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The conceptual development of natural number in preschoolers is well-researched. However, less is known about the conceptual development of zero. Recent studies suggest that children develop an understanding of zero after learning to count. It remains unclear, when a conceptual understanding of "zero" as number word for an empty set emerges. This paper integrates numerical and language theories about how, where and when the concept of zero is formed and is integrated into the class of natural numbers. The counting skills of 107 preschoolers were assessed for the number range between zero and eight as well as for their ordinal understanding of zero. The results show that compared to the natural numbers, zero was substantially more difficult. Children are able to list zero in a number word sequence (0, 1, 2, 3 .... or 3, 2, 1, 0), but were unable to describe a set as having zero numbers. This latter conception contradicts findings regarding natural numbers, in that an empty set is counter intuitive. Zero could be correctly placed when consecutive order was required, but addition and subtraction by counting was more difficult. The results suggest that the conceptual development of zero differs qualitatively from the natural numbers. Based on the results, the ordinal understanding of zero as a predecessor to one, together with its matching linguistic concepts is proposed to be the key to the conceptual development of zero.

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Silyl ethers fulfil a fundamental role in synthetic organic chemistry as protecting groups and their selective cleavage is an important factor in their application. We present here for the first time two enzymes, SilE−R and SilE−S, which are able to hydrolyse silyl ethers. They belong to the stress‐response dimeric A/B barrel domain (DABB) family and are able to cleave the Si−O bond with opposite enantiopreference. Silyl ethers containing aromatic, cyclic or aliphatic alcohols and, depending on the alcohol moiety, silyl functions as large as TBDMS are accepted. The X‐ray crystal structure of SilE−R, determined to a resolution of 1.98 Å, in combination with mutational studies, revealed an active site featuring two histidine residues, H8 and H79, which likely act synergistically as nucleophile and Brønsted base in the hydrolytic mechanism, which has not previously been described for enzymes. Although the natural function of SilE−R and SilE−S is unknown, we propose that these 'silyl etherases' may have significant potential for synthetic applications. [ABSTRACT FROM AUTHOR]

Background and Objectives German legislation establishes advance directives (ADs) as legally binding instruments that all involved parties need to adhere to. This applies also to family members who have been authorized as official surrogates of the AD's author. As surrogates, they are expected to make sure that the AD is being implemented. Our study aims at uncovering how family members experience their legally assigned role as an advocate of an AD. Research Design and Methods We conducted 25 episodic interviews with family surrogates of persons living with dementia and used thematic analysis to make sense of our interview data. Results Family surrogates expressed scepticism toward ADs as instruments for planning end-of-life care. They did not necessarily follow the decisions expressed in the AD. We found cases in which family surrogates intentionally refrained from bringing the ADs to the attention of health care providers as well as cases in which the ADs conflicted with self-related interests of family surrogates. Discussion and Implications Our findings lead us to critique the legal construction of family surrogates as advocates of the AD. Family members are directly and enduringly affected by the end-of-life care decisions that the AD sets out and are thus no neutral agents who have no stake in the matter. Expecting them to simply transmit decisions formulated in the AD means expecting them to render their own interests irrelevant—which, arguably, might be too much to ask. [ABSTRACT FROM AUTHOR]

Background: Cutaneous B‐cell lymphoma (CBCL) is part of dermatopathological routine diagnostics. However, in contrast to cutaneous T‐cell lymphomas, there are only a few studies on the prevalence and possible clinical impact of lymphatic vessel involvement. Therefore, this pilot study aimed to quantify the prevalence of lymphovascular involvement in CBCL and to assess the association between lymphovascular involvement and recurrence. Methods: Thirty‐nine patients from two tertiary care hospitals diagnosed with CBCL were retrospectively identified and their biopsies were histopathologically examined for the presence of lymphatic vessel involvement using H&E stain, and CD20 and D2‐40 immunohistochemistry. Clinical data were retrieved from our digital documentation files. Results: Thirty patients were included in the evaluation (nPCFCL = 15, nPCMZL = 10, and nPCLBCL = 5). Lymphovascular involvement occurred in all three types of lymphoma and was present in 14/30 specimens. The presence of lymphatic involvement did not show a significant impact on recurrence rate (p = 0.150). Conclusions: This immunohistochemical pilot study shows that lymphovascular involvement is a relatively frequent finding in primary CBCL. Although no definitive conclusion can be drawn from our findings because of the small sample size, there were no strong signs of tendencies for recurrence in either group. Future studies with larger sample size are warranted to assess the possible clinical implications. [ABSTRACT FROM AUTHOR]

