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In this review, we are pitting two theories against each other: the more accepted theory, the number sense theory, suggesting that a sense of number is innate and non-symbolic numerosity is being processed independently of continuous magnitudes (e.g., size, area, and density); and the newly emerging theory suggesting that (1) both numerosities and continuous magnitudes are processed holistically when comparing numerosities and (2) a sense of number might not be innate. In the first part of this review, we discuss the number sense theory. Against this background, we demonstrate how the natural correlation between numerosities and continuous magnitudes makes it nearly impossible to study non-symbolic numerosity processing in isolation from continuous magnitudes, and therefore, the results of behavioral and imaging studies with infants, adults, and animals can be explained, at least in part, by relying on continuous magnitudes. In the second part, we explain the sense of magnitude theory and review studies that directly demonstrate that continuous magnitudes are more automatic and basic than numerosities. Finally, we present outstanding questions. Our conclusion is that there is not enough convincing evidence to support the number sense theory anymore. Therefore, we encourage researchers not to assume that number sense is simply innate, but to put this hypothesis to the test and consider whether such an assumption is even testable in the light of the correlation of numerosity and continuous magnitudes.

Major environmental and genetic factors determining stress-related protein abundance are discussed.Major aspects of protein biological function including protein isoforms and PTMs, cellular localization and protein interactions are discussed.Functional diversity of protein isoforms and PTMs is discussed. Abiotic stresses reveal profound impacts on plant proteomes including alterations in protein relative abundance, cellular localization, post-transcriptional and post-translational modifications (PTMs), protein interactions with other protein partners, and, finally, protein biological functions. The main aim of the present review is to discuss the major factors determining stress-related protein accumulation and their final biological functions. A dynamics of stress response including stress acclimation to altered ambient conditions and recovery after the stress treatment is discussed. The results of proteomic studies aimed at a comparison of stress response in plant genotypes differing in stress adaptability reveal constitutively enhanced levels of several stress-related proteins (protective proteins, chaperones, ROS scavenging- and detoxification-related enzymes) in the tolerant genotypes with respect to the susceptible ones. Tolerant genotypes can efficiently adjust energy metabolism to enhanced needs during stress acclimation. Stress tolerance vs. stress susceptibility are relative terms which can reflect different stress-coping strategies depending on the given stress treatment. The role of differential protein isoforms and PTMs with respect to their biological functions in different physiological constraints (cellular compartments and interacting partners) is discussed. The importance of protein functional studies following high-throughput proteome analyses is presented in a broader context of plant biology. In summary, the manuscript tries to provide an overview of the major factors which have to be considered when interpreting data from proteomic studies on stress-treated plants.

Functional studies giving insight into the biology of circulating tumor cells (CTCs) remain scarce due to the low frequency of CTCs and lack of appropriate models. Here, we describe the characterization of a novel CTC‐derived breast cancer cell line, designated CTC‐ITB‐01, established from a patient with metastatic estrogen receptor‐positive (ER + ) breast cancer, resistant to endocrine therapy. CTC‐ITB‐01 remained ER + in culture, and copy number alteration (CNA) profiling showed high concordance between CTC‐ITB‐01 and CTCs originally present in the patient with cancer at the time point of blood draw. RNA‐sequencing data indicate that CTC‐ITB‐01 has a predominantly epithelial expression signature. Primary tumor and metastasis formation in an intraductal PDX mouse model mirrored the clinical progression of ER + breast cancer. Downstream ER signaling was constitutively active in CTC‐ITB‐01 independent of ligand availability, and the CDK4/6 inhibitor Palbociclib strongly inhibited CTC‐ITB‐01 growth. Thus, we established a functional model that opens a new avenue to study CTC biology. Synopsis Blood‐born dissemination and subsequent outgrowth of tumor cells ‐ a process called metastasis ‐ is the leading cause of cancer‐related death. Cell lines derived from circulating tumor cells (CTCs) in blood of cancer patients provide excellent models to study the largely unknown biology of CTCs. The cell line established from CTCs of an estrogen receptor (ER)‐positive breast cancer patient mirrored the in situ CTCs and provided therefore a realistic model to investigate CTC biology. Xenograft experiments demonstrated a pattern of metastasis similar to ER‐positive breast cancer patients involving bone, liver and lung as secondary organs. Growth pattern and protein analyses revealed subtle signs of epithelial‐mesenchymal transition (EMT) with CTCs falling on the more epithelial end of the EMT spectrum. CTCs carried mutations in druggable genes relevant to cancer therapy (e.g., PIK3CA mutations). In vitro drug screening experiments indicated a cytostatic activity of the CDK4/6 inhibitor Palbociclib on CTCs. Graphical Abstract Blood‐born dissemination and subsequent outgrowth of tumor cells ‐ a process called metastasis ‐ is the leading cause of cancer‐related death. Cell lines derived from circulating tumor cells (CTCs) in blood of cancer patients provide excellent models to study the largely unknown biology of CTCs.

