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Summary: The identification of switched systems amounts to a mixed integer nonlinear optimization problem, where the continuous variables are associated to the model parameterizations of the different modes, and the discrete ones are related to the switching signal (each data sample is assigned to a mode, and switching occurs when the mode assignment changes over time). In the batch form of the identification problem, the combinatorial complexity increases exponentially with the size of the training set, which makes the precise identification of the switching signal the most challenging task in the identification problem. To tackle this complexity we propose a distributed optimization approach, based on the solution of multiple instances of a much simpler problem, where switching can occur only at specific time instants (different for each subproblem), and an information sharing mechanism that preserves likely switching times to improve the local solutions. We employ an adapted version of a previously developed randomized algorithm to solve the individual subproblems. Another important feature of the proposed method is an a posteriori heuristic correction method, that is applied to further refine the switching locations based on the estimated local models before the information sharing phase. The performance of the proposed algorithm is analyzed and compared with other methods on synthetic datasets. [ABSTRACT FROM AUTHOR]

Aims: Yolk sac tumour postpubertal‐type (YSTpt) shows a wide range of histological patterns and is challenging to diagnose. Recently, forkhead box transcription factor A2 (FoxA2) emerged as a driver of YSTpt formation and a promising marker for diagnosing YSTpt. However, FoxA2 has not been tested in the different patterns of YSTpt. This study aimed to assess the staining pattern of FoxA2 in te different patterns of YSTpt and other germ cell tumours of the testis (GCTT), comparing it with glypican‐3 (GPC3) and α‐fetoprotein (AFP). Methods and results: FOXA2, GPC3 and AFP immunohistochemistry was performed on 24 YSTpt (24 microcystic/reticular, 10 myxoid, two macrocystic, five glandular/alveolar, two endodermal sinus/perivascular, four solid, two polyembryoma/embryoid body and two polyvesicular vitelline) and 81 other GCTT. The percentage of positive cells (0, 1+, 2+, 3+) and the intensity (0, 1, 2, 3) were evaluated regardless of and within each YSTpt pattern. FoxA2 was positive in all YSTpt (24 of 24) and all but one (23 of 24) exhibited 2+/3+ stain, with higher intensity [median value (mv): 2.6] than AFP (1.8) and GPC3 (2.5). Both FoxA2 and GPC3 were positive in all microcystic/reticular (24 of 24), myxoid (10 of 10), macrocystic (two of two), endodermal sinus/perivascular (four of four) and polyembryoma/embryoid body (two of two) patterns. Nevertheless, only FoxA2 was positive in all glandular/alveolar (five of five), solid (four of four) and polyvesicular vitelline (two of two) patterns. The intensity of FoxA2 was higher than AFP and GPC3 in almost all YST patterns. In the other GCTT, FoxA2 was positive only in teratoma postpubertal‐type (Tpt) [13 of 20 (65%)], with staining almost exclusively confined to the mature gastrointestinal/respiratory tract epithelium. Conclusions: FoxA2 is a highly sensitive and specific biomarker that supports the diagnosis of YSTpt. FoxA2 is superior to GPC3 and AFP, especially in rare and difficult‐to‐diagnose histological patterns of YSTpt, but mature glands of Tpt could represent a potential diagnostic pitfall. [ABSTRACT FROM AUTHOR]

Summary: Wheat‐based vegan muffins were formulated with increasing levels (0, 5 and 10 g per 100 g substitutes to flour) of dried grape pomace powder obtained after distillation (DGPP). The DGPP‐muffins showed a greater (P < 0.05) total dietary fibre and a lower (P < 0.05) total starch content to the control. The inclusion of DGPP influenced (P < 0.05) both the batter's rheological properties and the baked muffins' technological characteristics, including the baking loss, the volume, the firmness, the spread ratio and the colour. The in vitro antioxidant activity and the phenolic content increased (P < 0.05) following DGPP inclusion. The untargeted phenolic profiling by UHPLC‐HRMS revealed an (P < 0.05) increase of several phenolic classes (i.e. free and bound fractions) following the inclusion of DGPP in the recipe. Flavonoids, mainly anthocyanins, were the most abundant compounds. A quantitative descriptive sensory analysis detected the DGPP‐vegan muffins showed good sensory acceptability. The vegan muffin with 5 g per 100 g of DGPP obtained the highest overall acceptability score by the panellists. [ABSTRACT FROM AUTHOR]