Background: Lately scientific and societal concern has emerged about persistent (P), mobile (M) and toxic (T) chemicals. Such chemicals, like some polyfluoroalkyl acids (PFAAs), are of concern due to their high mobility and persistence in aquatic compartments which relates to long-term biotic exposure and difficult removal from drinking water. In this study, a screening approach for identification of PMT chemicals was developed and applied to 6158 diverse chemicals. Results: Chemicals are given a continuous score for P, M and T potential based on the modelled indicators (low to moderate potential is a score of 0–0.33, high potential is a score of 0.33–0.5 and very high potential a score of 0.5–1). The P score was based on the estimated aquatic environmental half life and the M score on the chemical's organic carbon/water partition coefficient (Koc) using respectively the BIOWIN3 and KocWIN QSAR models of EPISuite™. The T score was based on the indicators for five human health endpoints: carcinogenicity (c), mutaganicity (m), reprotoxicity (r), endocrine disruption (ED) and general repeated dose systemic toxicity. Structural alerts for these endpoints taken from the OECD QSAR Toolbox™ and Toxtree™ were used as indicators of potential (human) toxicity. Chemical similarity values to Substances of Very High Concern (SVHC) with c, m and/or r properties were also included. Value functions were developed to translate the presence of alerts and similarity to the existing SVHCs to values between 0 and 1. Subsequently, all values were also aggregated to an overall PMT score, again ranging from 0 to 1. Applying the approach to chemicals from the Inventory of Existing Commercial chemical Substances, which are also REACH registered, resulted in 15% of the chemicals receiving high scores (≥ 0.33) for all three (P-, M- and T-) indicators and 4% getting very high scores (≥ 0.5) for both the P- and M-indicators. Conclusions: The approach confirmed the properties of chemicals classified as SVHC due to PMT properties (e.g. 1,4-dioxane), illustrating the ability of the approach to identify PMT chemicals of concern. Water regulators, drinking water suppliers and others can use this approach to identify potential PMT/vPvM chemicals that need further investigation. [ABSTRACT FROM AUTHOR]

The currently accepted methods for neurotoxicity (NT) testing rely on animal studies. However, high costs and low testing throughput hinder their application for large numbers of chemicals. To overcome these limitations, in vitro methods are currently being developed based on human-induced pluripotent stem cells (hiPSC) that allow higher testing throughput at lower costs. We applied six different protocols to generate 3D BrainSphere models for acute NT evaluation. These include three different media for 2D neural induction and two media for subsequent 3D differentiation resulting in self-organized, organotypic neuron/astrocyte microtissues. All induction protocols yielded nearly 100% NESTIN-positive hiPSC-derived neural progenitor cells (hiNPCs), though with different gene expression profiles concerning regional patterning. Moreover, gene expression and immunocytochemistry analyses revealed that the choice of media determines neural differentiation patterns. On the functional level, BrainSpheres exhibited different levels of electrical activity on microelectrode arrays (MEA). Spike sorting allowed BrainSphere functional characterization with the mixed cultures consisting of GABAergic, glutamatergic, dopaminergic, serotonergic, and cholinergic neurons. A test method for acute NT testing, the human multi-neurotransmitter receptor (hMNR) assay, was proposed to apply such MEA-based spike sorting. These models are promising tools not only in toxicology but also for drug development and disease modeling. [ABSTRACT FROM AUTHOR]

For 3D neural cultures durable hydrogels are required, which persist over a long differentiation period and thus enable the maturation of neuronal networks (NN). Here, 3D models based on human induced pluripotent stem cell‐derived neural progenitor cells that are embedded in hydrogels of either pure alginate or alginate functionalized with the extracellular matrix protein laminin 111 (L111) are established. This study analyzes material characteristics such as porosity, L111 distribution and shear viscosity, cell compatibility of hydrogels by measuring viability and cytotoxicity, and neural function by monitoring cell migration, differentiation as well as NN formation and activity on multielectrode arrays. The addition of L111 increases neural migration and enhances differentiation into neurons and astrocytes as well as synaptogenesis in alginate hydrogels. NN formed in hydrogels are electrically active for up to 206 d and L111‐supplementation further increases electrical activity, network maturation, and synchronicity compared to 2D controls and NN grown in pure alginate hydrogels. L111 addition to alginate gels further accelerates recovery of electrical activity after blockage of sodium channels with tetrodotoxin. In conclusion, NN grown in alginate‐L111 hydrogel blends are promising models for future long‐term applications in disease modeling, drug or chemical evaluation. [ABSTRACT FROM AUTHOR]

