Aging induces region-specific dysregulation of hormone synthesis in the primate adrenal gland.

Adrenal glands, vital for steroid secretion and the regulation of metabolism, stress responses and immune activation, experience age-related decline, impacting systemic health. However, the regulatory mechanisms underlying adrenal aging remain largely uninvestigated. Here we established a single-nucleus transcriptomic atlas of both young and aged primate suprarenal glands, identifying lipid metabolism and steroidogenic pathways as core processes impacted by aging. We found dysregulation in centripetal adrenocortical differentiation in aged adrenal tissues and cells in the zona reticularis region, responsible for producing dehydroepiandrosterone sulfate (DHEA-S), were highly susceptible to aging, reflected by senescence, exhaustion and disturbed hormone production. Remarkably, LDLR was downregulated in all cell types of the outer cortex, and its targeted inactivation in human adrenal cells compromised cholesterol uptake and secretion of dehydroepiandrosterone sulfate, as observed in aged primate adrenal glands. Our study provides crucial insights into endocrine physiology, holding therapeutic promise for addressing aging-related adrenal insufficiency and delaying systemic aging.

Clinical characteristics and treatment patterns in patients with atherosclerotic cardiovascular disease with hypercholesterolemia: a retrospective analysis of a large US real-world database cohort.

OBJECTIVE: Guidelines developed by the American College of Cardiology/American Heart Association (ACC/AHA) recommend lipid-lowering therapies (LLTs) to reduce low-density lipoprotein cholesterol (LDL-C) and atherosclerotic cardiovascular disease (ASCVD) risk. This study described LLT utilization patterns and LDL-C goal achievement (to <70 mg/dL) among patients with ASCVD in the United States. METHODS: This retrospective study was conducted using Optum's de-identified Clinformatics Data Mart Database (CDM). Patients with their first ASCVD diagnosis (index date) in the CDM database between July 1, 2015, and December 31, 2018, were followed for ≥12 months to assess LLT utilization patterns and change in LDL-C. LLTs included were statins and non-statin LLTs (ezetimibe, fibrates, and proprotein convertase subtilisin/kexin type 9 inhibitors). Adherence was measured as the proportion of days covered (PDC), defined as the number of days with drug on-hand (or number of days exposed to drug) divided by the 12-month follow-up period. Patients with PDC ≥0.8 were considered adherent. RESULTS: Among the patients with ASCVD (N = 1,424,893) included in this study, only 621,978 (43.7%) had at least one LDL-C measurement at baseline (6 months prior to and 3 months after the index date). The mean age was 71.5 years, and almost half of the patients were female. Patients were followed for a mean (standard deviation [SD]) duration of 30.6 (11.4) months (median of 29.9 months). During the follow-up, about one-quarter of the patients did not receive any LLT. Among treated patients, 89.5% received statins and 10.5% received non-statin LLT. Less than half (47.6%) of the patients were adherent to the index treatment during the 12-month follow-up. Even in patients receiving combination therapy (statin + non-statin LLT), a sizable proportion (35.8%) showed an increase in LDL-C over the follow-up period. CONCLUSIONS: This retrospective study highlighted limited LDL-C monitoring in patients with ASCVD, and unmet need in terms of suboptimal utilization of non-stain LLTs, limited adherence to LLTs, and inadequate lipid control after treatment (among those with LDL-C measurements during the follow-up period) need to be addressed to improve outcomes in this patient cohort.

International societies of cardiologists recommend use of medications to lower the "bad" cholesterol, and its risk of cardiovascular diseases like stroke. We aimed to describe how those medications are being used and to what extent patients with cardiovascular diseases in the United States have their "bad" cholesterol under control. Results of this study indicate that cholesterol check-up among the patients was limited. Among recommended medications, statins were mostly used, whereas use of other recently approved medications was minimal. One-quarter of patients were not prescribed medications to control their cholesterol. Moreover, patients were not taking the medications as frequently as prescribed.

