Crosstalk between bone and brain in Alzheimer's disease: Mechanisms, applications, and perspectives.

Alzheimer's disease (AD) is a neurodegenerative disease that involves multiple systems in the body. Numerous recent studies have revealed bidirectional crosstalk between the brain and bone, but the interaction between bone and brain in AD remains unclear. In this review, we summarize human studies of the association between bone and brain and provide an overview of their interactions and the underlying mechanisms in AD. We review the effects of AD on bone from the aspects of AD pathogenic proteins, AD risk genes, neurohormones, neuropeptides, neurotransmitters, brain-derived extracellular vesicles (EVs), and the autonomic nervous system. Correspondingly, we elucidate the underlying mechanisms of the involvement of bone in the pathogenesis of AD, including bone-derived hormones, bone marrow-derived cells, bone-derived EVs, and inflammation. On the basis of the crosstalk between bone and the brain, we propose potential strategies for the management of AD with the hope of offering novel perspectives on its prevention and treatment. HIGHLIGHTS: The pathogenesis of AD, along with its consequent changes in the brain, may involve disturbing bone homeostasis. Degenerative bone disorders may influence the progression of AD through a series of pathophysiological mechanisms. Therefore, relevant bone intervention strategies may be beneficial for the comprehensive management of AD.

A unique case report of a revision extensor mechanism reconstruction using Marlex mesh in the setting of proximal tibial bone deficiency: The tantalum clamshell technique.

Extensor mechanism (EM) disruption is a rare but severe complication of total knee arthroplasty (TKA) that can greatly impair function. Treatment options for chronic patella tendon ruptures include primary repair, autograft augmentation, and reconstruction with allograft or synthetic material. Despite various techniques, failures can occur, and options for reconstruction after a failed allograft or mesh are limited, especially if the tibial component is well-fixed and cannot be easily removed, and if there is proximal tibial deficiency from a previous failed EM allograft. This case report presents a novel solution for revision EM reconstruction in a 72y.o. female patient with a history of multiple EM failures using an off-label Trabecular Metal Cone-Mesh-Cone (TM CMC) clamshell construct. The surgical procedure involved the removal of a non-viable allograft from the knee joint and the creation of a custom trabecular metal (TM) clamshell construct with a Marlex mesh graft in between the two TM implants. The customized TM cone was designed to cover the deficient anterior tibia and wrap around the ingrown TM cone. The Marlex mesh was cemented between the existing implant and the customized TM cone, and the construct was secured in place with two cancellous screws. The mesh was tunneled between soft tissue to prevent contact with the implant and rotated scar tissue was interposed to prevent abrasion of the mesh on the implant surfaces. The patient tolerated the procedure well and no complications were noted postoperatively. At a follow-up 12 months after the operation the patient remains satisfied with the result.

Prevalence of functional esophageal disorders and associated clinical characteristics in patients with proton-pump-inhibitor-unresponsive reflux symptoms.

BACKGROUND AND AIM: Patients with proton-pump-inhibitor (PPI)-unresponsive reflux symptoms, often caused by functional esophageal disorders (FED), are frequently encountered in clinical practice. We aimed to investigate the prevalence of FED and its associated clinical characteristics in patients with PPI-unresponsive reflux symptoms. METHODS: We retrospectively identified patients who were evaluated for persistent typical reflux symptoms, despite ≥8 weeks of PPI treatment, at the National Taiwan University Hospital from 2014 to 2023. All patients underwent a comprehensive evaluation comprising validated gastroesophageal reflux disease (GERD) symptom questionnaires, 5-item Brief Symptom Rating Scale (BSRS-5), Pittsburgh Sleep Quality Index (PSQI), esophagogastroduodenoscopy, high-resolution impedance manometry, and 24-h impedance-pH monitoring off PPI therapy. Diagnosis of FED and non-erosive reflux disease (NERD) was based on the Rome IV criteria. RESULTS: We analyzed 190 patients [46.8% male, median age 52 (interquartile range, 42-61) years], of whom 32 (16.8%) had NERD and 158 (83.2%) had FED (57.9% with functional heartburn and 25.3% with reflux hypersensitivity). Patients with FED had a lower body mass index than those with NERD and a higher prevalence of psychological comorbidities and poor sleep quality than healthy volunteers. The severity of reflux symptoms among FED patients was significantly associated with the severity of psychological comorbidities and sleep quality. CONCLUSIONS: A notably high prevalence (83.2%) of FED was observed among patients experiencing PPI-unresponsive reflux symptoms. Patients with FED had a higher level of psychological distress and diminished sleep quality, both of which were associated with reflux symptom severity.

