Pathologic TDP-43 downregulates myelin gene expression in the monkey brain.

Growing evidence indicates that non-neuronal oligodendrocyte plays an important role in Amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. In patient's brain, the impaired myelin structure is a pathological feature with the observation of TDP-43 in cytoplasm of oligodendrocyte. However, the mechanism underlying the gain of function by TDP-43 in oligodendrocytes, which are vital for the axonal integrity, remains unclear. Recently, we found that the primate-specific cleavage of truncated TDP-43 fragments occurred in cytoplasm of monkey neural cells. This finding opened up the avenue to investigate the myelin integrity affected by pathogenic TDP-43 in oligodendrocytes. In current study, we demonstrated that the truncated TDP-35 in oligodendrocytes specifically, could lead to the dysfunctional demyelination in corpus callosum of monkey. As a consequence of the interaction of myelin regulatory factor with the accumulated TDP-35 in cytoplasm, the downstream myelin-associated genes expression was downregulated at the transcriptional level. Our study aims to investigate the potential effect on myelin structure injury, affected by the truncated TDP-43 in oligodendrocyte, which provided the additional clues on the gain of function during the progressive pathogenesis and symptoms in TDP-43 related diseases.

Risk of secondary immune thrombocytopenia following alemtuzumab treatment for multiple sclerosis: a systematic review and meta-analysis.

Object: The purpose of this study was to evaluate the risk of secondary immune thrombocytopenia in multiple sclerosis patients treated with alemtuzumab through a meta-analysis. Methods: We searched databases including PubMed, Web of Science, OVID and EMBASE for studies reporting changes in platelet levels in MS patients treated with alemtuzumab from their inception until May 2023 and performed a meta-analysis. Information and data were screened and extracted by two researchers. The inclusion and exclusion criteria were established according to the PICOS principle. The obtained data were analyzed using the R software meta package and the quality assessment was conducted using Newcastle-Ottawa Scale (NOS). The causes of heterogeneity were analyzed using subgroup analysis and sensitivity analysis. Publication bias was evaluated using funnel plots and Egger test. Results: A total of 15 studies were included, encompassing 1,729 multiple sclerosis patients. Meta-analysis of overall secondary ITP in the included studies yielded a pooled rate of 0.0243. The overall incidence of secondary autoimmune events was 0.2589. In addition, subgroup analysis was applied using study regions and study types. The results showed that the incidence rate of secondary ITP in Europe was about 0.0207, while the incidence of autoimmune events (AEs) was 0.2158. The incidence rate of secondary ITP and AEs in North America was significantly higher than in Europe, being 0.0352 and 0.2622. And the analysis showed that the incidence rates of secondary ITP and AEs in prospective studies were 0.0391 and 0.1771. Retrospective studies had an incidence rate of secondary ITP at 2.16, and an incidence rate of AEs at 0.2743. Conclusion: This study found that there was a certain incidence of Immune thrombocytopenia in multiple sclerosis patients after treatment with alemtuzumab. Alemtuzumab may have some interference with platelet levels, and the mechanism may be associated with Treg cells. But due to the absence of a control group in the included literature, we cannot determine the specific impact of Alemtuzumab on platelet levels in patients with MS. Therefore, clinical physicians should perform a comprehensive assessment of the patient's benefit-to-risk ratio before initiating alemtuzumab. Systematic Review Registration: Inplasy website, DOI number is 10.37766/inplasy2024.3.0007.

A biological age model based on physical examination data to predict mortality in a Chinese population.

Biological age could be reflective of an individual's health status and aging degree. Limited estimations of biological aging based on physical examination data in the Chinese population have been developed to quantify the rate of aging. We developed and validated a novel aging measure (Balanced-AGE) based on readily available physical health examination data. In this study, a repeated sub-sampling approach was applied to address the data imbalance issue, and this approach significantly improved the performance of biological age (Balanced-AGE) in predicting all-cause mortality with a 10-year time-dependent AUC of 0.908 for all-cause mortality. This mortality prediction tool was found to be effective across different subgroups by age, sex, smoking, and alcohol consumption status. Additionally, this study revealed that individuals who were underweight, smokers, or drinkers had a higher extent of age acceleration. The Balanced-AGE may serve as an effective and generally applicable tool for health assessment and management among the elderly population.

