Miracle-dz/UniFAR-FTUs huggingface dataset:
Deciphering a Molecular Mechanism of Neonatal Diabetes Mellitus by the Chemical Synthesis of a Protein Diastereomer, [d-AlaB8]Human Proinsulin*

Background: Human proinsulin provides a model for studies of toxic protein misfolding. Results: Folding efficiency of proinsulin is controlled by stereochemistry at position B8. Conclusion: The sign of a single φ angle can facilitate or impede disulfide pairing. Significance: A monogenic diabetes syndrome suggests that insulin has evolved to the edge of non-foldability. Misfolding of proinsulin variants in the pancreatic β-cell, a monogenic cause of permanent neonatal-onset diabetes mellitus, provides a model for a disease of protein toxicity. A hot spot for such clinical mutations is found at position B8, conserved as glycine within the vertebrate insulin superfamily. We set out to investigate the molecular basis of the aberrant properties of a proinsulin clinical mutant in which residue GlyB8 is replaced by SerB8. Modular total chemical synthesis was used to prepare the wild-type [GlyB8]proinsulin molecule and three analogs: [d-AlaB8]proinsulin, [l-AlaB8]proinsulin, and the clinical mutant [l-SerB8]proinsulin. The protein diastereomer [d-AlaB8]proinsulin produced higher folding yields at all pH values compared with the wild-type proinsulin and the other two analogs, but showed only very weak binding to the insulin receptor. The clinical mutant [l-SerB8]proinsulin impaired folding at pH 7.5 even in the presence of protein-disulfide isomerase. Surprisingly, although [l-SerB8]proinsulin did not fold well under the physiological conditions investigated, once folded the [l-SerB8]proinsulin protein molecule bound to the insulin receptor more effectively than wild-type proinsulin. Such paradoxical gain of function (not pertinent in vivo due to impaired secretion of the mutant insulin) presumably reflects induced fit in the native mechanism of hormone-receptor engagement. This work provides insight into the molecular mechanism of a clinical mutation in the insulin gene associated with diabetes mellitus. These results dramatically illustrate the power of total protein synthesis, as enabled by modern chemical ligation methods, for the investigation of protein folding and misfolding.
Peyer’s Patches and Mesenteric Lymph Nodes Cooperatively Promote Enteropathy in a Mouse Model of Food Allergy

Background and Objective To improve the efficacy and safety of tolerance induction for food allergies, identifying the tissues responsible for inducing intestinal inflammation and subsequent oral tolerance is important. We used OVA23-3 mice, which express an ovalbumin-specific T-cell receptor, to elucidate the roles of local and systemic immune tissues in intestinal inflammation. Methods and Results OVA23-3 mice developed marked enteropathy after consuming a diet containing egg white (EW diet) for 10 days but overcame the enteropathy (despite continued moderate inflammation) after receiving EW diet for a total of 28 days. Injecting mice with anti-IL-4 antibody or cyclosporine A confirmed the involvement of Th2 cells in the development of the enteropathy. To assess the individual contributions of Peyer’s patches (PPs), mesenteric lymph nodes (MLNs), and the spleen to the generation of effector CD4+ T-cells, we analyzed the IL-4 production, proliferation in response to ovalbumin, and CD4+ T-cell numbers of these tissues. EW feeding for 10 days induced significant IL-4 production in PPs, the infiltration of numerous CD4+ T-cells into MLNs, and a decrease in CD4+ T-cell numbers in spleen. On day 28, CD4+ T-cells from all tissues had attenuated responses to ovalbumin, suggesting tolerance acquisition, although MLN CD4+ T-cells still maintained IL-4 production with proliferation. In addition, removal of MLNs but not the spleen decreased the severity of enteropathy and PP-disrupted mice showed delayed onset of EW-induced inflammatory responses. Disruption of peripheral lymphoid tissues or of both PPs and MLNs almost completely prevented the enteropathy. Conclusions PPs and MLNs coordinately promote enteropathy by generating effector T-cells during the initial and exacerbated phases, respectively; the spleen is dispensable for enteropathy and shows tolerogenic responses throughout EW-feeding. The regulation of PPs may suppress the initiation of intestinal inflammation, subsequently restricting MLNs and inhibiting the progression of food-allergic enteropathy.
Increased Incidence of Type II Diabetes Mellitus in Mexican Americans

