Plasma and CSF biomarkers of aging and cognitive decline in Caribbean vervets.

INTRODUCTION: Vervets are non-human primates that share high genetic homology with humans and develop amyloid beta (Aß) pathology with aging. We expand current knowledge by examining Aß pathology, aging, cognition, and biomarker proteomics. METHODS: Amyloid immunoreactivity in the frontal cortex and temporal cortex/hippocampal regions from archived vervet brain samples ranging from young adulthood to old age was quantified. We also obtained cognitive scores, plasma samples, and cerebrospinal fluid (CSF) samples in additional animals. Plasma and CSF proteins were quantified with platforms utilizing human antibodies. RESULTS: We found age-related increases in Aß deposition in both brain regions. Bioinformatic analyses assessed associations between biomarkers and age, sex, cognition, and CSF Aß levels, revealing changes in proteins related to immune-related inflammation, metabolism, and cellular processes. DISCUSSION: Vervets are an effective model of aging and early-stage Alzheimer's disease, and we provide translational biomarker data that both align with previous results in humans and provide a basis for future investigations. HIGHLIGHTS: We found changes in immune and metabolic plasma biomarkers associated with age and cognition. Cerebrospinal fluid (CSF) biomarkers revealed changes in cell signaling indicative of adaptative processes. TNFRSF19 (TROY) and Artemin co-localize with Alzheimer's disease pathology. Vervets are a relevant model for translational studies of early-stage Alzheimer's disease.

Crystal structures of the isomeric dipeptides l-glycyl-l-me-thio-nine and l-me-thionyl-l-glycine.

The oxidation of me-thionyl peptides can contribute to increased biological (oxidative) stress and development of various inflammatory diseases. The conformation of peptides has an important role in the mechanism of oxidation and the inter-mediates formed in the reaction. Herein, the crystal structures of the isomeric dipeptides Gly-Met (Gly = glycine and Met = me-thio-nine) and Met-Gly, both C7H14N2O3S, are reported. Both mol-ecules exist in the solid state as zwitterions with nominal proton transfer from the carb-oxy-lic acid to the primary amine group. The Gly-Met mol-ecule has an extended backbone structure, while Met-Gly has two nearly planar regions kinked at the C atom bearing the NH3 group. In the crystals, both structures form extensive three-dimensional hydrogen-bonding networks via N-H⋯O and bifurcated N-H⋯(O,O) hydrogen bonds having N⋯O distances in the range 2.6619 (13)-2.8513 (13) Šfor Gly-Met and 2.6273 (8)-3.1465 (8) Šfor Met-Gly.

Synthesis, spectroscopic analysis and crystal structure of (N-{2-[(2-amino-eth-yl)amino]-eth-yl}-4'-methyl-[1,1'-biphenyl]-4-sulfonamidato)tri-carb-on-ylrhenium(I).

The title compound, [Re(C17H22N3O2S)(CO)3] is a net neutral fac-Re(I)(CO)3 complex of the 4-methyl-biphenyl sulfonamide derivatized di-ethyl-enetri-amine ligand. The NNN-donor monoanionic ligand coordinates with the Re core in tridentate fashion, establishing an inner coordination sphere resulting in a net neutral complex. The complex possesses pseudo-octa-hedral geometry where one face of the octa-hedron is occupied by three carbonyl ligands and the other faces are occupied by one sp 2 nitro-gen atom of the sulfonamide group and two sp 3 nitro-gen atoms of the dien backbone. The Re-Nsp 2 bond distance, 2.173 (4) Å, is shorter than the Re-Nsp 3 bond distances, 2.217 (5) and 2.228 (6) Å, and is similar to the range reported for typical Re-Nsp 2 bond lengths (2.14 to 2.18 Å).

Mechanisms of response and tolerance to active RAS inhibition in KRAS-mutant NSCLC.

