Small extracellular vesicles derived from human induced pluripotent stem cell-differentiated neural progenitor cells mitigate retinal ganglion cell degeneration in a mouse model of optic nerve injury.

JOURNAL/nrgr/04.03/01300535-202502000-00034/figure1/v/2024-05-28T214302Z/r/image-tiff Several studies have found that transplantation of neural progenitor cells (NPCs) promotes the survival of injured neurons. However, a poor integration rate and high risk of tumorigenicity after cell transplantation limits their clinical application. Small extracellular vesicles (sEVs) contain bioactive molecules for neuronal protection and regeneration. Previous studies have shown that stem/progenitor cell-derived sEVs can promote neuronal survival and recovery of neurological function in neurodegenerative eye diseases and other eye diseases. In this study, we intravitreally transplanted sEVs derived from human induced pluripotent stem cells (hiPSCs) and hiPSCs-differentiated NPCs (hiPSC-NPC) in a mouse model of optic nerve crush. Our results show that these intravitreally injected sEVs were ingested by retinal cells, especially those localized in the ganglion cell layer. Treatment with hiPSC-NPC-derived sEVs mitigated optic nerve crush-induced retinal ganglion cell degeneration, and regulated the retinal microenvironment by inhibiting excessive activation of microglia. Component analysis further revealed that hiPSC-NPC derived sEVs transported neuroprotective and anti-inflammatory miRNA cargos to target cells, which had protective effects on RGCs after optic nerve injury. These findings suggest that sEVs derived from hiPSC-NPC are a promising cell-free therapeutic strategy for optic neuropathy.

Alkyl effects on charge recombination in copper electrolyte-based dye-sensitized solar cells: Insights for targeted molecular design towards high performance.

Two quinoxaline dyes utilized in copper-electrolyte-based dye-sensitized solar cells (Cu-DSSCs) are theoretically investigated to analyze the impact of alkyl chains on dye performance. The investigation shows that ZS4, known for its record efficiency of up to 13.2 %, exhibits higher electron coupling and fewer binding sites for dye-[Cu(tmby)2]2+ interaction compared to ZS5. Contrary to common belief, alkyl chains are found to not only provide shielding but also hinder the interaction between dye and [Cu(tmby)2]2+ by influencing the optimal conformation of dyes, thereby impeding the charge recombination process. It is crucial to consider the influence of alkyl chains on dye conformation when discussing the relationship between dye structure and performance, rather than oversimplifying it as often done traditionally. Building on these findings, eight dyes are strategically designed by adjusting the position of the alkyl chain to further decrease charge recombination compared to ZS4. Theoretical evaluation of these dyes reveals that changing the alkyl chain on the nitrogen atom from 2-ethylhexyl (ZS4) to 1-hexylheptyl (D3-2) not only reduces the charge recombination rate but also enhances light harvesting ability. Therefore, D3-2 shows potential as a candidate for experimental synthesis of high-performance Cu-DSSCs with improved efficiency.

Application value of dexmedetomidine in anesthesia for elderly patients undergoing radical colon cancer surgery.