Objective To determine whether Mexican Americans have an increased incidence of non-insulin-dependent (type II) diabetes mellitus relative to non-Hispanic whites. Currently, no study has reported on the incidence of this disorder in Mexican Americans. Research Design and Methods We determined the 8-yr incidence of type II diabetes in 617 Mexican Americans and 306 non-Hispanic whites who participated in the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease. Forty Mexican Americans (6.5%) and 6 non-Hispanic whites (2%) developed type II diabetes, as defined by World Health Organization criteria. The age-adjusted ethnic odds ratio (OR; Mexican Americans/non-Hispanic whites) for diabetes incidence was 8.13 (95% confidence interval [C1] 1.10–59.9) in men and 3.62 (95% CI 1.37–9.55) in women. We adjusted for age, sex, ethnicity, body mass index, and level of educational attainment with multiple logistic regression analyses. Results Mexican Americans continued to show a statistically significant increase in diabetes incidence (OR 2.72, 95% CI 1.02–7.28). Obesity and age were also positively related to diabetes incidence in this analysis (P < 0.001). In addition, subjects with at least some college education had a lower incidence of diabetes than those with less than a high school education (OR 0.51, 95% CI 0.26–0.99). Conclusions The incidence of type II diabetes in Mexican Americans is greater than in non-Hispanic whites, a difference that is not explained by ethnic differences in obesity, age, or level of educational attainment.
Platelet-activating factor in human luteal phase endometrium.

Platelet-activating factor (PAF; 1-O-alkyl-2-acetyl-sn-glycero-3-phosphorylcholine) is one of the most potent mediators of vascular permeability. PAF levels change in the rabbit endometrium just prior to implantation, which suggests that PAF may be a key substance transducing preimplantation embryonic signals. To study whether PAF was present in the human endometrium, and if so, to determine the cellular origin and hormonal regulation of endometrial PAF, specimens were obtained from 14 women (aged 23-42 yr) undergoing elective hysterectomy during the luteal phase of the cycle (plasma progesterone levels greater than 2 ng/ml). No specimens were taken from women with malignant uterine pathology. Stromal cells and epithelial glandular cells were separated by collagenase and DNAse digestion, and then cultured to confluence in vitro in medium 199. Radioimmunoassays of prostaglandin F (PGF) and prolactin in the culture media were used to confirm cell type and viability. PGF release into the culture medium from stromal cells was low (control 1.52 +/- 0.20 ng/ml), and unchanged by hormone treatment. In contrast, release of PGF from unstimulated glandular cells was 6.05 +/- 0.52 ng/ml, and was significantly increased (p less than 0.05) by estradiol or progesterone plus estradiol, to 12.17 +/- 1.67, and 8.60 +/- 0.81, respectively. Progesterone alone was without effect. Prolactin was secreted by stromal cell cultures, increasing steadily from 24 to 120 h. The levels in the medium were increased by progesterone. PAF activity was assessed by rabbit platelet aggregation and serotonin-release bioassays after lipid extraction and separation by thin-layer chromatography. (ABSTRACT TRUNCATED AT 250 WORDS)
End-of-life issues in advanced dementia: Part 1: goals of care, decision-making process, and family education.

OBJECTIVE To review the issues with setting goals of care for patients with advanced dementia, describe the respective roles of the physician and the patient's family in the decision-making process, and suggest ways to support families who need more information about the care options. SOURCES OF INFORMATION Ovid MEDLINE was searched for relevant articles that were published before March 7, 2014. There were no level I studies identified; most articles provided level III evidence. MAIN MESSAGE For patients with advanced dementia, their families have an important role in medical decision making. Families should receive timely information about the course of dementia and the care options. They need to understand that a palliative approach to care might be appropriate and does not mean abandonment of the patient. They might also want clarification about their role in the decision-making process, especially if withholding or withdrawing life-prolonging measures are considered. CONCLUSION Physicians should consider advanced dementia as a terminal disease for which there is a continuum of care that goes from palliative care with life-extending measures to symptomatic interventions only. Clarification of goals of care and family education are of paramount importance to avoid unwanted and burdensome interventions.
Detection of herpes simplex virus DNA from cerebrospinal fluid by PCR and a rapid, nonradioactive hybridization technique

A molecular assay for the detection of herpes simplex virus (HSV), including a novel, nonradioactive hybridization technique, was evaluated with a total of 123 cerebrospinal fluid specimens. After DNA extraction, specific HSV DNA sequences were amplified with digoxigenin-labeled primers derived from the DNA polymerase gene-coding region from HSV. Amplified products were detected by the Enzymun-Test DNA detection assay (Boehringer, Mannheim, Federal Republic of Germany), which uses biotinylated probes. Amplification with nonlabeled primers and then Southern blotting and nonradioactive detection of hybrids by the digoxigenin technique was the reference system. The sensitivities of the molecular assays were determined with 10-fold dilutions of plasmid pS4 with the SalI restriction fragment of the DNA polymerase gene obtained from the HSV type 1 strain Angelotti. The Enzymun assay was able to detect all of the 16 positive samples, giving 100% agreement with the Southern blot hybridization results. Optical density values were widely separated for the positive and negative groups of specimens. Ten copies of plasmid pS4 per microliter could be distinctly detected by the Enzymun assay. The cutoff was determined for the hybridization assay, and an equivocal zone was defined. The whole molecular assay including the Enzymun-Test DNA detection proved to be sensitive and easy to use. It may contribute to the rapid and safe detection of HSV DNA in cerebrospinal fluid.
Systematic identification of cell cycle-dependent yeast nucleocytoplasmic shuttling proteins by prediction of composite motifs

