"Now I Get It!": Eureka Experiences During the Acquisition of Mathematical Concepts.

Many famous scientists have reported anecdotes where a new understanding occurred to them suddenly, in an unexpected flash. Do people generally experience such "Eureka" moments when learning science concepts? And if so, do these episodes truly vehicle sudden insights, or is this impression illusory? To address these questions, we developed a paradigm where participants were taught the mathematical concept of geodesic, which generalizes the common notion of straight line to straight trajectories drawn on curved surfaces. After studying lessons introducing this concept on the sphere, participants (N = 56) were tested on their understanding of geodesics on the sphere and on other surfaces. Our findings indicate that Eureka experiences are common when learning mathematics, with reports by 34 (61%) participants. Moreover, Eureka experiences proved an accurate description of participants' learning, in two respects. First, Eureka experiences were associated with learning and generalization: the participants who reported experiencing Eurekas performed better at identifying counterintuitive geodesics on new surfaces. Second, and in line with the firstperson experience of a sudden insight, our findings suggest that the learning mechanisms responsible for Eureka experiences are inaccessible to reflective introspection. Specifically, reports of Eureka experiences and of participants' confidence in their own understanding were associated with different profiles of performance, indicating that the mechanisms bringing about Eureka experiences and those informing reflective confidence were at least partially dissociated. Learning mathematical concepts thus appears to involve mechanisms that operate unconsciously, except when a key computational step is reached and a sudden insight breaks into consciousness.

Abstract representations of small sets in newborns.

From the very first days of life, newborns are not tied to represent narrow, modality- and object-specific aspects of their environment. Rather, they sometimes react to abstract properties shared by stimuli of very different nature, such as approximate numerosity or magnitude. As of now, however, there is no evidence that newborns possess abstract representations that apply to small sets: in particular, while newborns can match large approximate numerosities across senses, this ability does not extend to small numerosities. In two experiments, we presented newborn infants (N = 64, age 17 to 98 h) with patterned sets AB or ABB simultaneously in the auditory and visual modalities. Auditory patterns were presented as periodic sequences of sounds (AB: triangle-drum-triangle-drum-triangle-drum …; ABB: triangle-drum-drum-triangle-drum-drum-triangle-drum-drum …), and visual patterns as arrays of 2 or 3 shapes (AB: circle-diamond; ABB: circle-diamond-diamond). In both experiments, we found that participants reacted and looked longer when the patterns matched across the auditory and visual modalities - provided that the first stimulus they received was congruent. These findings uncover the existence of yet another type of abstract representations at birth, applying to small sets. As such, they bolster the hypothesis that newborns are endowed with the capacity to represent their environment in broad strokes, in terms of its most abstract properties. This capacity for abstraction could later serve as a scaffold for infants to learn about the particular entities surrounding them.

Talkin' About a Revolution. Changes and Continuities in Fruit Use in Southern France From Neolithic to Roman Times Using Archaeobotanical Data (ca. 5,800 BCE - 500 CE).

The use and socio-environmental importance of fruits dramatically changed after the emergence of arboriculture and fruit domestication in the eastern Mediterranean, between the 5th and the 3rd millennia BCE. Domesticated fruits together with cultivation techniques apparently reached the western Mediterranean via colonial activities during the 1st millennium BCE - early 1st millennium CE. However, the pace and chronology of this diffusion as well as the recompositions in diversity, to adapt to new socio-environmental conditions, remain poorly known. In this study we investigate archaeobotanical records in Southern France from the Neolithic to the end of the Roman empire (ca. 5,800 BCE - 500 CE) to assess changes in fruit use as well as the emergence, spread and evolution of fruit cultivation. We explore changes in native traditions faced with innovations brought by Mediterranean colonization and how domesticated fruit cultivation spread from the Mediterranean to more temperate areas. Archaeobotanical data from 577 assemblages were systematically analyzed distinguishing two datasets according to preservation of plant remains (charred vs. uncharred), as this impacts on the quantity and diversity of taxa. The 47 fruit taxa identified were organized in broad categories according to their status and origin: exotic, allochtonous cultivated, indigenous cultivated, wild native. We also analyzed diversity, quantity of fruits compared to the total of economic plants and spatio-temporal variations in the composition of fruit assemblages using correspondence factor analyses. Archaeobotanical data reflect variations and continuities in the diversity of species used through time and space. In the Mediterranean area, significant changes related to the arrival of new plants and development of fruit cultivation occurred mainly, first during the Iron Age (6th-5th c. BCE), then in the beginning of the Roman period. Large cities played a major role in this process. In agreement with archeological information, archaeobotanical data reveal the predominance of viticulture in both periods. However, arboriculture also included other fruit species that have been subject to less intensive and specialized cultivation practices. Most significantly, this study pinpoints the continuous contribution of native, supposedly wild fruits throughout the chronology. Despite the homogenizing Roman influence, results reveal clear differences between the Mediterranean and temperate regions.