Exploring the Localization of Siderophore-Mediated Cargo Delivery in Gram-Negative Bacteria Using 3-Hydroxypyridin-4(1H)-one-Fluorescein Probes.

The design of siderophore-antibiotic conjugates is a promising strategy to overcome drug resistance in negative bacteria. However, accumulating studies have shown that only those antibiotics acting on the cell wall or cell membrane multiply their antibacterial effects when coupled with siderophores, while antibiotics acting on targets in the cytoplasm of bacteria do not show an obvious enhancement of their antibacterial effects when coupled with siderophores. To explore the causes of this phenomenon, we synthesized several conjugate probes using 3-hydroxypyridin-4(1H)-ones as siderophores and replacing the antibiotic cargo with 5-carboxyfluorescein (5-FAM) or malachite green (MG) cargo. By monitoring changes in the fluorescence intensity of FAM conjugate 20 in bacteria, the translocation of the conjugate across the outer membranes of Gram-negative pathogens was confirmed. Further, the use of the fluorogen activating protein(FAP)/MG system revealed that 3-hydroxypyridin-4(1H)-one-MG conjugate 26 was ultimately distributed mainly in the periplasm rather than being translocated into the cytosol of Escherichia coli and Pseudomonas aeruginosa PAO1. Additional mechanistic studies suggested that the uptake of the conjugate involved the siderophore-dependent iron transport pathway and the 3-hydroxypyridin-4(1H)-ones siderophore receptor-dependent mechanism. Meanwhile, we demonstrated that the conjugation of 3-hydroxypyridin-4(1H)-ones to the fluorescein 5-FAM can reduce the possibility of the conjugates crossing the membrane layers of mammalian Vero cells by passive diffusion, and the advantages of the mono-3-hydroxypyridin-4(1H)-ones as a delivery vehicle in the design of conjugates compared to the tri-3-hydroxypyridin-4(1H)-ones. Overall, this work reveals the localization rules of 3-hydroxypyridin-4(1H)-ones as siderophores to deliver the cargo into Gram-negative bacteria. It provides a theoretical basis for the subsequent design of siderophore-antibiotic conjugates, especially based on 3-hydroxypyridin-4(1H)-ones as siderophores.

Interstitial fibrosis increases the risk of end-stage kidney disease in patients with lupus nephritis.

OBJECTIVE: To evaluate the risk of end-stage kidney disease (ESKD) in lupus nephritis (LN) patients using tubulointerstitial lesion scores. METHODS: Clinical profiles and histopathological presentations of 151 biopsy-proven LN patients were retrospectively examined. Risk factors of ESKD based on characteristics and scoring of their tubulointerstitial lesions (e.g. interstitial inflammation [II], tubular atrophy [TA], and interstitial fibrosis [IF]) were analyzed. RESULTS: The mean age of 151 LN patients was 36 years old, and 136 (90.1%) were female. The LN cases examined included: class I/II (n = 3, 2%), class III/IV (n = 119, 78.8%), class V (n = 23, 15.2%), and class VI (n = 6, 4.0%). The mean serum creatinine level was 1.4 mg/dl. Tubulointerstitial lesions were recorded in 120 (79.5%) patients. Prior to receiving renal biopsy, 9 (6.0%) patients developed ESKD. During the follow-up period (mean, 58 months), an additional 47 patients (31.1%) progressed to ESKD. Multivariate analyses identified serum creatinine (hazard ratio [HR]: 1.7, 95% confidence interval [CI]: 1.42-2.03, p < 0.001) and IF (HR: 3.2, 95% CI: 1.58-6.49, p = 0.001) as independent risk factors of ESKD. Kaplan-Meier analysis further confirmed a heightened risk of ESKD associated with IF. CONCLUSION: Tubulointerstitial involvement is commonly observed in histopathological presentation of LN. However, IF, rather than II, or TA, was found to increase the risk of ESKD in our cohort. Therefore, to predict renal outcome in LN patients prior to adjusting immunosuppressive treatment, degree of IF should be reviewed.

