Miracle-dz/UniFAR-FTUs huggingface dataset:
The Adjuvant Activity of Alphavirus Replicons Is Enhanced by Incorporating the Microbial Molecule Flagellin into the Replicon

Ligands of pattern recognition receptors (PRRs) including Toll-like receptors (TLRs) stimulate innate and adaptive immune responses and are considered as potent adjuvants. Combinations of ligands might act in synergy to induce stronger and broader immune responses compared to stand-alone ligands. Alphaviruses stimulate endosomal TLRs 3, 7 and 8 as well as the cytoplasmic PRR MDA-5, resulting in induction of a strong type I interferon (IFN) response. Bacterial flagellin stimulates TLR5 and when delivered intracellularly the cytosolic PRR NLRC4, leading to secretion of proinflammatory cytokines. Both alphaviruses and flagellin have independently been shown to act as adjuvants for antigen-specific antibody responses. Here, we hypothesized that alphavirus and flagellin would act in synergy when combined. We therefore cloned the Salmonella Typhimurium flagellin (FliC) gene into an alphavirus replicon and assessed its adjuvant activity on the antibody response against co-administered antigen. In mice immunized with recombinant alphavirus, antibody responses were greatly enhanced compared to soluble FliC or control alphavirus. Both IgG1 and IgG2a/c responses were increased, indicating an enhancement of both Th1 and Th2 type responses. The adjuvant activity of FliC-expressing alphavirus was diminished but not abolished in the absence of TLR5 or type I IFN signaling, suggesting the contribution of several signaling pathways and some synergistic and redundant activity of its components. Thus, we have created a recombinant adjuvant that stimulates multiple signaling pathways of innate immunity resulting in a strong and broad antibody response.
Current and Future Applications of Photoactivated Chromophore for Keratitis-Corneal Collagen Cross-Linking (PACK-CXL): An Overview of the Different Treatments Proposed

ABSTRACT Purpose: To review the application of the PACK-CXL and to identify different treatment protocols according to the pathogens associated with keratitis. Methods: A systematic review of 21 articles. The primary outcome was the healing of a corneal ulcer, defined as epithelization, blocking corneal melting. The secondary end-point was the recovery of visual acuity. Results: We studied a total of 145 eyes. Infectious keratitis was associated with bacteria in 80 eyes (55.55%), fungus in 24 eyes (16.67%), and protozoa in 13 (8.97%). In 26 (18%), the microbiological culture was negative or not performed. The mean time of re-epithelization was 25.70±29.83days (1–180). A total of 27 patients needed corneal transplantation. The overall probability of blocking corneal melting was 84.13%. Three different protocols for each group of pathogens have been proposed. Conclusion: PACK-CXL still has a limit in its spread. In the future, we hope that each pathogen will be treated with the most efficient and least invasive protocols available.
Atypical resource allocation may contribute to many aspects of autism

Based on a review of the literature and on reports by people with autism, this paper suggests that atypical resource allocation is a factor that contributes to many aspects of autism spectrum conditions, including difficulties with language and social cognition, atypical sensory and attentional experiences, executive and motor challenges, and perceptual and conceptual strengths and weaknesses. Drawing upon resource theoretical approaches that suggest that perception, cognition, and action draw upon multiple pools of resources, the approach hypothesizes that compared with resources in typical cognition, resources in autism are narrowed or reduced, especially in people with strong sensory symptoms. In narrowed attention, resources are restricted to smaller areas and to fewer modalities, stages of processing, and cognitive processes than in typical cognition; narrowed resources may be more intense than in typical cognition. In reduced attentional capacity, overall resources are reduced; resources may be restricted to fewer modalities, stages of processing, and cognitive processes than in typical cognition, or the amount of resources allocated to each area or process may be reduced. Possible neural bases of the hypothesized atypical resource allocation, relations to other approaches, limitations, and tests of the hypotheses are discussed.
Bowel Functional Outcomes in Females With Perineal or Vestibular Fistula Treated With Anterior Sagittal Anorectoplasty: Controlled Results Into Adulthood

