Principal Candidate Research Articles

Nimbolide: A Potential Phytochemical Agent in Multimodal Pancreatic Cancer Therapies.

A significant contributor to cancer-related death, pancreatic cancer (PC) has a terrible prognosis in general that has not altered over many years. Currently, it is extremely difficult to prevent disease or discover it early enough to initiate treatment. The major challenge in PC is acquired chemo-radio resistance, which makes it very difficult to manage. PC is a challenging malignancy to treat, and several major impediments significantly impact the effectiveness of its treatment. These obstacles primarily include chemoresistance, drug toxicity, and limited drug bioavailability. Phytochemicals can be used as an alternative to chemotherapeutic drugs, or they can augment the anticancer properties of the chemotherapeutic agents. Nimbolide (NL) is a prominent limonoid compound found in Azadirachta indica, and has garnered substantial attention as a phytochemical with anticancer potential. It has powerful antiproliferative effects on a variety of cancer cell lines and is effective as a chemotherapeutic in preclinical studies. The primary modes of action of NL include suppression of metastasis and angiogenesis, activation of apoptosis, anti-proliferation, and control of enzymes that metabolize carcinogens. Despite numerous pharmacodynamic (PD) investigations, NL is still in the early stages of the drug development process because no comprehensive pharmacokinetic (PK) studies or long-term toxicity studies. Preclinical PK and toxicological assessments should be conducted to establish an appropriate dosage range, ensuring the safety of NL for its application in initial human clinical trials. This review endeavors to provide a comprehensive summary of the current developmental stage of NL along with nanoparticles as a principal candidate for therapeutic purposes in PC.

Countering the Conspiracy of Silence: Leveraging Race Talk and Data Dialogues as Equity Leaders Challenge Whiteness in Schools

While facilitating a data dialogue concerning racial opportunity gaps in an elementary school, Evelyn Nguyen, a preservice principal candidate, overheard a disturbing and racialized dialogue among third-grade teachers. Evelyn had to decide whether to move an uncomfortable and emotional discussion forward or segue to the next item on the agenda to manage her discomfort. The value and importance for school leaders to model anti-racist leadership by utilizing race talk while addressing whiteness, power, and positionality are key to the academic and social opportunities of racially minoritized students of color. This case explores equity-centered leadership and racial equity.

Long term potentiation-like neural plasticity and performance-based memory function

ObjectiveExperience-dependent modulation of the visual evoked potential (VEP) has emerged as a promising non-invasive proxy for assaying long term potentiation (LTP)-like plasticity in the cerebral cortex. LTP is considered the principal candidate mechanism underlying learning and memory. There is, however, a paucity of evidence exploring associations between LTP-like plasticity and performance-based learning and memory. The present study aimed to explore the relationship between VEP-plasticity and higher-order learning and memory in healthy adults. MethodVisual and verbal learning and memory was assessed using the Aggie Figures Learning Test (AFLT) and the Rey Auditory Verbal Learning Test (RAVLT). The study included 111 healthy adults (61.1% females; mean age 37.6 years, range 17–71) who underwent a VEP paradigm employing visual high-frequency stimulation to induce a change in visual evoked responses recorded by scalp EEG. In addition, a more comprehensive neuropsychological assessment was administered. ResultsSeveral significant moderate age-corrected positive correlations were found between modulation of the later VEP components (N1 and P1-N1 peak-to-peak) and both visual and verbal learning and memory performance. Further, there were significant differences in learning and memory performance between participants showing a higher degree of modulation (>1 SD above mean) compared to participants showing a lower degree of modulation. No significant associations were found between VEP-plasticity and other neurocognitive domains. ConclusionsThe current results suggest that LTP-like plasticity indexed by VEP modulation reflect processes specific to learning and memory. Future research is needed to further delineate the complex relationship between neural plasticity and learning and memory, specifically concerning possible clinical implications in populations with deficits in learning and memory function.

Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer's disease.

