Long non-coding RNAs (lncRNAs) are emerging as novel diagnostic markers of prostate cancer (PCa) and new determinants of castration-resistant PCa (CRPC), an aggressive and metastatic form of PCa. In ...addition to androgen receptor (AR) signaling, neuroendocrine differentiation (NED) is associated with CRPC. Recent reports demonstrate that the downregulation of repressor element-1 silencing transcription factor (REST) protein is a key step in NED of PCa cells. Here, we report HOTAIR as a novel REST-repressed lncRNA that is upregulated in NED PCa cells and in CRPC. HOTAIR overexpression is sufficient to induce, whereas knockdown of HOTAIR suppressed NED of PCa cells. Gene ontology (GO) analysis of differentially expressed genes under HOTAIR overexpression and in CRPC versus benign prostatic hyperplasia (BPH) suggests that HOTAIR may participate in PCa progression. Taken together, our results provide the first evidence of lncRNA HOTAIR as a driver for NED of PCa cells.
•LncRNA HOTAIR is a novel target of REST.•HOTAIR is upregulated in CRPC during progression.•HOTAIR is a novel driver for NED of PCa cells.
Objective. We aimed to establish a method to determine whether microRNA-193b (miR-193b) levels in ABCA1-labeled serum exosomes might serve as a marker for the diagnosis of Alzheimer’s disease. ...Methods. We used immunocapture methods to determine the levels of ABCA1-labeled exosomal miR-193b in cultures of white blood cells (WBCs), red blood cells (RBCs), mouse hippocampal neuron HT-22 cells, and primary mouse neuronal cells. ABCA1-labeled exosomal miR-193b levels were also evaluated in the cerebrospinal fluid (CSF) and serum of APP/PS1 double-transgenic mice, as well as control subjects (n=60) and study participants with subjective cognitive decline (SCD, n=89), stage and mild cognitive impairment (MCI, n=92), and dementia of the Alzheimer type (DAT, n=92). Results. ABCA1 levels of exosomes harvested from the medium of HT-22 cells and neurons were significantly higher than those of RBCs and WBCs (P<0.05). Exosomal ABCA1 from the CSF of APP/PS1 mice were transmitted to the serum of wild-type mice after injection, and high miR-193b levels were observed in both the serum and CSF after injection. The ABCA1-labeled exosomal miR-193b levels were higher in the CSF of MCI and DAT patients compared with the CSF of the control group (P<0.05). The ABCA1-labeled exosomal miR-193b were also slightly higher (P>0.05) in the serum of SCD patients and significantly higher in the serum of MCI and DAT patients compared with the serum of the control group (P<0.05). Conclusion. This study provides a method to capture specific exosomes. Detection of serum exosomes labeled with ABCA1 may facilitate the early diagnosis of AD.
MicroRNAs (miRs) are attractive molecules to be considered as one of the blood-based biomarkers for neurodegenerative disorders such as Alzheimer's disease (AD). The goal of this study was to explore ...their potential value as biomarkers for the diagnosis of AD.
The expression levels of exosomal miR−135a, −193b, and −384 in the serum from mild cognitive impairment (MCI), dementia of Alzheimer-type (DAT), Parkinson's disease with dementia (PDD), and vascular dementia (VaD) patients were measured with a real-time quantitative reverse transcriptase PCR (qRT-PCR) method.
Both serum exosome miR-135a and miR-384 were up-regulated while miR-193b was down-regulated in serum of AD patients compared with that of normal controls. Exosome miR-384 was the best among the three miRs to discriminate AD, VaD, and PDD. Using the cut-off value could better interpret these laboratory test results than reference intervals in the AD diagnosis. ROC curve showed that the combination of miR−135a, −193b, and −384 was proved to be better than a particular one for early AD diagnosis.
Our results indicated that the exosomal miRs in the serum were not only potential biomarker of AD early diagnosis, but might also provide novel insights into the screen and prevention of the disease.
Sparse representation-based classifier (SRC), a combined result of machine learning and compressed sensing, shows its good classification performance on face image data. However, SRC could not well ...classify the data with the same direction distribution. The same direction distribution means that the sample vectors belonging to different classes distribute on the same vector direction. This paper presents a new classifier, kernel sparse representation-based classifier (KSRC), based on SRC and the kernel trick which is a usual technique in machine learning. KSRC is a nonlinear extension of SRC and can remedy the drawback of SRC. To make the data in an input space separable, we implicitly map these data into a high-dimensional kernel feature space by using some nonlinear mapping associated with a kernel function. Since this kernel feature space has a very high (or possibly infinite) dimensionality, or is unknown, we have to avoid working in this space explicitly. Fortunately, we can indeed reduce the dimensionality of the kernel feature space by exploiting kernel-based dimensionality reduction methods. In the reduced subspace, we need to find sparse combination coefficients for a test sample and assign a class label to it. Similar to SRC, KSRC is also cast into an ℓ 1 -minimization problem or a quadratically constrained ℓ 1 -minimization problem. Extensive experimental results on UCI and face data sets show KSRC improves the performance of SRC.