BACKGROUND: Anterior sagittal anorectoplasty is a standardized operative treatment for females with congenital rectoperineal or vestibular fistula. The controlled, long-term outcomes require characterization. OBJECTIVE: The aim of this study was to define the bowel functional outcomes following anterior sagittal anorectoplasty in relation to age- and sex-matched controls. DESIGN: This cross-sectional study was conducted at a single institution. PATIENTS: All females treated for congenital perineal or vestibular fistula with anterior sagittal anorectoplasty between 1983 and 2006 were invited to answer a detailed, previously validated questionnaire on bowel function. Each patient was matched to 3 controls who had answered identical questionnaires. Ethical approval was obtained. Social continence was defined as soiling or fecal accidents <1/week and no requirement for changes of underwear or protective aids. SETTING: This study was conducted at the Hospital for Children and Adolescents, University of Helsinki, Finland. INTERVENTIONS: No interventions were performed. MAIN OUTCOME MEASURES: The primary outcomes measured were the prevalence of problems with rectal sensation, voluntary bowel control, soiling, fecal accidents, constipation, and social problems. Bowel function score (out of 20 items) was considered, as well as the age at completion of toilet training for stool. RESULTS: Of 34 respondents (79%; median age, 13 (4–28) years), all had voluntary bowel movements. Problems withholding defecation, soiling, and fecal accidents were significantly more common among patients than controls (p ⩽ 0.001). Eighty-five percent of patients and 100% of controls (p = 0.001) were socially continent; 41% of patients and 76% of controls were totally continent (p = 0.0003). Constipation tended to decline with age (from 59% to 25%; p = 0.16). The bowel functional outcome was good in 68% of patients, satisfactory in 26% of patients, and poor in 6% of patients. Diapers for stool had been discontinued at the same median age as controls. LIMITATIONS: Number of patients in comparative analysis of symptoms by age group. CONCLUSIONS: After anterior sagittal anorectoplasty for perineal or vestibular fistula, 2 of 3 of patients are likely to achieve bowel control comparable to normal in the long term, and the vast majority will be socially continent. The effective treatment of constipation is essential.
Self-esteem and obsessive compulsive disorder.

OBJECTIVE To explore the association between self-esteem and obsessive compulsive disorder in a low-income country, and to conduct an in-depth analysis into the said relationship by identifying any confounding variables that might exist. METHOD The cross-sectional study was conducted at the psychiatry out-patient clinic of Civil Hospital, Karachi, from January to March 2008, and comprised 65 patients diagnosed with obsessive compulsive disorder and 30 healthy controls. The participatnts completed the Janis and Field Social Adequacy scale and the Rosenberg Self-esteem scale. SPSS 15 was used for statistical analysis. RESULTS Significantly different scores were reported on both measures of self-esteem between the patients and the controls (p<0.001 each), indicating reduced levels of self-esteem in the patients compared to the controls. CONCLUSIONS Data replicated earlier findings from populations in high-income countries.
The effects of phytosterol in low fat milk on serum lipid levels among mild-moderately hypercholesterolemic subjects

One of the most important risk factors for CHD is dyslipidemia, among others hypercholesterolemia or high LDL-cholesterol. Plantsterols or phytosterols (PS) are among dietary factors known to lower blood cholesterol as part of therapeutic life-style changes diet. This study was aimed to evaluate the effect of PS properly solubilized in a-partly vegetable oil-filled low fat milk, on serum lipid levels in mild-moderate hypercholesterolemic subjects. Randomized, two-arm parallel control group trial was conducted at Department of Nutrition-University of Indonesia in Jakarta from June to November 2006. Each subject was randomly assigned to receive dietary lifestyle changes counseling plus 1.2 g phytosterol/day in low-fat milk (PS-group) or control group receiving the counseling alone for six weeks period. There were no significant changes of serum total and LDL-cholesterol of control group after a six week of dietary counseling (respectively 218.3 ± 18.6 mg/dL to 219.6 ± 24.3 mg/dL and 164.7±21.8 mg/dL to 160.0±26.4 mg/dL). There were a significant decreases of serum total and LDL-cholesterol (respectively p=0.01 and p=0.004) among subjects receiving PS after a six weeks observation period (respectively 233.5±24.6 mg/dL to 211.2±30.3 mg/dL and 176.9±24.7 mg/dL to 154.5±24.3 mg/dL). There was a significant difference in the LDL-lowering effects (p=0.024) among the PS-group after a six weeks (22.4±27.9 mg/dL) as compared to the control group (4.7±17.2 mg/dL). No significant changes were found on serum HDL-cholesterol and triglyceride levels in both groups. Although there was no significant difference found in daily nutrients intake between the-2 groups, however, significant reductions in body weight, body mass index and waist circumference were found only in the PS group (p=0.000; 0.000; 0.003, respectively). It is concluded that the lowering of total and LDL-cholesterol in those receiving life-style changes counseling plus 1.2 g PS daily for six weeks was significantly higher as compared to those of receiving counseling alone. (Med J Indones 2008; 17: 5-12)
External Uniqueness

