Phenotype-genotype comorbidity analysis of patients with rare disorders provides insight into their pathological and molecular bases.

Genetic and molecular analysis of rare disease is made difficult by the small numbers of affected patients. Phenotypic comorbidity analysis can help rectify this by combining information from individuals with similar phenotypes and looking for overlap in terms of shared genes and underlying functional systems. However, few studies have combined comorbidity analysis with genomic data. We present a computational approach that connects patient phenotypes based on phenotypic co-occurence and uses genomic information related to the patient mutations to assign genes to the phenotypes, which are used to detect enriched functional systems. These phenotypes are clustered using network analysis to obtain functionally coherent phenotype clusters. We applied the approach to the DECIPHER database, containing phenotypic and genomic information for thousands of patients with heterogeneous rare disorders and copy number variants. Validity was demonstrated through overlap with known diseases, co-mention within the biomedical literature, semantic similarity measures, and patient cluster membership. These connected pairs formed multiple phenotype clusters, showing functional coherence, and mapped to genes and systems involved in similar pathological processes. Examples include claudin genes from the 22q11 genomic region associated with a cluster of phenotypes related to DiGeorge syndrome and genes related to the GO term anterior/posterior pattern specification associated with abnormal development. The clusters generated can help with the diagnosis of rare diseases, by suggesting additional phenotypes for a given patient and potential underlying functional systems. Other tools to find causal genes based on phenotype were also investigated. The approach has been implemented as a workflow, named PhenCo, which can be adapted to any set of patients for which phenomic and genomic data is available. Full details of the analysis, including the clusters formed, their constituent functional systems and underlying genes are given. Code to implement the workflow is available from GitHub.

Genetic mapping for agronomic traits in a MAGIC population of common bean (Phaseolus vulgaris L.) under drought conditions.

BACKGROUND: Common bean is an important staple crop in the tropics of Africa, Asia and the Americas. Particularly smallholder farmers rely on bean as a source for calories, protein and micronutrients. Drought is a major production constraint for common bean, a situation that will be aggravated with current climate change scenarios. In this context, new tools designed to understand the genetic basis governing the phenotypic responses to abiotic stress are required to improve transfer of desirable traits into cultivated beans. RESULTS: A multiparent advanced generation intercross (MAGIC) population of common bean was generated from eight Mesoamerican breeding lines representing the phenotypic and genotypic diversity of the CIAT Mesoamerican breeding program. This population was assessed under drought conditions in two field trials for yield, 100 seed weight, iron and zinc accumulation, phenology and pod harvest index. Transgressive segregation was observed for most of these traits. Yield was positively correlated with yield components and pod harvest index (PHI), and negative correlations were found with phenology traits and micromineral contents. Founder haplotypes in the population were identified using Genotyping by Sequencing (GBS). No major population structure was observed in the population. Whole Genome Sequencing (WGS) data from the founder lines was used to impute genotyping data for GWAS. Genetic mapping was carried out with two methods, using association mapping with GWAS, and linkage mapping with haplotype-based interval screening. Thirteen high confidence QTL were identified using both methods and several QTL hotspots were found controlling multiple traits. A major QTL hotspot located on chromosome Pv01 for phenology traits and yield was identified. Further hotspots affecting several traits were observed on chromosomes Pv03 and Pv08. A major QTL for seed Fe content was contributed by MIB778, the founder line with highest micromineral accumulation. Based on imputed WGS data, candidate genes are reported for the identified major QTL, and sequence changes were identified that could cause the phenotypic variation. CONCLUSIONS: This work demonstrates the importance of this common bean MAGIC population for genetic mapping of agronomic traits, to identify trait associations for molecular breeding tool design and as a new genetic resource for the bean research community.

Chronic Primary Headache Subjects Have Greater Forward Head Posture than Asymptomatic and Episodic Primary Headache Sufferers: Systematic Review and Meta-analysis.