BACKGROUND: Colon cancer presents a substantial risk to the well-being of elderly people worldwide. With advancements in medical technology, surgical treatment has become the primary approach for managing colon cancer patients. However, due to age-related physiological changes, especially a decline in cognitive function, older patients are more susceptible to the effects of surgery and anesthesia, increasing the relative risk of postoperative cognitive dysfunction (POCD). Therefore, in the surgical treatment of elderly patients with colon cancer, it is of paramount importance to select an appropriate anesthetic approach to reduce the occurrence of POCD, protect brain function, and improve surgical success rates. AIM: To explore the value of dexmedetomidine (Dex) in anesthesia for elderly patients undergoing radical colon cancer surgery. METHODS: One hundred and seventeen patients with colon cancer who underwent elective surgery under general anesthesia were selected and divided into two groups: A and B. Group A received Dex before anesthesia induction, and B group received an equivalent amount of normal saline. Changes in the mini-mental state examination, regional cerebral oxygen saturation (rSO2), bispectral index, glucose uptake rate (GluER), lactate production rate (LacPR), serum S100ß and neuron-specific enolase (NSE), POCD, and adverse anesthesia reactions were compared between the two groups. RESULTS: Surgical duration, duration of anesthesia, and intraoperative blood loss were comparable between the two groups (P > 0.05). The overall dosage of anesthetic drugs used in group A, including propofol and remifentanil, was significantly lower than that used in group B (P < 0.05). Group A exhibited higher rSO2 values at the time of endotracheal intubation, 30 min after the start of surgery, and immediately after extubation, higher GluER values and lower LacPR values at the time of endotracheal intubation, 30 min after the start of surgery, immediately after extubation, and 5 min after extubation (P < 0.05). Group A exhibited lower levels of serum S100ß and NSE 24 h postoperatively and a lower incidence of cognitive dysfunction on the 1st and 5th postoperative days (P < 0.05). CONCLUSION: The use of Dex in elderly patients undergoing radical colon cancer surgery helps maintain rSO2 Levels and reduce cerebral metabolic levels and the incidence of anesthesia- and surgery-induced cognitive dysfunction.

[Research Progress in Detection of Bee Venom Allergens].

Hymenopteran insect stings are a risk factor that cannot be ignored for the people allergic to hymenopteran venoms.In China,the current diagnostic tools cannot provide accurate information to identify sensitized insects,thus affecting clinical diagnosis and treatment.Honeybee is a common hymenopteran insect.Due to its wide distribution,large number,and complex venom composition,researchers have carried out recombination schemes for the main allergens of honeybee venom,laying a theoretical foundation for the detection of allergens.The development of diagnostic technologies for allergen components can accurately detect bee venom allergens,providing a new set of clinical diagnosis and treatment schemes for the population allergic to bee venom.

Socioeconomic inequalities in uptake of outreach mammography before and after accessibility improvement of Taiwan's national universal breast cancer screening policy.

BACKGROUND: Taiwan implemented the Cancer Screening Quality Improvement Program (CAQIP) in 2010. The program sought to enhance mass breast cancer screening accessibility. This study aimed to examine socioeconomic disparities in outreach screening utilization pre-CAQIP (2005-2009) and post-CAQIP (2010-2014). METHOD: We conducted a nationwide population-based observational study in Taiwan, analyzing four population databases to evaluate socioeconomic disparities among women aged 50 to 69 years undergoing their first mammography screening pre-CAQIP. Multivariate logistic regression was used to examine changes in utilization of outreach screening pre- and post-CAQIP implementation, and to estimate the Slope Index of Inequity (SII) and Relative Index of Inequity (RII) values. RESULTS: Utilization of outreach screening through mobile mammography units (MMUs) increased from 6.12 to 32.87% between the two periods. Following CAQIP, a higher proportion of screened women were older, less educated, and from suburban or rural areas. The SII and RII for age, income, and urbanization levels decreased post-CAQIP. However, regarding education level, SII was - 0.592 and RII was 0.392 in the pre-CAQIP period, increasing to -0.173 and 0.804 post-CAQIP, respectively. CONCLUSIONS: Our study observed that utilization of outreach screening through MMUs increased after CAQIP. The MMUs made outreach screening services more accessible in Taiwan. Expanding outreach screening services and educational programs to promote mammography uptake in local communities could help reduce the potential effect of socioeconomic disparities, and thus may enhance early detection of breast cancer. Further study could focus on the accessibility of outreach screening and breast cancer outcomes.

Causal Association of Golgi Protein 73 With Coronary Artery Disease: Evidence from Proteomics and Mendelian Randomization.

