Explore the vast range of titles available.

The anti-diabetic drug metformin is one of the most widely prescribed medicines in the world. Together with its degradation product guanylurea, it is a major pharmaceutical pollutant in wastewater treatment plants and surface waters. An operon comprising two genes of the ureohydrolase family in Pseudomonas and Aminobacter species has recently been implicated in metformin degradation. However, the corresponding proteins have not been characterized. Here we show that these genes encode a Ni 2+ -dependent enzyme that efficiently and specifically hydrolyzes metformin to guanylurea and dimethylamine. The active enzyme is a heteromeric complex of α- and β- subunits in which only the α-subunits contain the conserved His and Asp residues for the coordination of two Ni 2+ ions in the active site. A crystal structure of metformin hydrolase reveals an α 2 β 4 stoichiometry of the hexameric complex, which is unprecedented in the ureohydrolase family. By studying a closely related but more widely distributed enzyme, we find that the putative predecessor specifically hydrolyzes dimethylguanidine instead of metformin. Our findings establish the molecular basis for metformin hydrolysis to guanylurea as the primary pathway for metformin biodegradation and provide insight into the recent evolution of ureohydrolase family proteins in response to an anthropogenic compound. The diabetes drug metformin and its degradation product guanylurea are major pharmaceutical contaminants in waste and surface water. Here, a Ni2+-dependent enzyme that hydrolysed metformin to guanylurea and its evolutionary predecessor are presented.

PURPOSE: The effect of brewers’ yeast (1,3)-(1,6)-beta-D-glucan consumption on the number of common cold episodes in healthy subject was investigated. METHODS: In a placebo-controlled, double-blind, randomized, multicentric clinical trial, 162 healthy participants with recurring infections received 900 mg of either placebo (n = 81) or an insoluble yeast (1,3)-(1,6)-beta-D-glucan preparation (n = 81) per day over a course of 16 weeks. Subjects were instructed to document each occurring common cold episode in a diary and to rate ten predefined infection symptoms during an infections period, resulting in a symptom score. The subjects were examined by the investigator during the episode visit on the 5th day of each cold episode. RESULTS: In the per protocol population, supplementation with insoluble yeast (1,3)-(1,6)-beta-glucan reduced the number of symptomatic common cold infections by 25 % as compared to placebo (p = 0.041). The mean symptom score was 15 % lower in the beta-glucan as opposed to the placebo group (p = 0.125). Beta-glucan significantly reduced sleep difficulties caused by cold episode as compared to placebo (p = 0.028). Efficacy of yeast beta-glucan was rated better than the placebo both by physicians (p = 0.004) participants (p = 0.012). CONCLUSION: The present study demonstrated that yeast beta-glucan preparation increased the body’s potential to defend against invading pathogens.

Understanding what structures ecological communities is vital to answering questions about extinctions, environmental change, trophic cascades, and ecosystem functioning. Optimal foraging theory was conceived to increase such understanding by providing a framework with which to predict species interactions and resulting community structure. Here, we use an optimal foraging model and allometries of foraging variables to predict the structure of real food webs. The qualitative structure of the resulting model provides a more mechanistic basis for the phenomenological rules of previous models. Quantitative analyses show that the model predicts up to 65% of the links in real food webs. The deterministic nature of the model allows analysis of the model's successes and failures in predicting particular interactions. Predacious and herbivorous feeding interactions are better predicted than pathogenic, parasitoid, and parasitic interactions. Results also indicate that accurate prediction and modeling of some food webs will require incorporating traits other than body size and diet choice models specific to different types of feeding interaction. The model results support the hypothesis that individual behavior, subject to natural selection, determines individual diets and that food web structure is the sum of these individual decisions.

