Miracle-dz/UniFAR-FTUs huggingface dataset:
Mechanistic and Evolutionary Insights from the Reciprocal Promiscuity of Two Pyridoxal Phosphate-dependent Enzymes

Enzymes that utilize the cofactor pyridoxal 5′-phosphate play essential roles in amino acid metabolism in all organisms. The cofactor is used by proteins that adopt at least five different folds, which raises questions about the evolutionary processes that might explain the observed distribution of functions among folds. In this study, we show that a representative of fold type III, the Escherichia coli alanine racemase (ALR), is a promiscuous cystathionine β-lyase (CBL). Furthermore, E. coli CBL (fold type I) is a promiscuous alanine racemase. A single round of error-prone PCR and selection yielded variant ALR(Y274F), which catalyzes cystathionine β-elimination with a near-native Michaelis constant (Km = 3.3 mm) but a poor turnover number (kcat ≈10 h−1). In contrast, directed evolution also yielded CBL(P113S), which catalyzes l-alanine racemization with a poor Km (58 mm) but a high kcat (22 s−1). The structures of both variants were solved in the presence and absence of the l-alanine analogue, (R)-1-aminoethylphosphonic acid. As expected, the ALR active site was enlarged by the Y274F substitution, allowing better access for cystathionine. More surprisingly, the favorable kinetic parameters of CBL(P113S) appear to result from optimizing the pKa of Tyr-111, which acts as the catalytic acid during l-alanine racemization. Our data emphasize the short mutational routes between the functions of pyridoxal 5′-phosphate-dependent enzymes, regardless of whether or not they share the same fold. Thus, they confound the prevailing model of enzyme evolution, which predicts that overlapping patterns of promiscuity result from sharing a common multifunctional ancestor.
A GENERALIZED DISTRIBUTED LAG MODEL FOR PREDICTING QUARTERLY EARNINGS

Despite much research, uncertainty still exists regarding the choice of appropriate time-series models for forecasting earnings and other purposes. One factor previously not explored is the role of nonaccounting information in forecasting earnings. In this paper, I propose an empirical methodology for forecasting earnings which allows the introduction of nonaccounting data via a distributed lag with macro (DLWM) variables model. Predictions from this model were compared with those of several models suggested in previous studies for a sample of capital goods and durable goods firms wherein I found that the DLWM methods moderated the explosive nature of earnings predictions errors encountered in recent years. However, the DLWM approach did not dominate other prediction methods in all cases. The conclusions of the study must be considered preliminary because (1) alternative specifications were not explored and (2) relatively crude methods were used to predict the macroeconomic variables themselves. Previous attempts to validate and compare various earnings predictions by using ex post error measurement have yielded inconsistent results across industries and time. These attempts used either of two approaches to the application of Box-Jenkins (BJ) techniques. One (the parsimonious approach) relies on earnings series to establish the structure of a general model, thus avoiding the problems encountered in fitting
Knowledge, attitude and practices about oral cancers among dental students in H.P Government Dental College, Shimla-Himachal Pradesh

Abstract Aim: The aim was to assess the knowledge, attitude and practices among undergraduate dental students about oral cancer. Materials and Methods: A cross-sectional questionnaire study was conducted among undergraduate dental students between the 3rd and 5th years in H.P Government Dental College, Shimla. The questionnaire consisted of 15 questions, five each on knowledge, attitudes and practices. The data were analyzed by Statistical Package for the Social Sciences (SPSS Inc., version 16 for Windows, Chicago, IL, USA). Results: The response rate of the study was 90.6%. There were 23 (21.5%) males and 84 (78.5%) females in the study. There was a predominance of females (78.5%). The average knowledge percentage for the entire population is 81.9% (excellent knowledge). Tobacco and alcohol were correctly identified by 63.5% of the subjects. Squamous cell carcinoma was described as the most common type of oral cancer by 105 (98.3%) of the students. 60.7% of the subjects strongly disagreed that their knowledge regarding the prevention and detection of oral cancer is current and adequate, and 99% agreed that there is a need for additional training/information regarding oral cancer. About 92.5% of the subjects used to educate their subjects about the harmful effects of tobacco and alcohol. Conclusion: The study implies that the knowledge, especially about the etiological factors of oral cancer needs to be reinforced throughout the undergraduate dental courses so that they can use the same in educating and motivating the masses to adapt healthy lifestyles.
Abrogation of NF‐κB signaling in human neutrophils induces neutrophil survival through sustained p38‐MAPK activation

