Search

Abstract The abundance of Lp(a) protein holds significant implications for the risk of cardiovascular disease (CVD), which is directly impacted by the copy number (CN) of KIV-2, a 5.5 kbp sub-region. KIV-2 is highly polymorphic in the population and accurate analysis is challenging. In this study, we present the DRAGEN KIV-2 CN caller, which utilizes short reads. Data across 166 WGS show that the caller has high accuracy, compared to optical mapping and can further phase approximately 50% of the samples. We compared KIV-2 CN numbers to 24 previously postulated KIV-2 relevant SNVs, revealing that many are ineffective predictors of KIV-2 copy number. Population studies, including USA-based cohorts, showed distinct KIV-2 CN, distributions for European-, African-, and Hispanic-American populations and further underscored the limitations of SNV predictors. We demonstrate that the CN estimates correlate significantly with the available Lp(a) protein levels and that phasing is highly important.

Lipoprotein (a) (Lp(a)) is a risk factor for cardiovascular diseases and mainly regulated by the complex LPA gene. We investigated the types of variation in the LPA gene and their predictive performance on Lp(a) concentration. We determined the Kringle IV-type 2 (KIV-2) copy number (CN) using the DRAGEN LPA Caller (DLC) and a read depth-based CN estimator in 8351 short-read whole genome sequencing samples from the GENESIS-HD study. The pentanucleotide repeat in the promoter region was genotyped with GangSTR and ExpansionHunter. Lp(a) concentration was available in 4861 population-based subjects. Predictive performance on Lp(a) concentration was investigated using random forests. The agreement of the KIV-2 CN between the two specialized callers was high (r = 0.9966; 95% confidence interval [CI] 0.9965–0.9968). Allele-specific KIV-2 CN could be determined in 47.0% of the subjects using the DLC. Lp(a) concentration can be better predicted from allele-specific KIV-2 CN than total KIV-2 CN. Two single nucleotide variants, 4925G>A and rs41272114C>T, further improved prediction. The genetically complex LPA gene can be analyzed with excellent agreement between different callers. The allele-specific KIV-2 CN is more important for predicting Lp(a) concentration than the total KIV-2 CN.

We present a hybrid trapping platform that allows us to levitate a charged nanoparticle in high vacuum using either optical fields, radio-frequency fields, or a combination thereof. Our hybrid approach combines an optical dipole trap with a linear Paul trap while maintaining a large numerical aperture (0.77 NA). We detail a controlled transfer procedure that allows us to use the Paul trap as a “safety net” to recover particles lost from the optical trap at high vacuum. The presented hybrid platform adds to the toolbox of levitodynamics and represents an important step towards fully controllable “dark” potentials, providing control in the absence of decoherence because of photon recoil.

Modern lifestyle greatly influences human well-being. Indeed, nowadays people are centered in the cities and this trend is growing with the ever-increasing population. The main habitat for modern humans is defined as the built environment (BE). The modulation of life quality in the BE is primarily mediated by a biodiversity of microbes. They derive from different sources, such as soil, water, air, pets, and humans. Humans are the main source and vector of bacterial diversity in the BE leaving a characteristic microbial fingerprint on the surfaces and spaces. This review, focusing on articles published from the early 2000s, delves into bacterial populations present in indoor and outdoor urban environments, exploring the characteristics of primary bacterial niches in the BE and their native habitats. It elucidates bacterial interconnections within this context and among themselves, shedding light on pathways for adaptation and survival across diverse environmental conditions. Given the limitations of culture-based methods, emphasis is placed on culture-independent approaches, particularly high-throughput techniques to elucidate the genetic and -omic features of BE bacteria. By elucidating these microbiota profiles, the review aims to contribute to understanding the implications for human health and the assessment of urban environmental quality in modern cities.

Generating macroscopic nonclassical quantum states is a long-standing challenge in physics. Anharmonic dynamics is an essential ingredient to generate these states, but for large mechanical systems, the effect of the anharmonicity tends to become negligible compared with the effect of decoherence. As a possible solution to this challenge, we propose using a motional squeezed state as a resource to effectively increase the anharmonicity. We analyze the production of negativity in the Wigner distribution of a quantum anharmonic resonator initially in a squeezed state. We find that initial squeezing increases the rate at which negativity is generated. We also analyze the effect of two common sources of decoherence—namely, energy damping and dephasing—and find that the detrimental effects of energy damping are suppressed by strong squeezing. In the limit of large squeezing, which is needed for state-of-the-art systems, we find good approximations for the Wigner function. Our analysis is significant for current experiments attempting to prepare macroscopic mechanical systems in genuine quantum states. We provide an overview of several experimental platforms featuring nonlinear behaviors and low levels of decoherence. In particular, we discuss the feasibility of our proposal with carbon nanotubes and levitated nanoparticles.

