VPAC2 Receptor Signaling Promotes Growth and Immunosuppression in Pancreatic Cancer.

Pancreatic cancer (PDAC) harbors a complex tumor microenvironment (TME), and crosstalk between cells in the TME can contribute to drug resistance and relapse. Vasoactive intestinal peptide (VIP) is overexpressed in PDAC, and VIP receptors expressed on T cells are a targetable pathway that sensitizes PDAC to immunotherapy. In this study, we showed that pancreatic cancer cells engage in autocrine VIP signaling through VIP receptor 2 (VPAC2). High co-expression of VIP with VPAC2 correlated with reduced relapse-free survival in PDAC patients. VPAC2 activation in PDAC cells upregulated piwi-like RNA-mediated gene silencing 2 (Piwil2), which stimulated cancer cell clonogenic growth. In addition, VPAC2 signaling increased expression of TGF-ß1 to inhibit T cell function. Loss of VPAC2 on PDAC cells led to reduced tumor growth and increased sensitivity to anti-PD1 immunotherapy in mouse models of PDAC. Overall, these findings expand our understanding of the role of VIP/VPAC2 signaling in PDAC and provide the rationale for developing potent VPAC2-specific antagonists for treating PDAC patients.

Branch-Chain-Rich Diisopropyl Ether with Steric Hindrance Facilitates Stable Cycling of Lithium Batteries at - 20 °C.

Li metal batteries (LMBs) offer significant potential as high energy density alternatives; nevertheless, their performance is hindered by the slow desolvation process of electrolytes, particularly at low temperatures (LT), leading to low coulombic efficiency and limited cycle stability. Thus, it is essential to optimize the solvation structure thereby achieving a rapid desolvation process in LMBs at LT. Herein, we introduce branch chain-rich diisopropyl ether (DIPE) into a 2.5 M Li bis(fluorosulfonyl)imide dipropyl ether (DPE) electrolyte as a co-solvent for high-performance LMBs at - 20 °C. The incorporation of DIPE not only enhances the disorder within the electrolyte, but also induces a steric hindrance effect form DIPE's branch chain, excluding other solvent molecules from Li+ solvation sheath. Both of these factors contribute to the weak interactions between Li+ and solvent molecules, effectively reducing the desolvation energy of the electrolyte. Consequently, Li (50 µm)||LFP (mass loading ~ 10 mg cm-2) cells in DPE/DIPE based electrolyte demonstrate stable performance over 650 cycles at - 20 °C, delivering 87.2 mAh g-1, and over 255 cycles at 25 °C with 124.8 mAh g-1. DIPE broadens the electrolyte design from molecular structure considerations, offering a promising avenue for highly stable LMBs at LT.

Zonular instability-associated morphologic features in eyes with primary angle closure disease using the swept-source anterior segment - optical coherence tomography system.

BACKGROUND: This study aims to investigate the morphologic features of the crystalline lens in Primary Angle Closure Disease (PACD) patients with zonular instability during cataract surgery using the swept-source CASIA 2 Anterior Segment-Optical Coherence Tomography (AS-OCT) system. METHODS: A total of 398 eyes (125 PACD eyes with zonular instability, 133 PACD eyes with zonular stability, and 140 cataract patient controls) of 398 patients who underwent cataract surgery combined or not glaucoma surgery between January 2021 and January 2023 were enrolled. The crystalline lens parameters were measured by CASIA2 AS-OCT. Then, logistic regression was performed to evaluate the risk factors associated with zonular instability. RESULTS: The results revealed that PACD eyes had a more anterior lens equator position, a steeper anterior curvature of lens, shorter Axial Length (AL), shallower Anterior Chamber Distance (ACD), higher Lens Vault (LV) and thicker Lens Thickness (LT), when compared to eyes in the cataract control group. Furthermore, PACD eyes in the zonular instability group had steeper front R, front Rs and Front Rf, flatter back Rf, thicker lens anterior part thickness, higher lens anterior-to-posterior part thickness ratios, shallower ACD, and greater LV, when compared to PACD eyes with zonular stability. The logistic regression analysis, which was adjusted for age and gender, revealed that zonular instability was positively correlated with anterior part thickness, lens anterior-to-posterior part thickness ratio, and LV, but was negatively correlated with lens anterior radius and ACD. CONCLUSION: Steeper anterior curvature, increased lens anterior part thickness, higher anterior-to-posterior part thickness ratio, shallower ACD, and greater LV are the anatomic features of PACD eyes associated with zonular instability.

