Mature Versions Research Articles

Comparative analysis of germline versus mature versions of the broadly neutralizing HIV-1 antibody PGZL1

Comparative analysis of germline versus mature versions of the broadly neutralizing HIV-1 antibody PGZL1

Engineered immunogens to elicit antibodies against conserved coronavirus epitopes

Immune responses to SARS-CoV-2 primarily target the receptor binding domain of the spike protein, which continually mutates to escape acquired immunity. Other regions in the spike S2 subunit, such as the stem helix and the segment encompassing residues 815-823 adjacent to the fusion peptide, are highly conserved across sarbecoviruses and are recognized by broadly reactive antibodies, providing hope that vaccines targeting these epitopes could offer protection against both current and emergent viruses. Here we employ computational modeling to design scaffolded immunogens that display the spike 815-823 peptide and the stem helix epitopes without the distracting and immunodominant receptor binding domain. These engineered proteins bind with high affinity and specificity to the mature and germline versions of previously identified broadly protective human antibodies. Epitope scaffolds interact with both sera and isolated monoclonal antibodies with broadly reactivity from individuals with pre-existing SARS-CoV-2 immunity. When used as immunogens, epitope scaffolds elicit sera with broad betacoronavirus reactivity and protect as “boosts” against live virus challenge in mice, illustrating their potential as components of a future pancoronavirus vaccine.

Time to act mature—Gearing eHealth evaluations towards technology readiness levels

It is challenging to design a proper eHealth evaluation. In our opinion, the evaluation of eHealth should be a continuous process, wherein increasingly mature versions of the technology are put to the test. In this article, we present a model for continuous eHealth evaluation, geared towards technology maturity. Technology maturity can be determined best via Technology Readiness Levels, of which there are nine, divided into three phases: the research, development, and deployment phases. For each phase, we list and discuss applicable activities and outcomes on the end-user, clinical, and societal front. Instead of focusing on a single perspective, we recommend to blend the end-user, health and societal perspective. With this article we aim to contribute to the methodological debate on how to create the optimal eHealth evaluation design.

Throwing the Baby out with the Bathwater: The Dangers of Global and Local Ontologies in Scientific Metaphysics

In the recent years, attempts to relate metaphysics and sciences have taken various alternative forms such as metaphysics applied to science, metaphysics of science, and scientific metaphysics. In this article, I focus on scientific metaphysics and specifically explore the challenges with developing ontologies through four arguments. The Argument from Representational Indeterminacy highlights that global ontologies fail to clearly identify their target phenomenon. The Argument from Independent Inaccessibility explores the methodological difficulty of accessing a world that is independent of specific sets of phenomena. The Argument from Conceptual Mismatch focuses on the tendency of local ontologies to pick out arbitrary scientific concepts, adapting them to study phenomena where they might not fit well. Finally, the Argument from Eliminative Prophecy details the possibility that local ontologies could eventually be rendered redundant by mature versions of scientific theories. In the end, given these challenges, I recommend an eliminativist stance toward ontology development.

MicroRNAs as disease specific diagnostic biomarkers for neoplastic aetiology-related and inflammatory-related pericardial fluid effusion