NF‐κB, an important transcription factor in the regulation of cellular inflammation, is one of the prime targets for novel anti‐inflammatory therapeutics. Nowadays, anti‐inflammatory therapies rely mostly on steroids, which among other effects, inhibit NF‐κB activity. However, steroids have only limited efficacy in the treatment on neutrophil‐driven diseases, such as COPD. Human neutrophils play an important role in the pathogenesis of COPD, and clearance of these cells by apoptosis is an effective pathway for resolution of inflammation. In this study, we tested the hypothesis that modulation of the NF‐κB pathway in human neutrophils affects survival. Importantly, the pharmacological NF‐κB inhibitor Bay 11‐7082 inhibited NF‐κB signaling in human neutrophils as expected. However, we found that complete inhibition of NF‐κB activity with 10 μM Bay 11‐7082 prolonged neutrophil survival significantly, which was not observed with inhibitors for other signaling pathways. Bay 11‐7082‐induced neutrophil survival was dependent on p38‐MAPK kinase activity, as the p38 kinase activity inhibitor SB203580 abrogated this response completely. Bay 11‐7082 induced rapid and sustained p38 activation that correlated with inhibited NF‐κB signaling and prolonged neutrophil survival. The precise role of NF‐κB in regulation of p38‐MAPK activation remains to be established. Under these conditions of survival, the stability of Bcl‐xL but not Mcl‐1 was enhanced. Although inhibition of NF‐κB leads to down‐regulation of inflammatory genes in many cell types, our results illustrate that interference with basal NF‐κB signaling in neutrophils as a drug target should be used with caution.
Structural change in agriculture and rural livelihoods : policy implications for the New Member States of the European Union

Table of Contents: Gertrud Buchenrieder and Judith Mollers, The transformation of the rural economy in the new member states of the European Union: Implications for empirical analyses of rural structural change and livelihoods . 1; Luka Juvancic and Tina Jaklic, Recent trends, drivers and impacts of structural change in agriculture . 37; Carmen Hubbard and Matthew Gorton, Lessons from established member states: translating good practices to the new member states . 61; Johan F.M. Swinnen and Kristine Van Herck, A comparative analysis of rural labour markets . 83; Judith Mollers, Gertrud Buchenrieder, Diana Traikova, Thomas Dufhues, Jana Fritzsch, and Cosmin Salasan, Rural livelihoods in transition: structural change beyond agriculture . 109; Sophia Davidova, Lena Fredriksson and Alastair Bailey1,Rural livelihoods in transition: market integration versus subsistence farming . 131; Dominika Milczarek-Andrzejewska, Tomasz Wolek, and Beata Łopaciuk- Gonczaryk, The role of social capital and informal cooperation: market Integration of farms in Poland . 159; Hauke J. Schnicke1, The impact of demographic patterns in Hungarian farm households on structural change . 181; Csaba Csaki and Attila Jambor, Policy conclusions and recommendations . 211
Somatization Revisited: Diagnosis and Perceived Causes of Common Mental Disorders

