Miracle-dz/UniFAR-FTUs huggingface dataset:
Genetic Analysis of Adult-Onset Autoimmune Diabetes

OBJECTIVE In contrast with childhood-onset type 1 diabetes, the genetics of autoimmune diabetes in adults are not well understood. We have therefore investigated the genetics of diabetes diagnosed in adults positive for autoantibodies. RESEARCH DESIGN AND METHODS GAD autoantibodies (GADAs), insulinoma-associated antigen-2 antibodies (IA-2As), and islet cell autoantibodies were measured at time of diagnosis. Autoantibody-positive diabetic subjects (n = 1,384) and population-based control subjects (n = 2,235) were genotyped at 20 childhood-onset type 1 diabetes loci and FCRL3, GAD2, TCF7L2, and FTO. RESULTS PTPN22 (1p13.2), STAT4 (2q32.2), CTLA4 (2q33.2), HLA (6p21), IL2RA (10p15.1), INS (11p15.5), ERBB3 (12q13.2), SH2B3 (12q24.12), and CLEC16A (16p13.13) were convincingly associated with autoimmune diabetes in adults (P ≤ 0.002), with consistent directions of effect as reported for pediatric type 1 diabetes. No evidence of an HLA-DRB1*03/HLA-DRB1*04 (DR3/4) genotype effect was obtained (P = 0.55), but it remained highly predisposing (odds ratio 26.22). DR3/4 was associated with a lower age at diagnosis of disease, as was DR4 (P = 4.67 × 10−6) but not DR3. DR3 was associated with GADA positivity (P = 6.03 × 10−6) but absence of IA-2A (P = 3.22 × 10−7). DR4 was associated with IA-2A positivity (P = 5.45 × 10−6). CONCLUSIONS Our results are consistent with the hypothesis that the genetics of autoimmune diabetes in adults and children are differentiated by only relatively few age-dependent genetic effects. The slower progression toward autoimmune insulin deficiency in adults is probably due to a lower genetic load overall combined with subtle variation in the HLA class II gene associations and autoreactivity.
Overexpression of Chromosome 21 miRNAs May Affect Mitochondrial Function in the Hearts of Down Syndrome Fetuses

Dosage-dependent upregulation of most of chromosome 21 (Hsa21) genes has been demonstrated in heart tissues of fetuses with Down syndrome (DS). Also miRNAs might play important roles in the cardiac phenotype as they are highly expressed in the heart and regulate cardiac development. Five Hsa21 miRNAs have been well studied in the past: miR-99a-5p, miR-125b-2-5p, let-7c-5p, miR-155-5p, and miR-802-5p but few information is available about their expression in trisomic tissues. In this study, we evaluated the expression of these miRNAs in heart tissues from DS fetuses, showing that miR-99a-5p, miR-155-5p, and let-7c-5p were overexpressed in trisomic hearts. To investigate their role, predicted targets were obtained from different databases and cross-validated using the gene expression profiling dataset we previously generated for fetal hearts. Eighty-five targets of let-7c-5p, 33 of miR-155-5p, and 10 of miR-99a-5p were expressed in fetal heart and downregulated in trisomic hearts. As nuclear encoded mitochondrial genes were found downregulated in trisomic hearts and mitochondrial dysfunction is a hallmark of DS phenotypes, we put special attention to let-7c-5p and miR-155-5p targets downregulated in DS fetal hearts and involved in mitochondrial function. The let-7c-5p predicted target SLC25A4/ANT1 was identified as a possible candidate for both mitochondrial and cardiac anomalies.
Antibody-drug conjugates and immunotoxins : from pre-clinical development to therapeutic applications