Background: Identification of the unknown pathogenic factor driving atherosclerosis not only enhances the development of disease biomarkers but also facilitates the discovery of new therapeutic targets, thus contributing to the improved management of coronary artery disease (CAD). We aimed to identify causative protein biomarkers in CAD etiology based on proteomics and 2-sample Mendelian randomization (MR) design. Methods: Serum samples from 33 first-onset CAD patients and 31 non-CAD controls were collected and detected using protein array. Differentially expressed analyses were used to identify candidate proteins for causal inference. We used 2-sample MR to detect the causal associations between the candidate proteins and CAD. Network MR was performed to explore whether metabolic risk factors for CAD mediated the risk of identified protein. Vascular expression of candidate protein in situ was also detected. Results: Among the differentially expressed proteins identified utilizing proteomics, we found that circulating Golgi protein 73 (GP73) was causally associated with incident CAD and other atherosclerotic events sharing similar etiology. Network MR approach showed low-density lipoprotein cholesterol and glycated hemoglobin serve as mediators in the causal pathway, transmitting 42.1% and 8.7% effects from GP73 to CAD, respectively. Apart from the circulating form of GP73, both mouse model and human specimens imply that vascular GP73 expression was also upregulated in atherosclerotic lesions and concomitant with markers of macrophage and phenotypic switching of vascular smooth muscle cells (VSMCs). Conclusions: Our study supported GP73 as a biomarker and causative for CAD. GP73 may involve in CAD pathogenesis mainly via dyslipidemia and hyperglycemia, which may enrich the etiological information and suggest future research direction on CAD.

Aldehyde dehydrogenase 2 preserves kidney function by countering acrolein-induced metabolic and mitochondrial dysfunction.

The prevalence of chronic kidney diseases (CKD) varies by race due to genetic and environmental factors. The Glu504Lys polymorphism in aldehyde dehydrogenase 2 (ALDH2), commonly observed among East Asians, alters the enzyme's function in detoxifying alcohol-derived aldehydes, impacting kidney function. This study investigated the association between variations in ALDH2 levels within the kidney and the progression of kidney fibrosis. Our clinical data indicates that diminished ALDH2 levels are linked to worse CKD outcomes, with correlations between ALDH2 expression, estimated glomerular filtration rate, urinary levels of acrolein, an aldehyde metabolized by ALDH2, and fibrosis severity. In mouse models of unilateral ureteral obstruction and folic acid nephropathy, reduced ALDH2 levels and elevated acrolein were observed in kidneys, especially in ALDH2 Glu504Lys knock-in mice. Mechanistically, acrolein modifies pyruvate kinase M2, leading to its nuclear translocation and co-activation of HIF-1α, shifting cellular metabolism to glycolysis, disrupting mitochondrial function, contributing to tubular damage and the progression of kidney fibrosis. Enhancing ALDH2 expression through adeno-associated virus vectors reduces acrolein and mitigates fibrosis in both wild-type and Glu504Lys knock-in mice. These findings underscore the potential therapeutic significance of targeting the dynamic interaction between ALDH2 and acrolein in CKD.

Thiazolidine Deprotection Using an Organic Solvent Extractable Aldehyde Scavenger for One-Pot Four-Segment Ligation.

We report a simple and convenient N-terminal thiazolidine (Thz) deprotection strategy and its application in one-pot multisegment ligation. In this strategy, O-benzylhydroxylamine (O-BHA) is used to efficiently and rapidly convert Thz into N-terminal cysteine. O-BHA can be easily separated from the ligation buffer by organic solvent extraction, avoiding the degradation of the peptide thioester by O-BHA. The utility of the O-BHA-based one-pot ligation strategy has been demonstrated in the assembly of CC chemokine ligand-2.

Discovery of 2-Aryl-4-aminoquinazolin-Based LSD1 Inhibitors to Activate Immune Response in Gastric Cancer.

LSD1 (histone lysine-specific demethylase 1) has been gradually disclosed to act as an immunomodulator to enhance antitumor immune response. Despite the identification of numerous potent LSD1 inhibitors, there remains a lack of LSD1 inhibitors approved for marketing. Novel LSD1 inhibitors with different mechanisms are therefore needed. Herein, we reported a series of novel quinazoline-based LSD1 inhibitors. Among them, compound Z-1 exhibited the best LSD1 inhibitory activity (IC50 = 0.108 µM). Z-1 also acted as a selective and cellular active as an LSD1 inhibitor. Furthermore, Z-1 promoted response of gastric cancer cells to T-cell killing effect by decreasing PD-L1 expression and further attenuated the PD-1/PD-L1 interaction. In vivo, Z-1 exhibited significant suppression effect on the growth of gastric cancer cells without obvious toxicity. Therefore, Z-1 represents a potential novel immunomodulator that targets LSD1, providing a lead compound with new function mechanism for gastric cancer treatment.

