Exploring the Potential Role of Oligodendrocyte-Associated PIP4K2A in Alzheimer's Disease Complicated with Type 2 Diabetes Mellitus via Multi-Omic Analysis.

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are two common diseases that affect the elderly population worldwide. The identification of common genes associated with AD and T2DM holds promise for potential biomarkers and intriguing pathogenesis of these two complicated diseases. This study utilized a comprehensive approach by integrating transcriptome data from multiple cohorts, encompassing both AD and T2DM. The analysis incorporated various data types, including blood and tissue samples as well as single-cell datasets, allowing for a detailed assessment of gene expression patterns. From the brain region-specific single-cell analysis, PIP4K2A, which encodes phosphatidylinositol-5-phosphate 4-kinase type 2 alpha, was found to be expressed mainly in oligodendrocytes compared to other cell types. Elevated levels of PIP4K2A in AD and T2DM patients' blood were found to be associated with key cellular processes such as vesicle-mediated transport, negative regulation of autophagosome assembly, and cytosolic transport. The identification of PIP4K2A's potential roles in the cellular processes of AD and T2DM offers valuable insights into the development of biomarkers for diagnosis and therapy, especially in the complication of these two diseases.

Downregulation of a mitochondrial micropeptide, MPM, promotes hepatoma metastasis by enhancing mitochondrial complex I activity.

We and others have shown that MPM (micropeptide in mitochondria) regulates myogenic differentiation and muscle development. However, the roles of MPM in cancer development remain unknown. Here we revealed that MPM was downregulated significantly in human hepatocellular carcinoma (HCC) tissues and its decrease was associated with increased metastasis potential and HCC recurrence. Gain- and loss-of-function investigations disclosed that in vitro migration/invasion and in vivo liver/lung metastasis of hepatoma cells were repressed by restoring MPM expression and increased by silencing MPM. Mechanism investigations revealed that MPM interacted with NDUFA7. Mitochondrial complex I activity was inhibited by overexpressing MPM and enhanced by siMPM, and this effect of siMPM was attenuated by knocking down NDUFA7. The NAD+/NADH ratio, which was regulated by complex I, was reduced by MPM but increased by siMPM. Treatment with the NAD+ precursor nicotinamide abrogated the inhibitory effect of MPM on hepatoma cell migration. Further investigations showed that miR-17-5p bound to MPM and inhibited MPM expression. miR-17-5p upregulation was associated with MPM downregulation in HCC tissues. These findings indicate that a decrease in MPM expression may promote hepatoma metastasis by increasing mitochondrial complex I activity and the NAD+/NADH ratio.

Weakened Effective Connectivity Related to Electroacupuncture in Stroke Patients with Prolonged Flaccid Paralysis: An EEG Pilot Study.

Flaccid paralysis in the upper extremity is a severe motor impairment after stroke, which exists for weeks, months, or even years. Electroacupuncture treatment is one of the most widely used TCM therapeutic interventions for poststroke flaccid paralysis. However, the response to electroacupuncture in different durations of flaccid stage poststroke as well as in the topological configuration of the cortical network remains unclear. The objectives of this study are to explore the disruption of the cortical network in patients in different durations of flaccid stage and observe dynamic network reorganization during and after electroacupuncture. Resting-state networks were constructed from 18 subjects with flaccid upper extremity by partial directed coherence (PDC) analysis of multichannel EEG. They were allocated to three groups according to time after flaccid paralysis: the short-duration group (those with flaccidity for less than two months), the medium-duration group (those with flaccidity between two months and six months), and the long-duration group (those with flaccidity over six months). Compared with short-duration flaccid subjects, weakened effective connectivity was presented in medium-duration and long-duration groups before electroacupuncture. The long-duration group has no response in the cortical network during electroacupuncture. The global network measures of EEG data (sPDC, mPDC, and N) indicated that there was no significant difference among the three groups. These results suggested that the network connectivity reduced and weakly responded to electroacupuncture in patients with flaccid paralysis for over six months. These findings may help us to modulate the formulation of electroacupuncture treatment according to different durations of the flaccid upper extremity.