Regulating the Oxygen Vacancy and Electronic Structure of NiCo Layered Double Hydroxides by Molybdenum Doping for High-Power Hybrid Supercapacitors.

Amelioration of nickel-cobalt layered double hydroxides (NiCo-LDH) with a high specific theoretical capacitance is of great desire for high-power supercapacitors. Herein, a molybdenum (Mo) doping strategy is proposed to improve the charge-storage performance of NiCo-LDH nanosheets growing on carbon cloth (CC) via a rapid microwave process. The regulation of the electronic structure and oxygen vacancy of the LDH is consolidated by the density functional theory (DFT) calculation, which demonstrates that Mo doping narrows the band gap, reduces the formation energy of hydroxyl vacancies, and promotes ionic and charge transfer as well as electrolyte adsorption on the electrode surface. The optimal Mo-doped NiCo-LDH electrode (MoNiCo-LDH-0.05/CC) has an amazing specific capacity of 471.1 mA h g-1 at 1 A g-1 , and excellent capacity retention of 84.8% at 32 A g-1 , far superior to NiCo-LDH/CC (258.3 mA h g-1 and 76.4%). The constructed hybrid supercapacitor delivers an energy density of 103.3 W h kg-1 at a power density of 750 W kg-1 and retains the cycle retention of 85.2% after 5000 cycles. Two assembled devices in series can drive thirty LED lamps, revealing a potential application prospect of the rationally synthesized MoNiCo-LDH/CC as an energy-storage electrode material.

SGF29 nuclear condensates reinforce cellular aging.

Phase separation, a biophysical segregation of subcellular milieus referred as condensates, is known to regulate transcription, but its impacts on physiological processes are less clear. Here, we demonstrate the formation of liquid-like nuclear condensates by SGF29, a component of the SAGA transcriptional coactivator complex, during cellular senescence in human mesenchymal progenitor cells (hMPCs) and fibroblasts. The Arg 207 within the intrinsically disordered region is identified as the key amino acid residue for SGF29 to form phase separation. Through epigenomic and transcriptomic analysis, our data indicated that both condensate formation and H3K4me3 binding of SGF29 are essential for establishing its precise chromatin location, recruiting transcriptional factors and co-activators to target specific genomic loci, and initiating the expression of genes associated with senescence, such as CDKN1A. The formation of SGF29 condensates alone, however, may not be sufficient to drive H3K4me3 binding or achieve transactivation functions. Our study establishes a link between phase separation and aging regulation, highlighting nuclear condensates as a functional unit that facilitate shaping transcriptional landscapes in aging.

An engineered cascade-sensitized red-emitting upconversion nanoplatform with a tandem hydrophobic hydration-shell and metal-phenolic network decoration for single 808 nm triggered simultaneous tumor PDT and PTT enhanced CDT.

Near-infrared light (NIR) driven lanthanide-doped upconversion nanoparticle (UCNP) based photo-dynamic therapy (PDT) holds a great promise for the non-invasive treatment of deep-seated tumors. However, it has also been highly hindered by the low upconversion luminescence (UCL) efficiency, hypoxia nature of solid tumors, and low therapeutic efficiency using single modality. Herein, we present a novel Nd3+ → Yb3+ → Tm3+ → Er3+ cascade-sensitized red-emitting UCNP with tandem hydrophobic hydration-shell (HHS) and metal-phenolic network (Fe-tannic acid, Fe-TA) decoration (UCNP@HHS@Fe-TA, denoted as UCFS@Fe-TA) for single 808 nm triggered simultaneous tumor PDT and photothermal therapy (PTT) enhanced chemo-dynamic therapy (CDT). The UCNP can supply intense red emission under high tissue penetrating/minimized tissue overheating 808 nm excitation, and their HHS coating with perfluorocarbon/photosensitizer Ce6 co-doping can not only realize UCL-based PDT, but also strengthen PDT of as-formed UCFS via O2-carrying/UCL protection capacity of the HHS. Fe-TA coating can supply 808 nm triggered PTT, and the rise in temperature during PTT leads to enhanced Fenton catalytic activity of Fe-TA and faster ˙OH production rate of CDT to match with the real-timely released 1O2 in PDT. The as-designed UCFS@Fe-TA thus can achieve a single 808 nm triggered simultaneous PDT and PTT enhanced CDT, leading to a PTT-assisted reactive oxygen species storm for efficient tumor suppression. Such a design also renders the nanoplatform lower cell dark toxicity. In addition, the single excitation-triggered multimodal therapy mode might address the excitation wavelength mismatch issue in dual laser-triggered PTT/PDT mode. This study has therefore presented an efficient nanotherapeutic platform enabling synergistic multimodal tumor therapies with high biocompatibility.

