Miracle-dz/UniFAR-FTUs huggingface dataset:
Tau mutants bind tubulin heterodimers with enhanced affinity

Significance The microtubule binding protein tau is implicated in the pathology of a number of devastating neurological disorders. Both loss of function arising from altered interactions with microtubules and gain of toxic function tied to tau aggregation are thought to have a role in disease etiology. Here, we demonstrate that point mutants of tau implicated in disease enhance the affinity between tau and tubulin dimers. Our results lend insight into the mechanism of tau-mediated microtubule polymerization. Importantly, our findings highlight the significance of the interaction between tau and free tubulin, introducing it as a new focus for research on the role of tau in neurodegeneration. Tau is a microtubule binding protein that forms pathological aggregates in the brain in Alzheimer’s disease and other tauopathies. Disease etiology is thought to arise from loss of native interactions between tau and microtubules, as well as from gain of toxicity tied to tau aggregation, although neither mechanism is well understood. Here we investigate the link between function and disease using disease-associated and disease-motivated mutants of tau. We find that mutations to highly conserved proline residues in repeats 2 and 3 of the microtubule binding domain have differential effects on tau binding to tubulin and the capacity of tau to enhance tubulin polymerization. Notably, mutations to these residues result in an increased affinity for tubulin dimers while having a negligible effect on binding to stabilized microtubules. We measure conformational changes in tau on binding to tubulin that provide a structural framework for the observed altered affinity and function. Additionally, we find that these mutations do not necessarily enhance aggregation, which could have important implications for tau therapeutic strategies that focus solely on searching for tau aggregation inhibitors. We propose a model that describes tau binding to tubulin dimers and a mechanism by which disease-relevant alterations to tau impact its function. Together, these results draw attention to the interaction between tau and free tubulin as playing an important role in mechanisms of tau pathology.
Differentiating patterns of substance misuse by subtypes of antisocial traits in male offenders

Abstract Among criminal offenders, two subtypes of antisocial traits, psychopathy and externalizing-only, are associated with an especially elevated risk for substance use disorders (SUDs). The present study examined the associations of these traits with patterns of substance misuse. In a sample of 1410 male offenders, we used diagnoses for alcohol, cannabis, opioids, and stimulants to examine the association between antisocial traits and SUD severity, as well as, age at substance use initiation. Results indicated that externalizing-only, but not psychopathic, traits predicted greater severity of SUDs (i.e. increased likelihood of dependence) across all substances. By contrast, psychopathic, but not externalizing-only, traits predicted earlier initiation of use across all substances. These differential patterns of substance misuse may be a reflection of distinct psychobiological processes. Ultimately, parsing the patterns of substance use across a continuum of clinically heterogeneous samples, rather than within circumscribed diagnostic categories, might help to refine the phenotype and improve the prediction of substance-related problems.
p‐Ethynylphenylalanine

Abstract: Tryptophan hydroxylase (TPH) is the initial and rate‐limiting enzyme in serotonin biosynthesis. The enzyme activity is dependent on molecular oxygen, a tetrahydropterin cosubstrate, and ferrous iron. The present study demonstrates that TPH is inhibited by a novel compound, p‐ethynylphenylalanine (pEPA), produced by the Heck reaction of trimethylsilylacetylene with N‐tert‐butyloxycarbonyl‐4‐iodo‐L‐phenylalanine methyl ester. pEPA is a more potent and specific inhibitor of TPH than p‐chlorophenylalanine (pCPA). In the present study, pEPA was demonstrated to inhibit competitively and reversibly TPH in vitro (Ki = 32.6 ± 6.2 μM vs. tryptophan). pEPA displayed little inhibitory activity toward tyrosine hydroxylase (EC 1.14.16.2), the initial and rate‐limiting enzyme for catecholamine biosynthesis, and no inhibition of phenylalanine hydroxylase or tyrosinase. In addition, pEPA was a poor ligand for the serotonin transporter and several serotonin receptors. Administration of pEPA (30 mg/kg) to rats produced a 95 ± 5% decrease in TPH activity in brain homogenates and a concomitant decrease in serotonin and 5‐hydroxyindole‐3‐acetic acid levels (85%) at 24 h after injection. In contrast, pCPA produced a similar effect (87 ± 5% decrease in TPH activity) only at 10 times the concentration (300 mg/kg). These results suggest that pEPA is a selective, reversible, and potent inhibitor of TPH both in vitro and in vivo. The potential for pEPA to inhibit selectively and reversibly the biosynthesis of serotonin may contribute to the characterization of the role of serotonin in behavioral and physiological activities.
Cross-Cultural Adaptation in the Discourse of Education and Motherhood: An Autoethnography of a Korean International Graduate Student Mother in the United States.

