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This article advocates for an interpretation of biblical stories that takes into account their nature and the way in which they are told. The argument begins with observing the predicament of the biblical interpreter in using contemporary historical and/or literary methods to interpret an ancient text expected to convey a theological message. It then offers a close reading of the Ark Narrative (1 Sam 4:1b–7:1) which exemplifies how theological conclusions can be drawn on the basis of the story alone once its literary structure and dramatic development are identified.

Avian influenza A of the subtype H7N9 has been responsible for almost 1,600 confirmed human infections and more than 600 deaths since its first outbreak in 2013. Although sustained human-to-human transmission has not been reported yet, further adaptations to humans in the viral genome could potentially lead to an influenza pandemic, which may have severe consequences due to the absence of pre-existent immunity to this strain at population level. Currently there is no influenza A (H7N9) vaccine available. Therefore, in case of a pandemic outbreak, alternative preventive approaches are needed, ideally even independent of the type of influenza virus outbreak. Bacillus Calmette–Guérin (BCG) is known to induce strong heterologous immunological effects, and it has been shown that BCG protects against non-related infection challenges in several mouse models. BCG immunization of mice as well as human induces trained innate immune responses, resulting in increased cytokine responses upon subsequent ex vivo peripheral blood mononuclear cell restimulation. We investigated whether BCG (Statens Serum Institut-Denmark)-induced trained immunity may protect against a lethal avian influenza A/Anhui/1/2013 (H7N9) challenge. Here, we show that isolated splenocytes as well as peritoneal macrophages of BCG-immunized BALB/c mice displayed a trained immunity phenotype resulting in increased innate cytokine responses upon ex vivo restimulation. However, after H7N9 infection, no significant differences were found between the BCG immunized and the vehicle control group at the level of survival, weight loss, pulmonary influenza A nucleoprotein staining, or histopathology. In conclusion, BCG-induced trained immunity did not result in protection in an oseltamivir-sensitive influenza A/Anhui/1/2013 (H7N9) challenge mouse model.

Despite the consensus about the importance of self-regulated learning for academic as well as for lifelong learning, it is still poorly understood as to how teachers can most effectively support their students in enacting self-regulated learning. This article provides a framework about how self-regulated learning can be activated directly through strategy instruction and indirectly by creating a learning environment that allows students to regulate their learning. In examining teachers' instructional attempts for SRL, we systematically review the literature on classroom observation studies that have assessed how teachers support their students' SRL. The results of the 17 retrieved studies show that in most classrooms, only little direct strategy instruction took place. Nevertheless, some teachers provided their students with learning environments that require and thus foster self-regulated learning indirectly. Based on a review of classroom observation studies, this article stresses the significance of: (1) instructing SRL strategies explicitly so that students develop metacognitive knowledge and skills to integrate the application of these strategies successfully into their learning process; and (2) the necessity of complementing classroom observation research with data gathered from student and teacher self-report in order to obtain a comprehensive view of the effectiveness of teacher approaches to support SRL. Finally, we discuss ten cornerstones for future directions for research about supporting SRL.

Retinal degenerations, including age-related macular degeneration and the retinitis pigmentosa family of diseases, are among the leading causes of legal blindness in the United States. We previously found that Stanniocalcin-1 (STC-1) reduced photoreceptor loss in the S334ter-3 and Royal College of Surgeons rat models of retinal degeneration. The results were attributed in part to a reduction in oxidative stress. Herein, we tested the hypothesis that long-term delivery of STC-1 would provide therapeutic rescue in more chronic models of retinal degeneration. To achieve sustained delivery, we produced an adeno-associated virus (AAV) construct to express STC-1 (AAV-STC-1) under the control of a retinal ganglion cell targeting promoter human synapsin 1 (hSYN1). AAV-STC-1 was injected intravitreally into the P23H-1 and S334ter-4 rhodopsin transgenic rats at postnatal day 10. Tissues were collected at postnatal day 120 for confirmation of STC-1 overexpression and histologic and molecular analysis. Electroretinography (ERG) was performed in a cohort of animals at that time. Overexpression of STC-1 resulted in a significant preservation of photoreceptors as assessed by outer nuclear thickness in the P23H-1 (P

