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Predicting interactions between biomolecules, such as protein-protein complexes, remains a challenging problem. Despite the many advancements done so far, the performances of docking protocols are deeply dependent on their capability of identify binding regions. In this context, we present a novel approach that builds upon our previous works modeling protein surface patches via sets of orthogonal polynomials to identify regions of high shape/electrostatic complementarity. By incorporating another key binding property, such as the balance between hydrophilic and hydrophobic contributions, we define new binding matrices that serve an effective inputs for training a neural network. Our approach also allows for the quantitative definition of a typical binding site area - approximately 10\AA~in radius - where hydrophobic contribution and shape complementarity, which reflects the Lennard-Jones interaction, are maximized. Using this new architecture, CIRNet (Core Interacting Residues Network), we achieve an accuracy of approximately 0.82 in identifying pairs of core interacting residues on a balanced dataset. In a blind search for core interacting residues, CIRNet distinguishes these from decoys with a ROC AUC of 0.72. This protocol can enahnce docking algorithms by rescaling the proposed poses. When applied to the top ten models from three popular docking server, CIRNet improves docking outcomes, reducing the the average RMSD between the refined poses and the native state by up to 58%., Comment: 15 pages, 5 figures, 1 table

Shape complementarity of molecular surfaces at the interfaces is a well-known characteristic of protein-protein binding regions, and it is critical in influencing the stability of the complex. Measuring such complementarity is at the basis of methods for both the prediction of possible interactions and for the design/optimization of speficic ones. However, only a limited number of tools are currently available to efficiently and rapidly assess it. Here, we introduce Zepyros, a webserver for fast measuring of the shape complementarity between two molecular interfaces of a given protein-protein complex using structural information. Zepyros is implemented as a publicly available tool with a user-friendly interface. Our server can be found at the following link (all major browser supported): https://zepyros.bio-groups.com, Comment: 4 pages, 1 figure

Understanding the molecular mechanisms driving the binding between bio-molecules is a crucial challenge in molecular biology. In this respect, characteristics like the preferentially hydrophobic composition of the binding interfaces, the role of van der Waals interactions (short range forces), and the consequent shape complementarity between the interacting molecular surfaces are well established. However, no consensus has yet been reached on how and how much electrostatic participates in the various stages of protein-protein interactions. Here, we perform extensive analyses on a large dataset of protein complexes for which both experimental binding affinity and pH data were available. We found that (i) although different classes of dimers do not present marked differences in the amino acid composition and charges disposition in the binding region, (ii) homodimers with identical binding region show higher electrostatic compatibility with respect to both homodimers with non-identical binding region and heterodimers. The level of electrostatic compatibility also varies with the pH of the complex, reaching the lowest values for low pH. Interestingly, (iii) shape and electrostatic complementarity behave oppositely when one stratifies the complexes by their binding affinity. Conversely, complexes with low values of binding affinity exploit Coulombic complementarity to acquire specificity, suggesting that electrostatic complementarity may play a greater role in transient (or less stable) complexes. In light of these results, (iv) we provide a fast and efficient method to measure electrostatic complementarity without the need of knowing the complex structure. Expanding the electrostatic potential on a basis of 2D orthogonal polynomials, we can discriminate between transient and permanent protein complexes with an AUC of the ROC of 0.8., Comment: 16 pages, 5 figures, 3 tables

There is a scientific and ethical imperative to embrace a multidimensional, continuous view of ancestry and move away from continental ancestry categories

Many of the molecular mechanisms underlying the pathological aggregation of proteins observed in neurodegenerative diseases are still not fully understood. Among the diseases associated with protein aggregates, for example, Amyotrophic Lateral Sclerosis (ALS) is of relevant importance. Although understanding the processes that cause the disease is still an open challenge, its relationship with protein aggregation is widely known. In particular, human TDP-43, an RNA/DNA binding protein, is a major component of pathological cytoplasmic inclusions described in ALS patients. The deposition of the phosphorylated full-length TDP-43 in spinal cord cells has been widely studied, and it has been shown that the brain cortex presents an accumulation of phosphorylated C-terminal fragments (CTFs). Even if it is debated whether CTFs represent a primary cause of ALS, they are a hallmark of TDP-43 related neurodegeneration in the brain. Here, we investigate the CTFs aggregation process, providing a possible computational model of interaction based on the evaluation of shape complementarity at the interfaces. To this end, extensive Molecular Dynamics (MD) simulations were conducted for different types of fragments with the aim of exploring the equilibrium configurations. Adopting a newly developed approach based on Zernike polynomials, for finding complementary regions of the molecular surface, we sampled a large set of exposed portions of the molecular surface of CTFs structures as obtained from MD simulations. The analysis proposes a set of possible associations between the CTFs, which could drive the aggregation process of the CTFs., Comment: 9 pages, 4 figures, 1 table