Primary cilium is a specialized sensory organelle that transmits environmental information into cells. Its length is tightly controlled by various mechanisms such as the frequency or the cargo size ...of the intraflagellar transport trains which deliver the building materials such as tubulin subunits essential for the growing cilia. Here, we show the sialoglycan interacting galectin 8 regulates the process of primary ciliogenesis. As the epithelia become polarized, there are more galectin 8 being apically secreted and these extracellular galectin 8 molecules apparently bind to a lipid raft enriched domain at the base of the primary cilia through interacting with lipid raft components, such as GD3 ganglioside and scaffold protein caveolin 1. Furthermore, the binding of galectin 8 at this critical region triggers rapid growth of primary cilia by perturbing the barrier function of the transition zone (TZ). Our study also demonstrates the functionality of this barrier depends on intact organization of lipid rafts at the cilia as genetically knockout of Cav1 and pharmacologically inhibition of lipid raft both phenocopy the effect of apical addition of recombinant galectin 8; that is, rapid elongation of primary cilia and redistribution of cilia proteins from TZ to the growing axoneme. Indeed, as cilia elongated, endogenous galectin 8, caveolin 1, and TZ component, TMEM231, also transited from the TZ to the growing axoneme. We also noted that the interaction between caveolin 1 and TMEM231 could be perturbed by exogenous galectin 8. Taken together, we proposed that galectin 8 promoted primary cilia elongation through impeding the barrier function of the TZ by interfering with the interaction between caveolin 1 and TMEM231.
The transition zone (TZ) serves as a diffusion barrier for ciliary transport and constitutes a region on the ciliary membrane enriched in both ganglioside and lipid raft scaffold proteins such as caveolin 1 (Cav1). During ciliogenesis, extracellular galectin 8 (Gal8) accumulates at TZ presumably through its interaction with sialylated oligosaccharide such as GD3 and Cav1 to promote primary cilia elongation by perturbing the balanced interaction between Cav1 and TZ component transmembrane protein 231 (TMEM231).
Amyloid precursor protein (APP) has an important function in the generation of Alzheimer's disease (AD). In our previous study, miR-193b was found to be downregulated in the hippocampi of 9-month-old ...APP/PS1 double-transgenic mice using microRNA (miR) array. In the present study, bioinformatic analyses showed that miR-193b was a miR that was predicted to potentially target the 3′-untranslated region (UTR) of APP. Subsequently, the function of miR-193b on APP was studied. The levels of miR-193b, exosomal miR-193b, Aβ, tau, p-tau, HCY and APOE in samples from APP/PS1 double-transgenic mice, mild cognitive impairment (MCI) and dementia of Alzheimer-type (DAT) patients, were measured. The results indicated that overexpression of miR-193b could repress the mRNA and protein expression of APP. The miR-193b inhibitor oligonucleotide induced upregulation of APP. Binding sites of miR-193b in the 3′-UTR of APP were identified by luciferase assay. MCI and DAT patients had lower exosomal miR-193b, but not total miR-193b, in the blood as compared with the controls. DAT patients had lower exosomal miR-193b levels in blood as compared with the MCI group. A decreased exosomal miR-193b expression level was additionally observed in the cerebral spinal fluid (CSF) of DAT patients. Negative correlations were found between exosomal miR-193b and Aβ42 in the CSF of DAT patients. In conclusion, these findings showed that miR-193b may function in the development of AD and exosomal miR-193b has potential as a novel, non-invasive, blood-based biomarker of MCI and DAT patients.
Amyloid precursor protein (APP) and beta -site amyloid precursor protein cleaving enzyme (BACE-1) play important roles in the generation of Alzheimer's disease (AD), a progressive neurodegenerative ...disorder. In the present study, microRNA (miR) microarray was used to analyze the miR expression profiles in the hippocampi from APP/PS1 transgenic and wild type mice. The miRs with significant alteration and putative targets on APP or BACE-1 were retrieved (miR-135a, -200b and -429). The deregulations of these miRs were confirmed in mice and further verified in AD patient samples by qPCR. Primary mouse hippocampal neurons, SH-SY5Y and HEK293 cells were used to study the function of miRs on APP and BACE-1. We found that miR-135a, which was downregulated significantly in hippocampi from APP/PS1 transgenic mice compared with the wild type control, directly interacted with the 3'-UTR of BACE-1 and repressed its expression and activity. On the other hand, miR-200b and -429, which were downregulated significantly in hippocampi from APP/PS1 transgenic mice compared with the wild type control, targeted the 3'-UTR of APP and repressed its expression. Furthermore, A beta 42 could downregulate miR-200b expression which may generate a vicious cycle resulted in accumulating A beta 42. The levels of miR-135a and -200b in the serum of DAT group were significantly lower than that of control groups (P<0.05). The serum miR-200b level of MCI group was higher than that of DAT group (P<0.05) and lower than that of control group (P<0.05). We also found decreased miR-135a and -200b levels in the cerebrospinal fluid of DAT group compared with the control group (P<0.05). In conclusion, these findings showed that miR-135a, -200b and -429 may take part in the progress of AD; miR-200b was of great potential as noninvasive and easily detected blood-based biomarkers of MCI and DAT patients.