PAHs removal by soil washing with thiacalix[4]arene tetrasulfonate.

Remediating soil contaminated with polycyclic aromatic hydrocarbons (PAHs) presents a significant environmental challenge due to their toxic and carcinogenic properties. Traditional PAHs remediation methods-chemical, thermal, and bioremediation-along with conventional soil-washing agents like surfactants and cyclodextrins face challenges of cost, ecological harm, and inefficiency. Here we show an effective and environmentally friendly calixarene derivative for PAHs removal through soil washing. Thiacalix[4]arene tetrasulfonate (TCAS) has a unique molecular structure of a sulfonate group and a sulfur atom, which enhances its solubility and facilitates selective binding with PAHs. It forms host-guest complexes with PAHs through π-π stacking, OH-π interactions, hydrogen bonding, van der Waals forces, and electrostatic interactions. These interactions enable partial encapsulation of PAH molecules, aiding their desorption from the soil matrix. Our results show that a 0.7% solution of TCAS can extract approximately 50% of PAHs from contaminated soil while preserving soil nutrients and minimizing adverse environmental effects. This research unveils the pioneering application of TCAS in removing PAHs from contaminated soil, marking a transformative advancement in resource-efficient and sustainable soil remediation strategies.

Enhanced recovery after surgery day surgery for MAKO® robotic-arm assisted TKA; better outcome for patients, improved efficiency for hospitals.

Introduction: Robotic-assisted Total Knee Arthroplasty (TKA) was designed to improve implant position accuracy by providing surgeons with real-time intra-operative data to tailor the operation to the patient. Proponents of robotic-assisted TKA believe that this translates into meaningful improvements in outcomes. However, there are concerns that the longer surgical duration associated with robotic-assisted TKA leads to longer length of stay (LOS). In this study, the authors investigated the outcome of MAKO® Robotic-arm Assisted TKA combined with ERAS protocol to assess its effect on LOS and short-term outcomes. Methods: All patients who had undergone unilateral MAKO® ERAS Day Surgery TKA from August 2020 to July 2021 were prospectively followed up and matched to patients who underwent conventional ERAS Day Surgery TKA in the same time period. Factors such as surgical duration, LOS, immediate reduction in pain, 30-days complications, and 6-month PROMs and knee ROM were compared between the two groups. Results: 42 patients underwent MAKO® ERAS Day surgery TKA and were matched to 42 patients who underwent conventional ERAS Day surgery TKA. The study found that despite the longer surgical duration, LOS was comparable between both groups (1.1 ± 0.9days in the MAKO® group vs 1.0 ± 0.3days in the conventional group, p = 0.755) with successful 24-hour discharge in 88.1 % of patients in the MAKO® group. The MAKO® group achieved significantly better ROM compared to the conventional group 6-months post operatively. Post-operative PROMs were comparable between both groups. Conclusion: ERAS Day Surgery protocol can significantly reduce the LOS of patient undergoing MAKO® Robotic-arm Assisted TKA, conferring cost savings and making it a valid option for patients.

Effect of Context Specificity on Response to the Shortened WOMAC Function Scale in Patients Undergoing Total Knee Arthroplasty.

