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ABSTRACT Aims/Introduction Delayed intensification of treatment, or therapeutic inertia, increases the risk of diabetic complications and death. The aim of this study was to determine the effect of mandatory monthly outpatient visits on therapeutic inertia in patients with suboptimal control of type 2 diabetes. Materials and Methods This retrospective cohort study used data from the Chang Gung Research Database and defined two study periods: the baseline period and the intervention period. The intervention period began when the Kaohsiung branch initiated a mandatory monthly outpatient visits program. Type 2 diabetes patients with baseline glycated hemoglobin (HbA1c) >7% and a follow‐up HbA1c measurement were enrolled in each period, and divided into a Kaohsiung branch (intervention) group and the other branches (control) group. Therapy intensification was evaluated by comparing prescriptions after the follow‐up HbA1c measurement with the prescriptions after the baseline HbA1c measurement. Results A total of 5,045 patients at the Kaohsiung branch and 13,400 participants at other branches were enrolled in the baseline period; and 5,573 and 15,603 patients, respectively, were enrolled in the intervention period. The adjusted odds ratio (AOR) for therapy intensification in patients with baseline HbA1c ≥9% was not significantly higher at 1.21 (95% CI, 1.00–1.47) in the intervention period at the Kaohsiung branch, but was significantly higher (AOR, 1.53; 95% CI, 1.02–2.30) in the subgroup with worsened HbA1c. Conclusions Mandatory monthly outpatient visits could improve therapeutic inertia in patients with poorly controlled type 2 diabetes, especially in those with worsened control. The trajectory of HbA1c could significantly influence the assessment of the prevalence of therapeutic inertia.

Abstract Background Little research has been done on ischemic outcomes related to left ventricular ejection fraction (EF) in acute decompensated heart failure (ADHF). Methods A retrospective cohort study was conducted between 2001 and 2021 using the Chang Gung Research Database. ADHF Patients discharged from hospitals between January 1, 2005, and December 31, 2019. Cardiovascular (CV) mortality and heart failure (HF) rehospitalization are the primary outcome components, along with all-cause mortality, acute myocardial infarction (AMI) and stroke. Results A total of 12,852 ADHF patients were identified, of whom 2,222 (17.3%) had HFmrEF, the mean (SD) age was 68.5 (14.6) years, and 1,327 (59.7%) were males. In comparison with HFrEF and HFpEF patients, HFmrEF patients had a significant phenotype comorbid with diabetes, dyslipidemia, and ischemic heart disease. Patients with HFmrEF were more likely to experience renal failure, dialysis, and replacement. Both HFmrEF and HFrEF had similar rates of cardioversion and coronary interventions. There was an intermediate clinical outcome between HFpEF and HFrEF, but HFmrEF had the highest rate of AMI (HFpEF, 9.3%; HFmrEF, 13.6%; HFrEF, 9.9%). The AMI rates in HFmrEF were higher than those in HFpEF (AHR, 1.15; 95% Confidence Interval, 0.99 to 1.32) but not in HFrEF (AHR, 0.99; 95% Confidence Interval, 0.87 to 1.13). Conclusion Acute decompression in patients with HFmrEF increases the risk of myocardial infarction. The relationship between HFmrEF and ischemic cardiomyopathy, as well as optimal anti-ischemic treatment, requires further research on a large scale.

Abstract Reduced brain volume including atrophy in grey and white matter is commonly seen in myotonic dystrophy type 1 (DM1). DM1 is caused by an expansion of CTG trinucleotide repeats in the 3’ untranslated region (UTR) of the Dystrophia Myotonica Protein Kinase (DMPK) gene. Mutant DMPK mRNA containing expanded CUG RNA (DMPK-CUGexp) sequesters cytoplasmic MBNL1, resulting in morphological impairment. How DMPK-CUGexp and loss of MBNL1 cause histopathological phenotypes in the DM1 brain remains elusive. Here, we show that BDNF-TrkB retrograde transport is impaired in neurons expressing DMPK-CUGexp due to loss of cytoplasmic MBNL1 function. We reveal that mature BDNF protein levels are reduced in the brain of the DM1 mouse model EpA960/CaMKII-Cre. Exogenous BDNF treatment did not rescue impaired neurite outgrowth in neurons expressing DMPK-CUGexp, whereas overexpression of the cytoplasmic MBNL1 isoform in DMPK-CUGexp-expressing neurons improved their responsiveness to exogenous BDNF. We identify dynein light chain LC8-type 2, DYNLL2, as an MBNL1-interacting protein and demonstrate that their interaction is RNA-independent. Using time-lapse imaging, we show that overexpressed MBNL1 and DYNLL2 move along axonal processes together and that MBNL1-knockdown impairs the motility of mCherry-tagged DYNLL2, resulting in a reduced percentage of retrograde DYNLL2 movement. Examination of the distribution of DYNLL2 and activated phospho-TrkB (pTrkB) receptor in EpA960/CaMKII-Cre brains revealed an increase in the postsynaptic membrane fraction (LP1), indicating impaired retrograde transport. Finally, our neuropathological analysis of postmortem DM1 tissue reveals that reduced cytoplasmic MBNL1 expression is associated with an increase in DYNLL2 and activated pTrkB receptor levels in the synaptosomal fraction. Together, our results support that impaired MBNL1-mediated retrograde BDNF-TrkB signaling may contribute to the histopathological phenotypes of DM1.