Laryngeal morphotypes have been hypothesized related to both phonation and to laryngeal pathologies. Morphotypes have not been validated or demonstrated quantitatively and sources of shape and size variation are incompletely understood but are critical for the explanation of behavioral changes (e.g., changes of physical properties of a voice) and for therapeutic approaches to the larynx. This is the first study to take this crucial step and results are likely to have implications for surgeons and speech language pathologists. A stratified human sample was interrogated for phenotypic variation of the vocal organ. First, computed tomography image stacks were used to generate three-dimensional reconstructions of the thyroid cartilage. Then cartilage shapes were quantified using multivariate statistical analysis of high dimensional shape data from margins and surfaces of the thyroid cartilage. The effects of sex, age, body mass index (BMI) and body height on size and shape differences were analyzed. We found that sex, age, BMI and the age–sex interaction showed significant effects on the mixed sex sample. Among males, only age showed a strong effect. The thyroid cartilage increased in overall size, and the angulation between left and right lamina decreased in older males. Age, BMI and the age–height interaction were statistically significant factors within females. The angulation between left and right lamina increased in older females and was smaller in females with greater BMI. A cluster analysis confirmed the strong age effect on larynx shape in males and a complex interaction between the age, BMI and height variables in the female sample. The investigation demonstrated that age and BMI, two risk factors in a range of clinical conditions, are associated with shape and size variation of the human larynx. The effects influence shape differently in female and male larynges. The male–female shape dichotomy is partly size-dependent but predominantly size-independent.

Epithelial cell adhesion molecule (Ep-CAM; CD326) is used as a target by many immunotherapeutic approaches, but little data are available about Ep-CAM expression in major human malignancies with respect to level, frequency, tumour stage, grade, histologic tumour type and impact on survival. We analysed by immunohistochemical staining tissue microarrays with 4046 primary human carcinoma samples from colon, stomach, prostate and lung cancers for both frequency and intensity of Ep-CAM expression under highly standardised conditions. A total of 3360 samples were analysable. High-level Ep-CAM expression was observed in 97.7% ( n =1186) of colon, 90.7% of gastric ( n =473), and 87.2% of prostate cancers ( n =414), and in 63.9% of lung cancers ( n =1287). No detectable Ep-CAM staining was found with only 0.4% of colon, 2.5% of gastric, 1.9% of prostate cancers, and 13.5% of lung cancers. The only significant correlation of Ep-CAM expression with tumour grading was observed in colon cancer where high-level Ep-CAM expression on grade 3 tumours was down to 92.1% ( P <0.0001). Adenosquamous and squamous carcinomas of the lung had a lower percentage of high-level Ep-CAM expression compared to adenocarcinomas with 35.4 and 53.6%, respectively, and with 45.5 and 17.3% of tumours being Ep-CAM negative. With the exception of moderately differentiated colon carcinoma, where patients not expressing Ep-CAM on their tumours showed an inferior survival ( P =0.0014), correlation of Ep-CAM expression with survival did not reach statistical significance for any of the other cancer indications and subgroups. In conclusion, the data strongly support the notion that Ep-CAM is a prime target for immunotherapies in major human malignancies. This is because the most common human cancers show (i) a low frequency of Ep-CAM-negative tumours, (ii) a high frequency of Ep-CAM expression on cells of a given tumour, and (iii) for most cancers, an insignificant influence of tumour staging, grading and histology on Ep-CAM expression.

The unique avian vocal organ, the syrinx, is located at the caudal end of the trachea. Although a larynx is also present at the opposite end, birds phonate only with the syrinx. Why only birds evolved a novel sound source at this location remains unknown, and hypotheses about its origin are largely untested. Here, we test the hypothesis that the syrinx constitutes a biomechanical advantage for sound production over the larynx with combined theoretical and experimental approaches. We investigated whether the position of a sound source within the respiratory tract affects acoustic features of the vocal output, including fundamental frequency and efficiency of conversion from aerodynamic energy to sound. Theoretical data and measurements in three bird species suggest that sound frequency is influenced by the interaction between sound source and vocal tract. A physical model and a computational simulation also indicate that a sound source in a syringeal position produces sound with greater efficiency. Interestingly, the interactions between sound source and vocal tract differed between species, suggesting that the syringeal sound source is optimized for its position in the respiratory tract. These results provide compelling evidence that strong selective pressures for high vocal efficiency may have been a major driving force in the evolution of the syrinx. The longer trachea of birds compared to other tetrapods made them likely predisposed for the evolution of a syrinx. A long vocal tract downstream from the sound source improves efficiency by facilitating the tuning between fundamental frequency and the first vocal tract resonance.

