Miracle-dz/UniFAR-FTUs huggingface dataset:
Immunosuppression and Chagas Disease: A Management Challenge

Immunosuppression, which has become an increasingly relevant clinical condition in the last 50 years, modifies the natural history of Trypanosoma cruzi infection in most patients with Chagas disease. The main goal in this setting is to prevent the consequences of reactivation of T. cruzi infection by close monitoring. We analyze the relationship between Chagas disease and three immunosuppressant conditions, including a description of clinical cases seen at our center, a brief review of the literature, and recommendations for the management of these patients based on our experience and on the data in the literature. T. cruzi infection is considered an opportunistic parasitic infection indicative of AIDS, and clinical manifestations of reactivation are more severe than in acute Chagas disease. Parasitemia is the most important defining feature of reactivation. Treatment with benznidazole and/or nifurtimox is strongly recommended in such cases. It seems reasonable to administer trypanocidal treatment only to asymptomatic immunosuppressed patients with detectable parasitemia, and/or patients with clinically defined reactivation. Specific treatment for Chagas disease does not appear to be related to a higher incidence of neoplasms, and a direct role of T. cruzi in the etiology of neoplastic disease has not been confirmed. Systemic immunosuppressive diseases or immunosuppressants can modify the natural course of T. cruzi infection. Immunosuppressive doses of corticosteroids have not been associated with higher rates of reactivation of Chagas disease. Despite a lack of evidence-based data, treatment with benznidazole or nifurtimox should be initiated before immunosuppression where possible to reduce the risk of reactivation. Timely antiparasitic treatment with benznidazole and nifurtimox (or with posaconazole in cases of therapeutic failure) has proven to be highly effective in preventing Chagas disease reactivation, even if such treatment has not been formally incorporated into management protocols for immunosuppressed patients. International consensus guidelines based on expert opinion would greatly contribute to standardizing the management of immunosuppressed patients with Chagas disease.
Recent Progress in Lab-on-a-Chip Technology and Its Potential Application to Clinical Diagnoses

We present the construction of the lab-on-a-chip (LOC) system, a state-of-the-art technology that uses polymer materials (i.e., poly[dimethylsiloxane]) for the miniaturization of conventional laboratory apparatuses, and show the potential use of these microfluidic devices in clinical applications. In particular, we introduce the independent unit components of the LOC system and demonstrate how each component can be functionally integrated into one monolithic system for the realization of a LOC system. In specific, we demonstrate microscale polymerase chain reaction with the use of a single heater, a microscale sample injection device with a disposable plastic syringe and a strategy for device assembly under environmentally mild conditions assisted by surface modification techniques. In this way, we endeavor to construct a totally integrated, disposable microfluidic system operated by a single mode, the pressure, which can be applied on-site with enhanced device portability and disposability and with simple and rapid operation for medical and clinical diagnoses, potentially extending its application to urodynamic studies in molecular level.
Improved Performance of Advance Encryption Standard using Parallel Computing

This paper presents the implementation of Advance encryption (AES) algorithm using parallel computing. Most of the research for improving performance of AES is based on hardware implementation. This paper presents the parallel implementation of AES using JPPF (Java Parallel Programming Framework) which provides flexibility & performance improvement in terms of speed-up. In this implementation there are two approaches data parallelism and control parallelism. In Data parallelism, xn plain text is taken where x is 128 bits and n is any integer. Further xn data will be divided into n parts and each part will be send to independent processing units. Value of n can be increased depending on processing units available. In control parallelism, four round functions of AES Subbyte , ShiftRow , Mixcolumn. AddroundKey are divided into two independent parts for which structure of round functions has been modified. These two independent parts are assigned to different processing units and these processing units will exchange their intermediate result for further processing. Finally, results are conducted on single processing unit and multiple processing units on different sets of 256 bits of data and the performance analysis shows improvement in terms of execution time.
V-region mutation in vitro, in vivo, and in silico reveal the importance of the enzymatic properties of AID and the sequence environment

