Akkermansia muciniphila isolated from forest musk deer ameliorates diarrhea in mice via modification of gut microbiota.

BACKGROUND: The forest musk deer, a rare fauna species found in China, is famous for its musk secretion which is used in selected Traditional Chinese medicines. However, over-hunting has led to musk deer becoming an endangered species, and their survival is also greatly challenged by various high incidence and high mortality respiratory and intestinal diseases such as septic pneumonia and enteritis. Accumulating evidence has demonstrated that Akkermannia muciniphila (AKK) is a promising probiotic, and we wondered whether AKK could be used as a food additive in animal breeding programmes to help prevent intestinal diseases. METHODS: We isolated one AKK strain from musk deer feces (AKK-D) using an improved enrichment medium combined with real-time PCR. After confirmation by 16S rRNA gene sequencing, a series of in vitro tests was conducted to evaluate the probiotic effects of AKK-D by assessing its reproductive capability, simulated gastrointestinal fluid tolerance, acid and bile salt resistance, self-aggregation ability, hydrophobicity, antibiotic sensitivity, hemolysis, harmful metabolite production, biofilm formation ability, and bacterial adhesion to gastrointestinal mucosa. RESULTS: The AKK-D strain has a probiotic function similar to that of the standard strain in humans (AKK-H). An in vivo study found that AKK-D significantly ameliorated symptoms in the enterotoxigenic Escherichia coli (ETEC)-induced murine diarrhea model. AKK-D improved organ damage, inhibited inflammatory responses, and improved intestinal barrier permeability. Additionally, AKK-D promoted the reconstitution and maintenance of the homeostasis of gut microflora, as indicated by the fact that AKK-D-treated mice showed a decrease in Bacteroidetes and an increase in the proportion of other beneficial bacteria like Muribaculaceae, Muribaculum, and unclassified f_Lachnospiaceae compared with the diarrhea model mice. CONCLUSION: Taken together, our data show that this novel AKK-D strain might be a potential probiotic for use in musk deer breeding, although further extensive systematic research is still needed.

Elimination of Intragrain Defect to Enhance the Performance of FAPbI3 Perovskite Solar Cells by Ionic Liquid.

Ionic liquids have been widely used to improve the efficiency and stability of perovskite solar cells (PSCs), and are generally believed to passivate defects on the grain boundaries of perovskites. However, few studies have focused on the relevant effects of ionic liquids on intragrain defects in perovskites which have been shown to be critical for the performance of PSCs. In this work, the effect of ionic liquid 1-hexyl-3-methylimidazolium iodide (HMII) on intragrain defects of formamidinium lead iodide (FAPbI3) perovskite is investigated. Abundant {111}c intragrain planar defects in pure FAPbI3 grains are found to be significantly reduced by the addition of the ionic liquid HMII, shown by using ultra-low-dose selected area electron diffraction. As a result, longer charge carrier lifetimes, higher photoluminescence quantum yield, better charge carrier transport properties, lower Urbach energy, and current-voltage hysteresis are achieved, and the champion power conversion efficiency of 24.09% is demonstrated. These observations suggest that ionic liquids significantly improve device performance resulting from the elimination of {111}c intragrain planar defects.

Chromosome-level genome assembly of the bethylid ectoparasitoid wasp Sclerodermus sp. 'alternatusi'.

The Bethylidae are the most diverse of Hymenoptera chrysidoid families. As external parasitoids, the bethylids have been widely adopted as biocontrol agents to control insect pests worldwide. Thus far, the genomic information of the family Bethylidae has not been reported yet. In this study, we crystallized into a high-quality chromosome-level genome of ant-like bethylid wasps Sclerodermus sp. 'alternatusi' (Hymenoptera: Bethylidae) using PacBio sequencing as well as Hi-C technology. The assembled S. alternatusi genome was 162.30 Mb in size with a contig N50 size of 3.83 Mb and scaffold N50 size of 11.10 Mb. Totally, 92.85% assembled sequences anchored to 15 pseudo-chromosomes. A total of 10,204 protein-coding genes were annotated, and 23.01 Mb repetitive sequences occupying 14.17% of genome were pinpointed. The BUSCO results showed that 97.9% of the complete core Insecta genes were identified in the genome, while 97.1% in the gene sets. The high-quality genome of S. alternatusi will not only provide valuable genomic information, but also show insights into parasitoid wasp evolution and bio-control application in future studies.