BACKGROUND: Grape pomace (GP), a wine‐making by‐product rich in dietary fiber (DF) and total phenolic compounds (TPC), is a potential functional ingredient in the fortification of baked goods. RESULTS: In the present study, fortified breadsticks samples were obtained by replacing wheat flour with 0, 5 and 10 g 100 g−1 of powdered GP (GPP). The GPP inclusion affected the rheological properties of the doughs by increasing the water absorption and tenacity (P) at the same time as reducing the extensibility (L), with a significant increase in the P/L value and a decrease in the swelling index (G) value and deformation energy (W). Textural characteristics of breadsticks were influenced by the GPP addition, showing a reduction in hardness and fracturability as the amount of GPP increased in the recipe. The GPP fortified breadsticks exhibited decreased pH, volume and specific volume values compared to the control. The TPC and the antioxidant capacity increased in GPP fortified breadsticks, whereas the increased amount of DF allowed the products to benefit from the claim 'high fiber content' at the highest level of GPP inclusion. The sensory evaluation revealed that GPP addition increased wine odor, acidity, bitterness, astringency and hardness, and decreased the regularity of alveolation and friability. Finally, the GPP fortified products achieved good sensorial acceptability. CONCLUSION: GPP improved the nutritional values of fortified breadsticks and changed the rheology of dough and breadsticks' technological properties without affecting sensory acceptability. © 2021 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Summary: Reducing food waste is a priority to move towards more sustainable food systems. Since agro‐food by‐products are often rich in healthy compounds, such as fibre, phytochemicals, protein, fatty acids, vitamins and minerals, the waste valorisation could move through their transformation into ingredients useful for the formulation of functional foods. Pasta is a staple food widely consumed all over the world representing an optimal carrier for nutrients delivery. The incorporation of ingredients of a high added value obtained by agro‐industrial by‐products in pasta can improve its nutritional value and provides several health benefits. At the same time, the inclusion of new ingredients could modify the physical, chemical and textural properties determining the change of the organoleptic characteristics of fortified pasta, affecting its acceptability. Thus, the preparation of new pasta formulations with high nutritional properties, good technological and sensory characteristics represents a challenge for the food industry. [ABSTRACT FROM AUTHOR]

In this study, we use temporally aligned word embeddings and a large diachronic corpus of English to quantify language change in a data‐driven, scalable way, which is grounded in language use. We show a unique and reliable relation between measures of language change and age of acquisition (AoA) while controlling for frequency, contextual diversity, concreteness, length, dominant part of speech, orthographic neighborhood density, and diachronic frequency variation. We analyze measures of language change tackling both the change in lexical representations and the change in the relation between lexical representations and the words with the most similar usage patterns, showing that they capture different aspects of language change. Our results show a unique relation between language change and AoA, which is stronger when considering neighborhood‐level measures of language change: Words with more coherent diachronic usage patterns tend to be acquired earlier. The results support theories positing a link between ontogenetic and ethnogenetic processes in language. [ABSTRACT FROM AUTHOR]