Refractive index adjustable intraocular lens design to achieve diopter control for improving the treatment of ametropia after cataract surgery.

Intraocular lens (IOL) implantation is currently the most effective clinical treatment for cataracts. Nevertheless, due to the growth of the eye axis in patients with congenital cataracts during the process of growth and development, the progressive incapacity of an IOL with a fixed focus does not meet the demands of practical usage, leading to the occurrence of ametropia. This work describes an innovative class of an IOL bulk material that offers good biosafety and light-controlled refractive index adjustment. Acrylate materials were synthesized for the preparation of IOLs by free radical polymerization of ethylene glycol phenyl ether methacrylate (EGPEMA), hydrophilic monomer 2-(2-ethoxyethoxy) ethyl acrylate (EA), and functional monomer hydroxymethyl coumarin methacrylate (CMA). Under 365/254 nm ultraviolet (UV) irradiation, the coumarin group could adjust the polymer material's refractive index through reversible photoinduced dimerization/depolymerization. Meanwhile, the potential for the IOL use is enabled by its satisfactory biosafety. Such a light-induced diopter adjustable IOL will be more appropriate for implantation during cataract surgery since it will not require the correction needed for ametropia and will offer more accurate and humane treatment. STATEMENT OF SIGNIFICANCE.

Polydopamine based photothermal/photodynamic synchronous coating modified intraocular lens for efficient and safer posterior capsule opacification prevention.

Posterior capsule opacification (PCO), as one of the most common late complications after intraocular lens (IOL) implantation in cataract surgery, seriously affects patients' postoperative vision and surgical satisfaction, and can only be treated by laser incision of the posterior capsule. Although drug eluting coating modification have been proved to inhibit PCO effectively, the complicated coating methods and the potential toxicity of the antiproliferative drugs hinders its actual application. In this study, an indocyanine green (ICG) loaded polydopamine (PDA) coating modified IOL (IP-IOL) was designed to prevented PCO. In vitro and in vivo studies have shown that IP-IOL can effectively eliminate lens epithelial cells and significantly reduce the degree of PCO. At the same time, it still has good imaging quality and optical properties. Furthermore, both the near-infrared irradiation and ICG loaded PDA coating modified IOLs have proved to possess high biological safety to eyes. Thus, with easy preparation and safer near-infrared irradiated photothermal/photodynamic synchronous properties, such ICG loaded PDA coating provides an effective yet easier and safer PCO prevention after IOL implantation.

Loss of TDP-43 mediates severe neurotoxicity by suppressing PJA1 gene transcription in the monkey brain.

The nuclear loss and cytoplasmic accumulation of TDP-43 (TAR DNA/RNA binding protein 43) are pathological hallmarks of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Previously, we reported that the primate-specific cleavage of TDP-43 accounts for its cytoplasmic mislocalization in patients' brains. This prompted us to investigate further whether and how the loss of nuclear TDP-43 mediates neuropathology in primate brain. In this study, we report that TDP-43 knockdown at the similar effectiveness, induces more damage to neuronal cells in the monkey brain than rodent mouse. Importantly, the loss of TDP-43 suppresses the E3 ubiquitin ligase PJA1 expression in the monkey brain at transcriptional level, but yields an opposite upregulation of PJA1 in the mouse brain. This distinct effect is due to the species-dependent binding of nuclear TDP-43 to the unique promoter sequences of the PJA1 genes. Further analyses reveal that the reduction of PJA1 accelerates neurotoxicity, whereas overexpressing PJA1 diminishes neuronal cell death by the TDP-43 knockdown in vivo. Our findings not only uncover a novel primate-specific neurotoxic contribution to the loss of function theory of TDP-43 proteinopathy, but also underscore a potential therapeutic approach of PJA1 to the loss of nuclear TDP-43.

