Miracle-dz/UniFAR-FTUs huggingface dataset:
Nonneutralizing Functional Antibodies: a New “Old” Paradigm for HIV Vaccines

ABSTRACT Animal and human data from various viral infections and vaccine studies suggest that nonneutralizing antibodies (nNAb) without neutralizing activity in vitro may play an important role in protection against viral infection in vivo. This was illustrated by the recent human immunodeficiency virus (HIV) RV144 vaccine efficacy trial, which demonstrated that HIV-specific IgG-mediated nNAb directed against the V2 loop of HIV type 1 envelope (Env) were inversely correlated with risk for HIV acquisition, while Env-specific plasma IgA-mediated antibodies were directly correlated with risk. However, tier 1 NAb in the subset of responders with a low level of plasma Env-specific IgA correlated with decreased risk. Nonhuman primate simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV) challenge studies suggest that Env-mediated antibodies are essential and sufficient for protection. A comparison of immune responses generated in human efficacy trials reveals subtle differences in the fine specificities of the antibody responses, in particular in HIV-specific IgG subclasses. The underlying mechanisms that may have contributed to protection against HIV acquisition in humans, although not fully understood, are possibly mediated by antibody-dependent cell-mediated cytotoxicity (ADCC) and/or other nonneutralizing humoral effector functions, such as antibody-mediated phagocytosis. The presence of such functional nNAb in mucosal tissues and cervico-vaginal and rectal secretions challenges the paradigm that NAb are the predominant immune response conferring protection, although this does not negate the desirability of evoking neutralizing antibodies through vaccination. Instead, NAb and nNAb should be looked upon as complementary or synergistic humoral effector functions. Several HIV vaccine clinical trials to study these antibody responses in various prime-boost modalities in the systemic and mucosal compartments are ongoing. The induction of high-frequency HIV-specific functional nNAb at high titers may represent an attractive hypothesis-testing strategy in future HIV vaccine efficacy trials.
Analyses of promoter hypermethylation for RUNX3 and other tumor suppressor genes in nasopharyngeal carcinoma.

BACKGROUND Aberrant methylation of cytosine in promoter CpG islands is a recognized contributory process to carcinogenesis. This study explores the methylation profile of RUNX3 in combination with p16, RASSF1A, CDH1 and hMLH1 in nasopharyngeal carcinoma (NPC) patients. MATERIALS AND METHODS Genomic DNA was extracted from 19 fresh frozen NPC biopsies, which were then subjected to bisulfite conversion and methylation-specific PCR for analysis of promoter hypermethylation for the five respective genes. Three cell lines, SNU1, RKO and LS174T, were used as controls. RESULTS The incidences of promoter methylation were as follows: RUNX3 0/19 (0%), p16 6/19 (32%), RASSF1A 13/19 (68%), CDH1 9/19 (47%) and hMLH1 4/19 (21%). Ninety-five percent of the tumor specimens displayed aberrant methylation in at least one of these genes. No significant correlation between methylation status of these genes and clinical parameters was found. CONCLUSION Methylation of multiple genes is involved in critical pathways for cancer development in NPC. Promoter hypermethylation for RUNX3 was, however, not present.
Molecular Mechanism of Peptide-Specific Pheromone Signaling in Enterococcus faecalis: Functions of Pheromone Receptor TraA and Pheromone-Binding Protein TraC Encoded by Plasmid pPD1

