Lactylation: The emerging frontier in post-translational modification.

Lactate, a metabolic byproduct, has gained recognition as a highly influential signaling molecule. Lactylation, an emerging form of post-translational modification derived from lactate, plays a crucial role in numerous cellular processes such as inflammation, embryonic development, tumor proliferation, and metabolism. However, the precise molecular mechanisms through which lactylation governs these biological functions in both physiological and pathological contexts remain elusive. Hence, it is imperative to provide a comprehensive overview of lactylation in order to elucidate its significance in biological processes and establish a foundation for forthcoming investigations. This review aims to succinctly outline the process of lactylation modification and the characterization of protein lactylation across diverse organisms. Additionally, A summary of the regulatory mechanisms of lactylation in cellular processes and specific diseases is presented. Finally, this review concludes by delineating existing research gaps in lactylation and proposing primary directions for future investigations.

Neolignans in Magnolia officinalis as natural anti-Alzheimer's disease agents: A systematic review.

BACKGROUND: Magnolia officinalis, a traditional herbal medicine widely used in clinical practice, exerts antibacterial, anti-tumor, anti-inflammatory, antioxidant, and anti-aging activities. Neolignans are the main active ingredients of M. officinalis and exert a wide range of pharmacological effects, including anti-Alzheimer's disease (AD) activity. OBJECTIVE: To summarize the published data on the therapeutic effect and mechanism of neolignans on AD in vivo and in vitro. METHODS: PubMed, Web of Science, Google Scholar, and Scopus were systematically reviewed (up to March 1, 2024) for pre-clinical studies. RESULTS: M. officinalis-derived neolignans (honokiol, magnolol, 4-O-methylhonokiol, and obovatol) alleviated behavioral abnormalities, including learning and cognitive impairments, in AD animal models. Mechanistically, neolignans inhibited Aß generation or aggregation, neuroinflammation, and acetylcholinesterase activity; promoted microglial phagocytosis and anti-oxidative stress; alleviated mitochondrial dysfunction and energy metabolism, as well as anti-cholinergic deficiency; and regulated intestinal flora. Furthermore, neolignans may achieve neuroprotection by regulating different molecular pathways, including the NF-κB, ERK, AMPK/mTOR/ULK1, and cAMP/PKA/CREB pathways. CONCLUSIONS: Neolignans exert anti-AD effects through multiple mechanisms and pathways. However, the exact targets, pharmacokinetics, safety, and clinical efficacy in patients with AD need further investigation in multi-center clinical case-control studies.

Air pollution, greenspace exposure and risk of Parkinson's disease: a prospective study of 441,462 participants.

BACKGROUND: The current understandings of the relationship between air pollution (AP), greenspace exposure and Parkinson's Disease (PD) remain inconclusive. METHODS: We engaged 441,462 participants from the UK Biobank who were not diagnosed with PD. Utilizing Cox proportional hazard regression model, relationships between AP [nitrogen dioxide (NO2), and nitrogen oxides (NOX), particulate matter < 2.5 µm in aerodynamic diameter(PM2.5), coarse particulate matter between 2.5 µm and 10 µm in aerodynamic diameter(PM2.5-10), particulate matter < 10 µm in aerodynamic diameter(PM10)], greenspace exposure, and PD risk were determined independently. Our analyses comprised three models, adjusted for covariates, and affirmed through six sensitivity analyses to bolster the robustness of our findings. Moreover, mediation analysis was deployed to discern the mediating effect of AP between greenspaces and PD. RESULTS: During a median follow-up of 12.23 years (5,574,293 person-years), there were 3,293 PD events. Each interquartile (IQR) increment in NO2 and PM10 concentrations were associated with 10% and 8% increase in PD onset risk, while the increases in NOX, PM2.5 and PM2.5-10 were not associated with PD risk. Additionally, greenspace may safeguard by reducing NO2 and PM10 levels, with the effect mediated by NO2 and PM10 in greenspace-PD relationship. CONCLUSION: Our findings indicate that an IQR increase in ambient NO2 and PM10 concentrations was associated with risk of PD development, while other pollutants (NOX, PM2.5 and PM2.5-10) were not associated with PD risk. Firstly, we find that augmented exposure to greenspace was associated with the lower PD risk by reducing NO2 and PM10 levels.