Existing approa hes to adding unique referen es to obje toriented programming languages su er from two problems, whi h we identify in this paper: the abstra tion problem and the orthogonality problem. To ounter these problems, we propose an alternative: external uniqueness. The idea is that an externally unique referen e is the only referen e into an aggregate obje t from outside the aggregate. An externally unique referen e is the only a tive referen e to an obje t, and is thus e e tively unique. We present a formal a ount of external uniqueness whi h relies essentially on deep ownership types, and, by demonstrating that it does not suffer from the two problems, argue that it is better suited to obje t-oriented programming than onventional uniqueness. We also dis uss a third problem, the de nitional problem, whi h we annot yet address satisfa torily.
High Osmolarity Extends Life Span in Saccharomyces cerevisiae by a Mechanism Related to Calorie Restriction

ABSTRACT Calorie restriction (CR) extends life span in many different organisms, including mammals. We describe here a novel pathway that extends the life span of Saccharomyces cerevisiae mother cells but does not involve a reduction in caloric content of the media, i.e., there is growth of yeast cells in the presence of a high concentration of external osmolytes. Like CR, this longevity-promoting response to high osmolarity requires SIR2, suggesting a common mechanism of life span regulation. Genetic and microarray analysis indicates that high osmolarity extends the life span by activating Hog1p, leading to an increase in the biosynthesis of glycerol from glycolytic intermediates. This metabolic shift likely increases NAD levels, thereby activating Sir2p and promoting longevity.
Activation of Hemostasis and Decline in Cognitive Function in Older People

Objective—To determine whether activation of hemostatic function (thrombosis and fibrinolysis) is associated with cognitive decline in older people. Methods and Results—We studied 5804 people (age, 70–82 years) in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). Mean follow-up was 3.2 years, including annual measurement of speed of information processing (letter, digit coding, and Stroop), verbal memory (picture–word naming), and basic and instrumental activities of daily living. Raised levels of markers of thrombin generation (d-dimer and prothrombin fragment 1+2) were associated independently with increased rate of cognitive decline (eg, Stroop increased by 4.44 s [SEM, 0.68] in bottom tertile of d-dimer compared to 5.46 [SEM, 0.71] in highest tertile; P<0.05) and deterioration in activities of daily living. This increased rate of decline was attenuated but not removed when subjects with incident nonfatal stroke were omitted from the analysis. It also persisted when adjustments were made for inflammation (C-reactive protein and IL-6). Conclusion—Older patients with increased markers of thrombin generation (d-dimer and prothrombin fragment 1+2) are at increased risk for cognitive decline and deterioration in ability to perform activities of daily living. This is likely attributable to increased risk of cerebral ischemic damage (including covert disease) associated with prothrombotic states.
Faster progression to AIDS and AIDS-related death among seroincident individuals infected with recombinant HIV-1 A3/CRF02_AG compared with sub-subtype A3.