Comparing HD knockin pigs and mice reveals the pathological role of IL-17.

Our previous work has established a knockin (KI) pig model of Huntington's disease (HD) that can replicate the typical pathological features of HD, including selective striatal neuronal loss, reactive gliosis, and axonal degeneration. However, HD KI mice exhibit milder neuropathological phenotypes and lack overt neurodegeneration. By performing RNA sequencing to compare the gene expression profiles between HD KI pigs and mice, we find that genes related to interleukin-17 (IL-17) signaling are upregulated in the HD pig brains compared to the mouse brains. Delivery of IL-17 into the brain striatum of HD KI mice causes greater reactive gliosis and synaptic deficiency compared to HD KI mice that received PBS. These findings suggest that the upregulation of genes related to IL-17 signaling in HD pig brains contributes to severe glial pathology in HD and identify this as a potential therapeutic target for treating HD.

Application of diffusion tensor imaging in the diagnosis of post-stroke aphasia: a meta-analysis and systematic review.

Introduction: Diffusion Tensor Imaging (DTI) indicators of different white matter (WM) fibers and brain region lesions for post-stroke aphasia (PSA) are inconsistent in existing studies. Our study examines the consistency and differences between PSA tests performed with DTI. In addition, obtaining consistent and independent conclusions between studies was made possible by utilizing DTI in PSA assessment. Methods: In order to gather relevant studies using DTI for diagnosing PSA, we searched the Web of Science, PubMed, Embase, and CNKI databases. Based on the screening and evaluation of the included studies, the meta-analysis was used to conduct a quantitative analysis. Narrative descriptions were provided for studies that met the inclusion criteria but lacked data. Results: First, we reported on the left hemisphere. The meta-analysis showed that fractional anisotropy (FA) of the arcuate fasciculus (AF) and superior longitudinal fasciculus (SLF), inferior frontal-occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), and uncinate fasciculus (UF) were decreased in the PSA group in comparison with the healthy controls (p < 0.00001). However, in the comparison of axial diffusivity (AD), there was no statistically significant difference in white matter fiber tracts in the dual-stream language model of the PSA group. Elevated radial diffusivity (RD) was seen only in the IFOF and ILF (PIFOF = 0.01; PILF = 0.05). In the classic Broca's area, the FA of the PSA group was decreased (p < 0.00001) while the apparent diffusion coefficient was elevated (p = 0.03). Secondly, we evaluated the white matter fiber tracts in the dual-stream language model of the right hemisphere. The FA of the PSA group was decreased only in the IFOF (p = 0.001). AD was elevated in the AF and UF (PAF < 0.00001; PUF = 0.009). RD was elevated in the AF and UF (PAF = 0.01; PUF = 0.003). The other fiber tracts did not undergo similar alterations. Conclusion: In conclusion, DTI is vital for diagnosing PSA because it detects WM changes effectively, but it still has some limitations. Due to a lack of relevant language scales and clinical manifestations, diagnosing and differentiating PSA independently remain challenging. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=365897.

Aberrant splicing of mutant huntingtin in Huntington's disease knock-in pigs.

Huntington's disease (HD) is an autosomal-dominant inherited neurodegenerative disease caused by a CAG repeat expansion in exon1 of the huntingtin gene (HTT). This expansion leads to the production of N-terminal mutant huntingtin protein (mHtt) that contains an expanded polyglutamine tract, which is toxic to neurons and causes neurodegeneration. While the production of N-terminal mHtt can be mediated by proteolytic cleavage of full-length mHtt, abnormal splicing of exon1-intron1 of mHtt has also been identified in the brains of HD mice and patients. However, the proportion of aberrantly spliced exon1 mHTT in relation to normal mHTT exon remains to be defined. In this study, HTT exon1 production was examined in the HD knock-in (KI) pig model, which more closely recapitulates neuropathology seen in HD patient brains than HD mouse models. The study revealed that aberrant spliced HTT exon1 is also present in the brains of HD pigs, but it is expressed at a much lower level than the normally spliced HTT exon products. These findings suggest that careful consideration is needed when assessing the contribution of aberrantly spliced mHTT exon1 to HD pathogenesis, and further rigorous investigation is required.