Antibody Directed Delivery for Treatment of Cancer: Antibody Drug Conjugates and Immunotoxins. - Antibody-Drug Conjugate Development. - Components of ADC Development: Assay Methodologies and Challenges. - Clinical Pharmacology Strategies in the Development of Antibody-Drug Conjugates. - Predictive Biomarkers for Antibody-Drug Conjugates. - Factors Involved in the Design of Cytotoxic Payloads for Antibody-Drug Conjugates. - Linker Technology and Impact of Linker Design on ADC Properties. - Antibody-drug conjugates for the treatment of B-cell malignancies. - Targeting CD19 with SAR3419, an anti-CD19-Maytansinoid Conjugate for the Treatment of B Cell Malignancies. - Brentuximab Vedotin (SGN-35) for CD30 Positive Malignancies. - Trastuzumab Emtansine (T-DM1) for the Treatment of HER2-Positive Cancer. - CDX-011 (Glembatumumab Vedotin, CR011-vcMMAE). - Case Study: An Antibody-Drug Conjugate Targeting MUC16 for Ovarian Cancer. - EphA2 Immunoconjugate. - Anti-PSMA Antibody-Drug Conjugates. - Targeting CD56 (NCAM)-expressing Neoplasms with Lorvotuzumab Mertansine. - Studies on the Metabolism of Antibody-Drug Conjugates. - Design, Development and Characterization of Recombinant Immunotoxins Targeting HER2/neu. - The Preclinical and Clinical Evaluation of VB6-845: An Immunotoxin with a De-Immunized Payload for the Systemic Treatment of Solid Tumors. - Index.
Longitudinal analysis of DNA methylation associated with birth weight and gestational age

Gestational age (GA) and birth weight have been implicated in the determination of long-term health. It has been hypothesized that changes in DNA methylation may mediate these long-term effects. We obtained DNA methylation profiles from cord blood and peripheral blood at ages 7 and 17 in the same children from the Avon Longitudinal Study of Parents and Children. Repeated-measures data were used to investigate changes in birth-related methylation during childhood and adolescence. Ten developmental phenotypes (e.g. height) were analysed to identify possible mediation of health effects by DNA methylation. In cord blood, methylation at 224 CpG sites was found to be associated with GA and 23 CpG sites with birth weight. Methylation changed in the majority of these sites over time, but neither birth characteristic was strongly associated with methylation at age 7 or 17 (using a conservative correction for multiple testing of P < 1.03 × 10–7), suggesting resolution of differential methylation by early childhood. Associations were observed between birth weight-associated CpG sites and phenotypic characteristics in childhood. One strong association involved birth weight, methylation of a CpG site proximal to the NFIX locus and bone mineral density at age 17. Analysis of serial methylation from birth to adolescence provided evidence for a lack of persistence of methylation differences beyond early childhood. Sites associated with birth weight were linked to developmental genes and have methylation levels which are associated with developmental phenotypes. Replication and interrogation of causal relationships are needed to substantiate whether methylation differences at birth influence the association between birth weight and development.
Fatal and nonfatal AIDS and non-AIDS events in HIV-1-positive individuals with high CD4 cell counts according to viral load strata

Background:This study compared the incidence of fatal and nonfatal AIDS and non-AIDS events in HIV-positive individuals with a CD4 cell count more than 350 cells/&mgr;l among viral load strata: low (<500 copies/ml), intermediate (500–9999.9 copies/ml) and high (≥10000 copies/ml). Methods:Individuals contributed person-years at risk if their most recent CD4 cell count was more than 350 cells/&mgr;l. Follow-up was censored if their CD4 cell count dropped below 350 cells/&mgr;l. Poisson regression analysis investigated the relationship between viraemia and the incidence of AIDS and non-AIDS events. Results:Three hundred and fifty-four AIDS events occurred during 51 732 person-years of follow-up (PYFU), crude incidence rate of AIDS across the three strata was 0.53, 0.90 and 2.12 per 100 PYFU, respectively. After adjustment, a higher rate of AIDS was observed in individuals with moderate [incidence rate ratio (IRR) 1.44, 1.02–2.05, P = 0.03] and high viraemia had a higher rate (IRR 3.91, 2.89–5.89, P < 0.0001) compared with low viraemia. Five hundred and seventy-two non-AIDS events occurred during 43 784 PYFU, the crude incidence rates were 1.28, 1.52, and 1.38 per 100 PYFU, respectively. After adjustment, particularly for age, region of Europe and starting combination antiretroviral therapy, there was a 61% (IRR 1.61, 1.21–2.14, P = 0.001) and 66% (IRR 1.66, 1.17–2.32, P = 0.004) higher rate of non-AIDS in individuals with intermediate and high viraemia compared with low viraemia. Conclusion:In individuals with a CD4 cell count more than 350 cells/&mgr;l, an increased incidence of AIDS and a slightly increased incidence of non-AIDS was found in those with uncontrolled viral replication. The association with AIDS was clear and consistent. However, the association with non-AIDS was only apparent after adjustment and no differences were observed between intermediate and high viraemia.
BOTH EXTRACELLULAR ATP AND SHEAR STRESS REGULATE THE RELEASE OF NITRIC OXIDE IN RAT CAUDAL ARTERY

1. To elucidate the physiological role of nitric oxide (NO) in regulating vascular tone, the effects of NG‐nitro‐L‐arginine methyl ester (L‐NAME), an NO synthase inhibitor, on the vasoconstrictor response to noradrenaline (NA) in rat caudal artery was examined.
SPECIFIC ADENOVIRUS COMPLEMENT-FIXING ANTIGENS IN VIRUS-FREE HAMSTER AND RAT TUMORS.