Isotypes of autoantibodies against novel differential 4-hydroxy-2-nonenal-modified peptide adducts in serum is associated with rheumatoid arthritis in Taiwanese women.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disorder with systemic inflammation and may be induced by oxidative stress that affects an inflamed joint. Our objectives were to examine isotypes of autoantibodies against 4-hydroxy-2-nonenal (HNE) modifications in RA and associate them with increased levels of autoantibodies in RA patients. METHODS: Serum samples from 155 female patients [60 with RA, 35 with osteoarthritis (OA), and 60 healthy controls (HCs)] were obtained. Four novel differential HNE-modified peptide adducts, complement factor H (CFAH)1211-1230, haptoglobin (HPT)78-108, immunoglobulin (Ig) kappa chain C region (IGKC)2-19, and prothrombin (THRB)328-345, were re-analyzed using tandem mass spectrometric (MS/MS) spectra (ProteomeXchange: PXD004546) from RA patients vs. HCs. Further, we determined serum protein levels of CFAH, HPT, IGKC and THRB, HNE-protein adducts, and autoantibodies against unmodified and HNE-modified peptides. Significant correlations and odds ratios (ORs) were calculated. RESULTS: Levels of HPT in RA patients were greatly higher than the levels in HCs. Levels of HNE-protein adducts and autoantibodies in RA patients were significantly greater than those of HCs. IgM anti-HPT78-108 HNE, IgM anti-IGKC2-19, and IgM anti-IGKC2-19 HNE may be considered as diagnostic biomarkers for RA. Importantly, elevated levels of IgM anti-HPT78-108 HNE, IgM anti-IGKC2-19, and IgG anti-THRB328-345 were positively correlated with the disease activity score in 28 joints for C-reactive protein (DAS28-CRP). Further, the ORs of RA development through IgM anti-HPT78-108 HNE (OR 5.235, p < 0.001), IgM anti-IGKC2-19 (OR 12.655, p < 0.001), and IgG anti-THRB328-345 (OR 5.761, p < 0.001) showed an increased risk. Lastly, we incorporated three machine learning models to differentiate RA from HC and OA, and performed feature selection to determine discriminative features. Experimental results showed that our proposed method achieved an area under the receiver operating characteristic curve of 0.92, which demonstrated that our selected autoantibodies combined with machine learning can efficiently detect RA. CONCLUSIONS: This study discovered that some IgG- and IgM-NAAs and anti-HNE M-NAAs may be correlated with inflammation and disease activity in RA. Moreover, our findings suggested that IgM anti-HPT78-108 HNE, IgM anti-IGKC2-19, and IgG anti-THRB328-345 may play heavy roles in RA development.

Hepatoma cell-secreted exosomal microRNA-103 increases vascular permeability and promotes metastasis by targeting junction proteins.

Increased vascular permeability facilitates metastasis. Emerging evidence indicates that secreted microRNAs (miRNAs) may mediate the crosstalk between cancer and stromal cells. To date, whether and how secreted miRNAs affect vascular permeability remains unclear. Based on deep sequencing and quantitative PCR, we found that higher level of serum miR-103 was associated with higher metastasis potential of hepatocellular carcinoma (HCC). The in vitro endothelial permeability and transendothelial invasion assays revealed that the conditioned media or exosomes derived from high miR-103-expressing hepatoma cells increased the permeability of endothelial monolayers, but this effect was attenuated if exosome secretion of hepatoma cells was blocked by silencing ALIX and HRS or if miR-103 within hepatoma or endothelial cells was antagonized. Most importantly, pretreating endothelial monolayers with exosomes that were from stable miR-103-expressing hepatoma cells facilitated the transendothelial invasion of tumor cells, and this role of exosomes was abrogated by inhibiting miR-103 in endothelial cells. Further in vivo analyses disclosed that mice with xenografts of stable miR-103-expressing hepatoma cells exhibited higher vascular permeability in tumor, higher level of exosomal miR-103 and greater number of tumor cells in blood circulation, and increased rates of hepatic and pulmonary metastases, compared to control mice. Mechanism investigations revealed that hepatoma cell-secreted miR-103 could be delivered into endothelial cells via exosomes, and then attenuated the endothelial junction integrity by directly inhibiting the expression of VE-Cadherin (VE-Cad), p120-catenin (p120) and zonula occludens 1. Moreover, miR-103 could also promote tumor cell migration by repressing p120 expression in hepatoma cells. CONCLUSION: Hepatoma cell-secreted exosomal miR-103 increases vascular permeability and promotes tumor metastasis by targeting multiple endothelial junction proteins, which highlights secreted miR-103 as a potential therapeutic target and a predictive marker for HCC metastasis. (Hepatology 2018).