Ultrasonic signals can be conveniently recorded using modern high-speed analog-to-digital converters and analyzed through digital signal processing algorithms. Sometimes, in some applications, such as in bioacoustics, it is necessary to convert digital data to analog signals with a special transformation that allows compressing and translating the spectrum toward audible frequencies. The process is called time expansion and can be conveniently achieved by slowing down the frequency clock of a digital-to-analog converter. This paper analyzes in detail the spectral characteristics of a time-expanded signal.

Abstract Genomics analyses use large reference sequence collections, like pangenomes or taxonomic databases. SPUMONI 2 is an efficient tool for sequence classification of both short and long reads. It performs multi-class classification using a novel sampled document array. By incorporating minimizers, SPUMONI 2’s index is 65 times smaller than minimap2’s for a mock community pangenome. SPUMONI 2 achieves a speed improvement of 3-fold compared to SPUMONI and 15-fold compared to minimap2. We show SPUMONI 2 achieves an advantageous mix of accuracy and efficiency in practical scenarios such as adaptive sampling, contamination detection and multi-class metagenomics classification.

Motivated by the increasing need of optimised micro-devices for droplet production in medical and biological applications, this paper introduces an integrated approach for the study of the liquid–liquid droplet creation in flow-focusing micro cross-junctions. The micro-junction considered is characterised by a restriction of the channels cross-sections in the junction, which has the function of focusing the flow in the region of the droplet formation. The problem is studied numerically in the OpenFOAM environment and validated by a comparison with experimental results obtained by high-speed camera images and micro-PIV measurements. The analysis of the forces acting on the dispersed phase during the droplet formation and the diameter of the droplets obtained numerically are considered for the development of a model of the droplet breakup under the squeezing regime. On the basis of energy balancing during the breakup, a relation between interfacial tension, the size of the cross-sections in the junction, and the time interval needed for droplet creation is obtained, which yields a novel correlation between the dimensionless length of the droplet and the dimensionless flow rate. This research expands our knowledge of the phenomenon of drop creation in micro-junctions with restrictions providing new aid for the optimal design of micro-drop generators.

Amelogenesis imperfecta (AI) is a heterogeneous group of genetic rare diseases disrupting enamel development (Smith et al., Front Physiol, 2017a, 8, 333). The clinical enamel phenotypes can be described as hypoplastic, hypomineralized or hypomature and serve as a basis, together with the mode of inheritance, to Witkop’s classification (Witkop, J Oral Pathol, 1988, 17, 547–553). AI can be described in isolation or associated with others symptoms in syndromes. Its occurrence was estimated to range from 1/700 to 1/14,000. More than 70 genes have currently been identified as causative.Objectives: We analyzed using next-generation sequencing (NGS) a heterogeneous cohort of AI patients in order to determine the molecular etiology of AI and to improve diagnosis and disease management.Methods: Individuals presenting with so called “isolated” or syndromic AI were enrolled and examined at the Reference Centre for Rare Oral and Dental Diseases (O-Rares) using D4/phenodent protocol (www.phenodent.org). Families gave written informed consents for both phenotyping and molecular analysis and diagnosis using a dedicated NGS panel named GenoDENT. This panel explores currently simultaneously 567 genes. The study is registered under NCT01746121 and NCT02397824 (https://clinicaltrials.gov/).Results: GenoDENT obtained a 60% diagnostic rate. We reported genetics results for 221 persons divided between 115 AI index cases and their 106 associated relatives from a total of 111 families. From this index cohort, 73% were diagnosed with non-syndromic amelogenesis imperfecta and 27% with syndromic amelogenesis imperfecta. Each individual was classified according to the AI phenotype. Type I hypoplastic AI represented 61 individuals (53%), Type II hypomature AI affected 31 individuals (27%), Type III hypomineralized AI was diagnosed in 18 individuals (16%) and Type IV hypoplastic-hypomature AI with taurodontism concerned 5 individuals (4%). We validated the genetic diagnosis, with class 4 (likely pathogenic) or class 5 (pathogenic) variants, for 81% of the cohort, and identified candidate variants (variant of uncertain significance or VUS) for 19% of index cases. Among the 151 sequenced variants, 47 are newly reported and classified as class 4 or 5. The most frequently discovered genotypes were associated with MMP20 and FAM83H for isolated AI. FAM20A and LTBP3 genes were the most frequent genes identified for syndromic AI. Patients negative to the panel were resolved with exome sequencing elucidating for example the gene involved ie ACP4 or digenic inheritance.Conclusion: NGS GenoDENT panel is a validated and cost-efficient technique offering new perspectives to understand underlying molecular mechanisms of AI. Discovering variants in genes involved in syndromic AI (CNNM4, WDR72, FAM20A … ) transformed patient overall care. Unravelling the genetic basis of AI sheds light on Witkop’s AI classification.