Heterozygous mutations in the GRN gene lead to progranulin (PGRN) haploinsufficiency and cause frontotemporal dementia (FTD), a neurodegenerative syndrome of older adults. Homozygous GRN mutations, on the other hand, lead to complete PGRN loss and cause neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease usually seen in children. Given that the predominant clinical and pathological features of FTD and NCL are distinct, it is controversial whether the disease mechanisms associated with complete and partial PGRN loss are similar or distinct. We show that PGRN haploinsufficiency leads to NCL-like features in humans, some occurring before dementia onset. Noninvasive retinal imaging revealed preclinical retinal lipofuscinosis in heterozygous GRN mutation carriers. Increased lipofuscinosis and intracellular NCL-like storage material also occurred in postmortem cortex of heterozygous GRN mutation carriers. Lymphoblasts from heterozygous GRN mutation carriers accumulated prominent NCL-like storage material, which could be rescued by normalizing PGRN expression. Fibroblasts from heterozygous GRN mutation carriers showed impaired lysosomal protease activity. Our findings indicate that progranulin haploinsufficiency caused accumulation of NCL-like storage material and early retinal abnormalities in humans and implicate lysosomal dysfunction as a central disease process in GRN-associated FTD and GRN-associated NCL.

Various instruments for assessing metacognitive skills and strategy use exist. Off-line self-reports are questionnaires and interviews administered either before or after task performance, while on-line measures are gathered during task performance through thinking aloud or observation. Multi-method studies in reading have shown that off-line methods suffer from serious validity problems, whereas the validity of on-line methods is adequate. Little is known, however, about the validity of methods for assessing metacognition in mathematics. Five instruments were administered to 30 secondary-school students: two prospective questionnaires (MSLQ and ILS) before a mathematics task, two on-line methods (observation and thinking aloud) concurrent to the mathematics task, and a task-specific retrospective questionnaire after the mathematics task. Mathematics performance was assessed by a posttest and GPA. Results confirm that prospective questionnaires have poor convergent and predictive validity in mathematics. Although the retrospective questionnaire does slightly better than prospective questionnaires, the validity of both on-line methods stands out. It is concluded that on-line instruments should be preferred over off-line instruments for the assessment of metacognitive skillfulness in mathematics.

Mutations in collagen, type IV, alpha 1 (COL4A1), a major component of basement membranes, cause multisystem disorders in humans and mice. In the eye, these include anterior segment dysgenesis, optic nerve hypoplasia and retinal vascular tortuosity. Here we investigate the retinal pathology in mice carrying dominant-negative Col4a1 mutations. To this end, we examined retinas longitudinally in vivo using fluorescein angiography, funduscopy and optical coherence tomography. We assessed retinal function by electroretinography and studied the retinal ultrastructural pathology. Retinal examinations revealed serous chorioretinopathy, retinal hemorrhages, fibrosis or signs of pathogenic angiogenesis with chorioretinal anastomosis in up to approximately 90% of Col4a1 mutant eyes depending on age and the specific mutation. To identify the cell-type responsible for pathogenesis we generated a conditional Col4a1 mutation and determined that primary vascular defects underlie Col4a1-associated retinopathy. We also found focal activation of Müller cells and increased expression of pro-angiogenic factors in retinas from Col4a1(+/Δex41)mice. Together, our findings suggest that patients with COL4A1 and COL4A2 mutations may be at elevated risk of retinal hemorrhages and that retinal examinations may be useful for identifying patients with COL4A1 and COL4A2 mutations who are also at elevated risk of hemorrhagic strokes.

