Identification of causal metabolites related to multiple autoimmune diseases.

Observational studies provide evidence that metabolites may be involved in the development of autoimmune diseases (ADs), but whether it is causal is still unknown. Based on the large-scale genome-wide association studies (GWAS) summary statistics, we performed two-sample Mendelian randomization (MR) to evaluate the causal associations between human blood metabolites and multiple ADs, which were inflammatory bowel disease (IBD), ulcerative colitis (UC), crohns disease (CD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), multiple sclerosis (MS), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). After Bonferroni adjustment, we identified 6 causal features of metabolites, i.e., glycerol 2-phosphate for T1D, hexadecanedioate, phenylacetylglutamine and laurylcarnitine for RA, glycine and arachidonate (20:4n6) for CD. Comprehensive sensitive analysis was further performed to validate the robustness of associations. We also observed some overlaps of metabolites among different ADs, implying similar or shared underlying mechanisms in such pathogenic processes. Multivariable MR analysis was then conducted to avoid potential pleiotropic effect of other complex traits. After controlling for several common traits, multivariable MR analysis ruled out most of potential pleiotropic effects and validated independence of identified metabolites. Finally, metabolic pathway analysis was performed based on suggestive metabolites for each AD respectively and a total of seven metabolic pathways were identified. In conclusion, this study provided novel insights into investigating causal role of blood metabolites in development of multiple ADs through a comprehensive genetic pathway.

Regioselective N-Trideuteromethylation of Tautomeric Polyaza Heterocycles.

Methods for regioselective N-trideuteromethylation of tautomeric polyaza heterocycles are highly sought-after. Disclosed herein is an N-trideuterated methylation reaction of imidazoles and pyrazoles with high regioselectivity and deuterium purity using easily available CF3SO3CD3 as the -CD3 source. This method enables the easy synthesis of important deuterium-labeled azoles, including dimetridazole-d3, ipronidazole-d3, hydroxy dimetridazole-d3, and ronidazole-d3.

Single Droplet Tweezer Revealing the Reaction Mechanism of Mn(II)-Catalyzed SO2 Oxidation.

Sulfate aerosol is one of the major components of secondary fine particulate matter in urban haze that has crucial impacts on the social economy and public health. Among the atmospheric sulfate sources, Mn(II)-catalyzed SO2 oxidation on aerosol surfaces has been regarded as a dominating one. In this work, we measured the reaction kinetics of Mn(II)-catalyzed SO2 oxidation in single droplets using an aerosol optical tweezer. We show that the SO2 oxidation occurs at the Mn(II)-active sites on the aerosol surface, per a piecewise kinetic formulation, one that is characterized by a threshold surface Mn(II) concentration and gaseous SO2 concentration. When the surface Mn(II) concentration is lower than the threshold value, the reaction rate is first order with respect to both Mn(II) and SO2, agreeing with our traditional knowledge. But when surface Mn(II) concentration is above the threshold, the reaction rate becomes independent of Mn(II) concentration, and the reaction order with respect to SO2 becomes greater than unity. The measured reaction rate can serve as a tool to estimate sulfate formation based on field observation, and our established parametrization corrects these calculations. This framework for reaction kinetics and parametrization holds promising potential for generalization to various heterogeneous reaction pathways.

Unraveling the relationship between high-sensitivity C-reactive protein and frailty: evidence from longitudinal cohort study and genetic analysis.

BACKGROUND: This study aimed to investigate the association of high-sensitivity C-reactive protein (hs-CRP) with incident frailty as well as its effects on pre-frailty progression and regression among middle-aged and older adults. METHODS: Based on the frailty index (FI) calculated with 41 items, 6890 eligible participants without frailty at baseline from China Health and Retirement Longitudinal Study (CHARLS) were categorized into health, pre-frailty, and frailty groups. Logistic regression models were used to estimate the longitudinal association between baseline hs-CRP and incident frailty. Furthermore, a series of genetic approaches were conducted to confirm the causal relationship between CRP and frailty, including Linkage disequilibrium score regression (LDSC), pleiotropic analysis, and Mendelian randomization (MR). Finally, we evaluated the association of hs-CRP with pre-frailty progression and regression. RESULTS: The risk of developing frailty was 1.18 times (95% CI: 1.03-1.34) higher in participants with high levels of hs-CRP at baseline than low levels of hs-CRP participants during the 3-year follow-up. MR analysis suggested that genetically determined hs-CRP was potentially positively associated with the risk of frailty (OR: 1.06, 95% CI: 1.03-1.08). Among 5241 participants with pre-frailty at baseline, we found pre-frailty participants with high levels of hs-CRP exhibit increased odds of progression to frailty (OR: 1.39, 95% CI: 1.09-1.79) and decreased odds of regression to health (OR: 0.84, 95% CI: 0.72-0.98) when compared with participants with low levels of hs-CRP. CONCLUSIONS: Our results suggest that reducing systemic inflammation is significant for developing strategies for frailty prevention and pre-frailty reversion in the middle-aged and elderly population.

