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Humans have an exceptional ability to extract specific audio streams of interest in a noisy environment; this is known as the cocktail party effect. It is widely accepted that this ability is related to selective attention, a mental process that enables individuals to focus on a particular object. Evidence suggests that sensory neurons can be modulated by top-down signals transmitted from the prefrontal cortex. However, exactly how the projection of attention signals to the cortex and subcortex influences the cocktail effect is unclear. We constructed computational models to study whether attentional modulation is more effective at earlier or later stages for solving the cocktail party problem along the auditory pathway. We modeled the auditory pathway using deep neural networks (DNNs), which can generate representational neural patterns that resemble the human brain. We constructed a series of DNN models in which the main structures were autoencoders. We then trained these DNNs on a speech separation task derived from the dichotic listening paradigm, a common paradigm to investigate the cocktail party effect. We next analyzed the modulation effects of attention signals during all stages. Our results showed that the attentional modulation effect is more effective at the lower stages of the DNNs. This suggests that the projection of attention signals to lower stages within the auditory pathway plays a more significant role than the higher stages in solving the cocktail party problem. This prediction could be tested using neurophysiological experiments.

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.

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.

Background Chronic hepatitis C virus (HCV) infection is associated with increased cardiovascular risks. We aimed to investigate the impact of direct acting antiviral (DAA) on HCV-associated cardiovascular events. Methods In this retrospective cohort study, patients with the diagnosis of chronic HCV were retrieved from multi-institutional electronic medical records, where diagnosis of HCV was based on serum HCV antibody and HCV–RNA test. The patients eligible for analysis were then separated into patients with DAA treatment and patient without DAA treatment. Primary outcomes included acute coronary syndrome, heart failure (HF), venous thromboembolism (VTE), stroke, cardiovascular death, major adverse cardiovascular event (MACE), and all-cause mortality. Outcomes developed during follow-up were compared between DAA treatment and non-DAA treatment groups. Results There were 41 565 patients with chronic HCV infection identified. After exclusion criteria applied, 1984 patients in the DAA treatment group and 413 patients in the non-DAA treatment group were compared for outcomes using inverse probability of treatment weighting. Compared to patients in non-DAA treatment group, patients in DAA treatment group were associated with significantly decreased HF (hazard ratio [HR]: 0.65, 95% confidence interval [CI]: 0.44–0.97, P = 0.035), VTE (HR: 0.19, 95% CI: 0.07–0.49, P = 0.001), MACE (HR: 0.73, 95% CI 0.59–0.92, P = 0.007), and all-cause mortality (HR: 0.50, 95% CI: 0.38–0.67, P Conclusions Chronic HCV patients treated with DAA experienced lower rates of cardiovascular events and all-cause mortality than those without treatment. The reduction of VTE was the most significant impact of DAA treatment among the cardiovascular outcomes.

(1) To investigate the functional and anatomical outcomes of anti-vascular endothelial growth factor (anti-VEGF) treatment in patients with exudative age-related macular degeneration (AMD) with or without obstructive sleep apnea (OSA); (2) In total, 65 patients with AMD with or without OSA who received three consecutive doses of intravitreal anti-VEGF injections were enrolled. The primary outcomes—best-corrected visual acuity (BCVA) and central macular thickness (CMT)—were assessed at 1 and 3 months. Moreover, morphological changes observed through optical coherence tomography were analyzed; (3) In total, 15 of the 65 patients had OSA and were included in the OSA group; the remaining 50 patients were included in the non-OSA (control) group. At 1 and 3 months after treatment, BCVA and CMT had improved but did not differ significantly between the groups. More patients in the OSA group demonstrated subretinal fluid (SRF) resorption at 3 months after treatment than in the non-OSA group (p = 0.009). Changes in other imaging biomarkers, such as intraretinal cysts, retinal pigment epithelium detachment, hyperreflective dots, and ellipsoid zone disruptions, did not differ significantly between the groups; (4) Our results suggest that the BCVA and CMT outcomes 3 months after anti-VEGF treatment are similar between patients with and without OSA. Moreover, patients with OSA may exhibit superior SRF resorption. A large-scale prospective study is mandatory to evaluate the association between SRF resorption and visual outcomes in AMD patients with OSA.

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.

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.

OBJECTIVE Data regarding the prevalence of depression and anxiety among cancer patients, especially before cancer diagnosis, remains scarce. This study investigated the prevalence of these conditions and associated drug use among cancer patients pre- and post-diagnosis. METHODS This population-based cohort study using data from Taiwan's National Health Insurance Research Database recruited patients with a registered cancer diagnosis and matched control between January 1, 2000, and December 31, 2011. We compared the prevalence of anxiety and depressive disorders between cancer patients and non-cancer participants during a 2-year period both pre- and post-diagnosis by Pearson's chi-square test. Psychiatric medication use was also examined for the associated mental condition. RESULTS We examined participants diagnosed with liver (N = 17,154), colorectal (N = 30,391), breast (N = 40,036), gynecological (N = 23,218), and lung (N = 15,671) cancer. Before the cancer diagnosis, the prevalence of depression was higher in non-cancer participants than in gynecological cancer patients (p = 0.018) but anxiety is higher in liver, colorectal, and lung cancer patients when compared to non-cancer participants (p

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.