Resistance to inactive state-selective RASG12C inhibitors frequently entails accumulation of RASGTP, rendering effective inhibition of active RAS potentially desirable. Here, we evaluated the anti-tumor activity of the RAS(ON) multi-selective tri-complex inhibitor RMC-7977 and dissected mechanisms of response and tolerance in KRASG12C-mutant NSCLC. Broad-spectrum, reversible RASGTP inhibition with or without concurrent covalent targeting of active RASG12C yielded superior and differentiated antitumor activity across diverse co-mutational KRASG12C-mutant NSCLC mouse models of primary or acquired RASG12C(ON) or (OFF) inhibitor resistance. Interrogation of time-resolved single cell transcriptional responses established an in vivo atlas of multi-modal acute and chronic RAS pathway inhibition in the NSCLC ecosystem and uncovered a regenerative mucinous transcriptional program that supports long-term tumor cell persistence. In patients with advanced KRASG12C-mutant NSCLC, the presence of mucinous histological features portended poor response to sotorasib or adagrasib. Our results have potential implications for personalized medicine and the development of rational RAS inhibitor-anchored therapeutic strategies.

Do newer drugs treat fewer diseases, controlling for time since launch? Evidence from France and the U.S.

Background: More recently approved drugs have significantly fewer indications than drugs approved many years ago. One possible reason for this may be that, controlling for the number of years since approval or launch, more recently approved drugs have fewer indications (e.g. at the time of launch). The role of precision and personalised medicine has increased, and the goal of precision medicine is to provide a more precise approach for the prevention, diagnosis and treatment of disease. Drugs that have fewer indications may be 'more precise' than drugs that have many indications. Methods: We use different kinds of data from two countries - France and the U.S. - to analyze the relationship across many drugs between the number of indications of a drug, the drug's vintage - i.e. the year in which the drug was first marketed or approved - and its age - the number of years it has been marketed. Results: All the evidence from both countries indicates that, controlling for drug age, more recently approved drugs tend to have fewer indications than drugs approved many years ago. In the U.S., a 10-year increase in vintage is associated with a 10.7% decline in the effective number of indications of all drugs, and a 19.4% decline in the effective number of indications of drugs approved after 1989. In France, the positive effect on the number of indications of the increase in drug age was more than offset by the negative effect of the increase in drug vintage. Conclusions: More recently approved drugs are less likely to be 'general-purpose technologies' (or even multi-purpose technologies) than older drugs. The relative importance of 'precision medicine' has increased in recent decades. Drugs that have fewer indications may be 'more precise' than drugs that have many indications.

Beyond MABEL: An Integrative Approach to First in Human Dose Selection of Immunomodulators by the Health and Environmental Sciences Institute (HESI) Immuno-Safety Technical Committee (ITC).

Administration of a new drug candidate in a first-in-human (FIH) clinical trial is a particularly challenging phase in drug development and is especially true for immunomodulators, which are a diverse and complex class of drugs with a broad range of mechanisms of action and associated safety risks. Risk is generally greater for immunostimulators, in which safety concerns are associated with acute toxicity, compared to immunosuppressors, where the risks are related to chronic effects. Current methodologies for FIH dose selection for immunostimulators are focused primarily on identifying the minimum anticipated biological effect level (MABEL), which has often resulted in sub-therapeutic doses, leading to long and costly escalation phases. The Health and Environmental Sciences Institute (HESI) - Immuno-Safety Technical Committee (ITC) organized a project to address this issue through two complementary approaches: (i) an industry survey on FIH dose selection strategies and (ii) detailed case studies for immunomodulators in oncology and non-oncology indications. Key messages from the industry survey responses highlighted a preference toward more dynamic PK/PD approaches as in vitro assays are seemingly not representative of true physiological conditions for immunomodulators. These principles are highlighted in case studies. To address the above themes, we have proposed a revised decision tree, which expands on the guidance by the IQ MABEL Working Group (Leach et al. 2021). This approach facilitates a more refined recommendation of FIH dose selection for immunomodulators, allowing for a nuanced consideration of their mechanisms of action (MOAs) and the associated risk-to-benefit ratio, among other factors.

One-year limb salvage and quality of life following mechanical aspiration thrombectomy in patients with acute lower extremity ischemia.

