Miracle-dz/UniFAR-FTUs huggingface dataset:
HLA DRB4 0101-restricted immunodominant T cell autoepitope of pyruvate dehydrogenase complex in primary biliary cirrhosis: evidence of molecular mimicry in human autoimmune diseases

We established six T cell clones specific for pyruvate dehydrogenase complex (PDC)-E2 peptides from four different patients with primary biliary cirrhosis using 33 different peptides of 17-20 amino acid residues corresponding to human PDC-E2 as stimulating antigens. The minimal T cell epitopes of these six T cell clones were all mapped to the same region of the PDC-E2 peptide 163-176 (GDLLAEIETDKATI), which corresponds to the inner lipoyl domain of PDC-E2. The HLA restriction molecules for this epitope were all identified as HLA DRB4 0101. The common essential amino acids of this epitope for these T cell clones were E, D, and K at positions 170, 172, and 173, respectively; other crucial amino acids for this epitope differed in each T cell clone. In addition, the alanine-substituted peptides at positions 170 and 173, but not 172, inhibited the proliferation of all T cell clones induced by the original peptide of human PDC-E2 163-176, indicating that amino acid D at position 172 is a critical MHC-binding site for all T cell clones tested. Interestingly, all T cell clones reacted to PDC-E2 peptide 36-49 (GDLIAEVETDKATV), which corresponds to the outer lipoyl domain of human PDC-E2. Furthermore, one T cell clone cross-reacted with exogenous antigens such as Escherichia coli PDC-E2 peptide 31- 44/134-147/235-248 (EQSLITVEGDKASM), which has an EXDK sequence. This is a definite demonstration of the presence of molecular mimicry at the T cell clonal level in human autoimmune diseases. It is also considered possible to design peptide-specific immunotherapy based on the findings of T cell autoepitopes in primary biliary cirrhosis.
Bootstrapping the Adoption of Internet Security Protocols

The deployment of network-wide security enhancements to the Internet has proven more dicult than many had initially anticipated. We leverage existing models of networks’ value to model the problem of bootstrapping the adoption of security technologies. We describe a variety of policy interventions and deployment strategies that can help to catalyze this adoption. Using this framework, we provide a series of short case studies for previous attempts to deploy security technologies to the Internet. We then provide a detailed study of strategies for deploying the security-enhanced protocols into the Internet’s Domain Name System (DNS). Finally, we show how the adoption of these DNS security enhancements can help to alleviate bootstrapping problems that have impeded the deployment of other security-enhanced protocols.
A Natural Experiment of Race-Based and Issue Voting: The 2001 City of Los Angeles Elections

The theory of racially polarized voting suggests that race is a primary determinant of vote choice in elections where a minority candidate is pitted against a white candidate. The spatial model of voting suggests that voters consider the issue positions of candidates and choose the candidate closest to their own positions. The unique context of the 2001 Los Angeles city election allows us to test these two theories. In each of two races in this election, a Latino candidate competed against a white candidate. In one race the white candidate was considered more liberal, while in the other race the Latino candidate was seen as more liberal. This particular ethnic and ideological composition provides us with a natural experimenting which to test the two competing theories. While voter ethnicity mattered, we show that consistent with the spatial model, voters also relied on issues and ideology as factors in their voting choices. By considering the choices voters are making in two different elections, we argue that estimates of the extent of racial voting in previous research may be overstated.
cDNA sequence, mRNA expression and genomic DNA of trypsinogen from the Indianmeal moth, Plodia interpunctella