ABSTRACT Conjugative transfer of the Enterococcus faecalisplasmid pPD1 is activated by cPD1, one of several peptide sex pheromones secreted by plasmid-free recipient cells, and is blocked by a donor-produced peptide inhibitor, iPD1. Using a tritiated pheromone, [3H]cPD1, we investigated how pPD1-harboring donor cells receive these peptide signals. Donor cells rapidly incorporated [3H]cPD1. The cell extract but not the membrane fraction of the donor strain exhibited significant [3H]cPD1-binding activity. On the basis of these data and those of tracer studies, it was demonstrated that cPD1 was internalized, where it bound to a high-molecular-weight compound. The cell extract of a strain carrying thetraA-bearing multicopy plasmid (pDLHH21) also exhibited high [3H]cPD1-binding activity. A recombinant TraA exhibited a dissociation constant of 0.49 ± 0.08 nM against [3H]cPD1. iPD1 competitively inhibited [3H]cPD1 binding to TraA, whereas pheromones and inhibitors relating to other plasmid systems did not. These results show that TraA is a specific intracellular receptor for cPD1 and that iPD1 acts as an antagonist for TraA. A strain carrying thetraC-bearing multicopy plasmid (pDLES23) exhibited significant [3H]cPD1-binding activity. A strain carryingtraC-disrupted pPD1 (pAM351CM) exhibited lower [3H]cPD1-binding activity as well as lower sensitivity to cPD1 than a wild-type donor strain. Some of the other pheromones and inhibitors inhibited [3H]cPD1 binding to thetraC transformant like cPD1 and iPD1 did. These results show that TraC, as an extracellular less-specific pheromone-binding protein, supports donor cells to receive cPD1.
The Role of the IL-2 Pathway in Costimulation Blockade-Resistant Rejection of Allografts1

Blockade of the CD40 and CD28 costimulatory pathways significantly prolongs allograft survival; however, certain strains of mice (i.e., C57BL/6) are relatively resistant to the effects of combined CD40/CD28 blockade. We have previously shown that the costimulation blockade-resistant phenotype can be attributed to a subset of CD8+ T cells and is independent of CD4+ T cell-mediated help. Here we explore the role of the IL-2 pathway in this process using mAbs against the high affinity IL-2R, CD25, and IL-2 in prolonging skin allograft survival in mice receiving combined CD40/CD28 blockade. We have also investigated the effects of treatment on effector function by assessment of cytotoxicity and the generation of IFN-γ-producing cells in response to allogeneic stimulators as well as proliferation in an in vivo graft-vs-host disease model. We find that additional blockade of either CD25 or IL-2 significantly extends allograft survival beyond that in mice receiving costimulation blockade alone. This correlates with diminished frequencies of IFN-γ-producing allospecific T cells and reduced CTL activity. Anti-CD25 therapy also synergizes with CD40/CD28 blockade in suppressing proliferative responses. Interestingly, depletion of CD4+ T cells, but not CD8+ cells, prevents prolongation in allograft survival, suggesting an IL-2-independent role for regulation in extended survival.
Neuroprotection in Parkinson models varies with toxin administration protocol

Numerous factors contribute to substantia nigra pars compacta (SNc) dopamine (DA) neuron death in Parkinson's disease (PD), thus complicating the search for effective neuroprotective agents for this disease. Although the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐treated mouse has been widely used for assessing neuroprotective agents for PD, the pathological processes resulting from MPTP exposure can vary greatly depending upon the MPTP administration protocol. This study assessed the degree to which the neuroprotective efficacy of particular agents may depend upon the MPTP administration protocol (i.e. acute vs. subacute toxin administration). Endpoints analysed were changes in tyrosine hydroxylase (TH) and NeuN cell numbers in the SNc, striatal DA and metabolite levels, and striatal TH+ fiber density. The efficacy of putative neuroprotective agents [i.e. LIGA 20, nicotinamide and pramipexole (PPX)] varied depending upon the MPTP administration protocol. LIGA 20 spared striatal DA levels in both MPTP models, while nicotinamide was only effective in the acute toxin administration model and PPX was only effective in the subacute model. In both MPTP models, LIGA 20 and nicotinamide significantly spared DAergic neurons; PPX only spared DAergic neurons in the subacute model. Only acute MPTP‐treated mice that received nicotinamide had a significant sparing of striatal DAergic fibers. These results underscore the need to assess putative neuroprotective agents for PD in multiple animal models using multiple endpoints. This strategy may better identify compounds with broad neuroprotective/neurorestorative profiles that may be more likely to be clinically effective.
A new rat model for vulnerability to epilepsy and autism spectrum disorders