SummaryBackgroundPhosphorylated tau (p-tau) epitopes in cerebrospinal fluid (CSF) are accurate biomarkers for a pathological and clinical diagnosis of Alzheimer's disease (AD) and are seen to be increased in preclinical stage of the disease. However, it is unknown if these increases transpire earlier, prior to amyloid-beta (Aβ) positivity as determined by position emission tomography (PET), and if an ordinal sequence of p-tau epitopes occurs at this incipient phaseMethodsWe measured CSF concentrations of p-tau181, p-tau217 and p-tau231 in 171 participants across the AD continuum who had undergone Aβ ([18F]AZD4694) and tau ([18F]MK6240) position emission tomography (PET) and clinical assessmentFindingsAll CSF p-tau biomarkers were accurate predictors of cognitive impairment but CSF p-tau217 demonstrated the largest fold-changes in AD patients in comparison to non-AD dementias and cognitively unimpaired individuals. CSF p-tau231 and p-tau217 predicted Aβ and tau to a similar degree but p-tau231 attained abnormal levels first. P-tau231 was sensitive to the earliest changes of Aβ in the medial orbitofrontal, precuneus and posterior cingulate before global Aβ PET positivity was reachedInterpretationWe demonstrate that CSF p-tau231 increases early in development of AD pathology and is a principal candidate for detecting incipient Aβ pathology for therapeutic trial applicationFundingCanadian Institutes of Health Research (CIHR), Canadian Consortium of Neurodegeneration and Aging, Weston Brain Institute, Brain Canada Foundation, the Fonds de Recherche du Québec.

Development of Toughened, Fine Grained, Recrystallized W-1.1%TiC

Tungsten (W) is a principal candidate as target material because of its high density and extremely high melting point. W inherently has a critical disadvantage of its brittleness at around room temperature (low temperature brittleness), recrystallization embrittlement, and irradiation embrittlement. TFGR (Toughened, Fine Grained, Recrystallized) W-1.1%TiC has been considered as a realized solution to the embrittlement problems. We started to fabricate TFGR W-1.1%TiC in 2016 under collaboration between KEK and Metal Technology Co. LTD (MTC). The TFGR W-1.1%TiC samples were successfully fabricated in June, 2018. As a result, the specimen showed slight bend ductility and 2.6 GPa of fracture strength.

Inelastic Material Models of Type 316H for Elevated Temperature Design of Advanced High Temperature Reactors

In this paper, the inelastic material models for Type 316H stainless steel, which is one of the principal candidate materials for elevated temperature design of the advanced high temperature reactors (HTRs) pressure retained components, are investigated and the required material parameters are identified to be used for both elasto-plastic models and unified viscoplastic models. In the constitutive equations of the inelastic material models, the kinematic hardening behavior is expressed with the Chaboche model with three backstresses, and the isotropic hardening behavior is expressed by the Voce model. The required number of material parameters is minimized to be ten in total. For the unified viscoplastic model, which can express both the time-independent plastic behavior and the time-dependent viscous behavior, the constitutive equations have the same kinematic and isotropic hardening parameters of the elasto-plastic material model with two additional viscous parameters. To identify the material parameters required for these constitutive equations, various uniaxial tests were carried out at isothermal conditions at room temperature and an elevated temperature range of 425–650 °C. The identified inelastic material parameters were validated through the comparison between tests and calculations.

Two Novel Rare Strongly Linked Missense SNPs (P27R and A85G) Within the GDF9 Gene Were Significantly Associated With Litter Size in Shaanbei White Cashmere (SBWC) Goats.