Preoperative Evidence-Based Practice for Prevention of Early Postoperative Infections in Patients Receiving a Liver Transplant.

BACKGROUND This study aimed to evaluate the effectiveness of implementing evidence-based preoperative nursing interventions in reducing postoperative infections and intensive care unit (ICU) length of stay among liver transplant recipients. MATERIAL AND METHODS A controlled study was conducted, comparing postoperative outcomes between an intervention group receiving standardized, evidence-based preoperative care and a control group receiving routine preoperative care. Patients undergoing elective liver transplantation from September 2020 to March 2021 were included and assigned to either the intervention or control group. The intervention group received preoperative interventions based on best available evidence, while the control group received standard preoperative care. The primary outcomes measured were postoperative infection rates and length of ICU stay. RESULTS In the control group the overall Intensive Care Unit (ICU) length of stay was 3 days and the infection rate was 33.30%, while in the intervention group it was 3 days and 13.80% (P<0.05). There was no significant difference in the length of ICU stay between the control and the intervention groups (P>0.05). There was a significant improvement in the awareness, acceptance, and compliance of doctors and nurses. CONCLUSIONS Using the best evidence-based intervention for preoperative nursing of liver transplantation patients can standardize preoperative nursing behavior. Although we did not find significant differences in outcomes before and after the intervention, it is necessary to prevent postoperative infection and improve nursing compliance.

A Cross-Sectional Survey of Fixed-Dose Combination Antihypertensive Medicine Prescribing in Twenty-Four Countries, Including Qualitative Insights.

Background: Treatment inertia, non-adherence and non-persistence to medical treatment contribute to poor blood pressure (BP) control worldwide. Fixed dose combination (FDC) antihypertensive medicines simplify prescribing patterns and improve adherence. The aim of this study was to identify factors associated with prescribing FDC antihypertensive medicines and to understand if these factors differ among doctors worldwide. Methods: A cross-sectional survey was conducted online from June 2023 to January 2024 to recruit doctors. We collaborated with an international network of researchers and clinicians identified through institutional connections. A passive snowballing recruitment strategy was employed, where network members forwarded the survey link to their clinical colleagues. The survey instrument, developed through a literature review, interviews with academic and clinical researchers, and pilot testing, assessed participants perspectives on prescribing FDC antihypertensive medicines for hypertension. Participants rated their level of agreement (5-point Likert scale) with statements representing six barriers and four facilitators to FDC use. Findings: Data from 191 surveys were available for analysis. 25% (n = 47) of participants worked in high-income countries, 38% (n = 73) in upper-middle income, 25% (n = 48) in lower-middle income, 6% (n = 10) in low-income countries. Forty percent (n = 70) of participants were between 36-45 years of age; two thirds were male. Cost was reported as a barrier to prescribing FDC antihypertensive medicines [51% (n = 87) agreeing or strongly agreeing], followed by doctors' confidence in BP measured in clinic [40%, (n = 70)], access [37%, (n = 67)], appointment duration [35%, (n = 61)], concerns about side-effects [(21%, n = 37)], and non-adherence [12%, (n = 21)]. Facilitators to FDC antihypertensive polypills prescribing were clinician facing, such as access to educational supports [79%, (n = 143)], more BP measurement data [67%, (n = 120)], a clinical nudge in health records [61%, (n = 109)] and patient-facing including improved patient health literacy [49%, (n = 88)]. The levels of agreement and strong agreement across all barriers and facilitators were similar for participants working in higher or lower income countries. Across all countries, participants rated FDC antihypertensive medications highly valuable for managing patients with non-adherence, (82% reported high or very high value), for patients with high pill burden (80%). Interpretation: Cost and access were the most common barriers to prescribing FDCs across high- and low-income countries. While greater educational support for clinicians was perceived as the leading potential facilitator of FDC use, this seems unlikely to be effective without addressing access.