Assessment of corticospinal tract remodeling based on diffusion tensor imaging in the treatment of motor dysfunction after ischemic stroke by acupuncture: A meta-analysis.

BACKGROUND: To investigate the efficacy of acupuncture in improving motor dysfunction after ischemic stroke (IS) and to investigate the effect of acupuncture on corticospinal tract (CST) remodeling using diffusion tensor imaging. METHODS: Published literature on the effect of acupuncture on CST remodeling after IS using diffusion tensor imaging in the form of randomized controlled trials (RCTs) were systematically retrieved and screened from Cochrane Library, Web of Science, PubMed, Embase, CNKI, CBM, VIP, and Wanfang databases from inception to December 2022. The methodological quality of the included studies was critically and independently evaluated by 2 reviewers using the Cochrane Risk of Bias Assessment Tool for RCTs. The correlated data were extracted using the pre-designed form, and all analyses were performed using Reviewer Manager version 5.4. RESULTS: Eleven eligible RCTs involving 459 patients were eventually included. The combined evidence results showed that the acupuncture group significantly improved patients' National Institute of Health stroke scale, Fugl-Meyer Assessment Scale, and Barthel index compared with conventional medical treatment. The acupuncture group significantly promoted remodeling of the CST, as reflected by an increase in fractional anisotropy (FA) throughout the CST [MD = 0.04, 95% CI (0.02, 0.07), P = .001], and in addition, subgroup analysis showed that the acupuncture group significantly improved FA in the infarct area compared with conventional medical treatment at around 4 weeks [MD = 0.04, 95% CI (0.02, 0.06), P = .0002] and FA of the affected cerebral peduncle [MD = 0.03, 95% CI (0.00, 0.07), P = .02]. Also, compared with conventional medical treatment, the acupuncture group significantly increased average diffusion coefficient of the affected cerebral peduncle [MD = -0.21, 95% CI (-0.28, -0.13), P < .00001]. CONCLUSION: The results of the meta-analysis suggest that acupuncture therapy can improve the clinical manifestations of motor dysfunction in patients after IS and advance a possibly beneficial effect on CST remodeling. However, due to the number and quality of eligible studies, these findings need to be further validated in more standardized, rigorous, high-quality clinical trials.

Loss of TDP-43 promotes somatic CAG repeat expansion in Huntington's disease knock-in mice.

TAR binding protein 43 (TDP-43) is normally present in the nucleus but mislocalized in the cytoplasm in a number of neurodegenerative diseases including Huntington's disease (HD). The nuclear loss of TDP-43 impairs gene transcription and regulation. However, it remains to be investigated whether loss of TDP-43 influences trinucleotide CAG repeat expansion in the HD gene, a genetic cause for HD. Here we report that CRISPR/Cas9 mediated-knock down of endogenous TDP-43 in the striatum of HD knock-in mice promoted CAG repeat expansion, accompanied by the increased expression of the DNA mismatch repair genes, Msh3 and Mlh1, which have been reported to increase trinucleotide repeat instability. Furthermore, suppressing Msh3 and Mlh1 by CRISPR/Cas9 targeting diminished the CAG repeat expansion. These findings suggest that nuclear TDP-43 deficiency may dysregulate the expression of DNA mismatch repair genes, leading to CAG repeat expansion and contributing to the pathogenesis of CAG repeat diseases.

Role of tear exosomes in the spread of herpes simplex virus type 1 in recurrent herpes simplex keratitis.