Orphan nuclear receptors-induced ALT-associated PML bodies are targets for ALT inhibition.

Orphan nuclear receptors (NRs), such as COUP-TF1, COUP-TF2, EAR2, TR2 and TR4, are implicated in telomerase-negative cancers that maintain their telomeres through the alternative lengthening of telomeres (ALT) mechanism. However, how telomere association of orphan NRs is involved in ALT activation remains unclear. Here, we demonstrate that telomeric tethering of orphan NRs in human fibroblasts initiates formation of ALT-associated PML bodies (APBs) and features of ALT activity, including ALT telomere DNA synthesis, telomere sister chromatid exchange, and telomeric C-circle generation, suggesting de novo ALT induction. Overexpression of orphan NRs exacerbates ALT phenotypes in ALT cells, while their depletion limits ALT. Orphan NRs initiate ALT via the zinc finger protein 827, suggesting the involvement of chromatin structure alterations for ALT activation. Furthermore, we found that orphan NRs and deficiency of the ALT suppressor ATRX-DAXX complex operate in concert to promote ALT activation. Moreover, PML depletion by gene knockout or arsenic trioxide treatment inhibited ALT induction in fibroblasts and ALT cancer cells, suggesting that APB formation underlies the orphan NR-induced ALT activation. Importantly, arsenic trioxide administration abolished APB formation and features of ALT activity in ALT cancer cell line-derived mouse xenografts, suggesting its potential for further therapeutic development to treat ALT cancers.

Single-Cell Insights into Mouse Testicular Toxicity under Peripubertal Exposure to Di(2-ethylhexyl) phthalate.

Male fertility depends on normal pubertal development. Di(2-ethylhexyl) phthalate (DEHP) is a potent antiandrogen chemical, and exposure to DEHP during peripuberty can damage the developing male reproductive system, especially the testis. However, the specific cellular targets and differentiation processes affected by DEHP, which lead to testicular toxicity, remain poorly defined. Herein, we presented the first single-cell transcriptomic profile of the pubertal mouse testis following DEHP exposure. To carry out the experiment, two groups (n = 8 each) of three-week old male mice were orally administered 0.5% carboxymethylcellulose sodium salt or 100 mg/kg body weight DEHP daily from postnatal day 21 to 48, respectively. Using single-cell RNA sequencing, a total of 31 distinct cell populations were identified, notably, Sertoli and Leydig cells emerged as important targets of DEHP. DEHP exposure significantly decreased the proportions of Sertoli cell clusters expressing mature Sertoli markers (Sox9 and Ar), and selectively reduced the expression of testosterone synthesis genes in fetal Leydig cells. Through cell-cell interaction analyses, we observed changed numbers of interactions in Sertoli cells 1 (SCs1), Leydig cells 1 (LCs1) and interstitial macrophages (ITMs), and we also identified cell-specific ligand gene expressions in these clusters, such as Inha, Fyn, Vcam1, and Apoe. Complementary in vitro assays confirmed that DEHP directly reduced the expression of genes related to Sertoli cell adhesion and intercellular communication. In conclusion, peripubertal DEHP exposure reduced the number of mature Sertoli cells and may disrupt testicular steroidogenesis by affecting the testosterone synthesis genes in fetal Leydig cells rather than adult Leydig cells.

LncRNA 4930581F22Rik promotes myogenic differentiation by regulating the ERK/MAPK signaling pathway.