The somatic hypermutation of Ig variable regions requires the activity of activation-induced cytidine deaminase (AID) which has previously been shown to preferentially deaminate WRC (W = A/T, R = A/G) motif hot spots in in vivo and in vitro assays. We compared mutation profiles of in vitro assays for the 3′ flanking intron of VhJ558-Jh4 region to previously reported in vivo profiles for the same region in the Msh2−/−Ung−/− mice that lack base excision and mismatch repair. We found that the in vitro and in vivo mutation profiles were highly correlated for the top (nontranscribed) strand, while for the bottom (transcribed) strand the correlation is far lower. We used an in silico model of AID activity to elucidate the relative importance of motif targeting in vivo. We found that the mutation process entails substantial complexity beyond motif targeting, a large part of which is captured in vitro. To elucidate the contribution of the sequence environment to the observed differences between the top and bottom strands, we analyzed intermutational distances. The bottom strand shows an approximately exponential distribution of distances in vivo and in vitro, as expected from a null model. However, the top strand deviates strongly from this distribution in that mutations approximately 50 nucleotides apart are greatly reduced, again both in vivo and in vitro, illustrating an important strand asymmetry. While we have confirmed that AID targeting of hot and cold spots is a key part of the mutation process, our results suggest that the sequence environment plays an equally important role.
Salicylic Acid, Yersiniabactin, and Pyoverdin Production by the Model Phytopathogen Pseudomonas syringae pv. tomato DC3000: Synthesis, Regulation, and Impact on Tomato and Arabidopsis Host Plants

ABSTRACT A genetically tractable model plant pathosystem, Pseudomonas syringae pv. tomato DC3000 on tomato and Arabidopsis thaliana hosts, was used to investigate the role of salicylic acid (SA) and iron acquisition via siderophores in bacterial virulence. Pathogen-induced SA accumulation mediates defense in these plants, and DC3000 contains the genes required for the synthesis of SA, the SA-incorporated siderophore yersiniabactin (Ybt), and the fluorescent siderophore pyoverdin (Pvd). We found that DC3000 synthesizes SA, Ybt, and Pvd under iron-limiting conditions in culture. Synthesis of SA and Ybt by DC3000 requires pchA, an isochorismate synthase gene in the Ybt genomic cluster, and exogenous SA can restore Ybt production by the pchA mutant. Ybt was also produced by DC3000 in planta, suggesting that Ybt plays a role in DC3000 pathogenesis. However, the pchA mutant did not exhibit any growth defect or altered virulence in plants. This lack of phenotype was not attributable to plant-produced SA restoring Ybt production, as the pchA mutant grew similarly to DC3000 in an Arabidopsis SA biosynthetic mutant, and in planta Ybt was not detected in pchA-infected wild-type plants. In culture, no growth defect was observed for the pchA mutant versus DC3000 for any condition tested. Instead, enhanced growth of the pchA mutant was observed under stringent iron limitation and additional stresses. This suggests that SA and Ybt production by DC3000 is costly and that Pvd is sufficient for iron acquisition. Further exploration of the comparative synthesis and utility of Ybt versus Pvd production by DC3000 found siderophore-dependent amplification of ybt gene expression to be absent, suggesting that Ybt may play a yet unknown role in DC3000 pathogenesis.
TRB3 Is Involved in Free Fatty Acid-Induced INS-1-Derived Cell Apoptosis via the Protein Kinase C δ Pathway

Chronic exposure to free fatty acids (FFAs) may induce β cell apoptosis in type 2 diabetes. However, the precise mechanism by which FFAs trigger β cell apoptosis is still unclear. Tribbles homolog 3 (TRB3) is a pseudokinase inhibiting Akt, a key mediator of insulin signaling, and contributes to insulin resistance in insulin target tissues. This paper outlined the role of TRB3 in FFAs-induced INS-1 β cell apoptosis. TRB3 was promptly induced in INS-1 cells after stimulation by FFAs, and this was accompanied by enhanced INS-1 cell apoptosis. The overexpression of TRB3 led to exacerbated apoptosis triggered by FFAs in INS-1-derived cell line and the subrenal capsular transplantation animal model. In contrast, cell apoptosis induced by FFAs was attenuated when TRB3 was knocked down. Moreover, we observed that activation and nuclear accumulation of protein kinase C (PKC) δ was enhanced by upregulation of TRB3. Preventing PKCδ nuclear translocation and PKCδ selective antagonist both significantly lessened the pro-apoptotic effect. These findings suggest that TRB3 was involved in lipoapoptosis of INS-1 β cell, and thus could be an attractive pharmacological target in the prevention and treatment of T2DM.
Managing DRAM Latency Divergence in Irregular GPGPU Applications