Biomarkers of aging.

Aging biomarkers are a combination of biological parameters to (i) assess age-related changes, (ii) track the physiological aging process, and (iii) predict the transition into a pathological status. Although a broad spectrum of aging biomarkers has been developed, their potential uses and limitations remain poorly characterized. An immediate goal of biomarkers is to help us answer the following three fundamental questions in aging research: How old are we? Why do we get old? And how can we age slower? This review aims to address this need. Here, we summarize our current knowledge of biomarkers developed for cellular, organ, and organismal levels of aging, comprising six pillars: physiological characteristics, medical imaging, histological features, cellular alterations, molecular changes, and secretory factors. To fulfill all these requisites, we propose that aging biomarkers should qualify for being specific, systemic, and clinically relevant.

Hierarchical core-shell nickel hydroxide@nitrogen-doped hollow carbon spheres composite for high-performance hybrid supercapacitor.

Designing electrode materials with high performance and maximum utilization is of great desire for supercapacitors, which highly depend on the intrinsic electrochemical properties and the optimal frameworks of the electrode materials. The hierarchical core-shell structure with various types of pores can make the most of the electrode material due to the easy access of electrolyte into the interior electrode and large exposure of electrode into the electrolyte. In this work, nickel hydroxide@nitrogen-doped hollow carbon spheres (Ni(OH)2@NHCSs) electrode material with a hierarchical core-shell structure was obtained using a hard template and the following chemical-precipitation method. Ni(OH)2@NHCSs electrode displays an excellent specific capacity of 214.8 mA h g-1 (that is 1546.6 F g-1), higher than the Ni(OH)2 counterpart (108.9 mA h g-1, that is 784.1 F g-1) at 1 A g-1 in 2 M KOH electrolyte. The assembled Ni(OH)2@NHCSs||NHCSs hybrid supercapacitor (HSC) delivers an energy density of 37.5 W h kg-1 at 800.0 W kg-1 and an outstanding stability with 79.2% of retention rate for 10,000 cycles at a current density of 8 A g-1. The Ni(OH)2@NHCSs electrode exhibits excellent electrochemical performance primarily contributed by its unique hierarchical core-shell structure, high specific surface area and enhanced electrical conductivity.

Large-scale chromatin reorganization reactivates placenta-specific genes that drive cellular aging.

Nuclear deformation, a hallmark frequently observed in senescent cells, is presumed to be associated with the erosion of chromatin organization at the nuclear periphery. However, how such gradual changes in higher-order genome organization impinge on local epigenetic modifications to drive cellular mechanisms of aging has remained enigmatic. Here, through large-scale epigenomic analyses of isogenic young, senescent, and progeroid human mesenchymal progenitor cells (hMPCs), we delineate a hierarchy of integrated structural state changes that manifest as heterochromatin loss in repressive compartments, euchromatin weakening in active compartments, switching in interfacing topological compartments, and increasing epigenetic entropy. We found that the epigenetic de-repression unlocks the expression of pregnancy-specific beta-1 glycoprotein (PSG) genes that exacerbate hMPC aging and serve as potential aging biomarkers. Our analyses provide a rich resource for uncovering the principles of epigenomic landscape organization and its changes in cellular aging and for identifying aging drivers and intervention targets with a genome-topology-based mechanism.