The potential protective role of peripheral immunophenotypes in Alzheimer's disease: a Mendelian randomization study.

Introduction: Alzheimer's disease (AD) is the most widespread neurodegenerative disease in the world. Previous studies have shown that peripheral immune dysregulation plays a paramount role in AD, but whether there is a protective causal relationship between peripheral immunophenotypes and AD risk remains ambiguous. Methods: Two-sample Mendelian randomization (MR) was performed using large genome-wide association study (GWAS) genetic data to assess causal effects between peripheral immunophenotypes and AD risk. Utilizing the genetic associations of 731 immune cell traits as exposures. We adopted the inverse variance weighted method as the primary approach. The Weighted median and MR-Egger regression methods were employed as supplements. Various sensitivity analyses were performed to assess the robustness of the outcomes. Results: Based on the IVW method, we identified 14 immune cell traits that significantly reduced the risk of AD, of which six demonstrated statistical significance in both IVW and Weighted median methods. Among the seven immune traits, four were related to regulatory T (Treg) cells : (1) CD25++ CD45RA- CD4 not regulatory T cell % T cell (odds ratio (OR) [95% confidence interval (CI)] = 0.96 [0.95, 0.98], adjusted P = 1.17E-02), (2) CD25++ CD45RA- CD4 not regulatory T cell % CD4+ T cell (OR [95% CI] = 0.97 [0.96, 0.99], adjusted P = 3.77E-02), (3) Secreting CD4 regulatory T cell % CD4 regulatory T cell (OR [95% CI] = 0.98 [0.97, 0.99], adjusted P = 7.10E-03), (4) Activated & secreting CD4 regulatory T cell % CD4 regulatory T cell(OR [95% CI] = 0.98 [0.97, 0.99], adjusted P = 7.10E-03). In addition, HLA DR++ monocyte % monocyte (OR [95% CI] = 0.93 [0.89, 0.98], adjusted P = 4.87E-02) was associated with monocytes, and HLA DR on myeloid Dendritic Cell (OR [95% CI] = 0.93 [0.89, 0.97], adjusted P = 1.17E-02) was related to dendritic cells (DCs). Conclusion: These findings enhance the comprehension of the protective role of peripheral immunity in AD and provide further support for Treg and monocyte as potential targets for immunotherapy in AD.

Acryloyl chitosan as a macro-crosslinker for freezing-resistant, self-healing and self-adhesive ionogels-based multicompetent flexible sensors.

Here, a polysaccharide derivative acryloyl chitosan (AcCS) is exploited as macro-crosslinker to synthesize a novel ionogel poly (acrylic acid-co-1-Vinyl-3-butyl imidazolium chloride) (AA-IL/AcCS) via a one-pot method. AcCS provides abundant physical and chemical crosslinking sites contributing to the high mechanical stretchability (elongation at break 600 %) and strength (tensile strength 137 kPa) of AA-IL/AcCS. The high-density of dynamic bonds (hydrogen bonds and electrostatic interactions) in the network of ionogels enables self-healing and self-adhesive features of AA-IL/AcCS. Meanwhile, AA-IL/AcCS exhibits high ionic conductivity (0.1 mS/cm) at room temperature and excellent antifreeze ability (-58 °C). The AA-IL/AcCS-based sensor shows diverse sensory capabilities towards temperature and humidity, moreover, it could precisely detect human motions and handwritings signals. Furthermore, AA-IL/AcCS exhibits excellent bactericidal properties against both gram-positive and gram-negative bacteria. This work opens the possibility of polysaccharides as a macro-crosslinkers for preparing ionogel-based sensors for wearable electronics.

Dysregulated serum lipid profile is associated with inflammation and disease activity in primary Sjögren's syndrome: a retrospective study in China.