New particle formation in the Arctic atmosphere is an important source of aerosol particles. Understanding the processes of Arctic secondary aerosol formation is crucial due to their significant impact on cloud properties and therefore Arctic amplification. We observed the molecular formation of new particles from low‐volatility vapors at two Arctic sites with differing surroundings. In Svalbard, sulfuric acid (SA) and methane sulfonic acid (MSA) contribute to the formation of secondary aerosol and to some extent to cloud condensation nuclei (CCN). This occurs via ion‐induced nucleation of SA and NH3 and subsequent growth by mainly SA and MSA condensation during springtime and highly oxygenated organic molecules during summertime. By contrast, in an ice‐covered region around Villum, we observed new particle formation driven by iodic acid but its concentration was insufficient to grow nucleated particles to CCN sizes. Our results provide new insight about sources and precursors of Arctic secondary aerosol particles. Plain Language Summary: Cloud properties are sensitive to the formation of new aerosol particles in the Arctic atmosphere, yet little is known about the chemistry and processes controlling this phenomenon. Here, based on comprehensive in situ measurements, we identify the very first steps of atmospheric new particle formation, that is, formation of small clusters from compounds present in the gas phase, and candidates for the subsequent growth of these clusters to larger sizes, at two Arctic sites: one surrounded by open waters, the other one by sea ice. We show how environmental differences affect secondary aerosol formation via emissions and atmospheric chemistry of aerosol precursor gases. Our results provide previously unidentified insight into how future changes in the Polar environment could be reflected in the chain of processes linking the Arctic biosphere and cryosphere to atmospheric aerosol particles, clouds, and climate. Key Points: Secondary aerosol formation studied at two sites in the atmosphere of the high ArcticIn situ measurements observing precursor gases and further following the growth of particles up to cloud condensation nuclei sizesWe observed significant differences of new particle formation above open ocean versus sea ice surroundings [ABSTRACT FROM AUTHOR]

Mutations in MECP2 cause several neurological disorders of which Rett syndrome (RTT) represents the best‐defined condition. Although mainly working as a transcriptional repressor, MeCP2 is a multifunctional protein revealing several activities, the involvement of which in RTT remains obscure. Besides being mainly localized in the nucleus, MeCP2 associates with the centrosome, an organelle from which primary cilia originate. Primary cilia function as "sensory antennae" protruding from most cells, and a link between primary cilia and mental illness has recently been reported. We herein demonstrate that MeCP2 deficiency affects ciliogenesis in cultured cells, including neurons and RTT fibroblasts, and in the mouse brain. Consequently, the cilium‐related Sonic Hedgehog pathway, which is essential for brain development and functioning, is impaired. Microtubule instability participates in these phenotypes that can be rescued by HDAC6 inhibition together with the recovery of RTT‐related neuronal defects. Our data indicate defects of primary cilium as a novel pathogenic mechanism that by contributing to the clinical features of RTT might impact on proper cerebellum/brain development and functioning, thus providing a novel therapeutic target. Synopsis: MeCP2 mutations affect homeostasis and functioning of the primary cilium, a "sensory antenna" whose defects are often linked with mental illness. Restoration of ciliogenesis promotes Mecp2 null neuronal maturation, suggesting new therapeutic approaches for Rett syndrome. MeCP2 deficiency affects ciliogenesis in cultured cells and in the mouse brain.The cilium‐related Sonic Hedgehog pathway, which is essential for brain development and functioning, is defective in cells modeling Rett syndrome.In Rett cells, the increased HDAC6 activity causes microtubule instability, therefore affecting ciliogenesis.HDAC6 inhibition at the primary cilium level ameliorates dendritic arborization and synaptogenesis in Mecp2 null neurons, therefore prompting future preclinical studies. [ABSTRACT FROM AUTHOR]

Summary: Kalman filtering for linear systems is known to provide the minimum variance estimation error, under the assumption that the model dynamics is known. While many system identification tools are available for computing the system matrices from experimental data, estimating the statistics of the output and process noises is still an open problem. Correlation‐based approaches are very fast and sufficiently accurate, but there are typically restrictions on the number of noise covariance elements that can be estimated. On the other hand, maximum likelihood methods estimate all elements with high accuracy, but they are computationally expensive, and they require the use of external optimization solvers. In this paper, we propose an alternative solution, tailored for process noise covariance estimation and based on stochastic approximation and gradient‐free optimization, that provides a good trade‐off in terms of performance and computational load, and is also easy to implement. The effectiveness of the method as compared to the state of the art is shown on a number of recently proposed benchmark examples. [ABSTRACT FROM AUTHOR]