A prospective observational cohort study of the efficacy of tofacitinib plus iguratimod on rheumatoid arthritis with usual interstitial pneumonia.

Objectives: This study aims to assess the efficacy of tofacitinib (TOF) plus iguratimod (IGU) in rheumatoid arthritis (RA) with usual interstitial pneumonia (UIP) (RA-UIP). Methods: This was a prospective observational cohort, single-center study. Data from 78 RA-UIP patients treated with TOF plus IGU, IGU plus conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), and csDMARDs were analyzed. Clinically relevant responses in RA activity assessment, pulmonary function tests (PFTs), and high-resolution computed tomography (HRCT) assessment at baseline and follow-up were compared between groups to evaluate the efficacy of TOF plus IGU. Results: A total of 78 patients were followed up for at least 6 months after treatment. There were significant changes in sedimentation rate (ESR), C reactive protein (CRP), and disease activity score (DAS) 28-CRP during the follow-up within each treatment group, but there was no statistically significant difference between the two groups. After 6 months of TOF plus IGU treatment, forced vital capacity (FVC)% (84.7 ± 14.7 vs. 90.7 ± 15.4) and HRCT fibrosis score (7.3 ± 3.4 vs. 7.0 ± 5.6) showed a significant improvement compared to the csDMARDs group (P = 0.031, P = 0.015). The TOF plus IGU-treated patients had a significantly higher regression and lower deterioration than the csDMARDs-treated patients (P = 0.026, P = 0.026) and had a significantly higher response (regression + stability), with overall response rates of 66.7% (16/24) vs. 35.7% (10/28) (P = 0.027), respectively. Conclusion: Our results indicate that TOF plus IGU can simultaneously relieve RA and RA-UIP and be better than the csDMARDs with a higher response rate in RA-UIP, which may be a potential choice for "dual treat-to-target".

Evaluation of the antibacterial activity of Elsholtzia ciliate essential oil against halitosis-related Fusobacterium nucleatum and Porphyromonas gingivalis.

The broad-spectrum antimicrobial activity of Elsholtzia ciliate essential oil (ECO) has been previously reported, but its effectiveness against halitosis-causing bacteria such as Fusobacterium nucleatum and Porphyromonas gingivalis is not well understood. In this study, we investigated the bacteriostatic activity of ECO against planktonic cells and biofilms of F. nucleatum and P. gingivalis, as well as its ability to inhibit bacterial metabolism and production of volatile sulfur compounds (VSCs) at sub-lethal concentrations. Our findings revealed that ECO exhibited comparable activities to chlorhexidine against these oral bacteria. Treatment with ECO significantly reduced the production of VSCs, including hydrogen sulfide, dimethyl disulfide, and methanethiol, which are major contributors to bad breath. As the major chemical components of ECO, carvacrol, p-cymene, and phellandrene, were demonstrated in vitro inhibitory effects on F. nucleatum and P. gingivalis, and their combined use showed synergistic and additive effects, suggesting that the overall activity of ECO is derived from the cumulative or synergistic effect of multiple active components. ECO was found to have a destructive effect on the bacterial cell membrane by examining the cell morphology and permeability. Furthermore, the application of ECO induced significant changes in the bacterial composition of saliva-derived biofilm, resulting in the elimination of bacterial species that contribute to halitosis, including Fusobacterium, Porphyromonas, and Prevotella. These results provide experimental evidence for the potential clinical applications of ECOs in the prevention and treatment of halitosis.

