Miracle-dz/UniFAR-FTUs huggingface dataset:
Integrative proteomics, genomics, and translational immunology approaches reveal mutated forms of Proteolipid Protein 1 (PLP1) and mutant‐specific immune response in multiple sclerosis

In order to gain mechanistic insights into multiple sclerosis (MS) pathogenesis, we utilized a multi‐dimensional approach to test the hypothesis that mutations in myelin proteins lead to immune activation and central nervous system autoimmunity in MS. Mass spectrometry‐based proteomic analysis of human MS brain lesions revealed seven unique mutations of PLP1; a key myelin protein that is known to be destroyed in MS. Surprisingly, in‐depth genomic analysis of two MS patients at the genomic DNA and mRNA confirmed mutated PLP1 in RNA, but not in the genomic DNA. Quantification of wild type and mutant PLP RNA levels by qPCR further validated the presence of mutant PLP RNA in the MS patients. To seek evidence linking mutations in abundant myelin proteins and immune‐mediated destruction of myelin, specific immune response against mutant PLP1 in MS patients was examined. Thus, we have designed paired, wild type and mutant peptide microarrays, and examined antibody response to multiple mutated PLP1 in sera from MS patients. Consistent with the idea of different patients exhibiting unique mutation profiles, we found that 13 out of 20 MS patients showed antibody responses against specific but not against all the mutant‐PLP1 peptides. Interestingly, we found mutant PLP‐directed antibody response against specific mutant peptides in the sera of pre‐MS controls. The results from integrative proteomic, genomic, and immune analyses reveal a possible mechanism of mutation‐driven pathogenesis in human MS. The study also highlights the need for integrative genomic and proteomic analyses for uncovering pathogenic mechanisms of human diseases.
On Incremental Deployment of Named Data Networking in Local Area Networks

A data-centric network architecture, Named Data Networking (NDN) has been developed to meet applications' growing demands of network effciency and resilience. Currently, the deployment of NDN in real network environments requires careful system design to not only enable NDN but also support IP traffc, considering IP network has been prevalent for decades and almost all the equipments and applications are IP-based. In this paper, we take the most popular local area network (LAN) technology, Ethernet, as an example to investigate incremental deployment of NDN. Assuming a local network with both NDN and IP traffc, we mainly layout three deployment scenarios: NDN-enabled hosts and all Ethernet switches, NDN-enabled hosts and all Dual-Stack switches (i.e., it can process both NDN and IP traffc), and a hybrid network with both Dual-Stack switches and Ethernet switches. We examine the technical issues involved in each scenario and present solutions. In particular, in the hybrid scenario, we propose heuristics to optimize the placement of Dual-Stack switches. Compared with traditional Ethernet, introducing Dual-Stack switches can improve network effciency and resiliency by utilizing more links, reducing each link's traffc load, and taking shorter paths, at the same time also maintaining the functionality of IP-based applications.
Enhancing the Thermostability of Rhizomucor miehei Lipase with a Limited Screening Library by Rational-Design Point Mutations and Disulfide Bonds

ABSTRACT Rhizomucor miehei lipase (RML), as a kind of eukaryotic protein catalyst, plays an important role in the food, organic chemical, and biofuel industries. However, RML retains its catalytic activity below 50°C, which limits its industrial applications at higher temperatures. Soluble expression of this eukaryotic protein in Escherichia coli not only helps to screen for thermostable mutants quickly but also provides the opportunity to develop rapid and effective ways to enhance the thermal stability of eukaryotic proteins. Therefore, in this study, RML was engineered using multiple computational design methods, followed by filtration via conservation analysis and functional region assessment. We successfully obtained a limited screening library (only 36 candidates) to validate thermostable single point mutants, among which 24 of the candidates showed higher thermostability and 13 point mutations resulted in an apparent melting temperature (Tmapp) of at least 1°C higher. Furthermore, both of the two disulfide bonds predicted from four rational-design algorithms were further introduced and found to stabilize RML. The most stable mutant, with T18K/T22I/E230I/S56C-N63C/V189C-D238C mutations, exhibited a 14.3°C-higher Tmapp and a 12.5-fold increase in half-life at 70°C. The catalytic efficiency of the engineered lipase was 39% higher than that of the wild type. The results demonstrate that rationally designed point mutations and disulfide bonds can effectively reduce the number of screened clones to enhance the thermostability of RML. IMPORTANCE R. miehei lipase, whose structure is well established, can be widely applied in diverse chemical processes. Soluble expression of R. miehei lipase in E. coli provides an opportunity to explore efficient methods for enhancing eukaryotic protein thermostability. This study highlights a strategy that combines computational algorithms to predict single point mutations and disulfide bonds in RML without losing catalytic activity. Through this strategy, an RML variant with greatly enhanced thermostability was obtained. This study provides a competitive alternative for wild-type RML in practical applications and further a rapid and effective strategy for thermostability engineering.
Cytochrome P450 isoform selectivity in human hepatic theobromine metabolism.