OBJECTIVE: Lower extremity acute limb ischemia (LE-ALI) is associated with high morbidity and mortality rates, and a burden on patient quality of life (QoL). There is limited medium- to long-term evidence on mechanical aspiration thrombectomy (MT) in patients with LE-ALI. The STRIDE study was designed to assess safety and efficacy of MT using the Indigo Aspiration System in patients with LE-ALI. Thirty-day primary and secondary endpoints and additional outcomes were previously published. Here, we report 365-day secondary endpoints and QoL data from STRIDE. METHODS: STRIDE was a multicenter, prospective, single-arm, observational cohort study that enrolled 119 patients across 16 sites in the United States and Europe. Patients were treated first-line with MT using the Indigo Aspiration System (Penumbra, Inc). The study completed follow-up in October 2023. Secondary endpoints at 365 days included target limb salvage and mortality. Additionally, the VascuQoL-6 questionnaire, developed for evaluating patient-centered QoL outcomes for peripheral arterial disease, was assessed at baseline and follow-up through 365 days. RESULTS: Seventy-three percent of patients (87/119) were available for 365-day follow-up. Mean age of these patients was 65.0 ± 13.3 years, and 44.8% were female. Baseline ischemic severity was classified as Rutherford I in 12.6%, Rutherford IIa in 51.7%, and Rutherford IIb in 35.6%. In general, baseline and disease characteristics (demographics, medical history, comorbidities, target thrombus) of these patients are similar to the enrolled cohort of 119 patients. The secondary endpoints at 365 days for target limb salvage was 88.5% (77/87) and mortality rate was 12.0% (12/100). VascuQoL-6 improved across all domains, with a median total score improvement from 12.0 (interquartile range, 9.0-15.0) at baseline to 19.0 (interquartile range, 16.0-22.0) at 365 days. CONCLUSIONS: These 365-day results from STRIDE demonstrate that first-line MT with the Indigo Aspiration System for LE-ALI portray continued high target limb salvage rates and improved patient-reported QoL. These findings indicate Indigo as a safe and effective therapeutic option for LE-ALI.

Cardiolipin clustering promotes mitochondrial membrane dynamics.

Cardiolipin (CL) is a mitochondria-specific phospholipid that forms heterotypic interactions with membrane-shaping proteins and regulates the dynamic remodeling and function of mitochondria. However, the precise mechanisms through which CL influences mitochondrial morphology are not well understood. In this study, employing molecular dynamics (MD) simulations, we observed CL localize near the membrane-binding sites of the mitochondrial fusion protein Optic Atrophy 1 (OPA1). To validate these findings experimentally, we developed a bromine-labeled CL probe to enhance cryoEM contrast and characterize the structure of OPA1 assemblies bound to the CL-brominated lipid bilayers. Our images provide direct evidence of interactions between CL and two conserved motifs within the paddle domain (PD) of OPA1, which control membrane-shaping mechanisms. We further observed a decrease in membrane remodeling activity for OPA1 in lipid compositions with increasing concentrations of monolyso-cardiolipin (MLCL). Suggesting that the partial replacement of CL by MLCL accumulation, as observed in Barth syndrome-associated mutations of the tafazzin phospholipid transacylase, compromises the stability of protein-membrane interactions. Our analyses provide insights into how biological membranes regulate the mechanisms governing mitochondrial homeostasis.

Insights into the molecular basis of reduced vancomycin susceptibility among three prominent Staphylococcus aureus clonal complexes.