Memory controllers in modern GPUs aggressively reorder requests for high bandwidth usage, often interleaving requests from different warps. This leads to high variance in the latency of different requests issued by the threads of a warp. Since a warp in a SIMT architecture can proceed only when all of its memory requests are returned by memory, such latency divergence causes significant slowdown when running irregular GPGPU applications. To solve this issue, we propose memory scheduling mechanisms that avoid inter-warp interference in the DRAM system to reduce the average memory stall latency experienced by warps. We further reduce latency divergence through mechanisms that coordinate scheduling decisions across multiple independent memory channels. Finally we show that carefully orchestrating the memory scheduling policy can achieve low average latency for warps, without compromising bandwidth utilization. Our combined scheme yields a 10.1% performance improvement for irregular GPGPU workloads relative to a throughput-optimized GPU memory controller.
Effect of Tungstate on Nitrate Reduction by the Hyperthermophilic Archaeon Pyrobaculum aerophilum

ABSTRACT Pyrobaculum aerophilum, a hyperthermophilic archaeon, can respire either with low amounts of oxygen or anaerobically with nitrate as the electron acceptor. Under anaerobic growth conditions, nitrate is reduced via the denitrification pathway to molecular nitrogen. This study demonstrates that P. aerophilumrequires the metal oxyanion WO42− for its anaerobic growth on yeast extract, peptone, and nitrate as carbon and energy sources. The addition of 1 μM MoO42−did not replace WO42− for the growth ofP. aerophilum. However, cell growth was completely inhibited by the addition of 100 μM MoO42−to the culture medium. At lower tungstate concentrations (0.3 μM and less), nitrite was accumulated in the culture medium. The accumulation of nitrite was abolished at higher WO42−concentrations (<0.7 μM). High-temperature enzyme assays for the nitrate, nitrite, and nitric oxide reductases were performed. The majority of all three denitrification pathway enzyme activities was localized to the cytoplasmic membrane, suggesting their involvement in the energy metabolism of the cell. While nitrite and nitric oxide specific activities were relatively constant at different tungstate concentrations, the activity of nitrate reductase was decreased fourfold at WO42− levels of 0.7 μM or higher. The high specific activity of the nitrate reductase enzyme observed at low WO42− levels (0.3 μM or less) coincided with the accumulation of nitrite in the culture medium. This study documents the first example of the effect of tungstate on the denitrification process of an extremely thermophilic archaeon. We demonstrate here that nitrate reductase synthesis inP. aerophilum occurs in the presence of high concentrations of tungstate.
The new paradigm of hepatitis C therapy: integration of oral therapies into best practices

Emerging data indicate that all‐oral antiviral treatments for chronic hepatitis C virus (HCV) will become a reality in the near future. In replacing interferon‐based therapies, all‐oral regimens are expected to be more tolerable, more effective, shorter in duration and simpler to administer. Coinciding with new treatment options are novel methodologies for disease screening and staging, which create the possibility of more timely care and treatment. Assessments of histologic damage typically are performed using liver biopsy, yet noninvasive assessments of histologic damage have become the norm in some European countries and are becoming more widespread in the United States. Also in place are new Centers for Disease Control and Prevention (CDC) initiatives to simplify testing, improve provider and patient awareness and expand recommendations for HCV screening beyond risk‐based strategies. Issued in 2012, the CDC recommendations aim to increase HCV testing among those with the greatest HCV burden in the United States by recommending one‐time testing for all persons born during 1945–1965. In 2013, the United States Preventive Services Task Force adopted similar recommendations for risk‐based and birth‐cohort‐based testing. Taken together, the developments in screening, diagnosis and treatment will likely increase demand for therapy and stimulate a shift in delivery of care related to chronic HCV, with increased involvement of primary care and infectious disease specialists. Yet even in this new era of therapy, barriers to curing patients of HCV will exist. Overcoming such barriers will require novel, integrative strategies and investment of resources at local, regional and national levels.
Clinical Impact of a Real-Time PCR Assay for Rapid Identification of Staphylococcal Bacteremia

