Advancements in Litchi chinensis Peel Processing: A Scientific Review of Drying, Extraction, and Isolation of Its Bioactive Compounds.

This article systematically reviews the advancements in processing litchi peel (Litchi chinensis), emphasizing drying, extraction, purification methods, and the potential of bioactive compounds obtained from litchi peel. This work also highlights the impact of various drying techniques on phytochemical profiles, focusing on how methods such as hot air and freeze-drying affect the preservation of bioactive compounds. The study delves into extraction methods, detailing how different solvents and techniques influence the efficiency of extracting bioactive compounds from litchi peel. Furthermore, the purification and characterization of active compounds, showcasing the role of chromatographic techniques in isolating specific bioactive molecules, is discussed. Biological properties and mechanisms of action, such as antioxidant, antihyperglycemic, cardioprotective, hepatoprotective, anti-atherosclerotic, and anticancer activities, are reviewed, providing insight into the potential health benefits of litchi peel compounds. This review highlights the importance of optimizing and selecting accurate drying and extraction methods to maximize the therapeutic effects of litchi peel and its bioactive compounds. This review also reveals the broad pharmacological potential of the isolated compounds, underscoring the need for further research to discover their specific actions and health benefits.

Glycemic Index, Glycemic Load and Dyslipidemia in Adolescents from Chiapas, Mexico.

Cardiovascular disease risk throughout the life course is increased by abnormal blood lipid levels in youth. The dietary glycemic index (GI) and glycemic load (GL) during adolescence might be related to abnormal blood lipids. This study aimed to analyze the association between dietary GI, GL and dyslipidemia in adolescents from two marginalized regions of Chiapas, Mexico. A cross-sectional study was conducted with 213 adolescents. Food intake was assessed using 24 h recalls. The association between dyslipidemia and dietary GI or GL was tested by using logistic regression models. Low HDL-c was the most prevalent risk factor (47.4%), followed by hypertriglyceridemia (25.4%). In this population, overall dietary GI was not associated with dyslipidemia. A high dietary GL was associated with 2.39 higher odds of low HDL-c (95% CI: 1.21-4.74) when compared to low GL. Female adolescents with high dietary GL had 3.20 higher odds of hypertriglyceridemia (95% CI: 1.03-9.88), whereas no association was found for males. No associations were observed between overall dietary GL and total cholesterol or LDL-c. In adolescents from urban and rural communities in Chiapas, a high dietary GL was associated with a detrimental effect on HDL-c. In female adolescents, high GL was associated with hypertriglyceridemia.

Tackling Brain and Muscle Dysfunction in Acute Respiratory Distress Syndrome Survivors: NHLBI Workshop Report.

Acute respiratory distress syndrome (ARDS) is associated with long-term impairments in brain and muscle function that significantly impact the quality of life of those who survive the acute illness. The mechanisms underlying these impairments are not yet well understood, and evidence-based interventions to minimize the burden on patients remain unproved. The NHLBI of the NIH assembled a workshop in April 2023 to review the state of the science regarding ARDS-associated brain and muscle dysfunction, to identify gaps in current knowledge, and to determine priorities for future investigation. The workshop included presentations by scientific leaders across the translational science spectrum and was open to the public as well as the scientific community. This report describes the themes discussed at the workshop as well as recommendations to advance the field toward the goal of improving the health and well-being of ARDS survivors.

Pulmonary Fibrosis Stakeholder Summit: A Joint NHLBI, Three Lakes Foundation, and Pulmonary Fibrosis Foundation Workshop Report.

Despite progress in elucidation of disease mechanisms, identification of risk factors, biomarker discovery, and the approval of two medications to slow lung function decline in idiopathic pulmonary fibrosis and one medication to slow lung function decline in progressive pulmonary fibrosis, pulmonary fibrosis remains a disease with a high morbidity and mortality. In recognition of the need to catalyze ongoing advances and collaboration in the field of pulmonary fibrosis, the NHLBI, the Three Lakes Foundation, and the Pulmonary Fibrosis Foundation hosted the Pulmonary Fibrosis Stakeholder Summit on November 8-9, 2022. This workshop was held virtually and was organized into three topic areas: 1) novel models and research tools to better study pulmonary fibrosis and uncover new therapies, 2) early disease risk factors and methods to improve diagnosis, and 3) innovative approaches toward clinical trial design for pulmonary fibrosis. In this workshop report, we summarize the content of the presentations and discussions, enumerating research opportunities for advancing our understanding of the pathogenesis, treatment, and outcomes of pulmonary fibrosis.