Low Levels of IgM and IgA Recognizing Acetylated C1-Inhibitor Peptides Are Associated with Systemic Lupus Erythematosus in Taiwanese Women.

The objective of this study was to identify novel acetylation (Ac) modifications of the C1-inhibitor (C1-INH) and explain the association of the levels of autoantibodies against acetylated C1-INH peptides with the risk of developing systemic lupus erythematosus (SLE). Ac modifications of the C1-INH were identified and validated through in-gel digestion, nano-liquid chromatography-tandem mass spectrometry, immunoprecipitation, and Western blotting by using serum protein samples obtained from patients with SLE and age-matched healthy controls (HCs). In addition, the levels of serum C1-INH, Ac-protein adducts, and autoantibodies against unmodified and acetylated C1-INH peptides were measured. C1-INH levels in patients with SLE were significantly lower than those in HCs by 1.53-fold (p = 0.0008); however, Ac-protein adduct concentrations in patients with SLE were significantly higher than those in HCs by 1.35-fold (p = 0.0009). Moreover, immunoglobulin M (IgM) anti-C1-INH367-385 Ac and IgA anti-C1-INH367-385 Ac levels in patients with SLE were significantly lower than those in HCs. The low levels of IgM anti-C1-INH367-385 (odds ratio [OR] = 4.725, p < 0.001), IgM anti-C1-INH367-385 Ac (OR = 4.089, p = 0.001), and IgA anti-C1-INH367-385 Ac (OR = 5.566, p < 0.001) indicated increased risks for the development of SLE compared with HCs.

Low Levels of IgG Recognizing the α-1-Antitrypsin Peptide and Its Association with Taiwanese Women with Primary Sjögren's Syndrome.

The aim of this study was to examine oxidative stress and low level of α-1-antitrypsin (A1AT) in primary Sjögren's syndrome (pSS), and evaluate the associated autoreactivity against unmodified and their 4-hydroxy-2-nonenal (HNE)-modified peptides with pSS. Two differentially expressed proteins, α-1-acid glycoprotein 1 (A1AG1) and A1AT, exhibited 2-fold differences, and their HNE modifications were identified by depleted-albumin and immunoglobulin G (IgG) serum protein, in-solution digestion, in-gel digestion, and nano-liquid chromatography-tandem mass spectrometry (nano-LC-MS/MS) from pSS patients and age-matched healthy controls (HCs). Furthermore, levels of proteins, confirmation of HNE modifications, HNE-protein adducts and autoreactivity against unmodified and their HNE-modified peptides were further validated. Levels of the HNE-protein adduct and A1AG1 were significantly higher in pSS patients than HCs, but levels of A1AT were significantly lower in pSS patients compared to HCs. Only the HNE modification of A1AT was confirmed. Our study suggests that elevated HNE-protein adduct, oxidative stress, level (odds ratio (OR) 4.877, p = 0.003), lowered A1AT level (OR 3.910, p = 0.010) and a decreased level of anti-A1AT50-63 IgG (OR 3.360, p = 0.010) showed an increased risk in pSS patients compared to HCs, respectively.

Effects of topical atropine on intraocular pressure and myopia progression: a prospective comparative study.