Although tumors induced in hamsters by adenovirus types 12 and 18 do not contain demonstrable infectious virus, turmorous animals develop high-level complement-fixing (CF) antibodies reactive with homotypic adenovirus tissue culture antigens. ' Likewise, hamsters carrying transplants of these noninfectious tumors show comparable CF antibody responses. " Hamsters which received virus or transplanted tumor tissue, but in which progressive tumor growth did not occur, did not develop CF antibody. , 2 In contrast to human CF antibody responses to adenovirus infections, in which the antibody is primarily formed against the group reactive "A"3 or "L"4 soluble antigen, the antibodies in the tumorous hamsters are essentially type-specific and are presumably reactive with antigens similar to the "C"3 or "E"4 soluble antigens. Thus, sera from hamsters with tumors induced by type 12 react in high titer with type 12 tissue culture antigen, are somewhat less reactive with type 18 antigen, and give no reaction with the other 26 human adenovirus types. Virus-neutralizing antibodies also develop in hamsters with primary and transplanted tumors, but only in those with highest levels of CF antibody. " 2 This report describes the direct demonstration of virus-specific CF antigens in the noninfectious or "virus-free" hamster tumors induced by adenovirus types 12 and 18, as well as in transplanted tumors' and tissue culture cell lines derived therefrom. Also, we describe the induction of tumors in rats by type 12, with comparable findings of noninfectious virus-specific antigens and antibodies in the tumorous animals. Preliminary information on specific CF antigens in hamster tumors induced by SV40 and Rous viruses is also plesented.
Macrophage activation and generation of tumoricidal activity by liposome-associated human C-reactive protein.

The effect of human C-reactive protein incorporated into multilamellar vesicles (CRP-MLV) was studied in assays of macrophage function. Peritoneal exudate macrophages from C57BL/6 mice phagocytosed CRP-MLV in vitro more rapidly than multilamellar vesicles bearing comparable amounts of immunoglobulin G. Exposure of peritoneal exudate macrophages in vitro to CRP-MLV resulted in development of tumoricidal activity against syngeneic T241 fibrosarcoma and B-16 melanoma cells and against allogeneic Sarcoma 1 cells. Peritoneal exudate macrophages obtained from mice given CRP-MLV i.p. demonstrated antitumor activity against the syngeneic T241 fibrosarcoma in a Winn-type assay, and when challenged in vitro with phorbol myristate acetate, they showed elevated superoxide anion production. Administration of CRP-MLV i.p. did not enhance natural killer activity of spleen cells, however. In superoxide anion assays, CRP-MLV were approximately 10 to 100 times more effective than free C-reactive protein. Results indicate that C-reactive protein is capable of activating macrophages, thus supporting the concept of C-reactive protein as an immunomodulator.
Taiwanofungus camphoratus (Syn Antrodia camphorata) Extract and Amphotericin B Exert Adjuvant Effects via Mitochondrial Apoptotic Pathway

The use of multiple drugs in cancer therapy increases the efficacy of the potential therapeutic effects. In this study, the authors investigated the adjuvant effects of an ethanol extract of solid-state cultivated Taiwanofungus camphoratus (TCEE) and amphotericin B (AmB) in the human cancer cell lines RPMI7951 and MG63. Taiwanofungus camphoratus is a well-known Chinese medicine in Taiwan, and AmB is a widely used antifungal agent. The authors demonstrated that TCEE pretreatment followed by AmB treatment effectively inhibited cell growth. The combination of sublethal doses of TCEE and AmB revealed a significant growth inhibitory effect in both cell lines. The combination of TCEE and AmB but not AmB alone induced phosphatidylserine externalization and loss of mitochondrial membrane potential. Cell cycle analyses revealed that combination of TCEE and AmB triggered G2/M arrest and significant apoptosis after 48 hours. These effects were greater than those achieved using TCEE or AmB alone. Furthermore, the authors demonstrated that the drugs increased the levels of p21Cip1/Waf1 and pro-apoptotic protein Bax and reduced the level of anti-apoptotic protein Bcl-2. Taken together, the results showed that the combination treatment of TCEE and AmB displays strong adjuvant effects, which are indicated by the inhibition of cell proliferation in 2 human cancer cell lines, RPMI7951 and MG63. These findings suggest possible therapeutic applications and alternative medicines using this drug combination.
Anterior ischemic optic neuropathy and intraocular pressure.