Abstract Background and aim Malignant involvement of the pericardium is seen in 1 to 20 percent of autopsies in patients with cancer. The most common metastatic tumor involving the pericardium is lung cancer [1]. We aimed to distinguish the origin of the pericardial fluid effusion (i.e. pericarditis vs cancer) based on miRNAs expression in peripheral blood plasma. Method 8 patients hospitalized for collection of pericardial fluid with pericardial effusion of neoplastic aetiology (lung cancer). Control group includes 8 patients with effusion of inflammatory aetiology. Plasma RNA was extracted by mirVANAPARISKit and quality of RNA was assessed by fluorometric assay. GEP analysis was performed using the Clariom D pico chips, analysed on the Affymetrix platform. Statistical analysis by TAC software. Additional analyses were performed in and R using Signal information obtained from the TAC output. We performed the following tests using log2 transformed data and all comparison groups (A-F). Additional FDR correction, logistic regression, Mann-whitney t-test was used depending of the variables. We calculated Area under the curve using ROCp R package. Scores were ranging from 0 to 1. Co-expression analysis to identify genes authentically expressed was performed using Spearman correlation (cutoff = 0.9, Rpval = 0.05). In order to identify the targets of DE miRNAs we used our wizbionet R package and previously developed pipelines [2,3]. We performed target screening using multimiR package, selecting top 20% predictions from all available databases. Results We analyzed targets for all mature versions, and if DE miR was identified as pre-miR we generated -3p and -5p version for it. We also screened DisgeNet database for genes associated with cancer and pericarditis, we identified 2823 and 157 such genes. After identification of the targets of DE miRNAs we performed data aggregation, summarization and obtained information how many targets overall and targets associated with IS are regulated by each DE miRNA. Additionally we identified top targets regulated by the top miRNAs. MiR-5695, miR-4446-5p, miR-572, miR-3131 and miR-4784 were found the most significantly differentially expressed miRNAs in blood plasma for patients with malignancy compared to pericarditis. MiR-22-3p, miR-642a, miR-6771, miR-140-3p, and miR660-5p were found the most significantly differentially expressed miRNAs in pericardial fluid plasma for patients with malignancy compared to pericarditis. Importantly, miR-500b, miR-5188, miR-490, miR-24-3p, miR-383-3p were found the most promising differentially diagnostic biomarkers for malignancy and inflammatory-related pericardial fluid effusion. Conclusions For the first time our results indicate the differentially diagnostic power of miRNAs based on comparison of circulating in peripheral blood and pericardial fluid in patients having excessive pericardial fluid effusion due to different etiologies. Funding Acknowledgement Type of funding sources: None. Figure 1Figure 2

Scaling of statically derived osteocyte lacunae in extant birds: implications for palaeophysiological reconstruction.

Osteocytes are mature versions of osteoblasts, bone-forming cells that develop in two ways: via 'static' osteogenesis, differentiating and ossifying tissue in situ to form a scaffold upon which other bone can form, or 'dynamic' osteogenesis, migrating to infill or lay down bone around neurovasculature. A previous study regressed the volume of osteocyte lacunae derived from dynamic osteogenesis (DO) of a broad sample of extant bird species against body mass, the growth rate constant ( k), mass-specific metabolic rate, genome size, and erythrocyte size. There were significant relationships with body mass, growth rate, metabolic rate, and genome size, with the latter being the strongest. Using the same avian histological dataset, we measured over 3800 osteocyte lacunar axes derived from static osteogenesis (SO) in order to look for differences in the strength of form-function relationships inferred for DO-derived lacunae at the cellular and tissue levels. The relationship between osteocyte lacunar volume and body mass was stronger when measuring SO lacunae, whereas relationships between osteocyte lacunar volume versus growth rate and basal metabolic rate disappeared. The relationship between osteocyte lacuna volume and genome size remained significant and moderately strong when measuring SO lacunae, whereas osteocyte lacuna volume was still unrelated to erythrocyte size. Our results indicate that growth and metabolic rate signals are contained in avian DO but not SO osteocyte lacunae, suggesting that the former should be used in estimating these parameters in extinct animals.

The Educator's World-view, the Problem of Meta-Ontology, and a Covenant Ontology

In replying to Rocha''s (2018) arguments regarding the necessity of the teacher''s world-view and the necessity of dealing with the ensuing metaphysical disputes in a diverse classroom, I formulate his concerns as an introduction to the problem of meta-ontology. Rocha recommends pragmatist methods to address metaphysical disputes that avoid this meta-ontology trap. I argue that these methods do not avoid this trap themselves. I explore the necessity of encountering other worldviews from within our own ― no metaphysical demand exists outside of one''s ontology that can change it from the outside. Any such position would then require an expansion of that ontology itself or would propose a higher-order ontology. This changes the question from, does the teacher need to choose another world-view, to the question of, how do these encounters affect the teacher, given their world-view? In this vein, I will introduce a covenant ontology in which reality is manifold and accessible in particular domains through discipline. I argue that one''s primary world-view tradition can be extended to a non-fascist teacher''s world-view, specifically through integration of limits and humility. I argue that the world-views people start from, before they are taught out of them, are longer-standing cultural intellectual traditions ― and if we are talking about their mature versions ― have better chances of producing humble pluralist teachers than do relatively novel pluralist world-views.

