Miracle-dz/UniFAR-FTUs huggingface dataset:
Melanoma therapy via peptide-targeted {alpha}-radiation.

PURPOSE The therapeutic efficacy of a unique melanoma-targeting peptide conjugated with an in vivo generated alpha-particle-emitting radionuclide was evaluated in the B16/F1 mouse melanoma animal model. alpha-Radiation is densely ionizing, resulting in high concentrations of destructive radicals and irreparable DNA double-strand breaks. This high linear energy transfer overcomes radiation-resistant tumor cells and oxygen effects resulting in potentially high therapeutic indices in tumors such as melanoma. EXPERIMENTAL DESIGN The melanoma targeting peptide, 1,4,7,10-tetraazacyclodecane-1,4,7,10-tetraacetic acid (DOTA)-Re(Arg(11))CCMSH, was radiolabeled with (212)Pb, the parent of (212)Bi, which decays via alpha and beta decay. Biodistribution and therapy studies were done in the B16/F1 melanoma-bearing C57 mouse flank tumor model. RESULTS (212)Pb[DOTA]-Re(Arg(11))CCMSH exhibited rapid tumor uptake and extended retention coupled with rapid whole body disappearance. Radiation dose delivered to the tumor was estimated to be 61 cGy/muCi (212)Pb administered. Treatment of melanoma-bearing mice with 50, 100, and 200 muCi of (212)Pb[DOTA]-Re(Arg(11))CCMSH extended their mean survival to 22, 28, and 49.8 days, respectively, compared with the 14.6-day mean survival of the placebo control group. Forty-five percent of the mice receiving 200 muCi doses survived the study disease-free. CONCLUSIONS Treatment of B16/F1 murine melanoma-bearing mice with (212)Pb[DOTA]-Re(Arg(11))CCMSH significantly decreased tumor growth rates resulting in extended mean survival times, and in many cases, complete remission of disease. (212)Pb-DOTA-Re(Arg(11))CCMSH seems to be a very promising radiopharmaceutical for targeted radionuclide therapy of melanoma.
Modulation of glucose metabolism and metabolic connectivity by β-amyloid

Glucose hypometabolism in the pre-clinical stage of Alzheimer’s disease (AD) has been primarily associated with the APOE ɛ4 genotype, rather than fibrillar β-amyloid. In contrast, aberrant patterns of metabolic connectivity are more strongly related to β-amyloid burden than APOE ɛ4 status. A major limitation of previous studies has been the dichotomous classification of subjects as amyloid-positive or amyloid-negative. Dichotomous treatment of a continuous variable, such as β-amyloid, potentially obscures the true relationship with metabolism and reduces the power to detect significant changes in connectivity. In the present work, we assessed alterations of glucose metabolism and metabolic connectivity as continuous function of β-amyloid burden using positron emission tomography scans from the Alzheimer’s Disease Neuroimaging Initiative study. Modeling β-amyloid as a continuous variable resulted in better model fits and improved power compared to the dichotomous model. Using this continuous model, we found that both APOE ɛ4 genotype and β-amyloid burden are strongly associated with glucose hypometabolism at early stages of Alzheimer’s disease. We also determined that the cumulative effects of β-amyloid deposition result in a particular pattern of altered metabolic connectivity, which is characterized by global, synchronized hypometabolism at early stages of the disease process, followed by regionally heterogeneous, progressive hypometabolism.
Passionate participation: Emotional experiences and expressions in deliberative forums

This article explores the emotional dimension of public participation. It contrasts the understanding of deliberative forums as spaces in which reasoned argument is intended to lead to good policy making, with the importance of values and emotions in motivating action within social movements. In the context of a widening of the participatory sphere and the increasing likelihood that social movement activists will also take part in officially sponsored participation initiatives, it considers the significance of the emotional content of experiences that service users and citizens bring to discussions about policy and service delivery. Drawing on a feminist ethic of care it suggests criteria for assessing the capacity of deliberative practices to encompass an emotional morality and to deliver on aspirations for enhanced well-being, welfare and social justice.
Lymphatics of the Heart

The anatomy of the cardiac lymphatic system of pigs, dogs, and humans has been studied by topical application of hydrogen peroxide and also by injection technics. In general, all three species have extensive subepicardial and subendocardial networks with collecting channels directed toward large ducts in the AV sulcus continuous with themain cardiac lymph duct. The subepicardial and subendocardial systems in dogs and pigs communicate via transmyocardial channels and channels in the supporting structures of the AV valves; in humans these communications have not been identified with certainty. Lymphatics are seen in both AV valves of dogs and pigs but have been seen only in the mitral valves of humans. The possible significance of these observations has been discussed.
Peroxisome Proliferator–Activated Receptor γ Polymorphism Pro12Ala Is Associated With Nephropathy in Type 2 Diabetes