Abstract Background In France, the Ministry of Health has implemented a comprehensive program for rare diseases (RD) that includes an epidemiological program as well as the establishment of expert centers for the clinical care of patients with RD. Since 2007, most of these centers have entered the data for patients with developmental disorders into the CEMARA population-based registry, a national online data repository for all rare diseases. Through the CEMARA web portal, descriptive demographic data, clinical data, and the chronology of medical follow-up can be obtained for each center. We address the interest and ongoing challenges of this national data collection system 10 years after its implementation. Methods Since 2007, clinicians and researchers have reported the “minimum dataset (MDS)” for each patient presenting to their expert center. We retrospectively analyzed administrative data, demographic data, care organization and diagnoses. Results Over 10 years, 228,243 RD patients (including healthy carriers and family members for whom experts denied any suspicion of RD) have visited an expert center. Among them, 167,361 were patients affected by a RD (median age 11 years, 54% children, 46% adults, with a balanced sex ratio), and 60,882 were unaffected relatives (median age 37 years). The majority of patients (87%) were seen no more than once a year, and 52% of visits were for a diagnostic procedure. Among the 2,869 recorded rare disorders, 1,907 (66.5%) were recorded in less than 10 patients, 802 (28%) in 10 to 100 patients, 149 (5.2%) in 100 to 1,000 patients, and 11 (0.4%) in > 1,000 patients. Overall, 45.6% of individuals had no diagnosis and 6.7% had an uncertain diagnosis. Children were mainly referred by their pediatrician (46%; n = 55,755 among the 121,136 total children referrals) and adults by a medical specialist (34%; n = 14,053 among the 41,564 total adult referrals). Given the geographical coverage of the centers, the median distance from the patient’s home was 25.1 km (IQR = 6.3 km-64.2 km). Conclusions CEMARA provides unprecedented support for epidemiological, clinical and therapeutic studies in the field of RD. Researchers can benefit from the national scope of CEMARA data, but also focus on specific diseases or patient subgroups. While this endeavor has been a major collective effort among French RD experts to gather large-scale data into a single database, it provides tremendous potential to improve patient care.

Abstract Background Pathogenic variants of the AUTS2 (Autism Susceptibility candidate 2) gene predispose to intellectual disability, autism spectrum disorder, attention deficit hyperactivity disorder, facial dysmorphism and short stature. This phenotype is therefore associated with neurocognitive disturbances and social cognition, indicating potential functional maladjustment in the affected subjects, and a potentially significant impact on quality of life. Although many isolated cases have been reported in the literature, to date no families have been described. This case reports on a family (three generations) with a frameshift variant in the AUTS2 gene. Case presentation The proband is 13 years old with short stature, dysmorphic features, moderate intellectual disability and autism spectrum disorder. His mother is 49 years old and also has short stature and similar dysmorphic features. She does not have autism disorder but presents an erotomaniac delusion. Her cognitive performance is heterogeneous. The two aunts are also of short stature. The 50-year-old aunt has isolated social cognition disorders. The 45-year-old aunt has severe cognitive impairment and autism spectrum disorder. The molecular analysis of the three sisters and the proband shows the same AUTS2 heterozygous duplication leading to a frame shift expected to produce a premature stop codon, p.(Met593Tyrfs*85). Previously reported isolated cases revealed phenotypic and cognitive impairment variability. In this case report, these variabilities are present within the same family, presenting the same variant. Conclusions The possibility of a phenotypic spectrum within the same family highlights the need for joint psychiatry and genetics research.

Abstract Genome wide optical maps are high resolution restriction maps that give a unique numeric representation to a genome. They are produced by assembling hundreds of thousands of single molecule optical maps, which are called Rmaps. Unfortunately, there are very few choices for assembling Rmap data. There exists only one publicly-available non-proprietary method for assembly and one proprietary software that is available via an executable. Furthermore, the publicly-available method, by Valouev et al. (Proc Natl Acad Sci USA 103(43):15770–15775, 2006), follows the overlap-layout-consensus (OLC) paradigm, and therefore, is unable to scale for relatively large genomes. The algorithm behind the proprietary method, Bionano Genomics’ Solve, is largely unknown. In this paper, we extend the definition of bi-labels in the paired de Bruijn graph to the context of optical mapping data, and present the first de Bruijn graph based method for Rmap assembly. We implement our approach, which we refer to as rmapper, and compare its performance against the assembler of Valouev et al. (Proc Natl Acad Sci USA 103(43):15770–15775, 2006) and Solve by Bionano Genomics on data from three genomes: E. coli, human, and climbing perch fish (Anabas Testudineus). Our method was able to successfully run on all three genomes. The method of Valouev et al. (Proc Natl Acad Sci USA 103(43):15770–15775, 2006) only successfully ran on E. coli. Moreover, on the human genome rmapper was at least 130 times faster than Bionano Solve, used five times less memory and produced the highest genome fraction with zero mis-assemblies. Our software, rmapper is written in C++ and is publicly available under GNU General Public License at https://github.com/kingufl/Rmapper .