Usage of long-acting muscarinic antagonists and biologics as add-on therapy for patients in the United States with moderate-to-severe asthma.

Many asthma patients remain uncontrolled on inhaled corticosteroids (ICS) and long-acting beta agonists (LABAs), but guidance for selecting add-on therapies, including long-acting muscarinic antagonists (LAMAs) or biologics, is limited. We describe how prescribing practices for add-on LAMA and biologic therapy have changed with increased treatment options and revised treatment guidelines. We further identify differences in treatment initiation and discontinuation rates by patient characteristics, including concomitant COPD.This retrospective cohort study analyzed insurance claims in the IBM Marketscan database for adult US asthma patients treated with medium- or high-dose ICS/LABA between 2012 and 2019 (n = 277,373). We used negative binomial regression models to evaluate LAMA and biologic initiation rates and their association with patient characteristics, and survival analysis methods for assessing discontinuation rates.Between 2012 and 2019, LAMA and biologic uptake increased approximately 5-fold and 20-fold, respectively. LAMA initiation was significantly higher among patients with concomitant COPD, a group typically unstudied in clinical trials, versus those with asthma only (rate ratio of 5.90, 95% CI: 5.76-6.04). High-dose ICS/LABA treatment and the need for oral corticosteroid (OCS) bursts had stronger associations with biologic initiation. Probability of discontinuation (i.e. non-persistence) in the first year was 40.5% and 22.7% for those initiating LAMAs and biologics, respectively, with higher LAMA discontinuation rates among patients with asthma only versus those with concomitant COPD.Our results provide insights into how clinicians apply treatment guidelines for initiating add-on LAMA and biologic therapies in moderate-to-severe asthma patients and highlight patients who have an unmet treatment need after discontinuation.

Real-world data on the incidence, mortality, and cost of ischaemic stroke and major bleeding events among non-valvular atrial fibrillation patients in England.

RATIONALE, AIMS, AND OBJECTIVES: Several novel oral anticoagulants (NOACs) are licensed for atrial fibrillation (AF) treatment in the United Kingdom. We describe the incidence and mortality from ischaemic stroke and major bleeding in non-valvular atrial fibrillation (NVAF) patients in England, including treatment patterns before/following introduction of NOACs, healthcare resource utilization (HRU), and costs post-onset of these events. METHOD: Data were extracted from the UK Clinical Practice Research Datalink linked to Hospital Episode Statistics secondary care and Office for National Statistics mortality data. RESULTS: Of 42 966 patients with a first AF record between 2011 and 2016, 9143 patients (21.3%) remained without AF (antiplatelets/antithrombotics) treatment post-index diagnosis. The proportion of patients receiving aspirin for ≥3 months post-index declined during the study (50.6%-5.5%), irrespective of CHA2 DS2 -VASc score, while the proportion prescribed NOACs increased (2.0%-70.1%). Rates of ischaemic stroke per 1000 patient-years (95% CI) were 9.4 (3.8-15.0) with NOACs, 10.4 (8.0-12.9) with warfarin, 20.1 (16.4-23.8) with aspirin, 21.3 (5.3-37.2) with other antiplatelets and 43.6 (39.3-47.8) in patients without AF prescription. Major bleeding occurred at a similar rate with different treatments. All-cause mortality rates were 42.8 (31.4-54.3) with NOACs, 46.3 (41.1-51.5) with warfarin, 56.5 (50.5-62.4) with aspirin, 102.2 (76.2-128.3) with other antiplatelets and 412.8 (399.6-426.0) with no AF prescription. Mean annual National Health Service healthcare costs up to 1 year post-index were lowest in patients receiving aspirin plus other antiplatelets without an event (£6152), and highest in patients with an event without AF prescriptions (£17 957). By extrapolation, national AF HRU in the United Kingdom in 2016 was estimated at £8-16 billion annually. CONCLUSIONS: These data provide temporal insights into AF treatment patterns and outcomes for NVAF patients in England and highlight the need to review higher stroke risk AF patients not receiving antiplatelet/antithrombotic prescriptions.

