Protonation controls ASIC1a activity via coordinated movements in multiple domains.

Acid-sensing ion channels (ASICs) are neuronal Na(+)-conducting channels activated by extracellular acidification. ASICs are involved in pain sensation, expression of fear, and neurodegeneration after ischemic stroke. Functional ASICs are composed of three identical or homologous subunits, whose extracellular part has a handlike structure. Currently, it is unclear how protonation of residues in extracellular domains controls ASIC activity. Knowledge of these mechanisms would allow a rational development of drugs acting on ASICs. Protonation may induce conformational changes that control the position of the channel gate. We used voltage-clamp fluorometry with fluorophores attached to residues in different domains of ASIC1a to detect conformational changes. Comparison of the timing of fluorescence and current signals identified residues involved in movements that preceded desensitization and may therefore be associated with channel opening or early steps leading to desensitization. Other residues participated in movements intimately linked to desensitization and recovery from desensitization. Fluorescence signals of all mutants were detected at more alkaline pH than ionic currents. Their midpoint of pH dependence was close to that of steady-state desensitization, whereas the steepness of the pH fluorescence relationship was closer to that of current activation. A sequence of movements was observed upon acidification, and its backward movements during recovery from desensitization occurred in the reverse order, indicating that the individual steps are interdependent. Furthermore, the fluorescence signal of some labeled residues in the finger domain was strongly quenched by a Trp residue in the neighboring β-ball domain. Upon channel activation, their fluorescence intensity increased, indicating that the finger moved away from the β ball. This extensive analysis of activity-dependent conformational changes in ASICs sheds new light on the mechanisms by which protonation controls ASIC activity

A promising new ELISA diagnostic test for cattle babesiosis based on Babesia bigemina Apical Membrane Antigen-1.

Babesiosis due to Babesia bigemina is a relevant tick‑borne disease, affecting cattle worldwide. Many surface proteins of the pathogen including the Apical Membrane Antigen 1 (AMA‑1) ‑ have been analysed for vaccine and diagnostic purposes. This study focused on B. bigemina AMA‑1 and on its use for the assessment of diagnostic tests. After bioinformatic analyses, AMA‑1 codifying region was amplified and cloned into an expression vector used to induce protein synthesis in Escherichia coli cells. AMA‑1 was purified by affinity chromatography and used to set up the best condition for an ELISA protocol. Bovine field sera positive to B. bigemina were used to evaluate the presence of anti‑AMA‑1 antibodies. In order to verify the assay specificity, sera positive to Babesia bovis or to the piroplasm Theileria annulata were also included. Significant differences were obtained between sera negative to both B. bigemina and B. bovis and samples positive to B. bigemina, to B. bovis or to both pathogens. No significant reaction was observed with T. annulata positive sera. The results showed that AMA‑1 protein is suitable to be used as antigen in diagnostic assays for babesiosis diagnosis in cattle, as it does not show any cross reaction with anti-T. annulata antibodies

Assembly line balancing and activity scheduling for customised products manufacturing

Nowadays, end customers require personalized products to match their specific needs. Thus, production systems must be extremely flexible. Companies typically exploit assembly lines to manufacture produces in great volumes. The development of assembly lines distinguished by mixed or multi models increases their flexibility concerning the number of product variants able to be manufactured. However, few scientific contributions deal with customizable products, i.e., produces which can be designed and ordered requiring or not a large set of available accessories. This manuscript proposes an original two-step procedure to deal with the multi-manned assembly lines for customized product manufacturing. The first step of the procedure groups the accessories together in clusters according to a specific similarity index. The accessories belonging to a cluster are typically requested together by customers and necessitate a significant mounting time. Thus, this procedure aims to split accessories belonging to the same cluster to different assembly operators avoiding their overloads. The second procedure step consists of an innovative optimization model which defines tasks and accessory assignment to operators. Furthermore, the developed model defines the activity time schedule in compliance with the task precedencies maximizing the operator workload balance. An industrial case study is adopted to test and validate the proposed procedure. The obtained results suggest superior balancing of such assembly lines, with an average worker utilization rate greater than 90%. Furthermore, in the worst case scenario in terms of customer accessories requirement, just 4 line operators out of 16 are distinguished by a maximum workload greater than the cycle time

Similarities and differences between molecular order in the nematic and twist-bend nematic phases of a symmetric liquid crystal dimer

The order parameter, Szz, where z is the para axis of the difluoroterphenyl groups in DTC5C9, have been obtained from chemical shift anisotropies measured by ¹³C – {¹1H} NMR experiments at temperatures throughout the nematic, NU, and twist-bend nematic, NTB, phases shown by this compound. The order parameter temperature profiles are unusual in having a maximum value in the NU phase and then decreasing until the NTB phase is reached. There is a small discontinuity (~2%) in Szz at T_(NN_TB )and then a gradual decrease until a new phase appears. This behaviour is interpreted as revealing a temperature-dependent tilting of local directors in both phases away from the applied magnetic field direction. In the enantiomorphic twist-bend phase this tilt is consistent with the structure of the phase as a helical arrangement of local directors, whilst in the high-temperature non-chiral nematic the tilt must involve a non-chiral arrangement. It is proposed that in both phases the tilting of directors has a common origin in the bent shape of the molecules

Overcoming Language Dichotomies: Toward Effective Program Comprehension for Mobile App Development