An outbreak of respiratory syncytial virus (RSV) has been observed in Taiwan since August 2020. We reviewed a central laboratory-based surveillance network established over 20 years by Taiwan Centres for Disease Control for respiratory viral pathogens between 2010 and 2020.A retrospective study of children

Here, we present TP-DB; a pattern-based search engine based on 1.67 million helices from the Protein Database (PDB). We demonstrate the utility of TP-DB in identifying microbe-specific antigens, as well as the design of antimicrobial peptides and Protein-protein interaction blockers.

Background/purpose: Sapoviruses (SaVs) become important pathogens causing both sporadic and outbreaks of acute gastroenteritis (AGE) after rotavirus vaccination era worldwide. SaVs were included in AGE screening items when norovirus and rotavirus were negative in Taiwan CDC since 2008. However, no complete SaV genome sequence of any genotype detected in Taiwan was determined. This study aimed to investigate SaVs infection and complete genome sequences detected in Taiwan. Methods: This prospective survey, SaVs samples with untyped or weak PCR result were selected for testing the new design qRT-PCR assay from AGE hospitalized children during 2008–2011, 2016–2017 and AGE outbreak in 2012–2014. Those were genetically characterized using long RT-PCR with different primer combinations as well as primer independent deep sequencing and with 5′ RACE and 3′ terminal region targeting RT-PCR. Results: Overall, 14 SaV-AGE hospitalized children and 4 SaV-AGE outbreaks were enrolled in this study. In addition to the AGE symptoms, 6 children also showed URI symptoms (cough, pharyngitis, rhinorrhea and nasal congestion). The detected 19 SaVs were classified as eight genotypes (GI.1, GI.2, GI.3, GII.2, GII.3, GII.5, GII.8, and GIV.1) and the complete genome sequence of representative strain for each genotype were determined except GI.3. The GII.3 was the most major genotype following GI.1 and GIV.1. Conclusion: Our result confirmed that SaV is one of the pathogens detected from Taiwanese AGE patients. Multiple SaV genotype strains would associate with AGE as similar to those detected in different countries/areas. The whole genome of SaV strains detected including rarely reported GII.8 was firstly determined.

In this study, thermal and argon (Ar) plasma/wetting treatments were combined to enhance the bonding strength of polyimide (PI) films. Attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) was used to analyze the changes in the PI imidization degrees. The contact angles of the PI films were also measured. The results show that the contact angles of the fully cured PI films markedly decreased from 78.54° to 26.05° after the Ar plasma treatments. X-ray photoelectron spectroscopy (XPS) analysis was also conducted on the PI surfaces. We found that the intensities of the C-OH and C-N-H bonds increased from 0% to 13% and 29% to 57%, respectively, after Ar plasma activation. Such increases in the C-OH and C-N-H intensities could be attributed to the generation of dangling bonds and the breakage of the imide ring or polymer long chains. Shear tests were also conducted to characterize the bonding strength of the PI films, which, after being treated with the appropriate parameters of temperature, plasma power, and wetting droplets, was found to be excellent at greater than 35.3 MPa.

This paper proposed a PM 2.5 forecasting model using Long Short-Term Model (LSTM) sequence to sequence combined with the statistical method. Correlation Analysis, XGBoost, and Chemical processed are used as the methods to select the essential features. The air pollution data is extracted from Taiwan Environmental Protection Agency (EPA) for the Taichung City dataset in 2014–2018. The study points out that chemical processed model of particulate matter 10 micrometers or less in diameter (PM10), Sulfur Dioxide (SO2), and Nitrogen Dioxide (NO2) have the highest accuracy or lowest Root Mean Square Error (RMSE) and more short training and testing time among the other models. The chemical processed model of PM10, SO2, and NO2 (model B) has the highest accuracy (lowest RMSE), approximately 1 point lower RMSE values, and the shortest training and testing period among the other models. Furthermore, RMSE calculations based on the stations reveal that training with the entire station dataset has a 3 point higher RMSE value than training with each station dataset.