The cell cycle-dependent nucleocytoplasmic transport of proteins is predominantly regulated by CDK kinase activities; however, it is currently difficult to predict the proteins thus regulated, largely because of the low prediction efficiency of the motifs involved. Here, we report the successful prediction of CDK1-regulated nucleocytoplasmic shuttling proteins using a prediction system for nuclear localization signals (NLSs). By systematic amino acid replacement analyses in budding yeast, we created activity-based profiles for different classes of importin-α-dependent NLSs that represent the functional contributions of different amino acids at each position within an NLS class. We then developed a computer program for prediction of the classical importin-α/β pathway-specific NLSs (cNLS Mapper, available at http//nls-mapper.iab.keio.ac.jp/) that calculates NLS activities by using these profiles and an additivity-based motif scoring algorithm. This calculation method achieved significantly higher prediction accuracy in terms of both sensitivity and specificity than did current methods. The search for NLSs that overlap the consensus CDK1 phosphorylation site by using cNLS Mapper identified all previously reported and 5 previously uncharacterized yeast proteins (Yen1, Psy4, Pds1, Msa1, and Dna2) displaying CDK1- and cell cycle-regulated nuclear transport. CDK1 activated or repressed their nuclear import activity, depending on the position of CDK1-phosphorylation sites within NLSs. The application of this strategy to other functional linear motifs should be useful in systematic studies of protein–protein networks.
Pharmacokinetics of 7‐carboxymethyloxy‐3‘,4’,5‐trimethoxy flavone (DA‐6034), a derivative of flavonoid, in mouse and rat models of chemically‐induced inflammatory bowel disease

The pharmacokinetics (including distribution in the gastrointestinal tract) of 7‐carboxymethyloxy‐3‘,4’,5‐trimethoxy flavone (DA‐6034) has been investigated in several mouse and rat models of chemically‐induced inflammatory bowel disease (IBD). In the female ICR mouse model, IBD was induced by dextran sulfate and the mice administered 30 mg kg−1 DA‐6034 intravenously or orally. In the male SJL mouse model of IBD induced by oxazolone, 30 mg kg−1 DA‐6034 was administered orally. In the male Sprague—Dawley rat model of IBD induced by trinitrobenzene sulfonic acid (TNBS), 10 mg kg−1 DA‐6034 was administered intravenously and orally. After intravenous administration, the total area under the plasma concentration—time curve from time zero to the last measured time, t, in plasma (AUC0‐t) values were comparable between control and dextran sulfate‐induced IBD mice, and between control and TNBS‐induced rats. This suggested that the disposition of DA‐6034 was not affected considerably by dextran sulfate in mice and TNBS in rats. However, after oral administration in mice and rats with IBD, the AUC0‐t values were greater compared with the respective controls. This could have been due to an increase (slow) in the gastrointestinal transit time (in IBD mice and rats, the percentages of the oral dose recovered from the rinsing fluid of the small intestine and large intestine as unchanged drug were greater and smaller, respectively), and an increase in intestinal permeability.
Spectral Subtraction and Cepstral Distance for Enhancing EEG Entropy

Electroencephalographic (EEG) signals are normally acquired in the presence of background noise which causes inaccurate or false entropy measurement throughout the signal. In this paper, spectral subtraction is used to pre-process EEG signals to improve the accuracy of computing the subband wavelet entropy (SWE). The silent period in the EEG signal is identified via cepstral distance which allows its entropy to be set to zero. The EEG signal presented in this paper represents various stages of brain recovery obtained from a rodent following global cerebral ischemia. The various subband entropies are calculated using wavelet decomposition in EEG subbands, namely delta, theta, alpha, beta and gamma. The utilization of spectral subtraction improved the accuracy of the SWE as compared to energy thresholding
The impact of dysarthria on everyday communication after traumatic brain injury: A pilot study