Disruption of a kasB homolog gene (kasB) causes attenuation of cell invasion and virulence of Nocardia seriolae.

Nocardia seriolae is the primary aetiological agent of nocardiosis in fish, which causes mass mortality in freshwater and marine fish. ß-ketoacyl-ACP synthase (KAS) is one of the essential enzymes in the synthesis of mycolic acids (MASs) in Mycobacterium spp. and has been chosen as the target for therapeutic intervention in mycobacterial diseases. In the present study, a kasB homologue gene (kasB) was identified in the genome of N. seriolae, and the gene-deficient mutant (ΔkasB) was generated based on a clinical isolate, XSYC-Ns. Compared to the wild-type (WT) strain, the ΔkasB showed a measurably growth defect in vitro but retained the acid-fastness in acid-fast staining. Observation of the cell ultrastructure showed some alterations in the cell wall of the ΔkasB strain. Compared to its original strain, the cell wall lipid layer seemed sparser, and a wider electron-transparent zone was observed in the cell wall of ΔkasB strain. Moreover, the ΔkasB strain showed impaired ability of cell invasion as well as intracellular survival in the cell line originating from the head-kidney of the large yellow croaker (LYC-hK), compared to its original strain. In addition, the deficiency of ΔkasB significantly attenuated the virulence of N. seriolae in largemouth bass. The present study suggested that the ΔkasB gene might be involved in the synthesis of extracellular cell-wall lipids in N. seriolae and play a crucial role in its pathogenicity.

PKM2 is a Novel Osteoporosis-Associated Protein in Chinese.

Purpose:Osteoporosis is characterized by low bone mineral density (BMD) and high risk of osteoporotic fracture (OF). Peripheral blood monocytes (PBM) can differentiate into osteoclasts to resorb bone. This study was to identify PBM-expressed proteins significant for osteoporosis in Chinese Han elderly population (>65 years), and focused on two phenotypes of osteoporosis: low BMD and OF. METHODS: Label-free quantitative proteomics was employed to profile PBM proteome and to identify differentially expressed proteins (DEPs) between OF (N=27) vs. non-fractured (NF, N=24) subjects and between low BMD (N=12) vs. high BMD (N=12) subjects in women. Western blotting (WB) was conducted to validate differential expression, and ELISA to evaluate translational value for secretory protein of interest. RESULTS: We discovered 59 DEPs with fold change (FC)>1.3 (P<1×10-5), and validated the significant up-regulation of pyruvate kinase isozyme 2 (PKM2) with osteoporosis (P<0.001). PKM2 protein upregulation with OF was replicated with PBM in men (P=0.04). Plasma PKM2 protein level was significantly elevated with OF in an independent sample (N=100, FC=1.68, P=0.01). Pursuant functional assays showed that extracellular PKM2 protein supplement not only promoted monocyte trans-endothelial migration, growth, and osteoclast differentiation (marker gene expression), but also inhibited osteoblast growth, differentiation (ALP gene expression), and activity. CONCLUSION: The above findings suggest that PKM2 protein is a novel osteoporosis-associated functional protein in Chinese Han elderly population. It may serve as a risk biomarker and drug target for osteoporosis.

[ICOPE Evaluations and Promoting Health in Older Adults: A Chinese Medicine Perspective].