Blood Pressure, Hypertension, and Antihypertensive Medication Use and Risk of Total and Fatal Prostate Cancer in Black and White Men in the Atherosclerosis Risk in Communities (ARIC) Study.

Black men are disproportionately burdened by hypertension and prostate cancer (PCa), and some cohorts suggest hypertension is associated with increased PCa risk. We investigated the association of hypertension and antihypertensive use with total (N = 889; 290 Black, 599 White) and fatal (N = 127; 42 Black, 85 White) PCa risk in 6658 (1578 Black, 5080 White) men in the Atherosclerosis Risk in Communities study. In adjusted Cox models, time-updated untreated stage 1 hypertension (systolic/diastolic blood pressure 130-139/80-89 mmHg) was associated with a higher risk of fatal PCa compared to untreated normal blood pressure (hazard ratio (HR) = 1.95; 95% confidence interval (CI) = 1.03-3.70). Compared to untreated normal/elevated blood pressure (combined given few events in those with untreated normal blood pressure), the association was significant in Black (HR = 3.35; 95% CI = 1.27-8.83), but not White (HR = 1.21; 95% CI = 0.58-2.55) men. Ever antihypertensive use was associated with a lower risk of fatal PCa compared to never use (HR = 0.52; 95% CI = 0.31-0.87), including short-term (< 10 years) and long-term (310 years) use (p-trend = 0.02) with similar inverse associations in Black and White men. Hypertension and antihypertensive use were not significantly associated with total PCa. The positive association of untreated stage 1 hypertension and fatal PCa warrants additional confirmation, especially in Black men, and characterization of the underlying mechanism.

Sociodemographic inequalities in cardiovascular risk factors among adolescents from indigenous areas in Chiapas, Mexico.

This study was aimed to determine the prevalence of cardiovascular risk factors among different sociodemographic groups of adolescents from indigenous communities in Chiapas, Mexico. A cross-sectional prevalence study was performed in urban and rural communities in the Tzotzil-Tzeltal and Selva regions of Chiapas. A sample of 253 adolescents was studied, of whom 48% were girls and 52% were boys. A descriptive analysis of quantitative variables was performed using measures of central tendency and dispersion. The prevalence of cardiovascular risk factors stratified by sex, geographical area, years of schooling, and ethnicity of the mothers was estimated. The prevalence of cardiovascular risk factors was analyzed in relation to the sociodemographic characteristics of the study population. Low HDL-c (51%) was the predominant cardiovascular risk factor. Girls had a higher prevalence of abdominal obesity, hypertriglyceridemia, and borderline total cholesterol than boys. High diastolic blood pressure was more prevalent in boys. Adolescents from urban areas had a higher prevalence of overweight/obesity and insulin resistance than adolescents from rural areas. The prevalence of overweight/obesity and abdominal obesity was higher in adolescents whose mothers had ≥ 7 years of schooling compared with adolescents with less educated mothers. Differences by maternal ethnicity also influenced the prevalence of insulin resistance. Among the main findings, this study associated sociodemographic and geographical inequalities with cardiovascular risk factors. Promoting a healthy lifestyle for this young population is absolutely necessary to prevent cardiovascular diseases in adulthood.

Association between the Neutrophil-to-Lymphocyte Ratio and Inpatient Mortality in Hospitalized Older Veterans with COVID-19 Infection.