OBJECTIVE: To determine, in patients undergoing total knee arthroplasty (TKA), whether increasing context specificity of selected items of the shortened version of the Western Ontario and McMaster Universities Osteoarthritis Index function (WOMAC-F) scale (ShortMAC-F) (1) enhanced the convergent validity of the ShortMAC-F with performance-based mobility measures (ii) affected mean scale score, structural validity, reliability, and interpretability. DESIGN: Secondary analysis of randomized clinical trial data. SETTING: A tertiary teaching hospital. PARTICIPANTS: Patients undergoing TKA (N=114). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The ShortMAC-F was modified by specifying the "ascending stairs" and "rising from sitting" items to enquire about difficulty in performing the tasks without reliance on compensatory strategies, whereas the modified "level walking" item enquired about difficulty in walking 400 m. Before and 12 weeks after TKA, patients completed the WOMAC-F questionnaire, modified ShortMAC-F questionnaire, knee pain scale questionnaire, sit-to-stand test, fast gait speed test, and stair climb test. Interpretability was evaluated by calculating anchor-based substantial clinical benefit estimates. RESULTS: The modified ShortMAC-F correlated significantly more strongly than ShortMAC-F or WOMAC-F with pooled performance measures (differences in correlation values, 0.12-0.14). Increasing item context specificity of the ShortMAC-F did not influence its psychometric properties of unidimensionality (comparative fit and Tucker-Lewis indices, >0.95; root mean square error of approximation, 0.05-0.08), reliability (Cronbach's α, 0.75-0.83), correlation with pain intensity (correlation values, 0.48-0.52), and substantial clinical benefit estimates (16 percentage points); however, it resulted in lower mean score (4.5-4.8 points lower). CONCLUSIONS: The modified ShortMAC-F showed sufficient measurement properties for clinical application, and it seemed more adept than WOMAC-F at correlating with performance-based measures in TKA.

A Lateral Flow-Recombinase Polymerase Amplification Method for Colletotrichum gloeosporioides Detection.

The greater yam (Dioscorea alata), a widely cultivated and nutritious food crop, suffers from widespread yield reduction due to anthracnose caused by Colletotrichum gloeosporioides. Latent infection often occurs before anthracnose phenotypes can be detected, making early prevention difficult and causing significant harm to agricultural production. Through comparative genomic analysis of 60 genomes of 38 species from the Colletotrichum genus, this study identified 17 orthologous gene groups (orthogroups) that were shared by all investigated C. gloeosporioides strains but absent from all other Colletotrichum species. Four of the 17 C. gloeosporioides-specific orthogroups were used as molecular markers for PCR primer designation and C. gloeosporioides detection. All of them can specifically detect C. gloeosporioides out of microbes within and beyond the Colletotrichum genus with different sensitivities. To establish a rapid, portable, and operable anthracnose diagnostic method suitable for field use, specific recombinase polymerase amplification (RPA) primer probe combinations were designed, and a lateral flow (LF)-RPA detection kit for C. gloeosporioides was developed, with the sensitivity reaching the picogram (pg) level. In conclusion, this study identified C. gloeosporioides-specific molecular markers and developed an efficient method for C. gloeosporioides detection, which can be applied to the prevention and control of yam anthracnose as well as anthracnose caused by C. gloeosporioides in other crops. The strategy adopted by this study also serves as a reference for the identification of molecular markers and diagnosis of other plant pathogens.

UHRF1P contributes to IL-17A-mediated systemic lupus erythematosus via UHRF1-MAP4K3 axis.

Inflammatory T cells contribute to the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). Analysis of the T-cell transcriptomics data of two independent SLE patient cohorts by three machine learning models revealed the pseudogene UHRF1P as a novel SLE biomarker. The pseudogene-encoded UHRF1P protein was overexpressed in peripheral blood T cells of SLE patients. The UHRF1P protein lacks the amino-terminus of its parental UHRF1 protein, resulting in missing the proteasome-binding ubiquitin-like (Ubl) domain of UHRF1. T-cell-specific UHRF1P transgenic mice manifested the induction of IL-17A and autoimmune inflammation. Mechanistically, UHFR1P prevented UHRF1-induced Lys48-linked ubiquitination and degradation of MAP4K3 (GLK), which is a kinase known to induce IL-17A. Consistently, IL-17A induction and autoimmune phenotypes of UHRF1P transgenic mice were obliterated by MAP4K3 knockout. Collectively, UHRF1P overexpression in T cells inhibits the E3 ligase function of its parental UHRF1 and induces autoimmune diseases.