Tremendous concern has arisen in response to the recent diagnostic outbreak of childhood developmental disorders, particularly involving attention deficit hyperactivity disorder (ADHD) and the autism spectrum disorders (ASD). Interestingly, similarities in clinical presentation across these disorders may suggest common predisposing factors. For instance, though not widely recognized, an increased predisposition toward seizure is a symptom that is very often associated with ADHD and ASD. Accordingly, a rat strain naturally bred to be seizure‐prone simultaneously developed behavioral and physical characteristics analogous to those observed in ADHD/ASD patients. These rats also show early signs of aberrant lipid handling, which is another symptom common to human patients with these disorders. As such, this rat strain could serve as an excellent model system through which to identify common pathophysiological events that constitute a“spectrum of vulnerability”toward ADHD/ASD and epilepsy.
Postoperative Complications After Transthoracic Esophagectomy for Cancer of the Esophagus and Gastroesophageal Junction Are Correlated With Early Cancer Recurrence: Role of Systematic Grading of Complications Using the Modified Clavien Classification

Objectives:To assess the impact of postoperative complications after transthoracic esophagectomy, using the modified Clavien classification, on recurrence and on its timing in patients with cancer of the esophagus or gastroesophageal junction. Background Data:It is hypothesized that complications after esophagectomy for cancer may have a negative effect on recurrence and its timing because of negative interference with the immune system. Methods:Out of 150 consecutive patients operated with curative intent between January 2005 and May 2006, the data of 138 patients with macroscopically complete resection and no synchronous other malignancy were graded according to the modified Clavien classification. Uni- and multivariable analyses were performed to study the impact of postoperative complications on tumor recurrence and its timing. Results:Mean age was 63.1 years, male-female ratio was 4:1; 76.1% of the patients underwent primary surgery, 23.9% received induction therapy, R0-resection rate was 92.8%. Adenocarcinoma was found in 75%. Complication rates according to the modified Clavien classification were grade 0: 29.7%, grade 2: 35.5%, grade 3: 17.4%, grade 4: 15.9%, and grade 5 (postoperative mortality): 1.4%. Ten patients developed recurrence within 6 months, 29 within 12 months, 39 within 18 months, 42 within 24 months, totaling up to 47 at 3 years. Univariable analysis retained complications, LN-status, number of positive nodes, extracapsular lymph node involvement (EC LNI), pStage, pT, and R1-status as factors significantly influencing occurrence of recurrence. In the multivariable model, presence of complications, EC LNI, and R1-status were independent negative factors. Cox-regression analysis also identified these same 3 factors as significant determinators for the timing of recurrence. Conclusions:This study indicates a correlation between complications and early recurrence and its timing. Modified Clavien classification, beside R1-status and EC LNI, appears to be a useful prognostic indicator of early recurrence and its timing. Achieving esophagectomy without postoperative complications is of utmost importance also for oncologic reasons given its negative potential on early oncologic outcome.
Towards safety improvement: implementation and assessment of new standards of competence for Electro-Technical Officers on ships

ABSTRACT The paper deals with education of ship engineers as an integral part of maritime policy in global shipping. The central problem, how to reconcile technological advancement with training en route to improving safety, is defined. A complete conceptual model for solving a central question is formulated and described. At the beginning, a short analysis of technological advances and the need for training is presented. Next, the basic components of conceptual model, including implementation and assessment of new standards of competences for Electro-Technical Officers in the wake of Maritime Education and Training (MET) development are discussed. A key point of the assessment procedure is focused on the formulation of criterion defining the impact of new standards on the given processes characterizing a professional carrier development of seafarers. These processes, which mean certification process and recruitment of candidates to seafarer profession, are strongly linked with and influenced on MET development and improving the safety of shipping. Empirical application by pointing the Polish case study to the framework of conceptual model under consideration is shown and analysed. Finally, the future works as well as the concluding remarks are formulated and commented on.
The Individuals with Disabilities Education Act

The Individuals with Disabilities Education Act (IDEA) is the main federal program concerning the education of children with disabilities. It authorizes state and local aid for special education and related services for children with disabilities and contains detailed due process protections for children with disabilities and their parents. On December 3, 2004, President Bush signed “The Individuals with Disabilities Education Act Improvement Act” (P.L. 108-446), a major reauthorization and revision of IDEA. One issue which was not addressed in the reauthorization was whether the parents or the school bears the burden of proof in special education due process hearings. On November 14, 2005, the Supreme Court resolved a split in the circuits and held that the burden of proof in an administrative hearing challenging a child’s individualized education program is on the party seeking the relief.
Nonshivering thermogenesis and its adequate measurement in metabolic studies