This study explores the cross-cultural adaption experience of myself as a Korean graduate student woman coming from a Confucian-heritage culture. The study focuses on the multiple roles I played as an Asian graduate student mother in the host cultural environment and the way I have undergone throughout the process of my adaptation. As a research method, this study adopted autoethnographic way of writing while using cartoons as a way of representing main themes. Drawing upon discourse and ideologies about Confucian values and gender roles, this dissertation aims to investigate how those discourses and ideologies impact on my life living as a marginalized figure. The main research questions explored in this study were as follows: (1) What does it mean for a Korean graduate student mother to have a cross-cultural adaptation experience and how did I deal with some challenges and conflicts? , (2) How does my cross-cultural mothering experience contribute to the general understanding of feminism in the context of a diverse society? , and (3) How does my cross-cultural adaptation experience contribute to the general understanding on expatriates in the context of a diverse society? As an international student coming from a Confucian-heritage culture, I found myself feeling uncomfortable with the non-power distance cultural aspects represented in American university; I made adaptive changes in attitudes during class, in addition to different student-faculty interactions, which seemed to require less obedience from the students and more active communication. My status as an international student was also a crucial factor influencing my decision about the timing of motherhood. Studying and becoming a mother in a foreign country would mean a double burden of childcare and study while living far away from home without possible familial support available. Thus,
Multiple clusters of A(H1N1)pdm09 virus circulating in severe cases of influenza during the 2010–2011 season: A phylogenetic and molecular analysis of the neuraminidase gene

The molecular characterization of circulating influenza A viruses is crucial to detect mutations potentially involved in increased virulence, drug resistance and immune escape. A molecular and phylogenetic analysis of A(H1N1)pdm09 neuraminidase (NA) gene sequences from different patient categories defined according to the severity of influenza infection were analyzed. A total of 126 influenza A(H1N1)pdm09 positive samples from patients with severe infections in comparison with those with moderate and mild infections was performed in Lombardy (Northern Italy, nearly 10 million inhabitants) during the 2010–2011 season. NA sequences included in this study segregated into five distinct clusters. Nineteen amino acid substitutions were detected exclusively in NA sequences of viruses identified in patients with severe or moderate influenza infection. Three of them (F74S, S79P, E287K) were observed in virus strains with the 222G/N hemagglutinin mutation. None of NA sequences under study had mutations related to the resistance to the NA inhibitors. Four out of 126 (3.2%) NA sequences from patients with severe infection lost a N‐linked glycosylation site due to the change from N to K at residue 386. Two additional N‐linked glycosylation sites in the NA stalk region (residues 42 and 44) were found in 12 (9.5%) NA sequences. Sporadic NA mutations were detected in NA viral sequences from critically ill patients, and no variants with reduced sensitivity to NA inhibitors were observed either in treated or untreated patients. J. Med. Virol. 85: 944–952, 2013. © 2013 Wiley Periodicals, Inc.
Dynamics of effective portfolio diversification among EFA markets: a heterogeneous panel analysis

This paper focuses on the role of various factors of international co-movement patterns among equity returns of frontier and emerging markets. This study originated from Markowitz portfolio theory (1952) after which Grubel (1968) applied his concepts of diversification. This study fills the previous gaps by providing information about role that various factors have on international stock market co-movement rather than relying only on the return correlation. We constructed an international co-movement index through rolling beta estimation method followed by the estimation of bilateral market and economic variables. In the end, we applied panel data analysis to find level of variance that these included markets, financial and macro-economic variables have on stock market co-movement. Results highlight significant role of market size differential and macro-economic variables in explaining return co-movement of Pakistan with rest of the countries. Significance of our macro-economic factors are in accordance with portfolio balance theory presented by Kodres and Pritsker (2002) stating that investors possess information about macro-economic variables thereby readjusting their portfolios for effective diversification.
Functional Anatomical Correlates of Controlled and Automatic Processing