OBJECTIVE: To summarize the cervical physical examination characteristics in subjects with chronic primary headache and compare those with a healthy population and a population with episodic primary headache. DESIGN: Systematic review and meta-analysis. SUBJECTS: Humans ≥18 years old. At least one of the study groups should be constituted by subjects diagnosed with one of the chronic primary headache subtypes according to the International Classification of Headache Disorders, 3rd Edition. COMPARISON: Neck physical examination outcomes of subjects with chronic primary headache compared with a healthy population or subjects with episodic primary headache. OUTCOMES: Forward head posture (FHP), cervical range of movement, motor control, neck muscle activity, and reproduction and resolution of symptoms. METHODS: Two reviewers assessed independently the MEDLINE, EMBASE, WOS, MEDES, PEDro, and CINAHL databases to select observational studies. First, both implemented an agreement for a search strategy. Then, they screened independently for duplicates, titles, abstracts, and full-text information. A meta-analysis was conducted to compare measures between groups. RESULTS: Twelve studies (N = 1,083) with moderate quality (mean ± SD = 7.75 ± 1.48 on the Newcastle Ottawa Scale) were selected for the qualitative analysis. The meta-analysis showed that patients with chronic primary headache presented greater forward head posture than asymptomatic participants (N = 275, Hg = 0.68, 95% CI = 0.25-1.1, Z = 3.14, P < 0.01) and patients with episodic primary headache (N = 268, Hg = 0.39, 95% CI = 0.13-0.65, Z = 2.98, P < 0.01). CONCLUSIONS: There is moderate to strong evidence that patients with chronic primary headache present greater FHP than asymptomatic individuals and moderate evidence that patients with chronic primary headache present greater forward head posture than those with episodic primary headache.

Effects of Immunonutrition in Advanced Human Immunodeficiency Virus Disease: A Randomized Placebo-controlled Clinical Trial (Promaltia Study).

Background: While nutritional interventions with prebiotics and probiotics seem to exert immunological effects, their clinical implications in human immunodeficiency virus (HIV)-infected subjects initiating antiretroviral therapy (ART) at advanced HIV disease remain unclear. Methods: This was a pilot multicenter randomized, placebo-controlled, double-blind study in which 78 HIV-infected, ART-naive subjects with <350 CD4 T cells/µL or AIDS were randomized to either daily PMT25341 (a mixture of synbiotics, omega-3/6 fatty acids and amino acids) or placebo for 48 weeks, each in combination with first-line ART. Primary endpoints were changes in CD4 T-cell counts and CD4/CD8 ratio from baseline to week 48 and safety. Secondary endpoints were changes in markers of T-cell activation, bacterial translocation, inflammation, and α and ß microbiota diversity. Results: Fifty-nine participants completed the follow-up with a mean CD4+ T-cell count of 221 ± 108 cells/µL and mean CD4/CD8 ratio of 0.26 ± 0.19. PMT25341 was well tolerated, without grade 3-4 adverse effects attributable to the intervention. While most of the assessed biomarkers improved during the follow-up in both arms, PMT25341-treated subjects did not experience any significant change, compared to placebo-treated subjects, in mean CD4+ T-cell count change (278 vs 250 cells/µL, P = .474) or CD4/CD8 ratio change (0.30 vs 0.32, P = .854). Similarly, we did not detect differences between treatment arms in secondary endpoints. Conclusions: In HIV-infected patients initiating ART at advanced disease, the clear immunological benefits of ART were not enhanced by this nutritional intervention targeting the gut-associated lymphoid tissue and microbiota. Clinical Trials Registration: NCT00870363.

Lipid-specific immunoglobulin M bands in cerebrospinal fluid are associated with a reduced risk of developing progressive multifocal leukoencephalopathy during treatment with natalizumab.