The skeletal muscle is the largest organ in mammals and is the primary motor function organ of the body. Our previous research has shown that long non-coding RNAs (lncRNAs) are significant in the epigenetic control of skeletal muscle development. Here, we observed progressive upregulation of lncRNA 4930581F22Rik expression during skeletal muscle differentiation. Knockdown of lncRNA 4930581F22Rik hindered skeletal muscle differentiation and resulted in the inhibition of the myogenic markers MyHC and MEF2C. Furthermore, we found that lncRNA 4930581F22Rik regulates myogenesis via the ERK/MAPK signaling pathway, and this effect could be attenuated by the ERK-specific inhibitor PD0325901. Additionally, in vivo mice injury model results revealed that lncRNA 4930581F22Rik is involved in skeletal muscle regeneration. These results establish a theoretical basis for understanding the contribution of lncRNAs in skeletal muscle development and regeneration.

Psychometric Properties of the Malay Translation of the Medication Adherence Rating Scale.

INTRODUCTION: The Medication Adherence Rating Scale (MARS) is a self-rated questionnaire that assesses medication compliance. AIM: This study aimed to validate the Malaysian language translation of the MARS (MARS-M). METHOD: The original scale was translated to Malay via forward and backward translation process. The psychometric properties of the MARS-M were validated on clinical samples (N = 54). RESULTS: The MARS-M was filled by 54 participants. Exploratory factor analysis supported a two-factor model. Factor 1 of the MARS-M consisted of four items (α = 0.84), while factor 2 consisted of three items (α = 0.78).Kaiser-Meyer-Olkin measure of sampling adequacy was 0.60, and Bartlett's test of sphericity was significant (X2 (28) = 66.4, p <0.001). CONCLUSION: The MARS-M is reliable and valid.

Therapeutic implications of quercetin and its derived-products in COVID-19 protection and prophylactic.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel human coronavirus, which has triggered a global pandemic of the coronavirus infectious disease 2019 (COVID-19). Outbreaks of emerging infectious diseases continue to challenge human health worldwide. The virus conquers human cells through the angiotensin-converting enzyme 2 receptor-driven pathway by mostly targeting the human respiratory tract. Quercetin is a natural flavonoid widely represented in the plant kingdom. Cumulative evidence has demonstrated that quercetin and its derivatives have various pharmacological properties including anti-cancer, anti-hypertension, anti-hyperlipidemia, anti-hyperglycemia, anti-microbial, antiviral, neuroprotective, and cardio-protective effects, because it is a potential treatment for severe inflammation and acute respiratory distress syndrome. Furthermore, it is the main life-threatening condition in patients with COVID-19. This article provides a comprehensive review of the primary literature on the predictable effectiveness of quercetin and its derivatives docked to multi-target of SARS-CoV-2 and host cells via in silico and some of validation through in vitro, in vivo, and clinically to fight SARS-CoV-2 infections, contribute to the reduction of inflammation, which suggests the preventive and therapeutic latency of quercetin and its derived-products against COVID-19 pandemic, multisystem inflammatory syndromes (MIS), and long-COVID.

Epigenetic silencing of LDHB promotes hepatocellular carcinoma by remodeling the tumor microenvironment.

Lactate dehydrogenase B (LDHB) reversibly catalyzes the conversion of pyruvate to lactate or lactate to pyruvate and expressed in various malignancies. However, the role of LDHB in modulating immune responses against hepatocellular carcinoma (HCC) remains largely unknown. Here, we found that down-regulation of lactate dehydrogenase B (LDHB) was coupled with the promoter hypermethylation and knocking down the DNA methyltransferase 3A (DNMT 3A) restored LDHB expression levels in HCC cell lines. Bioinformatics analysis of the HCC cohort from The Cancer Genome Atlas revealed a significant positive correlation between LDHB expression and immune regulatory signaling pathways and immune cell infiltrations. Moreover, immune checkpoint inhibitors (ICIs) have shown considerable promise for HCC treatment and patients with higher LDHB expression responded better to ICIs. Finally, we found that overexpression of LDHB suppressed HCC growth in immunocompetent but not in immunodeficient mice, suggesting that the host immune system was involved in the LDHB-medicated tumor suppression. Our findings indicate that DNMT3A-mediated epigenetic silencing of LDHB may contribute to HCC progression through remodeling the tumor immune microenvironment, and LDHB may become a potential prognostic biomarker and therapeutic target for HCC immunotherapy.