Summary Alterations in nonshivering thermogenesis are presently discussed as being both potentially causative of and able to counteract obesity. However, the necessity for mammals to defend their body temperature means that the ambient temperature profoundly affects the outcome and interpretation of metabolic experiments. An adequate understanding and assessment of nonshivering thermogenesis is therefore paramount for metabolic studies. Classical nonshivering thermogenesis is facultative, i.e. it is only activated when an animal acutely requires extra heat (switched on in minutes), and adaptive, i.e. it takes weeks for an increase in capacity to develop. Nonshivering thermogenesis is fully due to brown adipose tissue activity; adaptation corresponds to the recruitment of this tissue. Diet-induced thermogenesis is probably also facultative and adaptive and due to brown adipose tissue activity. Although all mammals respond to injected/infused norepinephrine (noradrenaline) with an increase in metabolism, in non-adapted mammals this increase mainly represents the response of organs not involved in nonshivering thermogenesis; only the increase after adaptation represents nonshivering thermogenesis. Thermogenesis (metabolism) should be expressed per animal, and not per body mass [not even to any power (0.75 or 0.66)]. A ‘cold tolerance test’ does not examine nonshivering thermogenesis capacity; rather it tests shivering capacity and endurance. For mice, normal animal house temperatures are markedly below thermoneutrality, and the mice therefore have a metabolic rate and food consumption about 1.5 times higher than their intrinsic requirements. Housing and examining mice at normal house temperatures carries a high risk of identifying false positives for intrinsic metabolic changes; in particular, mutations/treatments that affect the animal's insulation (fur, skin) may lead to such problems. Correspondingly, true alterations in intrinsic metabolic rate remain undetected when metabolism is examined at temperatures below thermoneutrality. Thus, experiments with animals kept and examined at thermoneutrality are likely to yield an improved possibility of identifying agents and genes important for human energy balance.
A Novel Consistent Random Forest Framework: Bernoulli Random Forests

Random forests (RFs) are recognized as one type of ensemble learning method and are effective for the most classification and regression tasks. Despite their impressive empirical performance, the theory of RFs has yet been fully proved. Several theoretically guaranteed RF variants have been presented, but their poor practical performance has been criticized. In this paper, a novel RF framework is proposed, named Bernoulli RFs (BRFs), with the aim of solving the RF dilemma between theoretical consistency and empirical performance. BRF uses two independent Bernoulli distributions to simplify the tree construction, in contrast to the RFs proposed by Breiman. The two Bernoulli distributions are separately used to control the splitting feature and splitting point selection processes of tree construction. Consequently, theoretical consistency is ensured in BRF, i.e., the convergence of learning performance to optimum will be guaranteed when infinite data are given. Importantly, our proposed BRF is consistent for both classification and regression. The best empirical performance is achieved by BRF when it is compared with state-of-the-art theoretical/consistent RFs. This advance in RF research toward closing the gap between theory and practice is verified by the theoretical and experimental studies in this paper.
REVIEW: PART OF A SPECIAL ISSUE ON DEVELOPMENTAL ROBUSTNESS AND SPECIES DIVERSITY Tinkering with transcription factor networks for developmental robustness of Ranunculales flowers

Background The flowers of core eudicots and monocots are generally determined by the number of floral organs they produce, and their developmental set-up tolerates little change from the bauplan once the floral primordium is initiated. Many species outside the core eudicots and monocots are more plastic in the number of floral organs they produce. For example, the Nymphaeales (water lilies), within the basal angiosperms, arrange their floral organs spirally and show smooth transitions between floral organs, and many Ranunculales (buttercups) produce variable numbers of stamens by adjusting the number of stamen whorls generated from a specialized ring meristem. However, the interactions of regulatory genes governing those processes are unknown. Scope and Conclusions This review provides an overview of the functional analyses of floral homeotic genes carried out in Ranunculales, summarizing knockdown and mutant phenotypes, and protein interactions to identify similarities and differences within the Ranunculales and in comparison with core eudicots. Floral gene regulatory networks in Ranunculales are identified showing intensive re-wiring amongst the floral homeotic genes to allow some degree of plasticity. The ‘fading-border’ model of floral organ identity evolution is extended by a hypothesis on how developmental plasticity can be achieved by interdependent regulation of floral homeotic genes. One aspect of floral plasticity may be achieved by regulation of the activity of a stamen-generating ring meristem and first ideas on its control are presented. While the amazing conservation of the major floral organ identity programme is being unravelled by analysing floral homeotic gene function and expression, we are only just beginning to understand the evolution of the gene network governing the organ identity genes, e.g. how plasticity can be achieved, and which aspects foster the robustness of the core eudicot floral bauplan.
Busy Auditors, Partner-Client Tenure, and Audit Quality: Evidence from an Emerging Market