Screening for Latent Tuberculosis Infection in Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Latent tuberculosis infection (LTBI) can progress to active tuberculosis disease, causing morbidity and mortality. Objective: To review the evidence on benefits and harms of screening for and treatment of LTBI in adults to inform the US Preventive Services Task Force (USPSTF). Data Sources: PubMed/MEDLINE, Cochrane Library, and trial registries through December 3, 2021; references; experts; literature surveillance through January 20, 2023. Study Selection: English-language studies of LTBI screening, LTBI treatment, or accuracy of the tuberculin skin test (TST) or interferon-gamma release assays (IGRAs). Studies of LTBI screening and treatment for public health surveillance or disease management were excluded. Data Extraction and Synthesis: Dual review of abstracts, full-text articles, and study quality; qualitative synthesis of findings; meta-analyses conducted when a sufficient number of similar studies were available. Main Outcomes and Measures: Screening test accuracy; development of active tuberculosis disease, transmission, quality of life, mortality, and harms. Results: A total of 113 publications were included (112 studies; N = 69 009). No studies directly evaluated the benefits and harms of screening. Pooled estimates for sensitivity of the TST were 0.80 (95% CI, 0.74-0.87) at the 5-mm induration threshold, 0.81 (95% CI, 0.76-0.87) at the 10-mm threshold, and 0.60 (95% CI, 0.46-0.74) at the 15-mm threshold. Pooled estimates for sensitivity of IGRA tests ranged from 0.81 (95% CI, 0.79-0.84) to 0.90 (95% CI, 0.87-0.92). Pooled estimates for specificity of screening tests ranged from 0.95 to 0.99. For treatment of LTBI, a large (n = 27 830), good-quality randomized clinical trial found a relative risk (RR) for progression to active tuberculosis at 5 years of 0.35 (95% CI, 0.24-0.52) for 24 weeks of isoniazid compared with placebo (number needed to treat, 112) and an increase in hepatotoxicity (RR, 4.59 [95% CI, 2.03-10.39]; number needed to harm, 279). A previously published meta-analysis reported that multiple regimens were efficacious compared with placebo or no treatment. Meta-analysis found greater risk for hepatotoxicity with isoniazid than with rifampin (pooled RR, 4.22 [95% CI, 2.21-8.06]; n = 7339). Conclusions and Relevance: No studies directly evaluated the benefits and harms of screening for LTBI compared with no screening. TST and IGRAs were moderately sensitive and highly specific. Treatment of LTBI with recommended regimens reduced the risk of progression to active tuberculosis. Isoniazid was associated with higher rates of hepatotoxicity than placebo or rifampin.

Guided Bone Regeneration in a Periodontally Compromised Individual with Autogenous Tooth Bone Graft: A Radiomics Analysis.

BACKGROUND: Autogenous tooth bone graft material (AutoBT) has been advocated as a bone substitute when conducting alveolar ridge preservation. This study is aimed at using a radiomics approach in order to evaluate and testify whether AutoBT can stimulate bone growth during socket preservation in severe periodontal cases. MATERIALS AND METHODS: For this study, 25 cases with severe periodontal diseases were selected. The patients' AutoBTs were inserted into the extraction sockets and covered with Bio-Gide® collagen membranes. 3D CBCT scans and 2D X-rays were taken of the patients before surgery and after 6 months post-surgery. For the retrospective radiomics analysis, the maxillary and mandibular images were compared in different groups. Maxillary bone height was analyzed at the buccal, middle, and palatal crest sites, while the mandibular bone height was compared at the buccal, center, and lingual crest sites. RESULTS: In the maxilla, the alveolar height was increased by -2.15 ± 2.90 mm at the buccal crest; -2.45 ± 2.36 mm at the center of the socket, and -1.62 ± 3.19 mm at the palatal crest, while the height of the buccal crest was increased by 0.19 ± 3.52 mm, and the height at the center of the socket was increased by -0.70 ± 2.71 mm in the mandible. The three-dimensional radiomics analysis demonstrated significant bone growth in the local alveolar height and high density. CONCLUSION: Based on clinical radiomics analysis, AutoBT could be used as an alternative bone material in socket preservation after tooth extraction in patients with severe periodontitis.

miR-128-3p inhibits the inflammation by targeting MAPK6 in penicillin-induced astrocytes.