PurposeEndoplasmic reticulum (ER) stress activates inositol requiring enzyme 1 (IRE1), a key regulator of the unfolded protein response. The ER stress activated indicator (ERAI) transgenic mouse expresses a yellow fluorescent GFP variant (Venus) when IRE1 is activated by ER stress. We tested whether ERAI mice would allow for real-time longitudinal studies of ER stress in living mouse eyes.MethodsWe chemically and genetically induced ER stress, and qualitatively and quantitatively studied the Venus signal by fluorescence ophthalmoscopy. We determined retinal cell types that contribute to the signal by immunohistology, and we performed molecular and biochemical assays using whole retinal lysates to assess activity of the IRE1 pathway.ResultsWe found qualitative increase in vivo in fluorescence signal at sites of intravitreal tunicamycin injection in ERAI eyes, and quantitative increase in ERAI mice mated to RhoP23H mice expressing ER stress-inducing misfolded rhodopsin protein. As expected, we found that increased Venus signal arose primarily from photoreceptors in RhoP23H/+;ERAI mice. We found increased Xbp1S and XBP1s transcriptional target mRNA levels in RhoP23H/+;ERAI retinas compared to Rho+/+;ERAI retinas, and that Venus signal increased in ERAI retinas as a function of age.ConclusionsFluorescence ophthalmoscopy of ERAI mice enables in vivo visualization of retinas undergoing ER stress. ER stress activated indicator mice enable identification of individual retinal cells undergoing ER stress by immunohistochemistry. ER stress activated indicator mice show higher Venus signal at older ages, likely arising from amplification of basal retinal ER stress levels by GFP's inherent stability.

PurposeMutations in the gene encoding collagen type IV alpha 1 (COL4A1) cause multisystem disorders including anterior segment dysgenesis (ASD) and optic nerve hypoplasia. The penetrance and severity of individual phenotypes depends on genetic context. Here, we tested the effects of a Col4a1 mutation in two different genetic backgrounds to compare how genetic context influences ocular dysgenesis, IOP, and progression to glaucoma.MethodsCol4a1 mutant mice maintained on a C57BL/6J background were crossed to either 129S6/SvEvTac or CAST/EiJ and the F1 progeny were analyzed by slit-lamp biomicroscopy and optical coherence tomography. We also measured IOPs and compared tissue sections of eyes and optic nerves.ResultsWe found that the CAST/EiJ inbred strain has a relatively uniform and profound suppression on the effects of Col4a1 mutation and that mutant CASTB6F1 mice were generally only very mildly affected. In contrast, mutant 129B6F1 mice had more variable and severe ASD and IOP dysregulation that were associated with glaucomatous signs including lost or damaged retinal ganglion cell axons and excavation of the optic nerve head.ConclusionsOcular defects in Col4a1 mutant mice model ASD and glaucoma that are observed in a subset of patients with COL4A1 mutations. We demonstrate that different inbred strains of mice give graded severities of ASD and we detected elevated IOP and glaucomatous damage in 129B6F1, but not CASTB6F1 mice that carried a Col4a1 mutation. These data demonstrate that genetic context differences are one factor that may contribute to the variable penetrance and severity of ASD and glaucoma in patients with COL4A1 mutations.

Depending on endoplasmic reticulum (ER) stress levels, the ER transmembrane multidomain protein IRE1α promotes either adaptation or apoptosis. Unfolded ER proteins cause IRE1α lumenal domain homo-oligomerization, inducing trans autophosphorylation that further drives homo-oligomerization of its cytosolic kinase/endoribonuclease (RNase) domains to activate mRNA splicing of adaptive XBP1 transcription factor. However, under high/chronic ER stress, IRE1α surpasses an oligomerization threshold that expands RNase substrate repertoire to many ER-localized mRNAs, leading to apoptosis. To modulate these effects, we developed ATP-competitive IRE1α Kinase-Inhibiting RNase Attenuators-KIRAs-that allosterically inhibit IRE1α's RNase by breaking oligomers. One optimized KIRA, KIRA6, inhibits IRE1α in vivo and promotes cell survival under ER stress. Intravitreally, KIRA6 preserves photoreceptor functional viability in rat models of ER stress-induced retinal degeneration. Systemically, KIRA6 preserves pancreatic β cells, increases insulin, and reduces hyperglycemia in Akita diabetic mice. Thus, IRE1α powerfully controls cell fate but can itself be controlled with small molecules to reduce cell degeneration.