What are the molecular mechanisms that dictate protein-protein binding stability and whether those are related to the ones behind protein fold stability are still largely open questions. Indeed, despite many past efforts, we still lack definitive models to account for experimental quantities like protein melting temperature or complex binding affinity. Here, we investigate and compare chemical and physical features on a dataset of protein with known melting temperature as well as a large dataset of protein-protein complexes with reliable experimental binding affinity. In particular, we probed the aminoacid composition and the organization of the network of intramolecular and intermolecular interaction energies among residues. We found that hydrophobic residues present on the protein surfaces are preferentially located in the binding regions, while charged residues behave oppositely. In addition, the abundance of polar amino acid like Serine and Proline correlates with the binding affinity of the complexes. Analysing the interaction energies we found that distant Coulombic interactions are responsible for thermal stability while the total inter-molecular van der Waals energy correlates with protein-protein binding affinity., Comment: 8 pages, 3 figures

Most proteins perform their biological function by interacting with one or more molecular partners. In this respect, characterizing the features of the molecular surface, especially in the portions where the interaction takes place, turned out to be a crucial step in the investigation of the mechanisms of recognition and binding between molecules. Predictive methods often rely on extensive samplings of molecular patches with the aim to identify hot spots on the surface. In this framework, analysis of large proteins and/or many molecular dynamics frames is often unfeasible due to the high computational cost. Thus, finding optimal ways to reduce the number of points to be sampled maintaining the biological information carried by the molecular surface is pivotal. Here, we present a new theoretical and computational algorithm with the aim of determining a subset of surface points, appropriately selected in space, in order to maximize the information of the overall shape of the molecule by minimizing the number of total points. We test our procedure by looking at the local shape of the surface through a recently developed method based on the formalism of Zernike polynomials in two dimensions, which is able to characterize the local shape properties of portions of molecular surfaces. The results of this method show that a remarkably higher ability of this algorithm to reproduce the information of the complete molecular surface compared to uniform random sampling., Comment: 8 pages, 5 figures

Many factors influence biomolecules binding, and its assessment constitutes an elusive challenge in computational structural biology. In this respect, the evaluation of shape complementarity at molecular interfaces is one of the main factors to be considered. We focus on the particular case of antibody-antigen complexes to quantify the complementarities occurring at molecular interfaces. We relied on a method we recently developed, which employs the 2D Zernike descriptors, to characterize investigated regions with an ordered set of numbers summarizing the local shape properties. Collected a structural dataset of antibody-antigen complexes, we applied this method and we statistically distinguished, in terms of shape complementarity, pairs of interacting regions from non-interacting ones. Thus, we set up a novel computational strategy based on \textit{in-silico} mutagenesis of antibody binding site residues. We developed a Monte Carlo procedure to increase the shape complementarity between the antibody paratope and a given epitope on a target protein surface. We applied our protocol against several molecular targets in SARS-CoV-2 spike protein, known to be indispensable for viral cell invasion. We, therefore, optimized the shape of template antibodies for the interaction with such regions. As the last step of our procedure, we performed an independent molecular docking validation of the results of our Monte Carlo simulations., Comment: 13 pages, 4 figures

Despite the huge effort to contain the infection, the novel SARS-CoV-2 coronavirus has rapidly become pandemics, mainly due to its extremely high human-to-human transmission capability, and a surprisingly high viral charge of symptom-less people. While the seek of a vaccine is still ongoing, promising results have been obtained with antiviral compounds. In particular, lactoferrin is found to have beneficial effects both in preventing and soothing the infection. Here, we explore the possible molecular mechanisms with which lactoferrin interferes with SARS-CoV-2 cell invasion, preventing attachment and/or entry of the virus. To this aim, we search for possible interactions lactoferrin may have with virus structural proteins and host receptors. Representing the molecular iso-electron surface of proteins in terms of 2D-Zernike descriptors, we (i) identified putative regions on the lactoferrin surface able to bind sialic acid receptors on the host cell membrane, sheltering the cell from the virus attachment; (ii) showed that no significant shape complementarity is present between lactoferrin and the ACE2 receptor, while (iii) two high complementarity regions are found on the N- and C-terminal domains of the SARS-CoV-2 spike protein, hinting at a possible competition between lactoferrin and ACE2 for the binding to the spike protein., Comment: 9 pages, 4 figures