Ultrasensitive detection of Salmonella typhi using a PAM-free Cas14a-based biosensor.

The effectiveness of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas14a1, widely utilized for pathogenic microorganism detection, has been limited by the requirement of a protospacer adjacent motif (PAM) on the target DNA strands. To overcome this limitation, this study developed a Single Primer isothermal amplification integrated-Cas14a1 biosensor (SPCas) for detecting Salmonella typhi that does not rely on a PAM sequence. The SPCas biosensor utilizes a novel primer design featuring an RNA-DNA primer and a 3'-biotin-modified primer capable of binding to the same single-stranded DNA (ssDNA) in the presence of the target gene. The RNA-DNA primer undergoes amplification and is blocked at the biotin-modified end. Subsequently, strand replacement is initiated to generate ssDNA assisted by RNase H and Bst enzymes, which activate the trans-cleavage activity of Cas14a1 even in the absence of a PAM sequence. Leveraging both cyclic chain replacement reaction amplification and Cas14a1 trans-cleavage activity, the SPCas biosensor exhibits a remarkable diagnostic sensitivity of 5 CFU/mL. Additionally, in the assessment of 20 milk samples, the SPCas platform demonstrated 100% diagnostic accuracy, which is consistent with the gold standard qPCR. This platform introduces a novel approach for developing innovative CRISPR-Cas-dependent biosensors without a PAM sequence.

Do Weather Conditions Still Have an Impact on the COVID-19 Pandemic? An Observation of the Mid-2022 COVID-19 Peak in Taiwan.

Since the onset of the COVID-19 pandemic in 2019, the role of weather conditions in influencing transmission has been unclear, with results varying across different studies. Given the changes in border policies and the higher vaccination rates compared to earlier conditions, this study aimed to reassess the impact of weather on COVID-19, focusing on local climate effects. We analyzed daily COVID-19 case data and weather factors such as temperature, humidity, wind speed, and a diurnal temperature range from 1 March to 15 August 2022 across six regions in Taiwan. This study found a positive correlation between maximum daily temperature and relative humidity with new COVID-19 cases, whereas wind speed and diurnal temperature range were negatively correlated. Additionally, a significant positive correlation was identified between the unease environmental condition factor (UECF, calculated as RH*Tmax/WS), the kind of Climate Factor Complex (CFC), and confirmed cases. The findings highlight the influence of local weather conditions on COVID-19 transmission, suggesting that such factors can alter environmental comfort and human behavior, thereby affecting disease spread. We also introduced the Fire-Qi Period concept to explain the cyclic climatic variations influencing infectious disease outbreaks globally. This study emphasizes the necessity of considering both local and global climatic effects on infectious diseases.

Self-Trapped Exciton Emission in Highly Polar 0D Hybrid Ammonium/Hydronium-Based Perovskites Triggered by Antimony Doping.

Various monovalent cations are employed to construct metal halide perovskites with various structures and functionalities. However, perovskites based on highly polar A-site cations have seldom been reported. Here, a novel hybrid 0D (NH4)x(OH3)3-xInCl6 perovskite with highly polar hydronium OH3+ cations is introduced in this study. Upon doping with Sb3+, hybrid 0D (NH4)x(OH3)3-xInCl6 single crystals exhibited highly efficient broadband yellowish-green (550 nm) and red (630 nm) dual emissions with a PLQY of 86%. The dual emission arises due to Sb3+ occupying two sites within the crystal lattice that possess different polarization environments, leading to distinct Stokes shift energies. The study revealed that lattice polarity plays a significant role in the self-trapped exciton emission of Sb3+-doped perovskites, contributing up to 25% of the Stokes shift energy for hybrid 0D (NH4)x(OH3)3-xInCl6:Sb3+ as a secondary source, in addition to the Jahn-Teller deformation. These findings highlight the potential of Sb3+-doped perovskites for achieving tunable broadband emission and underscore the importance of lattice polarity in determining the emission properties of perovskite materials.

Associations of sleep disorders with serum neurofilament light chain levels in Parkinson's disease.