Purpose Literature suggests that attention deficit hyperactivity disorder (ADHD) is associated with a high risk of unintentional injury. However, few studies have focused on whether risk of burn injury is relatively high among patients with ADHD. The aim of this study was to investigate whether ADHD affects the risk of burn injury. Materials and Methods Individuals aged

BACKGROUND: Pacing-induced cardiomyopathy is an undesired outcome in patients with atrioventricular block (AVB), and our animal model showed lipotoxic cardiomyopathy after pacing.OBJECTIVES: The purpose of this study was to explore the mechanisms and clinical outcomes of statins in AVB patients receiving pacing.METHODS: Rat ventricular cardiomyocytes were treated with atorvastatin, liver X receptor (LXR) agonist, and LXR antagonist during pacing. Pigs were divided into 3 groups: right ventricular pacing, pacing with concomitant atorvastatin treatment, and sham control. Clinically, we enrolled 1717 AVB patients who had received a permanent pacemaker from Chang Gung Memorial Hospital Medical database. The primary outcome (cardiovascular death or heart failure [HF] hospitalization) and individual outcome were compared between statin and nonstatin groups after inverse probability of treatment weighting.RESULTS: Lipid accumulation in rat cardiomyocytes by pacing was significantly reduced by treatment with LXR agonist and atorvastatin, whereas LXR antagonist counteracted the atorvastatin effect on lipid expression. Left ventricular ejection fraction (LVEF) was significantly lower in the AVB pig pacing group compared to the group concomitantly treated with atorvastatin. Moreover, lipid accumulation and fibronectin expression were significantly ameliorated by concomitant treatment with atorvastatin. In the clinical study, the statin group had a significantly lower risk of the primary outcome event (hazard ratio [HR] 0.69; 95% confidence interval [CI] 0.56-0.84), less HF hospitalization (HR 0.45; 95% CI 0.30-0.67), and higher LVEF than the nonstatin group.CONCLUSION: In experimental models, atorvastatin ameliorated lipid accumulation in cardiomyocytes and fibrosis in left ventricular myocardium induced by pacing. Clinically, treatment with statins was associated with less HF hospitalization and cardiovascular death in AVB patients receiving pacemaker therapy.

Rotavirus A (RVA) are a group of diverse viruses causing acute gastroenteritis (AGE) in humans and animals. Zoonotic transmission is an important mechanism for rotavirus evolution and strain diversity in humans, but the extent of pigs as a major reservoir for human infection is not clear.We have surveyed 153 pig farms across Taiwan with a total of 4588 porcine stool samples from three age groups from 2014 to 2017. Nursing piglets (less than one month of age) had higher detection rate for rotavirus than older age groups. Five VP7 (G) genotypes and 5 VP4 (P) genotypes were found in a total of 14 different G/P genotype combinations. In addition, porcine RVA strains had 2 NSP4 (E) genotypes and 3 VP6 (I) genotypes. A P[3]-like genotype was also discovered among strains collected in 2016 and 2017.Most of the genes from Taiwanese porcine strains clustered with each other and the lineages formed by these strains were distinct from the sequences of numerous regional variants or globally circulating porcine strains, suggesting an independent evolutionary history for Taiwanese rotavirus genotypes. The close relationship among porcine RVA strains and some unique porcine-like genotypes detected sporadically among human children in swine farms illustrates that pigs might serve as a reservoir for potential zoonotic transmission and novel genotype evolution in Taiwan's insular environment.

Background Studies have reported an association between allergy and panic disorder. However, few studies have explored the relationship between allergic rhinitis and panic disorder. Previous studies were limited by cross-sectional study designs, self-reported symptoms, absence of matched controls, and lack of consideration of the influence of steroid and comorbidities. This study aimed to explore the longitudinal association between allergic rhinitis and panic disorder in a large population-based cohort of young people. Methods In this study, 79,917 new cases of allergic rhinitis between 1998 and 2012 in individuals younger than 20 years were identified from Taiwan's National Health Insurance Research Database. One control (nonallergic rhinitis) per case (allergic rhinitis) was randomly selected from the remaining sample, matching for age, sex, residence, and insurance premium. Both groups were followed until the end of 2013 for incidence of panic disorder. Cox regression analysis was performed, adjusting for sex, age, residence, insurance premium, systemic steroids, asthma, atopic dermatitis, allergic conjunctivitis, attention deficit hyperactivity disorder, depression, and Charlson index. Results Allergic rhinitis was associated with a 2-fold increase in risk for panic disorder after adjustment for other variables. Additional independent risk factor of panic disorders were female sex, older age group, and depression. Limitations Lifestyle, substance use, smoking by the patient or family members, and psychosocial stressors were not evaluated. Conclusions Allergic rhinitis was associated with increased risk of panic disorder. Assessment and intervention of allergy rhinitis among young people with panic disorder are critical.

Background: Obesity has been regarded as a risk factor for epiblepharon. This study aims to investigate the age- and sex-specific relationship between epiblepharon and obesity in children.Methods: A retrospective case-control study was conducted using Chang Gung Research Database. Children ≤ 18 years of age with epiblepharon were identified from 1 January 2009 to 31 December 2019. Children were classified into four groups: underweight, normal, overweight and obese groups.Results: A total of 513 patients and 1026 controls (57.7% of males) aged 1 to 18 matched by sex and age were included in the analysis. The median body mass index (BMI) of children with epiblepharon was significantly higher than that of children without epiblepharon (p < 0.001). In the subgroup analysis, among boys aged 4 to 9 years, the BMI in boys with epiblepharon was significantly higher than that in boys without epiblepharon (p < 0.05) and the risk of epiblepahron in overweight and obese boys was significantly higher than in non-overweight boys (OR = 1.74, 95% CI = 1.07-2.82; OR = 3.06, 95% CI = 1.56-6.03). On the other hand, among girls aged 13 to 18 years, the BMI in adolescent girls with epiblepharon was significantly higher than that in the control group (p < 0.05) and overweight and obese girls had statistically higher risk of persistent epiblepharon than non-overweight girls (OR =3.70, 95% CI = 1.38-9.97).Conclusions: The association between obesity and epiblepharon varies in strength according to age in a sex-specific manner.