Abstract Background Synthesis of a variety of biological circuits for specific functional purposes has made a tremendous progress in recent years. The ultimate goal of combining molecular biology and engineering is to realize a functional biocomputer. To address this challenge, all previous efforts work toward building up the bio-computer as the ultimate goal. To this aim, there should be a key module, named control unit (CU), to direct a serious of logic or arithmetic operations within the processor. Methods This research task develops a bio-CU to work with a bio-ALU, which is realized from the combination of previously developed genetic logic gates to fulfill the kernel function of CPU as those done in the silicon computer. Results A possible framework of the bio-CPU has demonstrated how to connect a bio-CU with a bio-ALU to conduct a fetch-decode-execute cycle of a macro instruction. It presents not only capability of 4-bit full adder but coordination of related modules in biocomputer. Conclusions We have demonstrated computer simulation for applications of the genetic circuits in biocomputer construction. It’s expected to inspire follow-up study to synthesize potential configurations of the future biocomputer.

Summary: The Muscleblind-like protein family (MBNL) plays an important role in regulating the transition between differentiation and pluripotency and in the pathogenesis of myotonic dystrophy type 1 (DM1), a CTG expansion disorder. How different MBNL isoforms contribute to the differentiation and are affected in DM1 has not been investigated. Here, we show that the MBNL1 cytoplasmic, but not nuclear, isoform promotes neurite morphogenesis and reverses the morphological defects caused by expanded CUG RNA. Cytoplasmic MBNL1 is polyubiquitinated by lysine 63 (K63). Reduced cytoplasmic MBNL1 in the DM1 mouse brain is consistent with the reduced extent of K63 ubiquitination. Expanded CUG RNA induced the deubiqutination of cytoplasmic MBNL1, which resulted in nuclear translocation and morphological impairment that could be ameliorated by inhibiting K63-linked polyubiquitin chain degradation. Our results suggest that K63-linked ubiquitination of MBNL1 is required for its cytoplasmic localization and that deubiquitination of cytoplasmic MBNL1 is pathogenic in the DM1 brain. : Wang et al. find that MBNL1 ubiquitination is required for cytoplasmic localization and promotion of neurite outgrowth. In myotonic dystrophy, expanded CUG repeat RNA leads to MBNL1 deubiquitination, resulting in nuclear-translocation-associated morphological defects that can be rescued by preventing degradation of lysine 63-linked polyubiquitin chains or enhancing MBNL1 ubiquitination. Keywords: MBNL1, polyubiquitination, myotonic dystrophy, nucleocytoplasmic localization, neurite outgrowth

In Taiwan, acute gastroenteritis outbreaks caused by a new norovirus genotype GII.2 increased sharply toward the end of 2016. Unlike previous outbreaks, which often involved restaurants, GII.2 outbreaks mainly occurred in schools. Phylogenetic analysis indicates that these noroviruses are recombinant GII.P16-GII.2 strains.

[This corrects the article DOI: 10.1371/journal.pone.0173762.].

Attention-deficit hyperactivity disorder (ADHD) is associated with higher risk for fracture. Whether the medical treatment for ADHD would mitigate the risk remains unclear. In this study, we sought to investigate the effect of methylphenidate treatment on risk for fracture, as well the moderational role of treatment duration on the risk of fracture, in a large national sample. Cases less than 18 years old were identified from Taiwan's National Health Insurance Research Database with a new primary diagnosis of ADHD (ICD-9:314) between 1996 and 2013. A total of 6201 cases with ADHD were included as the study cohort. The cases were divided into 3 groups according to the duration of methylphenidate treatment (0, 1-180, and more than 180 days). All groups were followed until the end of 2013 for first diagnoses of fracture (ICD-9 codes 800 to 829). Cox proportional hazards models were applied. Compared to the group without methylphenidate treatment, the risk for fracture was lower among the group treated for more than 180 days. The adjusted hazard ratio was 0.77 (95% Confidence interval: 0.63-0.94). The groups treated for 180 days or fewer had no significant difference in the risk for fracture. In conclusion, methylphenidate treatment was associated with lower risk for fracture among ADHD patients. The association was evident only in the cohort treated for more than 180 days.