Consumers tend to hold a focal firm responsible for its suppliers' unsustainable practices (chain liability), suggesting that firms need effective responses that can mitigate negative consumer reactions. In applying psychological contract theory to investigate recovery efforts related to such chain liability, the current study addresses three broad focal firm responses: Do nothing, choose a nonsubstantive response that verbally clarifies its own and the supplier's roles in the incident, or substantively rectify the supplier's wrongdoing with sustainability‐focused responses, such as termination, monitoring or development. With a vignette‐based experiment, we examine consumer perceptions and behaviors in three stages: before the unsustainable supplier incident (pre‐incident), after the incident (post‐incident) and after the focal firm has responded (post‐response). A nonsubstantive, clarification response decreases consumers' purchase intentions; substantive focal firm activities increase purchase intentions, though not fully back to pre‐incident levels. For consumers, termination, monitoring and development seem like equally adequate responses. Although combining several substantive responses offers even greater effectiveness for recovering purchase intentions, it still falls short of reaching pre‐incident levels. Thus, our findings demonstrate the focal firm's capacity to address suppliers' unsustainable practices substantively and recover, at least partially, its damaged relationship with consumers. [ABSTRACT FROM AUTHOR]

Background: Conventional photodynamic therapy (c‐PDT) is a highly effective treatment for actinic keratoses. Besides pain as the main side effect, blood pressure (BP) increases and hypertensive crises may occur during treatment. Reducing the irradiation intensity while keeping the total dose constant (low‐irradiance PDT) can achieve a clinically relevant reduction in pain. This study aimed to evaluate the influence of li‐PDT on the BP and pulse (PR) during therapy and the incidence of post‐interventional hypertension compared with c‐PDT. Methods: We retrospectively analyzed the treatment data of 79 patients (39 c‐PDT and 40 li‐PDT). BP and PR measurements were performed in all patients before PDT, at mid‐exposure, and immediately after PDT. In addition, the pain was assessed by using the visual analog scale. Results: Patients treated with li‐PDT reported significantly lower pain than those receiving c‐PDT (p <.0005). Additionally, they showed less systolic (SBP) and diastolic (DBP) BP increase (∆SBP: p <.0005, ∆DBP: p =.015) and overall lower absolute BP values (SBP: p <.0005, DBP: p =.008) compared with c‐PDT. They were also significantly less likely to develop post‐interventional hypertension (p =.037) or higher stages of arterial hypertension. Regarding PR, there was no difference in absolute values between both groups, but the increase from onset to half irradiation duration was significantly higher in c‐PDT (p =.013). Conclusions: Li‐PDT is an excellent option to reduce the elevation of arterial BP and decrease the incidence of post‐interventional hypertension and hypertensive crisis. This finding has considerable relevance, especially with the risk profile of many PDT patients in mind (advanced age and cardiovascular history). [ABSTRACT FROM AUTHOR]

The goal of this study was to tackle two questions related to the systematics of small-flowering Euphrasia species from the Eastern Alps. Our first aim was to test the hypothesis of a wider distribution of diploid E. inopinata, considered endemic to the uppermost Ötztal valley in Austria based on ploidy screening of ca. 70 populations along a latitudinal transect. We failed to find new populations of E. inopinata but during the sampling campaign, a diploid population was detected in the eastern Ortler/Ortles mountain range (Italy), which could neither be assigned to E. inopinata nor to E. minima. Thus, our second aim was to clarify, based on a comprehensive sampling of individuals and the use of Amplified Fragment Length Polymorphisms (AFLPs) and/or morphometric data, if this diploid population is morphologically and genetically consistently divergent from both, tetraploid widespread E. minima and E. inopinata. As this was confirmed, we established the relationships of the new entity based on Internal Transcribed Spacer sequences, which uncovered a close relationship with E. minima and describe it here as a new diploid species, E. ultima, which, based on current knowledge, is locally endemic even if a bigger distribution area appears likely. [ABSTRACT FROM AUTHOR]