It's a New Day: Microsoft's Office 2007 Launch Campaign

Microsoft's Office team was developing the marketing communication plan for its new product, Office 2007. Office was a very mature product and several versions of the product had been introduced over more than 20 years. As such, the new version had to overcome the consumer perception that the versions of Microsoft Office that they already have are “good enough” for them. The Office 2007 marketing team has come up with a two-step campaign strategy that sought to first create awareness and intrigue using traditional media, followed by the heavy use of digital media to get consumer to experience the product through different types of “digital experiences.” The team needs to decide how much of its advertising spending it should shift from traditional media to digital media, how to design the most effective digital experiences and how to measure the effectiveness of digital experiences. The case is set at a time when digital media were emerging as a promising way to engage consumers more deeply with brands and products, but marketers were uncertain about the relative effectiveness of different digital marketing tactics and the optimal mix of traditional versus digital marketing channels for different product, market and campaign contexts.To introduce students to the possibilities of “engagement marketing” using emerging digital marketing channels To emphasize the complementary nature of traditional versus digital media and their relative effectiveness at different stages of the consumer journey from awareness to perception change to behavior. To highlight the opportunities and opportunities in designing and measuring the effectiveness of integrated marketing campaigns when digital channels are added to the marketing communications mix.

Children's supernatural thinking as a signalling behaviour in early childhood.

In this study, we analysed the reaction times of 137 college students when making decisions on pairs of hypothetical children verbalizing different types of vignettes and/or exhibiting different physical appearance (photographs of faces). Vignettes depicted immature and mature versions of both supernatural (e.g., 'The sun's not out today because it's mad' vs. 'The sun's not out today because the clouds are blocking it') and natural ('I can remember all 20 cards!' vs. 'I can remember 6 or 7 cards') explanations to ordinary phenomena. Photographs of children's faces were morphed with a physical appearance of approximately 4-7years old or approximately 8-10years old. In earlier research, immature supernatural thinking produced positive-affect reactions from adults and older adolescents (14-18years old) towards young children, with cognitive cues being more important than physical-appearance cues in influencing adults' judgements. Reaction times to make decisions varied for the Supernatural and Natural vignettes and for the immature and mature vignettes/faces, reflecting the differential cognitive effort adults used for making decisions about aspects of children's physical appearance and verbal expressions. The findings were interpreted in terms of the critical role that young children's immature supernatural thinking has on adults' perception, analogous to the evolved role of immature physical features on adults' perception of infants.

Expression and actions of corticotropin-releasing factor/diuretic hormone-like peptide (CDLP) and teneurin C-terminal associated peptide (TCAP) in the vase tunicate, Ciona intestinalis: Antagonism of the feeding response

Teneurin C-terminal associated peptide (TCAP) is a neuropeptide that bears some structural similarity to the corticotropin-releasing factor (CRF) family of peptides. TCAP and CRF are both implicated in the regulation of stress-related behaviors, as established in rodent models. However, in vertebrates, both TCAP and CRF possess three additional paralogous forms making vertebrate models difficult to assess with respect to TCAP-CRF interaction. As a urochordate, this species possesses single homologs of TCAP and of a CRF/Diuretic-like peptide (CDLP) in the genome, thereby establishing Ciona intestinalis as an excellent model organism to examine the interaction of these peptide systems. However, the lack of C. intestinalis synthetic peptides and specific antisera has complicated experimentation. We, therefore, prepared synthetic versions of CDLP and TCAP to prepare specific antisera and to investigate their bioactivity in this species. To analyze stress-related behaviors, a novel behavioral assay was used to characterize different types of contraction-based behaviors, using buccal opening contractions, cloacal opening contractions, lateral contractions, longitudinal contractions and expulsions. Protein and mRNA expression data indicate that the mature versions of both peptides are present in a number of tissues. With respect to behavioral activity, both TCAP- and CDLP-treated animals had distinct contraction profiles under ambient conditions. Moreover, food stimulation tests revealed that whereas CDLP-treated animals displayed a strong expulsion behavior in response to feeding, TCAP-treated animals did not show this effect. These actions are consistent with previous studies done in vertebrates.