The Asymmetrical Fe-O-Se Bonds in Fe2O(SeO3)2 Boosting Bifunctional Oxygen Electrocatalytic Performance for Zinc-Air Battery.

Here Fe2O(SeO3)2/Fe3C@NC catalysts with high performance were fabricated for zinc-air batteries (ZABs). The experimental results confirmed that the existence of Fe-O-Se bonds in Fe2O(SeO3)2 crystal phase, and the Fe-O-Se bonds could obviously enhance ORR and OER catalytic performance of Fe2O(SeO3)2/Fe3C@NC. Density functional theoretical calculations (DFT) confirmed that the Fe2O(SeO3)2 in Fe2O(SeO3)2/Fe3C@NC had a higher d-band center of Fe atom and a lower p-orbital coupling degree with its own lattice O atom than Fe2O3, which leads to Fe site of Fe2O(SeO3)2 being more likely to adsorb external oxygen intermediates. The Fe-O-Se bonds in Fe2O(SeO3)2 results in the modification of coordination environment of Fe atoms and optimizes the adsorption energy of Fe site for oxygen intermediates. Compared with Fe2O3/Fe3C@NC, the Fe2O(SeO3)2/Fe3C@NC showed obvious enhancements of ORR/OER catalytic activities with a half-wave potential of 0.91 V for ORR in 0.1 M KOH electrolyte and a low overpotential of 345 mV for OER at 10 mA cm-2 in a 1.0 M KOH electrolyte. The peak power density and specific capacity of Fe2O(SeO3)2/Fe3C@NC-based ZABs are higher than those of Pt/C+RuO2-ZABs. The above results demonstrate that the asymmetrical Fe-O-Se bonds in Fe2O(SeO3)2 plays a key role in improving the bifunctional catalytic activities of ORR/OER for ZABs.

Outcomes of Ticagrelor Versus High-dose Clopidogrel in CYP2C19 Intermediate Metabolizer Undergoing Percutaneous Coronary Intervention for Acute Coronary Syndromes.

ABSTRACT: Guidelines on antiplatelet recommendation for CYP2C19 intermediate metabolizer (IM) have not come to an agreement. This study aimed to evaluate the clinical benefit of ticagrelor when compared with high-dose clopidogrel in CYP2C19 IM after percutaneous coronary intervention for acute coronary syndromes. Patients were enrolled according to CYP2C19 genotype and individual antiplatelet therapy. Patient characteristics and clinical outcomes were collected through electronic medical record system. The primary outcome was major adverse cardiac and cerebrovascular event (MACCE), namely a composite of death from cardiovascular causes, myocardial infarction, stroke, and stent thrombosis within 12 months. The secondary outcome was Bleeding Academic Research Consortium scale bleeding events within 12 months. The Cox proportional hazards regression model was performed, with inverse probability treatment weighting (IPTW) adjusting for potential confounders. A total of 532 CYP2C19 IM were enrolled in this retrospective single-center study. No statistically significant difference in incidence rate of MACCE was found between patients receiving ticagrelor versus clopidogrel (7.01 vs. 9.52 per 100 patient-years; IPTW-adjusted hazard ratio 0.71; 95% confidence interval: 0.32-1.58; adjusted log-rank P = 0.396), but the incidence rate of Bleeding Academic Research Consortium type 2, 3, or 5 bleeding events was statistically higher in the loss of function-ticagrelor group than in the loss of function-clopidogrel group (13.53 vs. 6.16 per 100 patient-years; IPTW-adjusted hazard ratio: 2.29; 95% confidence interval: 1.10-4.78; adjusted log-rank P = 0.027). Ticagrelor treatment in CYP2C19 IM resulted in a statistically higher risk of bleeding compared with high-dose clopidogrel, whereas a clear association between treatments and MACCE warrants further investigations.

Effect of 5:2 intermittent fasting diet versus daily calorie restriction eating on metabolic-associated fatty liver disease-a randomized controlled trial.

