Abstract
Background
To evaluate the global burden of cataracts by year, age, region, gender, and socioeconomic status using disability-adjusted life years (DALYs) and prevalence from the Global ...Burden of Disease (GBD) study 2019.
Methods
Global, regional, or national DALY numbers, crude DALY rates, and age-standardized DALY rates caused by cataracts, by year, age, and gender, were obtained from the Global Burden of Disease Study 2019. Socio-demographic Index (SDI) as a comprehensive indicator of the national or regional development status of GBD countries in 2019 was obtained from the GBD official website. Kruskal-Wallis test, linear regression, and Pearson correlation analysis were performed to explore the associations between the health burden with socioeconomic levels, Wilcoxon Signed-Rank Test was used to investigate the gender disparity.
Results
From 1990 to 2019, global DALY numbers caused by cataracts rose by 91.2%, crude rates increased by 32.2%, while age-standardized rates fell by 11.0%. Globally, age-standardized prevalence and DALYs rates of cataracts peaked in 2017 and 2000, with the prevalence rate of 1283.53 95% uncertainty interval (UI) 1134.46–1442.93 and DALYs rate of 94.52 (95% UI 67.09–127.24) per 100,000 population, respectively. The burden was expected to decrease to 1232.33 (95% UI 942.33–1522.33) and 91.52 (95% UI 87.11–95.94) by 2050. Southeast Asia had the highest blindness rate caused by cataracts in terms of age-standardized DALY rates (99.87, 95% UI: 67.18–144.25) in 2019. Gender disparity has existed since 1990, with the female being more heavily impacted. This pattern remained with aging among different stages of vision impairments and varied through GBD super regions. Gender difference (females minus males) of age-standardized DALYs (equation: Y = -53.2*X + 50.0,
P
< 0.001) and prevalence rates (equation: Y = − 492.8*X + 521.6,
P
< 0.001) was negatively correlated with SDI in linear regression.
Conclusion
The global health of cataracts is improving but the steady growth in crude DALY rates suggested that health progress does not mean fewer demands for cataracts. Globally, older age, females, and lower socioeconomic status are associated with higher cataract burden. The findings of this study highlight the importance to make gender-sensitive health policies to manage global vision loss caused by cataracts, especially in low SDI regions.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Alzheimer's disease (AD) is characterized by profound synapse loss and impairments of learning and memory. Magnesium affects many biochemical mechanisms that are vital for neuronal properties and ...synaptic plasticity. Recent studies have demonstrated that the serum and brain magnesium levels are decreased in AD patients; however, the exact role of magnesium in AD pathogenesis remains unclear. Here, we found that the intraperitoneal administration of magnesium sulfate increased the brain magnesium levels and protected learning and memory capacities in streptozotocin-induced sporadic AD model rats. We also found that magnesium sulfate reversed impairments in long-term potentiation (LTP), dendritic abnormalities, and the impaired recruitment of synaptic proteins. Magnesium sulfate treatment also decreased tau hyperphosphorylation by increasing the inhibitory phosphorylation of GSK-3β at serine 9, thereby increasing the activity of Akt at Ser473 and PI3K at Tyr458/199, and improving insulin sensitivity. We conclude that magnesium treatment protects cognitive function and synaptic plasticity by inhibiting GSK-3β in sporadic AD model rats, which suggests a potential role for magnesium in AD therapy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Recent advances in wireless communication technologies and auto-mobile industry have triggered a significant research interest in the field of vehicular ad-hoc networks (VANETs) over the past few ...years. A vehicular network consists of vehicle-to-vehicle (V2V) and vehicle-to-infrastructure (V2I) communications supported by wireless access technologies such as IEEE 802.11p. This innovation in wireless communication has been envisaged to improve road safety and motor traffic efficiency in near future through the development of intelligent transportation system (ITS). Hence, governments, auto-mobile industries and academia are heavily partnering through several ongoing research projects to establish standards for VANETs. The typical set of VANET application areas, such as vehicle collision warning and traffic information dissemination have made VANET an interesting field of mobile wireless communication. This paper provides an overview on current research state, challenges, potentials of VANETs as well as the ways forward to achieving the long awaited ITS.
The cholinergic impairment is an early marker in Alzheimer's disease (AD), while the mechanisms are not fully understood. We investigated here the effects of glycogen synthase kinse‐3 (GSK‐3) ...activation on the cholinergic homoeostasis in nucleus basalis of Meynert (NBM) and frontal cortex, the cholinergic enriched regions. We activated GSK‐3 by lateral ventricular infusion of wortmannin (WT) and GF‐109203X (GFX), the inhibitors of phosphoinositol‐3 kinase (PI3‐K) and protein kinase C (PKC), respectively, and significantly decreased the acetylcholine (ACh) level via inhibiting choline acetyl transferase (ChAT) rather than regulating acetylcholinesterase (AChE). Neuronal axonal transport was disrupted and ChAT accumulation occurred in NBM and frontal cortex accompanied with hyperphosphorylation of tau and neurofilaments. Moreover, ChAT expression decreased in NBM attributing to cleavage of nuclear factor‐κB/p100 into p52 for translocation into nucleus to lower ChAT mRNA level. The cholinergic dysfunction could be mimicked by overexpression of GSK‐3 and rescued by simultaneous administration of LiCl or SB216763, inhibitors of GSK‐3. Our data reveal the molecular mechanism that may underlie the cholinergic impairments in AD patients.