Retrograde signaling for climbing fiber synapse elimination.

Neurons form exuberant synapses with target cells early in development. Then, necessary synapses are selectively strengthened whereas unnecessary connections are weakened and eventually eliminated during postnatal development. This process is known as synapse elimination and is a crucial step for shaping immature neural circuits into functionally mature versions. Accumulating evidence suggests that retrograde signaling from postsynaptic cells regulates synapse elimination, but the underlying mechanisms remain unknown. Here, we show that semaphorin3A (Sema3A) and semaphorin7A (Sema7A) mediate retrograde signals for elimination of redundant climbing fiber (CF) to Purkinje cell (PC) synapses in the developing cerebellum, a representative model of synapse elimination in the central nervous system. We picked up candidate retrograde signaling molecules that are expressed in PCs during the period of CF synapse elimination and the receptors of these candidate molecules that are present in CFs. We then assessed the effects of lentivirus-mediated RNAi-knockdown of these molecules on CF synapse elimination. By this systematic screening, we found that knockdown of Sema3A in PCs or its co-receptor, plexinA4 (PlxnA4), in CFs accelerated CF synapse elimination and decreased CF-mediated synaptic inputs. Conversely, knockdown of Sema7A in PCs or either of the two receptors for Sema7A, plexinC1 (PlxnC1) and integrinB1 (ItgB1), in CFs impaired CF synapse elimination. Importantly, the effect of Sema7A involves signaling by type 1 metabotropic glutamate receptor (mGluR1), a canonical pathway in PCs for the final stage of CF synapse elimination. These results demonstrate that specific semaphorins act as retrograde signaling molecules and regulate distinct processes of CF synapse elimination during postnatal cerebellar development.

On Capability and the Good Life: Theoretical Debates and their Practical Implications

The capability approach was first developed by Amartya Sen in his Tanner Lecture Equality of What? (Sen 1980). Canonical statements of the approach were published in the 1980s (for example, Sen 1985). Slightly modified statements were subsequently published in the early 1990s (for example, Sen 1993), with more mature versions published in Sen's Development as Freedom and The Idea of Justice (Sen 1999; 2009). Over the years, variations of the approach have emerged. In particular, Martha Nussbaum's version of the approach, which is distinguished by a different title--the capabilities approach--has emerged as a distinct view in moral and political theory. The capability approach is often seen as advancing a distinct view of human well-being. But at the same time it also supports Sen's claims that welfare is not the exclusive object of value in moral evaluation and that freedom has a value independent of welfare. The freedom to live a life we value and have reason to value--or the opportunity we have to lead a valuable or good life--is, very roughly, our capability. Those interested in alternative views of well-being or of the good life will ask: does this approach provide a distinctive account of what makes a life go well or better, or of human flourishing? If it does, does this view of the good life provide any new insights into public policies and about what governments and others should, or should not, promote? I argue in this paper that even if Sen does not advance a substantive view of the good life in developing his capability perspective, his theoretical commitments lead him to quite specific policy views. These strongly contrast with those adopted by one contemporary utilitarian: Richard Layard. Although Sen's views about policy typically overlap with those of others--like Nussbaum--who favor a version of the capability perspective, sometimes variations of the approach can diverge in their policy applications because of theoretical differences. The Capability Perspective The capability perspective emerged from an engagement with a variety of different theoretical approaches within philosophy and welfare economics. In both areas it started from a critical attitude to specific notions of welfare in utilitarian thinking, those that see welfare or utility in terms of the satisfaction of desires, pleasure, or happiness. In each case, the approach suggests that the metric of utility might be distorted in some way. The overworked indentured servant and the undernourished peasant may cut their desires, learn to find pleasure in mercies, or learn to be happy with their lot. Nonetheless, they suffer from significant deprivations and may be short on opportunities to live lives that are valuable. This adaptation (or small mercies) objection to utility-based analysis suggests that we should be concerned, in evaluating the quality of people's lives, with the opportunities they have and with what they are able to do or be. And it cautions us against focusing exclusively on people's level of utility understood in certain ways. Sen's capability approach asks us to include information on capability and functioning in the evaluation of the quality of life and social states more generally. Functioning here refers to states of the person, the various things a person can do and be. Indeed, on this approach lives can be understood as made up of functionings, and well-being is understood as an evaluation of functionings. The capability approach also asks us to consider the capability people have--where this is understood in terms of the collections or n-tuples of functionings from which a person can choose (see, for example, Sen 1993, 31). It asks us to consider the opportunities or range of lives that are open to each of us. If we return to the overworked indentured servant or the undernourished peasant, we need to evaluate their lives understood in terms of functionings and the range of lives open to them. …