BACKGROUND: Herpes simplex keratitis (HSK) is the most common but serious infectious keratitis with high recurrence. It is predominantly caused by herpes simplex virus type 1 (HSV-1). The spread mechanism of HSV-1 in HSK is not entirely clear. Multiple publications indicate that exosomes participate in the intercellular communication process during viral infections. However, there is rare evidence that HSV-1 spreads in HSK by exosomal pathway. This study aims to investigate the relationship between the spread of HSV-1 and tear exosomes in recurrent HSK. METHODS: Tear fluids collected from total 59 participants were included in this study. Tear exosomes were isolated by ultracentrifugation, then identified by silver staining and western blot. The size was determined by dynamic light scattering (DLS). The viral biomarkers were identified by western blot. The cellular uptake of exosomes was studied using labelled exosomes. RESULTS: Tear exosomes were indeed enriched in tear fluids. Collected exosomes own normal diameters consistent with related reports. The exosomal biomarkers existed in tear exosomes. Labelled exosomes were successfully taken up by human corneal epithelial cells (HCEC) in large numbers in a short time. After cellular uptake, HSK biomarkers were detectable by western blot in infected cells. CONCLUSIONS: Tear exosomes should be the latent sites of HSV-1 in recurrent HSK and might be involved in the spread of HSV-1. Besides, this study verifies HSV-1 genes can be indeed transferred between cells by exosomal pathway, providing new inspiration for the clinical intervention and treatment as well as the drug discovery of recurrent HSK.

Risk of Death Associated With Reversion From Prediabetes to Normoglycemia and the Role of Modifiable Risk Factors.

Importance: Individuals with prediabetes have a higher risk of death than healthy individuals. However, previous findings have suggested that individuals with reversion from prediabetes to normoglycemia may not have a lower risk of death compared with individuals with persistent prediabetes. Objectives: To investigate the associations between changes in prediabetes status and risk of death and to elucidate the roles of modifiable risk factors in these associations. Design, Setting, and Participants: This population-based prospective cohort study used data from 45 782 participants with prediabetes from the Taiwan MJ Cohort Study who were recruited between January 1, 1996, and December 31, 2007. Participants were followed up from the second clinical visit to December 31, 2011, with a median (IQR) follow-up of 8 (5-12) years. Participants were categorized into 3 groups according to changes in their prediabetes status within a 3-year period after initial enrollment: reversion to normoglycemia, persistent prediabetes, and progression to diabetes. Cox proportional hazards regression models were used to examine the associations between changes in prediabetes status at baseline (ie, the second clinical visit) and risk of death. Data analysis was performed between September 18, 2021, and October 24, 2022. Main Outcomes and Measures: All-cause mortality, cardiovascular disease (CVD)-related mortality, and cancer-related mortality. Results: Of 45 782 participants with prediabetes (62.9% male; 100% Asian; mean [SD] age, 44.6 [12.8] years), 1786 (3.9%) developed diabetes and 17 021 (37.2%) reverted to normoglycemia. Progression from prediabetes to diabetes within a 3-year period was associated with higher risks of all-cause death (hazard ratio [HR], 1.50; 95% CI, 1.25-1.79) and CVD-related death (HR, 1.61; 95% CI, 1.12-2.33) compared with persistent prediabetes, while reversion to normoglycemia was not associated with a lower risk of all-cause death (HR, 0.99; 95% CI, 0.88-1.10), cancer-related death (HR, 0.91; 95% CI, 0.77-1.08), or CVD-related death (HR, 0.97; 95% CI, 0.75-1.25). Among individuals who were physically active, reversion to normoglycemia was associated with a lower risk of all-cause death (HR, 0.72; 95% CI, 0.59-0.87) compared with those with persistent prediabetes who were physically inactive. Among individuals with obesity, risk of death varied between those who experienced reversion to normoglycemia (HR, 1.10; 95% CI, 0.82-1.49) and those who had persistent prediabetes (HR, 1.33; 95% CI, 1.10-1.62). Conclusions and Relevance: In this cohort study, although reversion from prediabetes to normoglycemia within a 3-year period did not mitigate the overall risk of death compared with persistent prediabetes, risk of death associated with reversion to normoglycemia varied based on whether individuals were physically active or had obesity. These findings highlight the importance of lifestyle modification among those with prediabetes status.