AIMS The plasma clearance of theobromine (TB; 3,7-dimethylxanthine) is known to be induced in cigarette smokers. To determine whether TB may serve as a model substrate for cytochrome P450 (CYP) 1A2, or possibly other isoforms, studies were undertaken to identify the individual human liver microsomal CYP isoforms responsible for the conversion of TB to its primary metabolites. METHODS The kinetics of formation of the primary TB metabolites 3-methylxanthine (3-MX), 7-methylxanthine (7-MX) and 3,7-dimethyluric acid (3,7-DMU) by human liver microsomes were characterized using a specific hplc procedure. Effects of CYP isoform-selective xenobiotic inhibitor/substrate probes on each pathway were determined and confirmatory studies with recombinant enzymes were performed to define the contribution of individual isoforms to 3-MX, 7-MX and 3,7-DMU formation. RESULTS The CYP1A2 inhibitor furafylline variably inhibited (0-65%) 7-MX formation, but had no effect on other pathways. Diethyldithiocarbamate and 4-nitrophenol, probes for CYP2E1, inhibited the formation of 3-MX, 7-MX and 3,7-DMU by approximately 55-60%, 35-55% and 85%, respectively. Consistent with the microsomal studies, recombinant CYP1A2 and CYP2E1 exhibited similar apparent Km values for 7-MX formation and CYP2E1 was further shown to have the capacity to convert TB to both 3-MX and 3,7-DMU. CONCLUSIONS Given the contribution of multiple isoforms to 3-MX and 7-MX formation and the negligible formation of 3,7-DMU in vivo, TB is of little value as a CYP isoform-selective substrate in humans.
Interactions of cheese and of its constituents with monoamine oxidase inhibitors.

Patients treated with monoamine oxidase inhibitors sometimes experience severe and occasionally fatal hypertensive attacks after eating cheese (Blackwell, 1963). Other factors must modify this adverse reaction since many patients treated with monoamine oxidase inhibitors eat cheese with impunity. Some inhibitors appear more likely to interact with cheese in man (Marks, 1965) and earlier animal experiments showed that several inhibitors possess intrinsic sympathomimetic actions which may potentiate or obscure the blood pressure effects of cheese (Blackwell & Marley, 1964). Preliminary studies in animals of interactions between cheese and amine oxidase inhibitors have been reported (Blackwell & Marley, 1964; Natoff, 1964) and an account of some of our experiments has been given to the British Pharmacological Society (Blackwell & Marley, July 1964). This paper reports the investigation of sympathomimetic effects due to cheese in three species with different dietary habits, together with the identification of responsible constituents and the factors which modify their actions on the blood pressure.
Flow cytometry, morphometry and histopathology as biomarkers of benzo[a]pyrene exposure in brown bullheads (ameiurus nebulosus)