The place of millet in food globalization during Late Prehistory as evidenced by new bioarchaeological data from the Caucasus.

Two millets, Panicum miliaceum and Setaria italica, were domesticated in northern China, around 6000 BC. Although its oldest evidence is in Asia, possible independent domestication of these species in the Caucasus has often been proposed. To verify this hypothesis, a multiproxy research program (Orimil) was designed to detect the first evidence of millet in this region. It included a critical review of the occurrence of archaeological millet in the Caucasus, up to Antiquity; isotopic analyses of human and animal bones and charred grains; and radiocarbon dating of millet grains from archaeological contexts dated from the Early Bronze Age (3500-2500 BC) to the 1st Century BC. The results show that these two cereals were cultivated during the Middle Bronze Age (MBA), around 2000-1800 BC, especially Setaria italica which is the most ancient millet found in Georgia. Isotopic analyses also show a significant enrichment in 13C in human and animal tissues, indicating an increasing C4 plants consumption at the same period. More broadly, our results assert that millet was not present in the Caucasus in the Neolithic period. Its arrival in the region, based on existing data in Eurasia, was from the south, without excluding a possible local domestication of Setaria italica.

Direct dating reveals the early history of opium poppy in western Europe.

This paper aims to define the first chrono-cultural framework on the domestication and early diffusion of the opium poppy using small-sized botanical remains from archaeological sites, opening the way to directly date minute short-lived botanical samples. We produced the initial set of radiocarbon dates directly from the opium poppy remains of eleven Neolithic sites (5900-3500 cal BCE) in the central and western Mediterranean, northwestern temperate Europe, and the western Alps. When possible, we also dated the macrobotanical remains originating from the same sediment sample. In total, 22 samples were taken into account, including 12 dates directly obtained from opium poppy remains. The radiocarbon chronology ranges from 5622 to 4050 cal BCE. The results show that opium poppy is present from at least the middle of the sixth millennium in the Mediterranean, where it possibly grew naturally and was cultivated by pioneer Neolithic communities. Its dispersal outside of its native area was early, being found west of the Rhine in 5300-5200 cal BCE. It was introduced to the western Alps around 5000-4800 cal BCE, becoming widespread from the second half of the fifth millennium. This research evidences different rhythms in the introduction of opium poppy in western Europe.

Immunotherapy of triple-negative breast cancer with cathepsin D-targeting antibodies.