OBJECTIVE: Progressive multifocal leukoencephalopathy (PML) is a serious side effect associated with natalizumab treatment in multiple sclerosis (MS). PML risk increases in individuals seropositive for anti-John Cunningham virus (JC) antibodies, with prolonged duration of natalizumab treatment, and with prior exposure to immunosuppressants. We explored whether the presence of lipid-specific immunoglobulin M oligoclonal bands in cerebrospinal fluid (CSF; IgM bands), a recognized marker of highly inflammatory MS, may identify individuals better able to counteract the potential immunosuppressive effect of natalizumab and hence be associated with a reduced risk of developing PML. METHODS: We studied 24 MS patients who developed PML and another 343 who did not suffer this opportunistic infection during natalizumab treatment. Patients were recruited at 25 university hospitals. IgM bands were studied by isoelectric focusing and immunodetection. CSF lymphocyte counts were explored in 151 MS patients recruited at Ramon y Cajal Hospital in Madrid, Spain. RESULTS: IgM bands were independently associated with decreased PML risk (odds ratio [OR] = 45.9, 95% confidence interval [CI] = 5.9-339.3, p < 0.0001) in patients treated with natalizumab. They were also associated with significantly higher CSF CD4, CD8, and B-cell numbers. Patients positive for IgM bands and anti-JC antibodies had similar levels of reduced PML risk to those who were anti-JC negative (OR = 1.55, 95% CI = 0.09-25.2, p = 1.0). Higher risk was observed in patients positive for anti-JC antibodies and negative for IgM bands (19% of the total cohort, OR = 59.71, 95% CI = 13.6-262.2). INTERPRETATION: The presence of IgM bands reflects a process that may diminish the risk of PML by counteracting the excess of immunosuppression that may occur during natalizumab therapy.

Assessment of the Impact of Humic Acids on Intestinal Microbiota, Gut Integrity, Ileum Morphometry, and Cellular Immunity of Turkey Poults Fed an Aflatoxin B1-Contaminated Diet.

A recent study published data on the growth performance, relative weights of the organs of the gastrointestinal tract, liver histology, serum biochemistry, and hematological parameters for turkey poults fed an experimental diet contaminated with aflatoxin B1 (AFB1) and humic acids (HA) extracted from vermicompost. The negative effects of AFB1 (250 ng AFB1/g of feed) were significantly reduced by HA supplementation (0.25% w/w), suggesting that HA might be utilized to ameliorate the negative impact of AFB1 from contaminated diets. The present study shows the results of the remaining variables, as an extension of a previously published work which aimed to evaluate the impact of HA on the intestinal microbiota, gut integrity, ileum morphometry, and cellular immunity of turkey poults fed an AFB1-contaminated diet. For this objective, five equal groups of 1-day-old female Nicholas-700 turkey poults were randomly assigned to the following treatments: negative control (basal diet), positive control (basal diet + 250 ng AFB1/g), HA (basal diet + 0.25% HA), HA + AFB1 (basal diet + 0.25% HA + 250 ng AFB1/g), and Zeolite (basal diet + 0.25% zeolite + 250 ng AFB1/g). In the experiment, seven replicates of ten poults each were used per treatment (n = 70). In general, HA supplementation with or without the presence of AFB1 showed a significant increase (p < 0.05) in the number of beneficial butyric acid producers, ileum villi height, and ileum total area, and a significant reduction in serum levels of fluorescein isothiocyanate-dextran (FITC-d), a marker of intestinal integrity. In contrast, poults fed with AFB1 showed a significant increase in Proteobacteria and lower numbers of beneficial bacteria, clearly suggesting gut dysbacteriosis. Moreover, poults supplemented with AFB1 displayed the lowest morphometric parameters and the highest intestinal permeability. Furthermore, poults in the negative and positive control treatments had the lowest cutaneous basophil hypersensitivity response. These findings suggest that HA supplementation enhanced intestinal integrity (shape and permeability), cellular immune response, and healthier gut microbiota composition, even in the presence of dietary exposure to AFB1. These results complement those of the previously published study, suggesting that HA may be a viable dietary intervention to improve gut health and immunity in turkey poults during aflatoxicosis.

Implementation of Spanish adaptation of the European guidelines on cardiovascular disease prevention in primary care.

BACKGROUND: The successful implementation of cardiovascular disease (CVD) prevention guidelines relies heavily on primary care physicians (PCPs) providing risk factor evaluation, intervention and patient education. The aim of this study was to ascertain the degree of awareness and implementation of the Spanish adaptation of the European guidelines on CVD prevention in clinical practice (CEIPC guidelines) among PCPs. METHODS: A cross-sectional survey of PCPs was conducted in Spain between January and June 2011. A random sample of 1,390 PCPs was obtained and stratified by region. Data were collected by means of a self-administered questionnaire. RESULTS: More than half (58%) the physicians were aware of and knew the recommendations, and 62% of those claimed to use them in clinical practice, with general physicians (without any specialist accreditation) being less likely to so than family doctors. Most PCPs (60%) did not assess cardiovascular risk, with the limited time available in the surgery being cited as the greatest barrier by 81%. The main reason to be sceptical about recommendations, reported by 71% of physicians, was that there are too many guidelines. Almost half the doctors cited the lack of training and skills as the greatest barrier to the implementation of lifestyle and behavioural change recommendations. CONCLUSIONS: Most PCPs were aware of the Spanish adaptation of the European guidelines on CVD prevention (CEIPC guidelines) and knew their content. However, only one third of PCPs used the guidelines in clinical practice and less than half CVD risk assessment tools.