The Integrated Care for Old People (ICOPE) guidelines were developed by the World Health Organization. These guidelines address functional abilities in older adults in six intrinsic capacity domains, including cognitive decline, limited mobility, malnutrition, visual impairment, hearing loss, and depressive symptoms with the goal of improving their assessment and management. In this article, aging is interpreted from the perspective of Chinese medicine and guided by the theory of Yin Yang, the five elements, the six ICOPE domains, and the five organs (liver, heart, spleen, lungs, and kidneys). Huang Di Nei Jing's concept of disease prevention is proposed in a manner that corresponds to the three-stage preventive public health strategy for promoting health, delaying the effects of aging, and improving quality of life in older adults.

Rheumatoid arthritis and osteoporosis: shared genetic effect, pleiotropy and causality.

Rheumatoid arthritis (RA) is associated with increased localized and generalized bone loss, but the complex genetic mechanism between them is still unknown. By leveraging large-scale genome-wide association studies summary statistics and individual-level datasets (i.e. UK Biobank), a series of genetic approaches were conducted. Linkage disequilibrium score regression reveals a shared genetic correlation between RA and estimated bone mineral density (eBMD) (rg = -0.059, P = 0.005). The PLACO analysis has identified 74 lead (8 novel) pleiotropic loci that could be mapped to 99 genes, the genetic functions of which reveal the possible mechanism underlying RA and osteoporosis. In European, genetic risk score (GRS) and comprehensive Mendelian randomization (MR) were utilized to evaluate the causal association between RA and osteoporosis in European and Asian. The increase in GRS of RA could lead to a decrease of eBMD (beta = -0.008, P = 3.77E-6) and a higher risk of facture [odds ratio (OR) = 1.012, P = 0.044]. MR analysis identified that genetically determined RA was causally associated with eBMD (beta = -0.021, P = 4.14E-05) and fracture risk (OR = 1.036, P = 0.004). Similar results were also observed in Asian that osteoporosis risk could be causally increased by RA (OR = 1.130, P = 1.04E-03) as well as antibodies against citrullinated proteins-positive RA (OR = 1.083, P = 0.015). Overall, our study reveals complex genetic mechanism between RA and osteoporosis and provides strong evidence for crucial role of RA in pathogenesis of osteoporosis.

Afterglow Electrochemiluminescence from Nitrogen-Deficient Graphitic Carbon Nitride.

Almost all current electrochemiluminescent reagents require real-time electrochemical stimulation to emit light. Here, we report a novel electrochemiluminescent reagent, nitrogen-deficient graphitic carbon nitride (CNx), that can emit afterglow electrochemiluminescence (ECL) after cessation of electric excitation. CNx obtained by post-thermal treatment of graphitic carbon nitride (CN) with KSCN has a cyanamide group and a nitrogen vacancy, which created defects to trap electrically injected electrons. The trapped electrons can slowly release and react with coreactants to emit light with longevity. The cathodic afterglow ECL lasts for 70 s after pulsing the CNx nanosheet (CNxNS-1.6)-modified glassy carbon electrode at -1.0 V for 20 s in 2.0 M PBS containing 1 mM K2S2O8. The afterglow ECL mechanism is revealed by investigation of its influencing factors and ECL wavelength. The discovery of afterglow ECL may open a new doorway for new significant applications of the ECL technique and provide a deeper understanding of the structure-property relationships of CN.

A novel long non-coding RNA, lnc-RNU12, influences the T-cell cycle via c-JUN and CCNL2 in rheumatoid arthritis.

OBJECTIVES: Long non-coding RNAs (lncRNAs) play important roles in RA pathogenesis. However, specific lncRNAs that regulate gene expression in RA pathogenesis are poorly known. This study was undertaken to characterize a novel lncRNA (lnc-RNU12) that has a lower-than-normal expression level in RA patients. METHODS: We performed initial genome-wide lncRNA microarray screening in peripheral blood mononuclear cells from 28 RA cases and 18 controls. Multiple methods were used to validate the detected associations between lncRNAs and RA. Furthermore, we identified the source and characteristics of the highlighted lncRNAs, detected the target genes, and determined the functional effect on immune cells through lncRNA knock-down in Jurkat T cell lines. RESULTS: lnc-RNU12 was downregulated in peripheral blood mononuclear cells and T cell subtypes of RA patients and was genetically associated with RA risk. lnc-RNU12 mediates the effect of microbiome alterations on RA risk. Activation of T cells caused low expression of lnc-RNU12. Knock-down of lnc-RNU12 in Jurkat T cells caused cell cycle S-phase arrest and altered the expression of protein-coding genes related to the cell cycle and apoptosis (e.g. c-JUN, CCNL2, CDK6, MYC, RNF40, PKM, VPS35, DNAJB6 and FLCN). Finally, c-JUN and CCNL2 were identified as target genes of lnc-RNU12 at the mRNA and protein expression levels. RNA-binding protein immunoprecipitation assays verified the interaction between lnc-RNU12 and the two proteins (c-Jun and cyclin L2) in Jurkat cells. CONCLUSIONS: Our study suggested that lnc-RNU12 was involved in the pathogenesis of RA by influencing the T cell cycle by targeting c-JUN and CCNL2.