OBJECTIVE Insulin resistance plays a part in diabetic nephropathy (DN). The association between the peroxisome proliferator–activated receptor γ Pro to Ala alteration at codon 12 (Pro12Ala) polymorphism and the risk of insulin resistance has been confirmed. The association between the polymorphism and DN risk has also been widely studied recently, but no consensus was available up to now. RESEARCH DESIGN AND METHODS A systematic search of electronic databases (MEDLINE, Embase, and China National Knowledge Infrastructure) and reference lists of relevant articles was carried out, and then 18 case-control studies involving 3,361 DN cases and 5,825 control subjects were identified. RESULTS In the overall analysis, the Ala12 variant was observed to be significantly associated with decreased DN risk (odds ratio 0.76 [95% CI 0.61–0.93]). Some evidence of heterogeneity among the included studies was detected, which could be explained by the difference of ethnicity and stage of DN. Subgroup analyses stratified by ethnicity and stage of DN were performed, and results indicated the Pro12Ala polymorphism was associated with the risk of DN in Caucasians but no similar association was observed in Asians. Additionally, we observed that Ala12 was associated with decreased risk of albuminuria. With only a few of subjects were available, we failed to detect statistically significant association between the polymorphism and end-stage renal disease (ESRD). CONCLUSIONS Our results indicated that the Ala12 variant is a significantly protective factor for DN. Future research should focus on the effect of Pro12Ala polymorphism on ESRD and gathering data of Africans.
Care for the elderly: welfare system, professionalisation and the question of inequality

Since the 1960s, the health system has seen the professionalisation of a new occupation, carer of the elderly. The form and result of this process differs between countries according to their welfare systems. In this paper, the differences will be analysed in a comparison between two countries, Germany and Sweden, the representatives of two prototypical welfare systems. Sweden is renowned for its state‐oriented universal welfare system, whereas Germany is considered to be an example of a conservative, family‐oriented system. The process of professionalisation and its consequences for the carer and the care receivers will be looked at from the perspective of gender and social inequality. On a theoretical basis, this paper includes gendered and mainstream welfare state approaches and thus combines issues of gender and social inequality, as well as theories in the area of professionalisation. Empirically, the development of the new occupation is examined in two phases. In the first step, it looks at the time‐period between the 60s and 80s, when the stateoriented vs. family‐oriented principles of care for the elderly were established. The 90s brought about change in both countries. In Germany, with the introduction of the Long‐term Care Insurance, a new mode of care has developed, shared between informal family care, and public or private providers. In Sweden, budget restrictions in the 90s in this area led to a reorganisation, restructuring and reduction of the role of the welfare state. The consequences of the different processes in both countries will be discussed from the perspective of the predominantly female employees and the receivers of care. The results reveal a complex interaction between patterns of gender and social inequality and welfare state policies for the carers and care receivers.
Morphological Changes of Paulownia Seedlings Infected Phytoplasmas Reveal the Genes Associated with Witches' Broom through AFLP and MSAP

Paulownia witches' broom (PaWB) caused by phytoplasma might result in devastating damage to the growth and wood production of Paulownia. To study the effect of phytoplasma on DNA sequence and to discover the genes related to PaWB occurrence, DNA polymorphisms and DNA methylation levels and patterns in PaWB seedlings, the ones treated with various concentration of methyl methane sulfonate (MMS) and healthy seedlings were investigated with amplified fragment length polymorphism (AFLP) and methylation-sensitive amplification polymorphism (MSAP). Our results indicated that PaWB seedlings recovered a normal morphology, similar to healthy seedlings, after treatment with more than 20 mg·L−1 MMS; Phytoplasma infection did not change the Paulownia genomic DNA sequence at AFLP level, but changed the global DNA methylation levels and patterns; Genes related to PaWB were discovered through MSAP and validated using quantitative real-time PCR (qRT-PCR). These results implied that changes of DNA methylation levels and patterns were closely related to the morphological changes of seedlings infected with phytoplasmas.
Youth and Adult Perceptions of Their Relationships Within Community-Based Youth Programs

This study examined perceptions and experiences of youth and adults engaged in various types of community-based youth-adult relationships. Involvement and interaction rating scales were completed by 108 participants involved in community groups from 12 communities in 10 states. The rating scale measured three constructs: youth involvement, adult involvement, and youth-adult interaction. Significant gender differences in participants’ perceptions were found on all three constructs, with females being more positive. Rural participants were found to be significantly more positive than urban participants on the construct of youth involvement. Finally, significant differences were found between all participants within categories of the youth-adult relationship continuum. Participants in youth-led collaborations were significantly more positive toward youth involvement than participants in adult-led collaborations. Moreover, adults in youth-adult partnerships were significantly more positive toward youth involvement and youth-adult interaction than those adults in adult-led collaborations.
Moving towards inclusion? The first‐degree results of students with and without disabilities in higher education in the UK: 1998–2005