Arsenic and mercury in native aquatic bryophytes: differences among species.

This study investigated the capacities of five species of aquatic bryophytes to accumulate As and Hg from their natural habitats in rivers in Galicia (NW Spain). The distributions of the concentrations of both elements in all species were skewed to the right, with a higher incidence of extreme values in the As data, which may indicate a greater degree of contamination by this metalloid. There were no significant differences in the accumulation of either of the elements between the different species studied, which justifies their combined use as biomonitors of As and Hg, at least in the study area.

Mr.Bean: a comprehensive statistical and visualization application for modeling agricultural field trials data.

Crop improvement efforts have exploited new methods for modeling spatial trends using the arrangement of the experimental units in the field. These methods have shown improvement in predicting the genetic potential of evaluated genotypes. However, the use of these tools may be limited by the exposure and accessibility to these products. In addition, these new methodologies often require plant scientists to be familiar with the programming environment used to implement them; constraints that limit data analysis efficiency for decision-making. These challenges have led to the development of Mr.Bean, an accessible and user-friendly tool with a comprehensive graphical visualization interface. The application integrates descriptive analysis, measures of dispersion and centralization, linear mixed model fitting, multi-environment trial analysis, factor analytic models, and genomic analysis. All these capabilities are designed to help plant breeders and scientist working with agricultural field trials make informed decisions more quickly. Mr.Bean is available for download at https://github.com/AparicioJohan/MrBeanApp.

Reduced choice-confidence in negative numerals.

Negative numbers are central in math. However, they are abstract, hard to learn, and manipulated slower than positive numbers regardless of math ability. It suggests that confidence, namely the post-decision estimate of being correct, should be lower than positives. We asked participants to pick the larger single-digit numeral in a pair and collected their implicit confidence with button pressure (button pressure was validated with three empirical signatures of confidence). We also modeled their choices with a drift-diffusion decision model to compute the post-decision estimate of being correct. We found that participants had relatively low confidence with negative numerals. Given that participants compared with high accuracy the basic base-10 symbols (0-9), reduced confidence may be a general feature of manipulating abstract negative numerals as they produce more uncertainty than positive numerals per unit of time.

Network-Based Methods for Approaching Human Pathologies from a Phenotypic Point of View.

Network and systemic approaches to studying human pathologies are helping us to gain insight into the molecular mechanisms of and potential therapeutic interventions for human diseases, especially for complex diseases where large numbers of genes are involved. The complex human pathological landscape is traditionally partitioned into discrete "diseases"; however, that partition is sometimes problematic, as diseases are highly heterogeneous and can differ greatly from one patient to another. Moreover, for many pathological states, the set of symptoms (phenotypes) manifested by the patient is not enough to diagnose a particular disease. On the contrary, phenotypes, by definition, are directly observable and can be closer to the molecular basis of the pathology. These clinical phenotypes are also important for personalised medicine, as they can help stratify patients and design personalised interventions. For these reasons, network and systemic approaches to pathologies are gradually incorporating phenotypic information. This review covers the current landscape of phenotype-centred network approaches to study different aspects of human diseases.

The numerator bias exists in millions of real-world comparisons.

Fractions are crucial, from math and science education to daily activities, but they are hard. A puzzling aspect of fractions is that people over-rely on the numerator when comparing a pair of fractions. Previous work has considered this numerator bias mostly as a reasoning mishap. Still, in a vast amount of pairwise comparisons, across many real-world domains, not just education textbooks, we report a high prior probability that the larger fraction has the larger numerator, and, for a relevant case, we provide formal arguments why. The existence of such a regularity suggests that the numerator bias may reflect a rational adaptation that detects and exploits likely events. In a pair of visual-proportion tasks (discrete and continuous fractions), we confirm that the numerator bias in participants adapts to experimented regularities. Even though weak education and math abilities play a role, adaptation to informative priors outside the classroom poses a challenge to educators, learners, and decision-makers.