Trypsin‐like enzymes are major insect gut enzymes that digest dietary proteins and proteolytically activate insecticidal proteins produced by the bacterium Bacillus thuringiensis (Bt). Resistance to Bt in a strain of the Indianmeal moth, Plodia interpunctella, was linked to the absence of a major trypsin‐like proteinase ( Oppert et al., 1997 ). In this study, trypsin‐like proteinases, cDNA sequences, mRNA expression levels and genomic DNAs from Bt‐susceptible and ‐resistant strains of the Indianmeal moth were compared. Proteinase activity blots of gut extracts indicated that the susceptible strain had two major trypsin‐like proteinases, whereas the resistant strain had only one. Several trypsinogen‐like cDNA clones were isolated and sequenced from cDNA libraries of both strains using a probe deduced from a conserved sequence for a serine proteinase active site. cDNAs of 852 nucleotides from the susceptible strain and 848 nucleotides from the resistant strain contained an open reading frame of 783 nucleotides which encoded a 261‐amino acid trypsinogen‐like protein. There was a single silent nucleotide difference between the two cDNAs in the open reading frame and the predicted amino acid sequence from the cDNA clones was most similar to sequences of trypsin‐like proteinases from the spruce budworm, Choristoneura fumiferana, and the tobacco hornworm, Manduca sexta. The encoded protein included amino acid sequence motifs of serine proteinase active sites, conserved cysteine residues, and both zymogen activation and signal peptides. Northern blotting analysis showed no major difference between the two strains in mRNA expression in fourth‐instar larvae, indicating that transcription was similar in the strains. Southern blotting analysis revealed that the restriction sites for the trypsinogen genes from the susceptible and resistant strains were different. Based on an enzyme size comparison, the cDNA isolated in this study corresponded to the gene for the smaller of two trypsin‐like proteinases, which is found in both the Bt‐susceptible and ‐resistant strains of the Indianmeal moth. The sequences reported in this paper have been deposited in the GenBank database (accession numbers AF064525 for the RC688 strain and AF064526 for HD198).
US Practice Patterns and Impact of Monitoring for Mucosal Inflammation After Biologic Initiation in Inflammatory Bowel Disease.

BACKGROUND We assessed practice patterns for monitoring mucosal inflammation after biologic initiation and the association between monitoring approaches and development of disease-related complications for Crohn's disease (CD) and ulcerative colitis (UC). METHODS This study used a Truven Health MarketScan (2007-2016) query for CD and UC patients initiating biologic therapy. Cumulative 24-month disease-related complications (corticosteroids, change of biologic, hospitalization, surgery) in patients undergoing proactive disease monitoring with lower endoscopy, fecal calprotectin, or cross-sectional radiographic enterography (computed tomography enterography or magnetic resonance enterography) within 6 months of biologic initiation vs no early monitoring after biologic initiation were compared. Cox proportional hazard ratios (HRs with 95% confidence intervals [CIs]) adjusted for propensity score were used. RESULTS Within the first 24 months after biologic initiation, monitoring (proactive or reactive) was performed in 56.4% of CD patients and 67.8% of UC patients, with considerable geographic variability. Early (within 6 months) proactive monitoring was endoscopy-based (87.9%), performed in 11% of CD (n = 2195/19,899) and 12.8% of UC (n = 925/7247) patients. Compared with no early monitoring, early proactive monitoring was associated with a reduction in disease-related complications for CD (adjusted HR [aHR], 0.90; 95% CI, 0.84-0.96) and UC (aHR, 0.87; 95% CI, 0.78-0.97) and predominately driven by a reduction in corticosteroid use (CD: aHR, 0.83; 95% CI, 0.77-0.90; UC: aHR, 0.77; 95% CI, 0.69-0.87). Results were consistent across multiple sensitivity analyses. CONCLUSIONS Early proactive monitoring of mucosal inflammation in CD and UC within 6 months of biologic initiation was associated with reduction in disease-related complications over 24 months, primarily related to reduced steroid utilization. Wide variation exists in practice patterns for monitoring of mucosal inflammation after biologic initiation.
Can we respond mindfully to distressing voices? A systematic review of evidence for engagement, acceptability, effectiveness and mechanisms of change for mindfulness-based interventions for people distressed by hearing voices