Research has shown that turn-by-turn navigation guidance has made users overly reliant on such guidance, impairing their independent wayfinding ability. This paper compares the impacts of two new types of navigation guidance - reference-based and orientation-based - on their users' ability to independently navigate to the same destinations, both as compared to each other, and as compared to two types of traditional turn-by-turn guidance, i.e., map-based and augmented-reality (AR) based. The results of our within-subjects experiment indicate that, while the use of reference-based guidance led to users taking more time to navigate when first receiving it, it boosted their subsequent ability to independently navigate to the same destination in less time, via more efficient routes, and with less assistance-seeking from their phones than either map-based or AR-based turn-by-turn navigation guidance did.

Failure to recognize a carotid-cavernous fistula (CCF) promptly may lead to worse prognosis due to a setback in providing proper treatment. To promote early diagnosis of non-traumatic CCF, we report a case with classic clinical symptoms and signs that was diagnosed and followed up with carotid Doppler sonography (CDS) and transcranial color-coded duplex (TCD).A 45-year-old woman developed an intermittent headache, pulsatile tinnitus, and double vision sequentially within ten days. Progressive left retro-orbital pain, continuous ringing in the left ear, sensory impairment of trigeminal nerve and abducens nerve palsy were also noted on examination. Despite insignificant findings on computed tomography (CT) of the brain, TCD revealed an aberrant flow pattern with high velocity and low resistance at the left carotid siphon. Digital subtraction angiography (DSA) later confirmed a left direct type CCF by illustrating a quick opacification of left cavernous sinus via the internal carotid artery.In addition to invasive DSA, non-invasive CDS and TCD may serve as useful apparatus during the initial evaluation and subsequent follow-ups. The positive sonographic clues, including abnormal turbulent and hemodynamic parameters, are quite exhibitive in the existence of CCFs.

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.

Objective To investigate the safety of adenoidectomy and risk factors of re-adenoidectomy, and intend to provide evidence-based information to clinicians for further consideration. Methods and materials This study was based on data obtained from Taiwan’s National Health Insurance Research Database from the period 2002–2011. We utilized that data from the hospitalization group and collected information regarding those individuals who accepted adenoidectomy with or without tonsillectomy and post-adenoidectomy bleeding. Thereafter, we performed univariate and multi-variate analysis to explore the possible risk factors of re-adenoidectomy. Results A total of 5435 individuals who accepted a first adenoidectomy with or without tonsillectomy were collected. After further tracing treatment of these individuals, 107 (1.97%) accepted the revision adenoidectomy until 2011. Post-op bleeding was approximately 0.28%. The revision rate associated with patient age showed the following: 0–4 years (0.61%), 4–12 years (2.06%) and 12–18 years (2.56%). The revision rate associated with surgeon age showed: 28–41 years (1.42%), 41–50 years (2.96%), 50–65 years (2.74%); the surgeons’ surgery volume showed low (4.34%), medium (0.71%), and higher (1.02%). There are 4 diseases (otitis media with effusion, sinusitis, chronic pharyngitis, and sleep disorder) that showed a significant relationship with the revision rate when subject to univariate and multivariate analysis. The revision rate incorporating hospital locations, volumes and levels revealed no significant difference with each other. Conclusions Adenoidectomy is a generally safe surgical procedure, with low complication and low revision rate. Our study indicated that the revision rate of adenoidectomy might be lower when performed by young visiting staff with medium to higher surgical volume in the medium to higher volume hospital. If patients had diseases such as otitis media with effusion, sinusitis, chronic pharyngitis, and sleep disorder, they would be subject to higher rate of re-adenoidectomy. Surgeons should be aware and sufficiently explain this information to the parents before surgery.

We report the first nationwide population-based cohort study using Taiwan's National Health Insurance Research Database on the association between enterovirus (EV) infection and the incidence of sleep disorders in a pediatric population.Two matched groups of children under 18 years of age were included in the analyses for nonapneic sleep disorder and obstructive sleep apnea (OSA). Among them, 316 subjects were diagnosed with OSA during the surveillance period, including 182 in the EV infection group and 134 in the non-EV infection group.Hospitalization because of EV infection was associated with OSA after adjusting for age, sex, urbanization atopic disease and perinatal complications (adjusted hazard ratio: 1.62, 95% confidence interval: 1.18-2.21; P = 0.003). An additional factor significantly associated with sleep apnea was allergic rhinitis (hazard ratio: 4.82, 95% confidence interval: 3.45-6.72).Children with severe EV infection (ie, requiring hospitalization) carry a significantly higher risk of developing OSA, particularly in those with allergic rhinitis. As pediatric obstructive sleep apnea is a treatable sleep disorder, we emphasize regular follow-up and early detection in children with EV infection.