Objective: Both 5:2 IF diet (intermittent fasting) and daily caloric restriction eating had been suggested for management of MAFLD (Metabolic-Associated Fatty Liver Disease), this study aimed to evaluate the effects of 5:2 IF diet on body weight and metabolic parameters in adults with MAFLD, in comparison to daily caloric restriction eating. Methods: This single-center, double-blind, prospective, randomized controlled trial included 60 patients with MAFLD, who were administered either a 5:2 IF diet limited calories consumed for 2 days each week with no restrictions on the remaining 5 (Group 5:2 IF diet) or a daily calorie restriction eating (Group daily calorie restriction). Fibrotouch-B instrument assessment, ultrasound assessment of hepatic steatosis, anthropometric indices and body composition analysis, blood sample measurements were conducted during two distinct visits: initially on the day of study commencement (T1), and subsequently at the conclusion of the 12-week intervention period (T2). Results: In comparison to daily calorie restriction eating, the 5:2 IF diet significantly decreased the proportion of hepatic steatosis ≥moderate (29.6% vs. 59.3%, p = 0.028) and the degree of hepatic fibrosis F ≥ 2 (3.7% vs. 25.9%, p = 0.05), and fewer percentage of patients were diagnosed with fatty liver via upper abdominal ultrasound in the 5:2 intermittent fasting diet group (33.3% vs. 63.0%, p = 0.029). Additionally, the CAP (controlled attenuation parameter) and LSM (liver stiffness measurements) value were significantly lower in the 5:2 IF diet group (p < 0.05). No statistically significant differences were observed between the two groups in terms of weight, BMI (body mass index), WC (waist circumference), HC (hip circumference), and WHR (waist to hip ratio). Similarly, there were no significant differences in lipid profile, glycemic indices and adverse events (p > 0.05). Conclusion: In summary, although both 5:2 IF diet and daily caloric restriction eating achieved similar effect on body weight, liver enzymes, lipid profile and glycemic indices after 12 weeks treatment, 5:2 IF diet demonstrates better improvement in fibrosis and steatosis scores independently from weight regulation. Consequently, it is anticipated to emerge as a viable dietary modality for lifestyle intervention among patients diagnosed with MAFLD. Clinical trial registration: https://www.crd.york.ac.uk/PROSPERO, identifier ChiCTR2400080292.

Increased peripheral leukocyte aggravates brain injury and leads to poor outcome in stroke patients receiving intravenous thrombolysis: A study based on clinical evidence.

Whether the dynamic development of peripheral inflammation aggravates brain injury and leads to poor outcome in stroke patients receiving intravenous thrombolysis (IVT), remains unclear and warrants further study. In this study, total of 1034 patients with acute ischemic stroke who underwent IVT were enrolled. Serum leukocyte variation (whether increase from baseline to 24 h after IVT), National Institutes of Health Stroke Scale (NIHSS), infarct volume, early neurologic deterioration (END), the unfavorable outcome at 3-month (modified Rankin Scale [mRS] score ≥3) and mortality were recorded. Serum brain injury biomarkers, including Glial fibrillary acidic protein (GFAP), ubiquitin c-terminal hydrolase L1 (UCH-L1), S100ß, neuron-specific enolase (NSE), were measured to reflect the extent of brain injury. We found that patients with increased serum leukocytes had elevated brain injury biomarkers (GFAP, UCH-L1, and S100ß), larger infarct volume, higher 24 h NIHSS, higher proportion of END, unfavorable outcome and mortality. Furthermore, an increase in serum leukocytes was independently associated with infarct volume, 24 h NIHSS, END, and unfavorable outcome at 3 months, and serum UCH-L1, S100ß, and NSE levels. These results suggest that an increase in serum leukocytes indicates severe brain injury and may be used to predict the outcome of patients with ischemic stroke who undergo IVT.

Risk factors of delayed upper gastrointestinal transit in capsule endoscopy.

