Miracle-dz/UniFAR-FTUs huggingface dataset:
Phosphatidylinositol‐3‐kinase (PI3K) is activated by influenza virus vRNA via the pathogen pattern receptor Rig‐I to promote efficient type I interferon production

The phosphatidylinositol‐3‐kinase (PI3K) was identified to be activated upon influenza A virus (IAV) infection. An early and transient induction of PI3K signalling is caused by viral attachment to cells and promotes virus entry. In later phases of infection the kinase is activated by the viral NS1 protein to prevent premature apoptosis. Besides these virus supporting functions, it was suggested that PI3K signalling is involved in dsRNA and IAV induced antiviral responses by enhancing the activity of interferon regulatory factor‐3 (IRF‐3). However, molecular mechanisms of activation remained obscure. Here we show that accumulation of vRNA in cells infected with influenza A or B viruses results in PI3K activation. Furthermore, expression of the RNA receptors Rig‐I and MDA5 was increased upon stimulation with virion extracted vRNA or IAV infection. Using siRNA approaches, Rig‐I was identified as pathogen receptor necessary for influenza virus vRNA sensing and subsequent PI3K activation in a TRIM25 and MAVS signalling dependent manner. Rig‐I induced PI3K signalling was further shown to be essential for complete IRF‐3 activation and consequently induction of the type I interferon response. These data identify PI3K as factor that is activated as part of the Rig‐I mediated anti‐pathogen response to enhance expression of type I interferons.
Attenuated, Replication-Competent Herpes Simplex Virus Type 1 Mutant G207: Safety Evaluation in Mice

ABSTRACT Herpes simplex virus type 1 (HSV-1) mutants that are attenuated for neurovirulence are being used for the treatment of cancer. We have examined the safety of G207, a multimutated replication-competent HSV-1 vector, in mice. BALB/c mice inoculated intracerebrally or intracerebroventricularly with 107 PFU of G207 survived for over 20 weeks with no apparent symptoms of disease. In contrast, over 80% of animals inoculated intracerebrally with 1.5 × 103 PFU of HSV-1 wild-type strain KOS and 50% of animals inoculated intracerebroventricularly with 104 PFU of wild-type strain F died within 10 days. Similarly, after intrahepatic inoculation of G207 (3 × 107 PFU) all animals survived for over 10 weeks, whereas no animals survived for even 1 week after inoculation with 106 PFU of KOS. After intracerebroventricular inoculation, LacZ expression was initially observed in the cells lining the ventricles and subarachnoid space; expression decreased until almost absent within 5 days postinfection, with no apparent loss of ependymal cells. G207 DNA could be detected by PCR in the brains of mice 8 weeks after intracerebral inoculation; however, no infectious virus could be detected after 2 days. As a model for latent HSV in the brain, we used survivors of an intracerebral inoculation of HSV-1 KOS at the 50% lethal dose. Inoculation of a high dose of G207 at the same stereotactic coordinates did not result in reactivation of detectable infectious virus or symptoms of disease. We conclude that G207 is safe at or above doses that were efficacious in mouse tumor studies.
Neural correlates of traumatic memories in posttraumatic stress disorder: a functional MRI investigation.

OBJECTIVE The neuronal circuitry underlying posttraumatic stress disorder (PTSD) was studied in traumatized subjects with and without PTSD. METHOD Traumatized subjects with (N=9) and without (N=9) PTSD were studied by using the script-driven symptom provocation paradigm adapted to functional magnetic resonance imaging at a 4-T field strength. RESULTS PTSD subjects showed significantly less activation of the thalamus, the anterior cingulate gyrus (Brodmann's area 32), and the medial frontal gyrus (Brodmann's area 10/11) than did the comparison subjects. CONCLUSIONS The findings suggest anterior cingulate, frontal, and thalamic involvement in the neuronal circuitry underlying PTSD.
Multi-Agent Modeling of Dynamical Systems: A Self-organized, Emergent, Homeostatic and Autopoietic Approach