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

Preventive effect of stimulants on the risk of brain injuries had been reported. The aim of this study is to determine the extent to which methylphenidate (MPH) prescription moderates the risk of traumatic brain injuries (TBI) in individuals with attention-deficit/hyperactivity disorder (ADHD). Individuals with a recent diagnosis of ADHD between January 1997 and December 2013 (n = 163,618) were identified from Taiwan's National Health Insurance Research Database. A total of 124,438 adolescents and children with ADHD and without prior TBI diagnoses were included and evaluated for subsequent TBI. Methylphenidate prescription duration was subgrouped by the annual average cumulative defined daily dose (DDD): 0, >0 to ≤28, > 28 to ≤84, and >84. We identified 11,463 diagnoses of TBI among 124,438 adolescents and children with ADHD. A Cox regression model was used to investigate whether MPH prescription influenced the risk for TBI after adjusting for sex, age, level of urbanization, seizure, autism and sedative-anxiolytics use. A reduced TBI incidence was observed with MPH prescription DDDs > 84. The protective effect of MPH against TBI persisted after adjusting for confounding factors [hazard ratio (HR) = 0.49; 95% confidence interval (CI): 0.47-0.51]. There was also statistically significant difference in risk for TBI in subjects receiving > 0 to ≤28 or >28 to ≤84 DDDs of MPH treatment (HR = 0.88, 95% CI = 0.83-0.92; HR = 0.76, 95% CI = 0.72-0.80, respectively) when compared with subjects not receiving treatment with MPH. Treatment with MPH for greater than 84 DDDs reduced the risk for TBI among children with ADHD.

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.

Aims Attention-deficit/hyperactivity disorder (ADHD) is associated with a higher risk of burn injury than in the normal population. Nevertheless, the influence of methylphenidate (MPH) on the risk of burn injury remains unclear. This retrospective cohort study analysed the effect of MPH on the risk of burn injury in children with ADHD. Method Data were from Taiwan's National Health Insurance Research Database (NHIRD). The sample comprised individuals younger than 18 years with a diagnosis of ADHD (n = 90 634) in Taiwan's NHIRD between January 1996 and December 2013. We examined the cumulative effect of MPH on burn injury risk using Cox proportional hazards models. We conducted a sensitivity analysis for immortal time bias using a time-dependent Cox model and within-patient comparisons using the self-controlled case series model. Results Children with ADHD taking MPH had a reduced risk of burn injury, with a cumulative duration of treatment dose-related effect, compared with those not taking MPH. Compared with children with ADHD not taking MPH, the adjusted hazard ratio for burn injury was 0.70 in children taking MPH for Conclusion This study showed that MPH treatment was associated with a lower risk of burn injury in a cumulative duration of treatment dose-related effect manner.

Hsuan Lee,1,* Vincent Chin-Hung Chen,2,3,* Yao-Hsu Yang,4– 6 Ting-Yu Kuo,4 Tzu-Chin Lin,7,8 Shu-I Wu,9,10 Kai-Liang Kao,11,12 Jun-Cheng Weng,3,13 Brent Allan Kelsen,14,15 Sophie Hsin-Yi Liang2,16 1Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; 2Department of Medicine, Chang Gung University, Taoyuan, Taiwan; 3Department of Psychiatry, Chang Gung Memorial Hospital at Chiayi,Chiayi,Taiwan; 4Health Information and Epidemiology Laboratory of Chang Gung Memorial Hospital, Chiayi Branch, Chiayi,Taiwan; 5Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital,Taiwan; 6School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan; 7Bethel Psychiatric Clinic, Taipei, Taiwan; 8Institute of Science, Technology and Society, National Yang-Ming University Taipei, Taiwan; 9Mackay Memorial Hospital, Section of Psychiatry, Taipei, Taiwan; 10Department of Medicine, Mackay Medical College, Taipei, Taiwan; 11Department of Pediatrics, Far Eastern Memorial Hospital, Taipei, Taiwan; 12Department of Industrial Management, Oriental Institute of Technology, Taipei, Taiwan; 13Department of Medical Imaging and Radiological Sciences, Chang Gung University, Taoyuan, Taiwan; 14Language Center, National Taipei University, New Taipei City, Taiwan; 15Department of Psychology, Auckland University of Technology, Auckland, New Zealand; 16Department of Child Psychiatry, Chang Gung Memorial Hospital at Taoyuan, Taoyuan, Taiwan*These authors contributed equally to this workCorrespondence: Sophie Hsin-Yi LiangDepartment of Child Psychiatry, Chang Gung Memorial Hospital at Taoyuan, No. 123, Dinghu Road, Guishan Township, Taoyuan 333, TaiwanEmail sophie.lhy@gmail.comBackground: Young individuals with attention-deficit hyperactivity disorder (ADHD) may have an elevated risk of influenza because of the difficulty in complying with the behavioral procedures that help protect against influenza. Moreover, the effects of sufficient methylphenidate treatment on influenza have received little attention.Objective: This study evaluated the association between ADHD medication usage and influenza and assessed the effect of duration of ADHD treatment on the risk of influenza using a nationwide population-based database.Methods: This study investigated methylphenidate usage and the risk of influenza among children and adolescents with ADHD. We identified 5259 young individuals aged less than 18 years who were diagnosed as having ADHD between 1996 and 2013 from the National Health Insurance Research Database of Taiwan, and we tested whether methylphenidate use affects influenza risk using Cox proportional hazard models.Results: After controlling for confounding factors, the results indicated that influenza risk significantly reduced in the group of ADHD patients who were prescribed methylphenidate for 90 days and more (hazard ratio [HR]: 0.62, 95% confidence interval [CI]: 0.52– 0.75, p< 0.001), demonstrating a 38% reduction in the risk of influenza in this group. However, this was not observed in the group of ADHD patients who used methylphenidate for 1– 90 days (HR: 0.69, 95% CI: 0.89– 1.05, p=0.12).Conclusion: The lower incidence of influenza observed in the group prescribed with methylphenidate for a longer period highlights the importance of compliance to medication and psychoeducation with regard to ADHD management.Keywords: ADHD, influenza, methylphenidate