BACKGROUND: Myopia-related maculopathy is one of the leading causes of blindness in the world. The prevalence of myopia has been reported as high as 90 % in some Asian countries. Therefore, controlling myopia progression is an urgent public issue. The purpose of this study is to evaluate the effects of topical atropine with different concentrations on intraocular pressure measurements and myopia progression in school-aged children in Taiwan. METHODS: Fifty-six myopic children were divided into three groups: 32 children were treated with 0.125 % atropine eyedrop; 12 of them were treated with 0.25 % atropine eye drop and another 12 served as a control group. IOP, auto-refractor and manifest refraction were measured at baseline and every 3 months following treatment for one year. RESULTS: There were no significant differences for the mean age, gender and baseline IOPs among the three groups. During the follow up period, no significant IOP difference was found among three groups. The change between final and baseline mean IOPs also revealed no significant differences: 0.54 mmHg, -1.28 mmHg, -0.33 mmHg for the 0.125 % atropine, 0.25 % atropine and control groups. The baseline mean spherical equivalent similarly did not differ significantly among groups but the control group showed a significant myopic progression compared to the 0.125 % atropine group 6 months after treatment, and persisted for one year. The change between final and baseline mean spherical equivalents were -0.05 D, 0 D, -1.05 D for the 0.125 % atropine, 0.25 % atropine and control groups, with both atropine-treated groups showing significant myopic retardation compared to the control group. CONCLUSIONS: Topical use of low concentration atropine for one year does not induce ocular hypertension and is effective for retarding myopic progression. However, further large scale studies with longer follow up period is necessary to validate the long term safety and efficacy. TRIAL REGISTRATION: ISRCTN33002849 , 2016/01/19, retrospectively registered.

A comprehensive bibliometric analysis of global research on the role of acrolein in Alzheimer's disease pathogenesis: involvement of amyloid-beta.

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive and behavioral decline. Acrolein, an environmental pollutant and endogenous compound, is implicated in AD development. This research employs bibliometric analysis to assess current trends and key areas concerning acrolein-AD interaction. Methods: The Web of Science was used to extensively review literature on acrolein and AD. Relevant data were systematically gathered and analyzed using VOSviewer, CiteSpace, and an online bibliometric tool. Results: We identified 120 English publications in this specialized field across 19 journals. The Journal of Alzheimer's Disease was the most prominent. The primary contributors, both in terms of scientific output and influence, were the USA, the University of Kentucky, and Ramassamy C, representing countries/regions, institutions, and authors, respectively. In this field, the primary focus was on thoroughly studying acrolein, its roles, and its mechanisms in AD utilizing both in vivo and in vitro approaches. A significant portion of the research was based on proteomics, revealing complex molecular processes. The main focuses in the field were "oxidative stress," "lipid peroxidation," "amyloid-beta," and "cognitive impairment." Anticipated future research trajectories focus on the involvement of the internalization pathway, covering key areas such as synaptic dysfunction, metabolism, mechanisms, associations, neuroinflammation, inhibitors, tau phosphorylation, acrolein toxicity, brain infarction, antioxidants, chemistry, drug delivery, and dementia. Our analysis also supported our previous hypothesis that acrolein can interact with amyloid-beta to form a protein adduct leading to AD-like pathology and altering natural immune responses. Conclusion: This study provides a broad and all-encompassing view of the topic, offering valuable insights and guidance to fellow researchers. These emerging directions underscore the continuous exploration of the complexities associated with AD. The analyses and findings aim to enhance our understanding of the intricate relationship between acrolein and AD for future research.

Dry eye after LASIK with a femtosecond laser or a mechanical microkeratome.