Behavioral studies have shown that consistent practice of a cognitive task can increase the speed of performance and reduce variability of responses and error rate, reflecting a shift from controlled to automatic processing. This study examines how the shift from controlled to automatic processing changes brain activity. A verbal Sternberg task was used with continuously changing targets (novel task, NT) and with constant, practiced targets (practiced task, PT). NT and PT were presented in a blocked design and contrasted to a choice reaction time (RT) control task (CT) to isolate working memory (WM)-related activity. The three-dimensional (3-D) PRESTO functional magnetic resonance imaging (fMRI) sequence was used to measure hemodynamic responses. Behavioral data revealed that task processing became automated after practice, as responses were faster, less variable, and more accurate. This was accompanied specifically by a decrease in activation in regions related to WM (bilateral but predominantly left dorsolateral prefrontal cortex (DLPFC), right superior frontal cortex (SFC), and right frontopolar area) and the supplementary motor area. Results showed no evidence for a shift of foci of activity within or across regions of the brain. The findings have theoretical implications for understanding the functional anatomical substrates of automatic and controlled processing, indicating that these types of information processing have the same functional anatomical substrate, but differ in efficiency. In addition, there are practical implications for interpreting activity as a measure for task performance, such as in patient studies. Whereas reduced activity can reflect poor performance if a task is not sensitive to practice effects, it can reflect good performance if a task is sensitive to practice effects.
Methods for measuring water activity (a w ) of foods and its applications to moisture sorption isotherm studies

ABSTRACT Moisture sorption isotherm is commonly determined by saturated salt slurry method, which has defects of long time cost, cumbersome labor, and microbial deterioration of samples. Thus, a novel method, aw measurement (AWM) method, has been developed to overcome these drawbacks. Fundamentals and applications of this fast method have been introduced with respects to its typical operational steps, a variety of equipment set-ups and applied samples. The resultant rapidness and reliability have been evaluated by comparing with conventional methods. This review also discussed factors impairing measurement precision and accuracy, including inappropriate choice of predryingwetting techniques and unachieved moisture uniformity in samples due to inadequate time. This analysis and corresponding suggestions can facilitate improved AWM method with more satisfying accuracy and time cost.
Pricing annuities: The role of taxation in retirement decisions

This paper investigates the role of taxation in individual annuitization decisions by exploiting differences in relative taxation between the one-off lump sum payment and the life-long annuity. In a first step taxes are imputed for both the lump sum and the annuity for each individual whose retirement choice is recorded in an administrative dataset from a large Swiss pension fund. Using a variety of measures of taxation we show that taxes can explain a significant part of the variation in annuity rates. Furthermore, exploiting kinks in the tax schedule within a regression discontinuity framework we find evidence for tax optimization strategies by individuals. The results of this paper suggest that individuals react strongly to tax incentives when making retirement choices.
Family factors associated with children's handwashing hygiene behavior

Despite the importance of children’s hand hygiene and family influence on children’s behaviors, few studies have been dedicated to identifying family factors affecting handwashing practice. This study investigated the entire group of sixth-grade students (N = 2323) and their parents (N = 2089) at 11 elementary schools randomly selected from the Seoul Metropolitan Area, Korea. The results show that parents’ handwashing practice, parent and child bonding, and shared time have a significant correlation with children’s hand hygiene practice. The thoroughness of hand cleansing is more likely to be associated with health education, parents’ practice of proper handwashing, greater parent–child bonding, and a greater amount of shared time with parents. Parent–child bonding and shared time are crucial in promoting children’s hand hygiene. These results imply that public health policies need to be targeted at not only providing health education but at increasing parent–child bonding and shared time in order to promote children’s health more effectively.
Fluoroscopically guided diagnostic and therapeutic injections into foot articulations: report of short-term patient responses and comparison of outcomes between various injection sites.