Among the many aspects that characterize the COVID-19 pandemic, two seem particularly challenging to understand: (i) the great geographical differences in the degree of virus contagiousness and lethality which were found in the different phases of the epidemic progression, and (ii) the potential role of the infected people's blood type in both the virus infectivity and the progression of the disease. A recent hypothesis could shed some light on both aspects. Specifically, it has been proposed that in the subject-to-subject transfer SARS-CoV-2 conserves on its capsid the erythrocytes' antigens of the source subject. Thus these conserved antigens can potentially cause an immune reaction in a receiving subject that has previously acquired specific antibodies for the source subject antigens. This hypothesis implies a blood type-dependent infection rate. The strong geographical dependence of the blood type distribution could be, therefore, one of the factors at the origin of the observed heterogeneity in the epidemics spread. Here, we present an epidemiological deterministic model where the infection rules based on blood types are taken into account and compare our model outcomes with the exiting worldwide infection progression data. We found an overall good agreement, which strengthens the hypothesis that blood types do play a role in the COVID-19 infection., Comment: 6 figures, 4 tables

We propose a novel numerical method able to determine efficiently and effectively the relationship of complementarity between portions of proteins surfaces. This innovative and general procedure, based on the representation of the molecular iso-electron density surface in terms of 2D Zernike polynomials, allows the rapid and quantitative assessment of the geometrical shape complementarity between interacting proteins, that was unfeasible with previous methods. We first tested the method with a large dataset of known protein complexes obtaining an overall area under the ROC curve of 0.76 in the blind recognition of binding sites and then applied it to investigate the features of the interaction between the Spike protein of SARS-Cov-2 and human cellular receptors. Our results indicate that SARS-CoV-2 uses a dual strategy: its spike protein could also interact with sialic acid receptors of the cells in the upper airways, in addition to the known interaction with Angiotensin-converting enzyme 2., Comment: 10 pages, 4 figures

The outcome of an epidemic is closely related to the network of interactions between the individuals. Likewise, protein functions depend on the 3D arrangement of their residues and on the underlying energetic interaction network. Borrowing ideas from the theoretical framework that has been developed to address the spreading of real diseases, we study the diffusion of a fictitious epidemic inside the protein non-bonded interaction network. Our approach allowed to probe the overall stability and the capability to propagate information in the complex 3D-structures and proved to be very efficient in addressing different problems, from the assessment of thermal stability to the identification of allosteric sites., Comment: 9 pages, 5 figures

Powerful Learning Conversations (PLC) sought to improve the feedback that teachers give to pupils in Year 9, by training them to apply techniques used in sports coaching. It is based on the idea that feedback in sports coaching is often provided immediately after a task is performed, and delivered in a way that children are more likely to respond positively to. The training programme adopted a 'cascade' model: expert teachers were trained in the approach and then expected to disseminate their training to English and Maths teachers in their school. PLC was developed in the UK secondary school context by the Youth Sport Trust (YST) in collaboration with the University of Exeter. This feasibility pilot study was conducted in 20 schools between January 2014 and November 2014. It had two aims: (1) to explore whether the programme is feasible and ready for a full-scale trial, and (2) to explore the effect on children's attainment and other outcomes of the programme. Key conclusions include: (1) There was no evidence that the programme had an impact on English attainment; (2) The evaluation detected a positive impact on Maths attainment, but this result is not secure and we are not able to draw firm conclusions about the programme's impact; (3) Interviews and observations with teachers found the programme was implemented in different ways and with different levels of understanding in different schools. This could be avoided by ensuring the programme and its underpinning concepts are more clearly defined; (4) The intervention is not ready to be evaluated using a large-scale trial without further development. In particular, it is important that the programme is more clearly defined and less open to interpretation by teachers; and (5) If the programme is taken to a full trial it is recommended that paper-based tests are used. The pilot provided mixed evidence of promise. There was no evidence that PLC had an impact on English attainment. The evaluation did detect an impact on Maths attainment, which was equivalent to six additional months' progress over the course of a year. However, it is important to note that these results, particularly the Maths result, should be treated with caution. The evaluation did not provide evidence of a differential impact on pupils eligible for free school meals or pupils with a low prior attainment. The evaluation provided mixed evidence regarding the programme's feasibility. The training was well attended by teachers and they appeared to be engaged. Nearly all teachers who took part in the training found it interesting, engaging and relevant to their teaching, and believed that their school as a whole would benefit from the programme. The programme is likely to be affordable if it was delivered at scale.