Growth differentiation factor 9 (GDF9) is a high-fertility candidate gene that plays a crucial role in early folliculogenesis in female mammals. In this study, direct sequencing was used to screen possible SNP loci in the goat GDF9 gene. Three SNP loci, p.proline27alanine (P27R), p.leucine61leucine (L61L), and p.alanine85glycine (A85G), were identified in Shaanbei white cashmere (SBWC) goats. Among the three SNPs, two rare missense SNP loci (P27R and A85G) were discovered to be strongly linked with each other (D′ value = 0.926, r2 value = 0.703). Both P27R and A85G loci had two genotypes: wild type and heterozygous type. A85G exerted a significant effect on litter size (P = 0.029) in SBWC goats, and the heterozygous genotype was superior in comparison with the wild type. The heterozygous genotype was also superior in P27R but no significant association was found. However, the combination genotypes of P27R and A85G were identified to have superior effects on litter size (P = 3.8E−15). This information suggested that these two SNPs influenced litter size in goats synergistically. Combining this information with our previous studies, we propose that the GDF9 gene is the principal high-fertility candidate gene and that the A85G locus is a promising SNP that affects litter size in goats. These results may fill a research gap regarding rare mutations as well as provide crucial molecular markers that could be useful in marker-assisted selection (MAS) goat rearing when selecting superior individuals.

Elevated temperature mechanical properties of Inconel 617 surface oxide using nanoindentation

Inconel 617 is a principal candidate material for helium gas cooled very-high-temperature reactors with outlet temperatures of 700–950 °C. Recent findings showed that this alloy develops unique surface oxide layers especially at high temperature (HT) helium environment with distinctive wear, friction and contact properties. This study investigates the elevated temperature mechanical properties of Inconel 617 top surface layers aged in HT helium environment. Nanoindentation technique is used to obtain load-displacement graphs of the alloy top surface oxide in temperatures ranging from 25 °C up to 600 °C. In addition, using finite element analysis along with an iterative regression technique, a semi-numerical method is developed to further measure and quantify the material parameters and, in particular, time-independent and creep characteristics of the oxide. While Young's modulus of the oxide is found to be relatively close to the bulk for the tested temperatures, the yield strength and hardness, in comparison to the bulk material, increase significantly as the material is oxidized after aging. The oxide exhibits significant softening as the temperature increases to 600 °C. Unlike the bulk material, diffusion through the grains is found to be the dominant creep mechanism for the oxide. Considerable difference between the mechanical properties of the oxide and the bulk material shows the need for accurate measurements of near surface mechanical properties, if reliable predictive contact and tribological models are sought at elevated temperatures.

A pilot study of preproinsulin peptides reactivity in Chinese patients with type 1 diabetes.

BackgroundThe aim of our study is to investigate whether preproinsulin (PPI) could trigger a proinflammatory CD4+ T cell response in Chinese patients with type 1 diabetes (T1D).MethodsPeripheral blood mononuclear cells were stimulated by a pool of 13 PPI peptides. Additional five PPI peptides previously proved to be antigenic in other cohorts of patients with T1D were also used. PPI reactive T cell responses were measured by interferon (IFN)‐γ ELISPOT assay.ResultsFifty‐one Chinese patients with T1D were enrolled in this study and 72.34% of them were positive for at least one islet autoantibody. The stimulation index (SI) value of IFN‐γ response to PPI peptide pool or peptides with dominant epitopes was below 3 in patients when SI≥3 was used as the positive cut‐off value. Two peptides (B9‐23 and C19‐A3) restricted to DQ8 or DR4 molecule failed to induce positive IFN‐γ response in patients with high‐risk HLA‐DQ8 or HLA‐DR4/DR9 alleles. RNA‐seq analysis of PPI specific CD4+ T cell lines further showed that most of the IFN‐γ associated genes remained unchanged.ConclusionsThis is the first report of CD4+ T cell epitope mapping of PPI in Chinese T1D. The lack of positive IFN‐γ response to PPI peptides indicates that PPI might not be the principal antigenic candidate for autoreactive CD4+ T cells in Chinese T1D. Therefore, the efficacy of PPI‐based immunotherapies in attenuating proinflammatory CD4+ T cell response requires further investigation.