OBJECTIVE: Epilepsy causes physical and mental damage to patients. As well known, microRNAs (miRNAs) provide therapeutic target potentials for patients with epilepsy. miR-128-3p was previously reported to be downregulated in temporal lobe epilepsy (TLE) patients, however, its detailed function in epilepsy is unknown. METHODS: Astrocytes function in epilepsy, penicillin-induced astrocytes can be used as a model for seizures in vitro. Currently, the expression levels of mitogen-activated protein kinase 6 (MAPK6), interleukin-1 beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α) were determined by western blot and reverse transcription-quantitative PCR analyses (RT-qPCR). The expression level of miR-128-3p was evaluated by RT-qPCR. TargetScan 7.1 and dual luciferase reporter assay were used for prediction and verification of interaction between miR-128-3p and MAPK6 3' untranslated region (UTR). Cell viability was detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. RESULTS: We found that penicillin-induced decrease in cell viability, and increase of TNF-α/IL-1ß in primary astrocytes. There were lower miR-128-3p and higher MAPK6 in penicillin-treated primary astrocytes. miR-128-3p overexpression rescued penicillin-induced reduction of cell viability, and upregulation of TNF-α/IL-1ß, which was partially abolished by MAPK6 overexpression. CONCLUSION: Altogether, miR-128-3p attenuates penicillin-induced cell injury and inflammation in astrocytes by targeting MAPK6, thus providing a protective role in epilepsy.

Effect of new-style anterior and posterior vaginal wall repair combined with modified ischial spine fascia fixation on patients with pelvic organ prolapse and their postoperative quality of life.

Objective: This study aims to explore the effect of new-style anterior and posterior vaginal wall repair combined with modified ischial spine fascia fixation on patients with pelvic organ prolapse (POP) and their postoperative quality of life. Methods: A total of 88 patients with POP and elective surgery admitted to Anqing Hospital affiliated to Anhui Medical University from March 2018 to March 2021 were retrospectively analyzed. According to their surgical methods, patients were divided into an observation group [44 cases, all underwent new-style anterior and posterior vaginal wall repair combined with modified ischial spine fascia fixation (new-style APVR-modified ISFF)] and a control group [44 cases, all underwent traditional anterior and posterior vaginal wall repair combined with sacrospinous ligament fixation (traditional APVR- SLF)]. The perioperative indicators were compared between the two groups. The pelvic floor function, pelvic organ prolapse quantification (POP-Q) classification, and quality of life were observed before operation, 3 months after operation, and 6 months after operation. All patients were followed-up. Results: Compared with the control group, the observation group had more advantages in intraoperative blood loss, operation time, urinary catheter indwelling time, postoperative anal exhaust time, and hospitalization time (P < 0.05). In terms of pelvic floor function, patients of both groups showed significant improvement at 3 months and 6 months after surgery (P < 0.05). In terms of quality of life, the two groups exhibited significant improvement at 6 months after surgery (P < 0.05). PFIQ-7, PFDI-20, and UDI-6P of the observational group were lower than those of the control group, while PISQ-12 was higher than that of the control group but all with no significant difference (P > 0.005). In addition, the total complication rate of the observation group was 2.27% (1/44), which was significantly lower than 22.73% (10/44) of the control group (P < 0.05). Conclusion: New-style APVR-modified ISFF can effectively treat POP and improve the quality of life of such patients, with less postoperative complications and high safety.

Targeting vasoactive intestinal peptide-mediated signaling enhances response to immune checkpoint therapy in pancreatic ductal adenocarcinoma.