ABSTRACT The purpose of this study was to evaluate the impact of real-time PCR reporting both on timely identification of clustered Gram-positive cocci (GPC) in blood cultures and on appropriate antibiotic treatment. This retrospective, interventional cohort study evaluated inpatients with blood cultures positive for GPC in the pre-PCR (15 January 2009 to 14 January 2010) and post-PCR (15 January 2010 to 14 January 2011) periods. Post-PCR implementation, laboratory services completed batched PCR; results other than methicillin-resistant Staphylococcus aureus (MRSA) were reported in the electronic medical record without additional interventions. The assay's sensitivity and specificity, time to identification of staphylococcal bacteremia, and clinically relevant outcomes, including time to optimal antibiotic therapy, were evaluated. Demographic information was also collected and analyzed. Sixty-eight and 58 patients with Staphylococcus aureus bacteremia from the pre- and post-PCR periods, respectively, met inclusion criteria. Similar numbers of consecutive patients with coagulase-negative staphylococci were analyzed for comparison. The time to identification was significantly reduced post-PCR implementation (mean, 13.2 h; 95% confidence interval [95% CI], 10.5 to 15.9 h; P < 0.0001). However, the time to optimal antibiotic therapy was not significantly reduced. We conclude that implementation of a PCR assay demonstrated the potential to improve appropriate antibiotic use based on clinically meaningful and statistically significant reductions in the time to microbiologic identification. However, in order to realize this potential benefit, processes must be optimized and additional interventions initiated to facilitate providers' use of the PCR result.
Efficacy of endoscopic ultrasonography and endoscopic ultrasonography-guided fine-needle aspiration for the diagnosis and grading of pancreatic neuroendocrine tumors

Abstract Background and aim: Pancreatic neuroendocrine tumors (pNETs) are histologically categorized according to the WHO 2010 classification by their mitotic index or Ki-67 index as G1, G2, or G3. The present study examined the efficacy of endoscopic ultrasonography (EUS) and EUS-guided fine-needle aspiration (EUS-FNA) in the diagnosis and grading of pNET. Methods: We retrospectively reviewed 61 pNETs in 51 patients who underwent EUS between January 2007 and June 2014. All lesions were pathologically diagnosed by surgical resection or EUS-FNA. We evaluated the detection rates of EUS for pNET and sensitivity of EUS-FNA, and compared the Ki-67 index between EUS-FNA samples and surgical specimens. EUS findings were compared between G1 and G2/G3 tumors. Results: EUS showed significantly higher sensitivity (96.7%) for identifying pNET than CT (85.2%), MRI (70.2%), and ultrasonography (75.5%). The sensitivity of EUS-FNA for the diagnosis of pNET was 89.2%. The concordance rate of WHO classification between EUS-FNA and surgical specimens was 69.2% (9/13). The concordance rate was relatively high (87.5%, 5/6) in tumors <20 mm but lower (57.1%; 4/7) in tumors ≥20 mm. Regarding EUS findings, G2/G3 tumors were more likely to be large (>20 mm), heterogeneous, and have main pancreatic duct (MPD) obstruction than G1 tumors. Multivariate analysis showed large diameter and MPD obstruction were significantly associated with G2/G3 tumors. Conclusions: EUS and EUS-FNA are highly sensitive and accurate diagnostic methods for pNET. Characteristic EUS findings such as large tumor size and MPD obstruction are suggestive of G2/G3 tumors and would be helpful for grading pNETs.
Cholesterol Feeding Increases C-Reactive Protein and Serum Amyloid A Levels in Lean Insulin-Sensitive Subjects