Aims
This study aims to develop and verify a physiologically based pharmacokinetic (PBPK) population model for the Chinese geriatric population in Simcyp.
Methods
Firstly, physiological information ...for the Chinese geriatric population was collected and later employed to develop the Chinese geriatric population model by recalibration of corresponding physiological parameters in the Chinese adult population model available in Simcyp (i.e., Chinese healthy volunteer model). Secondly, drug‐dependent parameters were collected for six drugs with different elimination pathways (i.e., metabolized by CYP1A2, CYP3A4 or renal excretion). The drug models were then developed and verified by clinical data from Chinese adults, Caucasian adults and Caucasian elderly subjects to ensure that drug‐dependent parameters are correctly inputted. Finally, the tested drug models in combination with the newly developed Chinese geriatric population model were applied to simulate drug concentration in Chinese elderly subjects. The predicted results were then compared with the observations to evaluate model prediction performance.
Results
Ninety‐eight per cent of predicted AUC, 95% of predicted Cmax, and 100% of predicted CL values were within two‐fold of the observed values, indicating all drug models were properly developed. The drug models, combined with the newly developed population model, were then used to predict pharmacokinetics in Chinese elderly subjects aged 60–93. The predicted AUC, Cmax, and CL values were all within two‐fold of the observed values.
Conclusion
The population model for the Chinese elderly subjects appears to adequately predict the concentration of the drug that was metabolized by CYP1A2, CYP3A4 or eliminated by renal clearance.
Depression is known to be one of the most common mental disorders raising global concerns. However, evidence regarding the association between short-term air pollution exposure and risk of ...development of depression is limited. The aim of this was to assess the relationship between short-term ambient air pollution exposure and depression in outpatient visits in Xi'an, a northwestern Chinese metropolis. Data for air pollutants including particulate matter (PM
10
), sulfur dioxide (SO
2
), and nitrogen dioxide (NO
2
) levels from October 1, 2010 to December 31, 2013 and number of daily depression outpatient visits (92,387 in total) were collected. A time-series quasi-Poisson regression model was adopted to determine the association between short-term air pollutant concentrations and frequency of outpatient visits for depression with different lag models. Consequently, 10 μg/m
3
increase of SO
2
and NO
2
levels corresponded to significant elevation in number of outpatient-visits for depression on concurrent days (lag 0), and this relationship appeared stronger in cool seasons (October to March). However, the association of PM
10
was only significant in males aged 30-50 at lag 0. Evidence indicated that short-term exposure to ambient air pollutants especially in cool seasons might be associated with increased risk of outpatient visits for depression.
Abstract
Background
Autophagy dysfunction plays a crucial role in tau accumulation and neurodegeneration in Alzheimer’s disease (AD). This study aimed to investigate whether and how the accumulating ...tau may in turn affect autophagy.
Methods
The primary hippocampal neurons, N2a and HEK293T cells with tau overexpression were respectively starved and treated with vinblastine to study the effects of tau on the initiating steps of autophagy, which was analysed by Student's two-tailed
t
-test. The rapamycin and concanamycin A were employed to inhibit the mammalian target of rapamycin kinase complex 1 (mTORC1) activity and the vacuolar H
+
-ATPase (v-ATPase) activity, respectively, which were analysed by One‐way ANOVA with post hoc tests. The Western blotting, co-immunoprecipitation and immunofluorescence staining were conducted to gain insight into the mechanisms underlying the tau effects of mTORC1 signaling alterations, as analysed by Student's two-tailed
t
-test or One‐way ANOVA with post hoc tests. The autophagosome formation was detected by immunofluorescence staining and transmission electron microscopy. The amino acids (AA) levels were detected by high performance liquid chromatography (HPLC).
Results
We observed that overexpressing human full-length wild-type tau to mimic AD-like tau accumulation induced autophagy deficits. Further studies revealed that the increased tau could bind to the prion-related domain of T cell intracellular antigen 1 (PRD-TIA1) and this association significantly increased the intercellular level of amino acids (Leucine,
P
= 0.0038; Glutamic acid,
P
= 0.0348; Alanine,
P
= 0.0037; Glycine,
P
= 0.0104), with concordant upregulation of mTORC1 activity phosphorylated eukaryotic translation initiation factor 4E-binding protein 1 (p-4EBP1),
P
< 0.0001; phosphorylated 70 kDa ribosomal protein S6 kinase 1 (p-p70S6K1),
P
= 0.0001, phosphorylated unc-51-like autophagy-activating kinase 1 (p-ULK1),
P
= 0.0015 and inhibition of autophagosome formation microtubule-associated protein light chain 3 II (LC3 II),
P
= 0.0073; LC3 puncta,
P
< 0.0001. As expected, this tau-induced deficit of autophagosome formation in turn aggravated tau accumulation. Importantly, we also found that blocking TIA1 and tau interaction by overexpressing PRD-TIA1, downregulating the endogenous TIA1 expression by shRNA, or downregulating tau protein level by a small proteolysis targeting chimera (PROTAC) could remarkably attenuate tau-induced autophagy impairment.