PURPOSE: To investigate the relationship between the lipid profiles of patients with primary Sjögren's syndrome (pSS) and other clinical characteristics, laboratory examination, disease activity, and inflammatory factors. In addition, the risk factors for hyperlipidemia-related complications of pSS and the effect of hydroxychloroquine (HCQ) usage on the lipid profile were incorporated into this study. METHODS: This is a single-center, retrospective study that included 367 patients who were diagnosed with pSS at Tongji Hospital, School of Medicine, Tongji University, China from January 2010 to March 2022. Initially, demographic information, clinical characteristics, medication records, and complications of the patients were gathered. A case-control analysis compared the 12 systems involvement (ESSDAI domain), clinical symptoms, and laboratory tests between pSS patients with and without dyslipidemia. A simple linear regression model was employed to investigate the relationship between serum lipid profile and inflammatory factors. Logistics regression analysis was performed to assess variables for hyperlipidemia-related complications of pSS. The paired t-test was then used to evaluate the improvement in lipid profile among pSS patients. RESULTS: 48.7 % of all pSS patients had dyslipidemia, and alterations in lipid levels were related to gender, age, and smoking status but not body mass index (BMI). Dyslipidemia is more prevalent in pSS patients who exhibit heightened autoimmunity and elevated levels of inflammation. Higher concentrations of multiple highly inflammatory factors correlate with a more severe form of dyslipidemia. Non-traditional cardiovascular risk factors may contribute to hyperlipidemia-related complications of pSS, such as increased, low complement 3 (C3) and low C4. According to our study, HCQ usage may protect against lipid-related disease in pSS. CONCLUSION: Attention should be paid to the dyslipidemia of pSS. This research aims to clarify the population portrait of pSS patients with abnormal lipid profiles and provides insights into the correlation between metabolism and inflammation in individuals with pSS and the potential role they play in the advancement of the disease. These findings provide novel avenues for further understanding the underlying mechanisms of pSS pathogenesis.

Association of Timely Outpatient Follow-Up and Readmission Risk in a Mobile Integrated Health Program.

The objective was to identify medical conditions associated with 30-day readmission, determine patient characteristics for which outpatient follow-up is most associated with reduced readmission, and evaluate how readmission risk changes with time to outpatient follow-up within a mobile integrated health-community paramedicine (MIH-CP) program. This retrospective observational study used data from 1,118 adult patient enrollments in a MIH-CP program operating in Baltimore, Maryland, from May 14, 2018, to December 21, 2021. Bivariate analysis identified chronic disease exacerbations associated with higher 30-day readmission risk. Kaplan-Meier curves and Cox proportional hazard regressions were used to measure how hazard of readmission changes with outpatient follow-up and how that association may vary with other factors. Receiver operating characteristic analysis was used to evaluate how well time to follow-up could predict 30-day readmission. Timely outpatient follow-up was associated with a significant reduction in hazard of readmission for patients aged 50 and younger and for patients with fewer than 5 social determinants of health needs identified. No significant association between readmission and specific chronic disease exacerbations was observed. An optimal follow-up time frame to reduce readmissions could not be identified. Timely outpatient follow-up may be effective for reducing readmissions in younger patients and patients who are less socially complex. Programs and policies aiming to reduce 30-day readmissions may have more success by expanding efforts to include these patients.

Fulvic acid alleviates the stress of low nitrogen on maize by promoting root development and nitrogen metabolism.

The potential of fulvic acid (FA) to improve plant growth has been acknowledged, but its effect on plant growth and nutrient uptake under nutrient stress remains unclear. This study investigated the effects of different FA application rates on maize growth and nitrogen utilization under low nitrogen stress. The results showed that under low nitrogen stress, FA significantly stimulated maize growth, particularly root development, biomass, and nitrogen content. The enhanced activity levels of key enzymes in nitrogen metabolism were observed, along with differential gene expression in maize, which enriched nitrogen metabolism, amino acid metabolism and plant hormone metabolism. The application of FA regulated the hormones' level, reduced abscisic acid content in leaves and Me-JA content in roots, and increased auxin and zeatin ribose content in leaves. This study concludes that, by promoting root development, nitrogen metabolism, and hormone metabolism, an appropriate concentration of FA can enhance plant tolerance to low nitrogen conditions and improve nitrogen use efficiency.

Association between irritable bowel syndrome and Parkinson's disease by Cohort study and Mendelian randomization analysis.