PURPOSE: Dry eye is the most common complication after LASIK procedure and is associated with corneal denervation. We conducted the study to compare dry eye parameters and corneal sensitivity (CS) after laser in situ keratomileusis (LASIK) with a femtosecond laser (FS) or microkeratome (MK). METHODS: In this prospective, nonrandomized, comparative study, 87 consecutive patients with myopia were assigned to receive either LASIK surgery with an FS (n = 44) or MK-assisted LASIK surgery (n = 43). The groups were age and sex matched. Corneal sensitivity, Schirmer testing, tear breakup time (TBUT), conjunctival and corneal stainings, and a subjective questionnaire (Ocular Surface Disease Index [OSDI]) were evaluated preoperatively, at 1 week, and at 1, 3, and 6 months postoperatively. RESULTS: Preoperative spherical equivalent and sphere, calculated ablation depth, and suction time differed significantly between the two groups (p < 0.01, all comparisons). Postoperatively, CS decreased in both groups and gradually recovered. Schirmer test values were not significantly different throughout the postoperative time points between the groups. Laser in situ keratomileusis-induced corneal epitheliopathy was also increased after operation in both groups. However, there was no significant difference between the groups in corneal and conjunctival staining scores. The OSDI scores were increased postoperatively in both groups. After adjustment for the calculated ablation depth, TBUT was the only parameter that was statistically higher in the FS group than in the MK group (p = 0.03). CONCLUSIONS: Both FS- and MK-assisted LASIK reduced CS and TBUT and increased corneal staining and OSDI scores. However, TBUT was significantly higher in the FS group than in the MK group after operation.

Effect of hinge position on corneal sensation and dry eye parameters after femtosecond laser-assisted LASIK.

PURPOSE: To evaluate the effect of superior- versus nasal-hinged flaps on corneal sensation and dry eye after femtosecond laser-assisted LASIK. METHODS: A total of 43 patients who had undergone bilateral femtosecond laser-assisted LASIK for myopia were evaluated in a prospective, nonrandomized, contralateral eye study to compare the difference between different hinges on corneal sensation and dry eye. Corneal esthesiometry, Schirmer basic tear secretion test (BST), tear break-up time (BUT), ocular surface stainings, and the Ocular Surface Disease Index (OSDI) questionnaire were used to evaluate corneal sensation and dry eye parameters preoperatively as well as at 1 week and 1, 3, and 6 months postoperatively. RESULTS: Corneal sensation decreased significantly in both groups 1 week after surgery (P<.05 in the nasal hinge group; P<.01 in the superior hinge group) and gradually recovered over the first 3 months. No significant change was noted in BUT after surgery in either group (P>.05). Significant increases were noted in BST values at 1 and 3 months (P<.05) and 6 months (P<.01) postoperatively in both groups. Corneal fluorescein staining increased significantly in both groups at 1 week (P<.01) and returned to baseline by 6 months. Conjunctival Rose Bengal staining decreased significantly by 6 months in the superior hinge group only (P<.05). The OSDI significantly increased 1 week after surgery (P<.01) and did not completely return to baseline by 6 months postoperatively in either group (P<.05). No significant differences were noted in any of the parameters between groups at any time point (P>.05). CONCLUSIONS: Hinge position had no significant effect on corneal sensation or dry eye parameters. Aggressive dry eye regimens are needed for patients with preoperative dry eye.

Using anti-malondialdehyde-modified peptide adduct autoantibodies in serum of taiwanese women to diagnose primary Sjogren's syndrome.

BACKGROUND: Sjogren's syndrome (SS) is a systemic autoimmune disease featured with a dry mouth and dry eyes. Several autoantibodies, including anti-SSA, anti-SSB, antinuclear antibodies can be detected in patients with SS. Oxidation-specific epitopes (OSEs) can be formed from malondialdehyde (MDA)-modified protein adducts and trigger chronic inflammation. In this study, our purposes were used serum levels of anti-MDA-modified peptide adducts autoantibodies to evaluate predictive performance by machine learning algorithms in primary Sjögren's syndrome (pSS) and assess the association between pSS and healthy controls. METHODS: Three novel MDA-modified peptide adducts, including immunoglobulin (Ig) gamma heavy chain 1 (IGHG1)102-131, complement factor H (CFAH)1045-1062, and Ig heavy constant alpha 1 (IGHA1)307-327 were identified and validated. Serum levels of protein, MDA-modified protein adducts, MDA, and autoantibodies recognizing unmodified peptides and MDA-modified peptide adducts were measured. Statistically significance in correlations and odds ratios (ORs) were estimated. RESULTS: The random forest classifier utilized autoantibodies combination composed of IgM anti-IGHG1102-131, IgM anti-IGHG1102-131 MDA and IgM anti-IGHA1307-327 achieved predictive performance as an accuracy of 88.0%, a sensitivity of 93.7%, and a specificity of 84.4% which may be as potential diagnostic biomarkers to differentiate patients with pSS from rheumatoid arthritis (RA), and secondary SS in RA and HCs. CONCLUSIONS: Our findings imply that low levels of IgA anti-IGHG1102-131 MDA (OR = 2.646), IgA anti-IGHG1102-131 (OR = 2.408), IgA anti-CFAH1045-1062 (OR = 2.571), and IgA anti-IGHA1307-327 (OR = 2.905) may denote developing risks of pSS, respectively.