Brown bullheads were given a single intraperitoneal dose of 0, 5, 25 or 125 mg kg−1 benzo[a]pyrene (BaP), a carcinogenic polycyclic aromatic hydrocarbon, and evaluated over 18 months. Flow cytometric analyses of hepatocyte DNA content indicated an increase in DNA synthesis in BaP‐exposed fish prior to day 14 post‐exposure. Thereafter, all flow cytometric variables returned to initial levels. Histopathological evaluation of livers from fish sampled at 18 months revealed significant differences among treatments in the amount of hepatic macrophage ceroid pigmentation and basophilic staining intensity. No neoplasms or changes in blood cell DNA content were detected. Significant morphometric variations existed among fish, but differences between sexes overshadowed differences attributable to dose. Flow cytometry yielded no evidence of long‐term DNA alterations from a single exposure to BaP; however, the differences detected by DNA analysis shortly after the toxic event suggest that flow cytometric cell cycle analysis may be useful for documenting continuing exposures.
Communicating With the Audience in Mind

Agricultural communication is a very young discipline and its professionals are still defining their function. An important element that must guide us in our search for identity, however, is knowing who our primary audience really is. Is it the organizalions for which we work? Should we focus our attention on the farmers and agribusiness owners, many of whom are highly educated and have, for the most part, many ways of obtaining innovative informalion? Or should we more properly address the needs of those who are agriculturally illiterate, and whose main source of information about how agriculture affects their lives seems to be us, the agricultural communicators. This author argues that the "poor masses out there" must be our main audience and asks the question: Do we know how to reach them with the information they so vitally need? This research is available in Journal of Applied Communications: https://newprairiepress.org/jac/vol73/iss2/5 Communicating With the Audience in Mind
Vinflunine: review of a new vinca alkaloid and its potential role in oncology

Objective: To review the pharmacology, pharmacokinetics, in vitro and in vivo efficacy, and safety profile of vinflunine in the treatment of various solid tumors. Data sources: A literature search was conducted using keywords included vinflunine, vinca alkaloid, Javlor, and solid tumor in PubMed/MEDLINE (1950—January 2009) and International Pharmaceutical Abstracts (1950—January 2009). Study selection and data extraction: Published studies, posters, and meeting abstracts evaluating the in vitro and in vivo efficacy of vinflunine were reviewed. Data synthesis: Vinflunine is the newest member of the vinca alkaloid family. It has the weakest affinity to tubulins, but is shown to have unique receptor-independent antiangiogenesis, and antimetastasis properties. After administration, it is distributed extensively into tissues, metabolized via the CYP3A4 system, and eventually excreted in urine and feces. Phase II/III trials reported activities of vinflunine in advanced stage nonsmall-cell lung cancer, metastatic breast cancer, metastatic renal cell carcinoma, transitional cell carcinomas of the urothelium, small-cell lung cancer, and malignant pleural mesothelioma as monotherapy and in combination with other chemotherapy agents. More ongoing trials are evaluating its use in other solid tumors and in combination regimens. The most common adverse events in these trials were hematological (anemia and neutropenia), constipation, fatigue, abdominal pain, and myalgia. Conclusions: Vinflunine is a new vinca alkaloid for the treatment of advanced staged solid tumors. Available data showed promising activities in various malignancies. Further studies are needed to further define vinflunine’s role in oncology.
Combination Therapies for HIV and Sexual Risk Behavior Among Gay Men

Objective: To examine optimism in the light of recent advances in HIV treatment among gay men and its association with sexual risk behavior. Methods: An anonymous questionnaire was completed by gay men who visited gyms in central London in March and April 1998 regarding their HIV status, unprotected anal intercourse (UAI) in the previous 3 months, and their response on a five‐point linear scale to two measures of optimism: “I am less worried about HIV now that treatments have improved,” and “I believe that new drug therapies make people with HIV less infectious. ” Results: Two thirds of the men (67.5%, 522 of 773) did not agree with the statement, “I am less worried about HIV now that treatments have improved,” and only 42 (5.4%) said they agreed quite a lot or a lot. HIV‐positive men were more likely to agree with this statement than HIV‐negative men (p = .001) and men who had never been tested (p < .001). There was no association between agreement with this statement and frequency of UAI among HIV‐positive or never‐tested men (p > .3); there was, however, a positive association among HIV‐negative men who reported UAI with a partner of unknown or discordant status (p = .003). The vast majority of men (81.4%; 634 of 779) did not agree with the statement, “I believe that new drug therapies make people with HIV less infectious. ” Regardless of HIV status, no significant association was seen between agreement with this statement and frequency of UAI (p > .1 for all comparisons). Conclusion: Most gay men surveyed in central London gyms did not endorse the optimism statements concerning improved treatments or reduced infectivity. Although HIV‐positive gay men were more likely to be optimistic than other men, there was no association between their optimism and sexual risk behavior. Among HIV‐negative men, optimism around improved treatments (but not around reduced infectivity) was associated with UAI with a partner of unknown or discordant HIV status. For some HIV‐negative men in London, optimism in the light of recent advances in HIV treatment may have triggered, or have been used as a justification for, sexual risk‐taking.
Reaching out to the people? Assessing the relationship between parliament and citizens in Finland