A paucity of effector T cells within tumors renders pancreatic ductal adenocarcinoma (PDAC) resistant to immune checkpoint therapies. While several under-development approaches target immune-suppressive cells in the tumor microenvironment, there is less focus on improving T cell function. Here we show that inhibiting vasoactive intestinal peptide receptor (VIP-R) signaling enhances anti-tumor immunity in murine PDAC models. In silico data mining and immunohistochemistry analysis of primary tumors indicate overexpression of the neuropeptide vasoactive intestinal peptide (VIP) in human PDAC tumors. Elevated VIP levels are also present in PDAC patient plasma and supernatants of cultured PDAC cells. Furthermore, T cells up-regulate VIP receptors after activation, identifying the VIP signaling pathway as a potential target to enhance T cell function. In mouse PDAC models, VIP-R antagonist peptides synergize with anti-PD-1 antibody treatment in improving T cell recruitment into the tumors, activation of tumor-antigen-specific T cells, and inhibition of T cell exhaustion. In contrast to the limited single-agent activity of anti-PD1 antibodies or VIP-R antagonist peptides, combining both therapies eliminate tumors in up to 40% of animals. Furthermore, tumor-free mice resist tumor re-challenge, indicating anti-cancer immunological memory generation. VIP-R signaling thus represents a tumor-protective immune-modulatory pathway that is targetable in PDAC.

Incidence and risk factor analysis for swelling after apical microsurgery.

BACKGROUND: Swelling after apical microsurgery is a postoperative reaction and may reduce quality of life during healing. AIM: To evaluate periapical swelling after apical microsurgery and determine potential risk factors. METHODS: Ninety-eight apical microsurgery patients were selected for this study. Before surgery, bone shadow volume and density of pathological tissue were measured by cone beam computed tomography. The other variables (age, gender, operative teeth number, fistula, preoperative swelling, drug use and preoperative root canal treatments) were assessed during examination. Swelling degree was confirmed by questionnaires for patients on postoperative days 1, 7, 14 and 21. Statistical analyses were performed to identify predictors for swelling. RESULTS: Majority of patients reported moderate (45.9%) or severe (34.7%) swelling on day 1, and moderate (44.9%) or mild (45.9%) on postoperative day 7. Ninety-nine percent of patients had no or mild swelling on postoperative day 14. The average swelling level peaked on day 1 postoperatively and gradually decreased. Of statistical significance, age, bone shadow volume and density of pathological tissue acted as predictors of swelling (P < 0.05). However, there was no significant difference in gender, tooth number, fistula, preoperative swelling, drug use, or preoperative root canal treatments (P > 0.05). CONCLUSION: Younger patients with larger shadow volume and density were significantly more likely to develop swelling after apical microsurgery.

Gold Nanostrip Array-Mediated Wireless Electrical Stimulation for Accelerating Functional Neuronal Differentiation.

Neural stem cell (NSC)-based therapy holds great promise for the treatment of neurodegenerative diseases. Presently, however, it is hindered by poor functional neuronal differentiation. Electrical stimulation is considered one of the most effective ways to promote neuronal differentiation of NSCs. In addition to surgically implanted electrodes, traditional electrical stimulation includes wires connected to the external power supply, and an additional surgery is required to remove the electrodes or wires following stimulation, which may cause secondary injuries and infections. Herein, a novel method is reported for generation of wireless electrical signals on an Au nanostrip array by leveraging the effect of electromagnetic induction under a rotating magnetic field. The intensity of the generated electrical signals depends on the rotation speed and magnetic field strength. The Au nanostrip array-mediated electric stimulation promotes NSC differentiation into mature neurons within 5 days, at the mRNA, protein, and function levels. The rate of differentiation is faster by at least 5 days than that in cells without treatment. The Au nanostrip array-based wireless device also accelerates neuronal differentiation of NSCs in vivo. The novel method to accelerate the neuronal differentiation of NSCs has the advantages of wireless, timely, localized and precise controllability, and noninvasive power supplementation.