OBJECTIVE A few studies have reported on short-term outcomes of patients receiving imaging-guided injections into the foot articulations, but none have compared patient responses depending on the anatomic site injected. This study includes a large sample size facilitating the investigation of postinjection pain reduction overall and by specific articulation. MATERIALS AND METHODS Three hundred forty-eight patients with imaging-guided diagnostic or therapeutic injections into the foot articulations, with complete preinjection and 20- to 30-minute postinjection numeric rating scale pain data were included. The proportions of patients reporting clinically relevant pain reduction (≥ 50%) were calculated overall and for specific subgroups. The risk ratio comparing patients with osteoarthritis to those without osteoarthritis was calculated. Analysis of variance was used to compare outcomes between subgroups of patients based on injection site. The unpaired Student t test was used to compare responses of men versus women, those with and without a diagnosis of osteoarthritis, and more experienced versus less experienced radiologists. RESULTS Sixty-four percent of patients (224/348) reported clinically relevant pain reduction. The average decrease overall was 56% (SD, 36). Injections into the Lisfranc articulation were significantly more effective (61% pain reduction, p = 0.007) compared with other sites, with 74% of patients obtaining clinically relevant pain relief. Patients with osteoarthritis reported more relief (62%) compared with those without (50%, p = 0.002). No difference in outcomes comparing musculoskeletal radiologists with residents or fellows in training was found. CONCLUSION Nearly two thirds of patients receiving imaging-guided injections into the foot articulations reported clinically relevant pain reduction. Lisfranc joint injections and patients with a diagnosis of osteoarthritis responded better.
Magnetic resonance imaging evaluation of the effects of juvenile rheumatoid arthritis on distal femoral weight-bearing cartilage.

OBJECTIVE To examine magnetic resonance imaging-derived T2 relaxation times in the weight-bearing cartilage of the distal femur in healthy children and in children with juvenile rheumatoid arthritis (JRA). METHODS T2 relaxation time maps were created for 39 girls (ages 4.9-10.9 years), 21 of whom were considered healthy and 18 of whom had JRA. The spatial distribution of T2 relaxation times for the distal femoral weight-bearing cartilage (including epiphyseal and articular cartilage) was mapped for each group as a whole. Average data sets for each group were then compared using paired t-tests to detect differences between the 2 populations. RESULTS The spatial distribution of T2 relaxation time values was nearly identical in the 2 groups, with a concave curve that was highest near the subchondral bone and articular surfaces. The average T2 relaxation times were significantly higher in the girls with JRA than in the group of healthy girls (P < 0.05). CONCLUSION The finding of an increased average T2 relaxation time in the children with JRA suggests that T2 relaxation time maps may reflect cartilage microstructure differences that occur in JRA. T2 relaxation time mapping may allow for early detection of cartilage changes and provide an objective, quantitative method of monitoring disease progression, with the long-term potential to guide therapy.
Validation of the Chinese Pain Catastrophizing Scale (HK-PCS) in patients with chronic pain.

OBJECTIVE This study was conducted to examine the psychometric properties of a Chinese translation of the Pain Catastrophizing Scale (HK-PCS). DESIGN/PATIENTS Patients aged 18-79 years (N = 130) with chronic nonmalignant pain attending an outpatient multidisciplinary pain center in Hong Kong participated in this cross-sectional study. METHOD Subjects completed a set of health-related instruments: HK-PCS, Hospital Anxiety and Depression Scale, Roland Morris Disability Questionnaire, SF-36 Health Survey, and a general demographic questionnaire. Data were analyzed for the distribution, internal consistency, reliability, and construct validity. RESULTS A satisfactory internal consistency was found (alpha = 0.927). The item-total correlation coefficients ranged from 0.575 to 0.777. The intraclass correlation coefficient was 0.969 for the total HK-PCS score, 0.956 for helplessness, 0.945 for magnification, and 0.910 for rumination. Confirmatory factor analysis verified a second-order factor structure with the comparative fit index = 1.00, root mean square error of approximation = 0.038, and normed fit index = 0.99 (chi(2) ((58)) = 68.84, P = 0.16). Significant correlations were found for pain intensity, disability, anxiety, and depression (r = 0.223-0.597, P < 0.01). The general health, social function, role emotional, and mental health domains of the SF-36 consistently demonstrated negative association with catastrophizing across all HK-PCS scores (r =-0.279 to -0.396, P < 0.01). No gender difference was noted for HK-PCS scores (P > 0.05), which is contrary to the existing literature. CONCLUSION This study has illustrated satisfactory psychometric properties of the HK-PCS. We provide evidence for the validity and reliability of the HK-PCS as an instrument for measuring pain catastrophizing in the Chinese patient with chronic pain.
Pharmacodynamic Evaluation of Extending the Administration Time of Meropenem using a Monte Carlo Simulation