The assessment of somatoform disorders is complicated by persistent theoretical and practical questions of classification and assessment. Critical rethinking of professional concepts of somatization suggests the value of complementary assessment of patients’ illness explanatory models of somatoform and other common mental disorders. We undertook this prospective study to assess medically unexplained somatic symptoms and their patient-perceived causes of illness and to show how patients’ explanatory models relate to professional diagnoses of common mental disorders and how they may predict the short-term course of illness. Tertiary care patients (N = 186) with prominent somatoform symptoms were evaluated with the Structured Clinical Interview for DSM-IV, a locally adapted Explanatory Model Interview to elicit patients’ illness experience (priority symptoms) and perceived causes, and clinical self-report questionnaires. The self-report questionnaires were administered at baseline and after 6 months. Diagnostic overlap between somatoform, depressive, and anxiety disorders occurred frequently (79.6%). Patients explained pure somatoform disorders mainly with organic causal attributions; they explained pure depressive and/or anxiety disorders mainly with psychosocial perceived causes, and patients in the diagnostic overlap group typically reported mixed causal attributions. In this last group, among patients with similar levels of symptom severity, organic perceived causes were related to a lower physical health sum score on the MOS Short Form, and psychosocial perceived causes were related to less severe depressive symptoms, assessed with the Hospital Anxiety and Depression Scale at 6 months. Among patients meeting criteria for comorbid somatoform with anxiety and/or depressive disorders, complementary assessment of patient-perceived causes, a key element of illness explanatory models, was related to levels of functional impairment and short-term prognosis. For such patients, causal attributions may be particularly useful to clarify clinically significant features of common mental disorders and thereby contribute to clinical assessment.
The Gi-coupled P2Y12 Receptor Regulates Diacylglycerol-mediated Signaling in Human Platelets*

Stimulation of Gq-coupled receptors activates phospholipase C and is supposed to promote both intracellular Ca2+ mobilization and protein kinase C (PKC) activation. We found that ADP-induced phosphorylation of pleckstrin, the main platelet substrate for PKC, was completely inhibited not only by an antagonist of the Gq-coupled P2Y1 receptor but also upon blockade of the Gi-coupled P2Y12 receptor. The role of Gi on PKC regulation required stimulation of phosphatidylinositol 3-kinase rather than inhibition of adenylyl cyclase. P2Y12 antagonists also inhibited pleckstrin phosphorylation, Rap1b activation, and platelet aggregation induced upon Gq stimulation by the thromboxane A2 analogue U46619. Importantly, activation of phospholipase C and intracellular Ca2+ mobilization occurred normally. Phorbol 12-myristate 13-acetate overcame the inhibitory effect of P2Y12 receptor blockade on PKC activation but not on Rap1b activation and platelet aggregation. By contrast, inhibition of diacylglycerol kinase restored both PKC and Rap1b activity and caused platelet aggregation. Stimulation of P2Y12 receptor or direct inhibition of diacylglycerol kinase potentiated the effect of membrane-permeable sn-1,2-dioctanoylglycerol on platelet aggregation and pleckstrin phosphorylation, in association with inhibition of its phosphorylation to phosphatidic acid. These results reveal a novel and unexpected role of the Gi-coupled P2Y12 receptor in the regulation of diacylglycerol-mediated events in activated platelets.
The herpes simplex virus (HSV) protein ICP34.5 is a virion component that forms a DNA-binding complex with proliferating cell nuclear antigen and HSV replication proteins

The replicative ability of ICP34.5-null herpes simplex virus (HSV) is cell type and state dependent. In certain cells, ICP34.5 interacts with protein phosphatase 1 to preclude host cell protein synthesis shutoff by dephosphorylation of the eukaryotic initiation factor eIF-2α. However, host cell shutoff is not induced by ICP34.5-null HSV in most cells, irrespective of type and state. In general, dividing cells support replication of ICP34.5-null HSV; nondividing cells cannot. Previously the authors showed that ICP34.5 binds to proliferating cell nuclear antigen (PCNA), a protein necessary for cellular DNA replication and repair. Here the authors demonstrate that (1) the interaction between ICP34.5 and PCNA involves two regions of the virus protein; (2) ICP34.5 forms a complex with HSV replication proteins that is DNA binding; (3) at early times in infection, ICP34.5 colocalizes with PCNA and HSV replication proteins in cell nuclei, before accumulating in the cytoplasm; and (4) ICP34.5 is a virion protein. In light of ongoing clinical trials assessing the safety and efficacy of ICP34.5-null HSV, it is vital that the roles of ICP34.5 in HSV replication are understood. The authors propose that in nondividing cells, ICP34.5 is required to switch PCNA from repair to replication mode, a prerequisite for the initiation of HSV replication.
Treatment of right heart thromboemboli.