Explicating Logical Independence

Accounts of (complete) logical independence which coincide when applied in the case of classical logic diverge elsewhere, raising the question of what a satisfactory all-purpose account of logical independence might look like. ‘All-purpose’ here means: working satisfactorily as applied across different logics, taken as consequence relations. Principal candidate characterizations of independence relative to a consequence relation are (i) that there the consequence relation concerned is determined by (= sound and complete w.r.t.) only by classes of (bivalent) valuations providing for all possible truth-value combinations for the formulas whose independence is at issue, and (ii) that the consequence relation ‘says’ nothing special about how those formulas are related that it does not say about arbitrary formulas. (The latter approach, we associate with de Jongh, though it is closely related to Marczewski’s notion of general algebraic independence, as well as to the absence of non-trivial logical relations as conceived by Lemmon.) Each of these proposals returns counterintuitive verdicts in certain cases—the truth-value inspired approach classifying certain cases one would like to describe as involving failures of independence as being cases of independence, and the de Jongh approach counting some intuitively independent pairs of formulas as not being independent after all. In final section, a modification of the latter approach is tentatively sketched to correct for these misclassifications. The attention is on conceptual clarification throughout, rather than the provision of technical results. Proofs, as well as further elaborations, are lodged in the ‘longer notes’ in a final Appendix.

Novel inhibitor candidates of TRPV2 prevent damage of dystrophic myocytes and ameliorate against dilated cardiomyopathy in a hamster model.

Transient receptor potential cation channel, subfamily V, member 2 (TRPV2) is a principal candidate for abnormal Ca2+-entry pathways, which is a potential target for therapy of muscular dystrophy and cardiomyopathy. Here, an in silico drug screening and the following cell-based screening to measure the TRPV2 activation were carried out in HEK293 cells expressing TRPV2 using lead compounds (tranilast or SKF96365) and off-patent drug stocks. We identified 4 chemical compounds containing amino-benzoyl groups and 1 compound (lumin) containing an ethylquinolinium group as candidate TRPV2 inhibitors. Three of these compounds inhibited Ca2+ entry through both mouse and human TRPV2, with IC50 of less than 10 μM, but had no apparent effect on other members of TRP family such as TRPV1 and TRPC1. Particularly, lumin inhibited agonist-induced TRPV2 channel activity at a low dose. These compounds inhibited abnormally increased Ca2+ influx and prevented stretch-induced skeletal muscle damage in cultured myocytes from dystrophic hamsters (J2N-k). Further, they ameliorated cardiac dysfunction, and prevented disease progression in vivo in the same J2N-k hamsters developing dilated cardiomyopathy as well as muscular dystrophy. The identified compounds described here are available as experimental tools and represent potential treatments for patients with cardiomyopathy and muscular dystrophy.

The TAM receptor Tyro3 regulates myelination in the central nervous system.

Myelin is an essential component of the mammalian nervous system, facilitating rapid conduction of electrical impulses by axons, as well as providing trophic support to neurons. Within the central nervous system, the oligodendrocyte is the specialized neural cell responsible for producing myelin by a process that is thought to be regulated by both activity dependent and independent mechanisms but in incompletely understood ways. We have previously identified that the protein Gas6, a ligand for a family of tyrosine kinase receptors known as the TAM (Tyro3, Axl, and Mertk) receptors, directly increases oligodendrocyte induced myelination in vitro. Gas6 can bind to and activate all three TAM receptors, but the high level of expression of Tyro3 on oligodendrocytes makes this receptor the principal candidate for transducing the pro-myelinating effect of Gas6. In this study, we establish that in the absence of Tyro3, the pro-myelinating effect of Gas6 is lost, that developmental myelination is delayed and that the myelin produced is thinner than normal. We show that this effect is specific to the myelination process and not due to changes in the proliferation or differentiation of oligodendrocyte precursor cells. We have further demonstrated that the reduction in myelination is due to the loss of Tyro3 on oligodendrocytes, and this effect may be mediated by activation of Erk1. Collectively, our findings indicate the critical importance of Tyro3 in potentiating central nervous system myelination. GLIA 2017 GLIA 2017;65:581-591.