OBJECTIVES: Determine the association of high neutrophil-to-lymphocyte ratio (NLR) values with inpatient mortality and other outcomes in older veterans hospitalized with coronavirus disease 2019 (COVID-19). METHODS: This was a retrospective, multicenter, cohort study of hospitalized adults, with laboratory-confirmed COVID-19 infection who were studied for 1 year after discharge or until death. The NLR was categorized into tertiles, and we determined frailty status with the 31-item Veterans Affairs Frailty Index. Multivariate logistic regression and adjusted odds ratios (aORs) with 95% confidence intervals (CIs) were performed to assess the association between NLR and clinical outcomes. RESULTS: The study included 615 hospitalized adult veterans, mean age 66.12 (standard deviation 14.79) years, 93.82% (n = 577) male, 57.56% (n = 354) White, 81.0% (n = 498) non-Hispanic, median body mass index of 30.70 (interquartile range 25.64-34.99, standard deviation 7.13), and median length of stay of 8 days (interquartile range 3-15). Individuals in the middle and upper tertile groups had higher inpatient mortality (8.37%, n = 17 and 18.36%, n = 38, respectively) as compared with the lower tertile (2.93%, n = 6, P < 0.001). Compared with the lowest tertile, the middle and upper tertiles had a higher risk of inpatient mortality (aOR 3.75, 95% CI 1.38-10.21, P = 0.01, and aOR 8.13, 95% CI 3.18-20.84, P < 0.001, respectively). The highest tertile had a higher odds of intensive care unit admission (aOR 4.47, 95% CI 2.33-8.58, P < 0.001) and intensive care unit transfer (aOR 3.54, 95% CI 1.84-6.81, P < 0.001). CONCLUSIONS: The NLR score is a clinically useful tool to predict in-hospital mortality in older patients with COVID-19.

Terminal Alkyne-Modified DNA Aptamers with Enhanced Protein Binding Affinities.

Nucleic acid-based receptors, known as aptamers, are relatively fast to discover and manufacture but lack the diverse functional groups of protein receptors (e.g., antibodies). The binding properties of DNA aptamers can be enhanced by attaching abiotic functional groups; for example, aromatic groups such as naphthalene slow dissociation from proteins. Although the terminal alkyne is a π-electron-rich functional group that has been used in small molecule drugs to enhance binding to proteins through noncovalent interactions, it remains unexplored for enhancing DNA aptamer binding affinity. Here, we demonstrate the utility of the terminal alkyne for improving the binding of DNA to proteins. We prepared a library of 256 terminal-alkyne-bearing variants of HD22, a DNA aptamer that binds the protein thrombin with nanomolar affinity. After a one-step thrombin-binding selection, a high-affinity aptamer containing two alkynes was discovered, exhibiting 3.2-fold tighter thrombin binding than the corresponding unmodified sequence. The tighter binding was attributable to a slower rate of dissociation from thrombin (5.2-fold slower than HD22). Molecular dynamics simulations with enhanced sampling by Replica Exchange with Solute Tempering (REST2) suggest that the π-electron-rich alkyne interacts with an asparagine side chain N-H group on thrombin, forming a noncovalent interaction that stabilizes the aptamer-protein interface. Overall, this work represents the first case of terminal alkynes enhancing the binding properties of an aptamer and underscores the utility of the terminal alkyne as an atom economical π-electron-rich functional group to enhance binding affinity with minimal steric perturbation.

Non-Native Site-Selective Enzyme Catalysis.

The ability to site-selectively modify equivalent functional groups in a molecule has the potential to streamline syntheses and increase product yields by lowering step counts. Enzymes catalyze site-selective transformations throughout primary and secondary metabolism, but leveraging this capability for non-native substrates and reactions requires a detailed understanding of the potential and limitations of enzyme catalysis and how these bounds can be extended by protein engineering. In this review, we discuss representative examples of site-selective enzyme catalysis involving functional group manipulation and C-H bond functionalization. We include illustrative examples of native catalysis, but our focus is on cases involving non-native substrates and reactions often using engineered enzymes. We then discuss the use of these enzymes for chemoenzymatic transformations and target-oriented synthesis and conclude with a survey of tools and techniques that could expand the scope of non-native site-selective enzyme catalysis.

Long-term survival with IDH wildtype glioblastoma: first results from the ETERNITY Brain Tumor Funders' Collaborative Consortium (EORTC 1419).