IMI Prevention of Myopia and Its Progression Jonas, Jost B; Ang, Marcus; Cho, Pauline ...
Investigative ophthalmology & visual science,
04/2021, Volume:
62, Issue:
5
Journal Article
Peer reviewed
Open access
The prevalence of myopia has markedly increased in East and Southeast Asia, and pathologic consequences of myopia, including myopic maculopathy and high myopia-associated optic neuropathy, are now ...some of the most common causes of irreversible blindness. Hence, strategies are warranted to reduce the prevalence of myopia and the progression to high myopia because this is the main modifiable risk factor for pathologic myopia. On the basis of published population-based and interventional studies, an important strategy to reduce the development of myopia is encouraging schoolchildren to spend more time outdoors. As compared with other measures, spending more time outdoors is the safest strategy and aligns with other existing health initiatives, such as obesity prevention, by promoting a healthier lifestyle for children and adolescents. Useful clinical measures to reduce or slow the progression of myopia include the daily application of low-dose atropine eye drops, in concentrations ranging between 0.01% and 0.05%, despite the side effects of a slightly reduced amplitude of accommodation, slight mydriasis, and risk of an allergic reaction; multifocal spectacle design; contact lenses that have power profiles that produce peripheral myopic defocus; and orthokeratology using corneal gas-permeable contact lenses that are designed to flatten the central cornea, leading to midperipheral steeping and peripheral myopic defocus, during overnight wear to eliminate daytime myopia. The risk-to-benefit ratio needs to be weighed up for the individual on the basis of their age, health, and lifestyle. The measures listed above are not mutually exclusive and are beginning to be examined in combination.
A power efficient reconfigurable output-capacitorless (OCL) low-drop-out (LDO) voltage regulator for low-power analog sensing front-end is proposed in this paper. This LDO consists of a floating-gate ...nMOS pass transistor, an adaptively biased error amplifier, and capacitive circuits for voltage reference generation and for feedback sensing. The error amplifier adopts a class-AB input differential pair and an adaptively biased regulated cascode topology to improve transient response under the stringent constraint of low quiescent current consumption. The reference voltage is implemented by programming charges on capacitors without employing a bandgap circuit. A prototype chip is designed and fabricated in a 0.35 μm CMOS process to demonstrate the reconfigurability and to validate the performance. The output voltage can be programmed in continuum in the range of 1.2 V to 2.5 V with measured temperature coefficients less than 45 ppm/°C. The maximum load current is designed to be 1 mA with output voltage drop less than 0.1%. With programmable quiescent current levels less than 1 μA, the current efficiency is higher than 99.9%. From measurements, the line regulation is 0.17 mV/V or -75 dB. The designed OCL LDO remains stable with maximum output load capacitance up to 1 nF under the zero load condition.
This study investigates the causes of interannual-to-interdecadal variability of the East Asian (EA; 0°–60°N, 100°–140°E) winter monsoon (EAWM) over the past 50 yr (1957–2006). The winter mean ...surface air temperature variations are dominated by two distinct principal modes that together account for 74%of the total temperature variance. The two modes have notably different circulation structures and sources of variability. The northern mode, characterized by a westward shift of the EA major trough and enhanced surface pressure over central Siberia, represents a cold winter in the northern EA resulting from cold-air intrusion from central Siberia. The southern mode, on the other hand, features a deepening EA trough and increased surface pressure over Mongolia, representing a cold winter south of 40°N resulting from cold-air intrusion from western Mongolia. The cold northern mode is preceded by excessive autumn snow covers over southern Siberia–Mongolia, whereas the cold southern mode is preceded by development of La Niña episodes and reduced snow covers over northeast Siberia. These remarkably different spatiotemporal structures and origins are primarily associated with interannual variations. On the decadal or longer time scale their structures are somewhat similar and are preceded by similar autumn sea surface temperature anomalies over the North Atlantic and tropical Indian Ocean. The two modes found for the EA region also represent the winter temperature variability over the entire Asian continent. Thus, study of the predictability of the two modes may shed light on understanding the predictable dynamics of the Asian winter monsoon.
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