KOLABORASI DAN SINERGI ANTAR LEMBAGA DALAM PENINGKATAN KOMPETENSI KEPALA SEKOLAH

<p>Collaboration and synergy among institutions in enhancing principal’s competence is very essential. This may cover many areas, from recruitment-including the system of selection-, until certification for principal, principal candidate’s training, and capacity building for principal. Optimizing role of each institutions and the parties which are involved in a collaborative and synergistic way in accordance with the systems and mechanisms, will determine the competence of the principal. This collaboration and synergy will create qualified principal according the demands and needs of autonomy in MEA era.</p>

Persepsi Kepala SMK terhadap Topik Materi Pelatihan Intrapreneur

The pros side says that, in order to increase the skill, training is needed. On the other hand, the contras side states that, although the training has been planned sophisticatedly, the implementation still employs conventional ways. This article presents four research findings, including topics of intrapreneurship material as an important component of the training quality. By sufficient intrapreneur skill, the managerial gap between school managerial and both businessman and entrepreneur hopefully can be reduced. Four issues discussed are the validity and reliability of intrapreneurship material topics, the present picture of training material for principal candidate, and the description of training model for principal candidate

The State of State Policies for Principal Preparation Program Approval and Candidate Licensure

Policies for principal preparation and licensure are important levers for improving school leadership. By developing a rubric of research-based practices, this University Council of Educational Administration study aims to provide a formative tool for policy makers. Using a policy analysis frame by Roach et al., this study explores the state code, rules and regulations, and accompanying state board/department of education documents to describe state policies for principal preparation program approval and candidate licensure. There is variation in the extent to which states have adopted policies in these areas. Proportionately, more states have adopted policies for licensure despite greater empirical evidence for preparation program approval.

Generically large nongaussianity in small multifield inflation

If forthcoming measurements of cosmic photon polarization restrict the primordial tensor-to-scalar ratio to r < 0.01, small field inflation will be a principal candidate for the origin of the universe. Here we show that small multifield inflation, without the hybrid mechanism, typically results in large squeezed nongaussianity. Small multifield potentials contain multiple flat field directions, often identified with the gauge invariant field directions in supersymmetric potentials. We find that unless these field directions have equal slopes, large nongaussianity arises. After identifying relevant differences between large and small two-field potentials, we demonstrate that the latter naturally fulfill the Byrnes-Choi-Hall large nongaussianity conditions. Computations of the primordial power spectrum, spectral index, and squeezed bispectrum, reveal that small two-field models which otherwise match observed primordial perturbations, produce excludably large nongaussianity if the inflatons' field directions have unequal slopes.

A comparative analysis of various antigenic proteins found in Haemonchus contortus--a review

Many innovative researches on the development and introduction of recombinant vaccines against many economically important parasites were carried out in the 20th century. Research continues to hold promise with the development of immunological and molecular approaches for control of these parasites and in this regard it has already been seen that blood-sucking parasites such as Haemonchus contortus and Ostertagia ostertagi are susceptible to control by vaccines containing "novel" or "concealed" antigens. Haemonchus contortus is primarily pathogenic to sheep and its blood-feeding behaviour causes effects ranging from mild anaemia to mortality in young animals. Current means of control which are dependent on repeated treatment with anthelmintics are responsible for the increasing drug resistance of this parasite. Together with the growing concern of residual chemicals in the environment and food chain, this has led to attempts to better understand the biology of the parasite with an aim to develop alternate means of control, including the development of molecular vaccines. More problematic and also important is the formulation and delivery strategy to induce expulsion of this parasite, using vaccines containing recombinant "conventional" antigens. Tremendous progress has been made in the last decade in identifying several antigens from Haemonchus contortus which in their native form stimulate useful levels of protective immunity. Vaccines have been developed against H. contortus using 'novel' gut antigens from the parasite, but variable responsiveness of the host sheep has resulted in varying degrees of protection which are stimulated by these vaccines. Computer models have also been used to simulate vaccine efficacy in worm control and have yielded good results. This review will try to summarise the protective efficacy and also the molecular properties of principal candidate antigens which are expressed by this parasite. The review will try to cover the aspirations, current success, limitations and problems faced by researchers in the control of this economically important parasite.