This thesis presents the theoretical, conceptual and methodological aspects that support the modeling of dynamical systems (DS) by using several agents. The modeling approach permits the assessment of properties representing order, change, equilibrium, adaptability, and autonomy, in DS. The modeling processes were supported by a conceptual corpus regarding systems dynamics, multi-agent systems, graph theory, and, particularly, the information theory. Besides to the specification of the dynamical systems as a computational network of agents, metrics that allow characterizing and assessing the inherent complexity of such systems were defined. As a result, properties associated with emergence, self-organization, complexity, homeostasis and autopoiesis were defined, formalized and measured. The validation of the underlying DS model was carried out on discrete systems (boolean networks and cellular automata) and ecological systems. The central contribution of this thesis was the development of a methodological approach for DS modeling. This approach includes a larger set of properties than in traditional studies, what allows us to deepen in questioning essential issues associated with the DS field. All this was achieved from a simple base of calculation and interpretation, which does not require advanced mathematical knowledge, and facilitates their application in different fields of science.
Aldose reductase gene polymorphism is associated with progression of diabetic nephropathy in Japanese patients with type 1 diabetes mellitus

Aim: The objective of this study was to investigate cross‐sectionally and longitudinally whether polymorphism of the (A‐C)n dinucleotide repeat sequence of the aldose reductase (AR) gene may modulate risk for diabetic nephropathy or retinopathy in Japanese patients with type 1 diabetes.
Role of Bordetella O Antigen in Respiratory Tract Infection

ABSTRACT Lipopolysaccharide (LPS), as the major surface molecule of gram-negative bacteria, interacts with the host in complex ways, both inducing and protecting against aspects of inflammatory and adaptive immunity. The membrane-distal repeated carbohydrate structure of LPS, the O antigen, can prevent antibody functions and may vary as a mechanism of immune evasion. Genes of the wbm locus are required for the assembly of O antigen on the animal pathogen Bordetella bronchiseptica and the human pathogen B. parapertussis. However, the important human pathogen B. pertussis lacks these genes and a number of in vitro and in vivo characteristics associated with O antigen in other organisms. To determine the specific functions of O antigen in these closely related Bordetella subspecies, we compared wbm deletion (Δwbm) mutants of B. bronchiseptica and B. parapertussis in a variety of assays relevant to natural respiratory tract infection. Complement was not activated or depleted by wild-type bordetellae expressing O antigen, but both Δwbm mutants activated complement and were highly sensitive to complement-mediated killing in vitro. Although the O-antigen structures appear to be substantially similar, the two mutants differed strikingly in their defects within the respiratory tract. The B. parapertussis Δwbm mutant was severely defective in colonization of the tracheas and lungs of mice, while the B. bronchiseptica Δwbm mutant showed almost no defect. While in vitro characteristics such as serum resistance may be attributable to O antigen directly, the role of O antigen during infection appears to be more complex, possibly involving factors differing among the closely related bordetellae or different interactions between each one and its host.
Impact and long-term protection of hepatitis B vaccination: 17 years after universal hepatitis B vaccination in Tunisia

SUMMARY Hepatitis B virus (HBV) vaccination has been part of the Expanded Programme of Immunization (EPI) in Tunisia since 1995. The aim of this study was to evaluate, for the first time, the impact of mass vaccination in Tunisia 17 years after this programme was implemented, and in parallel, assess the long-term persistence of anti-HBs antibody in the vaccinated Tunisian population. A total of 1422 students were recruited (703 vaccinated, 719 non-vaccinated). HBV seromarkers were checked. None of the students from either group had positive HBsAg. The overall prevalence of anti-HBc was 0·8%. A Significantly higher prevalence of anti-HBc was noted in unvaccinated students than in vaccinated (1·4% vs. 0·3%, P = 0·02). The overall seroprotection rate (anti-HBs titre ⩾10 mIU/ml) was 68·9% in vaccinated subjects. Seroprotection rates and geometric mean titres decreased significantly with increasing age, reflecting waning anti-HBs titre over time. No significant difference was detected between seroprotection rates and gender or students’ area of origin. Incomplete vaccination was the only factor associated with an anti-HBs titre <10 mIU/ml. This study demonstrates the excellent efficacy of the HBV vaccination programme in Tunisia 17 years after its launch. However, a significant decline of anti-HBs seroprotection has been observed in ⩾15-year-old adolescents which places them at risk of infection. Additional studies are needed in hyperendemic regions in Tunisia.
Simultaneous pasteurization and homogenization of human milk by combining heat and ultrasound: effect on milk quality