ABSTRACT Despite the Open Government (Parliament) initiatives and notions of a ‘democratic parliament’, the relationship between legislatures and citizens remains seriously under-researched. This article introduces a comprehensive analytical framework, combining the normative principles of visibility, accessibility, and permeability with practical indicators (parliament as public space, sharing of information, contact with MPs, media and digital engagement, transparency of legislative process, and actual participation in legislative decision-making) for assessing the public engagement of parliaments. Applying this framework to the Finnish Eduskunta, the authors show that despite recent reforms that have partially ‘opened up’ parliamentary proceedings and attempted to connect citizens to democratic process, there remains scope for reforms and innovations. The Eduskunta should embrace a more positive approach towards new forms of civic participation, particularly regarding how its influential committees operate. The findings reflect the tensions between, or the difficulties in reconciling, traditional forms of representative democracy with alternative and more direct channels of political participation.
Phase II trial of subcutaneously administered granulocyte‐macrophage colony‐stimulating factor in patients with metastatic renal cell carcinoma

Granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) is a cytokine that is involved in the differentiation and proliferation of various hematopoietic precursors. It also has been reported to enhance the antitumor activity of various mature effector cells. Previous reports have noted preclinical antitumor activity in a murine model utilizing genetically engineered tumor cells and instances of tumor regression in patients with solid tumors receiving GM‐CSF. In the present study, a Phase II trial of human recombinant GM‐CSF (GM‐CSFrh) in patients with metastatic renal cell carcinoma (RCC) was conducted to investigate further the potential antitumor activity of this cytokine.
Tensile strain dependence of Brillouin frequency shift in silica optical fibers

Brillouin frequency shift in a single-mode optical fiber has been measured as a function of tensile strain. The strain coefficient of normalized Brillouin frequency shift C identical to (dv/sub B//d epsilon )/v/sub B/ is found to be 4.4 for silica fibers. This result shows the potential of Brillouin spectroscopy to evaluate tensile strain in the fiber with the strain resolution of about 2*10/sup -4/. The origin of the large strain coefficient is discussed. <<ETX>>
Listeria spp. in the coastal environment of the Aqaba Gulf, Suez Gulf and the Red Sea

Listeria monocytogenes is an important pathogen which causes an infection called listeriosis. Because of the high mortality rate (~30%) associated with listeriosis, and the widespread nature of the organism, it is a major concern for food and water microbiologists since it has been isolated from various types of foods, including seafood, as well as from the aqueous environment. To investigate the prevalence of this pathogen in the Aqaba Gulf (12 sites), Suez Gulf (14 sites) and Red Sea (14 sites), 200 water samples (collected during five sampling cruises in 2004), 40 fresh fish samples and 15 shellfish samples were analysed using the enrichment procedure and selective agar medium. All water samples were also examined for the presence Listeria innocua which was the most common of the Listeria spp. isolated, followed by L. monocytogenes, with a low incidence of the other species. During the whole year, the percentage of Listeria spp. and L. monocytogenes in 200 water samples was 20·5% (41 samples) and 13% (26 samples) respectively. In fresh fish (40 samples) it was 37% (15 samples) and 17·3% (7 samples) and in shellfish (15 samples) 53% (8 samples) and 33% (5 samples) respectively. In water samples, there was an association between the faecal contamination parameters and the presence of the pathogen; however, water salinity, temperature, dissolved oxygen and pH did not influence the occurrence of this bacterium. These results may help in the water-quality evaluation of the coastal environments of these regions.
The effect of iron in MRI and transverse relaxation of amyloid‐beta plaques in Alzheimer's disease

