Natural product anticipation via chemical synthesis: Discovery of two new securinega alkaloids.

The isolation of a natural product conventionally precedes its chemical synthesis. Often, the isolation and structure determination of a natural product present in minute quantities in its natural source pose formidable challenges, akin to finding "a needle in a haystack." On the other hand, leveraging plausible biosynthetic insights and biomimetic synthetic expertise would allow for the prior synthesis of presumed natural products, followed by their verification in natural sources. In this study, we unveil two novel securinega alkaloids, securingines H and I, employing the natural product anticipation through synthesis approach. Structural analysis of securingines H and I suggests that they are biosynthetic derivatives of secu'amamine E and securinol A, respectively. We posit that this "synthesis first" strategy represents a valuable approach to the discovery of new natural products.

Ameliorating Effect of Standardized Rice Bran Supplement on Depressive-Like Behaviors in Ovariectomized Mice.

Menopausal depression, often associated with hormonal fluctuations such as decreased estrogen levels, imposes significant mental health burdens. Despite the antidepressant biological properties of standardized rice bran supplement (RBS), its impact on menopausal depression and underlying mechanisms remains largely unexplored. In this study, we investigated the antidepressant effects of RBS in a mouse model of estrogen deficiency-induced depression. Ovariectomized (OVX) mice received oral doses of RBS (250 and 1000 mg/kg) and 17ß estradiol over a 20-week period. RBS administration resulted in decreased immobility time in the tail suspension and forced swim tests, along with increased locomotor activity in the open field test. Furthermore, RBS enhanced nitric oxide production and neuronal nitric oxide synthase (nNOS) expression in the hippocampi of OVX mice. Additionally, RBS administration phosphorylated extracellular signal-regulated kinase (ERK), cAMP response element-binding protein (CREB), and tropomyosin receptor kinase B and increased the protein expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. These findings suggest that RBS alleviated depressive behaviors in OVX mice by augmenting hippocampal nNOS expression and activating the ERK-CREB-BDNF signaling pathway. Therefore, based on these results, we propose that RBS is a promising agent to treat menopausal depression, a challenging condition.

Predicting Postoperative Satisfaction with Breasts: How Important is the Preoperative BREAST-Q Score?

BACKGROUND: The role that preoperative Satisfaction with Breast plays in a patient's postoperative course after postmastectomy breast reconstruction (PMBR) is not understood. The aim of this study is to understand the impact of the preoperative score on postoperative outcome as an independent variable. METHODS: We examined patients who underwent PMBR between 2017 and 2021 and who completed the BREAST-Q Satisfaction with Breasts at 1 year postoperatively. Two multiple linear regression models (Model 1 with the preoperative Satisfaction with Breasts score and Model 2 without the preoperative score), likelihood ratio tests, simple t-statistics, and sample patient dataset to predict the 1 year score were performed. Multiple imputation was used to account for missing preoperative scores. RESULTS: Overall, 2324 patients were included. Model 1 showed that the preoperative score is significantly associated with the postoperative score (ß = 0.09, 95% confidence interval 0.04-0.14; p < 0.001). Comparing Model 1 and Model 2 demonstrated that including preoperative Satisfaction with Breasts in a regression significantly improves model fit (test statistic = 10.04; p = 0.0021). Using the absolute value of the t-statistics as a measure of variable importance in linear regression, the importance of the preoperative score was quantified as 3.39-more important than neoadjuvant radiation, mastectomy weight, body mass index, bilateral prophylactic mastectomy, and race, but less than adjuvant radiation, reconstruction type, and psychiatric diagnoses. CONCLUSION: Preoperative Satisfaction with Breasts scores are an important independent predictor of postoperative satisfaction after PMBR. Just as vital sign and work-up are carefully documented before surgery, preoperative scores should be collected to pre-emptively gauge patients' satisfaction and optimize postoperative outcomes.

Late-Onset Slowly Progressing Cone/Macular Dystrophy in Patients With the Biallelic Hypomorphic Variant p.Arg1933Ter in RP1.