Abstract Mitochondrial quality control is fundamental to all neurodegenerative diseases, including the most prominent ones, Alzheimer’s Disease and Parkinsonism. It is accomplished by mitochondrial network dynamics – continuous fission and fusion of mitochondria. Mitochondrial fission is facilitated by DRP1, while MFN1 and MFN2 on the mitochondrial outer membrane and OPA1 on the mitochondrial inner membrane are essential for mitochondrial fusion. Mitochondrial network dynamics are regulated in highly sophisticated ways by various different posttranslational modifications, such as phosphorylation, ubiquitination, and proteolytic processing of their key-proteins. By this, mitochondria process a wide range of different intracellular and extracellular parameters in order to adapt mitochondrial function to actual energetic and metabolic demands of the host cell, attenuate mitochondrial damage, recycle dysfunctional mitochondria via the mitochondrial autophagy pathway, or arrange for the recycling of the complete host cell by apoptosis. Most of the genes coding for proteins involved in this process have been associated with neurodegenerative diseases. Mutations in one of these genes are associated with a neurodegenerative disease that originally was described to affect retinal ganglion cells only. Since more and more evidence shows that other cell types are affected as well, we would like to discuss the pathology of dominant optic atrophy, which is caused by heterozygous sequence variants in OPA1, in the light of the current view on OPA1 protein function in mitochondrial quality control, in particular on its function in mitochondrial fusion and cytochrome C release. We think OPA1 is a good example to understand the molecular basis for mitochondrial network dynamics.

Snakebite envenoming can cause morbidity, permanent disability or death but treatment and prevention thereof remains highly inadequate in Africa. Overcoming structural and financial barriers that impede existing initiatives to improve medical management and mitigate human-snake conflict is urgently needed.

Abstract Foodborne disease resulting from food sold at urban informal markets is a major public health challenge in Sub-Saharan Africa. This study assessed the impact of an innovative nine-months multi-media campaign engaging a key influencer, aimed at empowering consumers to choose safer ready-to-eat chicken meat at informal street restaurants in Ouagadougou, Burkina Faso. A two-wave panel study assessed associations between recall of TV, radio, billboard, and social media advertisements, and self-reported behavior regarding purchasing and consumption of ready-to-eat chicken at outlets, consumer intentions, knowledge, attitudes, norms, and agency. A panel of randomly selected adult consumers (n = 852) were interviewed pre- and post-campaign, 12 months apart. 60% recalled at least one of the campaign channels when prompted. Mixed-effects models showed associations between prompted recall and feeling better informed about food safety (aOR 1.449) and increased knowledge (0.132 unit increase on total score). Social media recall was associated with higher perceived access to information (aOR 1.449) and knowledge. Billboard recall increased odds of higher perceived health benefits of paying attention to food safety behaviors when purchasing chicken (aOR 2.046). TV ad recall was associated with a 0.159 unit decrease in the gap between consumers’ intentions and behavior. An engaging consumer food safety multimedia campaign that engages key influencers improved food safety awareness and knowledge, ultimately supporting consumers to choose safer chicken at markets.

In the last decades, students increasingly have been placed in the role of active learners with responsibilities for their own learning. Students have to be able to plan their learning activities and execute them in a systematic and orderly way and to monitor and to evaluate their learning and to reflect on it. All aforementioned skills are components of metacognitive skillfulness. The first objective was to gain insight in the development of both quantity and quality of metacognitive skills in young adolescents (aged 12-15 years). The second objective was to establish whether development of metacognitive skills is intelligence related or relatively intelligence independent. Finally, the generality vs. domain specificity of developing metacognitive skills was investigated. In a 3-year longitudinal study, participants performed two different tasks (text studying and problem solving) in two different domains (history and math), while thinking aloud. Results show that between the age of 12 and 15 years, metacognitive skills do not develop linearly or at the same pace. Furthermore, metacognitive skills contribute to learning performance, partly independent of intellectual ability. Finally, the results show that metacognitive skills appear to be predominantly general by nature over the years. Although a smaller domain-specific component was found as well in the first 2 years, this component disintegrated in the third year. The age around 15 years appears to be a relevant point in time during the developmental trajectory of metacognitive skills: Growth is (temporarily) put on hold, while the nature of these skills becomes fully general.