Despite decades of research on the neurobiology of major depressive disorder (MDD), the mechanisms underlying its expression remain unknown. The medial prefrontal cortex (mPFC), a hub region involved in emotional processing and stress response elaboration, is highly impacted in MDD patients and animal models of chronic stress. Recent advances showed alterations in the morphology and activity of mPFC neurons along with profound changes in their transcriptional programs. Studies at the circuitry level highlighted the relevance of deciphering the contributions of the distinct prefrontal circuits in the elaboration of adapted and maladapted behavioral responses in the context of chronic stress. Interestingly, MDD presents a sexual dimorphism, a feature recognized in the molecular field but understudied on the circuit level. This review examines the recent literature and summarizes the contribution of the mPFC circuitry in the expression of MDD in males and females along with the morphological and functional alterations that change the activity of these neuronal circuits in human MDD and animal models of depressive-like behaviors.

The functional equation of associativity is the topic of Abel's first contribution to Crelle's Journal. Seventy years later, it was featured as the second part of Hilbert's Fifth Problem, and it was solved under successively weaker hypotheses by Brouwer (1909), Cartan (1930) and Aczel (1949). In 1958, B Schweizer and A Sklar showed that the “triangular norms” introduced by Menger in his definition of a probabilistic metric space should be associative; and in their book Probabilistic Metric Spaces, they presented the basic properties of such triangular norms and the closely related copulas. Since then, the study of these two classes of functions has been evolving at an ever-increasing pace and the results have been applied in fields such as statistics, information theory, fuzzy set theory, multi-valued and quantum logic, hydrology, and economics, in particular, risk analysis. This book presents the foundations of the subject of associative functions on real intervals. It brings together results that have been widely scattered in the literature and adds much new material. In the process, virtually all the standard techniques for solving functional equations in one and several variables come into play. Thus, the book can serve as an advanced undergraduate or graduate text on functional equations.

Brugada syndrome (BrS) is diagnosed by a coved-type ST-segment elevation in the right precordial leads on the electrocardiogram (ECG), and it is associated with an increased risk of sudden cardiac death (SCD) compared to the general population. Although BrS is considered a genetic disease, its molecular mechanism remains elusive in about 70–85% of clinically-confirmed cases. Variants occurring in at least 26 different genes have been previously considered causative, although the causative effect of all but the SCN5A gene has been recently challenged, due to the lack of systematic, evidence-based evaluations, such as a variant’s frequency among the general population, family segregation analyses, and functional studies. Also, variants within a particular gene can be associated with an array of different phenotypes, even within the same family, preventing a clear genotype–phenotype correlation. Moreover, an emerging concept is that a single mutation may not be enough to cause the BrS phenotype, due to the increasing number of common variants now thought to be clinically relevant. Thus, not only the complete list of genes causative of the BrS phenotype remains to be determined, but also the interplay between rare and common multiple variants. This is particularly true for some common polymorphisms whose roles have been recently re-evaluated by outstanding works, including considering for the first time ever a polygenic risk score derived from the heterozygous state for both common and rare variants. The more common a certain variant is, the less impact this variant might have on heart function. We are aware that further studies are warranted to validate a polygenic risk score, because there is no mutated gene that connects all, or even a majority, of BrS cases. For the same reason, it is currently impossible to create animal and cell line genetic models that represent all BrS cases, which would enable the expansion of studies of this syndrome. Thus, the best model at this point is the human patient population. Further studies should first aim to uncover genetic variants within individuals, as well as to collect family segregation data to identify potential genetic causes of BrS.