Purpose: Homozygous hypomorphic variants of the RP1 gene, including c.5797C>T, p.Arg1933Ter, have traditionally been considered non-pathogenic. This study aimed to elucidate the clinical manifestations of late-onset, slowly progressive cone/macular dystrophy in patients homozygous for p.Arg1933Ter in the RP1 gene. Methods: Five patients with biallelic p.Arg1933Ter in RP1 were retrospectively recruited, and their clinical profiles were analyzed. Copy number variation analysis and Alu insertion assessment of genes associated with inherited retinal diseases were conducted. The results of comprehensive ophthalmological examinations, multimodal imaging, and full-field electroretinogram tests were analyzed. Results: No specific sequencing errors or structural variations associated with the clinical phenotypes were identified. Alu element insertion in RP1 was not detected. The mean ± SD age at the first visit was 62.2 ± 9.8 years, with symptoms typically starting between 45 and 50 years of age. Two patients exhibited a mild form of cone/macular dystrophy, characterized by a relatively preserved fundus appearance and blurring of the ellipsoid zone on optical coherence tomography. Three patients had late-onset cone/macular dystrophy with significant atrophy. Conclusions: To our knowledge, this study is the first to report that a homozygous hypomorphic variant of RP1, previously considered non-pathogenic, leads to cone/macular dystrophy. Translational Relevance: The study introduces novel possibilities suggesting that the homozygous hypomorphic variant of RP1 may be linked to variant pathogenicity.

Collagenase and Tyrosinase Inhibitory Compounds from Fish Gut Bacteria Ruegeria atlantica and Pseudoalteromonas neustonica.

Ruegeria atlantica and Pseudoalteromonas neustonica are fish gut bacteria that have been isolated from the guts of Pagrus major and Acanthopagrus schlegelii, respectively. A total of 22 compounds (1-22) were isolated from these two bacteria; 16 compounds (1-16) from R. atalantica and 6 compounds (17-22) from P. neustonica. Their chemical structures were elucidated by spectroscopic and spectrometric data analysis and chemical synthesis. Compounds 11 and 13 showed strong collagenase inhibitory activity, with 31.91% and 36.43% at 20 µM, respectively, comparable to or surpassing that of the positive control epigallocatechin gallate (EGCG, 34.66%). Also, compounds 11 and 14 exhibited a mild tyrosinase inhibitory effect of 6.73% and 13.68%, respectively. All of the tested compounds displayed no significant antibacterial activity against Escherichia coli and Bacillus subtilis up to 100 µM. The collagenase- and tyrosinase-inhibitory compound 11, cyclo(l-Pro-d-Leu), was found to be stable under heat (50 °C) and UV light (254 and 365 nm) for up to 6 days. These results indicate that compound 11 could be developed into a cosmeceutical with antiaging effects.

Erratum: Prevalence of Severe Atopic Dermatitis and Comorbid Chronic Systemic Diseases Is Increasing in Korean Children and Adolescents.

This corrects the article on p. 300 in vol. 16, PMID: 38910287.

Synthesis and Structure Revision of Securingine E.

Chemical synthesis plays a crucial role in confirming and revising the structures of natural products. Through meticulous synthetic efforts, NMR spectroscopic and single-crystal X-ray diffraction analyses, DFT calculations, and mass spectrometric investigations, we revised the structure of securingine E. The revised structure of securingine E was unambiguously confirmed by its chemical synthesis.

Genetic polymorphisms and their association with methotrexate polyglutamates during maintenance treatment in Korean children and young adults with acute lymphoblastic leukemia.