Anxiety and depression are common emotional problems in children and adolescents. This study used a long-term tracking large database to investigate whether the proportion of children who were diagnosed with speech and language impairments were later diagnosed with anxiety or depression were significantly greater than that of matched group of the same age and gender without speech and language impairments. More than 4300 eligible children with speech and language impairments and matched controls were identified and assessed for anxiety and depression. The risk of anxiety and depressive disorders in children with speech and language impairments were examined with Cox regression analyses and adjusting for covariables (gender, age, and comorbidities). The results showed that speech and language impairments were positively associated with anxiety disorders (adjusted hazard ratio [AHR] 2.87, 95% confidence interval [CI] 2.20–3.76) and depressive disorders (AHR 2.51, 95% CI 1.52–4.13). The number of boys with speech and language impairments was more than twofold that of girls, but boys did not different from girls in the risk of anxiety disorders (AHR 0.95, 95% CI 0.75–1.20) and depressive disorders (AHR 0.72, 95% CI 0.47–1.11). Infantile autism and intellectual disabilities were positively associated with anxiety (AHR 1.54, 95% CI 1.07–2.21; AHR 1.47, 95% CI 1.09–1.98), and the latter was positively associated with depression (AHR 1.83, 95% CI 1.06–3.17). In addition to speech and language impairments interventions, our findings supported the necessity of identification and interventions in anxiety and depressive disorders among children with speech and language impairments from elementary school until youth.

In this paper, we consider a joint design of the user clustering and content caching in the cache-enabled heterogenous network (HetNet) in which users in the network have distinct content preferences. The joint clustering and caching in the HetNet relies on multitude of factors, such as channel gains in all links, which may not be fully known in practice. Besides, clustering and caching may exhibit a fundamental tradeoff between the content hit probability and the spectral efficiency. We are therefore motivated to tackle this challenging problem by the deep reinforcement learning (DRL). In particular, the deep deterministic policy gradient (DDPG) algorithm is employed to manage the dynamics of clustering and caching in the HetNet with a sizable action space. Simulation results are presented to demonstrate the effectiveness of the proposed algorithm.

To ensure a physicochemically desired sequence motif to adapt a specific type of secondary structures, we compile an α-helix database allowing complicate search patterns to facilitate a data-driven design of therapeutic peptides. Nearly 1.7 million helical peptides in >130 thousand proteins are extracted along with their interacting partners from the protein data bank (PDB). The sequences of the peptides are indexed with patterns and gaps and deposited in our Therapeutic Peptide Design dataBase (TP-DB). We here demonstrate its utility in three medicinal design cases. By our pattern-based search engine but not PHI-BLAST, we can identify a pathogenic protein, Helicobacter pylori neutrophil-activating protein (HP-NAP), a virulence factor of H. pylori, which contains a motif DYKYLE that belongs to the affinity determinant motif DYKXX[DE] of the FLAG-tag and can be recognized by the anti-FLAG M2 antibody. By doing so, the known purification-tag-specific antibody is repurposed into a diagnostic kit for H. pylori. Also by leveraging TP-DB, we discovered a stretch of helical peptide matching the potent membrane-insertion pattern WXXWXXW, elucidated by MD simulations. The newly synthesized peptide has a better minimal inhibitory concentration (MIC) and much lower cytotoxicity against Candida albicans (fungus) than that of previously characterized homologous antimicrobial peptides. In a similar vein, taking the discontinued anchoring residues in the helix-helix interaction interface as the search pattern, TP-DB returns several helical peptides as potential tumor suppressors of hepatocellular carcinoma (HCC) whose helicity and binding affinity were examined by MD simulations. Taken together, we believe that TP-DB and its pattern-based search engine provide a new opportunity for a (secondary-)structure-based design of peptide drugs and diagnostic kits for pathogens without inferring evolutionary homology between sequences sharing the same pattern. TP-DB is made available at http://dyn.life.nthu.edu.tw/design/.

