cell growth and the expression of LC3 II, PINK1, and Parkin, while inhibiting the cell apoptosis and the expression of LC3 I and p62 in the high glucose (HG) stimulated HK-2 cells. METTL3 silencing also decreased the ROS, TNF-α, and IL-6 levels in diabetic kidney disease. PINK1 silencing neutralized the function of sh-METTL3 in the HG stimulated HK-2 cells. The HE and Masson staining showed that METTL3 silencing alleviated the kidney injury induced by DKD. METTL3 silencing decreased the m6A levels of PINK1, while increased the mRNA levels of PINK1 which depended on YTHDF2. CONCLUSIONS: METTL3 silencing could inhibit the progression of diabetic nephropathy in vivo and in vitro by regulating the m6A modification of PINK1, which depends on YTHDF2. Our research lays the theoretical foundation for the precise treatment of diabetic kidney disease and the development of targeted drugs in the future.

Inhalable Bottlebrush Polymer Bioconjugates as Vectors for Efficient Pulmonary Delivery of Oligonucleotides.

Antisense oligonucleotides hold therapeutic promise for various lung disorders, but their efficacy is limited by suboptimal delivery. To address this challenge, we explored the use of inhaled bottlebrush polymer-DNA conjugates, named pacDNA, as a delivery strategy. Inhaled pacDNA exhibits superior mucus penetration, achieving a uniform and sustained lung distribution in mice. Targeting the 5' splice site of an aberrant enhanced green fluorescence protein (EGFP) pre-mRNA in EGFP-654 mice, inhaled pacDNA more efficiently corrects splicing than a B-peptide conjugate and restores EGFP expression in the lung. Additionally, in an orthotopic NCI-H358 non-small-cell lung tumor mouse model, inhaled pacDNA targeting wild-type KRAS mRNA effectively suppresses KRAS expression and inhibits lung tumor growth, requiring a substantially lower dosage compared to intravenously injected pacDNA. These findings demonstrate the potential of bottlebrush polymer-DNA conjugates as a promising agent for enhanced oligonucleotide therapy in the lung and advancing the treatment landscape for lung disorders.

Relationship between ozone and air temperature in future conditions: A case study in sichuan basin, China.

The Sichuan Basin (SCB) is located in southwestern China and has a unique topography where ozone (O3) pollution is frequent during summer. Few studies have clarified the relationship between O3 and air temperature in SCB. Here, the SCB was divided into four major urban agglomerations. The weather research and forecasting model-community multiscale air quality model (WRF-CMAQ) was used to analyze the meteorology, spatial distribution characteristics of pollutants, and interactions among the urban agglomerations in the SCB. WRF-CMAQ was used to study the historical changes in the climate penalty factor (CPF) from 2015 to 2020 and the climate pathways under the SSP2-4.5 CPF in values in 2030 for the ambitious pollution NDC-goal scenario (NDC) and current-goals scenario (Current). The results show that the SCB is warmer in the summer months with prevailing northeasterly winds. Ozone accumulated in the western part of the SCB, and a high CPF of O3 concentration was most prominent in NW urban agglomeration, where the O3 concentration increased by 4.12-5.40 ppb for every 1 °C increase in air temperature. The observed CPF in the SCB in 2020 averaged 3.64 ppb/°C. The average CPF in the SCB in 2030 was 1.152 ppb/°C under the NDC scenario and 1.269 ppb/°C under the current scenario. This study is critical for understanding the relationship between O3 concentration and air temperature in China.

On-Demand Opioid Effect Reversal with an Injectable Light-Triggered Polymer-Naloxone Conjugate.

Misuse of opioids can lead to a potential lethal overdose. Timely administration of naloxone is critical for survival. Here, we designed a polymer-naloxone conjugate that can provide on-demand phototriggered opioid reversal. Naloxone was attached to the polymer poly(lactic-co-glycolic acid) via a photocleavable coumarin linkage and formulated as injectable nanoparticles. In the absence of irradiation, the formulation did not release naloxone. Upon irradiation with blue (400 nm) light, the nanoparticles released free naloxone, reversing the effect of morphine in mice. Such triggered events could be performed days and weeks after the initial administration of the nanoparticles and could be performed repeatedly.

Advancements in engineered exosomes for wound repair: current research and future perspectives.

Wound healing is a complex and prolonged process that remains a significant challenge in clinical practice. Exosomes, a type of nanoscale extracellular vesicles naturally secreted by cells, are endowed with numerous advantageous attributes, including superior biocompatibility, minimal toxicity, and non-specific immunogenicity. These properties render them an exceptionally promising candidate for bioengineering applications. Recent advances have illustrated the potential of exosome therapy in promoting tissue repair. To further augment their therapeutic efficacy, the concept of engineered exosomes has been proposed. These are designed and functionally modifiable exosomes that have been tailored on the attributes of natural exosomes. This comprehensive review delineates various strategies for exosome engineering, placing specific emphasis on studies exploring the application of engineered exosomes for precision therapy in wound healing. Furthermore, this review sheds light on strategies for integrating exosomes with biomaterials to enhance delivery effectiveness. The insights presented herein provide novel perspectives and lay a robust foundation for forthcoming research in the realm of cutaneous wound repair therapies.

Early versus delayed antihypertensive treatment in patients with acute ischaemic stroke: multicentre, open label, randomised, controlled trial.