Evaluating performance of local case-mix system by international comparison: a case study in Beijing, China

Case-mix is an important tool for health planning and management in many countries. As a major developing country, China is considering the introduction of the case-mix system in the health reform. Beijing, the capital of China, developed a local case-mix version whose performance needs to be evaluated before utilization. The objective of this study was to evaluate the performance of the case-mix system developed in Beijing by comparing it with those used in Australia and the U.S.A. A total of 1.3 million inpatient records from 154 hospitals in Beijing in 2008 were grouped respectively using three case-mix systems: (i) Beijing Diagnosis Related Groups (BJ-DRGs); (ii) US-based All Patient DRGs; and (iii) Australian Refined DRGs. Coefficient of variation (CV) and reduction in variance (RIV) were used to measure the performance of DRGs system. The BJ-DRGs produced the best CV and RIV results for expenditure. However, at the level of Major Diagnostic Category (MDC), three MDCs of BJ-DRGs gave the poorest RIVs for both expenditure and length of stay. Although the performance of BJ-DRGs was acceptable, further revision and improvement is needed. Comparisons with other mature DRGs versions can assist in identifying the improvement priorities of the local version.

Condition Number of Acoustic Infinite Element

Various shape function and weight function of infinite element are researched and summarized into eight methods, and then various infinite element methods can be summarized as general equation, the condition number of which can reflect merits of infinite method. Condition number of various methods versus frequency and the node number are calculated in this paper. Finally, most optimal infinite element method is summed up. The infinite element method [1-12] is among the most successful techniques used to solve boundary-value problems on unbounded domains and whose solutions satisfy some condition at infinity. Two ideas make the infinite element method attractive: the idea of partition and the idea of approximation. The partition idea covers unbounded domains by attaching infinite strips to finite element partitions of bounded domains. More mature versions of infinite element method involved the approximation idea. These ideas make it possible that the finite element/infinite element method yields significantly greater computational efficiency than other methods such as the boundary element method. There have been a large number of infinite element methods, in which some methods have obvious advantages and some methods have fewer advantages. However, there is less research literature about merits of various infinite element methods appear at home and abroad. Thus, condition number of matrix equation is applied to verify merits of various infinite methods in this paper.

Chlorophyllase is a rate-limiting enzyme in chlorophyll catabolism and is posttranslationally regulated.

Chlorophyll is a central player in harvesting light energy for photosynthesis, yet the rate-limiting steps of chlorophyll catabolism and the regulation of the catabolic enzymes remain unresolved. To study the role and regulation of chlorophyllase (Chlase), the first enzyme of the chlorophyll catabolic pathway, we expressed precursor and mature versions of citrus (Citrus sinensis) Chlase in two heterologous plant systems: (1) squash (Cucurbita pepo) plants using a viral vector expression system; and (2) transiently transformed tobacco (Nicotiana tabacum) protoplasts. Expression of full-length citrus Chlase resulted in limited chlorophyll breakdown in protoplasts and no visible leaf phenotype in whole plants, whereas expression of a Chlase version lacking the N-terminal 21 amino acids (ChlaseDeltaN), which corresponds to the mature protein, led to extensive chlorophyll breakdown in both tobacco protoplasts and squash leaves. ChlaseDeltaN-expressing squash leaves displayed a dramatic chlorotic phenotype in plants grown under low-intensity light, whereas under natural light a lesion-mimic phenotype occurred, which was demonstrated to follow the accumulation of chlorophyllide, a photodynamic chlorophyll breakdown product. Full-length and mature citrus Chlase versions were localized to the chloroplast membrane fraction in expressing tobacco protoplasts, where processing of the N-terminal 21 amino acids appears to occur. Results obtained in both plant systems suggest that Chlase functions as a rate-limiting enzyme in chlorophyll catabolism controlled via posttranslational regulation.