This study aimed to investigate the association between irritable bowel syndrome (IBS) and Parkinson's disease (PD) utilizing prospective cohort study and Mendelian randomization. The dataset contained a substantial cohort of 426,911 participants from the UK Biobank, discussing the association between IBS and PD with Cox proportional hazards models and case-control analysis while adjusting for covariates such as age, gender, ethnicity and education level. In univariate Cox regression model, the risk of PD was reduced in IBS patients (HR: 0.774, 95%CI: 0.625-0.956, P = 0.017), but the statistical significance diminished in the three models after adjusting for other variables. In a few subgroup analyses, IBS patients are less likely to develop into PD, and patients diagnosed with IBS after 2000 also had a lower risk (HR: 0.633, 95%CI: 0.403-0.994, P = 0.047) of subsequently developing PD. In addition, we matched five healthy control participants based on gender and age at the end of the study for each IBS patient diagnosed during the follow-up period, and logistic regression results (OR:1.239, 95%CI: 0.896-1.680, P = 0.181) showed that IBS was not associated with the risk of PD. Mendelian randomization did not find significant evidence of the causal relationship between IBS and Parkinson's disease (OR: 0.801, 95%CI: 0.570-1.278, P = 0.204). Overall, we suggest that IBS status is not associated with the risk of developing PD, and that these findings provide valuable insights into the clinical management and resource allocation of patients with IBS.

Functional significance of DNA methylation: epigenetic insights into Sjögren's syndrome.

Sjögren's syndrome (SjS) is a systemic, highly diverse, and chronic autoimmune disease with a significant global prevalence. It is a complex condition that requires careful management and monitoring. Recent research indicates that epigenetic mechanisms contribute to the pathophysiology of SjS by modulating gene expression and genome stability. DNA methylation, a form of epigenetic modification, is the fundamental mechanism that modifies the expression of various genes by modifying the transcriptional availability of regulatory regions within the genome. In general, adding a methyl group to DNA is linked with the inhibition of genes because it changes the chromatin structure. DNA methylation changes the fate of multiple immune cells, such as it leads to the transition of naïve lymphocytes to effector lymphocytes. A lack of central epigenetic enzymes frequently results in abnormal immune activation. Alterations in epigenetic modifications within immune cells or salivary gland epithelial cells are frequently detected during the pathogenesis of SjS, representing a robust association with autoimmune responses. The analysis of genome methylation is a beneficial tool for establishing connections between epigenetic changes within different cell types and their association with SjS. In various studies related to SjS, most differentially methylated regions are in the human leukocyte antigen (HLA) locus. Notably, the demethylation of various sites in the genome is often observed in SjS patients. The most strongly linked differentially methylated regions in SjS patients are found within genes regulated by type I interferon. This demethylation process is partly related to B-cell infiltration and disease progression. In addition, DNA demethylation of the runt-related transcription factor (RUNX1) gene, lymphotoxin-α (LTA), and myxovirus resistance protein A (MxA) is associated with SjS. It may assist the early diagnosis of SjS by serving as a potential biomarker. Therefore, this review offers a detailed insight into the function of DNA methylation in SjS and helps researchers to identify potential biomarkers in diagnosis, prognosis, and therapeutic targets.

A proof-of-concept study on bioorthogonal-based pretargeting and signal amplify radiotheranostic strategy.

BACKGROUND: Radiotheranostics differs from the vast majority of other cancer therapies in its capacity for simultaneous imaging and therapy, and it is becoming more widely implemented. A balance between diagnostic and treatment requirements is essential for achieving effective radiotheranostics. Herein, we propose a proof-of-concept strategy aiming to address the profound differences in the specific requirements of the diagnosis and treatment of radiotheranostics. RESULTS: To validate the concept, we designed an s-tetrazine (Tz) conjugated prostate-specific membrane antigen (PSMA) ligand (DOTA-PSMA-Tz) for 68Ga or 177Lu radiolabeling and tumor radiotheranostics, a trans-cyclooctene (TCO) modified Pd@Au nanoplates (Pd@Au-PEG-TCO) for signal amplification, respectively. We then demonstrated this radiotheranostic strategy in the tumor-bearing mice with the following three-step procedures: (1) i.v. injection of the [68Ga]Ga-PSMA-Tz for diagnosis; (2) i.v. injection of the signal amplification module Pd@Au-PEG-TCO; (3) i.v. injection of the [177Lu]Lu-PSMA-Tz for therapy. Firstly, this strategy was demonstrated in 22Rv1 tumor-bearing mice via positron emission tomography (PET) imaging with [68Ga]Ga-PSMA-Tz. We observed significantly higher tumor uptake (11.5 ± 0.8%ID/g) with the injection of Pd@Au-PEG-TCO than with the injection [68Ga]Ga-PSMA-Tz alone (5.5 ± 0.9%ID/g). Furthermore, we validated this strategy through biodistribution studies of [177Lu]Lu-PSMA-Tz, with the injection of the signal amplification module, approximately five-fold higher tumor uptake of [177Lu]Lu-PSMA-Tz (24.33 ± 2.53% ID/g) was obtained when compared to [177Lu]Lu-PSMA-Tz alone (5.19 ± 0.26%ID/g) at 48 h post-injection. CONCLUSION: In summary, the proposed strategy has the potential to expand the toolbox of pretargeted radiotherapy in the field of theranostics.