Key points: Tymothy syndrome (TS) is a multisystem disorder featuring cardiac arrhythmias, autism and adrenal gland dysfunction that originates from a de novo point mutation in the gene encoding the Cav1.2 (CACNA1C) L‐type channel.To study the role of Cav1.2 channel signals in autism, the autistic TS2‐neo mouse has been generated bearing the G406R point‐mutation associated with TS type‐2.Using heterozygous TS2‐neo mice, we report that the G406R mutation reduces the rate of inactivation and shifts leftward the activation and inactivation of L‐type channels, causing marked increase of resting Ca2+ influx ('window' Ca2+ current).The increased 'window current' causes marked reduction of NaV channel density, switches normal tonic firing to abnormal burst firing, reduces mitochondrial metabolism, induces cell swelling and decreases catecholamine release.Overnight incubations with nifedipine rescue NaV channel density, normal firing and the quantity of catecholamine released. We provide evidence that chromaffin cell malfunction derives from altered Cav1.2 channel gating. L‐type voltage‐gated calcium (Cav1) channels have a key role in long‐term synaptic plasticity, sensory transduction, muscle contraction and hormone release. A point mutation in the gene encoding Cav1.2 (CACNA1C) causes Tymothy syndrome (TS), a multisystem disorder featuring cardiac arrhythmias, autism spectrum disorder (ASD) and adrenal gland dysfunction. In the more severe type‐2 form (TS2), the missense mutation G406R is on exon 8 coding for the IS6‐helix of the Cav1.2 channel. The mutation causes reduced inactivation and induces autism. How this occurs and how Cav1.2 gating‐changes alter cell excitability, neuronal firing and hormone release on a molecular basis is still largely unknown. Here, using the TS2‐neo mouse model of TS we show that the G406R mutation altered excitability and reduced secretory activity in adrenal chromaffin cells (CCs). Specifically, the TS2 mutation reduced the rate of voltage‐dependent inactivation and shifted leftward the activation and steady‐state inactivation of L‐type channels. This markedly increased the resting 'window' Ca2+ current that caused an increased percentage of CCs undergoing abnormal action potential (AP) burst firing, cell swelling, reduced mitochondrial metabolism and decreased catecholamine release. The increased 'window' Ca2+ current caused also decreased NaV channel density and increased steady‐state inactivation, which contributed to the increased abnormal burst firing. Overnight incubation with the L‐type channel blocker nifedipine rescued the normal AP firing of CCs, the density of functioning NaV channels and their steady‐state inactivation. We provide evidence that CC malfunction derives from the altered Cav1.2 channel gating and that dihydropyridines are potential therapeutics for ASD. Key points: Tymothy syndrome (TS) is a multisystem disorder featuring cardiac arrhythmias, autism and adrenal gland dysfunction that originates from a de novo point mutation in the gene encoding the Cav1.2 (CACNA1C) L‐type channel.To study the role of Cav1.2 channel signals in autism, the autistic TS2‐neo mouse has been generated bearing the G406R point‐mutation associated with TS type‐2.Using heterozygous TS2‐neo mice, we report that the G406R mutation reduces the rate of inactivation and shifts leftward the activation and inactivation of L‐type channels, causing marked increase of resting Ca2+ influx ('window' Ca2+ current).The increased 'window current' causes marked reduction of NaV channel density, switches normal tonic firing to abnormal burst firing, reduces mitochondrial metabolism, induces cell swelling and decreases catecholamine release.Overnight incubations with nifedipine rescue NaV channel density, normal firing and the quantity of catecholamine released. We provide evidence that chromaffin cell malfunction derives from altered Cav1.2 channel gating. [ABSTRACT FROM AUTHOR]

Objectives: To assess the predictive accuracy and the clinical value of a recent nomogram predicting cancer‐specific mortality‐free survival after surgery in pN1 prostate cancer patients through an external validation. Methods: We evaluated 518 prostate cancer patients treated with radical prostatectomy and pelvic lymph node dissection with evidence of nodal metastases at final pathology, at 10 tertiary centers. External validation was carried out using regression coefficients of the previously published nomogram. The performance characteristics of the model were assessed by quantifying predictive accuracy, according to the area under the curve in the receiver operating characteristic curve and model calibration. Furthermore, we systematically analyzed the specificity, sensitivity, positive predictive value and negative predictive value for each nomogram‐derived probability cut‐off. Finally, we implemented decision curve analysis, in order to quantify the nomogram's clinical value in routine practice. Results: External validation showed inferior predictive accuracy as referred to in the internal validation (65.8% vs 83.3%, respectively). The discrimination (area under the curve) of the multivariable model was 66.7% (95% CI 60.1–73.0%) by testing with receiver operating characteristic curve analysis. The calibration plot showed an overestimation throughout the range of predicted cancer‐specific mortality‐free survival rates probabilities. However, in decision curve analysis, the nomogram's use showed a net benefit when compared with the scenarios of treating all patients or none. Conclusions: In an external setting, the nomogram showed inferior predictive accuracy and suboptimal calibration characteristics as compared to that reported in the original population. However, decision curve analysis showed a clinical net benefit, suggesting a clinical implication to correctly manage pN1 prostate cancer patients after surgery. [ABSTRACT FROM AUTHOR]