BACKGROUND: Sleep disorders are a prevalent non-motor symptom of Parkinson's disease (PD), although reliable biological markers are presently lacking. OBJECTIVES: To explore the associations between sleep disorders and serum neurofilament light chain (NfL) levels in individuals with prodromal and early PD. METHODS: The study contained 1113 participants, including 585 early PD individuals, 353 prodromal PD individuals, and 175 healthy controls (HCs). The correlations between sleep disorders (including rapid eye movement sleep behavior disorder (RBD) and excessive daytime sleepiness (EDS)) and serum NfL levels were researched using multiple linear regression models and linear mixed-effects models. We further investigated the correlations between the rates of changes in daytime sleepiness and serum NfL levels using multiple linear regression models. RESULTS: In baseline analysis, early and prodromal PD individuals who manifested specific behaviors of RBD showed significantly higher levels of serum NfL. Specifically, early PD individuals who experienced nocturnal dream behaviors (ß = 0.033; P = 0.042) and movements of arms or legs during sleep (ß = 0.027; P = 0.049) showed significantly higher serum NfL levels. For prodromal PD individuals, serum NfL levels were significantly higher in individuals suffering from disturbed sleep (ß = 0.038; P = 0.026). Our longitudinal findings support these baseline associations. Serum NfL levels showed an upward trend in early PD individuals who had a higher total RBDSQ score (ß = 0.002; P = 0.011) or who were considered as probable RBD (ß = 0.012; P = 0.009) or who exhibited behaviors on several sub-items of the RBDSQ. In addition, early PD individuals who had a high total ESS score (ß = 0.001; P = 0.012) or who were regarded to have EDS (ß = 0.013; P = 0.007) or who exhibited daytime sleepiness in several conditions had a trend toward higher serum NfL levels. CONCLUSION: Sleep disorders correlate with higher serum NfL, suggesting a link to PD neuronal damage. Early identification of sleep disorders and NfL monitoring are pivotal in detecting at-risk PD patients promptly, allowing for timely intervention. Regular monitoring of NfL levels holds promise for tracking both sleep disorders and disease progression, potentially emerging as a biomarker for evaluating treatment outcomes.

Depression and anxiety between nurses and nursing assistants working in long-term care facilities during the COVID-19 pandemic.

AIM: This study investigated the levels of depression and anxiety in nurses and nursing assistants working in long-term care facilities during the COVID-19 pandemic. We also explored the potential causes of depression and anxiety in nurses and nursing assistants working in long-term care facilities during the pandemic. BACKGROUND: The COVID-19 pandemic has had a considerable impact on long-term care facilities. The high infection and mortality rates for COVID-19 have resulted in an increased workload for caregivers. INTRODUCTION: The COVID-19 pandemic exposed caregivers working in long-term care facilities to higher risks of anxiety and depression. Additionally, the high risk of infection in the work environment and concerns about spreading COVID-19 to family members and long-term care facility residents led to various forms of stress among caregivers. METHODS: The present study was a cross-sectional study. Questionnaires were used to investigate depression and anxiety among regarding nurses and nursing assistants working in long-term care facilities during the pandemic. RESULTS: The depression and anxiety levels of the nurses were higher than nursing assistants, but had no statistically significant difference (p = 0.551). The factors influencing levels of depression and anxiety in nurses contained facility affiliation and experience working. In terms of nursing assistants, age, marital status, and facility affiliation were correlated with the levels of depression and anxiety. DISCUSSION: The pandemic has severely impacted caregivers. In the process of implementing pandemic prevention measures and providing care for COVID-19 patients, safeguarding the psychological health of caregivers is also essential. CONCLUSION: The levels of depression and anxiety in nurses were higher than in nursing assistants working in long-term care facilities during the pandemic. IMPLICATION FOR NURSING AND HEALTH POLICY: Long-term care facilities managers are recommended to enhance the education and training process for caregivers. Managers are also recommended to ensure provision of sufficient amounts of pandemic prevention equipment and resources.

[Mechanism of bulleyaconitine A in inhibiting bone destruction of rheumatoid arthritis via Src/PI3K/Akt signaling pathway].