Background: The aim of this study was to compare the risk of developing sudden sensorineural hearing loss (SSHL) in patients with hypopharyngeal cancer with that in patients with nasopharyngeal carcinoma (NPC). Methods: A population-based, retrospective cohort study was performed using the Taiwan National Health Research Database databank. Patients selected for this study were diagnosed with hypopharyngeal cancer or NPC and treated with radiotherapy in the period from 2001 to 2004. Routine follow-up was conducted for 8 years (2004-2012), and the incidence of SSHL was calculated at the final follow-up. Results: There was no significant difference in the risk of developing SSHL between the hypopharyngeal cancer group and its control group (p = 1.000). In hypopharyngeal cancer and NPC groups, the rates of SSHL were 0.12% and 1.00%, respectively (p < 0.001). The cumulative hazard of SSHL during the follow-up period was significantly higher in the NPC group than in the control group (p < 0.001). Conclusion: Radiotherapy in patients with hypopharyngeal cancer did not increase the risk of developing SSHL, but postirradiation NPC was significantly associated with an increased incidence of SSHL. [ABSTRACT FROM AUTHOR]

Site-directed mutagenesis (SDM) has been widely used for studying the structure and function of proteins. A one-step polymerase chain reaction (PCR)-based multiple site-directed plasmid mutagenesis method with extended non-overlapping sequence at the 3' end of the primer increases the PCR amplification efficiency and the capacity of multi-site mutagenesis. Here, we introduced silent restriction sites in the primers used in this PCR-based SDM method by utilizing SDM-Assist software to generate mutants of Helicobacter pylori neutrophil-activating protein (HP-NAP), whose gene has low GC content. The HP-NAP mutants were efficiently generated by this modified mutagenesis method and quickly identified by a simple restriction digest due to the presence of the silent restriction site. This modified PCR-based SDM method with the introduction of a silent restriction site on the primer is efficient for generation and identification of mutations in the gene of interest. [ABSTRACT FROM AUTHOR]

Increasing applications of fundamental biological gates have been successfully built during this decade. Proceeding to the current development, this study presents a genetic arithmetic and logical unit (ALU) design based on a series of genetic logic gates. The system level's architecture consists of three parts: temp register, ALU and accumulator register. Using the concept of the ALU on the digital computer, the authors present the fundamental function of the genetic ALU via full adder register and also build the bio-storage devices to store data generated from the genetic ALU. The system in this study shows the capability of computing and storage on the biocomputer. [ABSTRACT FROM AUTHOR]

Background: Helicobacter pylori neutrophil-activating protein (HP-NAP) is involved in H. pylori-induced gastric inflammation. Due to its immunogenic and immunomodulatory properties, HP-NAP has been used for developing vaccines against H. pylori infection and new drugs for cancer therapy. Results: Here, we provide a simple process for high-yield production of HP-NAP by applying one-step negative chromatography to purify recombinant HP-NAP expressed in Escherichia coli (E. coli). In our E. coli expression system, recombinant HP-NAP constitutes nearly 70% of the total protein. Overexpressed recombinant HP-NAP is almost completely soluble upon cell lysis at pH 9.5. Under the optimal condition at pH 8.0, recombinant HP-NAP with purity higher than 95% can be obtained from E. coli by collecting the unbound fraction using diethylaminoethyl (DEAE) Sephadex resin in batch mode. The overall yield of HP-NAP from a 50-ml E. coli culture is ∼19 mg. The purified HP-NAP folds into a multimer with a secondary structure of α-helix and is able to trigger the production of reactive oxygen species by neutrophils. Conclusions: Purification of recombinant HP-NAP overexpressed in E. coli using DEAE Sephadex negative mode batch chromatography is an efficient method for high-yield production of highly pure HP-NAP in its native state. The purified HP-NAP is useful for various clinical applications including vaccine development, diagnosis, and new drug development. [ABSTRACT FROM AUTHOR]

J. Neurochem. (2010) 114, 1381–1392. While neuronal activity regulates neurite outgrowth and branching, the details of the underlying mechanisms are still largely unclear. This study investigated the effect of the glutamate receptors on neuritogenesis using cultured hippocampal neurons. At 3–4 days in vitro, NMDA treatment promoted axon branching but not primary axon extension. In contrast, blockade of the NMDA receptor (NMDAR) by AP5 treatment enhanced primary axon extension. NMDAR activation also increased dendrite number and total dendrite length. These results suggest that NMDAR controls axon and dendrite morphogenesis. A previous study demonstrated that knockdown of the zinc finger transcription factor B cell lymphoma 11A-long (Bcl11A-L) reduces deleted in colorectal cancer (DCC) and microtubule-associated protein (MAP) 1b expression, thereby promoting axon branching. Here, glutamate stimulation down-regulated the levels of the Bcl11A-L, DCC, MAP1b, and MAP2c proteins. Over-expression of either Bcl11A-L or DCC countered the effect of NMDA or glutamate on axon branching and dendrite outgrowth, indicating that the Bcl11A-L/DCC pathway is an important downstream effector of glutamate receptors in neurite arborization. Because knockdown of Bcl11A-L did not down-regulate MAP2c, our results suggest that glutamate receptors also use a Bcl11A-L-independent pathway to control dendrite outgrowth. To summarize, this study reveals novel pathways downstream of glutamate receptors that regulate axon and dendrite arborization. [ABSTRACT FROM AUTHOR]