Implementation of a full-color holographic system using RGB-D salient object detection and divided point cloud gridding.

At present, a real objects-based full-color holographic system usually uses a digital single-lens reflex (DSLR) camera array or depth camera to collect data. It then relies on a spatial light modulator to modulate the input light source for the reconstruction of the 3-D scene of the real objects. However, the main challenges the high-quality holographic 3-D display faced were the limitation of generation speed and the low accuracy of the computer-generated holograms. This research generates more effective and accurate point cloud data by developing an RGB-D salient object detection model in the acquisition unit. In addition, a divided point cloud gridding method is proposed to enhance the computing speed of hologram generation. In the RGB channels, we categorized each object point into depth grids with identical depth values. The depth girds are divided into M × N parts, and only the effective parts will be calculated. Compared with traditional methods, the calculation time is dramatically reduced. The feasibility of our proposed approach is established through experiments.

Binocular full-color holographic three-dimensional near eye display using a single SLM.

A binocular full-color holographic three-dimensional near eye display system using a single spatial light modulator (SLM) is proposed. In the display system, the frequency spectrum shifting operation and color spectrum shifting operation are adopted to realize the frequency division multiplexing (FDM) and frequency superposition multiplexing (FSM) by manipulating the frequency spectrums of each color- and view-channel sub-holograms. The FDM combined with polarization multiplexing will be used to implement binocular display using a single SLM, and the FSM working with a bandpass filter for each view-channel will be used to achieve full-color display from single frame hologram. The optical analysis and experiments with 3D color objects confirm the feasibility of the proposed system in the practical application.

Role of WSOCs and pH on Ammonium Nitrate Aerosol Efflorescence: Insights into Secondary Aerosol Formation.

Efflorescence of ammonium nitrate (AN) aerosols significantly impacts atmospheric secondary aerosol formation, climate, and human health. We investigated the effect of representative water-soluble organic compounds (WSOCs) (sucralose (SUC), glycerol (GLY), and citric acid (CA) on AN:WSOC aerosol efflorescence using vacuum Fourier transform infrared spectroscopy. Combining efflorescence relative humidity (ERH) measurements, heterogeneous nucleation rates, and model predictions, we found that aerosol viscosity, correlating with molecular diffusion, effectively predicted ERH variations among the AN:WSOC aerosols. WSOCs with higher viscosity (SUC and CA) hindered efflorescence, while GLY with a lower viscosity showed a minor effect. At a low AN:CA molar ratio (10:1), CA promoted ERH, likely due to CA crystallization. Increasing the droplet pH inhibited AN:CA aerosol efflorescence. In contrast, for AN:SUC and AN:GLY aerosols, efflorescence is pH-insensitive. With the addition of trivial sulfate, AN:SUC droplets exhibited two-stage efflorescence, coinciding with ammonium sulfate and AN efflorescence. Given the atmospheric abundance, the morphology, phase, and mixing state of nitrate aerosols are significant for atmospheric chemistry and physics. Our results suggest that AN:WSOCs aerosols can exist in the amorphous phase in the atmosphere, with efflorescence behavior depending on the aerosol composition, viscosity, pH, and the cation and anion interactions in a complex manner.

A Middle Eocene lowland humid subtropical "Shangri-La" ecosystem in central Tibet.