Urinary incontinence and its association with socioeconomic status among middle-aged and older persons in Taiwan: A population-based study.

AIM: This study aimed to explore the association between socioeconomic status and urinary incontinence (UI). METHODS: We used data from the three waves of the Taiwan Longitudinal Study on Aging. This study included 2458 women and 2866 men aged ≥50 years. We used logistic random effects models to examine the associations of interest, adjusting for demographics, health-related behaviors, disability, number of health conditions and prostate problems for men and numbers of children for women. RESULTS: In adjusted analysis, women with secondary education least frequently reported UI compared with women with no formal education (adjusted odds ratio [AOR] 0.41, 95% confidence interval [95% CI] 0.22-0.79). Those with severe economic hardships (vs those with no economic hardships) had an increased risk of UI among men and women (AOR 2.71, 95% CI 1.72-4.25 and AOR 1.94, 95% CI 1.31-2.88, respectively). Compared with men doing mentally demanding jobs, service workers/salesperson and retired men were more prone to UI (AOR 2.67, 95% CI 1.14-6.36 and AOR 2.41, 95% CI 1.19-4.87, respectively). Further analysis showed that the associations of economic hardship with UI were attenuated when adjusting for access to healthcare. CONCLUSION: No formal education in women and severe economic hardship in both the sexes were associated with an increased risk of UI among middle-aged and older persons. The disparities should be taken into account in interventions for prevention, treatment and management of UI. Geriatr Gerontol Int 2021; 21: 245-253.

Diversity-Oriented Synthesis of Spiropentadiene Pyrazolones and 1H-Oxepino[2,3-c]pyrazoles from Doubly Conjugated Pyrazolones via Intramolecular Wittig Reaction.

An efficient method for the diversity-oriented synthesis of spiropentadiene pyrazolones and 1H-oxepino[2,3-c]pyrazoles is reported. The methodology attributes O-acylation of phosphorus zwitterions which were formed by a tandem phospha-1,6-addition of PBu3 to α,ß,γ,δ-unsaturated pyrazolones, further generating betaine intermediates that preferentially resulted in the aforementioned cyclic products in a diversity-oriented manner. The mechanistic investigations revealed that formation of the betaines is the key step to provide the products via an intramolecular Wittig reaction or an unprecedented δ-C-acylation/cyclization/Wittig reaction.

The Impact of Electroacupuncture at Hegu, Shousanli, and Quchi Based on the Theory "Treating Flaccid Paralysis by Yangming Alone" on Stroke Patients' EEG: A Pilot Study.

BACKGROUND: In China, electroacupuncture based on meridians theory "treating flaccid paralysis by Yangming alone" has been widely used for stroke rehabilitation in clinical practice. The aim of this study was to explore the electroencephalography change of electroacupuncture intervention on strokes patients with flaccid paralysis. METHODS: Twenty-three stroke patients with flaccid paralysis and six stroke patients with spasticity accepted electroacupuncture with the acupoints Hegu [LI4], Shousanli [LI10], and Quchi [LI11] for 20 minutes and their EEG data were recorded before, during, and after the electroacupuncture intervention. RESULTS: Compared with the baseline EEG signals before electroacupuncture, the ipsilesional and contralesional beta-band average power of patients with flaccid paralysis and spasticity were significantly increased during the needles retention stage and decreased slightly after removing the needles. The significant decrease of the ipsilesional and contralesional delta band average power in patients with flaccid paralysis occurred during the electroacupuncture stimulation, and they increased after the removal of the needles. The ipsilesional delta band average power of patients with spasticity significantly decreased during the electroacupuncture stimulation. CONCLUSION: From this pilot electrophysiological study, we provided a possible electrophysiological mechanism of the curative effect of electroacupuncture for stroke rehabilitation.