Staphylococcus aureus is a leading cause of healthcare-associated infections globally. Vancomycin-resistant S. aureus (VRSA), those with high-level resistance [minimum inhibitory concentration (MIC) of 16-32 µg/mL vancomycin], are uncommon, whereas vancomycin-intermediate S. aureus (VISA; MIC of 4-8 µg/mL), are isolated more frequently and develop during long-term and/or repeated use of the antibiotic. VISA can be difficult to eradicate and infections may persist. Our knowledge of mechanisms that underlie the development of VISA is incomplete. We used a genomics approach to investigate the VISA phenotype in three prominent S. aureus lineages. All VISA clinical isolates tested had increased cell wall thickness compared with vancomycin-susceptible S. aureus strains. Growth rates of clonal complex (CC) 5, CC8, and CC45 clinical isolates were reduced in 2 µg/mL vancomycin compared to media alone. Culture in 2 and 4 µg/mL vancomycin sequentially for two weeks reduced susceptibility to daptomycin, televancin, tigecycline, and vancomycin in a majority of CC5, CC8, and CC45 isolates tested. We identified alleles reported previously to contribute to the VISA phenotype, but unexpectedly, these alleles were unique to each CC. A subtherapeutic concentration of vancomycin elicited changes in the VISA transcriptome-common and unique-among the three CCs tested. Multiple genes, including those encoding a glycerate kinase, an M50 family metallopeptidase, and an uncharacterized membrane protein, were upregulated among all three lineages and not reported previously as associated with VISA. Although there are lineage-specific changes in DNA sequence, our findings suggest changes in the VISA transcriptome constitute a general response to stress that confers reduced susceptibility to multiple antibiotics. IMPORTANCE: Our understanding of the mechanisms that underlie the development of vancomycin-intermediate Staphylococcus aureus (VISA) is incomplete. To provide a more comprehensive view of this process, we compared genome sequences of clonal complex (CC) 5, CC8, and CC45 VISA clinical isolates and measured changes in the transcriptomes of these isolates during culture with a subtherapeutic concentration of vancomycin. Notably, we identified differentially expressed genes that were lineage-specific or common to the lineages tested, including genes that have not been previously reported to contribute to a VISA phenotype. Changes in gene expression were accompanied by reduced growth rate, increased cell wall thickness, and reduced susceptibility to daptomycin, televancin, tigecycline, and vancomycin. Our results provide support to the idea that changes in gene expression contribute to the development of VISA among three CCs that are a prominent cause of human infections.

On Chemical Bonding in ht-Ga3Rh and Its Effect on Structural Organization and Thermoelectric Behavior.

In the course of systematic studies of intermetallic compounds Ga3TM (TM─transition metal), the compound Ga3Rh is synthesized by direct reaction of the elements at 700 °C. The material obtained is characterized as a high-temperature modification of Ga3Rh. Powder and single-crystal X-ray diffraction analyses reveal tetragonal symmetry (space group P42/mnm, No. 146) with a = 6.4808(2) Å and c = 6.5267(2) Å. Large values and strong anisotropy of the atomic displacement parameters of Ga atoms indicate essential disorder in the crystal structure. A split-position technique is applied to describe the real crystal structure of ht-Ga3Rh. Bonding analysis in ht-Ga3Rh performed on ordered models with the space groups P1̅, P42nm, and P42212 shows, besides the omnipresent heteroatomic Ga-Rh bonds in the rhombic prisms ∞3[Ga8/2Rh2], the formation of homoatomic Ga-Ga bonds bridging the Rh-Rh contacts and the absence of significant Rh-Rh bonding. These features are essential reasons for the experimentally observed disorder in the lattice. In agreement with the calculated electronic density of states, ht-Ga3Rh shows temperature-dependent electrical resistivity of a "bad metal". The very low lattice thermal conductivity of less than 0.5 W m-1 K-1 at 300 K, being lower than those for most other Ga3TM compounds, correlates with the enhanced bonding complexity.

Thoracic Stent Grafts Induce Persistent Aortic Remodeling in Aortic Coarctation.