Background—Inflammatory markers associated with elevated cardiovascular risk are increased by cholesterol feeding in animal models. However, whether dietary cholesterol increases inflammatory marker levels in humans is not known. Methods and Results—C-reactive protein (CRP), serum amyloid A (SAA), and lipoprotein levels were compared in 201 healthy subjects on an American Heart Association–National Cholesterol Education Program step 1 diet at baseline and after addition of 4 eggs per day for 4 weeks. Subjects were classified a priori into 3 groups based on their body mass index (BMI) and insulin sensitivity index (SI): lean insulin sensitive (LIS), mean±SEM BMI, 23.2±0.3 kg/m2, and SI, 6.7±0.3×10−4min−1/(&mgr;U/mL), n=66; lean insulin resistant (LIR), BMI, 24.5±0.2 kg/m2 and SI, 2.9±0.1×10−4min−1/(&mgr;U/mL), n=76; or obese insulin resistant (OIR), BMI, 31.4±0.5 kg/m2 and SI, 2.1±0.1×10−4min−1/(&mgr;U/mL), n=59. Insulin resistance and obesity each were associated with increased baseline levels of both CRP (P for trend, <0.001) and SAA (P for trend=0.015). Egg feeding was associated with significant increases in both CRP and SAA in the LIS group (both P<0.01) but not in the LIR or OIR groups. Egg feeding also was associated with a significant increase in non-HDL cholesterol (P<0.001) in LIS subjects; however, there was no correlation between the change in non-HDL cholesterol or changes in either CRP or SAA in this group. Conclusions—A high-cholesterol diet leads to significant increases in both inflammatory markers and non-HDL cholesterol levels in insulin-sensitive individuals but not in lean or obese insulin-resistant subjects.
Improved accuracy of cell surface shaving proteomics in Staphylococcus aureus using a false‐positive control

Proteolytic treatment of intact bacterial cells is an ideal means for identifying surface‐exposed peptide epitopes and has potential for the discovery of novel vaccine targets. Cell stability during such treatment, however, may become compromised and result in the release of intracellular proteins that complicate the final analysis. Staphylococcus aureus is a major human pathogen, causing community and hospital‐acquired infections, and is a serious healthcare concern due to the increasing prevalence of multiple antibiotic resistances amongst clinical isolates. We employed a cell surface “shaving” technique with either trypsin or proteinase‐K combined with LC‐MS/MS. Trypsin‐derived data were controlled using a “false‐positive” strategy where cells were incubated without protease, removed by centrifugation and the resulting supernatants digested. Peptides identified in this fraction most likely result from cell lysis and were removed from the trypsin‐shaved data set. We identified 42 predicted S. aureus COL surface proteins from 260 surface‐exposed peptides. Trypsin and proteinase‐K digests were highly complementary with ten proteins identified by both, 16 specific to proteinase‐K treatment, 13 specific to trypsin and three identified in the control. The use of a subtracted false‐positive strategy improved enrichment of surface‐exposed peptides in the trypsin data set to approximately 80% (124/155 peptides). Predominant surface proteins were those associated with methicillin resistance–surface protein SACOL0050 (pls) and penicillin‐binding protein 2′ (mecA), as well as bifunctional autolysin and the extracellular matrix‐binding protein Ebh. The cell shaving strategy is a rapid method for identifying surface‐exposed peptide epitopes that may be useful in the design of novel vaccines against S. aureus.
Delayed rescue of N-methyl-D-aspartate receptor-mediated neuronal injury in cortical culture.

The present study explored the neuroprotective efficacy of delayed manipulations performed after completion of an excitotoxic insult. Many cultured murine cortical neurons that would otherwise die after exposure to 500 microM N-methyl-D-aspartate (NMDA) or glutamate could be rescued by the late addition of NMDA antagonists to the bathing medium. D-2-Amino-5-phosphonovalerate (D-APV), MK-801 (5-methyl-10, 11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine maleate) and dextrorphan all produced concentration-dependent neuroprotection, with EC50 about 10, 0.3 and 3 microM, respectively, and similar efficacy. The fraction of the doomed neuronal population that could be rescued depended on the time interval between washout of NMDA and antagonist addition, starting at a maximum of 40 to 80% with immediate addition, and decaying to zero after 30 min. D-APV only needed to be present for 30 min for near maximal protection. The ability of NMDA antagonists to rescue doomed neurons was not mimicked by several other drugs: 1 mM gamma-D-glutamyl-aminomethyl sulfonate, 1 mM L-glutamate diethyl ester, 10 microM 6-nitro-7-cyano-quinoxaline-2,3-dione, 1 mM secobarbital, 100 microM diphenylhydantoin, 10 microM nifedipine or 3 microM tetrodotoxin. The broad spectrum glutamate antagonist kynurenate had a protective action similar to that of D-APV, but when added to D-APV did not improve neuroprotection. Neurons could also be rescued by the delayed removal of extracellular calcium for 30 min after exposure to NMDA. In contrast, replacement of sodium with choline actually enhanced resultant neuronal damage. (ABSTRACT TRUNCATED AT 250 WORDS)