BACKGROUND: Median survival with glioblastoma remains in the range of 12 months on population levels. Only few patients survive for more than 5 years. Patient and disease features associated with long-term survival remain poorly defined. METHODS: European Organization for Research and Treatment of Cancer (EORTC) 1419 (ETERNITY) is a registry study supported by the Brain Tumor Funders Collaborative in the US and the EORTC Brain Tumor Group. Patients with glioblastoma surviving at least 5 years from diagnosis were identified at 24 sites in Europe, US, and Australia. In patients with isocitrate dehydrogenase (IDH) wildtype tumours, prognostic factors were analysed using the Kaplan-Meier method and the Cox proportional hazards model. A population-based reference cohort was obtained from the Cantonal cancer registry Zurich. RESULTS: At the database lock of July 2020, 280 patients with histologically centrally confirmed glioblastoma (189 IDH wildtype, 80 IDH mutant, 11 incompletely characterised) had been registered. In the IDH wildtype population, median age was 56 years (range 24-78 years), 96 patients (50.8%) were female, 139 patients (74.3%) had tumours with O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Median overall survival was 9.9 years (95% confidence interval [95% CI] 7.9-11.9). Patients without recurrence experienced longer median survival (not reached) than patients with one or more recurrences (8.92 years) (p < 0.001) and had a high rate (48.8%) of MGMT promoter-unmethylated tumours. CONCLUSIONS: Freedom from progression is a powerful predictor of overall survival in long-term survivors with glioblastoma. Patients without relapse often have MGMT promoter-unmethylated glioblastoma and may represent a distinct subtype of glioblastoma.

Associations between MICA and MICB Genetic Variants, Protein Levels, and Colorectal Cancer: Atherosclerosis Risk in Communities (ARIC).

BACKGROUND: The MHC class I chain-related protein A (MICA) and protein B (MICB) participate in tumor immunosurveillance and may be important in colorectal cancer, but have not been examined in colorectal cancer development. METHODS: sMICA and sMICB blood levels were measured by SomaScan in Visit 2 (1990-92, baseline) and Visit 3 (1993-95) samples in cancer-free participants in the Atherosclerosis Risk in Communities Study. We selected rs1051792, rs1063635, rs2516448, rs3763288, rs1131896, rs2596542, and rs2395029 that were located in or in the vicinity of MICA or MICB and were associated with cancer or autoimmune diseases in published studies. SNPs were genotyped by the Affymetrix Genome-Wide Human SNP Array. We applied linear and Cox proportional hazards regressions to examine the associations of preselected SNPs with sMICA and sMICB levels and colorectal cancer risk (236 colorectal cancers, 8,609 participants) and of sMICA and sMICB levels with colorectal cancer risk (312 colorectal cancers, 10,834 participants). In genetic analyses, estimates adjusted for ancestry markers were meta-analyzed. RESULTS: Rs1051792-A, rs1063635-A, rs2516448-C, rs3763288-A, rs2596542-T, and rs2395029-G were significantly associated with decreased sMICA levels. Rs2395029-G, in the vicinity of MICA and MICB, was also associated with increased sMICB levels. Rs2596542-T was significantly associated with decreased colorectal cancer risk. Lower sMICA levels were associated with lower colorectal cancer risk in males (HR = 0.68; 95% confidence interval, 0.49-0.96) but not in females (Pinteraction = 0.08). CONCLUSIONS: Rs2596542-T associated with lower sMICA levels was associated with decreased colorectal cancer risk. Lower sMICA levels were associated with lower colorectal cancer risk in males. IMPACT: These findings support an importance of immunosurveillance in colorectal cancer.

Pathogenic mechanisms of post-acute sequelae of SARS-CoV-2 infection (PASC).

COVID-19, with persistent and new onset of symptoms such as fatigue, post-exertional malaise, and cognitive dysfunction that last for months and impact everyday functioning, is referred to as Long COVID under the general category of post-acute sequelae of SARS-CoV-2 infection (PASC). PASC is highly heterogenous and may be associated with multisystem tissue damage/dysfunction including acute encephalitis, cardiopulmonary syndromes, fibrosis, hepatobiliary damages, gastrointestinal dysregulation, myocardial infarction, neuromuscular syndromes, neuropsychiatric disorders, pulmonary damage, renal failure, stroke, and vascular endothelial dysregulation. A better understanding of the pathophysiologic mechanisms underlying PASC is essential to guide prevention and treatment. This review addresses potential mechanisms and hypotheses that connect SARS-CoV-2 infection to long-term health consequences. Comparisons between PASC and other virus-initiated chronic syndromes such as myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome will be addressed. Aligning symptoms with other chronic syndromes and identifying potentially regulated common underlining pathways may be necessary for understanding the true nature of PASC. The discussed contributors to PASC symptoms include sequelae from acute SARS-CoV-2 injury to one or more organs, persistent reservoirs of the replicating virus or its remnants in several tissues, re-activation of latent pathogens such as Epstein-Barr and herpes viruses in COVID-19 immune-dysregulated tissue environment, SARS-CoV-2 interactions with host microbiome/virome communities, clotting/coagulation dysregulation, dysfunctional brainstem/vagus nerve signaling, dysautonomia or autonomic dysfunction, ongoing activity of primed immune cells, and autoimmunity due to molecular mimicry between pathogen and host proteins. The individualized nature of PASC symptoms suggests that different therapeutic approaches may be required to best manage specific patients.