Is the currently selective UK higher education (HE) system becoming more inclusive? Between 1998/99 and 2004/05, in relation to talented students with disabilities, has the UK government’s HE policy implementation moved HE towards achieving two of the government’s key HE objectives for 2010? These objectives are: (a) increasing HE participation rates of students with and without disabilities; and (b) maintaining the HE academic standards of students with and without disabilities. The findings reported are based on data drawn from six cohorts of students at UK higher education institutions (HEI) who satisfactorily completed their first degrees between the years 1998/99 and 2004/05. A total of 1 502 658 students were involved. Key variables included: Cohort (N = 6), Gender (N = 2), Disability category (N = 10) and degree classification (N = 5). The patterns of change in numbers and percentages of students successfully completing first degrees across cohorts for all students, with and without disability, are presented. Descriptive statistical analyses of changes in first‐degree academic standards over time are provided. Academic standards are operationally defined as the degree class obtained by students. Particular attention is paid to changes over time in the numbers and percentages of students obtaining the highest level of award – a first‐class honours degree. In summary, in absolute terms, the numbers of both male and female students with and without disabilities successfully completing their first degrees have increased markedly over time. First‐class honours degree standards appear to have been maintained, and possibly improved. Limitations in the nature of key variables in the research are identified. Critical acumen is essential in interpreting the analyses. Important theoretical and applied questions arise. Eight of these questions indicate challenging but promising lines of research and are presented at the end of the paper.
Microbioreactor Arrays for Full Factorial Screening of Exogenous and Paracrine Factors in Human Embryonic Stem Cell Differentiation

Timed exposure of pluripotent stem cell cultures to exogenous molecules is widely used to drive differentiation towards desired cell lineages. However, screening differentiation conditions in conventional static cultures can become impractical in large parameter spaces, and is intrinsically limited by poor spatiotemporal control of the microenvironment that also makes it impossible to determine whether exogenous factors act directly or through paracrine-dependent mechanisms. We detail here the development of a continuous flow microbioreactor array platform that combines full-factorial multiplexing of input factors with progressive accumulation of paracrine factors through serially-connected culture chambers, and further, the use of this system to explore the combinatorial parameter space of both exogenous and paracrine factors involved in human embryonic stem cell (hESC) differentiation to a MIXL1-GFP+ primitive streak-like population. We show that well known inducers of primitive streak (BMP, Activin and Wnt signals) do not simply act directly on hESC to induce MIXL1 expression, but that this requires accumulation of surplus, endogenous factors; and, that conditioned medium or FGF-2 supplementation is able to offset this. Our approach further reveals the presence of a paracrine, negative feedback loop to the MIXL1-GFP+ population, which can be overcome with GSK-3β inhibitors (BIO or CHIR99021), implicating secreted Wnt inhibitory signals such as DKKs and sFRPs as candidate effectors. Importantly, modulating paracrine effects identified in microbioreactor arrays by supplementing FGF-2 and CHIR in conventional static culture vessels resulted in improved differentiation outcomes. We therefore demonstrate that this microbioreactor array platform uniquely enables the identification and decoding of complex soluble factor signalling hierarchies, and that this not only challenges prevailing strategies for extrinsic control of hESC differentiation, but also is translatable to conventional culture systems.
Latent Acquisition of Timed Responses in Cerebellar Cortex

Evidence indicates that rabbit eyelid conditioning is mediated by plasticity in the interpositus cerebellar nucleus and in cerebellar cortex. Although the relative contributions of these sites are not fully characterized, evidence suggests that plasticity in the cerebellar cortex influences conditioned response amplitude and timing, whereas plasticity in the interpositus nucleus is necessary or permissive for conditioned response expression. Recent empirical and computational analyses suggest that, during training, plasticity is initially established in the cerebellar cortex, whereas conditioned response expression begins later as plasticity is induced in the interpositus nucleus. We used the dependence of response timing on the interstimulus interval (ISI) to test this latent learning hypothesis. Rabbits were initially trained using a tone conditioned stimulus (CS) with a relatively long ISI to a low-criterion threshold. The relative absence of plasticity in the interpositus nucleus was then examined via reversible disconnection of the cerebellar cortex. Later, to induce plasticity in the interpositus nucleus, subjects were trained to robust levels of conditioned response expression using a shorter ISI. Reversible disconnection of the cerebellar cortex at this time confirmed the presence of robust interpositus nucleus plasticity after the second phase. Subsequent probe trials with the long CS alone then revealed double-peaked responses whose peaks were appropriately timed to the two ISIs. The results are consistent with the hypothesis that temporally specific learning occurs first in the cerebellar cortex before the appearance of conditioned responses. This latent learning is expressed only after plasticity is induced in the interpositus nucleus.
Use of Real-Time PCR and Fluorimetry for Rapid Detection of Rifampin and Isoniazid Resistance-Associated Mutations in Mycobacterium tuberculosis

