Miracle-dz/UniFAR-FTUs huggingface dataset:
Understanding User Behaviour through Action Sequences: From the Usual to the Unusual

Action sequences, where atomic user actions are represented in a labelled, timestamped form, are becoming a fundamental data asset in the inspection and monitoring of user behaviour in digital systems. Although the analysis of such sequences is highly critical to the investigation of activities in cyber security applications, existing solutions fail to provide a comprehensive understanding due to the complex semantic and temporal characteristics of these data. This paper presents a visual analytics approach that aims to facilitate a user-involved, multi-faceted decision making process during the identification and the investigation of “unusual” action sequences. We first report the results of the task analysis and domain characterisation process. Then we describe the components of our multi-level analysis approach that comprises of constraint-based sequential pattern mining and semantic distance based clustering, and multi-scalar visualisations of users and their sequences. Finally, we demonstrate the applicability of our approach through a case study that involves tasks requiring effective decision-making by a group of domain experts. Although our solution here is tightly informed by a user-centred, domain-focused design process, we present findings and techniques that are transferable to other applications where the analysis of such sequences is of interest.
Genomic variation underlying complex life-history traits revealed by genome sequencing in Chinook salmon

A broad portfolio of phenotypic diversity in natural organisms can buffer against exploitation and increase species persistence in disturbed ecosystems. The study of genomic variation that accounts for ecological and evolutionary adaptation can represent a powerful approach to extend understanding of phenotypic variation in nature. Here we present a chromosome-level reference genome assembly for Chinook salmon (Oncorhynchus tshawytscha; 2.36 Gb) that enabled association mapping of life-history variation and phenotypic traits for this species. Whole-genome re-sequencing of populations with distinct life-history traits provided evidence that divergent selection was extensive throughout the genome within and among phylogenetic lineages, indicating that a broad portfolio of phenotypic diversity exists in this species that is related to local adaptation and life-history variation. Association mapping with millions of genome-wide SNPs revealed that a genomic region of major effect on chromosome 28 was associated with phenotypes for premature and mature arrival to spawning grounds and was consistent across three distinct phylogenetic lineages. Our results demonstrate how genomic resources can enlighten the genetic basis of known phenotypes in exploited species and assist in clarifying phenotypic variation that may be difficult to observe in naturally occurring organisms.
Printable Graphene Oxide Micropatterns for a Bio‐Subretinal Chip

Recently, implantable artificial subretinal chips using electronic components have replaced photoreceptors to serve as the most feasible treatment for retinal diseases. As such a chip that is meant to be implanted and used for very long periods, growing retinal cells on it to improve the electrical stimulation efficiency and attraction of neuronal elements remains a challenge. Here, an inkjet printing technology is employed to create graphene oxide (GO) micropatterns onto microelectrodes of a photovoltaic‐powered implantable retinal chip. These GO micropatterns allow human retinal pigment epithelium (RPE) cells to specially attach and grow in each microelectrode. In addition, the cell proliferation, viability, and tight junction of RPE cells are improved during culturing. The development of a simple surface‐coating technology would pave the way for the development of the first fully integrated and encapsulated retinal prostheses with biocompatible on‐chip microelectrodes for long‐term implantation, which could be effectively applied in retina tissue engineering and therapy.
Molecular identification and antifungal susceptibility profiles of clinical strains of Fonsecaea spp. isolated from patients with chromoblastomycosis in Rio de Janeiro, Brazil

Background Chromoblastomycosis (CBM) is a difficult-to-treat chronic subcutaneous mycosis. In Brazil, the main agent of this disease is Fonsecaea pedrosoi, which is phenotypically very similar to other Fonsecaea species, differing only genetically. The correct species identification is relevant since different species may differ in their epidemiologic aspects, clinical presentation, and treatment response. Methodology/Principal findings Partial sequencing of the internal transcribed spacer (ITS) was used to identify twenty clinical isolates of Fonsecaea spp. Their in vitro antifungal susceptibility was determined using the broth microdilution method, according to the M38-A2 protocol. Amphotericin B (AMB), flucytosine (5FC), terbinafine (TRB), fluconazole (FLC), itraconazole (ITC), ketoconazole (KTC), posaconazole (POS), voriconazole (VRC), ravuconazole (RVC), caspofungin (CAS), and micafungin (MFG) were tested. The association between ITC/TRB, AMB/5FC, and ITC/CAS was studied by the checkerboard method to check synergism. The available patients’ data were correlated with the obtained laboratory results. Fonsecaea monophora (n = 10), F. pedrosoi (n = 5), and F. nubica (n = 5) were identified as CBM’ agents in the study. TRB and VRC were the drugs with the best in vitro activity with minimal inhibitory concentrations (MIC) lower than 0.25 mg/L. On the other hand, FLC, 5FC, AMB, and MFG showed high MICs. The AMB/5FC combination was synergistic for three F. monophora strains while the others were indifferent. Patients had moderate or severe CBM, and ITC therapy was not sufficient for complete cure in most of the cases, requiring adjuvant surgical approaches. Conclusions/Significance F. monophora, the second most frequent Fonsecaea species in South America, predominated in patients raised and born in Rio de Janeiro, Brazil, without cerebral involvement in these cases. TRB, VRC, and the AMB/5FC combination should be further investigated as a treatment option for CBM.
Super analgesia of intrathecal morphine may be related to ABCB1 (MDR1) gene polymorphism