Directed Evolution of an Iron(II)- and α-Ketoglutarate-Dependent Dioxygenase for Site-Selective Azidation of Unactivated Aliphatic C-H Bonds.

FeII - and α-ketoglutarate-dependent halogenases and oxygenases can catalyze site-selective functionalization of C-H bonds via a variety of C-X bond forming reactions, but achieving high chemoselectivity for functionalization using non-native functional groups remains rare. The current study shows that directed evolution can be used to engineer variants of the dioxygenase SadX that address this challenge. Site-selective azidation of succinylated amino acids and a succinylated amine was achieved as a result of mutations throughout the SadX structure. The installed azide group was reduced to a primary amine, and the succinyl group required for azidation was enzymatically cleaved to provide the corresponding amine. These results provide a promising starting point for evolving additional SadX variants with activity on structurally distinct substrates and for enabling enzymatic C-H functionalization with other non-native functional groups.

Sociodemographic inequalities in cardiovascular risk factors among adolescents from indigenous areas in Chiapas, Mexico / Desigualdades sociodemográficas como factores de riesgo cardiovascular para adolescentes de zonas indígenas de Chiapas, México / Desigualdades sociodemográficas como fatores de risco cardiovascular para adolescentes de áreas indígenas de Chiapas, México

Abstract: This study was aimed to determine the prevalence of cardiovascular risk factors among different sociodemographic groups of adolescents from indigenous communities in Chiapas, Mexico. A cross-sectional prevalence study was performed in urban and rural communities in the Tzotzil-Tzeltal and Selva regions of Chiapas. A sample of 253 adolescents was studied, of whom 48% were girls and 52% were boys. A descriptive analysis of quantitative variables was performed using measures of central tendency and dispersion. The prevalence of cardiovascular risk factors stratified by sex, geographical area, years of schooling, and ethnicity of the mothers was estimated. The prevalence of cardiovascular risk factors was analyzed in relation to the sociodemographic characteristics of the study population. Low HDL-c (51%) was the predominant cardiovascular risk factor. Girls had a higher prevalence of abdominal obesity, hypertriglyceridemia, and borderline total cholesterol than boys. High diastolic blood pressure was more prevalent in boys. Adolescents from urban areas had a higher prevalence of overweight/obesity and insulin resistance than adolescents from rural areas. The prevalence of overweight/obesity and abdominal obesity was higher in adolescents whose mothers had ≥ 7 years of schooling compared with adolescents with less educated mothers. Differences by maternal ethnicity also influenced the prevalence of insulin resistance. Among the main findings, this study associated sociodemographic and geographical inequalities with cardiovascular risk factors. Promoting a healthy lifestyle for this young population is absolutely necessary to prevent cardiovascular diseases in adulthood.

Resumen: El objetivo de este estudio fue estimar la prevalencia de los factores de riesgo cardiovascular entre diferentes grupos sociodemográficos de adolescentes de comunidades indígenas de Chiapas, México. Se realizó un estudio transversal de prevalencia en comunidades urbanas y rurales de las regiones Tzotzil-Tzeltal y Selva, en Chiapas. Participó una muestra de 253 adolescentes, en la cual el 48% eran niñas y el 52% niños. Se realizó un análisis descriptivo de las variables cuantitativas utilizando medidas de tendencia central y dispersión. Se estimó la prevalencia de los factores de riesgo cardiovascular, estratificados por sexo, área geográfica, nivel de estudios y etnia de las madres. Se analizó la prevalencia de los factores de riesgo cardiovascular con relación a las características sociodemográficas de la población estudiada. El HDL-c bajo (51%) fue el factor de riesgo cardiovascular predominante. Se observó una mayor prevalencia de obesidad abdominal, hipertrigliceridemia y colesterol total en las niñas que en los niños. La alta presión arterial diastólica prevaleció en los niños. Los adolescentes del área urbana tuvieron una mayor prevalencia de sobrepeso/obesidad y resistencia a la insulina que los del área rural. La prevalencia de sobrepeso/obesidad y obesidad abdominal fue mayor en los adolescentes cuyas madres tenían nivel de estudios ≥ 7 años que aquellos cuyas madres tenían bajo nivel de estudios. Las diferencias en la etnicidad materna también influyeron en la prevalencia de resistencia a la insulina. Entre las principales conclusiones de este estudio, se destacan las desigualdades sociodemográficas y geográficas entre los factores de riesgo cardiovascular. La promoción de un estilo de vida saludable entre la población joven es lo indicado para prevenir las enfermedades cardiovasculares en la edad adulta.