Fast Prediction of Lipophilicity of Organofluorine Molecules: Deep Learning-Derived Polarity Characters and Experimental Tests.

Fast and accurate estimation of lipophilicity for organofluorine molecules is in great demand for accelerating drug and materials discovery. A lipophilicity data set of organofluorine molecules (OFL data set), containing 1907 samples, is constructed through density functional theory (DFT) calculations and experimental measurements. An efficient and interpretable model, called PoLogP, is developed to predict the n-octanol/water partition coefficient, log Po/w, of organofluorine molecules on the basis of the descriptors of polarization, which is a combination of polarity descriptors, including the molecular polarity index and molecular polarizability (α), and hydrogen bond (HBs) index, consisting of the number of donors (NHBD) and acceptors (NHBA and NHB-FA). The present PoLogP with a combination of polarity descriptors is demonstrated to perform better than the dipole moment (µ) alone for the F-contained molecules. With the aid of a multilevel attention graph convolutional neural network model, the fast generation of polarity descriptors of organofluorine molecules could be achieved with the DFT accuracy based only on a topological molecular graph structure. The performance of PoLogP is further validated on synthesized organofluorine molecules and 2626 non-fluorinated molecules with satisfactory accuracy, highlighting the potential usage of PoLogP in high-throughput screening of the functional molecules with the desired solubility in various solvent media.

Molecular partition coefficient from machine learning with polarization and entropy embedded atom-centered symmetry functions.

Efficient prediction of the partition coefficient (log P) between polar and non-polar phases could shorten the cycle of drug and materials design. In this work, a descriptor, named 〈q - ACSFs〉conf, is proposed to take the explicit polarization effects in the polar phase and the conformation ensemble of energetic and entropic significance in the non-polar phase into consideration. The polarization effects are involved by embedding the partial charge directly derived from force fields or quantum chemistry calculations into the atom-centered symmetry functions (ACSFs), together with the entropy effects, which are averaged according to the Boltzmann distribution of different conformations taken from the similarity matrix. The model was trained with high-dimensional neural networks (HDNNs) on a public dataset PhysProp (with 41 039 samples). Satisfactory log P prediction performance was achieved on three other datasets, namely, Martel (707 molecules), Star & Non-Star (266) and Huuskonen (1870). The present 〈q - ACSFs〉conf model was also applicable to n-carboxylic acids with the number of carbons ranging from 2 to 14 and 54 kinds of organic solvent. It is easy to apply the present method to arbitrary sized systems and give a transferable atom-based partition coefficient.

A Small Molecular Symmetric All-Organic Lithium-Ion Battery.

The structural designability of organic electrode materials makes them attractive for symmetric all-organic batteries (SAOBs) by virtue of different plateaus. However, quite a few works have reported all-organic batteries and it is still challenging to develop a high-performance organic material for SAOBs. Herein, a small molecule, 2,3,7,8-tetraaminophenazine-1,4,6,9-tetraone (TAPT), is reported for SAOBs. The rich C=O and C=N groups ensure the high capacity at both plateaus for C=O/C-O and C=N/C-N redox reactions, which are hence utilized as cathodic and anodic active centers respectively. Moreover, the presence of C=O, C=N and NH2 groups resulted in plentiful strong intermolecular interactions, leading to layered structures, insolubility and high stability. The rich functional groups also facilitated the chelation of N and O with Li cations and hence benefited the storage of Li cations. The electrochemical performances of TAPT-based SAOBs outperformed all of the previously reported SAOBs.

In Situ Synthesis of Organopolysulfides Enabling Spatial and Kinetic Co-Mediation of Sulfur Chemistry.