Donor plasmacytoid dendritic cells limit graft-versus-host disease through vasoactive intestinal polypeptide expression.

Vasoactive intestinal polypeptide (VIP), an anti-inflammatory neuropeptide with pleiotropic cardiovascular effects, induces differentiation of hematopoietic stem cells into regulatory dendritic cells that limit graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplant (HSCT) recipients. We have previously shown that donor plasmacytoid dendritic cells (pDCs) in bone marrow (BM) donor grafts limit the pathogenesis of GVHD. In this current study we show that murine and human pDCs express VIP, and that VIP-expressing pDCs limit T-cell activation and expansion using both in vivo and in vitro model systems. Using T cells or pDCs from transgenic luciferase+ donors in murine bone marrow transplantation (BMT), we show similar homing patterns of donor pDCs and T cells to the major sites for alloactivation of donor T cells: spleen and gut. Cotransplanting VIP-knockout (KO) pDCs with hematopoietic stem cells and T cells in major histocompatibility complex mismatched allogeneic BMT led to lower survival, higher GVHD scores, and more colon crypt cell apoptosis than transplanting wild-type pDCs. BMT recipients of VIP-KO pDCs had more T helper 1 polarized T cells, and higher plasma levels of granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-α than recipients of wild-type pDCs. T cells from VIP-KO pDC recipients had increasing levels of bhlhe40 transcripts during the first 2 weeks posttransplant, and higher levels of CyclophilinA/Ppia transcripts at day 15 compared with T cells from recipients of wild-type pDCs. Collectively, these data indicate paracrine VIP synthesis by donor pDCs limits pathogenic T-cell inflammation, supporting a novel mechanism by which donor immune cells regulate T-cell activation and GVHD in allogeneic BMT.

PI3Kδ/γ inhibition promotes human CART cell epigenetic and metabolic reprogramming to enhance antitumor cytotoxicity.

Current limitations in using chimeric antigen receptor T(CART) cells to treat patients with hematological cancers include limited expansion and persistence in vivo that contribute to cancer relapse. Patients with chronic lymphocytic leukemia (CLL) have terminally differentiated T cells with an exhausted phenotype and experience low complete response rates after autologous CART therapy. Because PI3K inhibitor therapy is associated with the development of T-cell-mediated autoimmunity, we studied the effects of inhibiting the PI3Kδ and PI3Kγ isoforms during the manufacture of CART cells prepared from patients with CLL. Dual PI3Kδ/γ inhibition normalized CD4/CD8 ratios and maximized the number of CD8+ T-stem cell memory, naive, and central memory T-cells with dose-dependent decreases in expression of the TIM-3 exhaustion marker. CART cells manufactured with duvelisib (Duv-CART cells) showed significantly increased in vitro cytotoxicity against CD19+ CLL targets caused by increased frequencies of CD8+ CART cells. Duv-CART cells had increased expression of the mitochondrial fusion protein MFN2, with an associated increase in the relative content of mitochondria. Duv-CART cells exhibited increased SIRT1 and TCF1/7 expression, which correlated with epigenetic reprograming of Duv-CART cells toward stem-like properties. After transfer to NOG mice engrafted with a human CLL cell line, Duv-CART cells expressing either a CD28 or 41BB costimulatory domain demonstrated significantly increased in vivo expansion of CD8+ CART cells, faster elimination of CLL, and longer persistence. Duv-CART cells significantly enhanced survival of CLL-bearing mice compared with conventionally manufactured CART cells. In summary, exposure of CART to a PI3Kδ/γ inhibitor during manufacturing enriched the CART product for CD8+ CART cells with stem-like qualities and enhanced efficacy in eliminating CLL in vivo.

Targeted Regulation of the Electronic States of Nickel Toward the Efficient Electrosynthesis of Benzonitrile and Hydrogen Production.