Postponement of total knee arthroplasties due to pandemic causes significant deterioration on patients' preoperative knee and quality of life scores.

Introduction: Elective surgeries were postponed during the COVID-19 pandemic to alleviate healthcare strains, affecting majority of elective orthopaedic surgeries such as total knee arthroplasties (TKAs). The aim of this study is to evaluate the impact on knee function and quality of life of patients who had their planned TKA postponed due to the pandemic. Methods: This is a retrospective analysis of data collected in a tertiary hospital. Patients included were diagnosed with primary knee osteoarthritis and they were initially scheduled for primary TKA between January to April 2020 but surgery was postponed by at least 6 months from the initial operative date. 160 patients were included in this study (53 males and 107 females, mean age 68.0 ± 8.1). Patients were assessed prior to initial surgery date and assessed again, prior to the postponed surgery date. Clinical scores included Knee Society Function Score (KSFS), Knee Society Knee Score (KSKS), Oxford Knee scores (OKS) and Short-Form 36 Physical and Mental Component Scores. (SF36 PCS and MCS). Paired T-test was performed for parametric data whereas Wilcoxon signed-rank analysis was performed for non-parametric data. Results: Comparing initial preoperative versus postponement preoperative scores, the cohort had significantly poorer KSKS (38.4 ± 15.4 and 36.5 ± 15.4, p = 0.034), SF36 PCS (34.3 ± 9.2 and 32.7 ± 8.6, p = 0.02) and OKS (34.9 ± 0.77 and 35.8 ± 8.6, p = 0.02) scores respectively. Conclusion: The postponement of elective TKAs has resulted in a significant deterioration of knee scores and physical quality of live scores of patients in a short span of 6 months. Further studies can evaluate if there are repercussions on long term TKAs outcomes. Level of evidence: Retrospective study, Level III.

Paediatric Orbital Juvenile Xanthogranuloma: A Case Series and Review of the Literature.

PURPOSE: Juvenile xanthogranuloma (JXG) is a subtype of histiocytosis characterised histologically by foamy non-Langerhan cells with Touton giant cells. It typically manifests as a single self-limiting cutaneous nodule in the paediatric population. Orbital JXG is extremely rare, and its clinical course and management are not well understood or defined. Herein we present 3 cases of orbital JXG and provide a detailed literature review. METHODS: Review of 3 cases with orbital JXG and literature review of all published cases. RESULTS: Three presented cases demonstrate the heterogeneous clinical course of orbital JXG. Although centred around the use of steroids, there is neither robust evidence nor consensus on its management. The wider JXG literature is currently concentrated around the classification of JXG with respect to histiocytosis, especially the exclusion of extracutaneous JXG as separate diseases. This separation is based on clinical, histopathological, and molecular findings. It is unclear where orbital JXG best fits in this emerging classification of JXG. CONCLUSION: Our review of the cases and literature on orbital JXG show that it may manifest with variable clinical course and its molecular pathogenic mechanism may be different to that of the cutaneous JXG.

Unicompartmental knee arthroplasty in obese patients, poorer survivorship at 15 years.