BACKGROUND Human immunodeficiency virus type 1 (HIV-1) is divided into subtypes and circulating recombinant forms (CRFs) but the impact of subtype/CRF on disease progression is not fully understood. METHODS We determined the HIV-1 subtype/CRF of 152 seroincident individuals from Guinea-Bissau, based on the C2-V3 region of env. Disease progression was measured as time from estimated seroconversion to AIDS and AIDS-related death. Hazard ratios (HRs) were calculated using a Cox proportional hazard model, adjusting for gender and age at seroconversion. RESULTS The major subtypes/CRFs identified were CRF02_AG (53%), A3 (29%), and A3/02 (a recombinant of A3 and CRF02_AG) (13%). Infection with A3/02 was associated with a close to 3-fold increased risk of AIDS and AIDS-related death compared to A3 (HR = 2.6 [P = 0.011] and 2.9 [P = 0.032], respectively). The estimated time from seroconversion to AIDS and AIDS-related death was 5.0 and 8.0 years for A3/02, 6.2 and 9.0 years for CRF02_AG, and 7.2 and 11.3 years for A3. CONCLUSION Our results show that there are differences in disease progression between HIV-1 A-like subtypes/CRFs. Individuals infected with A3/02 have among the fastest progression rates to AIDS reported to date. Determining the HIV-1 subtype of infected individuals could be important in the management of HIV-1 infections.
Prospective pilot study of living kidney donor decision‐making and outcomes

Abstract: In its recent report on organ donation, the Institute of Medicine has recommended rigorous studies of how living organ donors make the decision to donate. In this pilot study, 65 donor applicants were interviewed while being evaluated in the outpatient donor clinic and 20 were surveyed again three months after donation. Fifteen and six of these subjects were surveyed again in six and 12 months respectively. Several strategies for retaining donors in a prospective longitudinal study are discussed. Half of the donors indicated that the decision to donate was a shared family decision. Married donors were slightly more likely than non‐married donors to involve another family member in this decision. Several donors made practical recommendations for improved education of donors during what many perceived to be a very lengthy evaluation process. Some subjects recommended more discussion about post‐operative pain and the expected pace of recovery after discharge. Others spoke of the challenge of completing basic homemaking tasks when the donor and recipient were in the same nuclear family. We are continuing to explore these and other aspects of donor decision‐making and outcomes and have expanded our sample to include non‐donors in the post‐evaluation period.
Somatic cells efficiently join unrelated DNA segments end-to-end

Molecular substrates for probing nonhomologous recombination in somatic cells were constructed by inserting pBR322 sequences at selected sites on the simian virus 40 (SV40) genome. The chimeric products are too large to be packaged into an SV40 capsid. Therefore, production of viable progeny requires that most of the pBR322 sequences be deleted without altering any SV40 sequences that are essential for lytic infection. As judged by plaque assay, these recombination events occur at readily detectable frequencies after transfection into CV1 monkey kidney cells. Depending on the site of pBR322 insertion, the infectivities of the full-length circular or linear chimeras ranged from 0.02 to 2% of the infectivity of linear wild-type SV40 DNA. Nucleotide sequence analysis of several recombinant progeny revealed three distinct classes of recombination junction and indicated that the causative recombination events were minimally dependent on sequence homology. Potential mechanisms involving recombination at internal sites or at ends were distinguished by measuring the infectivity of chimeric molecules from which various lengths of pBR322 had been removed. These data support end-to-end joining as the primary mechanism by which DNA segments recombine nonhomologously in somatic cells. This end joining appears to be very efficient, since SV40 genomes with complementary single-stranded tails or with short non-complementary pBR322 tails were comparably infectious. Overall, this study indicates that mammalian somatic cells are quite efficient at the willy-nilly end-to-end joining of unrelated DNA segments.
Tubulo-Glomerular Feedback Activation in Humans before and after Nephrectomy

Background/Aims: Tubulo-glomerular feedback (TGF) is a key mechanism for controlling glomerular filtration. Nephrectomy for kidney donation provides a good opportunity for studying TGF status before and after a defined loss of renal function. Methods: A total of 22 kidney donors were studied before and one year after nephrectomy. Effective renal plasma flow and glomerular filtration rate were measured by means of para-amino-hippurate and inulin plasma clearances before and after intravenous acetazolamide. Results: TGF activation was not dependent on sex, age or familiality for hypertension either before or after nephrectomy, however, it increased the filtration fraction before, but not after nephrectomy. Nephrectomy did not affect TGF response, but elicited a correlation between TGF response and renal plasma flow, not present in the intact state. Donors with a more activated TGF before nephrectomy had a lower filtration fraction that increased after nephrectomy, while subjects with a less activated TGF before nephrectomy had a higher basal filtration fraction that showed a blunted increase after nephrectomy. Conclusion: TGF is a stable mechanism quantitatively unaltered by nephrectomy, age, sex, menopausal status or family history of hypertension. However, its degree of activation before nephrectomy determines different responses to the loss of a kidney.
CD28/B7 Deficiency Attenuates Systolic Overload-Induced Congestive Heart Failure, Myocardial and Pulmonary Inflammation, and Activated T Cell Accumulation in the Heart and Lungs