Quantitative analysis of pertussis, tetanus, and diphtheria antibodies in sera and breast milk from Tdap vaccinated women using a qualified multiplex assay.

Pertussis (whooping cough) is a reemergent, highly contagious respiratory infection of public health concern. Infants prior to initiation of their primary vaccination series are the most vulnerable to severe infection, and even death. Vaccination during pregnancy is an efficacious means of reducing infection in infants. This approach relies on boosting maternal immunity and passive transfer of antibodies to the infant via placenta and breast milk. Similarly, maternal vaccination post-partum can enhance maternal-infant immunity. To support the analysis of pertussis immunity in the context of maternal-infant immunization, we developed a high throughput multiplex assay for simultaneous quantification of serum IgG antibodies against pertussis vaccine antigens: pertussis toxin (PT), filamentous hemagglutinin (FHA), pertactin (PRN), and fimbriae (FIM2/3), and against tetanus (TT) and diphtheria toxoids (DT), using the Meso Scale Discovery (MSD) platform. The assay was qualified, and specificity, sensitivity, accuracy, precision, linearity, and robustness were demonstrated. The assay was subsequently adapted for quantification of IgG and IgA in breast milk. Applied to a serological survey of pregnant women living in the United States and sub-Saharan Africa, this method revealed differences in magnitude and breadth of antibody profile, consistent with history of vaccination. A longitudinal analysis of Tdap responses in women vaccinated post-partum demonstrated a rapid increase in serum IgG that remained elevated for up to 24 months. Likewise, high levels of vaccine-specific IgA and IgG antibodies were present in breast milk, although they exhibited faster decay. This multiplex MSD assay is a reliable and practical tool for quantification of pertussis, tetanus, and diphtheria antibodies in serum and breast milk in serosurveys or vaccine studies. IMPORTANCE: Pertussis (whooping cough) has reemerged in recent years. Vaccination during pregnancy is an effective approach to prevent illness during the first months of life. We developed a multiplex assay for quantification of pertussis, tetanus, and diphtheria serum antibodies using the Meso Scale Discovery (MSD) platform; the method was qualified, and specificity, precision, accuracy, linearity, and limits of quantification were defined. It was also adapted for quantification of antibodies in breast milk. We successfully determined serostatus in women from different regions and with different vaccination histories, as well as responses to Tdap in blood and breast milk post-partum. This is the first description of a multiplex assay for the quantification of pertussis, tetanus, and diphtheria antibodies in breast milk.

Compensatory Interactions between Corneal and Internal Astigmatism despite Lifestyle Changes.

This study explores whether children's refractive errors and visual behaviors reverted to pre-COVID-19 levels a year after normal schooling resumed in Hong Kong as well as the impact of corneal and internal astigmatism on refractive astigmatism development. Vision survey data and questionnaire results collected in 2022 (n = 119) and 2020 (n = 173) were compared. Cross-sectional data showed similar proportions of astigmatism (cylindrical power ≥ 0.75 D) in the 2020 (49.1%) and 2022 cohorts (55.5%). Despite a 0.28 D increase in corneal astigmatism, a compensatory 0.24 D increase in internal astigmatism of opposite direction kept refractive astigmatism relatively stable. The questionnaire data showed that children spent an additional 0.5 h/day outdoors on weekends post-resumption of normal schooling but engaged in more near-work activities, especially non-screen near-work, by approximately 1 h/day on both weekdays and weekends. These findings were supported by longitudinal data from 72 children who participated in both surveys. This study highlights the significant role of corneal and internal astigmatism in refractive astigmatism changes. Despite the return to in-person classes, children's total near-work time increased and astigmatism remained high. These findings underscore the need for comprehensive strategies to reduce the high environmental risks for refractive error development in children.