Adapted mindfulness-based interventions (MBIs) could be of benefit for people distressed by hearing voices. This paper presents a systematic review of studies exploring this possibility and we ask five questions: (1) Is trait mindfulness associated with reduced distress and disturbance in relation to hearing voices? (2) Are MBIs feasible for people distressed by hearing voices? (3) Are MBIs acceptable and safe for people distressed by hearing voices? (4) Are MBIs effective at reducing distress and disturbance in people distressed by hearing voices? (5) If effective, what are the mechanisms of change through which MBIs for distressing voices work? Fifteen studies were identified through a systematic search (n = 479). In relation to the five review questions: (1) data from cross-sectional studies showed an association between trait mindfulness and distress and disturbance in relation to hearing voices; (2) evidence from qualitative studies suggested that people distressed by hearing voices could engage meaningfully in mindfulness practice; (3) MBIs were seen as acceptable and safe; (4) there were no adequately powered RCTs allowing conclusions about effectiveness to be drawn; and (5) it was not possible to draw on robust empirical data to comment on potential mechanisms of change although findings from the qualitative studies identified three potential change processes; (i) reorientation of attention; (ii) decentring; and (iii) acceptance of voices. This review provided evidence that MBIs are engaging, acceptable, and safe. Evidence for effectiveness in reducing distress and disturbance is lacking however. We call for funding for adequately powered RCTs that will allow questions of effectiveness, maintenance of effects, mechanisms of change and moderators of outcome to be definitively addressed.
Elastic stable intramedullary nailing of midclavicular fractures in athletes

Background: Intramedullary fixation of midclavicular fractures may be a better option than non-operative treatment for high performance/professional athletes because of the potential reduction in recovery time. Objectives: To evaluate the effectiveness of intramedullary fixation in high performance athletes and the time required to return to sporting activity. Methods: Data were taken from a prospective study on intramedullary fixation techniques using the elastic stable Ti nail (TEN, Synthes) for the treatment of displaced midclavicular fractures, initiated in 1996. The patients in 12 cases were classified as high performance/professional athletes. These cases were used to evaluate the technique specifically in this population. Fractures were classified according to the Orthopaedic Trauma Association (OTA) system. Patients were evaluated before and after surgery for shoulder function and subjective pain. After the operation, radiological assessments documented fracture healing, and clinical outcomes scores were obtained. Time required to return to training and competition was documented. Results: All fractures were transverse or oblique. Mean (SD) shoulder abduction increased from 36.3 (8)° before surgery to 154.2 (17)° afterwards (p<0.001). Mean subjective pain score using a visual analogue scale (0–100) decreased from 71.7 (18) points before surgery to 19.2 (6) points (p<0.001) three days after. There were no complications. Hospital stay averaged 2.9 (1) days. Mean delay to resumption of training was 5.9 (1) days, and to resumption of competition it was 16.8 (5) days. The mean Constant clinical outcomes score one year after hardware removal was 98.3 (2) points. Conclusions: Intramedullary fixation of displaced midclavicular fracture was successful in terms of clinical outcome and rapid resumption of sporting activities. This treatment should be offered to athletes as an alternative to non-operative treatment.
The effect of dissolved oxygen on the metabolic profile of a murine hybridoma grown in serum-free medium in continuous culture.

The murine B-lymphocyte hybridoma, CC9C10 was grown at steady state under serum-free conditions in continuous culture at dissolved oxygen (DO) concentrations in the range of 10% to 150% of air saturation. Cells could be maintained with this range at high viability in a steady state at a dilution rate of 1 d(-1), although with lower cell concentrations at higher DO. A higher specific antibody production measured at higher DO was matched by a decrease in the viable cell concentration at steady state, so that the volumetric antibody titre was not changed significantly. An attempt to grow cells at 250% of air saturation was unsuccessful but the cells recovered to normal growth once the DO was decreased.There was a requirement for cellular adaptation at each step-wise increase in dissolved oxygen. Adaptation to a DO of 100% was associated with an increase in the specific activities of glutathione peroxidase (x18), glutathione S-transferase (x11) and superoxide dismutase (x6) which are all known antioxidant enzymes. At DO above 100%, the activities of GPX and GST decreased possibly as a result of inactivation by reactive oxygen radicals.The increase in dissolved oxygen concentration caused changes in energy metabolism. The specific rate of glucose uptake increased at higher dissolved oxygen concentrations with a higher proportion of glucose metabolized anaerobically. Short-term radioactive assays showed that the relative flux of glucose through glycolysis and the pentose phosphate pathway increased whereas the flux through the tricarboxylic acid cycle decreased at high DO. Although the specific glutamine utilization rate increased at higher DO, there was no evidence for a change in the pattern of metabolism. This indicates a possible blockage of glycolytic metabolites into the TCA cycle, and is compatible with a previous suggestion that pyruvate dehydrogenase is inhibited by high oxygen concentrations.Analysis of the oxygen uptake rate of cell suspensions at steady state under all conditions showed a pronounced Crabtree effect which was manifest by a decrease (up to 40%) in oxygen consumption on addition of glucose. This indicates that the degree of aerobic metabolism in these cultures is highly sensitive to the glucose concentration.
Creep of anisotropic clay: Microplane model