The aim of this study was to investigate the impact of genetic polymorphisms on methotrexate (MTX) metabolism in Korean children and young adults with acute lymphoblastic leukemia, specifically focusing on MTX polyglutamates (MTX-PGs) in erythrocytes, which have been rarely studied. Korean children and young adult patients undergoing maintenance therapy for acute lymphoblastic leukemia, who were receiving weekly oral MTX doses of 20 mg/m²/week, were prospectively included. We investigated erythrocyte MTX-PG (PG1 to PG5) levels, MTX-PG/MTX dose ratios, and 222 genetic polymorphisms spanning 78 genes and three intergenic areas related to MTX transport, folate cycle metabolism, purine/pyrimidine pathways, and non-pathway genes (including TPMT and NUDT15 genotypes) to explore their association with MTX metabolism. MTX-PG levels were associated with MTX dose (p < 0.05), and MTX-PG3 comprised the majority of the total MTX-PGs, with a median of 39.3%. Various polymorphisms within the same gene demonstrated differing associations with each type of MTX-PG, underscoring the complexity of MTX pharmacogenetics. Among the polymorphisms examined, 14 across 13 genes showed significant associations with MTX-PG2-5 levels, even after adjusting for the false discovery rate (ABCC5, ATG16L1, CEP72, FSTL5, GMPS, HTR3A, IMPDH1, NT5C2, SLC28A3, SLCO1B3, SUCLA2, TPMT, and TYMS). This study enhances our understanding of genetic polymorphisms in MTX metabolism and therapeutic monitoring for MTX maintenance, promoting personalized medicine in acute lymphoblastic leukemia patients.

Peroxiredoxin 1 inhibits streptozotocin-induced Alzheimer's disease-like pathology in hippocampal neuronal cells via the blocking of Ca2+/Calpain/Cdk5-mediated mitochondrial fragmentation.

Oxidative stress plays an essential role in the progression of Alzheimer's disease (AD), the most common age-related neurodegenerative disorder. Streptozotocin (STZ)-induced abnormal brain insulin signaling and oxidative stress play crucial roles in the progression of Alzheimer's disease (AD)-like pathology. Peroxiredoxins (Prxs) are associated with protection from neuronal death induced by oxidative stress. However, the molecular mechanisms underlying Prxs on STZ-induced progression of AD in the hippocampal neurons are not yet fully understood. Here, we evaluated whether Peroxiredoxin 1 (Prx1) affects STZ-induced AD-like pathology and cellular toxicity. Prx1 expression was increased by STZ treatment in the hippocampus cell line, HT-22 cells. We evaluated whether Prx1 affects STZ-induced HT-22 cells using overexpression. Prx1 successfully protected the forms of STZ-induced AD-like pathology, such as neuronal apoptosis, synaptic loss, and tau phosphorylation. Moreover, Prx1 suppressed the STZ-induced increase of mitochondrial dysfunction and fragmentation by down-regulating Drp1 phosphorylation and mitochondrial location. Prx1 plays a role in an upstream signal pathway of Drp1 phosphorylation, cyclin-dependent kinase 5 (Cdk5) by inhibiting the STZ-induced conversion of p35 to p25. We found that STZ-induced of intracellular Ca2+ accumulation was an important modulator of AD-like pathology progression by regulating Ca2+-mediated Calpain activation, and Prx1 down-regulated STZ-induced intracellular Ca2+ accumulation and Ca2+-mediated Calpain activation. Finally, we identified that Prx1 antioxidant capacity affected Ca2+/Calpain/Cdk5-mediated AD-like pathology progress. Therefore, these findings demonstrated that Prx1 is a key factor in STZ-induced hippocampal neuronal death through inhibition of Ca2+/Calpain/Cdk5-mediated mitochondrial dysfunction by protecting against oxidative stress.

Management of renal artery aneurysms: A retrospective study.

BACKGROUND: Although renal artery aneurysms (RAAs) are rare and often asymptomatic with slow growth, their natural progression and optimal management are not well understood. Treatment recommendations for RAAs do exist; however, they are supported by limited data. METHODS: A retrospective cohort study was conducted to explore the management of patients diagnosed with an RAA at our institution from January 1st, 2013, to December 31st, 2020. Patients were identified through a search of our radiological database, followed by a comprehensive chart review for further assessment. Data collection encompassed patient and aneurysm characteristics, the rationale for initial imaging, treatment, surveillance, and all-cause mortality. RESULTS: One hundred eighty-five patients were diagnosed with or treated for RAAs at our center during this timeframe, with most aneurysms having been discovered incidentally. Average aneurysm size was 1.40 cm (±0.05). Of those treated, the mean size was 2.38 cm (±0.24). Among aneurysms larger than 3 cm in size, comprising 3.24% of the total cases, 83.3% underwent treatment procedures. Only 20% of women of childbearing age received treatment for their aneurysms. There was one instance of aneurysm rupture, with no associated mortality or significant morbidity. CONCLUSIONS: Our institution's management of RAAs over the period of the study generally aligned with guidelines. One potential area of improvement is more proactive intervention for women of childbearing age.