Teaching and assessing metacognitive activities are important educational objectives, and teachers are calling for efficient instruments. The advantages of questionnaires in measuring metacognitive activities are obvious, but serious validity issues appear. For example, correlations of questionnaire data with think-aloud measures are generally moderate to low. An explanation may be that these questionnaires are not constructed in line with the metacognitive activities measured by the think-aloud method. In the present study, a questionnaire is constructed based directly on a taxonomy for coding think-aloud protocols. Twenty ninth-graders studied a text while thinking aloud, after which they immediately received the questionnaire. The overall correlation between the questionnaire and the think-aloud protocols (r?=?0.63) was promising. However, scale and item analyses clearly demonstrate some new validity issues. Comparing the questionnaire and the think-aloud results, the students seem to report overt metacognitive activities corresponding more with their behavior reported in the protocols than covert ones. In-depth explorations are presented.

Studies about metacognition, intelligence and learning have rendered equivocal results. The mixed model assumes joint as well as independent influences of intelligence and metacognition on learning results. In this study, intelligence was measured by standard tests for reasoning, spatial ability and memory. Participants were 13-year-old school students. Measures of metacognitive activity were gathered by analyses of thinking-aloud protocols within two task domains, i.e., history and physics. Prior knowledge and learning results were measured by tests constructed by the researchers. The results showed that metacognitive activity did not relate to learning results in either task domain. For history, the learning result was only determined by prior knowledge. For physics, intelligence influenced the learning result via prior knowledge, but the effect of execution activity, i.e., exercise, appeared more important. It is possible that "learning by doing", i.e., exercise, is a powerful mean for promoting the application of knowledge in physics. (Contains 5 tables and 4 figures.)

This study shows the results of a two-year longitudinal study where the same participants were followed for two consecutive years as they enter secondary school (aged 12-14 years). The main issue was to investigate the development of both the quantity and the quality of metacognitive skills. Another issue was to establish whether the development of metacognitive skillfulness is intelligence-related or relatively intelligence-independent. Finally, the generality vs. domain-specificity of developing metacognitive skillfulness was investigated. Thirty-two secondary school students participated in this study. While thinking aloud they performed two different tasks representing two different domains: A text-studying task for history and a problem-solving task for math. Participants' intellectual ability, metacognitive skillfulness and learning performance were assessed. Results show a quantitative as well as a qualitative growth in metacognitive skillfulness. Furthermore, results of both years show that metacognitive skillfulness contributed to learning performance (partly) independent of intellectual ability. A parallel development of metacognitive and intellectual ability was found. Finally, metacognitive skills predominantly appear to be general. Domain-specific metacognitive skills, however, played a substantial, but minor role as well in both years. Instructional implications are being discussed. (Contains 5 tables.)

This study uses logistic and Poisson regression models to examine the factors influencing the adoption of sustainable land management (SLM) practices in Mali using two rounds of the nationally representative survey Enquête Agricole de Conjoncture Intégrée aux Conditions de Vie des Ménages. The SLMs considered include the application of organic fertilizers, the application of inorganic fertilizers, the use of improved seeds, and the practice of intercropping. On average the application of organic fertilizers (39.2%), and inorganic fertilizers (28.7%) are the most frequent SLM practices among Malian farmers, and between 2014 and 2017, we observe a decline in the practice of intercropping. The regression results show that farmers’ adoption of different SLMs is significantly associated with biophysical factors (average temperature, climate type, plot size, plot shape, and location), demographic factors (age, gender, education, household size), and socioeconomic factors (number of cultivated plots, livelihood diversification, type of crop grown, market access, credit access, economic shocks, and social capital). Our findings suggest that policymakers and agricultural development agencies in Mali need to adopt a multidimensional policy framework to unlock the untapped potential of SLM practices in promoting sustainable agriculture and food security.