The combination of ultrasound and heat (thermoultrasound) is an emerging food preservation technique that retains higher quantities of bioactive components compared with current thermal pasteurization practice, but has not yet been assessed for pasteurizing human milk. Artificially contaminated human milk samples were treated with ultrasound (20 kHz, 150 watts) with and without heating. The retention of four human milk proteins was quantified by biochemical assay and laser scattering particle sizing was used to determine the extent of homogenization. While ultrasonic treatment was effective at inactivating Escherichia coli (D4 °C=5·94 min), Staphylococcus epidermidis exhibited resistance (D4 °C=16·01 min). Thermoultrasonic treatment was considerably more effective (Esch. coli D45 °C=1·74 min, D50 °C=0·89 min; Staph. epidermidis D45 °C=2·08 min, D50 °C=0·94 minutes) with a predicted retention (2·8 min treatment, 50°C) of secretory IgA lysozyme, lactoferrin and bile salt stimulated lipase of 91, 80, 77, and 45%, respectively. Homogenization of the milk samples occurred after 5 min and 2 min of ultrasonic and thermoultrasonic treatment, respectively. Thermoultrasonic treatment is an effective method for pasteurizing donor human milk and retaining a greater proportion of bioactive components compared with current practices. However, further studies are required to assess the practicality of applying this technique routinely to donor human milk.
Dose‐escalation study evaluating pegylated interferon alpha‐2a in patients with cutaneous T‐cell lymphoma

This open‐label, multicenter, dose‐escalation study evaluated the safety, tolerability, and efficacy of subcutaneous pegylated (40 kD) interferon α‐2a (PEG‐IFN α‐2a) in patients with cutaneous T‐cell lymphoma (CTCL).
DIURNAL VARIATION IN ENDOTOXIN-INDUCED MORTALITY IN MICE: CORRELATION WITH PROINFLAMMATORY FACTORS

Many immune parameters exhibit daily and circadian oscillations, including the number of circulating cells and levels of cytokines in the blood. Mice also have a differential susceptibility to lipopolysaccharide (LPS or endotoxin)-induced endotoxic shock, depending on the administration time in the 24 h light-dark (LD) cycle. We replicated these results in LD, but we did not find temporal differences in LPS-induced mortality in constant darkness (DD). Animals challenged with LPS showed only transient effects on their wheel locomotor activity rhythm without modification of circadian period and phase. Levels of several key factors involved in the pathology of sepsis and septic shock were tested in LD. We found that LPS-induced levels of interleukin (IL)-1β, IL-6, JE (MCP-1), and MIP1α were significantly higher at zeitgeber time (ZT) 11 (time of increased mortality) than at ZT19 (ZT12 = time of lights-off in the animal quarters for the 12L:12D condition). Our results indicate that the differences found in mortality that are dependent on the time of LPS-challenge are not directly related to an endogenous circadian clock, and that some relevant immune factors in the development of sepsis are highly induced at ZT11, the time of higher LPS-induced mortality, compared to ZT19. (Author correspondence: dgolombek@unq.edu.ar)
Imbalanced classification using genetically optimized cost sensitive classifiers

Classification is one of the most researched problems in machine learning, since the 1960s a myriad of different techniques have been proposed. The purpose of a classification algorithm, also known as a `classifier', is to identify what class, or category an observation belongs to. In many real-world scenarios, datasets tend to suffer from class imbalance, where the number of observations belonging to one class greatly outnumbers that of the observations belonging to other classes. Class imbalance has been shown to hinder the performance of classifiers, and several techniques have been developed to improve the performance of imbalanced classifiers. Using a cost matrix is one such technique for dealing with class imbalance, however it requires a matrix to be either pre-defined, or manually optimized. This paper proposes an approach for automatically generating optimized cost matrices using a genetic algorithm. The genetic algorithm can generate matrices for classification problems with any number of classes, and is easy to tailor towards specific use-cases. The proposed approach is compared against unoptimized classifiers and alternative cost matrix optimization techniques using a variety of datasets. In addition to this, storage system failure prediction datasets are provided by Seagate UK, the potential of these datasets is investigated.
Insulin sensitivity and secretory response in adults born preterm: the Helsinki Study of Very Low Birth Weight Adults.