Gravitational wave astronomy is on a path to increase the sensitivity and bandwidth of their detectors to afford the possibility to study a larger variety of sources and physical processes. The authors present solutions to enhance the sensitivity of a laser interferometric gravitational wave detector in the frequency band of 1-5 kHz using optomechanics-based white light signal recycling technologies, overcoming previous limitations of signal recycling.

A technique devised some years ago permits us to develop a theory regarding a regime of strong perturbations. This translates into a gradient expansion that, at the leading order, can recover the Belinsky-Kalathnikov-Lifshitz solution for general relativity. We solve exactly the leading order Einstein equations in a spherical symmetric case, assuming a Schwarzschild metric under the effect of a time-dependent perturbation, and we show that the 4-velocity in such a case is multiplied by an exponential warp factor when the perturbation is properly applied. This factor is always greater than one. We will give a closed form solution of this factor for a simple case. Some numerical examples are also given.

Background: Achondroplasia is the most common short-limbed skeletal dysplasia resulting from gain-of-function pathogenic variants in fibroblast growth factor receptor 3 ( FGFR3 ) gene, a negative regulator of endochondral bone formation. Most treatment options are symptomatic, targeting medical complications. Infigratinib is an orally bioavailable, FGFR1–3 selective tyrosine kinase inhibitor being investigated as a direct therapeutic strategy to counteract FGFR3 overactivity in achondroplasia. Objectives: The main objective of PROPEL is to collect baseline data of children with achondroplasia being considered for future enrollment in interventional studies sponsored by QED Therapeutics. The objectives of PROPEL 2 are to obtain preliminary evidence of safety and efficacy of oral infigratinib in children with achondroplasia, to identify the infigratinib dose to be explored in future studies, and to characterize the pharmacokinetic (PK) profile of infigratinib and major metabolites. Design: PROPEL (NCT04035811) is a prospective, noninterventional clinical study designed to characterize the natural history and collect baseline data of children with achondroplasia over 6−24 months. PROPEL 2 (NCT04265651), a prospective, phase II, open-label study of infigratinib in children with achondroplasia, consists of a dose-escalation, dose-finding, and dose-expansion phase to confirm the selected dose, and a PK substudy. Methods and analysis: Children aged 3−11 years with achondroplasia who completed ⩾6 months in PROPEL are eligible for PROPEL 2. Primary endpoints include treatment-emergent adverse events and change from baseline in annualized height velocity. Four cohorts at ascending dose levels are planned for dose escalation. The selected dose will be confirmed in the dose-expansion phase. Ethics: PROPEL and PROPEL 2 are being conducted in accordance with the International Conference on Harmonization Good Clinical Practice guidelines, principles of the Declaration of Helsinki, and relevant human clinical research and data privacy regulations. Protocols have been approved by local health authorities, ethics committees, and institutions as applicable. Parents/legally authorized representatives are required to provide signed informed consent; signed informed assent by the child is also required, where applicable. Discussion: PROPEL and PROPEL 2 will provide preliminary evidence of the safety and efficacy of infigratinib as precision treatment of children with achondroplasia and will inform the design of future studies of FGFR-targeted agents in achondroplasia. Registration: ClinicalTrials.gov: NCT04035811; NCT04265651.

Abstract Background The European Reference Networks, ERNs, are virtual networks for healthcare providers across Europe to collaborate and share expertise on complex or rare diseases and conditions. As part of the ERNs, the Clinical Patient Management System, CPMS, a secure digital platform, was developed to allow and facilitate web-based, clinical consultations between submitting clinicians and relevant international experts. The European Reference Network on Intellectual Disability, TeleHealth and Congenital Anomalies, ERN ITHACA, was formed to harness the clinical and diagnostic expertise in the sector of rare, multiple anomaly and/or intellectual disability syndromes, chromosome disorders and undiagnosed syndromic disorders. We present the first year results of CPMS use by ERN ITHACA as an example of a telemedicine strategy for the diagnosis and management of patients with rare developmental disorders. Results ERN ITHACA ranked third in telemedicine activity amongst 24 European networks after 12 months of using the CPMS. Information about 28 very rare cases from 13 different centres across 7 countries was shared on the platform, with diagnostic or other management queries. Early interaction with patient support groups identified data protection as of primary importance in adopting digital platforms for patient diagnosis and care. The first launch of the CPMS was built to accommodate the needs of all ERNs. The ERN ITHACA telemedicine process highlighted a need to customise the CPMS with network-specific requirements. The results of this effort should enhance the CPMS utility for telemedicine services and ERN-specific care outcomes. Conclusions We present the results of a long and fruitful process of interaction between the ERN ITHACA network lead team and EU officials, software developers and members of 38 EU clinical genetics centres to organise and coordinate direct e-healthcare through a secure, digital platform. The variability of the queries in just the first 28 cases submitted to the ERN ITHACA CPMS is a fair representation of the complexity and rarity of the patients referred, but also proof of the sophisticated and variable service that could be provided through a structured telemedicine approach for patients and families with rare developmental disorders. Web-based approaches are likely to result in increased accessibility to clinical genomic services.