BACKGROUND The presence of right heart thromboemboli complicating pulmonary thromboemboli carries with it an increased mortality rate compared to pulmonary thromboemboli alone, but little is known about the optimal management of this difficult clinical situation. This fact is highlighted in the case study of a patient with a 19-cm right atrial thrombus complicating bilateral pulmonary thromboemboli. STUDY OBJECTIVES We sought to determine the effects of anticoagulation therapy, thrombolysis, and surgical embolectomy on mortality rate in patients with right heart thromboemboli. DESIGN Retrospective analysis of all reported cases in the English language literature (1966 to 2000) of right heart thromboembolism in which age, sex, therapy, and outcome were reported. MEASUREMENTS AND RESULTS We analyzed 177 cases of right heart thromboembolism. Pulmonary thromboembolism was present in 98% of the cases. The patients were evenly divided by gender with an average age of 59.8 years (SD, 16.6 years) years. Dyspnea (54.2%), chest pain (22.6%), and syncope (17.5%) were the most common presenting symptoms. The treatments administered were none (9%), anticoagulation therapy (35.0%), surgical procedure (35.6%), or thrombolytic therapy (19.8%). The overall mortality rate was 27.1%. The mortality rate associated with no therapy, anticoagulation therapy, surgical embolectomy, and thrombolysis was 100.0%, 28.6%, 23.8%, and 11.3%, respectively. Using multivariate modeling with survival as the primary outcome, age and gender were not associated with mortality rate, but thrombolytic therapy was associated with an improved survival rate (p < 0.05) when compared either to anticoagulation therapy or surgery. CONCLUSION The presence of right heart thromboemboli may have diagnostic and therapeutic implications in pulmonary thromboembolism patients. A well-designed prospective, randomized trial is needed to determine the optimal treatment of right heart thromboemboli.
An effect-size analysis of the relative efficacy and tolerability of serotonin selective reuptake inhibitors for panic disorder.

OBJECTIVE Serotonin selective reuptake inhibitors (SSRIs) are now considered the first-line pharmacotherapy for panic disorder. The preferential use and the presumption of greater tolerability of SSRIs relative to older agents, such as tricyclic antidepressants, occurred without direct comparisons between the two classes of medication. In this study the authors used an effect-size analysis to provide an initial comparison. METHOD The authors conducted an effect-size analysis of 12 placebo-controlled, efficacy trials of SSRIs for panic disorder and compared these results to findings obtained in a recent meta-analysis of non-SSRI treatments for panic disorder. RESULTS The mean effect size for acute treatment outcome for SSRIs relative to placebo was 0.55, not significantly different from that for antidepressants in general (0.55) and for imipramine in particular (0.48). More recent studies of SSRIs, and studies using larger samples, were associated with lower effect sizes. No significant differences were found in dropout rates between those taking SSRIs and those taking older agents during acute treatment. CONCLUSIONS An effect-size analysis of controlled studies of treatments for panic disorder revealed no significant differences between SSRIs and older antidepressants in terms of efficacy or tolerability in short-term trials. An inverse relationship was evident between sample size and effect size for SSRIs. Early studies of small samples may have led to initial overestimations of the efficacy of SSRIs for panic disorder.
Time trends and seasonal variation in hospital admissions for childhood asthma in the Athens region of Greece: 1978-88.

BACKGROUND--The aim of the study was to determine the trend and seasonal variation in hospital admissions for childhood asthma in the Athens region of Greece. METHODS--Data were obtained from hospital registries of the three main children's hospitals in Athens between 1978 and 1988. Children admitted with the diagnosis of asthma, asthmatic bronchitis, or wheezy bronchitis were included. The data were expressed as admission rates per 100,000 of the same aged population. RESULTS--There were 9795 admissions for asthma over the 11 years and the admission rate rose by 294%. Admissions among those aged 0-4 and 5-14 rose by 272% and 379% respectively. Monthly admissions showed a pronounced seasonal variation, rising during the cold damp period in the 0-4 age group, but peaking around May in the 5-14 age group. CONCLUSIONS--These findings suggest that hospital admissions due to asthma in the Athens region have increased considerably since 1978, and that clear cut seasonal variations exist which are specific to age.
Breastfeeding initiation in women with gestational diabetes mellitus.