Primary objective: To compare the everyday communication of individuals with mild and moderate dysarthria and concomitant cognitive-communication impairments following traumatic brain injury (TBI). Methods and procedures: Five participants with mild dysarthria and five with moderate dysarthria following TBI were recorded during telephone service enquiries with bus timetable call centre operators. Transcripts were analysed using exchange structure analysis derived from systemic functional linguistics. Listener comfort ratings were collected using a novel equal appearing interval scale to measure how comfortable people would feel interacting with the participants. Main outcomes and results: Participants with moderate dysarthria were not necessarily penalized for having poorer intelligibility during bus timetable service encounters. While participants with moderate dysarthria were given poorer listener comfort ratings, this did not affect the way information was exchanged with bus timetable call centre operators. These findings were attributed to the powerful interactional role of TBI participants as customers, the amount of disability awareness training and experience held by call centre operators and the highly structured nature of bus timetable service enquiries. Listener comfort ratings could be predicted with moderate accuracy from intelligibility scores. Conclusions: Service encounters where individuals with TBI are placed in a powerful interactional role of customer may be functional generalization tasks for people with moderate dysartrhia. Training and education of service providers may also impact on the communicative effectiveness of individuals with TBI.
Representations of the human body in the production and imitation of complex movements

Abstract Previous investigations suggest that there are at least three distinct types of representation of the human body. One representation codes structural information about body part location (body structural description), the second codes knowledge about body parts (body semantics or body image), and the third provides a dynamic mapping of the current positions of body parts relative to one another (body schema) (Buxbaum & Coslett, 2001; Schwoebel, Coslett, & Buxbaum, 2001; Sirigu, Grafman, Bressler, & Sunderland, 1991). In this study we used an influential "two route" model of gesture performance (Gonzalez Rothi, Ochipa, & Heilman, 1991) to derive predictions about the body representations expected to underlie the production and imitation of meaningful and meaningless movements. The relationships between these measures were examined in 55 patients with unilateral left-hemisphere lesions. Multiple regression analyses demonstrated that performance on body semantics and body schema tasks were significant and unique predictors of meaningful gesture performance, whereas the body schema measure alone predicted imitation of meaningless movements. Body structural descriptions did not enter into any of the models. These findings are consistent with performance of meaningful actions via a semantic route that accesses body semantics and other action knowledge, and performance of meaningless movements via a "direct" route that bypasses this information.
Combined analysis of support vector machine and principle component analysis for IDS

In the modern world we are using the smart devices for storing data, retrieving data and processing the data on the cloud which is energy users to manage a wide variety of subscribers, reading devices for measuring, billing, disconnection and connection of subscribers from the connection management is an important issue. The performance of these intelligent systems is based on information transfer in the context of storing Big data, so reported data from network should be managed to avoid the malicious activities that including the issues that could affect the quality of service the system. In this paper for control of the reported wireless data and to ensure the veracity of the obtained information, using intrusion detection system is proposed based on the support vector machine and principle component analysis (PCA) to recognize and identify the intrusions and attacks in the smart grid. Here, the operation of intrusion detection systems for different kernel of SVM when using support vector machine (SVM) and PCA simultaneously is studied. To evaluate the algorithm, based on data KDD99, numerical simulation is done on five different kernels for an intrusion detection system using support vector machine with PCA simultaneously. Also comparison analysis is investigated for presented intrusion detection algorithm in terms of time — response, rate of increase network efficiency and increase system error and differences in the use or lack of use PCA. The results indicate that correct detection rate and the rate of attack error detection have best value when PCA is used, and when the core of algorithm is radial type, in SVM algorithm reduces the time for data analysis and enhances performance of intrusion detection.
Response rates in studies of couples coping with cancer: a systematic review.

OBJECTIVE Recruiting couples for psychological studies can be challenging. This brief report is the first to examine the average couples' response rate and to systematically review the quality of reporting of couples' response rate in studies of couples coping with cancer. METHOD A systematic review (1980-2011) was conducted, including 83 studies meeting the inclusion criteria of being published in peer-reviewed journals, describing quantitative findings using a cross-sectional or longitudinal design. RESULTS Overall reporting was unsatisfactory in more than half of the included studies. As a consequence, the couples' response rate (CRR; all analyzed couples divided by the number of eligible partnered patients/couples approached) could be calculated for only 33 samples. This CRR varied considerably across studies from 25% to 90% (CRRM = 58%, SD = 17%). The rates reported in the articles (M = 65%) were often higher than the average CRR (CRRM = 57%) of these samples. CONCLUSIONS This systematic review revealed incomplete reporting of response rate. Therefore, it cannot be firmly concluded that the average CRR reported is representative for all studies on couples coping with cancer. Finally, the figures presented, which are often more favorable than the CRR, may create the impression that the sample is more representative of the target population than it actually is. This has consequences for implementing the findings of such studies into practice. The results are critically discussed, and recommendations for improvement are provided.