Applications of quantum information processing require distribution of quantum states for linking nodes in networks and mechanical oscillators can create versatile links. Here, the authors describe continuous variable entanglement between two optical modes mediated by a mechanical oscillator.

Supplying a piezoelectric transducer with constant voltage or constant power during a frequency sweep can lead to different results in the determination of the acoustofluidic resonance frequencies, which are observed when studying the acoustophoretic displacements and velocities of particles suspended in a liquid-filled microchannel. In this work, three cases are considered: (1) Constant input voltage into the power amplifier, (2) constant voltage across the piezoelectric transducer, and (3) constant average power dissipation in the transducer. For each case, the measured and the simulated responses are compared, and good agreement is obtained. It is shown that Case 1, the simplest and most frequently used approach, is largely affected by the impedance of the used amplifier and wiring, so it is therefore not suitable for a reproducible characterization of the intrinsic properties of the acoustofluidic device. Case 2 strongly favors resonances at frequencies yielding the lowest impedance of the piezoelectric transducer, so small details in the acoustic response at frequencies far from the transducer resonance can easily be missed. Case 3 provides the most reliable approach, revealing both the resonant frequency, where the power-efficiency is the highest, as well as other secondary resonances across the spectrum.

The need for single-camera 3D particle tracking methods is growing, among others, due to the increasing focus in biomedical research often relying on single-plane microscopy imaging. Defocusing-based methods are ideal for a wide-spread use as they rely on basic microscopy imaging rather than requiring additional non-standard optics. However, a wide-spread use has been limited by the lack of accessible and easy-to-use software. 'DefocusTracker' is an open-source toolbox based on the universal principles of General Defocusing Particle Tracking (GDPT) relying solely on a reference look-up table and image recognition to connect a particle’s image and its respective out-of-plane depth coordinate. The toolbox is built in a modular fashion, allowing for easy addition of new image recognition methods, while maintaining the same workflow and external user interface. 'DefocusTracker' is implemented in MATLAB, while a parallel implementation in Python is in the preparation.

Summary: Nanopore sequencing is an increasingly powerful tool for genomics. Recently, computational advances have allowed nanopores to sequence in a targeted fashion; as the sequencer emits data, software can analyze the data in real time and signal the sequencer to eject “nontarget” DNA molecules. We present a novel method called SPUMONI, which enables rapid and accurate targeted sequencing using efficient pan-genome indexes. SPUMONI uses a compressed index to rapidly generate exact or approximate matching statistics in a streaming fashion. When used to target a specific strain in a mock community, SPUMONI has similar accuracy as minimap2 when both are run against an index containing many strains per species. However SPUMONI is 12 times faster than minimap2. SPUMONI's index and peak memory footprint are also 16 to 4 times smaller than those of minimap2, respectively. This could enable accurate targeted sequencing even when the targeted strains have not necessarily been sequenced or assembled previously.

We propose a method for the estimation of the spectral response of a photodetector, using only the variation of the temperature of a black body source without the need of an expensive monochromator or a circular filter. The proposed method is suitable especially for infrared detectors in which the cut-off wavelength and the responsivity vs. wavelength is not exactly known. The method provides a rough estimation of the spectral response solving a Fredholm integral equation of the first kind. The precision of this technique depends on the temperatures at which the detector output is measured. Some examples are given for illustration.