Resumo: O objetivo deste estudo foi determinar a prevalência de fatores de risco cardiovascular entre diferentes grupos sociodemográficos de adolescentes de comunidades indígenas em Chiapas, México. Foi realizado um estudo transversal de prevalência em comunidades urbanas e rurais das regiões de Tzotzil-Tzeltal e Selva de Chiapas. Foi estudada uma amostra de 253 adolescentes, sendo 48% meninas e 52% meninos. Foi realizada uma análise descritiva das variáveis quantitativas por meio de medidas de tendência central e dispersão. Foram estimadas as prevalências de fatores de risco cardiovascular, estratificadas por sexo, área geográfica, escolaridade e etnia das mães. A prevalência dos fatores de risco cardiovascular foi analisada em relação às características sociodemográficas da população estudada. O HDL-c baixo (51%) foi o fator de risco cardiovascular predominante. Prevalências mais elevadas de obesidade abdominal, hipertrigliceridemia e colesterol total limítrofe foram mais observadas em meninas do que em meninos. A pressão arterial diastólica elevada prevaleceu nos meninos. Adolescentes da área urbana apresentaram prevalências de sobrepeso/obesidade e resistência à insulina maiores do que os da área rural. A prevalência de sobrepeso/obesidade e obesidade abdominal foi maior nos adolescentes cujas mães possuíam escolaridade ≥ 7 anos do que naqueles indivíduos cujas mães tinham baixa escolaridade. As diferenças de etnia das mães também foram observadas na prevalência de resistência à insulina. Dentre as principais conclusões, foram encontradas, neste estudo, desigualdades sociodemográficas e geográficas entre fatores de risco cardiovascular. Promover estilos de vida saudáveis entre a população jovem é o ideal para prevenir doenças cardiovasculares na vida adulta.

Lactoferrin: An Effective Weapon in the Battle Against Bacterial Infections.

The emergence of multidrug-resistant bacterial strains with respect to commercially available antimicrobial drugs has marked a watershed in treatment therapies to fight pathogens and has stimulated research on alternative remedies. Proteins of the innate immune system of mammals have been highlighted as potentially yielding possible treatment options for infections. Lactoferrin (Lf) is one of these proteins; interestingly, no resistance to it has been found. Lf is a conserved cationic nonheme glycoprotein that is abundant in milk and is also present in low quantities in mucosal secretions. Moreover, Lf is produced and secreted by the secondary granules of neutrophils at infection sites. Lf is a molecule of approximately 80 kDa that displays multiple functions, such as antimicrobial, anti-viral, anti-inflammatory, and anticancer actions. Lf can synergize with antibiotics, increasing its potency against bacteria. Lactoferricins (Lfcins) are peptides resulting from the N-terminal end of Lf by proteolytic cleavage with pepsin. They exhibit several anti-bacterial effects similar to those of the parental glycoprotein. Synthetic analog peptides exhibiting potent antimicrobial properties have been designed. The aim of this review is to update understanding of the structure and effects of Lf and Lfcins as anti-bacterial compounds, focusing on the mechanisms of action in bacteria and the use of Lf in treatment of infections in patients, including those studies where no significant differences were found. Lf could be an excellent option for prevention and treatment of bacterial diseases, mainly in combined therapies with antibiotics or other antimicrobials.

Non-Native Anionic Ligand Binding and Reactivity in Engineered Variants of the Fe(II)- and α-Ketoglutarate-Dependent Oxygenase, SadA.