Tibet's ancient topography and its role in climatic and biotic evolution remain speculative due to a paucity of quantitative surface-height measurements through time and space, and sparse fossil records. However, newly discovered fossils from a present elevation of ∼4,850 m in central Tibet improve substantially our knowledge of the ancient Tibetan environment. The 70 plant fossil taxa so far recovered include the first occurrences of several modern Asian lineages and represent a Middle Eocene (∼47 Mya) humid subtropical ecosystem. The fossils not only record the diverse composition of the ancient Tibetan biota, but also allow us to constrain the Middle Eocene land surface height in central Tibet to ∼1,500 ± 900 m, and quantify the prevailing thermal and hydrological regime. This "Shangri-La"-like ecosystem experienced monsoon seasonality with a mean annual temperature of ∼19 °C, and frosts were rare. It contained few Gondwanan taxa, yet was compositionally similar to contemporaneous floras in both North America and Europe. Our discovery quantifies a key part of Tibetan Paleogene topography and climate, and highlights the importance of Tibet in regard to the origin of modern Asian plant species and the evolution of global biodiversity.

The galU gene is required for in vivo survival of pseudomonas plecoglossicida in large yellow croaker (Larimichthys crocea).

Pseudomonas plecoglossicida is an important pathogenic bacterium in aquaculture that causes visceral granulomas in large yellow croaker (Larimichthys crocea). Uridine diphosphate glucose phosphorylase encoded by galU plays a key role in biosynthesis of the bacterial envelope, particularly lipopolysaccharide and the capsule. In this study, we inactivated the galU gene in the P. plecoglossicida isolate XSDHY-P. The galU mutant strain showed impaired growth in the early exponential stage and lacked the O polysaccharide side chain in lipopolysaccharide, but almost no defect in biofilm formation was detected. The galU mutant strain also exhibited significantly more sensitivity to the bactericidal action of normal fish serum mediated by the complement system compared to the wild-type strain. In a cell model originating from the head kidney of large yellow croaker, the galU mutant strain showed lower capacities of adhesion, invasion, and intracellular survival compared to the wild-type strain. In addition, the deficiency of the galU mutant drastically decreased bacterial loads in tissues and attenuated P. plecoglossicida virulence in fish. These results suggest that the galU gene of P. plecoglossicida is required for in vivo survival in large yellow croaker.

Establishment of reference intervals for bone turnover markers in healthy Chinese older adults.

BACKGROUND: Reference ranges for bone turnover markers (BTMs) are still lacking in the healthy Chinese population. AIM: To establish reference intervals for BTMs and to investigate the correlations between BTMs and bone mineral density (BMD) in Chinese older adults. SUBJECTS AND METHODS: A community-based cross-sectional study was conducted among 2511 Chinese subjects aged over 50 yrs residing in Zhenjiang, Southeast China. Reference intervals for BTMs (i.e. procollagen type I N-terminal propeptide, P1NP; ß cross-linked C-terminal telopeptide of type I collagen, ß-CTX) were calculated as the central 95% range of all measurements in Chinese older adults. RESULTS: The reference intervals of P1NP, ß-CTX and P1NP/ß-CTX were 15.8-119.9 ng/mL, 0.041-0.675 ng/mL and 49.9-1261.5 for females and 13.6-111.4 ng/mL, 0.038-0.627 ng/mL and 41.0-1269.1 for males, respectively. In the multiple linear regression analysis, only ß-CTX was negatively associated with BMD after adjusting for age and body mass index (BMI) in both sex-stratified groups (all p < .05). CONCLUSION: This study established age- and sex-specific reference intervals for BTMs in a large sample of healthy Chinese participants ≥ 50 and < 80 years of age and explored the correlations between BTMs and BMD, which provides an effective reference for the assessment of bone turnover in the clinical practice of osteoporosis.

Diagnostic Value of MRI Features in Dual-phenotype Hepatocellular Carcinoma: A Preliminary Study.