Joint analysis of proteome, transcriptome, and multi-trait analysis to identify novel Parkinson's disease risk genes.

Genome-wide association studies (GWAS) have identified multiple risk variants for Parkinson's disease (PD). Nevertheless, how the risk variants confer the risk of PD remains largely unknown. We conducted a proteome-wide association study (PWAS) and summary-data-based mendelian randomization (SMR) analysis by integrating PD GWAS with proteome and protein quantitative trait loci (pQTL) data from human brain, plasma and CSF. We also performed a large transcriptome-wide association study (TWAS) and Fine-mapping of causal gene sets (FOCUS), leveraging joint-tissue imputation (JTI) prediction models of 22 tissues to identify and prioritize putatively causal genes. We further conducted PWAS, SMR, TWAS, and FOCUS using a multi-trait analysis of GWAS (MTAG) to identify additional PD risk genes to boost statistical power. In this large-scale study, we identified 16 genes whose genetically regulated protein abundance levels were associated with Parkinson's disease risk. We undertook a large-scale analysis of PD and correlated traits, through TWAS and FOCUS studies, and discovered 26 casual genes related to PD that had not been reported in previous TWAS. 5 genes (CD38, GPNMB, RAB29, TMEM175, TTC19) showed significant associations with PD at both the proteome-wide and transcriptome-wide levels. Our study provides new insights into the etiology and underlying genetic architecture of PD.

Efficacy of typhoid conjugate vaccine: final analysis of a 4-year, phase 3, randomised controlled trial in Malawian children.

BACKGROUND: Randomised controlled trials of typhoid conjugate vaccines among children in Africa and Asia have shown high short-term efficacy. Data on the durability of protection beyond 2 years are sparse. We present the final analysis of a randomised controlled trial in Malawi, encompassing more than 4 years of follow-up, with the aim of investigating vaccine efficacy over time and by age group. METHODS: In this phase 3, double-blind, randomised controlled efficacy trial in Blantyre, Malawi, healthy children aged 9 months to 12 years were randomly assigned (1:1) by an unmasked statistician to receive a single dose of Vi polysaccharide conjugated to tetanus toxoid vaccine (Vi-TT) or meningococcal capsular group A conjugate (MenA) vaccine. Children had to have no previous history of typhoid vaccination and reside in the study areas for inclusion and were recruited from government schools and health centres. Participants, their parents or guardians, and the study team were masked to vaccine allocation. Nurses administering vaccines were unmasked. We did surveillance for febrile illness from vaccination until follow-up completion. The primary outcome was first occurrence of blood culture-confirmed typhoid fever. Eligible children who were randomly assigned and vaccinated were included in the intention-to-treat analyses. This trial is registered at ClinicalTrials.gov, NCT03299426. FINDINGS: Between Feb 21, 2018, and Sept 27, 2018, 28 130 children were vaccinated; 14 069 were assigned to receive Vi-TT and 14 061 to receive MenA. After a median follow-up of 4·3 years (IQR 4·2-4·5), 24 (39·7 cases per 100 000 person-years) children in the Vi-TT group and 110 (182·7 cases per 100 000 person-years) children in the MenA group were diagnosed with a first episode of blood culture-confirmed typhoid fever. In the intention-to-treat population, efficacy of Vi-TT was 78·3% (95% CI 66·3-86·1), and 163 (129-222) children needed to be vaccinated to prevent one case. Efficacies by age group were 70·6% (6·4-93·0) for children aged 9 months to 2 years; 79·6% (45·8-93·9) for children aged 2-4 years; and 79·3% (63·5-89·0) for children aged 5-12 years. INTERPRETATION: A single dose of Vi-TT is durably efficacious for at least 4 years among children aged 9 months to 12 years and shows efficacy in all age groups, including children younger than 2 years. These results support current WHO recommendations in typhoid-endemic areas for mass campaigns among children aged 9 months to 15 years, followed by routine introduction in the first 2 years of life. FUNDING: Bill & Melinda Gates Foundation.