Abstract Background Insufficient elastin synthesis leads to vascular complications and arterial hypertension in children with Williams-Beuren syndrome. Restoring sufficient quantity of elastin should then result in prevention or inhibition of vascular malformations and improvement in arterial blood pressure. Methods The aim of this study was to assess the efficacy and safety of minoxidil on Intima Media Thickness (IMT) on the right common carotid artery after twelve-month treatment in patient with Williams-Beuren syndrome. We performed a randomized placebo controlled double blind trial. All participants were treated for 12 months and followed for 18 months. The principal outcome was assessed by an independent adjudication committee blinded to the allocated treatment groups. Results The principal outcome was available for 9 patients in the placebo group and 8 patients in the minoxidil group. After 12-month treatment, the IMT in the minoxidil group increased by 0.03 mm (95% CI -0.002, 0.06) compared with 0.01 mm (95%CI - 0.02, 0.04 mm) in the placebo group (p = 0.4). Two serious adverse events unrelated to the treatment occurred, one in the minoxidil and 1 in the placebo group. After 18 months, the IMT increased by 0.07 mm (95% CI 0.04, 0.10 mm) in the minoxidil compared with 0.01 mm (95% CI -0.02, 0.04 mm) in the placebo group (p = 0.008). Conclusion Our results suggest a slight increase after 12 and 18-month follow-up in IMT. More understanding of the biological changes induced by minoxidil should better explain its potential role on elastogenesis in Williams-Beuren syndrome. Trials registration US National Institutes of Health Clinical Trial Register (NCT00876200). Registered 3 April 2009 (retrospectively registered).

Abstract Williams Beuren syndrome (WBS) is a multiple malformations/intellectual disability (ID) syndrome caused by 7q11.23 microdeletion and clinically characterized by a typical neurocognitive profile including excessive talkativeness and social disinhibition, often defined as “overfriendliness” and “hyersociability”. WBS is generally considered as the polar opposite phenotype to Autism Spectrum Disorder (ASD). Surprisingly, the prevalence of ASD has been reported to be significantly higher in WBS (12%) than in general population (1%). Our study aims to investigate the molecular basis of the peculiar association of ASD and WBS. We performed chromosomal microarray analysis and whole exome sequencing in six patients presenting with WBS and ASD, in order to evaluate the possible presence of chromosomal or gene variants considered as pathogenic. Our study shows that the presence of ASD in the recruited WBS patients is due to i) neither atypically large deletions; ii) nor the presence of pathogenic variants in genes localized in the non-deleted 7q11.23 allele which would unmask recessive conditions; iii) moreover, we did not identify a second, indisputable independent genetic diagnosis, related to pathogenic Copy Number Variations or rare pathogenic exonic variants in known ID/ASD causing genes, although several variants of unknown significance were found. Finally, imprinting effect does not appear to be the only cause of autism in WBS patients, since the deletions occurred in alleles of both maternal and paternal origin. The social disinhibition observed in WBS does not follow common social norms and symptoms overlapping with ASD, such as restricted interests and repetitive behavior, can be observed in “typical” WBS patients: therefore, the terms “overfriendliness” and “hypersociability” appear to be a misleading oversimplification. The etiology of ASD in WBS is likely to be heterogeneous. Further studies on large series of patients are needed to clarify the observed variability in WBS social communication, ranging from excessive talkativeness and social disinhibition to absence of verbal language and social deficit.

I partecipanti alla tavola rotonda sono chiamati a discutere i quattro quesiti forniti dalla rivista su riviste multidisciplinari, internazionalizzazione, indicizzazione e peer review. The round table participants are asked to discuss the four questions provided by the Journal on multidisciplinary journals, internationalization, indexing and peer review.

Soil salinization, one of the most common causes of soil degradation, negatively affects plant growth, reproduction, and yield in plants. Saline conditions elicit some physiological changes to cope with the imposed osmotic and oxidative stresses. Inoculation of plants with some bacterial species that stimulate their growth, i.e., plant growth-promoting bacteria (PGPB), may help plants to counteract saline stress, thus improving the plant’s fitness. This manuscript reports the effects of the inoculation of a salt-sensitive cultivar of Brassica napus (canola) with five different PGPB species (separately), i.e., Azospirillum brasilense, Arthrobacter globiformis, Burkholderia ambifaria, Herbaspirillum seropedicae, and Pseudomonas sp. on plant salt stress physiological responses. The seeds were sown in saline soil (8 dS/m) and inoculated with bacterial suspensions. Seedlings were grown to the phenological stage of rosetta, when morphological and physiological features were determined. In the presence of the above-mentioned PGPB, salt exposed canola plants grew better than non-inoculated controls. The water loss was reduced in inoculated plants under saline conditions, due to a low level of membrane damage and the enhanced synthesis of the osmolyte proline, the latter depending on the bacterial strain inoculated. The reduction in membrane damage was also due to the increased antioxidant activity (i.e., higher amount of phenolic compounds, enhanced superoxide dismutase, and ascorbate peroxidase activities) in salt-stressed and inoculated Brassica napus. Furthermore, the salt-stressed and inoculated plants did not show detrimental effects to their photosynthetic apparatus, i.e., higher efficiency of PSII and low energy dissipation by heat for photosynthesis were detected. The improvement of the response to salt stress provided by PGPB paves the way to further use of PGPB as inoculants of plants grown in saline soils.