Long noncoding RNA-GAS5 attenuates progression of glioma by eliminating microRNA-10b and Sirtuin 1 in U251 and A172 cells.

Long noncoding RNA (lncRNA) growth arrest-specific 5 (GAS5) is implicated in several cancers via modulating microRNAs (miRs). However, little information is available about the correlation between GAS5 and miR-10b. Therefore, we sought out to investigate the biological role of GAS5-miR-10b node mainly in glioma cells. We artificially modulated GAS5 to explore its roles in viability assayed by cell counting kit-8 (CCK-8), motile activities by 24-Transwell assay, as well as apoptosis by a flow cytometer and Western blot assay. miR-10b and Sirtuin 1 (Sirt1) were quantified by qRT-PCR. After co-transfection, we analyzed the viability, migration, invasion, apoptosis, and Sirt1 expression. Western blot was implemented to detect the phosphorylated forms of PTEN, PI3K, AKT, MEK, and ERK. GAS5 inhibited proliferation and motile behaviors, and fortified apoptosis. As for the viability and motile activities, the property of GAS5 was reversed in miR-10b-replenished U251 and A172 cells, while maintained in miR-10b-deficient cells. Additionally, GAS5-induced apoptosis was abolished by miR-10b overexpression while fortified by miR-10b silence. Besides, GAS5 negatively modulated Sirt1 via miR-10b. Moreover, Sirt1 negatively modulated PTEN and positively mediated the abovementioned regulators. GAS5 represses the process of glioma cells by decreasing miR-10b, which as accompanied by Sirt1 silence-induced inactivation of PTEN/PI3K/AKT and MEK/ERK cascades.

Treatment Patterns in Patients with Incident Parkinson's Disease in the United States.

BACKGROUND: Treatment patterns in Parkinson's disease (PD) have not been extensively studied for nearly two decades. Insurance claims are appropriate for such analysis. OBJECTIVE: To understand the standard of care use of symptomatic treatments in new cases of PD and factors associated with treatment choice. METHODS: Retrospective cohort study using claims data from the United States between 2008 and 2016. We used Kaplan-Meier methodology to estimate time to treatment start and switch or add-on therapy and Cox proportional hazards models to identify predictors. RESULTS: We identified 68,532 patients eligible for treatment pattern analyses. Median time from diagnosis until first treatment was 37 days (95% confidence interval: 36-38). Two distinct patterns of treatment initiation were identified: fast initiators and patients with delayed treatment start (or no recorded treatment). Levodopa therapies were the most commonly prescribed treatment class (52.6%). Increased age was associated with shorter time to start of treatment with levodopa. Younger age was associated with shorter time to initiation of dopamine agonists and other symptomatic treatments. Patients that initiated treatment with levodopa/combinations had the fewest switches/add-ons [30.4%; median time 7.29 (6.71, 8.13) years]. Older patients had fewer switch/add-on therapies, but only in the group that started with levodopa/combination therapy. CONCLUSIONS: Time from diagnosis to treatment start was relatively short, suggesting that PD diagnosis, as reflected in the database, is closely linked to start of symptomatic treatment. Levodopa treatment remains the most common treatment, especially for older patients. Delayed treatment start was associated with increased age and comorbidity.

[EFFECTIVENESS OF REPAIRING OR RECONSTRUCTING DEFECTS OF FOREFOOT].