Virtual experiments (VEs) and digital twins (DTs), pivotal for realizing European strategic policies on sustainability and digitalization within Industry 4.0 and the European Green Deal, simulate physical systems and characteristics in a virtual environment, with DTs incorporating dynamic inputs from and outputs to the real-world counterpart. To ensure confidence in their use and outcomes, traceability and methods to evaluate measurement uncertainty are needed, topics that are hardly covered by the literature so far. This paper provides a harmonized definition of VEs and DTs and introduces a framework for evaluating measurement uncertainty. Furthermore, it discusses how to propagate the uncertainty of the contributions coming from the different parts of the DT. For the core part of the DT, the framework derived for VEs can be used. For the physical-to-virtual (P2V) connection and the virtual-to-physical (V2P) connection, additional sources of uncertainty need to be considered. This paper provides a metrological framework for taking all these uncertainty contributions into account while describing a framework to establish traceability for DTs. Two case studies are presented to demonstrate the proposed methodology considering industrially relevant measuring instruments and devices, namely, a coordinate measuring machine (CMM) and a collaborative robot arm (cobot).

Abstract Background Although mitral valve repair is the preferred surgical strategy in children with mitral valve disease, there are cases of irreparable severe dysplastic valves that require mitral valve replacement. The aim of this study is to analyze long-term outcomes following mitral valve replacement in children in a tertiary referral center. Methods A total of 41 consecutive patients underwent mitral valve replacement between February 2001 and February 2021. The study data was prospectively collected and retrospectively analyzed. Primary outcomes were in-hospital mortality, long-term survival, and long-term freedom from reoperation. Results Median age at operation was 23 months (IQR 5–93), median weight was 11.3 kg (IQR 4.8–19.4 kg). One (2.4%) patient died within the first 30 postoperative days. In-hospital mortality was 4.9%. Four (9.8%) patients required re-exploration for bleeding, and 2 (4.9%) patients needed extracorporeal life support. Median follow-up was 11 years (IQR 11 months − 16 years). Long-term freedom from re-operation after 1, 5, 10 and 15 years was 97.1%, 93.7%, 61.8% and 42.5%, respectively. Long-term survival after 1, 5, 10 and 15 years was 89.9%, 87%, 87% and 80.8%, respectively. Conclusion If MV repair is not feasible, MV replacement offers a good surgical alternative for pediatric patients with MV disease. It provides good early- and long-term outcomes.

The first objective of this study was to establish the relation between intellectual ability and metacognitive skillfulness as predictors of learning performance in young students (aged 12 years). Furthermore, the generality vs. domain-specificity of metacognitive skillfulness was investigated. Thirty-two first-year secondary-school students participated in this study. While thinking aloud they performed two different tasks representing two different domains: A text-studying task for history and a problem-solving task for mathematics. Participants' intelligence, metacognitive skillfulness and learning performance were assessed. Results show that metacognitive skillfulness contributed to learning performance (partly) independent of intellectual ability. Results also show that metacognitive skills predominantly appear to be general. Domain-specific metacognitive skills, however, played a substantial, but minor role as well.

Three models representing different relations between intellectual ability, metacognitive skills, and learning were compared. The conditions under which each of these models holds were investigated, on the basis of the threshold of problematicity theory [Elshout, J. J. (1987). Problem solving and education. In E. De Corte, H. Lodewijks, R. Parmentier, & P. Span (Eds.), "Learning and instruction" (pp. 259-273). Oxford/Leuven: Pergamon Books/University Press]. Novice and advanced learners (N = 44) passed through a computer-simulated inductive-learning environment of different complexity levels. Results show that correlational patterns between intellectual ability, metacognitive skilfulness, and learning outcomes of novice learners at the easy level were similar to the patterns of advanced learners at the intermediate level. Metacognitive skilfulness rather than intellectual ability appears essential for learning when learners operate at the boundary of their knowledge.