BACKGROUND In the United States, breastfeeding initiation (BFI) is reported for 75% of all live births; however, little information is available regarding mothers affected by gestational diabetes mellitus (GDM). OBJECTIVE To examine feeding practices and factors associated with BFI in women with GDM and their infants. METHODS A total of 303 GDM (58 late preterm and 245 term) pregnancies were studied. Infant feeding preference was ascertained on admission to labor and delivery. Variables known to influence BFI including maternal age, smoking, obesity, racial and educational characteristics were assessed. RESULTS On admission 188 women intended to BF, 60 intended to feed formula and 55 were undecided. None of the women who wished to feed formula and 27% of the originally undecided later initiated BF. Regardless of feeding preference 163 (54%) of all mothers initiated BF. Similar BFI rates were found for 176 Class A1 and 127 class A2 women. Logistic regression analysis showed that intention to BF was the most significant predictor of BFI. Factors associated with BFI failure included African American race, lower education, smoking, obesity and admission to NICU. Following delivery 264 (87%) infants received well baby care while 39 (13%) were admitted to the NICU. Among 188 women who intended to BF, BFI involved 81% of 160 infants receiving well baby care and 61% of the 28 admitted to the NICU. CONCLUSIONS More than half of women with GDM, who intended to BF, initiated BF. BFI failure remains associated with race, lower education level, smoking, obesity, preference for formula feeding and admission to NICU.
Multi-Watt Semiconductor Disk Laser by Low Temperature Wafer Bonding

We present wafer bonding techniques applied for the first time in integrating GaAs-based distributed Bragg reflectors (DBRs) with InP-based active regions in optically pumped semiconductor disk lasers. The bonding procedures are performed at a modest temperature of 200 °C and enable multi-watt output powers from 1.3 μm semiconductor disk lasers. These technologies are critical for vertical-cavity lasers emitting in the range 1.3-1.6 μm since monolithically grown lattice-matched InP structures suffer from DBRs with low refractive index contrast and poor thermal conductivity when compared with GaAs-based DBRs.
Exploring centrality measures and their extensions through an influence network

In this paper, we propose an empirical study of the centrality of actors in network. The data was collected among publicly available information of the boards members of organisations, including charities in Quebec. A first contribution of this paper is a set of new measures of centralities and variations on classical measures. From the application point of view, the strategical position of professionals (accountants and lawyers in this case) within the network is shown.
Partial Ossicular Reconstruction: Comparison of Three Different Prostheses in Clinical and Experimental Studies

Objective: To compare the reconstruction results of a long incus process defect using 3 different partial ossicular replacement prostheses (PORP). Study Design: Temporal bone experiments and retrospective case review. Setting: Tertiary referral center. Experimental Material and Patients: The experimental study was performed on 18 temporal bones; 66 patients with retraction pockets, chronic otitis media with or without cholesteatoma. Interventions: Ossiculoplasty using 3 different PORP: titanium angle prosthesis, autologous incus interposition, and titanium clip prosthesis. Main Outcome Measures: Laser Doppler vibrometry in temporal bones measured transmission properties of the PORP. Patients were retrospectively assessed up to 5 years after surgery. Audiologic data were analyzed for preoperative and postoperative air conduction and air-bone gap at 0.5, 1, 2, 3, and 4 kHz. Statistical analyses compared the outcome in the experimental and clinical setting. Results: Experimentally, the titanium PORP showed similar transmission properties because the overall difference to the intact specimen was −4.14 ± 0.59 dB for the titanium angle prosthesis and −4.61 ± 0.57 dB for the titanium clip prosthesis. The transmission after an autologous incus interposition was significantly worse (−9.32 ± 0.39 dB, p ≤ 0.001) compared with the other prostheses. Patients' mean postoperative air-bone gap was 25.5 ± 1.2 dB and less than 20 dB in at least 66% of cases without any significant differences between the groups. Conclusion: In the clinical setting, the confounding factors that influence the acoustic outcome after partial ossiculoplasty obscure the prosthesis-related transmission factors that can otherwise be derived in the experimental setting. The results do not generally favor the use of 1 specific prosthesis, rather they suggest that the correct choice of a prosthesis be based on the anatomic and pathophysiologic conditions found in the individual patient.