Genetic Correlation Between Fe and Zn Biofortification and Yield Components in a Common Bean (Phaseolus vulgaris L.).

Common bean (Phaseolus vulgaris L.) is the most important legume for direct human consumption worldwide. It is a rich and relatively inexpensive source of proteins and micronutrients, especially iron and zinc. Bean is a target for biofortification to develop new cultivars with high Fe/Zn levels that help to ameliorate malnutrition mainly in developing countries. A strong negative phenotypic correlation between Fe/Zn concentration and yield is usually reported, posing a significant challenge for breeders. The objective of this study was to investigate the genetic relationship between Fe/Zn. We used Quantitative Trait Loci (QTLs) mapping and Genome-Wide Association Studies (GWAS) analysis in three bi-parental populations that included biofortified parents, identifying genomic regions associated with yield and micromineral accumulation. Significant negative correlations were observed between agronomic traits (pod harvest index, PHI; pod number, PdN; seed number, SdN; 100 seed weight, 100SdW; and seed per pod, Sd/Pd) and micronutrient concentration traits (SdFe and SdZn), especially between pod harvest index (PHI) and SdFe and SdZn. PHI presented a higher correlation with SdN than PdN. Seventy-nine QTLs were identified for the three populations: 14 for SdFe, 12 for SdZn, 13 for PHI, 11 for SdN, 14 for PdN, 6 for 100SdW, and 9 for Sd/Pd. Twenty-three hotspot regions were identified in which several QTLs were co-located, of which 13 hotpots displayed QTL of opposite effect for yield components and Fe/Zn accumulation. In contrast, eight QTLs for SdFe and six QTLs for SdZn were observed that segregated independently of QTL of yield components. The selection of these QTLs will enable enhanced levels of Fe/Zn and will not affect the yield performance of new cultivars focused on biofortification.

Perspectives on Kidney Disease Education and Recommendations for Improvement Among Latinx Patients Receiving Emergency-Only Hemodialysis.

Importance: In most states, undocumented Latinx immigrants with kidney failure receive dialysis in acute care settings on an emergency-only basis. How much kidney disease education Latinx immigrants receive and how to improve kidney disease education and outreach among Latinx populations are unknown. Objective: To understand the kidney disease educational gaps of Latinx individuals who need but lack access to scheduled outpatient dialysis. Design, Setting, and Participants: This qualitative study used semistructured interviews in a Texas hospital system from March 2020 to January 2021 with 15 individuals who received emergency-only dialysis when they were first diagnosed with kidney failure. Demographic information was collected, and a thematic analysis was performed using the constant comparative method on interviews after they were audio-recorded, translated, and transcribed verbatim. Data analysis was performed from April 2020 to February 2021. Main Outcomes and Measures: Subthemes and themes from semistructured interviews. Results: All 15 persons interviewed (9 male individuals [60%]; mean [SD] age, 51 [17] years) identified as Hispanic, 11 (73%) were born in Mexico, and none reported knowing about their kidney disease more than 6 months before starting dialysis. The themes identified were (1) lack of kidney disease awareness, (2) education provided was incomplete and poor quality, (3) lack of culturally concordant communication and care, (4) elements that Latinx patients receiving emergency-only dialysis want in their education, (5) facilitators of patient activation and coping, and (6) Latinx patient recommendations to improve community outreach. Conclusions and Relevance: Latinx adults receiving emergency-only dialysis are usually unaware of their kidney disease until shortly before or after they start dialysis, and the education they receive is poor quality and often not culturally tailored. Participants made feasible recommendations on how to improve education and outreach among Latinx communities.

A New Pipeline to Automatically Segment and Semi-Automatically Measure Bone Length on 3D Models Obtained by Computed Tomography.