BACKGROUND: This study's objective is to describe outcomes of adult patients who underwent thoracic stent graft placement treatment for primary or recurrent aortic coarctation. METHODS: This is a retrospective study of 30 adult patients who underwent thoracic stent graft placement for aortic coarctation at our institution. Average age was 46.5 years, with 53.3% of patients presented with no prior treatment or repair for coarctation. Indications for repair included gradient ≥20 mm Hg with anatomic evidence of coarctation on imaging with left ventricular hypertrophy, pseudoaneurysm, aneurysm, refractory hypertension, or claudication. Stent grafts used for repair included MDT (Medtronic, Santa Rosa, CA) and GORE TAG (W. L. Gore & Associates, Flagstaff, AZ). RESULTS: Patients were observed for a median of 979 days, with one death during the study. All patients had complete resolution of symptoms with no recurrences. Thoracic endovascular aortic repair significantly reduced the gradient across the coarctation (P < 0.0001). Aortic coarctation diameter significantly increased at 30 days postoperatively and continued to increase up to 5 years posttreatment. At 3+ years, aortic remodeling was observed at the coarctation site and surrounding regions. At 30 days, systolic, diastolic, and mean arterial pressure were all reduced. Systolic and diastolic blood pressure and mean arterial pressure continued to significantly improve 1-year posttreatment. CONCLUSIONS: Stent grafts are a safe and effective treatment for aortic coarctation. We observed a clinically significant improvement in blood pressure and longitudinal aortic remodeling of the coarctation segment and the entire aorta that persisted more than more than 3 years.

Optimizing extraction methods by a comprehensive experimental approach and characterizing polyphenol compositions of Ecklonia radiata.

Brown seaweed Ecklonia radiata harbors valuable polyphenols, notably phlorotannins, prized for their health benefits. This study optimized phlorotannin extraction via conventional solvent extraction and ultrasound-assisted extraction methods, utilizing variable concentrations of ethanol. Employing fractional factorial designs, key variables were identified. Steepest ascent/descent method and central composite rotatable designs refined optimal conditions, enhancing phlorotannin and polyphenol yields, and antioxidant capacities. Under optimized conditions, phlorotannin contents reached 2.366 ± 0.01 and 2.596 ± 0.04 PGE mg/g, total polyphenol contents peaked at 10.223 ± 0.03 and 10.836 ± 0.02 GAE mg/g. Robust antioxidant activity was observed: DPPH and OH radical scavenging capacities measured 27.891 ± 0.06 and 17.441 ± 0.08 TE mg/g, and 37.498 ± 1.12 and 49.391 ± 0.82 TE mg/g, respectively. Reducing power capacities surged to 9.016 ± 0.02 and 28.110 ± 0.10 TE mg/g. Liquid chromatography-mass spectrometry (LC-MS) and high-performance liquid chromatography (HPLC) analyses revealed enriched antioxidant compounds. Variations in polyphenol profiles were noted, potentially influencing antioxidant capacity nuances. This study illuminated the potential of E. radiata potential as a polyphenol source and offers optimized extraction methods poised to benefit various industries.

A Meta-Analysis of the Effects of Dietary Betaine on Milk Production, Growth Performance, and Carcass Traits of Ruminants.

Betaine improves growth performance and health in monogastric animals under both thermoneutral and heat stress conditions, but results in ruminants have been more equivocal. This meta-analysis investigated the effects of betaine supplementation on productive performance, milk production and composition, and carcass traits of ruminants due to betaine supplementation. A comprehensive search for published studies investigating the effect of betaine was performed using Google Scholar, ScienceDirect, PubMed, and Scopus databases. Effect size analysis, random effects models, I2 statistics, and meta-regression analysis were utilized to assess differences in production parameters. Dietary betaine supplementation increased milk yield (+1.0 kg/d (weighted mean differences presented in this abstract), p < 0.001), dry matter intake (+0.15 kg/d, p < 0.001), and milk lactose (+0.05%, p = 0.010) in dairy cows housed under thermoneutral conditions. In the few studies conducted on small ruminants, there was an increase in milk yield in response to dietary betaine (0.45 kg/d, p = 0.040). Under heat stress conditions or grazing pasture during summer, dietary betaine increased milk yield (+1.0 kg/d, p < 0.001) and dry matter intake (+0.21 kg/d, p = 0.020). Dietary betaine increased final liveweight (+2.33 kg, p = 0.050) and back fat thickness (+0.74 cm, p < 0.001) in beef cattle. Dietary betaine increased final liveweight (0.14 kg, p = 0.010), daily gain (+0.019 kg/d, p < 0.001), and carcass weight (+0.80 kg, p < 0.001) but not backfat in small ruminants. These meta-analyses showed that dietary betaine increases liveweight in small ruminants and beef cattle and increases feed intake and milk yield in dairy cattle.