METHODS: Between February 2006 and February 2013, 57 patients with defects of the forefoot were treated. There were 41 males and 16 females with an average age of 38.9 years (range, 19-68 years). The disease causes included motor vehicles crush injury in 28 cases, crashing injury in 17 cases, and machine extrusion injury in 12 cases. The left side was involved in 25 cases and the right side in 32 cases, with a mean disease duration of 4.7 hours (range, 0.5-75.0 hours). Defect located at the 1st metatarsus in 9 cases, at the 5th metatarsus in 8 cases, at the 1st and the 2nd metatarsus in 16 cases, at the 4th and 5th metatarsus in 11 cases, at multiple metatarsus and the forefoot in 13 cases. The bone defect ranged from 2.5 cm x 1.9 cm x 1.4 cm to 13.3 cm x 11.2 cm x 2.7 cm. The soft tissue defect ranged from 12.4 cm x 6.3 cm to 27.2 cm x 18.7 cm. The iliac bone or vascularized iliac bone or vascularized fibula bone was used to rebuild the arch of the foot, and free flap was used to repair defects of the forefoot. The donor site was sutured directly or covered with skin graft. RESULTS: Venous crisis and partial necrosis occurred in 3 and 2 flaps respectively, which healed after symptomatic treatment. The other flaps and grafted skins survived, and wounds healed primarily. Fifty-one cases were followed up 1.5-2.5 years (mean, 2.1 years). The appearance was excellent and the feeling of the flap recovered at different levels. The two-point discrimination was 8.4-19.8 mm (mean, 13.7 mm) at 1.5 years after operation. According to upper extremity functional evaluation standard by hand surgery branch of Chinese Medical Association, sensation recovered to 52 in 6 cases, to 53 in 18 cases, and to 54 in 27 cases. The patients began to walk with weight loading at 2-6 months after operation (mean, 3.9 months). The bone healing time was 3-6 months (mean, 4.2 months). Based on American Orthopaedic Foot and Ankle Society (AOFAS) standards, the results were excellent in 19 cases, good in 24 cases, fair in 7 case, and poor in 1 case, and the excellent and good rate was 84.3%. CONCLUSION: It is a good solution to treat defects of the forefoot to use iliac bone or vascularized iliac bone or vascularized fibula bone for rebuilding the arch of the foot and use free flap for repairing defect.

Morbidity and medication in a large population of individuals with Down syndrome compared to the general population.

AIM: The aim of this study was to describe the incidence of morbidities and the prevalence of medical prescriptions in a large Down syndrome population. METHOD: A retrospective cohort study was carried out using the UK Clinical Practice Research Datalink from 1 January 2004 to 31 December 2013. We matched individuals with Down syndrome to randomly selected control participants by practice site, sex, birth year, and recording period. RESULTS: A total of 6430 individuals with Down syndrome (3009 females, 3421 males) and 19 176 controls (8966 females, 10,210 males) were included in the study. The incidence of cardiovascular disorders, gastrointestinal diseases (incidence rate ratio [IRR] 7.9 at 3 to <6y: yearly prevalence ratio [YPR] for laxatives 4.7), and sleeping disorders (IRR 4.8 in 3 to <6y) was increased in children with Down syndrome versus control participants. New onset of congenital heart malformation, ear diseases, eye disorders, autism, hypothyroidism, diabetes, and obesity were more frequent in childhood and remained elevated in adulthood (overall IRR 35.5, 1.7, 3.1, 4.4, 13.1, 1.3, and 2.6 respectively), whereas the gap widened in adulthood for epilepsy and intellectual disability (IRR 15.2 and 158 respectively, in participants older than 30y). At ≥ 30 years, the incidence of hypotension and dementia was raised (IRR 3.0 and 92.1 respectively; YPR for dementia drugs: 76.3); and that of hypertension, depression and anxiety was lowered (IRR 0.2, 0.5, and 0.4 respectively). INTERPRETATION: The profile of newly occurring morbidities in Down syndrome varies across the developmental lifespan.

Facile synthesis of peptidyl salicylaldehyde esters and its use in cyclic peptide synthesis.

An efficient solid phase synthetic protocol for salicylaldehyde ester peptides is reported. With a Ser or Thr at the N-terminus, these salicylaldehyde ester peptides can be easily converted to Ser/Thr containing cyclic peptides.