Home-based up-dosing of wheat oral immunotherapy: Real-world effectiveness and predictive factor analysis.

BACKGROUND: Wheat allergy is one of the most prevalent allergens in Korea, decreasing quality of life and causing nutritional repercussions. OBJECTIVE: We aimed to investigate the efficacy and safety of the home-based wheat oral immunotherapy (OIT) using wheat noodles in children with a wheat allergy. METHODS: We conducted a retrospective study involving 72 children aged 3 to 17 years diagnosed with a wheat allergy. Patients received wheat OIT using wheat noodles (n = 50) and were compared with a historical control group (n = 22). Baseline characteristics, adverse events, and immunological changes were assessed. Predictors of successful desensitization were identified using logistic regression analysis. RESULTS: Among 50 patients completing the up-dosing phase, 82.0% achieved desensitization to 2,400 mg of wheat protein, compared to 4.5% in the control group (p < 0.001). During the up-dosing period, the median number of adverse reactions per person was 2, and anaphylaxis occurred in 30.0% (15/50). However, there were no life-threatening adverse events. In multivariable analysis, the presence of asthma (adjusted odds ratio [aOR], 8.88; 95% confidence interval [CI], 1.10-71.97; p = 0.041) and a higher ratio of specific IgE (sIgE) to ω-5-gliadin and total IgE (aOR 19.09, 95%CI 1.21-300.80, p = 0.036) were significantly associated with treatment outcomes of wheat OIT. CONCLUSION: Our study showed the safety and efficacy of home-based wheat OIT using boiled noodles in Korean children with wheat allergies. Careful consideration is warranted for patients with elevated baseline sIgE to ω-5-gliadin to total IgE ratio and a history of asthma.

Magnetite addition reduces nitrite requirement for efficient anaerobic ammonium oxidation by facilitating mutualism of ANAMMOX and FEAMMOX bacteria.

Partial nitrification (PN) is crucial for anaerobic ammonium oxidation (ANAMMOX), but faces challenges such as high energy demands and process control. Recent research has highlighted additives like magnetite as potential alternatives to conventional electron acceptors (O2 and NO2-) for enhancing ammonium (NH4+) oxidation with lower energy consumption. This study investigated the effect of adding 50 mg/L of magnetite to ANAMMOX reactors, resulting in improved nitrogen (N) removal efficiency. The magnetite-added ANAMMOX (M-ANA) reactor yielded N removal efficiencies of 71 %, 66 %, and 57 % for NH4+:NO2- molar ratios of 1:1.3, 1:0.8, and 1:0.5, respectively. The M-ANA reactor operated under a 0.5 mol lower NO2- concentration achieved similar performance to the control ANAMMOX (C-ANA) reactor operated with a theoretical amount of NO2-. Moreover, the M-ANA reactor showed the potential to remove NH4+ by 56 % without any NO2- supplementation. Metagenomic analysis showed that the addition of magnetite significantly improved the relative abundance of microorganisms involved in the FEAMMOX reaction, such as Fimbriimonas ginsengisoli and Pseudomonas stutzeri. It also facilitated positive mutualism between ANAMMOX and FEAMMOX reactions. In addition, M-ANA granules exhibited a dense and compact structure compared with C-ANA, and the presence of magnetite facilitated the formation of resilient granules. Notably, the useful protein (Heme C) concentration and specific microbial activity in the M-ANA reactor were 1.3 and 2.2 times higher than those in the C-ANA reactor. Overall, the results demonstrate that an appropriate amount of magnetite can enhance the N removal efficiency while reducing the energy input requirements and associated carbon emissions. These findings can guide the future development of carbon- and energy-neutral N removal processes.

Breast-Conserving Therapy Versus Postmastectomy Breast Reconstruction: Propensity Score-Matched Analysis.