Mononuclear non-heme Fe(II)- and α-ketoglutarate-dependent oxygenases (FeDOs) catalyze a site-selective C-H hydroxylation. Variants of these enzymes in which a conserved Asp/Glu residue in the Fe(II)-binding facial triad is replaced by Ala/Gly can, in some cases, bind various anionic ligands and catalyze non-native chlorination and bromination reactions. In this study, we explore the binding of different anions to an FeDO facial triad variant, SadX, and the effects of that binding on HO• vs X• rebound. We establish not only that chloride and bromide enable non-native halogenation reactions but also that all anions investigated, including azide, cyanate, formate, and fluoride, significantly accelerate and influence the site selectivity of SadX hydroxylation catalysis. Azide and cyanate also lead to the formation of products resulting from N3•, NCO•, and OCN• rebound. While fluoride rebound is not observed, the rate acceleration provided by this ligand leads us to calculate barriers for HO• and F• rebound from a putative Fe(III)(OH)(F) intermediate. These calculations suggest that the lack of fluorination is due to the relative barriers of the HO• and F• rebound transition states rather than an inaccessible barrier for F• rebound. Together, these results improve our understanding of the FeDO facial triad variant tolerance of different anionic ligands, their ability to promote rebound involving these ligands, and inherent rebound preferences relative to HO• that will aid efforts to develop non-native catalysis using these enzymes.

The association of a frailty index from laboratory tests and vital signs with clinical outcomes in hospitalized older adults.

BACKGROUND: Frailty, a state of vulnerability to stressors resulting from loss of physiological reserve due to multisystemic dysfunction, is common among hospitalized older adults. Hospital clinicians need objective and practical instruments that identify older adults with frailty. The FI-LAB is based on laboratory values and vital signs and may capture biological changes of frailty that predispose hospitalized older adults to complications. The study's aim was to assess the association of the FI-LAB versus VA-FI with hospital and post-hospital clinical outcomes in older adults. METHODS: Retrospective cohort study was conducted on Veterans aged ≥60 admitted to a VA hospital. We identified acute hospitalizations January 2011-December-2014 with 1-year follow-up. A 31-item FI-LAB was created from blood laboratory tests and vital signs collected within the first 48 h of admission and scores were categorized as low (<0.25), moderate (0.25-0.40), and high (>0.40). For each FI-LAB group, we obtained odds ratio (OR) and confidence intervals (CI) for hospital and post-hospital outcomes using multivariate binomial logistic regression. Additionally, we calculated hazard ratios (HR) and CI for all-cause in-hospital mortality comparing the high and moderate FI-LAB group with the low group. RESULTS: Patients were 1407 Veterans, mean age 72.7 (SD = 9.0), 67.8% Caucasian, 96.1% males, 47.0% (n = 661), 41.0% (n = 577), and 12.0% (n = 169) were in the low, moderate, and high FI-LAB groups, respectively. Moderate and high scores were associated with prolonged LOS, OR:1.62 (95% CI:1.29-2.03); and 3.36 (95% CI:2.27-4.99), ICU admission, OR:1.40 (95% CI:1.03-1.90); and OR:2.00 (95% CI:1.33-3.02), nursing home placement OR:2.36 (95% CI:1.26-4.44); and 5.99 (95% CI:2.83-12.70), 30-day readmissions OR:1.74 (95% CI:1.20-2.52); and 2.20 (95% CI:1.30-3.74), 30-day mortality OR: 2.51 (95% CI:1.01-6.23); and 8.97 (95% CI:3.42-23.53), 6-month mortality OR:3.00 (95% CI:1.90-4.74); and 6.16 (95% CI:3.55-10.71), and 1-year mortality OR: 2.66 (95% CI:1.87-3.79); and 4.76 (95% CI:3.00-7.54) respectively. The high FI-LAB group showed higher risk of in-hospital mortality, HR:18.17 (95% CI:4.01-80.52) with an area-under-the-curve of 0.843 (95% CI:0.75-0.93). CONCLUSIONS: High and moderate FI-LAB scores were associated with worse in-hospital and post-hospital outcomes. The FI-LAB may identify hospitalized older patients with frailty at higher risk and assist clinicians in implementing strategies to improve outcomes.