ABSTRACT Very fast amplification of DNA in small volumes can be continuously monitored with a rapid cycler that incorporates fluorimetric detection. Primers were designed to amplify a 157-bp fragment of therpoB gene spanning codons 526 and 531 and a 209-bp fragment of the katG gene spanning codon 315 of Mycobacterium tuberculosis. Most mutations associated with resistance to rifampin (RMP) and isoniazid (INH) in clinical isolates occur in these codons. Two pairs of hybridization probes were synthesized; one in each pair was 3′ labeled with fluorescein and hybridized upstream of the codon with the mutation; the other two probes were 5′ labeled with LightCycler-Red 640. Each pair of probes recognized adjacent sequences in the amplicon. After DNA amplification was finished by using a LightCycler, the temperature at which the Red 640 probe melted from the product was determined in a 3-min melt program. Twenty M. tuberculosis clinical isolates susceptible to streptomycin, INH, RMP, and ethambutol and 36 antibiotic-resistant clinical M. tuberculosis isolates (16 resistant to RMP, 16 to INH, and 4 to both antimicrobial agents) were amplified, and the presence of mutations was determined using single-strand conformation polymorphism analysis, the LiQor automated sequencer, and the LightCycler system. Concordant results were obtained in all cases. Within 30 min, the LightCycler method correctly genotyped all the strains without the need of any post-PCR sample manipulation. Overall, this pilot study demonstrated that real-time PCR coupled to fluorescence detection is the fastest available method for the detection of RMP and INH resistance-associated mutations in M. tuberculosis clinical isolates.
The Network Paradigm: New Departures in Corporate and Regional Development

Networking is a much-discussed organisational practice. The authors analyse the nature and extent of networking activity within and between firms, making the criticism that present organisational theory pays insufficient attention to network relations between firms and public or quasi-public intermediary agencies. This is an especially important phenomenon in small and medium-sized firms. A critical depiction of networking at the interregional and, more especially, the intraregional levels then follows. Detailed accounts are provided of network interactions in the economically strong regions of Baden-Württemherg and Emilia-Romagna, The experiences of regions that have sought to learn from strong regions are explored, the cases of the Basque Country and Wales being highlighted. It is concluded that, although it is unreasonable to expect regional networking policies to enable reconversion regions to reproduce the accomplishments of strong regional economies, it has become normal for such regions to be engaged in a productive learning and adaptation process based on the analysis of key mechanisms of intraorganisational and interorganisational networking.
High-throughput sequence-based epigenomic analysis of Alu repeats in human cerebellum

DNA methylation, the only known covalent modification of mammalian DNA, occurs primarily in CpG dinucleotides. 51% of CpGs in the human genome reside within repeats, and 25% within Alu elements. Despite that, no method has been reported for large-scale ascertainment of CpG methylation in repeats. Here we describe a sequencing-based strategy for parallel determination of the CpG-methylation status of thousands of Alu repeats, and a computation algorithm to design primers that enable their specific amplification from bisulfite converted genomic DNA. Using a single primer pair, we generated amplicons of high sequence complexity, and derived CpG-methylation data from 31 178 Alu elements and their 5′ flanking sequences, altogether representing over 4 Mb of a human cerebellum epigenome. The analysis of the Alu methylome revealed that the methylation level of Alu elements is high in the intronic and intergenic regions, but low in the regions close to transcription start sites. Several hypomethylated Alu elements were identified and their hypomethylated status verified by pyrosequencing. Interestingly, some Alu elements exhibited a strikingly tissue-specific pattern of methylation. We anticipate the amplicons herein described to prove invaluable as epigenome representations, to monitor epigenomic alterations during normal development, in aging and in diseases such as cancer.
Rethinking achievement goals: When are they adaptive for college students and why?

The types of goals that students adopt in educational settings and the consequences of those goals an 2 important educational outcomes-performance and intrinsic motivation-are discussed. In the case of performance, we briefly review and evaluate a large body of theory and research conducted by other investigators. In particular, we consider the possibility that some commonly accepted conclusions about the effects of achievement goals are premature. In the case of intrinsic motivation, we describe a theoretical model that has guided our own work on this topic and provide some recent experimental results. We believe that this model and our experimental results can contribute to a more comprehensive understanding of goals and optimal motivation. Finally, we return to the college classroom environment and examine the consequences of goals for both performance and intrinsic motivation, offering a broader analysis of success in college courses.