This study aimed to explore the magnetic resonance imaging (MRI) features of dual-phenotype hepatocellular carcinoma (DPHCC) and their diagnostic value.The data of 208 patients with primary liver cancer were retrospectively analysed between January 2016 and June 2021. Based on the pathological diagnostic criteria, 27 patients were classified into the DPHCC group, 113 patients into the noncholangiocyte-phenotype hepatocellular carcinoma (NCPHCC) group, and 68 patients with intrahepatic cholangiocarcinoma (ICC) were classified into the ICC group. Two abdominal radiologists reviewed the preoperative MRI features by a double-blind method. The MRI features and key laboratory and clinical indicators were compared between the groups. The potentially valuable MRI features and key laboratory and clinical characteristics for predicting DPHCC were identified by univariate and multivariate analyses, and the odds ratios (ORs) were recorded. In multivariate analysis, tumour without capsule (P = 0.046, OR = 9.777), dynamic persistent enhancement (P = 0.006, OR = 46.941), and targetoid appearance on diffusion-weighted imaging (DWI) (P = 0.021, OR = 30.566) were independently significant factors in the detection of DPHCC compared to NCPHCC. Serum alpha-fetoprotein (AFP) > 20 µg/L (P = 0.036, OR = 67.097) and prevalence of hepatitis B virus (HBV) infection (P = 0.020, OR = 153.633) were independent significant factors in predicting DPHCC compared to ICC. The differences in other tumour marker levels and imaging features between the groups were not significant. In MR enhanced and diffusion imaging, tumour without capsule, persistent enhancement and DWI targetoid findings, combined with AFP > 20 µg/L and HBV infection-positive laboratory results, can help to diagnose DPHCC and differentiate it from NCPHCC and ICC. These results suggest that clinical, laboratory and MRI features should be integrated to construct an AI diagnostic model for DPHCC.

The Effect of Physical Activity on Body Constitution and Psychological Health in Older Adults: Evidence From an Analysis of a Biobank Research Database.

This study aims to describe the relationship between physical activity, suboptimal health status based on traditional Chinese medicine, and psychological health in older people in Taiwan. A total of 4,497 older individuals were selected from the Taiwan Biobank Research Database. Suboptimal health status was assessed using a body constitution questionnaire to measure yang deficiency, yin deficiency, and stasis. The results showed that older adults involved in physical activity had a lower likelihood of yang/yin deficiency and stasis constitutions than physically inactive people. Participants with yang deficiency or stasis constitutions had a higher likelihood of poor psychological health, whereas those with yin deficiency had a greater likelihood of depression. People involved in physical activity had a lower likelihood of depression than physically inactive people. Compared with male older adults, females had a lower percentage of physical activity habits, poorer body constitutions, and poorer psychological health.

High-Throughput Preparation and High-Throughput Detection of Polymer-Dispersed Liquid Crystals Based on Ink-Jet Printing and Grayscale Value Analysis.

In this paper, based on high-throughput technology, polymer dispersed liquid crystals (PDLC) composed of pentaerythritol tetra (2-mercaptoacetic acid) (PETMP), trimethylolpropane triacrylate (TMPTA), and polyethylene glycol diacrylate (PEGD 600) were investigated in detail. A total of 125 PDLC samples with different ratios were quickly prepared using ink-jet printing. Based on the method of machine vision to identify the grayscale level of samples, as far as we know, it is the first time to realize high-throughput detection of the electro-optical performance of PDLC samples, which can quickly screen out the lowest saturation voltage of batch samples. Additionally, we compared the electro-optical test results of manual and high-throughput preparation PDLC samples and discovered that they had very similar electro-optical characteristics and morphologies. This demonstrated the viability of PDLC sample high-throughput preparation and detection, as well as promising application prospects, and significantly increased the efficiency of PDLC sample preparation and detection. The results of this study will contribute to the research and application of PDLC composites in the future.

Channel Modeling and Quantization Design for 3D NAND Flash Memory.

As the technology scales down, two-dimensional (2D) NAND flash memory has reached its bottleneck. Three-dimensional (3D) NAND flash memory was proposed to further increase the storage capacity by vertically stacking multiple layers. However, the new architecture of 3D flash memory leads to new sources of errors, which severely affects the reliability of the system. In this paper, for the first time, we derive the channel probability density function of 3D NAND flash memory by taking major sources of errors. Based on the derived channel probability density function, the mutual information (MI) for 3D flash memory with multiple layers is derived and used as a metric to design the quantization. Specifically, we propose a dynamic programming algorithm to jointly optimize read-voltage thresholds for all layers by maximizing the MI (MMI). To further reduce the complexity, we develop an MI derivative (MID)-based method to obtain read-voltage thresholds for hard-decision decoding (HDD) of error correction codes (ECCs). Simulation results show that the performance with jointly optimized read-voltage thresholds can closely approach that with read-voltage thresholds optimized for each layer, with much less read latency. Moreover, the MID-based MMI quantizer almost achieves the optimal performance for HDD of ECCs.