ABSTRACT: Using a sample of public firms listed in the Chinese market for the years 2000–2009, we find that audit partners with more public clients are associated with lower audit quality, consistent with the “busyness” effect that auditing multiple clients dissipates audit partner effort and, thus, reduces audit quality. However, the negative association is more pronounced for auditors with short audit partner-client tenure, supporting the idea that the lack of client-specific knowledge exacerbates the busyness effect. Collectively, these findings contribute to a better understanding of audit partner behavior in an emerging market. JEL Classifications: M42.
Prevalence of low‐risk and high‐risk types of human papillomavirus and other risk factors for HPV infection in Germany within different age groups in women up to 30 years of age: An epidemiological observational study

Human papillomavirus (HPV) infection is frequent in young women and persistent infection may lead to cervical cancer. Therefore, vaccination against HPV is recommended for young women in the age group from 12–17 years in Germany. However, epidemiological data on the prevalence of HPV types and risk factors for infection for younger women in Germany is scarce. To address this, an observational study was performed in Germany including 1,692 women aged 10–30 years. After a routine Pap smear, cervical swabs were tested for high‐risk and low‐risk HPV, respectively, using the Hybrid Capture 2 (HC2) test, and genotyped using the PCR‐based tests SPF10/LiPA25 and PapilloCheck®. In addition, the women were interviewed regarding their medical history and lifestyle factors. Three hundred seventy‐seven (22.28%) women had positive HC2 results. The proportion of HPV positive women was highest in the 20–22 age group with 28.3%. Predominant HPV types were HPV 16, 42, 51 and HPV 16, 51, 31 as defined by PapilloCheck® and SPF10/LiPA25, respectively. 95.8% of women did not show signs of any cervical lesion. Adjusted analysis identified number of sexual partners (OR:1.105; 95% CI:[1.069–1.142]), smoking (OR:1.508; [1.155–1.968]), and vaccination against HPV (OR:0.589; [0.398–0.872]) rather than increasing age as risk associated with HPV infection. Comparison of the genotyping assays showed that they correspond well regarding the high‐risk HPV types but less well for low‐risk HPV types. This epidemiological study shows that high‐risk HPV infection is common in young women in Germany. According to our data, vaccination of young women could have a potential impact on the prevention of HPV infection and cervical disease. J. Med. Virol. 82:1928–1939, 2010. © 2010 Wiley‐Liss, Inc.
Experimental acute sinusitis in rabbits. Energy metabolism in sinus mucosa and secretion.

In previous studies, sinus secretions have been analysed concerning pO2, pCO2 and pH. In this study the energy metabolism in the maxillary sinus mucosa and secretion was studied in 33 New Zealand White rabbits. In freeze-dried samples, glucose and lactate were analysed by enzymatic assays and ATP by HPLC. In the purulent sinusitis, lactate concentration in the mucosa was 5.67 mmol X kg-1 w.w. and significantly higher than in the control sinus. Also in the non-purulent sinusitis, lactate was increased in the mucosa. The lactate concentrations in the secretion were 9.8 and 8.4 mmol X kg-1 w.w. in purulent and non-purulent secretions respectively and are probably the result of a diffusion from the mucosal cells and of leukocyte metabolism. A reduced ATP content, with increases in ADP and AMP, in the sinus mucosa of the purulent sinusitis suggests a relative energy depletion which could result in impaired epithelial function.