OBJECTIVES: To compared the effect of early antihypertensive treatment started within 24-48 h of stroke onset versus delaying treatment until day eight on reducing dependency or death. DESIGN: Multicentre, randomised, open label trial. SETTING: 106 hospitals in China between 13 June 2018 and 10 July 2022. PARTICIPANTS: 4810 patients (≥40 years) were enrolled with acute ischaemic stroke within 24-48 h of symptom onset and elevated systolic blood pressure between 140 mm Hg and <220 mm Hg. INTERVENTIONS: Patients were randomly assigned to receive antihypertensive treatment immediately after randomisation (aimed at reducing systolic blood pressure by 10%-20% within the first 24 h and a mean blood pressure <140/90 mm Hg within seven days) or to discontinue antihypertensive medications for seven days if they were taking them, and then receive treatment on day 8 (aimed at achieving mean blood pressure <140/90 mm Hg). MAIN OUTCOME MEASURES: The primary outcome was the combination of functional dependency or death (modified Rankin scale score ≥3) at 90 days. Intention to treat analyses were conducted. RESULTS: 2413 patients were assigned to the early treatment group and 2397 were assigned to the delayed treatment group. Mean systolic blood pressure was reduced by 9.7% (from 162.9 mm Hg to 146.4 mm Hg) in the early treatment group and by 4.9% (from 162.8 mm Hg to 154.3 mm Hg) in the delayed treatment group within 24 h after randomisation (P for group difference <0.001). Mean systolic blood pressure was 139.1 mm Hg in the early treatment group and 150.9 mm Hg in the delayed treatment group on day seven (P for group difference <0.001). Additionally, 54.6% of patients in the early treatment group and 22.4% in the delayed treatment group had blood pressure of less than 140/90 mm Hg (P<0.001 for group difference) on day seven. At day 90, 289 trial participants (12.0%) in the early treatment group, compared with 250 (10.5%) in the delayed treatment group, had died or experienced a dependency (odds ratio 1.18 (95% confidence interval 0.98 to 1.41), P=0.08). No significant differences in recurrent stroke or adverse events were reported between the two groups. CONCLUSIONS: Among patients with mild-to-moderate acute ischaemic stroke and systolic blood pressure between 140 mm Hg and <220 mm Hg who did not receive intravenous thrombolytic treatment, early antihypertensive treatment did not reduce the odds of dependency or death at 90 days. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03479554.

Aromatized liposomes for sustained drug delivery.

Insufficient drug loading and leakage of payload remain major challenges in designing liposome-based drug delivery systems. These phenomena can limit duration of effect and cause toxicity. Targeting the rate-limiting step in drug release from liposomes, we modify (aromatized) them to have aromatic groups within their lipid bilayers. Aromatized liposomes are designed with synthetic phospholipids with aromatic groups covalently conjugated onto acyl chains. The optimized aromatized liposome increases drug loading and significantly decreases the burst release of a broad range of payloads (small molecules and macromolecules, different degrees of hydrophilicity) and extends their duration of release. Aromatized liposomes encapsulating the anesthetic tetrodotoxin (TTX) achieve markedly prolonged effect and decreased toxicity in an application where liposomes are used clinically: local anesthesia, even though TTX is a hydrophilic small molecule which is typically difficult to encapsulate. Aromatization of lipid bilayers can improve the performance of liposomal drug delivery systems.

Immune checkpoint blockade therapy mitigates systemic inflammation and affects cellular FLIP-expressing monocytic myeloid-derived suppressor cells in non-progressor non-small cell lung cancer patients.

Cancer cells favor the generation of myeloid cells with immunosuppressive and inflammatory features, including myeloid-derived suppressor cells (MDSCs), which support tumor progression. The anti-apoptotic molecule, cellular FLICE (FADD-like interleukin-1ß-converting enzyme)-inhibitory protein (c-FLIP), which acts as an important modulator of caspase-8, is required for the development and function of monocytic (M)-MDSCs. Here, we assessed the effect of immune checkpoint inhibitor (ICI) therapy on systemic immunological landscape, including FLIP-expressing MDSCs, in non-small cell lung cancer (NSCLC) patients. Longitudinal changes in peripheral immunological parameters were correlated with patients' outcome. In detail, 34 NSCLC patients were enrolled and classified as progressors (P) or non-progressors (NP), according to the RECIST evaluation. We demonstrated a reduction in pro-inflammatory cytokines such as IL-8, IL-6, and IL-1ß in only NP patients after ICI treatment. Moreover, using t-distributed stochastic neighbor embedding (t-SNE) and cluster analysis, we characterized in NP patients a significant increase in the amount of lymphocytes and a slight contraction of myeloid cells such as neutrophils and monocytes. Despite this moderate ICI-associated alteration in myeloid cells, we identified a distinctive reduction of c-FLIP expression in M-MDSCs from NP patients concurrently with the first clinical evaluation (T1), even though NP and P patients showed the same level of expression at baseline (T0). In agreement with the c-FLIP expression, monocytes isolated from both P and NP patients displayed similar immunosuppressive functions at T0; however, this pro-tumor activity was negatively influenced at T1 in the NP patient cohort exclusively. Hence, ICI therapy can mitigate systemic inflammation and impair MDSC-dependent immunosuppression.

Potential of Akkermansia muciniphila and its outer membrane proteins as therapeutic targets for neuropsychological diseases.

The gut microbiota varies dramatically among individuals, and changes over time within the same individual, due to diversities in genetic backgrounds, diet, nutrient supplementations and use of antibiotics. Up until now, studies on dysbiosis of microbiota have expanded to a wider range of diseases, with Akkermansia muciniphila at the cross spot of many of these diseases. A. muciniphila is a Gram-negative bacterium that produces short-chain fatty acids (SCFAs), and Amuc_1100 is one of its most highly expressed outer membrane proteins. This review aims to summarize current knowledge on correlations between A. muciniphila and involved neuropsychological diseases published in the last decade, with a focus on the potential of this bacterium and its outer membrane proteins as therapeutic targets for these diseases, on the basis of evidence accumulated from animal and clinical studies, as well as mechanisms of action from peripheral to central nervous system (CNS).