The characterization of developmental phenotypes often relies on the accurate linear measurement of structures that are small and require laborious preparation. This is tedious and prone to errors, especially when repeated for the multiple replicates that are required for statistical analysis, or when multiple distinct structures have to be analyzed. To address this issue, we have developed a pipeline for characterization of long-bone length using X-ray microtomography (XMT) scans. The pipeline involves semi-automated algorithms for automatic thresholding and fast interactive isolation and 3D-model generation of the main limb bones, using either the open-source ImageJ plugin BoneJ or the commercial Mimics Innovation Suite package. The tests showed the appropriate combination of scanning conditions and analysis parameters yields fast and comparable length results, highly correlated with the measurements obtained via ex vivo skeletal preparations. Moreover, since XMT is not destructive, the samples can be used afterward for histology or other applications. Our new pipelines will help developmental biologists and evolutionary researchers to achieve fast, reproducible and non-destructive length measurement of bone samples from multiple animal species.

Decoding Neuromuscular Disorders Using Phenotypic Clusters Obtained From Co-Occurrence Networks.

Neuromuscular disorders (NMDs) represent an important subset of rare diseases associated with elevated morbidity and mortality whose diagnosis can take years. Here we present a novel approach using systems biology to produce functionally-coherent phenotype clusters that provide insight into the cellular functions and phenotypic patterns underlying NMDs, using the Human Phenotype Ontology as a common framework. Gene and phenotype information was obtained for 424 NMDs in OMIM and 126 NMDs in Orphanet, and 335 and 216 phenotypes were identified as typical for NMDs, respectively. 'Elevated serum creatine kinase' was the most specific to NMDs, in agreement with the clinical test of elevated serum creatinine kinase that is conducted on NMD patients. The approach to obtain co-occurring NMD phenotypes was validated based on co-mention in PubMed abstracts. A total of 231 (OMIM) and 150 (Orphanet) clusters of highly connected co-occurrent NMD phenotypes were obtained. In parallel, a tripartite network based on phenotypes, diseases and genes was used to associate NMD phenotypes with functions, an approach also validated by literature co-mention, with KEGG pathways showing proportionally higher overlap than Gene Ontology and Reactome. Phenotype-function pairs were crossed with the co-occurrent NMD phenotype clusters to obtain 40 (OMIM) and 72 (Orphanet) functionally coherent phenotype clusters. As expected, many of these overlapped with known diseases and confirmed existing knowledge. Other clusters revealed interesting new findings, indicating informative phenotypes for differential diagnosis, providing deeper knowledge of NMDs, and pointing towards specific cell dysfunction caused by pleiotropic genes. This work is an example of reproducible research that i) can help better understand NMDs and support their diagnosis by providing a new tool that exploits existing information to obtain novel clusters of functionally-related phenotypes, and ii) takes us another step towards personalised medicine for NMDs.

Genetic Architecture and Genomic Prediction of Cooking Time in Common Bean (Phaseolus vulgaris L.).

Cooking time of the common bean is an important trait for consumer preference, with implications for nutrition, health, and environment. For efficient germplasm improvement, breeders need more information on the genetics to identify fast cooking sources with good agronomic properties and molecular breeding tools. In this study, we investigated a broad genetic variation among tropical germplasm from both Andean and Mesoamerican genepools. Four populations were evaluated for cooking time (CKT), water absorption capacity (WAC), and seed weight (SdW): a bi-parental RIL population (DxG), an eight-parental Mesoamerican MAGIC population, an Andean (VEF), and a Mesoamerican (MIP) breeding line panel. A total of 922 lines were evaluated in this study. Significant genetic variation was found in all populations with high heritabilities, ranging from 0.64 to 0.89 for CKT. CKT was related to the color of the seed coat, with the white colored seeds being the ones that cooked the fastest. Marker trait associations were investigated by QTL analysis and GWAS, resulting in the identification of 10 QTL. In populations with Andean germplasm, an inverse correlation of CKT and WAC, and also a QTL on Pv03 that inversely controls CKT and WAC (CKT3.2/WAC3.1) were observed. WAC7.1 was found in both Mesoamerican populations. QTL only explained a small part of the variance, and phenotypic distributions support a more quantitative mode of inheritance. For this reason, we evaluated how genomic prediction (GP) models can capture the genetic variation. GP accuracies for CKT varied, ranging from good results for the MAGIC population (0.55) to lower accuracies in the MIP panel (0.22). The phenotypic characterization of parental material will allow for the cooking time trait to be implemented in the active germplasm improvement programs. Molecular breeding tools can be developed to employ marker-assisted selection or genomic selection, which looks to be a promising tool in some populations to increase the efficiency of breeding activities.