Intrathecal morphine provides superior analgesia and minimizes side effects with ~1/300th of the oral dose necessary to achieve this effect. The conversion ratios from oral route to intrathecal route vary greatly among individuals, and this may be related with polymorphisms of the ATP-binding cassette B1 (ABCB1)/multiple drug resistance 1 (MDR1) gene encoding the transporter P-glycoprotein in the blood–brain barrier. In the case presented herein, a patient with cancer pain for over 3 months was treated with oxycodone hydrochloride prolonged-release tablets (Oxycontin) and morphine hydrochloride tablets for breakthrough pain. The patient was admitted due to intolerable adverse effects of Oxycontin. During this admission, he was implanted with an intrathecal morphine pump which can deliver morphine into the cerebrospinal fluid. To our surprise, intrathecal morphine at a dose of ~1/540th of oral morphine equivalent dose produced complete analgesia. Our finding revealed homogenous CC at position 3435 (C3435T) in the ABCB1/MDR1 gene in this patient, which encodes P-glycoprotein with good efflux pump functionality. As intrathecal morphine bypasses the blood–brain barrier that oral medications have to pass through, the good pump functionality may have contributed to the super analgesia of intrathecal morphine in this case. Genetic analysis of ABCB1/MDR1 gene polymorphisms can be useful for personalized pain management in patients with intrathecal morphine pump.
Structure of ScpC, a virulence protease from Streptococcus pyogenes, reveals the functional domains and maturation mechanism.

Group A Streptococcus (GAS; Streptococcus pyogenes) causes a wide range of infections, including pharyngitis, impetigo, and necrotizing fasciitis, and results in over half a million deaths annually. GAS ScpC (SpyCEP), a 180-kDa surface-exposed, subtilisin-like serine protease, acts as an essential virulence factor that helps S. pyogenes evade the innate immune response by cleaving and inactivating C-X-C chemokines. ScpC is thus a key candidate for the development of a vaccine against GAS and other pathogenic streptococcal species. Here, we report the crystal structures of full-length ScpC wild-type, the inactive mutant, and the ScpC-AEBSF inhibitor complex. We show ScpC to be a multi-domain, modular protein consisting of nine structural domains, of which the first five constitute the PR + A region required for catalytic activity. The four unique C-terminal domains of this protein are similar to collagen-binding and pilin proteins, suggesting an additional role for ScpC as an adhesin that might mediate the attachment of S. pyogenes to various host tissues. The Cat domain of ScpC is similar to subtilisin-like proteases with significant difference to dictate its specificity toward C-X-C chemokines. We further show that ScpC does not undergo structural rearrangement upon maturation. In the ScpC-inhibitor complex, the bound inhibitor breaks the hydrogen bond between active-site residues, which is essential for catalysis. Guided by our structure, we designed various epitopes and raised antibodies capable of neutralizing ScpC activity. Collectively, our results demonstrate the structure, maturation process, inhibition, and substrate recognition of GAS ScpC, and reveal the presence of functional domains at the C-terminal region.
Advanced iterative procedures for solving the implicit Colebrook equation for fluid flow friction