Conclusions
Our findings reveal that AD-like tau accumulation inhibits autophagosome formation and induces autophagy deficits by activating the TIA1/amino acid/mTORC1 pathway, and thus this work reveals new insight into tau-associated neurodegeneration and provides evidence supporting the use of new therapeutic targets for AD treatment and that of related tauopathies.
Magnetic nanoparticles (MNPs) chelating with metal ions can specifically interact with poly-histidine peptides and facilitate immobilization and purification of proteins with poly-histidine tags. ...Fabrication of MNPs is generally complicated and time consuming. In this paper, we report the preparation of Ni(
ii
) ion chelated MNPs (Ni-MNPs) in two stages for protein immobilization and purification. In the first stage, organic ligands including pentadentate tris (carboxymethyl) ethylenediamine (TED) and tridentate iminodiacetic acid (IDA) and inorganic Fe
3
O
4
-SiO
2
MNPs were synthesized separately. In the next stage, ligands were grafted to the surface of MNPs and MNPs with a TED or IDA modified surface were acquired, followed by chelating with Ni(
ii
) ions. The Ni(
ii
) ion chelated forms of MNPs (Ni-MNPs) were characterized including morphology, surface charge, structure, size distribution and magnetic response. Taking a his-tagged glycoside hydrolase DspB (Dispersin B) as the protein representative, specific interactions were confirmed between DspB and Ni-MNPs. Purification of his-tagged DspB was achieved with Ni-MNPs that exhibited better performance in terms of purity and activity of DspB than commercial Ni-NTA. Ni-MNPs as enzyme carriers for DspB also exhibited good compatibility and reasonable reusability as well as improved performance in various conditions.
This article reports a novel approach for synthesizing magnetic nanoparticles with a modified surface for purification and immobilization of histidine-tagged proteins.
Aging‐related alterations in hepatic enzyme activity, particularly of the CYP3A, significantly impact drug efficacy and safety in older adults, making it essential to understand how aging affects CYP ...function for optimal drug therapy. The exogenous probe substrate method, a minimally invasive approach to assess liver metabolic enzyme activity in vivo , is effective in studying these changes. Amlodipine being extensively metabolized (> 90%) in the liver, primarily via cytochrome P450 enzyme CYP3A was selected as a probe to investigate and quantify the factors affecting the aging‐related changes of CYP3A in the Chinese older population. Amlodipine concentration data were collected from an ongoing noninterventional clinical study conducted at Peking University Third Hospital. A physiologically‐based pharmacokinetic modeling approach, grounded in population pharmacokinetic (PPK) analysis, was employed to physiologically quantify the aging‐related changes in CYP3A function. A total of 132 amlodipine concentrations from 69 patients were obtained from the clinical study. PPK analysis shows that frailty phenotype but not age is a significant influence and frail patients have 37% greater plasma amlodipine exposure than nonfrail patients. This difference in CYP3A function may be attributed to a 63.2% lower CYP3A relative abundance in the frail patients, compared with that in the nonfrail patients. In the context of dose selection for older adults, focusing on frailty rather than chronological age should be recognized as a more relevant approach, because frailty might more accurately reflect the individual's biological age. Our study suggested a need to shift the research focus from chronological age to biological age.
Weak fault detection of rolling bearing presents difficult, because the periodic transient signature produced via localized incipient damage is easily submerged by various interference components and ...background noise. Hybrid intelligent fusion method is a breakthrough strategy for revealing feature frequency of rolling bearing fault by comprehensively using a variety of intelligent signal processing technologies, possessing the advantage of each technology. Considering the rolling bearing often construct a transmission device combination with gear and shaft, its vibration signal is often vulnerable to other multi-morphology components, such as harmonic modulation, noise. Thus, how to identify the fault frequency in repetitive transients is crucial to accurately identify rolling bearing fault detection. To address this issue, a novel hybrid intelligent method is proposed to effectively apply on periodic transients extraction, enhancement and rolling bearing fault diagnosis. The innovation of this method is to solve three problems, namely, the separation of multi-morphology components, noise reduction without periodic transients distortion, weak fault frequency enhancement. The proposed method is tested and validated on simulated signal, rolling bearing fault signal from accelerated rolling bearing degradation rig. In addition, comparisons with other classical rolling bearing fault detection methods have been conducted to highlight the superiority of the proposed methodology.
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