Highly efficient electro-oxidation of benzylamine to generate value-added chemicals coupled with the hydrogen evolution reaction (HER) is crucial but challenging. Herein, targeted regulation of the electronic states of Ni sites was realized via simple yet precise nitridation engineering. Benefiting from the insertion of N atoms into the Ni lattice, the Ni3N electrode exhibits superior activity, selectivity, and stability for the benzylamine oxidation reaction (BOR). Especially, under the industrially relevant current (∼250 mA), the Ni3N catalyst remains ∼95% selective for benzonitrile production, reaching 1.43 mmol h-1 cm-2. Experimental and theoretical findings reveal that the formation of Ni-N bonds upshifts the Ni d-band center and optimizes the electrophilic properties of Ni sites, which contributes to the adsorption and dehydrogenations process of benzylamine. Furthermore, due to the work function difference between Ni and Ni3N, a strong mutual interaction occurs at the heterogeneous interface for Ni-Ni3N, which endows it with the appropriate H* adsorption energy and thus excellent HER performance. Impressively, the integrated solar-energy-driven BOR coupled with the HER electrolyzer affords 10 mA cm-2 at an ultralow voltage of 1.4 V and exhibits a promising practical application (ηsolar-to-hydrogen = 13.8%). This work offers a new perspective for the bifunctional design of nitrides in the field of electrosynthesis.

Synovial Fluid-Induced Aggregation Occurs across Staphylococcus aureus Clinical Isolates and is Mechanistically Independent of Attached Biofilm Formation.

Rapid synovial fluid-induced aggregation of Staphylococcus aureus is currently being investigated as an important factor in the establishment of periprosthetic joint infections (PJIs). Pathogenic advantages of aggregate formation have been well documented in vitro, including recalcitrance to antibiotics and protection from host immune defenses. The objective of the present work was to determine the strain dependency of synovial fluid-induced aggregation by measuring the degree of aggregation of 21 clinical S. aureus isolates cultured from either PJI or bloodstream infections using imaging and flow cytometry. Furthermore, by measuring attached bacterial biomass using a conventional crystal violet assay, we assessed whether there is a correlation between the aggregative phenotype and surface-associated biofilm formation. While all of the isolates were stimulated to aggregate upon exposure to bovine synovial fluid (BSF) and human serum (HS), the extent of aggregation was highly variable between individual strains. Interestingly, the PJI isolates aggregated significantly more upon BSF exposure than those isolated from bloodstream infections. While we were able to stimulate biofilm formation with all of the isolates in growth medium, supplementation with either synovial fluid or human serum inhibited bacterial surface attachment over a 24 h incubation. Surprisingly, there was no correlation between the degree of synovial fluid-induced aggregation and quantity of surface-associated biofilm as measured by a conventional biofilm assay without host fluid supplementation. Taken together, our findings suggest that synovial fluid-induced aggregation appears to be widespread among S. aureus strains and mechanistically independent of biofilm formation. IMPORTANCE Bacterial infections of hip and knee implants are rare but devastating complications of orthopedic surgery. Despite a widespread appreciation of the considerable financial, physical, and emotional burden associated with the development of a prosthetic joint infection, the establishment of bacteria in the synovial joint remains poorly understood. It has been shown that immediately upon exposure to synovial fluid, the viscous fluid in the joint, Staphylococcus aureus rapidly forms aggregates which are resistant to antibiotics and host immune cell clearance. The bacterial virulence associated with aggregate formation is likely a step in the establishment of prosthetic joint infection, and as such, it has the potential to be a potent target of prevention. We hope that this work contributes to the future development of therapeutics targeting synovial fluid-induced aggregation to better prevent and treat these infections.

Analysis of Extended Resection of Limb Soft Tissue Leiomyosarcoma.