Undrained constant‐volume creep of anisotropically consolidated specimens of clay is mathematically described by the microplane model, which is based on the assumption that the shear strain rates on the contact planes between mutually sliding clay platelets (the microplanes) are the resolved components of the macroscopic strain rate. Thus, the microstructure is assumed to be kinematically constrained. The rate of shear on the microplanes is assumed to be governed by activation energy (rate process theory). The matrix of the current viscosities is obtained as an integral over all spatial directions involving the shear strain rates for the microplanes. This integral, which is evaluated numerically as a summation, gives the dependence of the viscosity matrix on the applied macroscopic stress. Anisotropy of the clay is characterized by a function of the spherical angles describing the relative frequency of clay platelets of various orientations. This function can be approximately estimated from X‐ray diffract.
Two Distinct Pathways for Targeting Proteins from the Cytoplasm to the Vacuole/Lysosome

Stress conditions lead to a variety of physiological responses at the cellular level. Autophagy is an essential process used by animal, plant, and fungal cells that allows for both recycling of macromolecular constituents under conditions of nutrient limitation and remodeling the intracellular structure for cell differentiation. To elucidate the molecular basis of autophagic protein transport to the vacuole/lysosome, we have undertaken a morphological and biochemical analysis of this pathway in yeast. Using the vacuolar hydrolase aminopeptidase I (API) as a marker, we provide evidence that the autophagic pathway overlaps with the biosynthetic pathway, cytoplasm to vacuole targeting (Cvt), used for API import. Before targeting, the precursor form of API is localized mostly in restricted regions of the cytosol as a complex with spherical particles (termed Cvt complex). During vegetative growth, the Cvt complex is selectively wrapped by a membrane sac forming a double membrane-bound structure of ∼150 nm diam, which then fuses with the vacuolar membrane. This process is topologically the same as macroautophagy induced under starvation conditions in yeast (Baba, M., K. Takeshige, N. Baba, and Y. Ohsumi. 1994. J. Cell Biol. 124:903–913). However, in contrast with autophagy, API import proceeds constitutively in growing conditions. This is the first demonstration of the use of an autophagy-like mechanism for biosynthetic delivery of a vacuolar hydrolase. Another important finding is that when cells are subjected to starvation conditions, the Cvt complex is now taken up by an autophagosome that is much larger and contains other cytosolic components; depending on environmental conditions, the cell uses an alternate pathway to sequester the Cvt complex and selectively deliver API to the vacuole. Together these results indicate that two related but distinct autophagy-like processes are involved in both biogenesis of vacuolar resident proteins and sequestration of substrates to be degraded.
SPECT Imaging of Joint Inflammation with Nanobodies Targeting the Macrophage Mannose Receptor in a Mouse Model for Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease occurring in approximately 1% of the worldwide population. The disease primarily affects the joints, where inflammatory cells, such as macrophages, invade the synovium and cause cartilage and bone destruction. Currently, it is difficult to efficiently diagnose and monitor early-stage RA. In this study, we investigated whether SPECT/micro-CT imaging with 99mTc-labeled Nanobodies directed against the macrophage mannose receptor (MMR) is a useful tool for monitoring and quantifying joint inflammation in collagen-induced arthritis (CIA), a mouse model for RA. The expression of MMR was analyzed on macrophages and osteoclasts generated in vitro and in cells obtained from various organs from mice with CIA. Methods: CIA was induced in DBA/1 mice by injection of collagen type II in complete Freund adjuvant, and cell suspensions from the inflamed joints and other organs were obtained. Macrophages and osteoclasts were generated in vitro from bone marrow cells. Expression of MMR was quantified by quantitative polymerase chain reaction and flow cytometry with specific Nanobodies and conventional antibodies. SPECT/micro-CT imaging was performed with 99mTc-labeled MMR and control Nanobodies. Results: MMR was highly expressed on macrophages and to a lesser extent on osteoclasts generated in vitro. In mice with CIA, MMR expression was detected on cells from the bone marrow, lymph nodes, and spleen. In synovial fluid of arthritic joints, MMR was expressed on CD11b+F4/80+ macrophages. On in vivo SPECT/micro-CT imaging with consecutive injections of MMR and control Nanobodies, a strong MMR signal was seen in the knees, ankles, and toes of arthritic mice. Quantification of the SPECT imaging confirmed the specificity of the MMR signal in inflamed joints as compared with the control Nanobody. Dissection of the paws revealed an additional significant MMR signal in nonarthritic paws of affected mice (i.e., mice displaying symptoms of arthritis in other paws). Conclusion: Our data show that MMR is expressed on macrophages in vitro and in vivo in synovial fluid of inflamed paws, whereas expression is relatively low in other tissues. The use of Nanobodies against MMR in SPECT/micro-CT imaging generates the possibility to track inflammatory cells in vivo in arthritic joints.
Transcranial Direct Current Stimulation of the Left Dorsolateral Prefrontal Cortex Shifts Preference of Moral Judgments