Purpose: The larynx plays a role in swallowing, respiration, and voice production. All three functions change during ontogeny. We investigated ontogenetic shape changes using a mouse model to inform our understanding of how laryngeal form and function are integrated. We understand the characterization of developmental changes to larynx anatomy as a critical step toward using rodent models to study human vocal communication disorders. Method: Contrast-enhanced micro-computed tomography image stacks were used to generate three-dimensional reconstructions of the CD-1 mouse (\"Mus musculus\") laryngeal cartilaginous framework. Then, we quantified size and shape in four age groups: pups, weanlings, young, and old adults using a combination of landmark and linear morphometrics. We analyzed postnatal patterns of growth and shape in the laryngeal skeleton, as well as morphological integration among four laryngeal cartilages using geometric morphometric methods. Acoustic analysis of vocal patterns was employed to investigate morphological and functional integration. Results: Four cartilages scaled with negative allometry on body mass. Additionally, thyroid, arytenoid, and epiglottic cartilages, but not the cricoid cartilage, showed shape change associated with developmental age. A test for modularity between the four cartilages suggests greater independence of thyroid cartilage shape, hinting at the importance of embryological origin during postnatal development. Finally, mean fundamental frequency, but not fundamental frequency range, varied predictably with size. Conclusion: In a mouse model, the four main laryngeal cartilages do not develop uniformly throughout the first 12 months of life. High-dimensional shape analysis effectively quantified variation in shape across development and in relation to size, as well as clarifying patterns of covariation in shape among cartilages and possibly the ventral pouch.

The mammalian larynx is a complex structure of mixed embryological origin, with its evolutionary diversification and its form–function relationship of interest to biologists and clinicians. This study compared the size and shape of the laryngeal cartilaginous framework and airway in two phylogenetically distant mouse species, the California mouse and House mouse, with distinct vocal behaviours. Using three-dimensional imaging and geometric morphometrics, we analysed ontogenetic shape changes from birth to old age to assess species differences, developmental trajectories and integration of cartilage shape. While statistically significant species-specific differences were found, they were minor, and neither species exhibited sexual dimorphism in laryngeal shape or size. A pronounced ontogenetic change in the relative size of the ventral pouch was observed in California mice but not in House mice. Shape changes from neonatal to adult stages were largely conserved across species, with the notable exception of the arytenoid cartilage, which exhibited divergent postnatal trajectories and integration patterns. Despite differences in vocal behaviour and phylogenetic distance, overall laryngeal morphology was remarkably similar. These findings highlight the need to consider additional selective pressures beyond vocal function in shaping laryngeal anatomy across rodents.

Diversification of animal vocalizations plays a key role in behavioral evolution and speciation. Vocal organ morphology represents an important source of acoustic variation, yet its small size, complex shape, and absence of homologous landmarks pose major challenges to comparative analyses. Here, we use a geometric morphometric approach based on geometrically homologous landmarks to quantify shape variation of laryngeal cartilages of four rodent genera representing three families. Reconstructed cartilages of the larynx from contrast-enhanced micro-CT images were quantified by variable numbers of three-dimensional landmarks placed on structural margins and major surfaces. Landmark sets were superimposed using generalized Procrustes analysis prior to statistical analysis. Correlations among pairwise Procrustes distances were used to identify the minimum number of landmarks necessary to fully characterize shape variation. We found that the five species occupy distinct positions in morphospace, with variation explained in part by phylogeny, body size, and differences in vocal production mechanisms. Our findings provide a foundation for quantifying the contribution of vocal organ morphology to acoustic diversification.

Two-neutrino double electron capture (2νECEC) is a second-order weak-interaction process with a predicted half-life that surpasses the age of the Universe by many orders of magnitude1. Until now, indications of 2νECEC decays have only been seen for two isotopes2,3,4,5, 78Kr and 130Ba, and instruments with very low background levels are needed to detect them directly with high statistical significance6,7. The 2νECEC half-life is an important observable for nuclear structure models8,9,10,11,12,13,14 and its measurement represents a meaningful step in the search for neutrinoless double electron capture—the detection of which would establish the Majorana nature of the neutrino and would give access to the absolute neutrino mass15,16,17. Here we report the direct observation of 2νECEC in 124Xe with the XENON1T dark-matter detector. The significance of the signal is 4.4 standard deviations and the corresponding half-life of 1.8 × 1022 years (statistical uncertainty, 0.5 × 1022 years; systematic uncertainty, 0.1 × 1022 years) is the longest measured directly so far. This study demonstrates that the low background and large target mass of xenon-based dark-matter detectors make them well suited for measuring rare processes and highlights the broad physics reach of larger next-generation experiments18,19,20.