Based on the sarcoma receptor coactivator(Src)/phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt) signaling pathway, the mechanism of action of bulleyaconitine A in the treatment of bone destruction of experimental rheumatoid arthritis(RA) was explored. Firstly, key targets of RA bone destruction were collected through GeneCards, PharmGKB, and OMIM databa-ses. Potential targets of bulleyaconitine A were collected using SwissTargetPrediction and PharmMapper databases. Next, intersection targets were obtained by the Venny 2.1.0 platform. Protein-protein interaction(PPI) network and topology analysis were managed by utilizing the STRING database and Cytoscape 3.8.0. Then, Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analyses were conducted in the DAVID database. AutoDock Vina was applied to predict the molecular docking and binding ability of bulleyaconitine A with key targets. Finally, a receptor activator of nuclear factor-κB(RANKL)-induced osteoclast differentiation model was established in vitro. Quantitative real-time polymerase chain reaction(qRT-PCR) was used to detect the mRNA expression levels of related targets, and immunofluorescence and Western blot were adopted to detect the protein expression level of key targets. It displayed that there was a total of 29 drug-disease targets, and Src was the core target of bulleyaconitine A in anti-RA bone destruction. Furthermore, KEGG enrichment analysis revealed that bulleyaconitine A may exert an anti-RA bone destruction effect by regulating the Src/PI3K/Akt signaling pathway. The molecular docking results showed that bulleyaconitine A had better bin-ding ability with Src, phosphatidylinositol-4,5-diphosphate 3-kinase(PIK3CA), and Akt1. The result of the experiment indicated that bulleyaconitine A not only dose-dependently inhibited the mRNA expression levels of osteoclast differentiation-related genes cathepsin K(CTSK) and matrix metalloproteinase-9(MMP-9)(P<0.01), but also significantly reduced the expression of p-c-Src, PI3K, as well as p-Akt in vitro osteoclasts(P<0.01). In summary, bulleyaconitine A may inhibit RA bone destruction by regulating the Src/PI3K/Akt signaling pathway. This study provides experimental support for the treatment of RA bone destruction with bulleyaconitine A and lays a foundation for the clinical application of bulleyaconitine A.

Deferasirox Causes Leukaemia Cell Death through Nrf2-Induced Ferroptosis.

Acute lymphoblastic leukaemia (ALL) is the most prevalent cancer in children, and excessive iron buildup resulting from blood transfusions and chemotherapy potentially has a negative impact on treatment outcomes and prognosis in patients with ALL. Therefore, initiating early iron chelation therapy during ALL treatment is a logical approach. Ideally, the selected iron chelator should also possess anti-leukaemia properties. The aim of the present study was to explore the potential impact and underlying mechanism of deferasirox (DFX) in ALL therapy. This study proved that DFX, an iron chelator, is capable of inducing leukaemia cell death through ferroptosis, which is achievable by increasing the expression of acetylated nuclear factor erythroid 2-related factor 2 (NRF2). More specifically, NRF2 acetylation on Lys599 was facilitated by acetyltransferase-p300/CBP. These findings indicate that DFX could serve as a potent adjunctive medication for patients with ALL. Moreover, DFX may offer dual benefits in ALL treatment, functioning as both an iron chelator and NRF2-modulating agent. Further research and clinical trials are necessary to fully elucidate the therapeutic potential of DFX in patients with ALL and incorporate it into treatment protocols.

Salivary proteins NlSP5 and NlSP7 are required for optimal feeding and fitness of the brown planthopper, Nilaparvata lugens.