CONTEXT Preterm birth is associated with an increased risk of type 2 diabetes in adult life. The mechanisms are poorly known. OBJECTIVE We studied insulin sensitivity and secretion in adults born preterm at very low birth weight (VLBW; < 1500 g). DESIGN Longitudinal Birth Cohort Study (Helsinki Study of Very Low Birth Weight Adults). SETTING The study was conducted at Uusimaa, Finland. PARTICIPANTS One hundred seven adults born at VLBW and 100 controls born at term not small for gestational age (SGA), group-matched for sex, age, and birth hospital. The mean age was 25.0 years. MAIN OUTCOME MEASURES We performed a 14-sample intravenous glucose tolerance test and calculated insulin sensitivity (Si), insulin secretory response (AIR), and disposition index, by Minimal Model (Minmod Millennium®). RESULTS Compared with controls, VLBW adults had lower Si (mean difference -11.9%, 95% CI -22.1 to -0.4%, adjusted for sex, age, and body mass index) and higher AIR (19.9%; 4.4-37.7%). The association with Si attenuated when further adjusted for height, parental diabetes, parental education, smoking, maternal smoking, hormonal contraception, and physical activity, but the association with AIR remained. Disposition index was similar. There was no difference between the 40 VLBW adults born SGA and the remaining VLBW adults. CONCLUSIONS Adults born preterm at VLBW have lower insulin sensitivity than their term-born peers with a similar body size. In young adulthood, this remains compensated by higher insulin secretion. We suggest that this represents an early stage in the pathway leading to type 2 diabetes. Our results underline the importance of a healthy lifestyle and prompt vigilance in the screening of type 2 diabetes and impaired glucose tolerance in adults born preterm.
Prospective evaluation of the cause of acute pancreatitis, with special attention to medicines.

AIM To investigate the cause of acute pancreatitis (AP) by conducting a thorough investigation of drugs and their possible etiological role. METHODS We investigated the cause of AP in a large retrospective cohort of 613 adult patients admitted with AP at the Akershus University Hospital, Norway, from 2000 until 2009, who were evaluated with standard ward investigations. This group was compared with a prospectively evaluated group (n = 57) admitted from January 2010 until September 2010 who investigated more extensively using medical history and radiological assessment. RESULTS The groups were comparable with regards to gender, age, comorbidity and severity. The most common etiology was bile stones and alcohol, occurring in 60% in both groups. The prospective group was examined more thoroughly with regards to the use of alcohol and medicines. An increased number of radiological investigations during hospital stay and at follow-up were also performed. A more extensive use of radiological evaluation did not increase the detection frequency of bile stones. In the prospective group, more than half of the patients had two or more possible causes of pancreatitis, being mostly a combination of bile stones and drugs. No possible cause was found in only 3.5% of these patients, compared with 29.7% in the retrospective group. CONCLUSION A detailed medical history and extensive radiological evaluation may determine a possible etiology in almost all cases of AP. Many patients have several possible risk factors, and uncertainty remains in establishing the definitive etiology.
Inhibition of creatine kinase reduces the rate of fatigue‐induced decrease in tetanic [Ca2+]i in mouse skeletal muscle

1 Ca2+‐phosphate (Pi) precipitation in the sarcoplasmic reticulum (SR) may cause reduced SR Ca2+ release in skeletal muscle fatigue. To study this, we inhibited the creatine kinase (CK) reaction with 2,4‐dinitro‐1‐fluorobenzene (DNFB). The hypothesis was that with inhibition of CK, phosphocreatine would not break down to creatine and Pi. Therefore Pi transport into the SR would be limited and Ca2+‐Pi precipitation would not occur. 2 Intact single fibres from a mouse foot muscle were fatigued by repeated short tetani under control conditions or after exposure to DNFB (10 μM). The free myoplasmic concentrations of Ca2+ ([Ca2+]i) and Mg2+ ([Mg2+]i) were measured with indo‐1 and mag‐indo‐1, respectively. Changes in [Mg2+]i were assumed to reflect alterations in myoplasmic ATP concentration. 3 During the first 10 fatiguing tetani, tetanic [Ca2+]i increased both in control and after DNFB exposure. Thereafter tetanic [Ca2+]i fell and the rate of fall was about fourfold lower after DNFB exposure compared with control. 4 Under control conditions, there was a good relationship between declining tetanic [Ca2+]i and increasing [Mg2+]i during the final part of fatiguing stimulation. This correlation was lost after DNFB exposure. 5 In conclusion, the present data fit with a model where Ca2+‐Pi precipitation inhibits SR Ca2+ release in fatigue produced by repeated short tetani. Furthermore, the results suggest that the rate of Pi transport into the SR critically depends on the myoplasmic Mg2+/ATP concentration.
Production of gamma interferon in mice immune to Rickettsia tsutsugamushi