Introduction: The preclusion of obese patients from unicompartmental knee arthroplasty (UKA) has increasingly been challenged. This study aimed to evaluate the impact of Body Mass Index (BMI) on UKA at 15-year follow-up. Materials and methods: 169 unilateral UKA patients from 2003 to 2007 were followed-up prospectively for at least 15 years. 70 patients were left for analysis after accounting for patient demise, revision surgery and loss to follow-up. 48 of these patients (69%) were in the Control group (BMI <30 kg/m2) and 22 (31%) were in the Obese group (BMI ≥30 kg/m2). Patients were assessed before and after operation using the Knee Society Function Score (KSFS), Knee Society Knee Score (KSKS), Oxford Knee Score (OKS), and Physical (PCS) and Mental (MCS) component of the Short Form 12. Survivorship analysis was also performed. Results: Obese patients went through UKA at an earlier age than the non-obese patients (54.7 ± 4.7 years compared to 59.9 ± 7.8 years, p = 0.005). At 2, 10, and 15-year follow-up, both groups achieved clinically significant improvements in outcomes. There was no significant association found between obesity and outcome using multiple linear regression. While propensity matching found PCS improvement at 2 years to be greater in obese patients, no significant association between obesity and 15-year outcome was found. All 13 patients who required revision, underwent total knee arthroplasty (TKA). The overall 15-year survivorship was 74.2% within the obese group and 92.4% within the control group. Conclusion: Compared to non-obese patients, obese patients had poorer 15-year survivorship with greater odds of requiring revision surgery. However, assuming implant survival, obese patients can expect a non-inferior outcome relative to their non-obese counterparts in all patient reported outcome measures 15 years after surgery.

Preventive and Therapeutic Potential of Streptococcus cristatus CA119 in Experimental Periodontitis in Rats.

Periodontitis is an inflammatory condition of the oral cavity caused by a mixed infection of various bacteria, which not only severely affects the alveolar bone and connective tissues but also displays potential correlations with distal intestinal inflammation. In this study, we aimed to elucidate the therapeutic effects of Streptococcus cristatus CA119 on experimental periodontitis in rats and its impact on intestinal morphology. The results demonstrate that CA119 is capable of colonizing the oral cavity and exerting antagonistic effects on Porphyromonas gingivalis and Fusobacterium nucleatum, thus leading to a significant reduction in the oral pathogen load. Following CA119 intervention, there was a significant alleviation of weight loss in rats induced by periodontitis (P < 0.001). CA119 also regulated the expression of IL-6 (P < 0.05), IL-1ß (P < 0.001), IL-18 (P < 0.001), COX-2 (P < 0.001), iNOS (P < 0.001), and MCP-1 (P < 0.01) in the gingival tissue. Additionally, CA119 reduced oxidative stress levels in rats and enhanced their antioxidant capacity. Microcomputed tomography (micro-CT) and histological analysis revealed that CA119 significantly reduced alveolar bone loss and reversed the downregulation of OPG/RANKL (P < 0.001). Furthermore, CA119 exhibited a significant protective effect against intestinal inflammation induced by periodontal disease and improved the colonic morphology in rats. In conclusion, this study demonstrates the role of CA119 as a potential oral probiotic in the prevention and treatment of experimental periodontitis, underscoring the potential of probiotics as a complementary approach to traditional periodontal care.

Antimicrobial activity of eravacycline and other comparative agents on aerobic and anaerobic bacterial pathogens in Taiwan: A clinical microbiological study.