Identification, tissue characterization, and innate immune role of Angiogenin-4 expression in young broiler chickens.

Intestinal epithelial cells are major producers of antimicrobial proteins, which play an important role in innate immunity. In addition to defensins, the Ribonuclease A superfamily includes important antimicrobial proteins involved in host-defense mechanisms in vertebrates. Angiogenin-4 (Ang4), a member of this RNase superfamily, has been demonstrated to be secreted by Paneth cells in mice. We have successfully cloned and characterized a new chicken gene (chAng4), found for the first time in a nonmammalian species, from intestinal epithelial and lymphoid cells. Characterization of chAng4 revealed 99% nucleotide and 97% amino acid sequence homology to mouse Ang4. Similar functional regions were identified, suggesting a role in innate immunity and regulation of gut microbiota. Furthermore, the mRNA expression pattern of chAng4 was studied in broilers in the presence or absence of beneficial bacteria (probiotics) and organic acids. The results showed that one-day-old chickens expressed low levels of Ang4 in almost all the evaluated tissues (crop, proventriculus, duodenum, jejunum, ileum, and cecal tonsils), except in the bursa of Fabricius that presented the highest expression level. The addition of probiotics and organic acids for either 7 or 14 consecutive days demonstrated a direct effect of probiotics and organic acids on chAng4 expression; moreover, broilers receiving probiotics and organic acids for only 7 D showed higher levels of chAng4 expression compared with those treated for 14 D. Broilers without treatment had a constant high level of expression in cecal tonsils and bursa. In conclusion, we were able to identify and characterize a new antimicrobial gene in chickens (chAng4) throughout the gastrointestinal tract. chAng4 mRNA gene expression was associated with the presence of naturally occurring and supplemented (probiotic) bacteria. The encoded protein might have a potential bactericidal effect against intestinal nonpathogenic and pathogenic microbes, modulating the intestinal microbiota and the innate immunity, and thereby may help minimize the use of antibiotics in poultry feed.

Confidence judgments during ratio comparisons reveal a Bayesian bias.

Rational numbers are essential in mathematics and decision-making but humans often and erroneously rely on the magnitude of the numerator or denominator to determine the relative size of a quotient. The source of this flawed whole number strategy is poorly understood. Here we test the Bayesian hypothesis that the human bias toward large values in the numerator or denominator of a ratio estimate is the result of higher confidence in large samples. Larger values are considered a better (more certain) instance of that ratio than the same ratio composed of smaller values. We collected confidence measures explicitly (Experiment 1) and implicitly (Experiment 2) during subjects' comparisons of non-symbolic proportions (images with arrays of orange and blue dots). We manipulated the discernibility of the fractions to control difficulty and varied the cardinality and congruency of the numerators, denominators, and ratio values (e.g. 8/20 vs. 5/10 and 16/40 vs. 10/20). The results revealed that subjects' confidence during ratio comparisons was modulated by the numerical magnitude of the fraction's components, consistent with a Bayesian perception of relative ratios. The results suggest that the large number bias could arise from greater confidence in large samples.

A threshold-free model of numerosity comparisons.

A dominant mechanism in the Judgment and Decision Making literature states that information is accumulated about each choice option until a decision threshold is met. Only after that threshold does a subject start to execute a motor response to indicate their choice. However, recent research has revealed spatial gradients in motor responses as a function of comparison difficulty as well as changes-of-mind in the middle of an action, both suggesting continued accumulation and processing of decision-related signals after the decision boundary. Here we present a formal model and supporting data from a number comparison task that a continuous motor planner, combined with a simple statistical inference scheme, can model detailed behavioral effects without assuming a threshold. This threshold-free model reproduces subjects' sensitivity to numerical distance in reaching, accuracy, reaction time, and changes of mind. We argue that the motor system positions the effectors using an optimal biomechanical feedback controller, and continuous statistical inference on outputs from cognitive processes.