ABSTRACT A Monte Carlo simulation demonstrated that 1 g of meropenem (MEM) every 8 h (q8h) (3-h infusion) has a higher target attainment rate against Pseudomonas aeruginosa than either 500 mg of MEM q8h (3-h infusion) or 0.5 g of imipenem-cilastatin (I-C) q6h (1-h infusion). For other pathogens, 500 mg of MEM q8h was equivalent or superior to I-C.
Plasma cortisol levels in depression and other psychiatric disorders: a study of newly admitted psychiatric patients

Synopsis Morning and evening plasma cortisol levels were checked in 123 consecutively newly admitted psychiatric patients with a variety of diagnoses. Questions asked were whether there were differences among groups with more severe illness, type of depression, alcohol abuse, or particular symptoms. Morning cortisol elevation was found in 33% of patients and was not associated with any particular diagnostic category. Evening cortisol elevation occurred in 85% of the subjects. It was significantly higher in those with unipolar depression and organic brain syndrome, also in those patients who abused alcohol regardless of diagnosis. Evening cortisol elevation was twice as common in patients with diagnoses of more severe psychiatric illness than in those with minor disorders. Further study is suggested to see if these patterns of cortisol elevation are sustained beyond the stress-of-admission period.
Cochlear Dysfunction in IDDM Patients With Subclinical Peripheral Neuropathy

OBJECTIVE To investigate the function of the auditory pathway from the cochlea to the auditory cortex in subjects with IDDM. RESEARCH DESIGN AND METHODS Brain stem, middle-, and long-latency auditory-evoked responses and evoked otoacoustic emissions were measured in 48 normally hearing IDDM patients and in age- and sex-matched nondiabetic subjects. Peripheral neuropathy was diagnosed by nerve conduction velocity (NCV) at the peroneal and sural nerves. Auditory brain stem responses (ABRs) reflect auditory pathway function within the brain stem; middle-latency responses (MLRs) and long-latency responses (LLRs) originate from the auditory cortex; and evoked otoacoustic emissions (EOAEs) give objective information about preneural, mechanical elements of the cochlear function. RESULTS A subclinical peripheral neuropathy was found in 12 diabetic patients. We found higher latencies of waves I (t = 4.4, P < 0.0001), III (t = 3.7, P = 0.0004), and V (t = 2.7, P = 0.008) of ABRs in diabetic patients (I: 1.7 ± 0.13 ms; III: 3.9 ± 0.17 ms; V: 5.7 ± 0.24 ms), compared with those of the control group (I: 1.6 ± 0.13 ms; III: 3.7 ± 0.18 ms; V: 5.6 ± 0.17 ms). However, neither central transmission time (i.e., the wave interpeak I-V) nor MLRs and LLRs were found to be significantly different in diabetic and control subjects. Mean EOAE amplitude was found to be significantly reduced (F = 4.2, P = 0.02) in diabetic patients with a reduced NCV (7.6 ± 3.9 dB; Scheffé test: P = 0.03), but not in those without neuropathy (9.1 ± 4.2 dB), compared with the control group (10.8 ± 3.1 dB). No correlations were found between duration of diabetes and EOAEs or between sural NCV and peroneal NCV and metabolic control. EOAEs were not correlated with peroneal and sural NCVs. CONCLUSIONS Our results indicate that the early preneural dysfunction of cochlear receptors causes a prolonged activation of the peripheral portion of the auditory pathway, while signal conduction along the central auditory pathway was shown to be normal in diabetes.