Li-S batteries have been regarded as one of the most promising alternatives of the next-generation Li batteries. However, the dissolution and shuttling of lithium polysulfides lead to low cycle stability and low Coulombic efficiency, which intensively hinder the practical application of Li-S batteries. Herein, we propose a strategy to simultaneously promote the redox kinetics and inhibit the shuttle of lithium polysulfides, through in situ synthesis of insoluble organopolysulfides by adding a special additive. Attractively, the thus-formed insoluble organopolysulfides in the form of nanoparticle aggregates are also capable of adsorbing unconverted lithium polysulfides and hence effectively spatially suppress the shuttle effect. Furthermore, the organopolysulfides served as active redox mediators, showing faster redox kinetics of S chemistry than that of lithium polysulfides. As a result, the Li-S batteries showed impressive capacity, improved rate performance, and long cycling stability even under lean-electrolyte and high sulfur loading conditions.

Low-Glycemic Index Diets as an Intervention in Metabolic Diseases: A Systematic Review and Meta-Analysis.

We aimed to investigate the effects of a low-glycemic index (GI) diet on the body mass and blood glucose of patients with four common metabolic diseases by conducting a systematic review and meta-analysis of studies comparing a low-GI diet (LGID) and other types of diet. Search terms relating to population, intervention, comparator, outcomes, and study design were used to search three databases: PubMed, Embase, and the Cochrane Library. We identified 24 studies involving 2002 participants. Random-effects models were used for 16 studies in the meta-analysis and stratified analyses were performed according to the duration of the intervention. The systematic review showed that LGIDs slightly reduced body mass and body mass index (BMI) (p < 0.05). BMI improved more substantially after interventions of >24 weeks and there was no inter-study heterogeneity (I2 = 0%, p = 0.48; mean difference (MD) = -2.02, 95% confidence interval (CI): -3.05, -0.98). Overall, an LGID had superior effects to a control diet on fasting blood glucose (FBG) and glycosylated hemoglobin. When the intervention exceeded 30 days, an LGID reduced FBG more substantially (MD = -0.34, 95% CI: -0.55, -0.12). Thus, for patients with metabolic diseases, an LGID is more effective at controlling body mass and blood glucose than a high-GI or other diet.

SQSTM1-mediated clearance of cytoplasmic mutant TARDBP/TDP-43 in the monkey brain.

The cytoplasmic accumulation and aggregates of TARDBP/TDP-43 (TAR DNA binding protein) are a pathological hallmark in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. We previously reported that the primate specific cleavage of TARDBP accounts for its cytoplasmic mislocalization in the primate brains, prompting us to further investigate how the cytoplasmic TARDBP mediates neuropathology. Here we reported that cytoplasmic mutant TARDBP reduced SQSTM1 expression selectively in the monkey brain, when compared with the mouse brain, by inducing SQSTM1 mRNA instability via its binding to the unique 3'UTR sequence (GU/UG)n of the primate SQSTM1 transcript. Overexpression of SQSTM1 could diminish the cytoplasmic C-terminal TARDBP accumulation in the monkey brain by augmenting macroautophagy/autophagy activity. Our findings provide additional clues for the pathogenesis of cytoplasmic TARDBP and a potential therapy for mutant TARDBP-mediated neuropathology.

Neuroinflammation in Huntington's disease: From animal models to clinical therapeutics.

Huntington's disease (HD) is a progressive neurodegenerative disease characterized by preferential loss of neurons in the striatum in patients, which leads to motor and cognitive impairments and death that often occurs 10-15 years after the onset of symptoms. The expansion of a glutamine repeat (>36 glutamines) in the N-terminal region of huntingtin (HTT) has been defined as the cause of HD, but the mechanism underlying neuronal death remains unclear. Multiple mechanisms, including inflammation, may jointly contribute to HD pathogenesis. Altered inflammation response is evident even before the onset of classical symptoms of HD. In this review, we summarize the current evidence on immune and inflammatory changes, from HD animal models to clinical phenomenon of patients with HD. The understanding of the impact of inflammation on HD would help develop novel strategies to treat HD.