The Changing Mindsets project sought to improve academic attainment by supporting pupils to develop a growth mindset: the belief that intelligence is not a fixed characteristic and can be increased through effort. Previous research (Good et al., 2003; Blackwell et al., 2007) has suggested that holding this belief enables pupils to work harder and achieve better results. The project consisted of two separate interventions: (1) an intervention that taught pupils directly about the malleability of intelligence through six workshops, which were delivered by undergraduates from the University of Portsmouth, and four further sessions delivered by two local organisations: the Education Business Partnership, and Pompey Study Centre (now called Portsmouth in the Community); and (2) a professional development course that trained teachers on approaches to developing and reinforcing growth mindsets through their teaching. This course consisted of two half days of instruction. The project targeted Year 5 pupils in Portsmouth, Southampton and Hampshire. The delivery of the interventions was led by the University of Portsmouth and took place between January and May 2013. Key conclusions included: (1) Pupils who received the growth mindset workshops made an average of two additional months' progress in English and maths. These findings were not statistically significant, which means that we cannot be confident that they did not occur by chance. However, the finding for English was close to statistical significance, and this suggests evidence of promise; (2) Pupils whose teachers received the professional development intervention made no additional progress in maths compared to pupils in the control group. These pupils made less progress in English than the control group, but this finding is not statistically significant and we cannot be sure that it did not occur by chance; (3) Free School Meal (FSM)-eligible pupils who were involved in the professional development intervention gained a better understanding of the malleability of intelligence; (4) Intervention and control schools were already using some aspects of the growth mindsets approach. This may have weakened any impact of the interventions; and (5) Future trials could examine the impact of a programme that combines the two interventions and runs for a longer period of time. Findings from the process evaluation highlight some key issues relevant to future use of Mindsets in UK schools, including EEF target schools and pupils. These concern: (1) the appeal of mindset approaches to teachers; (2) the 'fit' of mindset with schools' ethos; (3) its relative simplicity and ease of use; and (4) understanding of the approach by pupils and, potentially, parents.

By exhibiting a measurable bandgap and exotic valley physics, atomically-thick tungsten disulfide (WS2) offers exciting prospects for optoelectronic applications. The synthesis of continuous WS2 films on other two-dimensional (2D) materials would greatly facilitate the implementation of novel all-2D photoactive devices. In this work we demonstrate the scalable growth of WS2 on graphene and hexagonal boron nitride (h-BN) via a chemical vapor deposition (CVD) approach. Spectroscopic and microscopic analysis reveal that the film is bilayer-thick, with local monolayer inclusions. Photoluminescence measurements show a remarkable conservation of polarization at room temperature peaking 74% for the entire WS2 film. Furthermore, we present a scalable bottom-up approach for the design of photoconductive and photoemitting patterns., Comment: 17 pages, 3 Figures in the main text, supplementary information included

Recent efforts to survey the numerous softwares available to perform single molecule tracking (SMT) highlighted a significant dependence of the outcomes on the specific method used, and the limitation encountered by most techniques to capture fast movements in a crowded environment. Other approaches to identify the mode and rapidity of motion of fluorescently labeled biomolecules, that do not relay on the localization and linking of the images of isolated single molecules are, however, available.This direct comparison shows that correlative imaging analysis approaches complement effectively current SMT methods in circumstances when, due to either the density of the sample, the low signal to noise ratio or molecular blinking, trajectory linking does not allow to capture long-range or fast motion., Comment: 6 pages, 4 figures

Mind the Gap sought to improve the metacognition and academic attainment of pupils in Year 4. There were two aspects to the intervention. The first involved training teachers in how to embed metacognitive approaches in their work, and how to continue to effectively and strategically involve parents. This training took place over a day and was provided by a consultant. The second component focused on parental engagement and offered families the opportunity to participate in a series of facilitated workshops where children and parents work together to create an animated film. Sessions were coordinated by a practitioner who helped participants to think about how they are learning, create learning goals and reflect on their progress; to be metacognitive about the learning process they were engaged in together. The families were offered 2 hours of workshops per week for 5 weeks (10 hours in total). The project targeted schools in four areas of England: Birmingham, Devon, London and Manchester. It was delivered by the Campaign for Learning, with assessments carried out by Durham University. Delivery started in September 2012 and finished in October 2013. The project was evaluated using a randomised controlled trial, which compared the interventions to a 'business-as-usual' control group. It is important to note that it was eligibility for the animation course, not participation, that was randomised, so the results must be regarded as estimating the effect of being offered the animation course (alone or in combination with teacher training, as appropriate) rather than participating in it. Among the key conclusions were: (1) The headline findings provide no evidence of a statistically significant impact of Mind the Gap on attainment; (2) The estimate of the programme's impact on pupils' metacognition was positive and statistically significant; and (3) Participating families and staff felt the intervention enhanced home-school relationships and strengthened the learning relationship between children and parents.