Attitude to morality, reflecting cultural norms and values, is considered unique to human social behavior. Resulting moral behavior in a social environment is controlled by a widespread neural network including the dorsolateral prefrontal cortex (DLPFC), which plays an important role in decision making. In the present study we investigate the influence of neurophysiological modulation of DLPFC reactivity by means of transcranial direct current stimulation (tDCS) on moral reasoning. For that purpose we administered anodal, cathodal, and sham stimulation of the left DLPFC while subjects judged the appropriateness of hard moral personal dilemmas. In contrast to sham and cathodal stimulation, anodal stimulation induced a shift in judgment of personal moral dilemmas towards more non-utilitarian actions. Our results demonstrate that alterations of left DLPFC activity can change moral judgments and, in consequence, provide a causal link between left DLPFC activity and moral reasoning. Most important, the observed shift towards non-utilitarian actions suggests that moral decision making is not a permanent individual trait but can be manipulated; consequently individuals with boundless, uncontrollable, and maladaptive moral behavior, such as found in psychopathy, might benefit from neuromodulation-based approaches.
Influence of age, sex, body size, smoking, and β blockade on key gas exchange exercise parameters in an adult population

Aims Cardiopulmonary exercise testing (CPET) is a widely applied clinical procedure. There is uncertainty to what extent nutritional status, β blockers and smoking should be taken into account in the interpretation of exercise parameters to describe abnormality. This study planned to consider the impact of these factors on CPET values and develop reference equations on the basis of a large-scale population-based survey. Methods and results An incremental cycle exercise protocol was applied to 1708 volunteers. Individuals with structural heart disease, echocardiographic or lung function pathologies were excluded. Age, height, weight, smoking, and β blockers were analysed for their influencing power in each sex. Reference values of CPET parameters were determined by regression analyses. The final study sample consisted of 1203 volunteers (626 female), aged 25–85 years. Exercise capacity, gas exchange, and ventilatory efficiency for carbon dioxide removal were significantly dependent on sex, age, height, weight, and cigarette smoking. In the dosages used, β blockers did not significantly interfere with gas exchange. Conclusion Sex, height, weight, and age significantly influence gas exchange. This study provides a comprehensive set of reference values in a large number of volunteers within a population-based survey, with reference values corrected for influencing factors.