OPA1-Exon4b Binds to mtDNA D-Loop for Transcriptional and Metabolic Modulation, Independent of Mitochondrial Fusion.

Optic Atrophy 1 (OPA1) has well-established roles in both mitochondrial fusion and apoptotic crista remodeling and is required for the maintenance and distribution of mitochondrial DNA (mtDNA), which are essential for energy metabolism. However, the relationship between OPA1 and mitochondrial metabolism and the underlying mechanisms remain unclear. Here, we show that OPA1-Exon4b modulates mitochondrial respiration and rescues inner mitochondrial membrane potential (Δψm), independent of mitochondrial fusion. OPA1-Exon4b is required for the maintenance of normal TFAM distribution and enhances mtDNA transcription by binding the D-loop of mtDNA. Finally, we show that mRNA levels of OPA1 isoforms containing Exon4b are specifically downregulated in hepatocellular carcinoma (HCC), leading to a reduction in Δψm. Thus, our study demonstrates a novel mitochondrial functional self-recovery pathway involving enhanced mtDNA transcription-mediated recovery of mitochondrial respiratory chain proteins. This mitochondrial fusion-independent pathway may contribute to mitochondrial multi-functional switches in tumorigenesis.

A novel mitochondrial micropeptide MPM enhances mitochondrial respiratory activity and promotes myogenic differentiation.

Micropeptides belong to a class of newly identified small molecules with <100 amino acids in length, and their functions remain largely unknown. Here, we identified a novel muscle-enriched micropeptide that was localized to mitochondria (named MPM, micropeptide in mitochondria) and upregulated during in vitro differentiation of C2C12 myoblasts and in vivo early postnatal skeletal muscle development, and muscle regeneration after cardiotoxin (CTX) damage. Downregulation of MPM was observed in the muscular tissues of tibial muscular dystrophy and Duchenne muscular dystrophy patients. Furthermore, MPM silencing inhibited the differentiation of C2C12 myoblasts into myotubes, whereas MPM overexpression stimulated it. MPM-/- mice exhibited smaller skeletal muscle fibers and worse muscle performance, such as decrease in the maximum grip force of limbs, the latency to fall off rotarod, and the exhausting swimming time. Muscle regeneration was also impaired in MPM-/- mice, as evidenced by lower expression of Pax7, MyoD, and MyoG after CTX injection and smaller regenerated myofibers, compared with wild-type mice. Mechanistical investigations based on both gain- and loss-of function studies revealed that MPM increased oxygen consumption and ATP production of mitochondria. Moreover, ectopic expression of PGC-1α, which can enhance mitochondrial respiration, attenuated the inhibitory effect of siMPM on myogenic differentiation. These results imply that MPM may promote myogenic differentiation and muscle fiber growth by enhancing mitochondrial respiratory activity, which highlights the importance of micropeptides in the elaborate regulatory network of both myogenesis and mitochondrial activity and implicates MPM as a potential target for muscular dystrophy therapy.

Capillary electrophoresis of aminoglycosides with argon-ion laser-induced fluorescence detection.

A new analytical method for aminoglycosides (kanamycin, bekanamycin, paromomycin and tobramycin) based on capillary electrophoretic separation and argon-ion laser-induced fluorescence detection has been developed. 6-Carboxyfluorescein succinimidyl ester (CFSE) was used for precolumn derivatization of the non-fluorescent aminoglycosides. Optimal separation and detection were obtained with an electrophoretic buffer of 30 mM sodium borate (pH 9.0) and an air-cooled argon-ion laser (excitation at 488 nm, emission at 520 nm). The concentration limits of detection in aqueous solution were 3.9-8.2 nM. Combined with a simple cleanup procedure, this method can be applied to the determination of aminoglycosides in human plasma. A calibration curve ranging from 0.15 to 30 microM was shown to be linear. The limits of detection of aminoglycosides in human plasma were between 14.4 and 24.0 nM. Recoveries of spiked aminoglycosides in human plasma were between 92 and 105%.