New particle formation has been estimated to produce around half of cloud-forming particles in the present-day atmosphere, via gas-to-particle conversion. Here we assess the importance of new particle formation (NPF) for both the present-day and the preindustrial atmospheres. We use a global aerosol model with parametrizations of NPF from previously published CLOUD chamber experiments involving sulfuric acid, ammonia, organic molecules, and ions. We find that NPF produces around 67% of cloud condensation nuclei at 0.2% supersaturation (CCN0.2%) at the level of low clouds in the preindustrial atmosphere (estimated uncertainty range 45-84%) and 54% in the present day (estimated uncertainty range 38-66%). Concerning causes, we find that the importance of biogenic volatile organic compounds (BVOCs) in NPF and CCN formation is greater than previously thought. Removing BVOCs and hence all secondary organic aerosol from our model reduces low-cloud-level CCN concentrations at 0.2% supersaturation by 26% in the present-day atmosphere and 41% in the preindustrial. Around three quarters of this reduction is due to the tiny fraction of the oxidation products of BVOCs that have sufficiently low volatility to be involved in NPF and early growth. Furthermore, we estimate that 40% of preindustrial CCN0.2% are formed via ion-induced NPF, compared with 27% in the present day, although we caution that the ion-induced fraction of NPF involving BVOCs is poorly measured at present. Our model suggests that the effect of changes in cosmic ray intensity on CCN is small and unlikely to be comparable to the effect of large variations in natural primary aerosol emissions. [ABSTRACT FROM AUTHOR]

Correct orientation of cell division is considered an important factor for the achievement of normal brain size, as mutations in genes that affect this process are among the leading causes of microcephaly. Abnormal spindle orientation is associated with reduction of the neuronal progenitor symmetric divisions, premature cell cycle exit, and reduced neurogenesis. This mechanism has been involved in microcephaly resulting from mutation of ASPM, the most frequently affected gene in autosomal recessive human primary microcephaly ( MCPH), but it is presently unknown how ASPM regulates spindle orientation. In this report, we show that ASPM may control spindle positioning by interacting with citron kinase ( CITK), a protein whose loss is also responsible for severe microcephaly in mammals. We show that the absence of CITK leads to abnormal spindle orientation in mammals and insects. In mouse cortical development, this phenotype correlates with increased production of basal progenitors. ASPM is required to recruit CITK at the spindle, and CITK overexpression rescues ASPM phenotype. ASPM and CITK affect the organization of astral microtubules ( MT), and low doses of MT-stabilizing drug revert the spindle orientation phenotype produced by their knockdown. Finally, CITK regulates both astral- MT nucleation and stability. Our results provide a functional link between two established microcephaly proteins. [ABSTRACT FROM AUTHOR]

This article looks at 20 years of applications of agent-based models ( ABMs) in sociology and, in particular, their explanatory achievements and methodological insights. These applications have helped sociologists to examine agent interaction in social outcomes and have helped shift analyses away from structural and aggregate factors, to the role of agency. They have improved the realism of the micro-behavioral foundations of sociological models, by complementing analytic modeling and game theory-inspired analyses. Secondly, they have helped us to dissect the role of social structures in constraining individual behavior more precisely than in variable-based sociology. Finally, simulation outcomes have given us a more dynamic view of the interplay between individual behavior and social structures, thus promoting a more evolutionary and process-based approach to social facts. Attention here has been paid to social norms, social influence, and culture dynamics, across different disciplines such as behavioral sciences, complexity science, sociology, and economics. We argue that these applications can help sociology to achieve more rigorous research standards, by promoting a modeling environment and providing tighter cross-disciplinary integration. Recently, certain methodological improvements toward model standardization, replication, and validation have been achieved. As a result, the impact of these models in sociology is expected to grow even more in the future. WIREs Comput Stat 2015, 7:284-306. doi: 10.1002/wics.1356 For further resources related to this article, please visit the . Conflict of interest: The authors have declared no conflicts of interest for this article. [ABSTRACT FROM AUTHOR]