Leiomyosarcoma is an uncommon soft tissue sarcoma that composed of malignant mesenchymal cells with distinct features of the smooth muscle lineage. Typically affects the uterus and gastrointestinal tract, it can rarely be seen in large blood vessels, lymphatic and glandular duts, the mesentery, the omentum, retroperitoneum, and limbs. Occurrence is particularly rare in the limb region. Retrospective study based on patient records and postoperative pathological histological features. Four patients with limb leiomyosarcoma that were operated between 2016 and 2020 were included, three of them arising in the subcutis of the thigh region and one in cubitus. Extend resection with satisfactory outcomes is reported. Pathological examination showed that masses were composed of a fascicular arrangement of hyperchromatic spindle-shaped cells, characterized by the proliferation of epithelioid cells with eosinophilic cytoplasm for epithelioid leiomyosarcoma. Leiomyosarcomas that arise in the soft tissue, although rare, should be differentiated from other lesions, such as neurilemoma, neurofibroma, liomyoma,lipomyoma, synoviosarcoma, rhabdomyosarcoma, malignant fibrous histiotoma, and malignant neurinoma.

Hydroxyapatite Nanorods Function as Safe and Effective Growth Factors Regulating Neural Differentiation and Neuron Development.

Neural stem cell (NSC) transplantation is one of the most promising therapeutic strategies for neurodegenerative diseases. However, the slow spontaneous differentiation of NSCs often hampers their application in neural repair. Although some biological growth factors accelerate the differentiation of NSCs, their high cost, short half-life, and unpredictable behavior in vivo, as well as the complexity of the operation, hinder their clinical use. In this study, it is demonstrated that hydroxyapatite (HAp), the main component of bone, in the form of nanorods, can regulate the neural differentiation of NSCs and maturation of the newly differentiated cells. Culturing NSCs with HAp nanorods leads to the differentiation of NSCs into mature neurons that exhibit well-defined electrophysiological behavior within 5 days. The state of these neurons is much better than when culturing the cells without HAp nanorods, which undergo a 2-week differentiation process. Furthermore, RNA-sequencing data reveal that the neuroactive ligand-receptor interaction pathway is dominant in the enriched differentiated neuronal population. Hence, inorganic growth factors like HAp act as a feasible, effective, safe, and practical tool for regulating the differentiation of NSCs and can potentially be used in the treatment of neurodegenerative diseases.

Wireless Localized Electrical Stimulation Generated by an Ultrasound-Driven Piezoelectric Discharge Regulates Proinflammatory Macrophage Polarization.

Proinflammatory (M1) macrophages play a vital role in antitumor immunity, and regulation of proinflammatory macrophage polarization is critical for immunotherapy. The polarization of macrophages can be regulated by biological or chemical stimulation, but investigations of the regulatory effect of physical stimulation are limited. Herein, regulating macrophage polarization with localized electrical signals derived from a piezoelectric ß-phase poly(vinylidene fluoride) (ß-PVDF) film in a wireless mode is proposed. Charges released on the surface of the ß-PVDF film driven by ultrasonic irradiation can significantly enhance the M1 polarization of macrophages. Mechanistic investigation confirms that electrical potentials rather than reactive oxygen species and mechanical forces enable Ca2+ influx through voltage-gated channels and establishment of the Ca2+-CAMK2A-NF-κB axis to promote the proinflammatory macrophage response during ultrasound treatment. Piezoelectric material-mediated electrical signal-activated proinflammatory macrophages significantly inhibit tumor cell proliferation. A method for electrogenetic regulation of immune cells as well as a powerful tool for engineering macrophages for immunotherapy is provided here.

A versatile and low-toxicity material for photothermal therapy in deeper tissues.

The limited depth of the near infrared (NIR) response is one of the major flaws of the present photothermal therapy (PTT). In this article, thermosensitive polyurethane urea (TPUU) was synthesized by polymerization. Subsequent experiments showed that, compared with classical photosensitizers, TPUU has higher photothermal effects and lower cytotoxicity. These valuable properties could make the present PTT research provide more therapeutic options among different tissues and organs. As a practical example, TPUU was applied to regulate the intestinal flora through external NIR irradiation, which implied its promising expanded applications in deeper tissues.