OBJECTIVE: The purpose was to investigate the risk factors for delayed upper gastrointestinal transit (DUGT) in small bowel capsule endoscopy (SBCE) and to improve the efficacy of SBCE. METHODS: The medical records of patients who underwent SBCE in Renji hospital between January 2015 and January 2023 were retrospectively reviewed. Data collection included patient demographics and potential risk factors for DUGT such as indications for the examination, underlying diseases, hospitalization status, anemia, inflammation. Risk factors were analyzed using univariable and multivariable logistic regression models. DUGT was defined as failure of a capsule to pass through the pylorus within 1 h. RESULTS: A total of 1459 patients who underwent SBCE were included in the study. 306 Cases (21%) experienced DUGT and all received conservative observation, medication treatment, endoscopic intervention, and other measures based on specific circumstances. The overall completion rate (CR) of the examination was 95.5% (1394/1459). Logistic regression analysis showed that hospitalization status (p = 0.030), diarrhea (p = 0.017), diabetes (p = 0.027) and cerebrovascular disease (p = 0.038) were significant risk factors for DUGT. CONCLUSIONS: In our study, DUGT of SBCE was associated with hospitalization status, diarrhea, diabetes and cerebrovascular disease. Therefore, for the patients with the above risk factors, we should closely check the capsule status during the examination process, in order to take appropriate intervention measures as soon as possible.

Plastome structure and phylogenetic relationships of genus Hydrocotyle (apiales): provide insights into the plastome evolution of Hydrocotyle.

BACKGROUND: The genus Hydrocotyle Tourn. ex L. is a key group for further study on the evolution of Apiales, comprising around 170 species globally. Previous studies mainly focused on separate sections and provided much information about this genus, but its infrageneric relationships are still confusing. In addition, the genetic basis of its adaptive evolution remains poorly understood. To investigate the phylogeny and evolution of the genus, we selected ten representative species covering two of three diversity distribution centers and exhibiting rich morphology diversity. Comparative plastome analysis was conducted to clarify the structural character of Hydrocotyle plastomes. Positive selection analyses were implemented to assess the evolution of the genus. Phylogenetic inferences with protein-coding sequences (CDS) of Hydrocotyle and 17 related species were also performed. RESULTS: Plastomes within Hydrocotyle were generally conservative in structure, gene order, and size. A total of 14 regions (rps16-trnK, trnQ-rps16, atpI-atpH, trnC-petN-psbM, ycf3-trnS, accD-psaI-ycf4, petA-psbJ, rps12-rpl20, rpl16 intron, rps3-rpl16 intron, rps9-rpl22, ndhF-rpl32, ndhA intron, and ycf1a) were recognized as hotspot regions within the genus, which suggested to be promising DNA barcodes for global phylogenetic analysis of Hydrocotyle. The ycf15 gene was suggested to be a protein-coding gene for Hydrocotyle species, and it could be used as a DNA barcode to identify Hydrocotyle. In phylogenetic analysis, three monophyletic clades (Clade I, II, III) were identified with evidence of rapid radiation speciation within Clade I. The selective pressure analysis detected that six CDS genes (ycf1b, matK, atpF, accD, rps14, and psbB) of Hydrocotyle species were under positive selection. Within the genus, the last four genes were conservative, suggesting a relation to the unique evolution of the genus in Apiales. Seven genes (atpE, matK, psbH, ycf1a, ycf1b, rpoA, and ycf2) were detected to be under some degree of positive selection in different taxa within the genus Hydrocotyle, indicating their role in the adaptive evolution of species. CONCLUSIONS: Our study offers new insights into the phylogeny and adaptive evolution of Hydrocotyle. The plastome sequences could significantly enhance phylogenetic resolution and provide genomic resources and potential DNA markers useful for future studies of the genus.

Long-term safety and influence on growth in patients receiving sirolimus: a pooled analysis.