Context We have previously demonstrated peripheral nerve enlargement in acromegaly. Objective The aim of this study was to use ultrasound (US) to assess any changes in the peripheral nerves of patients with acromegaly 1 year after the first evaluation. Patients We prospectively examined the median and ulnar nerve cross-sectional area (CSA) in 34 non-diabetic, patients with acromegaly (18 females and 16 males; 18–79 years) and 34 age-, sex-, BMI-matched controls, using a 17–5 MHz US probe. Intervention The median nerve was examined at the mid-forearm (MN-f) and at the carpal tunnel (MN-Ct) levels; the ulnar nerve at mid-forearm (UN-f) and at distal arm (UN-a). Patients were grouped according to the clinical control of the disease: ‘improved’; ‘always controlled’; ‘always uncontrolled’; and ‘worsened’. Results The median nerve at mid-forearm (MN-f), the ulnar nerve at mid-forearm (UN-f) and at distal arm (UN-a) were significantly reduced after 1-year follow-up in all patients ( P < 0·001, P < 0·008, P < 0·012, respectively). In the ‘improved’ group, there was a significant reduction of median nerve CSA examined at mid-forearm (MN-f) ( P = 0·02), and distal arm ulnar nerve CSA (UN-a) ( P = 0·002). In the other groups no statistically significant differences in ultrasound parameters were recorded. However, UN-a, UN-f, MN-f, MN-ct were still significantly higher in all groups compared with controls ( P < 0·001). Conclusion These data demonstrate that median and ulnar nerves CSA are reduced after 1 year follow-up, in line with the reduction of GH/IGF-I levels. However, as the control of the disease incompletely reverts nerve enlargement, this phenomenon could be only partially reversible. [ABSTRACT FROM AUTHOR]

Hormones and neuropeptides may influence the activities of lymphoid organs and cells via endocrine and local autocrine/paracrine pathways. A paradigm of the interactions between the neuroendocrine and immune system is sophisticatedly represented in the thymus. Indeed, receptors for these molecules are heterogeneously expressed in all subsets of thymic cells, and the communications are tuned by feedback circuitries. Herein, we focus on somatostatin (SS), a ubiquitous peptide that regulates several physiological cell processes and acts via five specific receptor (SSR) subtypes (sst1–5). Neuronal and accessory cells, so-called neuroendocrine cells, and immune cells, heterogeneously express SSRs. The functional characterization of SSRs in vivo by nuclear medicine techniques opened a complex scenario on the significance of SS/SSR pathway in immune system and related diseases. Several studies have established that SSR scintigraphy may benefit patients with chronic inflammatory and granulomatous diseases, as well as lymphoproliferative diseases. The results are sufficiently promising to warrant larger studies aimed at defining the exact role of these techniques. The development of SS analogs with antisecretory and antiproliferative effects has radically changed the management of neuroendocrine tumors. Moreover, very important recent findings, emerging from in vitro studies on SSR physiology in immune cells, will certainly expand the potential applications of SS analogs for in vivo diagnostic and therapeutic options. Indeed, the anti-inflammatory and analgesic effects of these drugs remain incompletely understood, but may prove useful in a number of autoimmune diseases. Because SS expression is absent in different immune tissues where SSRs are present, the existence of another ligand was hypothesized. In fact, it has been recently demonstrated that human lymphoid tissues and immune cells may express cortistatin (CST). CST is known to bind SSRs and shares many pharmacological and functional properties with SS. However, CST has also properties distinct from SS, and the higher expression of CST in immune cells supports the hypothesis that CST rather than SS may act as a potential endogenous ligand for SSRs in the human immune system. [ABSTRACT FROM AUTHOR]