BACKGROUND: Triple-negative breast cancer (TNBC) treatment is currently restricted to chemotherapy. Hence, tumor-specific molecular targets and/or alternative therapeutic strategies for TNBC are urgently needed. Immunotherapy is emerging as an exciting treatment option for TNBC patients. The aspartic protease cathepsin D (cath-D), a marker of poor prognosis in breast cancer (BC), is overproduced and hypersecreted by human BC cells. This study explores whether cath-D is a tumor cell-associated extracellular biomarker and a potent target for antibody-based therapy in TNBC. METHODS: Cath-D prognostic value and localization was evaluated by transcriptomics, proteomics and immunohistochemistry in TNBC. First-in-class anti-cath-D human scFv fragments binding to both human and mouse cath-D were generated using phage display and cloned in the human IgG1 λ format (F1 and E2). Anti-cath-D antibody biodistribution, antitumor efficacy and in vivo underlying mechanisms were investigated in TNBC MDA-MB-231 tumor xenografts in nude mice. Antitumor effect was further assessed in TNBC patient-derived xenografts (PDXs). RESULTS: High CTSD mRNA levels correlated with shorter recurrence-free survival in TNBC, and extracellular cath-D was detected in the tumor microenvironment, but not in matched normal breast stroma. Anti-cath-D F1 and E2 antibodies accumulated in TNBC MDA-MB-231 tumor xenografts, inhibited tumor growth and improved mice survival without apparent toxicity. The Fc function of F1, the best antibody candidate, was essential for maximal tumor inhibition in the MDA-MB-231 model. Mechanistically, F1 antitumor response was triggered through natural killer cell activation via IL-15 upregulation, associated with granzyme B and perforin production, and the release of antitumor IFNγ cytokine. The F1 antibody also prevented the tumor recruitment of immunosuppressive tumor-associated macrophages M2 and myeloid-derived suppressor cells, a specific effect associated with a less immunosuppressive tumor microenvironment highlighted by TGFß decrease. Finally, the antibody F1 inhibited tumor growth of two TNBC PDXs, isolated from patients resistant or not to neo-adjuvant chemotherapy. CONCLUSION: Cath-D is a tumor-specific extracellular target in TNBC suitable for antibody-based therapy. Immunomodulatory antibody-based strategy against cath-D is a promising immunotherapy to treat patients with TNBC.

Hepatitis C virus intragenomic interactions are modulated by the SLVI RNA structure of the core coding sequence.

Several RNA interactions are thought to play a role in the regulation of the hepatitis C virus (HCV) life cycle. Most of these interactions involve the 5BSL3.2 domain and therefore occur at the 3' end of the viral genomic RNA. A long-range interaction has also been described between 5BSL3.2 and the 5' untranslated region (UTR). Another interaction involves the SLVI stem loop of the core coding region and the 5'UTR. We aimed to analyse the role of this SLVI domain, which likely interferes with others interactions. By evaluating RNA stability, translation and RNA synthesis, we showed that the SLVI stem loop extensively modulates the effect of the interactions mediated by the 5BSL3.2 domain and strongly affects the IIId/5BSL3.2 interaction. Numerous interactions in HCV genomic RNA have been described in the UTRs and the coding sequence but their roles are poorly understood. We showed that the SLVI domain located in the core coding sequence plays an important role in the translation of the polyprotein, but also in the modulation of long-range RNA interactions centred on the 5BSL3.2 domain. The SLVI domain has been absent from most studies, especially from the extensively used subgenomic replicon; our data highlight the importance of this domain in the studies of these long-range interactions in the HCV life cycle.

Conventional and reduced radiation dose of 16-MDCT for detection of nephrolithiasis and ureterolithiasis.

OBJECTIVE: Our purpose was to prospectively compare the reader compatibility and acceptability of a range of reduced-dose 16-MDCT images with standard-dose 16-MDCT images for the detection of nephroureterolithiasis using a dose reduction simulation technique. SUBJECTS AND METHODS: The study was HIPAA compliant and institutional review board approved. Fifty consecutive patients with suspected nephrolithiasis were recruited to undergo conventional renal stone unenhanced 16-MDCT with at least 160 mA. Noise was then artificially introduced to simulate levels of 70, 100, and 130 mA. Three blinded independent readers interpreted the original and simulated-dose scans for the location and number of renal and ureteral calculi and secondary signs of obstruction using a 5-point confidence scale. RESULTS: Reader acceptability of scans was inversely related to noise. There was no significant reduction in readers' confidence in detection or exclusion of renal collecting system calculi with simulated reduction of mA of 70, 100, and 130 compared with the standard-dose study. However, for ureteral calcifications, there was a decrease in confidence for the detection or exclusion of ureterolithiasis at an mA of 70 (35 mAs). CONCLUSION: An mA as low as 70 (35 mAs) is acceptable for evaluation of nephrolithiasis. However, the evaluation of ureterolithiasis is compromised with an mA of 70.

Abdominal pain: coronal reformations from isotropic voxels with 16-section CT--reader lesion detection and interpretation time.