BACKGROUND: Sirolimus is increasingly utilized in treating diseases associated with mTOR pathway overactivation. Despite its potential, the lack of evidence regarding its long-term safety across all age groups, particularly in pediatric patients, has limited its further application. This study aims to assess the long-term safety of sirolimus, with a specific focus on its impact on growth patterns in pediatric patients. METHODS: This pooled analysis inlcudes two prospective cohort studies spanning 10 years, including 1,738 participants (aged 5 days to 69 years) diagnosed with tuberous sclerosis and/or lymphangioleiomyomatosis. All participants were mTOR inhibitor-naive and received 1 mg/m²/day of sirolimus, with dose adjustments during a two-week titration period to maintain trough blood concentrations between 5 and 10 ng/ml (maximum dose 2 mg). Indicators of physical growth, hematopoietic, liver, renal function, and blood lipid levels were all primary outcomes and were analyzed. The adverse events and related management were also recorded. RESULTS: Sirolimus administration did not lead to deviations from normal growth ranges, but higher doses exhibited a positive association with Z-scores exceeding 2 SD in height, weight, and BMI. Transient elevations in red blood cell and white blood cell counts, along with hyperlipidemia, were primarily observed within the first year of treatment. Other measured parameters remained largely unchanged, displaying only weak correlations with drug use. Stomatitis is the most common adverse event (920/1738, 52.9%). In adult females, menstrual disorders were observed in 48.5% (112/217). CONCLUSIONS: Sirolimus's long-term administration is not associated with adverse effects on children's physical growth pattern, nor significant alterations in hematopoietic, liver, renal function, or lipid levels. A potential dose-dependent influence on growth merits further exploration. TRIAL REGISTRATION: Pediatric patients: Chinese clinical trial registry, No. ChiCTR-OOB-15,006,535. Adult patients: ClinicalTrials, No. NCT03193892.

Selective sodium halide over potassium halide binding and extraction by a heteroditopic halogen bonding [2]catenane.

The synthesis and ion-pair binding properties of a heteroditopic [2]catenane receptor exhibiting highly potent and selective recognition of sodium halide salts are described. The receptor design consists of a bidentate halogen bonding donor motif for anion binding, as well as a di(ethylene glycol)-derived cation binding pocket which dramatically enhances metal cation affinity over previously reported homo[2]catenane analogues. 1H NMR cation, anion and ion-pair binding studies reveal significant positive cooperativity between the cation and anion binding events in which cation pre-complexation to the catenane subsequently 'switches-on' anion binding. Notably, the heteroditopic catenane displayed impressive selectivity for sodium halide recognition over the corresponding potassium halides. We further demonstrate that the catenane is capable of extracting solid alkali metal salts into organic media. Crucially, the observed solution phase binding selectivity for sodium halides translates to superior functional extraction capabilities of these salts relative to potassium halides, overcoming the comparatively higher lattice enthalpies NaX > KX dictated by the smaller alkali metal sodium cation. This is further exemplified in competitive solid-liquid experiments which revealed the exclusive extraction of sodium halide salts from solid mixtures of sodium and potassium halide salts.

Multi-trajectories in different domains of social supports and subjective motoric cognitive risk syndrome: a 16-year group-based multi-trajectory analysis.

OBJECTIVE: The aim of this study was to examine the longitudinal relationships between the trajectories of distinct subtypes of various domains of social supports and risk of subjective motoric cognitive risk (MCR) syndrome. DESIGN: Longitudinal cohort study. SETTING AND PARTICIPANTS: 2,279 participants in the Taiwan Longitudinal Study on Aging (TLSA) between 1999 and 2011. METHOD: A group-based multi-trajectory modeling (GBMTM) was implemented to identify distinct trajectory subtypes within various social support domains, encompassing social networks, emotional support, instrumental support, as well as working and economic status. Logistic regression models were then utilized to evaluate the associations between these trajectory subtypes and the risk of subjective MCR. RESULTS: Among 2,279 participants, GBMTM identified four distinct trajectory subtypes: "low social support" (n = 371), "medium social support " (n = 862), "high social support" (n = 292), and "high social support with employment" (n = 754). The incidence rates of subjective MCR for these groups were 9.4%, 9.0%, 4.1%, and 0.8%, respectively. After adjusting for age, sex, education level, and comorbidities, both "low social support" (adjusted odds ratio (aOR) 4.07, 95% CI [1.60-10.34]) and "medium social support" (aOR 3.10, 95% CI [1.26-7.66]) were significantly associated with an increased risk of subjective MCR compared to the "high social support with employment" group. CONCLUSIONS AND IMPLICATIONS: The current study demonstrates that social support significantly reduces the risk of subjective MCR, with lower support levels correlating to higher risk, necessitating further intervention studies to confirm the link between social support and risk of subjective MCR.