To the Editor. —I have often read "Correspondence" in which researchers bristle when other researchers fail to replicate prior work or draw different conclusions about the same clinical events, and honest men do disagree. I have not with-stood the temptation to view such correspondence as defensive, petty, whiny, and self-serving. I apologize for my own hypocrisies. The report by Kalenak et al 1 in the May 1991 issue of theArchivespurportedly demonstrating no association between anterior ischemic optic neuropathy (AION) and elevated intraocular pressure (IOP) troubles me for several reasons. I believe such a conclusion is not warranted on the basis of the data reported. I am troubled by the criteria Kalenak et al used for diagnosing AION; although a combination of criteria was used, it is not clear if all patients fulfilled all criteria; the implication is that not all patients fulfilled all criteria. I am troubled with
Differences between blood donors and a population sample: implications for case-control studies.

BACKGROUND Selecting appropriate controls for studies of genetic variation in case series is important. The two major candidates involve the use of blood donors or a random sample of the population. METHODS We compare and contrast the two different populations of controls for studies of genetic variation using data from parents enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC). In addition we compute different biases using a series of hypothetical assumptions. RESULTS The study subjects who had been blood donors differed markedly from the general population in social, health-related, anthropometric, and personality-related variables. Using theoretical examples, we show that blood donors are a poor control group for non-genetic studies of diseases related to environmentally, behaviourally, or socially patterned exposures. However, we show that if blood donors are used as controls in genetic studies, these factors are unlikely to make a major difference in detecting true associations with relatively rare disorders (cumulative incidence through life of <10%). Nevertheless, for more common disorders, the reduction in accuracy resulting from the inclusion in any control population of individuals who have or will develop the disease in question can create a greater bias than can socially patterned factors. CONCLUSIONS Information about the medical history of a control and the parents of the control (as a proxy for whether the control will develop the disease) is more important with regard to the choice of controls than whether the controls are a random population sample or blood donors.
A scheme to account for the effects of Rb+ and K+ on inward rectifier K channels of bovine artery endothelial cells

An electrochemical gating model is presented to account for the effects described in the companion paper by M. R. Silver, M. S. Shapiro, and T. E. DeCoursey (1994. Journal of General Physiology, 103:519-548) of Rb+ and Rb+/K+ mixtures on the kinetics and voltage dependence of an inwardly rectifying (IR) K+ channel. The model proposes that both Rb+ and K+ act as allosteric modulators of an intrinsically voltage dependent isomerization between open and closed states. Occupancy of binding sites on the outside of the channel promotes channel opening and stabilizes the open state. Rb+ binds to separate sites within the pore and plugs IR channels. Occupancy of the pore by Rb+ can modify the rates of isomerization and the affinity of the allosteric sites for activator ions. The model also incorporates the proposed triple- barreled nature of the IR channel (Matsuda, H., 1988. Journal of Physiology. 397:237-258.) by proposing that plugging of the channel is a cooperative process involving a single site in each of the three bores, 80% of the way through the membrane field. Interaction between bores during plugging and permeation is consistent with correlated flux models of the properties of the IR channel. Parallel bores multiply the number allosteric sites associated with the macromolecular channel and allow for steep voltage dependence without compromising the parallel shift of the half-activation potential with reversal potential. Our model proposes at least six and possibly 12 such allosteric binding sites for activator ions. We derive algebraic relations that permit derivation of parameters that define simple versions of our model from the data of Silver et al. (1994). Numerical simulations based on those parameters closely reproduce that data. The model reproduces the RS+ induced slowing of IR kinetics and the negative shift of the relation between the half-activation voltage (V1/2) and reversal potential when channel plugging is associated with (a) a slowing of the isomerization rates; (b) an increase in the affinity of allosteric sites on closed channels that promote opening; and (c) a decrease in the affinity of sites on open channels that slow closing. Rb+ also slows closing at positive potentials where open channel blockade is unlikely. Allowing Rb+ to be 1.5 times more potent than K+ as an activator in the model can account for this effect and improves the match between the predicted and observed relation between the Rb+ to K+ mole fraction and the opening rate at V1/2. (ABSTRACT TRUNCATED AT 400 WORDS)
A Dynamic Multi-swarm Particle Swarm Optimizer for blocking flow shop scheduling