// Erh-Hsuan Lin 1, 2, 3, 4 , Yu-Rung Kao 1 , Chih-An Lin 5 , Ting-Yu Kuo 4 , Sheng-Ping Yang 2 , Chiung-Fang Hsu 1 , Teh-Ying Chou 3, 6 , Chao-Chi Ho 7 , Cheng-Wen Wu 1, 2, 3, 4 1 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan 2 Institute of Microbiology and Immunology, National Yang Ming University, Taipei, Taiwan 3 Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan 4 Institute of Biochemistry and Molecular Biology, National Yang Ming University, Taipei, Taiwan 5 Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University Medical College, Taipei, Taiwan 6 Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan 7 Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University Medical College, Taipei, Taiwan Correspondence to: Cheng-Wen Wu, e-mail: cwwu@ym.edu.tw Keywords: lung adenocarcinoma, Hedgehog pathway, HHIP, drug resistance, HGF/MET Received: July 30, 2015 Accepted: March 02, 2016 Published: March 22, 2016 ABSTRACT Hedgehog (HH) pathway plays an important role in embryonic development, but is largely inactive in adult except for tissue repair. Aberrant activation of HH pathway has been found in a variety of cancer types. In non-small cell lung cancer, however, the role and importance of HH pathway remain controversial. In the current study, we found that HH pathway was maintained in low activity in lung adenocarcinoma (LAC) cells under normal culture condition, but was highly induced in response to stress conditions. Activation of HH pathway promoted cell survival, growth, and invasion partially through HGF and MET signaling. Hedgehog-Interacting Protein (HHIP), a cell-surface negative regulator of HH pathway, was epigenetically silenced in LAC. Overexpression of HHIP blocked the activation of HH and HGF/MET pathways, and made cells significantly more susceptible to stress conditions. In LAC cells with acquired resistance to Epidermal Growth Factor Receptor Tyrosin Kinase Inhibitor (EGFR-TKI), we found that a part of tumor cells were much more sensitive to HH or HGF/MET inhibitors, suggesting an oncogenic addiction shift from EGFR to HH and HGF/MET pathways. In conclusion, this study showed that HH pathway is a survival signaling that drives LAC cell growth under stress conditions, and HHIP is a key regulator to block the induction of HH pathway. Targeting the HH pathway through inhibitors or HHIP thus holds promise to address EGFR-TKI resistance in LAC in clinic.

This study theoretically investigates plasmon-mediated optical binding forces, which are exerted on metal homo or heterodimers, induced by the normal illumination of a linearly polarized plane wave or Gaussian beam. Using the multiple multipole method, we analyzed the optical force in terms of Maxwell׳s stress tensor for various interparticle distance at some specific wavelengths. Numerical results show that for a given wavelength there are several stable equilibrium distances between two nanoparticles (NPs) of a homodimer, which are slightly shorter than some integer multiples of the wavelength in medium, such that metal dimer acts as bonded together. At these specific interparticle distances, the optical force between dimer is null and serves a restoring force, which is repulsive and attractive, respectively, as the two NPs are moving closer to and away from each other. The spring constant of the restoring force at the first stable equilibrium is always the largest, indicating that the first stable equilibrium distance is the most stable one. Moreover, the central line (orientation) of a dimer tends to be perpendicular to the polarization of light. For the cases of heterodimers, the phenomenon of stable equilibrium interparticle distance still exists, except there is an extra net photophoretic force drifting the heterodimer as one. Moreover, gradient force provided by a Gaussian beam may reduce the stability of these equilibriums, so larger NPs are preferred to stabilize a dimer under illumination of Gaussian beam. The finding may pave the way for using optical manipulation on the gold or silver colloidal self-assembly.

Magnetic resonance imaging (MRI) has been one of the most frequently-used diagnostic tools with high dimensional precision and positioning accuracy in clinical practices. To achieve contrast enhancement, utilization of high-efficient MR imaging contrast agents becomes a prime consideration and is indispensably reinforced the diagnosis precision, especially for the emerging precision medicine. Gadolinium (Gd)-based complexes has been widely used in current clinical MRI operations, however, numerous side effects were reported and highlighted in clinic. Those drawbacks render specific unmet needs to be clinically and technically improved with a new version of Gd-based compound. Here we report a newly-synthesized amphiphilic Gadodiamide-conjugated-carboxymethyl-hexanoyl chitosan (termed as CHC-Gd) hybrid. The gadodiamide was selected is due to it's smallest molecular size among other Gd-based complexes reported in literature, which assumed to give least influence on the resulting physicochemical properties such as colloidal stability, nanostructural evolution, and cytocompability, particularly self-assembly capability, of the resulting hybrid upon practical uses. Experimental outcomes showed a successful synthesis of the CHC-Gd hybrid using a one-pot synthesis protocol, where the gadodiamide complexes were covalently attached to the carboxyl groups along the CHC backbone. Self-assembly behavior can be observed to form a sphere-like nanoparticle of 100–200 nm in size as of amphiphilic native CHC macromolecule. Experimental outcomes indicated a largely improved cytocompatibility of the hybrid, compared with free Gd, suggesting the Gd⁺³ ions were well stabilized in the CHC nanostructure. Excellent contrastability in-vitro and in particular in vivo were measured, where for in-vivo test, a 10-40-folded reduction in dosage, compared with clinical Gd dose, was used and demonstrated a comparative-to-better imaging resolution and brightness. Therefore, from this preliminary investigation, a potential translation to clinical practice through the use of newly-synthesized amphiphilic CHC-Gd hybrid appears to be relatively promising. Refereed/Peer-reviewed