Dysregulation of neural iron is known to occur during the progression of Alzheimer's disease. The visualization of amyloid‐beta (Aβ) plaques with MRI has largely been credited to rapid proton relaxation in the vicinity of plaques as a result of focal iron deposition. The goal of this work was to determine the relationship between local relaxation and related focal iron content associated with Aβ plaques. Alzheimer's disease (n = 5) and control tissue (n = 3) sample slices from the entorhinal cortex were treated overnight with the iron chelator deferoxamine or saline, and microscopic gradient‐echo MRI datasets were taken. Subsequent to imaging, the same slices were stained for Aβ and iron, and then compared with regard to parametric R2* relaxation maps and gradient‐echo‐weighted MR images. Aβ plaques in both chelated and unchelated tissue generated MR hypo‐intensities and showed relaxation rates significantly greater than the surrounding tissue. The transverse relaxation rate associated with amyloid plaques was determined not to be solely a result of iron load, as much of the relaxation associated with Aβ plaques remained following iron chelation. The data indicate a dual relaxation mechanism associated with Aβ plaques, such that iron and plaque composition synergistically produce transverse relaxation.Copyright © 2014 John Wiley & Sons, Ltd.
Islamic Finance and Financial Stability: A Review of the Literature

This paper provides a critical review of the Islamic Economics (IEs) and Finance (IF) literature that have examined the stability of the Islamic Financial System (IFS) and its institutions vis-a-vis the conventional interest-based system. The paper analyzes forty studies over the last thirty-year period (1983- 2013). Two sub-periods: pre-and post-subprime financial crisis are compared. The pre-crisis period focuses on theoretical investigations while the post-crisis focuses on empirical research. The results show that the crisis seems to have triggered more attention to the stability of IF. Seventy five percent of the reviewed literature has been carried out in the post-crisis era; about five studies have been produced per year during the last five years (2008-2013) in contrast to less than one study per year in its antecedent period. In addition, Z-score indicator has come out as the most commonly used proxy for measuring the stability of Islamic financial intermediaries. The results also show that there is a significant divergence between the theory and practice of IF. Theoretical studies claim the ‘superiority’ of the IFS based primarily on equity and participatory modes of financing, while empirical studies are not yet conclusive.
[Clinical applications of ultrasound biomicroscopy in diagnosis and treatment of lens subluxation].

OBJECTIVE To evaluate the clinical value in diagnosis and treatment of lens subluxation using ultrasound biomicroscopy (UBM). METHOD This study comprised 29 patients (32 eyes) that had cataract with subluxated lenses due to different causes admitted into our hospital between November 2000 and January 2002. All eyes received UBM examination preoperatively and postoperatively. Capsular tension ring (CTR) implantations were performed using different technique according to UBM examination. Then all patients received phacoemulsification and intraocular lens (IOL) implantation. The location of IOL and CTR and complications were evaluated postoperatively. RESULTS Different kinds of subluxated lens shown different manifestations in UBM. The degree of zonular defect can be evaluated with UBM preoperatively. With UBM examination preoperatively, extent of lens subluxation less than 1/2 quadrant in 19 eyes while more than 1/2 quadrant in other 13 eyes were observed. Postoperative UBM examination in this series shown that CTRs were holding in place except one attached to the iris root. IOLs in 29 eyes were in proper position while IOLs in 3 patients were slightly tilted. CONCLUSIONS The degree and extent of lens subluxation can be evaluated using UBM examinations preoperatively, which is necessary in the selection of surgical protocol. With postoperative UBM examinations, a precise observation on the actual location of CTR and IOL can be achieved to produce an objective evaluation of the surgical outcomes.