BACKGROUND: Although studies have compared patient-reported outcomes (PROs) after breast conserving-therapy (BCT) and postmastectomy breast reconstruction (PMBR), they often have been confounded by treatment or other factors that complicate a direct comparison. This study aimed to compare PROs after BCT and PMBR by using propensity score-matching analysis. METHODS: Patients who underwent BCT or PMBR between 2010 and 2022 and completed the BREAST-Q were identified. Each BCT patient was matched to a PMBR patient using nearest-neighbor 1:1 matching with replacement for each BREAST-Q time point. Outcomes included all prospectively collected BREAST-Q domains preoperatively, at 6 months, and at 1, 2, and 3 years postoperatively. A 4-point difference was considered clinically meaningful. RESULTS: For this study, 6215 patients (2501 BCT [40.2%] and 3714 PMBR [59.8%] patients) were eligible, and 2616 unique patients were matched. Preoperatively, 463 BCT and 463 PMBR patients were matched for analysis (6 months [443 matched pairs], 1 year [639 matched pairs], 2 years [421 matched pairs], 3 years [254 matched pairs]). At 6 months postoperatively, the BCT patients scored higher on all BREAST-Q domains than the PMBR patients (p < 0.05; differences > 4 points). At 1, 2, and 3 years, the patients who underwent BCT consistently had superior Satisfaction With Breasts, Psychosocial Well-Being, and Sexual Well-Being (p < 0.05), and the differences were clinically meaningful. CONCLUSION: In this statistically powered study, the BCT patients reported higher quality of life than the PMBR patients in early assessment and also through 3 years of follow-up evaluation. Given the equivalency in survival and recurrence outcomes between BCT and PMBR, patients eligible for either surgery should be counseled regarding the superiority of BCT in terms of PROs.

Breast Conserving Therapy Preserves Sexual Well-Being More Than Postmastectomy Breast Reconstruction: Trends, Factors, and Interventions.

BACKGROUND: Up to 85% of breast cancer patients report sexual health concerns, but their concerns are not adequately addressed by providers. Sexual dysfunction among breast cancer patients remains understudied. We aimed to investigate the impact of breast-conserving therapy (BCT) and postmastectomy breast reconstruction (PMBR) on the sexual health of breast cancer patients and frequency of sexual medicine consultation in postoperative care. METHODS: We conducted a retrospective analysis of patients who underwent BCT or PMBR and completed the Sexual Well-being of the BREAST-Q BCT and Reconstruction modules from January 2010 to October 2022. We compared Sexual Well-being scores between BCT and PMBR patients overtime up to 5-years postoperatively, delineated associated demographic and clinical factors with Sexual Well-being, and evaluated the frequency of sexual medicine consultations. RESULTS: Of 15,857 patients, 8,510 (53.7%) underwent BCT and 7,347 (46.3%) underwent PMBR. PMBR patients had significantly lower Sexual Well-being scores than BCT patients from preoperative to 5-year postoperative. Regression analyses showed that PMBR patients scored 7.6 points lower at 1-year than BCT patients. Separated marital status, higher body mass index, cardiovascular disease, hyperlipidemia, psychiatric diagnosis, and neoadjuvant chemotherapy were associated with significantly lower Sexual Well-being. 299 (3.5%) of BCT and 400 (5.4%) of PMBR patients received sexual medicine consultations. CONCLUSION: Sexual health concerns must be considered in breast cancer care, particularly among patients who undergo PMBR. Although many patients experience sexual dysfunction, most do not receive a sexual medicine consultation, suggesting an opportunity for providers to improve breast cancer patients' sexual health.

The Application of Lag Screws and Digital Positioning Guide in Treating Sagittal Split Fracture of the Mandible.

Sagittal mandibular fractures are challenging to manage using traditional open reduction and internal fixation techniques due to the difficulty in manually reducing mandibular fragments and performing osteosynthesis on the lingual side. In addition, there is a risk of damaging dental roots with screws during fixation. In this case, the authors employed the lag screw technique combined with digitally guided surgery to effectively perform osteosynthesis on the fragments and avoid iatrogenic tooth and nerve injury.