Brain-derived neurotrophic factor Val66Met polymorphism, human memory, and synaptic neuroplasticity.

Some people have much better memory than others, and there is compelling evidence that a considerable proportion of this variation in memory ability is genetically inherited. A form of synaptic plasticity known as long-term potentiation (LTP) is the principal candidate mechanism underlying memory formation in neural circuits, and it might be expected, therefore, that a genetic influence on the degree of LTP might in turn influence memory abilities. Of the genetic variations thought to significantly influence mnemonic ability in humans, the most likely to have its effect via LTP is a single nucleotide polymorphism affecting brain-derived neurotrophic factor [BDNF (Val66Met)]. However, although it is likely that BDNF influences memory via a modulation of acute plasticity (i.e., LTP), BDNF also has considerable influence on structural development of neural systems. Thus, the influence of BDNF (Val66Met) on mnemonic performance via influences of brain structure as well as function must also be considered. In this brief review, we will describe the phenomenon of LTP and its study in non-human animals. We will discuss the relatively recent attempts to translate this work to studies in humans. We will describe how this has enabled investigation of the effect of the BDNF polymorphism on LTP, on brain structure, and on memory performance.

Quorum sensing activity and control of yeast-mycelium dimorphism in Ophiostoma floccosum.

Quorum sensing (QS) activity in Ophiostoma fungi has not been described. We have examined the growth conditions on the control of dimorphism in Ophiostoma floccosum, an attractive biocontrol agent against blue-stain fungi, and its relationship with QS activity. In a defined culture medium with L-proline as the N source, a high inoculum size (10(7)c.f.u.ml(-1)) was the principal factor that promoted yeast-like growth. Inoculum size effect can be explained by the secretion of a QS molecule(s) (QSMs) responsible for inducing yeast morphology. QSM candidates were extracted from spent medium and their structure was determined by GC-MS. Three cyclic sesquiterpenes were found. The most abundant molecule, and therefore the principal candidate to be the QSM responsible for yeast growth of O. floccosum, was 1,1,4a-trimethyl-5,6-dimethylene-decalin (C15H24). Other two compounds were also detected.

Electricity versus hydrogen for passenger cars under stringent climate change control

In this article we analyze how passenger car transportation in Europe may change this century under permanent high oil prices and stringent climate control policy. We focus on electricity and hydrogen as principal candidate energy carriers, because these two options are increasingly believed to become the long-term competitors in the transport sector. We complement a concise stylistic analysis with an in-depth investigation performed with the energy system optimization model TIAM-ECN, which we ran only for the European regions for this study. This bottom-up model, belonging to the TIMES family, has been adapted for the purpose of researching – amongst others – the transport sector. We particularly inspect the use of passenger cars and find that, if oil prices amount to 100–150$/bl during the remainder of the century, the transport sector could be little affected in the sense that it may continue to rely predominantly on (liquid or gaseous) fossil fuels: our model suggests that it could be optimal to start replacing gasoline and diesel by natural gas around the middle of the century if sufficient oil and gas reserves are available within this price range. If the European Commission achieves implementing its ambitious carbon mitigation plan, however, a massive restructuring of the transport sector away from fossil fuels could take place, which in three decades would transform it to broadly rely on hydrogen as main energy carrier according to our model runs. Under a broad set of sensitivity scenarios with varying assumptions regarding our most important modeling parameters, we find that if battery costs are reduced by at least 60% in comparison to our reference cost decline path, the passenger car sector could predominantly run on electricity from around 2050.