PURPOSE: To retrospectively assess if reader detection of intraabdominal pathologic findings on coronal reformations from isotropic voxels at 16-section computed tomography (CT) was similar to reader detection on transverse scans. MATERIALS AND METHODS: The institutional review board approved this HIPAA-compliant study, and a waiver of informed consent was obtained. Twenty-nine consecutive patients (12 men, 17 women; mean age, 48 years; age range, 21-93 years) with abdominal pain underwent 16-section CT with coronal reformations. Eight independent readers reviewed randomized scans (transverse and coronal) and identified pathologic findings in multiple organ systems. Timing for each interpretation was recorded. One month later, readers reviewed the scan reformatted in the other imaging plane. Agreement between transverse and coronal scans was measured by using Cohen kappa coefficients. RESULTS: Agreement was moderate to near perfect between transverse and coronal interpretations for intraabdominal anatomic and pathologic findings (kappa=0.59-1.00). For transverse interpretations, more thoracic pathologic findings were noted than for coronal interpretations; for coronal interpretations, more lymph nodes were noted than for transverse interpretations. Mean transverse interpretation time was 4.9 minutes+/-1.1 (standard deviation) (range, 2.9-6.5 minutes); mean coronal interpretation time was 5.1 minutes+/-0.8 (range, 3.3-6.7 minutes). For each reader, there was no statistically significant difference in interpretation time between transverse and coronal scans (P=.06). CONCLUSION: With regard to the presence of intraabdominal pathologic findings, coronal reformations from isotropic voxels are similar to transverse scans in terms of interpretation time and reader agreement.

Review of internal hernias: radiographic and clinical findings.

OBJECTIVE: Internal hernias, including paraduodenal (traditionally the most common), pericecal, foramen of Winslow, and intersigmoid hernias, account for approximately 0.5-5.8% of all cases of intestinal obstruction and are associated with a high mortality rate, exceeding 50% in some series. To complicate matters, the incidence of internal hernias is increasing because of a number of relatively new surgical procedures now being performed, including liver transplantation and gastric bypass surgery. A significant increase in hernias is occurring in patients undergoing transmesenteric, transmesocolic, and retroanastomotic surgical procedures. It is important for radiologists to be familiar with and to understand the various types of internal hernias and their imaging features so that prompt and accurate diagnosis of these conditions can be made. CONCLUSION: This article illustrates the imaging findings of internal hernias, with emphasis placed on the CT findings, especially in transmesenteric, transmesocolic, and retroanastomotic types of internal hernias.

Small-bowel obstruction: coronal reformations from isotropic voxels at 16-section multi-detector row CT.

PURPOSE: To retrospectively assess the added value of coronal reformations of the abdomen and pelvis from isotropic voxels by using 16-section multi-detector row computed tomography (CT) for the diagnosis of small-bowel obstruction (SBO). MATERIALS AND METHODS: This HIPAA-compliant study was approved by the institutional review board of this medical center with a waiver of informed consent. One hundred consecutive patients (40 men and 60 women; mean age, 55 years) suspected of having SBO and abdominal pain underwent 16-section multi-detector row CT with coronal reformations. Twenty-nine patients had a final diagnosis of SBO, and 71 patients did not. Three independent readers blinded to the diagnosis interpreted the CT scout scan, then transverse scans alone, and then transverse plus coronal scans for the presence of SBO and abnormal wall enhancement. Confidence was scored with a 1-5 scale (1 = absent, 5 = present). RESULTS: Mean sensitivity and specificity of CT scout alone, transverse CT alone, and transverse plus coronal CT for the diagnosis of SBO were 88% and 86%, 87% and 87%, and 87% and 90%, respectively (not significant). In patients without SBO, transverse plus coronal CT enhanced confidence in the exclusion of SBO (P = .01). In patients with SBO, transverse plus coronal CT enhanced confidence in the diagnosis of SBO and identification of abnormal wall enhancement (P = .01). CONCLUSION: Transverse 16-section multi-detector row CT data sets are an excellent test for the diagnosis of SBO, while the addition of coronal reformations obtained from these isotropic data sets adds confidence to the diagnosis and exclusion of SBO.