Nutraceuticals are biologically active molecules present in foods; they can have beneficial effects on health, but they are not available in large enough quantities to perform this function. Plant metabolites, such as polyphenols, are widely diffused in the plant kingdom, where they play fundamental roles in plant development and interactions with the environment. Among these, flavonoids are of particular interest as they have significant effects on human health. In vitro and/or in vivo studies described flavonoids as essential nutrients for preventing several diseases. They display broad and promising bioactivities to fight cancer, inflammation, bacterial infections, as well as to reduce the severity of neurodegenerative and cardiovascular diseases or diabetes. Therefore, it is not surprising that interest in flavonoids has sharply increased in recent years. More than 23,000 scientific publications on flavonoids have described the potential anticancer activity of these natural molecules in the last decade. Studies, in vitro and in vivo, show that flavonoids exhibit anticancer properties, and many epidemiological studies confirm that dietary intake of flavonoids leads to a reduced risk of cancer. This review provides a glimpse of the mechanisms of action of flavonoids on cancer cells.

Introduzione /Introduction

Abstract Background Pallister–Killian syndrome (PKS) is a rare sporadic disorder caused by tetrasomy of the short arm of chromosome 12. The main clinical manifestations are global developmental delay, intellectual disability, epilepsy, dysmorphic features, hypopigmented and/or hyperpigmented lesions, and multiple congenital anomalies. PKS is associated with tissue mosaicism, which is difficult to diagnose through peripheral blood sample by conventional cytogenetic methods and fluorescence in situ hybridization. Methods Here, we report five patients with PKS. We delineate their clinical phenotypes and we compare them with previously published cases. We used array Comparative Genomic Hybridization (aCGH) with DNA extracted from peripheral blood samples. The five patients have also been tested by conventional cytogenetics techniques. Results Four out of five patients showed tetrasomy 12p by aCGH. Three of the four patients have typical i(12p) and one of the four demonstrated atypical tetrasomy 12p. The percentage of mosaicism was as low as 20%. Our cohort exhibited the typical PKS phenotypes. Conclusion Our results demonstrate the efficacy of aCGH for the diagnosis of PKS from DNA extracted from lymphocytes. Thus, for patients suspected of PKS, we recommend performing aCGH on lymphocytes at an early age before proceeding to skin biopsy. aCGH on peripheral blood samples is sensitive in detecting low level of mosaicism and it is less invasive method than skin biopsy. We reviewed also the literature concerning the previously published PKS patients diagnosed by aCGH.

The present work aimed to study suitability of a consortium of Azospirillum brasilense, Gluconacetobacter diazotrophicus, Herbaspirillum seropedicae, and Burkholderia ambifaria as biofertilizers. Strains were assayed for plant growth-promoting characteristics (i.e., auxins production, phosphate solubilizing capability, and 1-aminocyclopropane-1-carboxylate deaminase activity). The consortium of four bacteria was then inoculated on carrot seeds and tested in an open field experiment. During the open field experiment, plant growth (morphological parameters, chlorophylls, and carotenoids), soil chemical analysis, and molecular and physiological profiles of soils were investigated. Each strain produced different amounts of indole-3acetic acid and several indole-derivates molecules. All strains showed phosphate solubilization capability, while 1-aminocyclopropane-1-carboxylate deaminase activity was only detected in H. seropedicae and B. ambifaria. The bacterial consortium of the four strains gave interesting results in the open field cultivation of carrot. Plant development was positively affected by the presence of the consortium, as was soil fertility and microbial community structure and diversity. The present work allowed for deepening our knowledge on four bacteria, already known for years for having several interesting characteristics, but whose interactions were almost unknown, particularly in view of their use as a consortium in a valid fertilization strategy, in substitution of agrochemicals for a sustainable agriculture.

This study aimed to characterize the halotolerant capability, in vitro, of selected actinomycetes strains and to evaluate their competence in promoting halo stress tolerance in durum wheat in a greenhouse experiment. Fourteen isolates were tested for phosphate solubilization, indole acetic acid, hydrocyanic acid, and ammonia production under different salt concentrations (i.e., 0, 0.25, 0.5, 0.75, 1, 1.25, and 1.5 M NaCl). The presence of 1-aminocyclopropane-1-carboxylate deaminase activity was also investigated. Salinity tolerance was evaluated in durum wheat through plant growth and development parameters: shoot and root length, dry and ash-free dry weight, and the total chlorophyll content, as well as proline accumulation. In vitro assays have shown that the strains can solubilize inorganic phosphate and produce indole acetic acid, hydrocyanic acid, and ammonia under different salt concentrations. Most of the strains (86%) had 1-aminocyclopropane-1-carboxylate deaminase activity, with significant amounts of α-ketobutyric acid. In the greenhouse experiment, inoculation with actinomycetes strains improved the morpho-biochemical parameters of durum wheat plants, which also recorded significantly higher content of chlorophylls and proline than those uninoculated, both under normal and stressed conditions. Our results suggest that inoculation of halotolerant actinomycetes can mitigate the negative effects of salt stress and allow normal growth and development of durum wheat plants.