The inflammatory response regulates congestive heart failure (CHF) development. T cell activation plays an important role in tissue inflammation. We postulate that CD28 or B7 deficiency inhibits T cell activation and attenuates CHF development by reducing systemic, cardiac, and pulmonary inflammation. We demonstrated that chronic pressure overload–induced end-stage CHF in mice is characterized by profound accumulation of activated effector T cells (CD3+CD44high cells) in the lungs and a mild but significant increase of these cells in the heart. In knockout mice lacking either CD28 or B7, there was a dramatic reduction in the accumulation of activated effector T cells in both hearts and lungs of mice under control conditions and after transverse aortic constriction. CD28 or B7 knockout significantly attenuated transverse aortic constriction–induced CHF development, as indicated by less increase of heart and lung weight and less reduction of left ventricle contractility. CD28 or B7 knockout also significantly reduced transverse aortic constriction–induced CD45+ leukocyte, T cell, and macrophage infiltration in hearts and lungs, lowered proinflammatory cytokine expression (such as tumor necrosis factor-&agr; and interleukin-1&bgr;) in lungs. Furthermore, CD28/B7 blockade by CTLA4-Ig treatment (250 &mgr;g/mouse every 3 days) attenuated transverse aortic constriction–induced T cell activation, left ventricle hypertrophy, and left ventricle dysfunction. Our data indicate that CD28/B7 deficiency inhibits activated effector T cell accumulation, reduces myocardial and pulmonary inflammation, and attenuates the development of CHF. Our findings suggest that strategies targeting T cell activation may be useful in treating CHF.
Human Cationic Trypsinogen

Mutation Asn-21 → Ile in human cationic trypsinogen (Tg-1) has been associated with hereditary pancreatitis. Recent studies with rat anionic Tg (Tg-2) indicated that the analogous Thr-21 → Ile mutation stabilizes the zymogen against autoactivation, whereas it has no effect on catalytic properties or autolytic stability of trypsin (Sahin-Tóth, M. (1999) J. Biol. Chem.274, 29699–29704). In the present paper, human cationic Tg (Asn-21-Tg) and mutants Asn-21 → Ile (Ile-21-Tg) and Asn-21 → Thr (Thr-21-Tg) were expressed in Escherichia coli, and zymogen activation, zymogen degradation, and trypsin autolysis were studied. Enterokinase activated Asn-21-Tg approximately 2-fold better than Ile-21-Tg or Thr-21-Tg, and catalytic parameters of trypsins were comparable. At 37 °C, in 5 mm Ca2+, all three trypsins were highly stable. In the absence of Ca2+, Asn-21- and Ile-21-trypsins suffered autolysis in an indistinguishable manner, whereas Thr-21-trypsin exhibited significantly increased stability. In sharp contrast to observations with the rat proenzyme, at pH 8.0, 37 °C, autoactivation kinetics of Asn-21-Tg and Ile-21-Tg were identical; however, at pH 5.0, Ile-21-Tg autoactivated at an enhanced rate relative to Asn-21-Tg. Remarkably, at both pH values, Thr-21-Tg showed markedly higher autoactivation rates than the two other zymogens. Finally, autocatalytic proteolysis of human zymogens was limited to cleavage at Arg-117, and no digestion at Lys-188 was detected. The observations indicate that zymogen stabilization by Ile-21 as observed in rat Tg-2 is not characteristic of human Tg-1. Instead, an increased propensity to autoactivation under acidic conditions might be relevant to the pathomechanism of the Asn-21 → Ile mutation in hereditary pancreatitis. In the same context, faster autoactivation and increased trypsin stability caused by the Asn-21 → Thr mutation in human Tg-1 might provide a rationale for the evolutionary divergence from Thr-21 found in other mammalian trypsinogens.