Detection of common diarrhea-causing pathogens in Northern Taiwan by multiplex polymerase chain reaction.

Conventional methods for identifying gastroenteritis pathogens are time consuming, more likely to result in a false-negative, rely on personnel with diagnostic expertise, and are dependent on the specimen status. Alternatively, molecular diagnostic methods permit the rapid, simultaneous detection of multiple pathogens with high sensitivity and specificity. The present study compared conventional methods with the Luminex xTAG Gastrointestinal Pathogen Panel (xTAG GPP) for the diagnosis of infectious gastroenteritis in northern Taiwan. From July 2015 to April 2016, 217 clinical fecal samples were collected from patients with suspected infectious gastroenteritis. All specimens were tested using conventional diagnostic techniques following physicians' orders as well as with the xTAG GPP. The multiplex polymerase chain reaction (PCR) approach detected significantly more positive samples with bacterial, viral, and/or parasitic infections as compared to conventional analysis (55.8% vs 40.1%, respectively; P < .001). Moreover, multiplex PCR could detect Escherichia coli O157, enterotoxigenic E coli, Shiga-like toxin-producing E coli, Cryptosporidium, and Giardia, which were undetectable by conventional methods. Furthermore, 48 pathogens in 23 patients (10.6%) with coinfections were identified only using the multiplex PCR approach. Of which, 82.6% were from pediatric patients. Because the detection rates using multiplex PCR are higher than conventional methods, and some pediatric pathogens could only be detected by multiplex PCR, this approach may be useful in rapidly diagnosing diarrheal disease in children and facilitating treatment initiation. Further studies are necessary to determine if multiplex PCR improves patient outcomes and reduces costs.

Isotypes of autoantibodies against differentially expressed novel malondialdehyde-modified peptide adducts in serum of Taiwanese women with rheumatoid arthritis.

This study identified and validated four differentially expressed novel malondialdehyde (MDA)-modified peptide adducts and evaluated autoantibodies against native and MDA-modified peptides among Taiwanese women patients with rheumatoid arthritis (RA), osteoarthritis (OA) and healthy controls (HCs). Ig kappa chain C region76-99, alpha-1-antitrypsin284-298, alpha-2-macroglobulin824-841, and apolipoprotein B-1004022-4040 exhibiting 2-fold differences in relative modification ratios were identified by concanavalin A (Con A) affinity chromatography, 1D SDS-PAGE, in-gel digestion, nano-LC/MS/MS and nano-LC/MS using pooled serum-derived Con A-captured proteins from 9 RA and 9 age-matched HCs. Furthermore, the levels of proteins, serum MDA, and MDA-modified protein adducts were further validated against individual serum from 20 RA and 20 HCs, and autoantibodies against native and their MDA-modified peptides used 45 RA, 30 OA and 45 HCs. Levels of serum MDA and MDA-modified protein adducts were significantly higher in RA than HCs but protein levels were not significantly different. Serum Igs G and M against MDA-modified peptides showed better diagnostic performance in differentiating among patients with RA, OA and HCs, with an area under the receiver operating characteristic curve of 0.96-0.98, sensitivity of 88.9%-97.8%, and specificity of 88.9%-100%. Autoantibodies against MDA-modified epitopes become useful clinical biomarkers for RA. BIOLOGICAL SIGNIFICANCE: By using a label-free relative quantitative proteomic analysis of concanavalin A (Con A)-bound serum samples, the current study discovered and validated malondialdehyde (MDA)-modified peptide adducts as novel biomarkers for differentiating between rheumatoid arthritis (RA) patients and healthy controls (HCs). In addition, the serum levels of MDA, proteins, and MDA-modified protein adducts as well as the MDA modification of proteins were determined. Isotypes of autoantibodies against MDA-modified peptide adducts can be used as serological biomarkers for further discriminating among RA patients, osteoarthritis patients and HCs. This strategy can become the basis for identifying potential diagnostic and pathological biomarkers for RA.