Complexation and extraction of trivalent actinides over lanthanides using highly soluble phenanthroline diamide ligands with different side chains.

Although phenanthroline diamide ligands have been widely reported, their limited solubility in organic solvents and poor performance in the separation of trivalent actinides (An(III)) and lanthanides (Ln(III)) at high acidity are still clear demerits. In this study, we designed and synthesized three highly soluble phenanthroline diamide ligands with different side chains. By introducing alkyl chains and ester groups, the ligands solubility in 3-nitrotrifluorotoluene is increased to over 600 mmol/L, significantly higher than the previous reported phenanthroline diamide ligands. Based on anomalous aryl strengthening, benzene ring was incorporated to enhance ligand selectivity toward Am(III). Extraction experiments demonstrated favorable selectivity of all the three ligands towards Am(III). The optimal separation factor (SFAm/Eu) reaches 53 at 4 mol/L HNO3, representing one of the most effective separation of An(III) over Ln(III) under high acidity. Slope analysis, single crystal structure analysis, as well as titration of ultraviolet visible spectroscopy, mass spectrometry, and nuclear magnetic resonanc confirmed the formation of 1:1 and 1:2 complex species between the metal ions and the ligands depending on the molar ratio of metal ions in the reaction mixture. The findings of this study offer valuable insights for developing phenanthroline diamide ligands for An(III)/Ln(III) separation.

Synchronous myopia development induced by bilateral form deprivation in chicks.

Form deprivation (FD) is a widely employed experimental paradigm, typically used to induce unilateral myopia in animal models. This model is weakened by potential influence upon the FD eye from vision in the freely-viewing contralateral eye, which could be eliminated by imposing FD in both eyes; but while a few previous studies have explored the feasibility of inducing bilateral FD in chicks, substantial discrepancies in treatment outcomes were noted. Consequently, this study aimed to establish a bilateral FD myopia model in chicks, with validation by investigating the associated ocular growth patterns, feeding, and social behavior. Six-day-old chicks were treated with bilateral (n = 21) or unilateral (n = 10) FD for 12 days; the fellow untreated eyes in the unilateral FD group served as controls. Refractive error, corneal power, and ocular axial dimensions were measured at 4-day intervals after the onset of form deprivation, with a Hartinger refractometer, a custom-made videokeratography system, and a high-resolution A-scan ultrasonographer, respectively. Body weight was monitored to assess the chick's physical development. Our results showed that birds treated with bilateral FD grew as robustly as the unilaterally form-deprived chicks, with similar or slightly heavier body weights and mortalities. Unilateral FD induced significantly higher myopia in the treated eye, with stronger corneal power, deeper anterior and vitreous chambers, and longer axial length. Moreover, either bilaterally or unilaterally FD eyes developed similar refractive error (bilateral FD, left: -28.03 ± 9.06 D, right: -28.44 ± 9.45 D; unilateral FD: -29.48 ± 8.26 D) and ocular biometric changes; but choroidal thickness was thicker in bilaterally FD eyes, rather than thinner as in unilaterally FD eyes. In addition to the highly synchronized (symmetrical, parallel) development reported previously in bilateral FD, we found in this study that the correlations between bilaterally form-deprived eyes were highest for ocular biometric parameters directly contributing to myopia development, including corneal power (r = 0.74 to 0.93), anterior chamber depth (r = 0.60 to 0.85), vitreous chamber depth (r = 0.92 to 0.94), and axial length (r = 0.90 to 0.96). The remarkably synchronized growth pattern confirmed the feasibility of the bilateral FD paradigm for future research on myopia.

Factors associated with patient-to-healthcare personnel (HCP) and HCP-to-subsequent patient transmission of methicillin-resistant Staphylococcus aureus.