BACKGROUND: Saliva has a crucial role in determining the compatibility between piercing-sucking insects and their hosts. The brown planthopper (BPH) Nilaparvata lugens, a notorious pest of rice in East and Southeast Asia, secretes gelling and watery saliva when feeding on rice sap. Nlsalivap-5 (NlSP5) and Nlsalivap-7 (NlSP7) were identified as potential planthopper-specific gelling saliva components, but their biological functions remain unknown. RESULTS: Here, we showed by transcriptomic analyses that NlSP5 and NlSP7 were biasedly expressed in the salivary glands of BPHs. Using the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated genome-editing system, we constructed NlSP5 and NlSP7 homozygous mutants (NlSP5-/- and NlSP7-/-). Electrical penetration graph assay showed that NlSP5-/- and NlSP7-/- mutants exhibited abnormal probing and feeding behaviors. Bioassays revealed that the loss-of-function of NlSP5 and NlSP7 significantly reduced the fitness of BPHs, with extended developmental duration, shortened lifespan, reduced weight, and impaired fecundity and hatching rates. CONCLUSION: These findings deepen our understanding of the BPH-host interaction and may provide potential targets for the management of rice planthoppers. © 2024 Society of Chemical Industry.

Complete Removal of Residual Particles and Realization of Mechanical Properties to Improve Osseointegration in Additively Manufactured Ti6Al4 V Scaffolds through Flowing Acid Etching.

Massive unmelted Ti6Al4 V (Ti64) particles presented across all surfaces of additively manufactured Ti64 scaffolds significantly impacted the designed surface topography, mechanical properties, and permeability, reducing the osseointegration of the scaffolds. In this study, the proposed flowing acid etching (FAE) method presented high efficiency in eliminating Ti64 particles and enhancing the surface modification capacity across all surfaces of Ti64 scaffolds. The Ti64 particles across all surfaces of the scaffolds were completely removed effectively and evenly. The surface topography of the scaffolds closely resembled the design after the 75 s FAE treatment. The actual elastic modulus of the treated scaffolds (3.206 ± 0.040 GPa) was closer to the designed value (3.110 GPa), and a micrometer-scale structure was constructed on the inner and outer surfaces of the scaffolds after the 90 s FAE treatment. However, the yield strength of scaffolds was reduced to 89.743 ± 0.893 MPa from 118.251 ± 0.982 MPa after the 90 s FAE treatment. The FAE method also showed higher efficiency in decreasing the roughness and enhancing the hydrophilicity and surface energy of all of the surfaces. The FAE treatment improved the permeability of scaffolds efficiently, and the permeability of scaffolds increased to 11.93 ± 0.21 × 10-10 mm2 from 8.57 ± 0.021 × 10-10 mm2 after the 90 s FAE treatment. The treated Ti64 scaffolds after the 90 s FAE treatment exhibited optimized osseointegration effects in vitro and in vivo. In conclusion, the FAE method was an efficient way to eliminate unmelted Ti64 particles and obtain ideal surface topography, mechanical properties, and permeability to promote osseointegration in additively manufactured Ti64 scaffolds.

CETP inhibition enhances monocyte activation and bacterial clearance and reduces streptococcus pneumonia-associated mortality in mice.

Sepsis is a leading cause of mortality worldwide, and pneumonia is the most common cause of sepsis in humans. Low levels of high-density lipoprotein cholesterol (HDL-C) levels are associated with an increased risk of death from sepsis, and increasing levels of HDL-C by inhibition of cholesteryl ester transfer protein (CETP) decreases mortality from intraabdominal polymicrobial sepsis in APOE*3-Leiden.CETP mice. Here, we show that treatment with the CETP inhibitor (CETPi) anacetrapib reduced mortality from Streptococcus pneumoniae-induced sepsis in APOE*3-Leiden.CETP and APOA1.CETP mice. Mechanistically, CETP inhibition reduced the host proinflammatory response via attenuation of proinflammatory cytokine transcription and release. This effect was dependent on the presence of HDL, leading to attenuation of immune-mediated organ damage. In addition, CETP inhibition promoted monocyte activation in the blood prior to the onset of sepsis, resulting in accelerated macrophage recruitment to the lung and liver. In vitro experiments demonstrated that CETP inhibition significantly promoted the activation of proinflammatory signaling in peripheral blood mononuclear cells and THP1 cells in the absence of HDL; this may represent a mechanism responsible for improved bacterial clearance during sepsis. These findings provide evidence that CETP inhibition represents a potential approach to reduce mortality from pneumosepsis.