This paper presents a Dynamic Multi-Swarm Particle Swarm Optimizer (DMS-PSO) for solving blocking flow shop scheduling problems with makespan criterion. Using small swarms and a regrouping schedule, DMS-PSO has a better global search ability. In order to improve its local search ability, a special designed local search phase is added into the algorithm. The experimental results indicate that the proposed DMS-PSO has a better performance on the blocking flow shop scheduling problems comparing some other algorithms.
Concurrent effect of noise exposure and smoking on extended high-frequency pure-tone thresholds

Abstract Objective: Concurrent effect of noise and smoking on hearing loss is a recent concern. In this study, the concurrent effect of noise and smoking on hearing loss in conventional frequencies and frequencies higher than 8 kHz was assessed. Design: This was a cross-sectional study on workers exposed to noise who were divided into two groups: smokers and non-smokers. Hearing thresholds were assessed by conventional audiometry, and HFA. Data were analysed using non-parametric tests and Student's t-test. Study sample: There were 212 workers. Results: Ninety-seven subjects were smokers and 115 individuals were non-smokers. All subjects were exposed to 92.1 ± 2.4 dBA (Leq8h). The highest threshold in conventional and high-frequency audiometry was observed at 6 kHz and 16 kHz, respectively. Hearing threshold at frequencies above 1 kHz was significantly higher in the smokers than non-smokers. There was no correlation between hearing thresholds and pack-years of smoking. Conclusions: Concurrent exposure to noise and smoking may be associated with more hearing loss than exposure to noise alone in the conventional and high frequencies. However, other differences between smokers and non-smokers may explain these differences as well.
Development and Initial Validation of the Iowa Sleep Disturbances Inventory

The Iowa Sleep Disturbances Inventory (ISDI) is a new measure of self-reported sleep difficulties, which was designed to help facilitate research on the overlap of sleep disturbances and psychopathology. This instrument was developed in two large student samples using principal factor analyses; the psychometric properties of the scales were then examined in three additional samples (students, psychiatric patients, sleep disorder patients). The ISDI consists of 11 specific scales (Nightmares, Initial Insomnia, Fatigue, Fragmented Sleep, Nonrestorative Sleep, Anxiety at Night, Light Sleep, Movement at Night, Sensations at Night, Excessive Sleep, Irregular Schedule) and 1 general scale (Daytime Disturbances). The structure of the ISDI generalizes across both patient and nonpatient samples. In addition, the ISDI scales are internally consistent, show good retest reliability, demonstrate convergent and discriminant validity with widely used measures of sleep disturbances, and display criterion validity in relation to psychiatric patient status and specific symptoms of depression and anxiety.
Large‐scale determination of SNP allele frequencies in DNA pools using MALDI‐TOF mass spectrometry

One of the major challenges in the near future is the identification of genes that contribute to complex disorders. Large scale association studies that utilize a dense map of single nucleotide polymorphisms (SNPs) have been considered as a valuable tool for this purpose. However, genome‐wide screens are limited by costs of genotyping thousands of SNPs in a large number of individuals. Here we present a pooling strategy that enables high‐throughput SNP validation and determination of allele frequencies in case and control populations. Quantitative analysis of allele frequencies of SNPs in DNA pools is based on matrix‐assisted laser desorption/ionization time of flight (MALDI‐TOF) mass spectrometry of primer extension assays. We demonstrate the accuracy and reliability of this approach on pools of eight previously genotyped individuals with an allele frequency representation in the range of 0.1 to 0.9. The accuracy of measured allele frequencies was shown in DNA pools of 142 to 186 individuals using additional markers. Allele frequencies determined from the pooled samples deviate from the real frequencies by about 3%. The described method reduces costs and time and enables genotyping of up to thousands of samples by taking advantage of the high‐throughput MALDI‐TOF technology. © 2002 Wiley‐Liss, Inc.