C3H/He mice immunized by subcutaneous infection with Rickettsia tsutsugamushi Gilliam were examined for the production of immune interferon after intravenous administration of irradiated strain Gilliam antigen, in supernatants of immune lymphocytes stimulated with specific antigen, and after a secondary challenge with viable rickettsiae. Mice administered various doses of irradiated whole-organism antigen 28 days after immunization showed circulating levels of interferon which peaked 4 h after inoculation and were antigen dose dependent. The interferon produced was pH 2 sensitive and stable at 56 degrees C for 1 h and was neutralized by antiserum directed against immune, but not against alpha/beta, interferon. The production of another lymphokine, macrophage migration inhibition factor, paralleled that of interferon. The interferon produced by cultures of spleen cells obtained from immune animals was antigen specific and dose dependent. Peak levels were obtained 48 to 72 h after the addition of antigen. The interferon produced by spleen cell cultures after stimulation with Gilliam antigen was characterized as immune interferon by the same physical and antigenic criteria used for serum interferon. Interferon was produced in vitro by the Thy-1.2+ lymphocyte and required the presence of a spleen-adherent cell population. Immune mice produced high circulating levels of immune interferon after intraperitoneal challenge with viable rickettsiae, which suggested a possible role for interferon in the resistance of immune mice to rechallenge with R. tsutsugamushi.
Alteration of DNA demethylation dynamics by in vitro culture conditions in rabbit pre-implantation embryos

Alterations to DNA methylation have been attributed to in vitro culture and may affect normal embryo development. We chose to analyze DNA methylation reprogramming in the rabbit which, of the species with delayed transcriptional activation of the embryonic genome, allows easy comparisons between in vivo-developed (IVD) and in vitro-cultured (IVC) embryos. In this species, variations in DNA methylation had not previously been quantified, even in IVD embryos. IVD and IVC embryos were recovered at the 2, 4, 8 and 16-cell, morula and blastocyst stages. Immunostaining for 5-methyl-cytidine and normalization of the quantity of methylated DNA vs. the total DNA content were then performed. Our quantitative results evidenced DNA demethylation during pre-implantation development in both IVD and IVC embryos, but with different kinetics. Demethylation occurred earlier in vitro than in vivo between the 2 and 8-cell stages in IVC embryos, reaching its lowest level, while it only started at the 4-cell stage and ended at the 16-cell stage in IVD embryos. We also showed that an absence of serum from the culture medium significantly altered the degree of DNA demethylation. Finally, at the blastocyst stage, ICM was more methylated than the trophectoderm in all cases. Despite a morphological delay observed in in vitro cultured blastocysts, the difference in DNA methylation between ICM and trophectoderm cells appeared at the same time post-fertilization in IVD and IVC embryos, which may reflect another difference in the dynamics of DNA methylation during blastocyst formation. Our data thus clearly establish an effect of embryonic environment on DNA methylation reprogramming during pre-implantation development in a non-rodent species.
Clinical Application of Volatile Organic Compound Analysis for Detecting Infectious Diseases

SUMMARY This review article introduces the significance of testing of volatile organic compounds (VOCs) in clinical samples and summarizes important features of some of the technologies. Compared to other human diseases such as cancer, studies on VOC analysis in cases of infectious diseases are limited. Here, we have described results of studies which have used some of the appropriate technologies to evaluate VOC biomarkers and biomarker profiles associated with infections. The publications reviewed include important infections of the respiratory tract, gastrointestinal tract, urinary tract, and nasal cavity. The results highlight the use of VOC biomarker profiles resulting from certain infectious diseases in discriminating between infected and healthy subjects. Infection-related VOC profiles measured in exhaled breath as well as from headspaces of feces or urine samples are a source of information with respect to disease detection. The volatiles emitted in clinical matrices may on the one hand represent metabolites of the infecting pathogen or on the other hand reflect pathogen-induced host responses or, indeed, a combination of both. Because exhaled-breath samples are easy to collect and online instruments are commercially available, VOC analysis in exhaled breath appears to be a promising tool for noninvasive detection and monitoring of infectious diseases.