OBJECTIVES: Eravacycline, a new tetracycline derivative, exhibits broad-spectrum antimicrobial susceptibility. This study aimed to comprehensively investigate in vitro activities of eravacycline, tigecycline, and ertapenem against various Gram-positive, Gram-negative, and anaerobic bacteria. METHODS: Minimum inhibitory concentrations (MICs) were determined using the broth microdilution method. The following bacterial species were collected: vancomycin-sensitive (VS) Enterococci species, vancomycin-resistant Enterococci species (VRE), Staphylococcus aureus, Streptococcus anginosus, Bacteroides species, Clostridioides difficile, Clostridium innocuum, Clostridium perfringens, Parabacteroides distasonis, and Stenotrophomonas maltophilia. RESULTS: We found that eravacycline exhibited superior in vitro activity compared to tigecycline and ertapenem. Notably, it exhibited the lowest MIC90 for several bacterial species, including VS E. faecalis (0.12 µg/mL), VS E. faecium (0.12 µg/mL), and others. Besides, VRE was susceptible to eravacycline (MIC90:0.12 µg/mL) and tigecycline (MIC90:0.12 µg/mL), but was all resistant to ertapenem (MIC90 > 64 µg/mL). S. aureus was also susceptible to eravacycline (MIC90:0.5 µg/mL) as well as tigecycline (MIC90:1.0 µg/mL). Furthermore, S. anginosus showed higher susceptibility to eravacycline (MIC90:2.0 µg/mL) and tigecycline (MIC90:4.0 µg/mL), but lower to ertapenem (MIC90:32.0 µg/mL). Eravacycline and tigecycline also demonstrated good susceptibility to anaerobes, including Bacteroides species (susceptibility rate: 100%), P. distasonis (100%), C. difficile (94.1‒100%), C. innocuum (94.1‒96.1%), and C. perfringens (88.9‒96.3%). For S. maltophilia, both tigecycline and eravacycline showed an MIC90 of 2 µg/mL. A moderate-to-strong correlation (rho = 0.608-0.804, P < 0.001) was noted between the MIC values of eravacycline and tigecycline against various bacterial species. CONCLUSIONS: Our study highlights the potential of eravacycline as an effective treatment option for multidrug-resistant bacterial infections.

Cajaninstilbene acid derivatives conjugated with siderophores of 3-hydroxypyridin-4(1H)-ones as novel antibacterial agents against Gram-negative bacteria based on the Trojan horse strategy.

The low permeability of the outer membrane of Gram-negative bacteria is a serious obstacle to the development of new antibiotics against them. Conjugation of antibiotic with siderophore based on the "Trojan horse strategy" is a promising strategy to overcome the outer membrane obstacle. In this study, series of antibacterial agents were designed and synthesized by conjugating the 3-hydroxypyridin-4(1H)-one based siderophores with cajaninstilbene acid (CSA) derivative 4 which shows good activity against Gram-positive bacteria by targeting their cell membranes but is ineffective against Gram-negative bacteria. Compared to the inactive parent compound 4, the conjugates 45c or 45d exhibits significant improvement in activity against Gram-negative bacteria, including Escherichia coli, Klebsiella pneumoniae and especially P. aeruginosa (minimum inhibitory concentrations, MICs = 7.8-31.25 µM). The antibacterial activity of the conjugates is attributed to the CSA derivative moiety, and the action mechanism is by disruption of bacterial cell membranes. Further studies on the uptake mechanisms showed that the bacterial siderophore-dependent iron transport system was involved in the uptake of the conjugates. In addition, the conjugates 45c and 45d showed a lower cytotoxic effects in vivo and in vitro and a positive therapeutic effect in the treatment of C. elegans infected by P. aeruginosa. Overall, our work describes a new class and a promising 3-hydroxypyridin-4(1H)-one-CSA derivative conjugates for further development as antibacterial agents against Gram-negative bacteria.

A Rad50-null mutation in mouse germ cells causes reduced DSB formation, abnormal DSB end resection and complete loss of germ cells.

The conserved MRE11-RAD50-NBS1/Xrs2 complex is crucial for DNA break metabolism and genome maintenance. Although hypomorphic Rad50 mutation mice showed normal meiosis, both null and hypomorphic rad50 mutation yeast displayed impaired meiosis recombination. However, the in vivo function of Rad50 in mammalian germ cells, particularly its in vivo role in the resection of meiotic double strand break (DSB) ends at the molecular level remains elusive. Here, we have established germ cell-specific Rad50 knockout mouse models to determine the role of Rad50 in mitosis and meiosis of mammalian germ cells. We find that Rad50-deficient spermatocytes exhibit defective meiotic recombination and abnormal synapsis. Mechanistically, using END-seq, we demonstrate reduced DSB formation and abnormal DSB end resection occurs in mutant spermatocytes. We further identify that deletion of Rad50 in gonocytes leads to complete loss of spermatogonial stem cells due to genotoxic stress. Taken together, our results reveal the essential role of Rad50 in mammalian germ cell meiosis and mitosis, and provide in vivo views of RAD50 function in meiotic DSB formation and end resection at the molecular level.