Fur seal mothers memorize subsequent versions of developing pups’ calls: adaptation to long-term recognition or evolutionary by-product?

In pinnipeds and especially in otariids, mothers and pups develop the capacity to recognize each other's voices. Pups become able to discriminate their mother's voice a few days after birth. For females, this discrimination seems to occur earlier, probably during the few hours after parturition. However, during lactation, mothers are confronted with a major problem: the change of the characteristics of their pup's calls. To investigate this problem, we first performed an acoustic analysis of pups’ calls from birth to weaning to identity the successive different versions of these calls. Secondly, we performed playback experiments just before weaning to test if females retain these different versions over a long time period. The acoustic analysis of pups’ calls reveals that several characteristics of their vocalizations change with age. Playback experiments demonstrate that females still recognize all the successive immature and mature versions of their pup's calls. In our opinion, this long-term memorization seems to be a by-product of the permanent pups’ voice learning from birth to weaning since no apparent adaptive benefit seems to arise from this capacity. © 2003 The Linnean Society of London, Biological Journal of the Linnean Society, 2003, 80, 305–312.

Post-translational Secretion of Fusion Proteins in the Halophilic Archaea Haloferax volcanii

Although protein secretion occurs post-translationally in bacteria and is mainly a cotranslational event in Eukarya, the relationship between the translation and translocation of secreted proteins in Archaea is not known. To address this question, the signal peptide-encoding region of the surface layer glycoprotein gene from the Haloarchaea Haloferax volcanii was fused either to the cellulose-binding domain of the Clostridium thermocellum cellulosome or to the cytoplasmic enzyme dihydrofolate reductase from H. volcanii. Signal peptide-cleaved mature versions of both the cellulose-binding domain and dihydrofolate reductase could be detected in the growth medium of transformed H. volcanii cells. Immunoblot analysis revealed, however, the presence of full-length signal peptide-bearing forms of both proteins inside the cytoplasm of the transformed cells. Proteinase accessibility assays confirmed that the presence of cell-associated signal peptide-bearing proteins was not due to medium contamination. Moreover, the pulse-radiolabeled signal peptide cellulose-binding domain chimera could be chased from the cytoplasm into the growth medium even following treatment with anisomycin, an antibiotic inhibitor of haloarchaeal protein translation. Thus, these results provide evidence that, in Archaea, at least some secreted proteins are first synthesized inside the cell and only then translocated across the plasma membrane into the medium.

DO BABYFACED ADULTS RECEIVE MORE HELP? THE (CROSS-CULTURAL) CASE OF THE LOST RESUME

The hypothesis that babyish-looking adult faces would elicit help was tested in a field experiment using the “lost letter” technique. Digitized images of African-American and European-American adult male and female faces were made to look babyish (neotenous) by substituting enlarged eyes and lips for normal ones. Eyes and lips were reduced in size to make faces look mature. As expected, neotenous features made adults appear submissive, weak, naive, feminine, compassionate, and honest, but not more or less attractive, relative to mature features. Neotenous or mature faces were printed on (fictional) resumes, attached to stamped, addressed envelopes, and “lost” in the US (n = 408) and Kenya (n = 176). “Helping” was indexed by whether resumes were posted (returned) or not. Most results supported predictions; across nations, resumes depicting neotenous, white and black female faces and neotenous, white male faces were returned more often than were resumes displaying the mature versions of these faces. Returns for neotenous and mature black male faces, however, were not significantly different. Overall, support was found for the hypothesis that neotenous, submissive-looking facial characteristics cue social approach and elicit help while mature, dominant-looking facial traits cue avoidance.