Plants grown in saline soils undergo osmotic and oxidative stresses, affecting growth and photosynthesis and, consequently, the yield. Therefore, the increase in soil salinity is a major threat to crop productivity worldwide. Plant’s tolerance can be ameliorated by applying simple methods that induce them to adopt morphological and physiological adjustments to counteract stress. In this work, we evaluated the effects of seed priming on salt stress response in three cultivars of rapeseed (Brassica napus L.) that had different tolerance levels. Seed chemical priming was performed with 2.5 mM spermine (SPM), 5 mM spermidine (SPD), 40 mM NaCl and 2.5 mM Ca (NO3)2. Primed and not primed seeds were sown on saline and not saline (controls) media, and morphological and physiological parameters were determined. Since SPD treatment was effective in reducing salinity negative effects on growth, membrane integrity and photosynthetic pigments, we selected this priming to further investigate plant salt stress response. The positive effects of this seed treatment on growth and physiological responses were evident when primed plants were compared to not primed ones, grown under the same saline conditions. SPD priming ameliorated the tolerance towards saline stress, in a genotype-independent manner, by increasing photosynthetic pigments, proline amounts and antioxidant responses in all cultivars exposed to salt. These results may open new perspectives for crop productivity in the struggle against soil salinization.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The possibility to test a radio frequency transceiver through the use of appropriate channel emulators allows evaluating their performance under various operating conditions. Many systems are able to operate with a relatively limited instantaneous bandwidth by applying known statistical models. Sometimes, it is necessary to evaluate the performance of a RF transceiver installed on high or very high speed platforms over predictable trajectories using optionally DEM (Digital Elevation Model) data of the terrain to estimate the number of stimulated paths and their contributions during the flight. When the instantaneous bandwidth of the signal becomes high (over several hundreds of MHz), one of the most important phenomena to consider is the Doppler spread induced by the channel and traditional narrowband models become useless. This paper presents some results when a time expansion is adopted to emulate the transceiver dynamic and the consequent Doppler spread with the aim of controlling the spectral purity of the emulated propagation channel.

The paper investigates the theory of operation of a passive millimeter-wave seeker sensor using a fast electronic sequential-lobing technique and the experimental validation obtained through laboratory trials. The paper analyzes in detail the theoretical performance of a difference channel sensor and a pseudo-monopulse sensor deriving agile formulas for the estimation of target angular tracking accuracy and the subsequent experimental validation.

The worldwide distribution of dengue is expanding, in part due to globalized traffic and trade. Aedes albopictus is a competent vector for dengue viruses (DENV) and is now established in numerous regions of Europe. Viremic travellers arriving in Europe from dengue-affected areas of the world can become catalysts of local outbreaks in Europe. Local dengue transmission in Europe is extremely rare, and the last outbreak occurred in 1927-28 in Greece. However, autochthonous transmission was reported from France in September 2010, and from Croatia between August and October 2010.We compiled data on areas affected by dengue in 2010 from web resources and surveillance reports, and collected national dengue importation data. We developed a hierarchical regression model to quantify the relationship between the number of reported dengue cases imported into Europe and the volume of airline travellers arriving from dengue-affected areas internationally.In 2010, over 5.8 million airline travellers entered Europe from dengue-affected areas worldwide, of which 703,396 arrived at 36 airports situated in areas where Ae. albopictus has been recorded. The adjusted incidence rate ratio for imported dengue into European countries was 1.09 (95% CI: 1.01-1.17) for every increase of 10,000 travellers; in August, September, and October the rate ratios were 1.70 (95%CI: 1.23-2.35), 1.46 (95%CI: 1.02-2.10), and 1.35 (95%CI: 1.01-1.81), respectively. Two Italian cities where the vector is present received over 50% of all travellers from dengue-affected areas, yet with the continuing vector expansion more cities will be implicated in the future. In fact, 38% more travellers arrived in 2013 into those parts of Europe where Ae. albopictus has recently been introduced, compared to 2010.The highest risk of dengue importation in 2010 was restricted to three months and can be ranked according to arriving traveller volume from dengue-affected areas into cities where the vector is present. The presence of the vector is a necessary, but not sufficient, prerequisite for DENV onward transmission, which depends on a number of additional factors. However, our empirical model can provide spatio-temporal elements to public health interventions.

During 2009–2012, Greece experienced a resurgence of domestic malaria transmission. To help guide malaria response efforts, we used spatial modeling to characterize environmental signatures of areas suitable for transmission. Nonlinear discriminant analysis indicated that sea-level altitude and land-surface temperature parameters are predictive in this regard.