Although TRPV1 ion channel has been attracting researchers’ attention for many years, its functions in animal organisms, the principles of regulation, and the involvement in pathological processes have not yet been fully clarified. Mutagenesis experiments and structural studies have identified the structural features of the channel and binding sites for its numerous ligands; however, these studies are far from conclusion. This review summarizes recent achievements in the TRPV1 research with special focus on structural and functional studies of the channel and on its ligands, which are extremely diverse in their nature and interaction specificity to TRPV1. Particular attention was given to the effects of numerous endogenous agonists and antagonists that can fine-tune the channel sensitivity to its usual activators, such as capsaicin, heat, acids, or their combination. In addition to the pain sensing not covered in this review, the TRPV1 channel was found to be involved in the regulation of many important physiological and pathological processes and, therefore, can be considered as a promising therapeutic target in the treatment of various diseases, such as pneumonia, ischemia, diabetes, epilepsy, schizophrenia, psoriasis, etc.

The tanning hormone (Bursicon) is a heterodimer secreted by the insect nervous system, playing a crucial role in the process of cuticle darkening and hardening and wing expansion in insects. In this study, we knocked out the gene using RNAi, thereby impairing the flight ability of adult males by affecting wing development, laying the groundwork for further control of the damage they cause to alpine meadows. The gene was successfully characterized and expressed at all developmental stages of , with higher expression in 5th instar larvae and wing primordia. In order to investigate the potential role of the gene in wing development, we used RNAi technology to inhibit the expression of the gene by in vivo injection of into male adults of , with the aim of affecting their flight ability. The silencing efficiency of the gene was 86.12%, 97.27%, 65.61%, and 30.51% in each tissue (thorax, abdomen, wing, and wing base) 12 h after injection. In addition, 12 h after injection of exogenous hormones (20E, JH, and Insulin) and a PKA inhibitor (H-89), we found that the gene was affected by 20E, H-89, JH, and Insulin, and its overexpression and gene silencing were observed in the thorax, abdomen, wings, and wing primordia of male adults of . These results indicate that the gene plays a crucial role in the wing development of male adults of . Furthermore, a decrease in gene expression further affects the extension and expansion of the wings, thereby impacting the insect's flight ability.

PurposeFamilial hypercholesterolemia (FH) is an autosomal disorder of lipid metabolism presenting with increased cardiovascular risk. Although more than 1,700 variants have been associated with FH, the great majority have not been functionally proved to affect the low-density lipoprotein receptor cycle. We aimed to classify all described variants associated with FH and to establish the proportion of variants that lack evidence to support their pathogenicity.MethodsWe followed American College of Medical Genetics and Genomics (ACMG) guidelines for the classification, and collected information from a variety of databases and individual reports. A worldwide overview of publicly available FH variants was also performed.ResultsA total of 2,104 unique variants were identified as being associated with FH, but only 166 variants have been proven by complete in vitro functional studies to be causative of disease. Additionally, applying the ACMG guidelines, 1,097 variants were considered pathogenic or likely pathogenic. Only seven variants were found in all five continents.ConclusionThe lack of functional evidence for about 85% of all variants found in FH patients can compromise FH diagnosis and patient prognosis. ACMG classification improves variant interpretation, but functional studies are necessary to understand the effect of about 40% of all variants reported. Nevertheless, ACMG guidelines need to be adapted to FH for a better diagnosis.