Stress Affects Mast Cell Proteases in Murine Skin in a Model of Atopic Dermatitis-like Allergic Inflammation.

Stress exposure worsens allergic inflammatory diseases substantially. Mast cells (MCs) play a key role in peripheral immune responses to neuroendocrine stress mediators such as nerve growth factor (NGF) and substance P (SP). Mast cell proteases (MCPs) and cholinergic factors (Chrna7, SLURP1) were recently described to modulate MC stress response. We studied MCPs and Chrna7/SLURP1 and their interplay in a mouse model for noise induced stress (NiS) and atopic dermatitis-like allergic inflammation (AlD) and in cultured MC lacking Chrna7. We found that the cholinergic stress axis interacts with neuroendocrine stress mediators and stress-mediator cleaving enzymes in AlD. SP-cleaving mMCP4+ MC were upregulated in AlD and further upregulated by stress in NiS+AlD. Anti-NGF neutralizing antibody treatment blocked the stress-induced upregulation in vivo, and mMCP4+ MCs correlated with measures of AlD disease activity. Finally, high mMCP4 production in response to SP depended on Chrna7/SLURP1 in cultured MCs. In conclusion, mMCP4 and its upstream regulation by Chrna7/SLURP1 are interesting novel targets for the treatment of allergic inflammation and its aggravation by stress.

The Effect of One Year Aneurysm Sac Dynamics on Five Year Mortality and Continued Aneurysm Sac Evolution.

OBJECTIVE: One year aneurysm sac dynamics after endovascular abdominal aortic aneurysm repair (EVAR) were independently associated with greater risk of all-cause mortality in prior registry studies but were limited in completeness and granularity. This retrospective analysis aimed to study the impact of sac dynamics on survival within the Endurant Stent Graft Global Registry (ENGAGE) with five year follow up. METHODS: A total of 1 263 subjects were enrolled in the ENGAGE Registry between March 2009 and April 2011. One year aneurysm sac changes were calculated from one month post-operative imaging scans and the scan closest to the time of one year follow up. Sac regression was defined as a sac decrease of ≥ 5 mm and sac expansion as aneurysm sac growth ≥ 5 mm. The primary outcome was rate of five year all-cause mortality. Kaplan-Meier estimates for freedom from all-cause mortality were calculated. Multivariable Cox regression was used to determine the association between sac dynamics and all-cause mortality. RESULTS: At one year, 441 of the 949 study participants with appropriate imaging (46%) had abdominal aortic aneurysm sac regression, 462 (49%) remained stable, and 46 (4.8%) had sac expansion. For patients with sac regression, five year all-cause mortality was 20%, compared with 28% for stable sac (p = .007) and 37% for the sac expansion (p = .010) cohorts. After adjustment, sac expansion and stable sac cohorts were associated with greater all-cause mortality (expansion: hazard ratio [HR] 1.8; 95% CI 1.1 - 3.2; p = .032; stable: HR 1.4; 95% CI 1.1 - 1.9; p = .019). CONCLUSION: In the ENGAGE Global Registry, one year rate of sac regression was 46%, and one year sac regression was observed to be associated with greater five year survival, corroborating prior findings utilising data from vascular registries. Sac regression could become the new standard for success after EVAR.

Ischemic Stroke with Comorbid Cancer Has Specific miRNA-mRNA Networks in Blood That Vary by Ischemic Stroke Mechanism.