Objective Psoriasis is a chronic inflammatory disease putatively associated with dementia. However, the epidemiologic evidence of the relationship between psoriasis and dementia has been limited. We used a large national sample to investigate this relationship as well as the association between systemic therapy for psoriasis and incident dementia. Methods The cases were identified as a first recorded diagnosis of psoriasis (ICD-9-CM codes: 696.0, 696.1, or 696.8) between 1996 and 2013 from Taiwan's National Health Insurance Research Database (NHIRD). Each selected case of psoriasis was compared with 4 sex-, age-, and urbanization-matched comparison subjects. The first diagnosis of dementia (ICD-9-CM codes: 290.0-290.4, 294.1-294.2, 331.0-331.2, or 331.82) that covered vascular and nonvascular subtypes until the end of 2013 was tracked in both groups. Cox regression analyses and a competing risk model were applied to evaluate the risk, adjusting for sex, urbanization, age, hypertension, diabetes, heart disease, hyperlipidemia, stroke, and depression. The association between systemic therapy and incidence of dementia in the psoriasis group was examined in further stratified analyses. Results Overall, 3,820 patients with psoriasis and 15,280 comparisons were identified. After adjustment, a significantly higher risk of dementia was identified in the psoriasis group than in the comparison group (adjusted hazard ratio [aHR] = 1.23; 95% CI, 1.06-1.42). A significant association between psoriasis and dementia was identified for nonvascular dementia (aHR = 1.25, 95% CI, 1.07-1.45) but not for vascular dementia (aHR = 1.27, 95% CI, 0.83-1.93). Receiving systemic therapy for psoriasis for more than 90 days significantly reduced the risk of developing dementia compared with no systemic therapy (aHR = 0.66; 95% CI, 0.45-0.97). Compared with those who received no systemic therapy, the patients who received disease-modifying antirheumatic drugs and/or biologics had a significantly lower risk of dementia incidence (aHR = 0.69; 95% CI, 0.50-0.97), which was not the case in patients who received only phototherapy. Conclusions Individuals with psoriasis have a significantly higher incidence of dementia, particularly the nonvascular type. Systemic therapy might be protective in preventing dementia in patients with psoriasis.

Patients with risk factors including younger age, mastoiditis, external ear disease, treatment by older surgeons, and concomitant mastoidectomy should receive detailed management to minimize the probability of re-operation for chronic otitis media (COM).Although COM remains a common ear disease requiring surgical intervention, its re-operation risks are less well-documented. This study aimed to compare patients with COM who underwent re-operation and those patients with no re-operation, and identify the risks of re-operation.This retrospective cohort study analyzed the trend of COM surgery from 1999-2009, and identified the re-operation risks of 18 895 patients with COM who underwent surgery from 2002-2006 using the National Health Insurance Research Database in Taiwan.Among the study population, 129 patients underwent revision surgery during a 5.5 ± 1.5 year follow-up period. A univariate logistic regression analysis showed that the re-operation rate was significantly higher in patients under 18 years of age, those with mastoiditis, disorders of external ear, treatment by surgeons of 50-64 years of age, use of a very high volume surgeon, and combined surgery with mastoidectomy. A multivariate analysis further limited the re-operation risk factors to younger patients, those with mastoiditis, external ear disorders, treatment by older surgeons, and concomitant mastoidectomy.

Helicobacter pylori neutrophil-activating protein (HP-NAP) activates several innate leukocytes including neutrophils, monocytes, and mast cells. It has been reported that HP-NAP induces degranulation and interleukin-6 (IL-6) secretion of rat peritoneal mast cells. However, the molecular mechanism is not very clear. Here, we show that HP-NAP activates human mast cell line-1 (HMC-1) cells to secrete histamine and IL-6. The secretion depends on pertussis toxin (PTX)-sensitive heterotrimeric G proteins but not on Toll-like receptor 2. Moreover, HP-NAP induces PTX-sensitive G protein-mediated activation of extracellular signal-regulated kinase 1/2 (ERK1/2), p38-mitogen-activated protein kinase (p38 MAPK), and Akt in HMC-1 cells. Inhibition of ERK1/2, p38 MAPK, or phosphatidylinositol 3-kinase (PI3K) suppresses HP-NAP-induced release of histamine and IL-6 from HMC-1 cells. Thus, the activation of HMC-1 cells by HP-NAP is through Gi-linked G protein-coupled receptor-mediated MAPKs and PI3K/Akt pathways.

Both virus-induced asthma and enterovirus (EV) infection are common in children; however, the relationship between EV infection and virus-induced asthma has not been systematically investigated in a cohort study. This nationwide population-based cohort study investigated the association between EV infection and asthma.We used data from the Taiwan National Health Insurance Research Database. The study sample consisted of insured children who were younger than 18 years and had EV infection between 1997 and 2013 and were followed until December 2013. We identified 36,935 children with EV infection and compared them based on 36,935 age-, sex-, urbanization- and income-matched controls to analyze the risk of subsequent asthma. Cox regression analyses were performed and adjusted for sex, age, urbanization, income, preterm labor and small for gestational age, perinatal complications, allergic rhinitis, allergic conjunctivitis, atopic dermatitis and bronchiolitis.The mean follow-up interval for all patients was 8.59 years (standard deviation = 4.35 years). The mean latency period between initial EV infection and onset of asthma was 2.77 years (standard deviation = 2.43 years). EV infection was significantly associated with a higher incidence of asthma (hazard ratio = 1.65; 95% confidence interval: 1.60-1.71).A significant association was observed between EV infection and asthma in children. Health providers should be aware of the higher potential for children with EV to develop asthma in the future.

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.

Myotonic dystrophy type 1 (DM1) is caused by an expansion of CTG repeats in the 3' untranslated region (UTR) of the dystrophia myotonia protein kinase (DMPK) gene. Cognitive impairment associated with structural change in the brain is prevalent in DM1. How this histopathological abnormality during disease progression develops remains elusive. Nuclear accumulation of mutant DMPK mRNA containing expanded CUG RNA disrupting the cytoplasmic and nuclear activities of muscleblind-like (MBNL) protein has been implicated in DM1 neural pathogenesis. The association between MBNL dysfunction and morphological changes has not been investigated. We generated a mouse model for postnatal expression of expanded CUG RNA in the brain that recapitulates the features of the DM1 brain, including the formation of nuclear RNA and MBNL foci, learning disability, brain atrophy and misregulated alternative splicing. Characterization of the pathological abnormalities by a time-course study revealed that hippocampus-related learning and synaptic potentiation were impaired before structural changes in the brain, followed by brain atrophy associated with progressive reduction of axon and dendrite integrity. Moreover, cytoplasmic MBNL1 distribution on dendrites decreased before dendrite degeneration, whereas reduced MBNL2 expression and altered MBNL-regulated alternative splicing was evident after degeneration. These results suggest that the expression of expanded CUG RNA in the DM1 brain results in neurodegenerative processes, with reduced cytoplasmic MBNL1 as an early event response to expanded CUG RNA.