Role of Epstein-Barr Virus in Breast Cancer: Correlation with Clinical Outcome and Survival Analysis.

Background: Breast cancer is the most prevalent cancer among women worldwide. The potential involvement of Epstein-Barr virus (EBV) in breast cancer pathogenesis has been a subject of debate, but its correlation with clinical outcomes remains uncertain. Methods: In this study, we collected 276 pathologically confirmed breast cancer tissue samples from the tissue bank of MacKay Memorial Hospital and the National Health Research Institutes in Taiwan. DNA was extracted from frozen tissue using The QIAamp DNA Mini Kit. The Taqman quantitative PCR method was employed to assess the EBV copy number per cell in these samples, using NAMALWA cells as a reference. We performed statistical analyses, including 2 × 2 contingency tables, Cox regression analysis, and Kaplan-Meier survival curves, to explore the association between clinicopathologic factors and survival outcomes in breast cancer patients. We analyzed both relapse survival, which reflects the period patients remain free from cancer recurrence post-treatment, and overall survival, which encompasses all-cause mortality. Results: Our results revealed a significant association between EBV status and relapse survival (hazard ratio: 2.75, 95% CI: 1.30, 5.86; p = 0.008) in breast cancer patients. However, no significant association was found in overall survival outcomes. Additionally, we observed significant associations between ER status and tumor histologic grade with both overall and relapse survival. Patients with EBV-positive tumors exhibited higher recurrence rates compared to those with EBV-negative tumors. Furthermore, we noted significant correlations between EBV status and HER-2 (p = 0.0005) and histological grade (p = 0.02) in our cohort of breast cancer patients. Conclusions: The presence of EBV in breast cancer tumors appears to exert an impact on patient outcomes, particularly concerning recurrence rates. Our findings highlight the significance of considering EBV status as a potential prognostic marker in breast cancer patients. Nonetheless, further research is essential to elucidate the underlying molecular mechanisms and develop novel therapeutic approaches.

Selective dissolution of zinc and lead from duplex ß-phase brasses in low and high conductivity water.

This study provides insights regarding the selective metal leaching of brass in various tap water conditions, which benefits water utilities to predict the potential of metal released from brass water meters. The long-term time-dependent selective metal dissolution of brass with various ß phase fractions have not previously been investigated. In this study, a 201-d immersion experiment was carried out in low and high conductivity tap water (LCTW and HCTW, respectively). Three commercialized brass samples in different ß phase fractions (ß = 51%, ß = 43%, ß = 39%), named brass 51, brass 43, and brass 39, respectively, were used. The results showed that brass 51 had the most negative corrosion potential (-0.17 V) and the lowest polarization resistance (8.5 kΩ) compared to brass 43 and brass 39 (-0.04 V and 10.1-14.7 kΩ, respectively) in LCTW. This trend was verified by the 201-d immersion experiment in which brass 51 exhibited the highest zinc leaching rate (21-30 µg L-1 cm-2 d-1), followed by brass 43 and brass 39 (16-23 µg L-1 cm-2 d-1) in both waters. The leaching amounts of lead and copper were extremely low compared to zinc. In LCTW, the uniform corrosion (UC) mechanism dominated from day 1 to day 120. Afterwards, UC was replaced by the galvanic corrosion (GC) mechanism, with the selective leaching coefficient of Zn over Cu (SZn/Cu) increasing from 10 to 25 to 40-80. In HCTW, however, the SZn/Cu reached 300-1000, and the transition of UC to GC occurred earlier on day 30 due to the rapid formation of the ZnO layer on the brass surface that hindered the ion attack.

Targeting the intracellular neurexin interactome by in vivo proximity ligation.

In a recent study, Profes, Tiroumalechetty, and colleagues used the in vivo proximity ligation technique TurboID to scrupulously characterize the interactome of the intracellular domain (ICD) of neurexin, revealing that this domain may be involved in presynaptic actin assembly by interacting with actin-associated proteins.