OBJECTIVE: Approximately half of ischemic strokes (IS) in cancer patients are cryptogenic, with many presumed cardioembolic. We evaluated whether there were specific miRNA and mRNA transcriptome architectures in peripheral blood of IS patients with and without comorbid cancer, and between cardioembolic versus noncardioembolic IS etiologies in comorbid cancer. METHODS: We studied patients with cancer and IS (CS; n = 42), stroke only (SO; n = 41), and cancer only (n = 28), and vascular risk factor-matched controls (n = 30). mRNA-Seq and miRNA-Seq data, analyzed with linear regression models, identified differentially expressed genes in CS versus SO and in cardioembolic versus noncardioembolic CS, and miRNA-mRNA regulatory pairs. Network-level analyses identified stroke etiology-specific responses in CS. RESULTS: A total of 2,085 mRNAs and 31 miRNAs were differentially expressed between CS and SO. In CS, 122 and 35 miRNA-mRNA regulatory pairs, and 5 and 3 coexpressed gene modules, were associated with cardioembolic and noncardioembolic CS, respectively. Complement, growth factor, and immune/inflammatory pathways showed differences between IS etiologies in CS. A 15-gene biomarker panel assembled from a derivation cohort (n = 50) correctly classified 81% of CS and 71% of SO participants in a validation cohort (n = 33). Another 15-gene panel correctly identified etiologies for 13 of 13 CS-cardioembolic and 11 of 11 CS-noncardioembolic participants upon cross-validation; 11 of 16 CS-cryptogenic participants were predicted cardioembolic. INTERPRETATION: We discovered unique mRNA and miRNA transcriptome architecture in CS and SO, and in CS with different IS etiologies. Cardioembolic and noncardioembolic etiologies in CS showed unique coexpression networks and potential master regulators. These may help distinguish CS from SO and identify IS etiology in cryptogenic CS patients. ANN NEUROL 2024.

Metabolomic and transcriptomic analyses of yellow-flowered crocuses to infer alternative sources of saffron metabolites.

BACKGROUND: The increasing demand for saffron metabolites in various commercial industries, including medicine, food, cosmetics, and dyeing, is driven by the discovery of their diverse applications. Saffron, derived from Crocus sativus stigmas, is the most expensive spice, and there is a need to explore additional sources to meet global consumption demands. In this study, we focused on yellow-flowering crocuses and examined their tepals to identify saffron-like compounds. RESULTS: Through metabolomic and transcriptomic approaches, our investigation provides valuable insights into the biosynthesis of compounds in yellow-tepal crocuses that are similar to those found in saffron. The results of our study support the potential use of yellow-tepal crocuses as a source of various crocins (crocetin glycosylated derivatives) and flavonoids. CONCLUSIONS: Our findings suggest that yellow-tepal crocuses have the potential to serve as a viable excessive source of some saffron metabolites. The identification of crocins and flavonoids in these crocuses highlights their suitability for meeting the demands of various industries that utilize saffron compounds. Further exploration and utilization of yellow-tepal crocuses could contribute to addressing the growing global demand for saffron-related products.

Hearing Impairment and Physical Activity and Physical Functioning in Older Adults: Baseline Results From the ACHIEVE Trial.

BACKGROUND: Hearing loss is associated with restricted physical activity (PA) and impaired physical functioning, yet the relationship between severity of hearing impairment (HI) and novel PA measures in older adults with untreated HI is not well understood. METHODS: Analyses included 845 participants aged ≥70 years (mean = 76.6 years) with a better-hearing ear pure-tone average (PTA) ≥30 and <70 dB in the Aging and Cognitive Health Evaluation in Elders (ACHIEVE) study who wore an ActiGraph accelerometer for 7 days. Physical functioning measures included grip strength and the Short Physical Performance Battery (SPPB). Linear regression models estimated the association by HI level (moderate or greater [PTA ≥ 40 dB] vs mild [PTA < 40 dB]) and continuous hearing with total daily activity counts, active minutes/day, activity fragmentation, grip strength, and gait speed. Logistic regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs) of poor performance on the SPPB (≤6) and its subtests (≤2). Mixed-effects models estimated differences by HI level in activity by time of day. RESULTS: Participants with moderate or greater HI had poorer physical functioning, particularly balance (OR = 2.17, 95% CI = 1.29-3.67), versus those with mild impairment. There was no association of HI level with activity quantities or fragmentation. For diurnal patterns of activity, participants with moderate or greater HI had fewer activity counts in the afternoon (12:00 pm -05:59 pm). CONCLUSIONS: Older adults with worse hearing had shifted diurnal patterns and poorer balance performance. Exercise programs should be tailored to older adults with different levels of HI to maintain PA and physical functioning, particularly balance control.