BACKGROUND: Transient acquisition of methicillin-resistant Staphylococcus aureus (MRSA) on healthcare personnel (HCP) gloves and gowns following patient care has been examined. However, the potential for transmission to the subsequent patient has not been studied. We explored the frequency of MRSA transmission from patient to HCP, and then in separate encounters from contaminated HCP gloves and gowns to a subsequent simulated patient as well as the factors associated with these 2 transmission pathways. METHODS: We conducted a prospective cohort study with 2 parts. In objective 1, we studied MRSA transmission from random MRSA-positive patients to HCP gloves and gowns after specific routine patient care activities. In objective 2, we simulated subsequent transmission from random HCP gloves and gowns without hand hygiene to the next patient using a manikin proxy. RESULTS: For the first objective, among 98 MRSA-positive patients with 333 randomly selected individual patient-HCP interactions, HCP gloves or gowns were contaminated in 54 interactions (16.2%). In a multivariable analysis, performing endotracheal tube care had the greatest odds of glove or gown contamination (OR, 4.06; 95% CI, 1.3-12.6 relative to physical examination). For the second objective, after 147 simulated HCP-patient interactions, the subsequent transmission of MRSA to the manikin proxy occurred 15 times (10.2%). CONCLUSION: After caring for a patient with MRSA, contamination of HCP gloves and gown and transmission to subsequent patients following HCP-patient interactions occurs frequently if contact precautions are not used. Proper infection control practices, including the use of gloves and gown, can prevent this potential subsequent transmission.

Development of small-molecular-based radiotracers for PET imaging of PD-L1 expression and guiding the PD-L1 therapeutics.

PURPOSE: Programmed cell death protein ligand 1 (PD-L1) is a crucial biomarker for immunotherapy. However, nearly 70% of patients do not respond to PD-L1 immune checkpoint therapy. Accurate monitoring of PD-L1 expression and quantification of target binding during treatment are essential. In this study, a series of small-molecule radiotracers were developed to assess PD-L1 expression and direct immunotherapy. METHODS: Radiotracers of [68Ga]Ga-D-PMED, [68Ga]Ga-D-PEG-PMED, and [68Ga]Ga-D-pep-PMED were designed based on a 2-methyl-3-biphenyl methanol scaffold and successfully synthesized. Cellular experiments and molecular docking assays were performed to determine their specificity for PD-L1. PD-L1 status was investigated via positron emission tomography (PET) imaging in MC38 tumor models. PET imaging of [68Ga]Ga-D-pep-PMED was performed to noninvasively quantify PD-L1 blocking using an anti-mouse PD-L1 antibody (PD-L1 mAb). RESULTS: The radiosyntheses of [68Ga]Ga-D-PMED, [68Ga]Ga-D-PEG-PMED, and [68Ga]Ga-D-pep-PMED were achieved with radiochemical yields of 87 ± 6%, 82 ± 4%, and 79 ± 9%, respectively. In vitro competition assays demonstrated their high affinities (the IC50 values of [68Ga]Ga-D-PMED, [68Ga]Ga-D-PEG-PMED, and [68Ga]Ga-D-pep-PMED were 90.66 ± 1.24, 160.8 ± 1.35, and 51.6 ± 1.32 nM, respectively). At 120 min postinjection (p.i.) of the radiotracers, MC38 tumors displayed optimized tumor-to-muscle ratios for all radioligands. Owing to its hydrophilic modification, [68Ga]Ga-D-pep-PMED had the highest target-to-nontarget (T/NT) ratio of approximately 6.2 ± 1.2. Interestingly, the tumor/liver ratio was hardly affected by different concentrations of the inhibitor BMS202. We then evaluated the impacts of dose and time on accessible PD-L1 levels in the tumor during anti-mouse PD-L1 antibody treatment. The tumor uptake of [68Ga]Ga-D-pep-PMED significantly decreased with increasing PD-L1 mAb dose. Moreover, after 8 days of treatment with a single antibody, the uptake of [68Ga]Ga-D-pep-PMED in the tumor significantly increased but remained lower than that in the saline group. CONCLUSION: PET imaging with [68Ga]Ga-D-pep-PMED, a small-molecule radiotracer, is a promising tool for evaluating PD-L1 expression and quantifying the target blockade of PD-L1 to assist in the development of effective therapeutic regimens.