Mobile devices and platforms have become an established target for modern software developers due to performant hardware and a large and growing user base numbering in the billions. Despite their popularity, the software development process for mobile apps comes with a set of unique, domain-specific challenges rooted in program comprehension. Many of these challenges stem from developer difficulties in reasoning about different representations of a program, a phenomenon we define as a "language dichotomy". In this paper, we reflect upon the various language dichotomies that contribute to open problems in program comprehension and development for mobile apps. Furthermore, to help guide the research community towards effective solutions for these problems, we provide a roadmap of directions for future work.Comment: Invited Keynote Paper for the 26th IEEE/ACM International Conference on Program Comprehension (ICPC'18

Massive star cluster formation and evolution in tidal dwarf galaxies

Reproduced with permission from Astronomy & Astrophysics. © 2019 ESOThe formation of globular clusters remains an open debate. Dwarf starburst galaxies are efficient at forming young massive clusters with similar masses as globular clusters and may hold the key to understanding their formation. We study star cluster formation in a tidal debris - including the vicinity of three tidal dwarf galaxies - in a massive gas dominated collisional ring around NGC~5291. These dwarfs have physical parameters which differ significantly from local starbursting dwarfs. They are gas-rich, highly turbulent, have a gas metallicity already enriched up to half-solar, and are expected to be free of dark matter. The aim is to study massive star cluster formation in this as yet unexplored type of environment. We use imaging from the Hubble Space Telescope using broadband filters covering the wavelength range from the near-ultraviolet to the near-infrared. We determine the masses and ages of the cluster candidates by using the spectral energy distribution-fitting code CIGALE, carefully considering age-extinction degeneracy effects on the estimation of the physical parameters. We find that the tidal dwarf galaxies in the ring of NGC 5291 are forming star clusters with an average efficiency of $\sim40\%$, comparable to blue compact dwarf galaxies. We also find massive star clusters for which the photometry suggests that they were formed at the very birth of the tidal dwarf galaxies and have survived for several hundred million years. Therefore our study shows that extended tidal dwarf galaxies and compact clusters may be formed simultaneously. In the specific case observed here, the young star clusters are not massive enough to survive for a Hubble time. However one may speculate that similar objects at higher redshift, with higher star formation rate, might form some of the long lived globular clusters.Peer reviewedFinal Accepted Versio

Do dogs and cats passively carry sars-cov-2 on hair and pads?

The epidemiological role of domestic animals in the spread and transmission of SARS-CoV-2 to humans has been investigated in recent reports, but some aspects need to be further clarified. To date, only in rare cases have dogs and cats living with COVID-19 patients been found to harbour SARS-CoV-2, with no evidence of pet-to-human transmission. The aim of the present study was to verify whether dogs and cats act as passive mechanical carriers of SARS-CoV-2 when they live in close contact with COVID-19 patients. Cutaneous and interdigital swabs collected from 48 dogs and 15 cats owned by COVID-19 patients were tested for SARS-CoV-2 by qRT-PCR. The time elapsed between owner swab positivity and sample collection from pets ranged from 1 to 72 days, with a median time of 23 days for dogs and 39 days for cats. All samples tested negative, suggesting that pets do not passively carry SARS-CoV-2 on their hair and pads, and thus they likely do not play an important role in the virus transmission to humans. This data may contribute to confirming that the direct contact with the hair and pads of pets does not represent a route for the transmission of SARS-CoV-2

Automatic Detection of GUI Design Smells: The Case of Blob Listener

International audienceGraphical User Interfaces (GUIs) intensively rely on event-driven programming: widgets send GUI events, which capture users' interactions, to dedicated objects called controllers. Controllers implement several GUI listeners that handle these events to produce GUI commands. In this work, we conducted an empirical study on 13 large Java Swing open-source software systems. We study to what extent the number of GUI commands that a GUI listener can produce has an impact on the change-and fault-proneness of the GUI listener code. We identify a new type of design smell, called Blob listener that characterizes GUI listeners that can produce more than two GUI commands. We show that 21 % of the analyzed GUI controllers are Blob listeners. We propose a systematic static code analysis procedure that searches for Blob listener that we implement in InspectorGuidget. We conducted experiments on six software systems for which we manually identified 37 instances of Blob listener. InspectorGuidget successfully detected 36 Blob listeners out of 37. The results exhibit a precision of 97.37 % and a recall of 97.59 %. Finally, we propose coding practices to avoid the use of Blob listeners

Changes in the folding landscape of the WW domain provide a molecular mechanism for an inherited genetic syndrome

WW domains are small domains present in many human proteins with a wide array of functions and acting through the recognition of proline-rich sequences. The WW domain belonging to polyglutamine tract-binding protein 1 (PQBP1) is of particular interest due to its direct involvement in several X chromosome-linked intellectual disabilities, including Golabi-Ito-Hall (GIH) syndrome, where a single point mutation (Y65C) correlates with the development of the disease. The mutant cannot bind to its natural ligand WBP11, which regulates mRNA processing. In this work we use high-field high-resolution NMR and enhanced sampling molecular dynamics simulations to gain insight into the molecular causes the disease. We find that the wild type protein is partially unfolded exchanging among multiple beta-strand-like conformations in solution. The Y65C mutation further destabilizes the residual fold and primes the protein for the formation of a disulphide bridge, which could be at the origin of the loss of function