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.

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.

Post-traumatic endocrine dysfunction is a complication of traumatic brain injury (TBI). However, there is lack of long-term follow-up and large sample size studies. This study included patients suffering from TBI registered in the Health Insurance Database. Endocrine disorders were identified using the ICD codes: 244 (acquired hypothyroidism), 253 (pituitary dysfunction), 255 (disorders of the adrenal glands), 258 (polyglandular dysfunction), and 259 (other endocrine disorders) with at least three outpatient visits within 1 year or one admission diagnosis. Overall, 156,945 insured subjects were included in the final analysis. The 1- and 5-year incidence rates of post-traumatic endocrinopathies were 0.4% and 2%, respectively. The risks of developing a common endocrinopathy (p

Helicobacter pylori neutrophil-activating protein (HP-NAP) is a major virulence factor of Helicobacter pylori (H. pylori). It plays a critical role in H. pylori-induced gastric inflammation by activating several innate leukocytes including neutrophils, monocytes, and mast cells. The immunogenic and immunomodulatory properties of HP-NAP make it a potential diagnostic and vaccine candidate for H. pylori and a new drug candidate for cancer therapy. In order to obtain substantial quantities of purified HP-NAP used for its clinical applications, an efficient method to purify this protein with high yield and purity needs to be established. In this protocol, we have described a method for one-step negative chromatographic purification of recombinant HP-NAP overexpressed in Escherichia coli (E. coli) by using diethylaminoethyl (DEAE) ion-exchange resins (e.g., Sephadex) in batch mode. Recombinant HP-NAP constitutes nearly 70% of the total protein in E. coli and is almost fully recovered in the soluble fraction upon cell lysis at pH 9.0. Under the optimal condition at pH 8.0, the majority of HP-NAP is recovered in the unbound fraction while the endogenous proteins from E. coli are efficiently removed by the resin. This purification method using negative mode batch chromatography with DEAE ion-exchange resins yields functional HP-NAP from E. coli in its native form with high yield and purity. The purified HP-NAP could be further utilized for the prevention, treatment, and prognosis of H. pylori-associated diseases as well as cancer therapy.

Palatoplasty can significantly decrease their middle ear re-intubation rate with a relatively lower hazard ratio compared to children who underwent VTI only.In children with cleft palate, questions remain about the overall effect of ventilation tube insertion (VTI) and palatoplasty for their OME. A large-scale study might offer more evidence for the roles of palatal surgery.This was a retrospective birth cohort study based upon a national database. We analyzed children born between 1999-2004 and diagnosed as cleft palate and/or lips. These children, according to their surgeries, were separated into two groups: (1) VTI only, and (2) VTI and palatoplasty. Kaplan-Meier analysis and log-rank test were used to calculate their cumulative tube re-insertion rates. Their hazard ratios of tube re-insertion were also analyzed.In total, 1205 cleft children were collected, with 151 in the VTI only group and 1054 in the VTI + palatoplasty group. Ventilation tube re-insertion rates were significantly lower in the VTI + palatoplasty group (p = 0.002). The cumulative re-insertion rates also showed a significant difference (p = 0.001). When compared to the VTI only group, the adjusted hazard ratio was 0.528 in the VTI + palatoplasty group (p = 0.001).

The extension of axon branches is important for target innervation but how axon branching is regulated is currently not well understood. Here, we report that Bcl11A/CTIP1/Evi9, a zinc finger transcription factor, downregulates axon branching. Knockdown of Bcl11A induced axon branching and multi-axon formation, as well as dendrite outgrowth. Due to alternative splicing, a single Bcl11A gene encodes two protein products, Bcl11A-L and -S. Bcl11A-L was found to be the main Bcl11A player in regulation of neurite arborization; Bcl11A-S is an antagonist of Bcl11A-L. Time-lapse study further suggests that Bcl11A-L knockdown enhances axon dynamics and increases the duration of axon outgrowth. Finally, the expression of DCC and MAP1b, two molecules involved in direction and branching of axon outgrowth, is controlled by Bcl11A-L. DCC overexpression rescues the phenotype induced by Bcl11A-L knockdown. In conclusion, this report provides the first evidence that Bcl11A is important for neurite arborization.

We introduce an idea of synthesizing a class of genetic registers based on the existing sequential biological circuits, which are composed of fundamental biological gates. In the renowned literature, biological gates and genetic oscillator have been unveiled and experimentally realized in recent years. These biological circuits have formed a basis for realizing a primitive biocomputer. In the traditional computer architecture, there is an intermediate load-store section, i.e. a register, which serves as a part of the digital processor. With which, the processor can load data from a larger memory into it and proceed to conduct necessary arithmetic or logic operations. Then, manipulated data are stored back to the memory by instruction via the register. We propose here a class of bio-registers for the biocomputer. Four types of register structures are presented. In silicon experiments illustrate results of the proposed design.

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.