The empirical Colebrook equation from 1939 is still accepted as an informal standard way to calculate the friction factor of turbulent flows (4000 < Re < 108) through pipes with roughness between negligible relative roughness (ε/D ⟶ 0) to very rough (up to ε/D = 0.05). The Colebrook equation includes the flow friction factor λ in an implicit logarithmic form, λ being a function of the Reynolds number Re and the relative roughness of inner pipe surface ε/D: λ = f(λ, Re, ε/D). To evaluate the error introduced by the many available explicit approximations to the Colebrook equation, λ ≈ f(Re, ε/D), it is necessary to determinate the value of the friction factor λ from the Colebrook equation as accurately as possible. The most accurate way to achieve that is by using some kind of the iterative method. The most used iterative approach is the simple fixed-point method, which requires up to 10 iterations to achieve a good level of accuracy. The simple fixed-point method does not require derivatives of the Colebrook function, while the most of the other presented methods in this paper do require. The methods based on the accelerated Householder’s approach (3rd order, 2nd order: Halley’s and Schröder’s method, and 1st order: Newton–Raphson) require few iterations less, while the three-point iterative methods require only 1 to 3 iterations to achieve the same level of accuracy. The paper also discusses strategies for finding the derivatives of the Colebrook function in symbolic form, for avoiding the use of the derivatives (secant method), and for choosing an optimal starting point for the iterative procedure. The Householder approach to the Colebrook’ equations expressed through the Lambert W-function is also analyzed. Finally, it is presented one approximation to the Colebrook equation with an error of no more than 0.0617%.
Post-diapause synthesis of ArHsp40-2, a type 2 J-domain protein from Artemia franciscana, is developmentally regulated and induced by stress

Post-diapause cysts of Artemia franciscana undergo a well-defined developmental process whereby internal differentiation leads to rupture of the cyst shell, release of membrane-enclosed nauplii and hatching to yield swimming larvae. The post-diapause development of A. franciscana has been examined at biochemical and molecular levels, yet little is known about molecular chaperone function during this process. In addressing this we recently described ArHsp40, a type 1 J-domain protein in post-diapause A. franciscana cysts and larvae. The current report describes ArHsp40-2, a second J-domain protein from A. franciscana. ArHsp40-2 is a type 2 J-domain protein, lacking a zinc binding domain but containing other domains characteristic of these proteins. Notably, ArHsp40-2 possesses a double barrel β-domain structure in its substrate binding region, as does ArHsp40. qPCR revealed a relatively low amount of ArHsp40-2 mRNA in 0 h cysts which increased significantly until the E1 stage, most likely as a result of enhanced transcription, after which it declined. An antibody specific to ArHsp40-2 was produced and used to show that like its mRNA, ArHsp40-2 accumulated until the E1 stage and then decreased to amounts lower than those in 0 h cysts. The synthesis of ArHsp40-2 was induced by heat shock indicating that ArHsp40-2 is involved in stress resistance in cysts and nauplii. Accumulation in cysts during early post-diapause development followed by its sharp decline suggests a role in protein disaggregation/refolding, a function of Hsp40s from other organisms, where ArHsp40-2 assists in the rescue of proteins sequestered during diapause by p26, an abundant small heat shock protein (sHsp) in A. franciscana cysts.
Structure–function analyses of the bacterial zinc metalloprotease effector protein GtgA uncover key residues required for deactivating NF-κB

The closely related type III secretion system zinc metalloprotease effector proteins GtgA, GogA, and PipA are translocated into host cells during Salmonella infection. They then cleave nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) transcription factor subunits, dampening activation of the NF-κB signaling pathway and thereby suppressing host immune responses. We demonstrate here that GtgA, GogA, and PipA cleave a subset of NF-κB subunits, including p65, RelB, and cRel but not NF-κB1 and NF-κB2, whereas the functionally similar type III secretion system effector NleC of enteropathogenic and enterohemorrhagic Escherichia coli cleaved all five NF-κB subunits. Mutational analysis of NF-κB subunits revealed that a single nonconserved residue in NF-κB1 and NF-κB2 that corresponds to the P1′ residue Arg-41 in p65 prevents cleavage of these subunits by GtgA, GogA, and PipA, explaining the observed substrate specificity of these enzymes. Crystal structures of GtgA in its apo-form and in complex with the p65 N-terminal domain explained the importance of the P1′ residue. Furthermore, the pattern of interactions suggested that GtgA recognizes NF-κB subunits by mimicking the shape and negative charge of the DNA phosphate backbone. Moreover, structure-based mutational analysis of GtgA uncovered amino acids that are required for the interaction of GtgA with p65, as well as those that are required for full activity of GtgA in suppressing NF-κB activation. This study therefore provides detailed and critical insight into the mechanism of substrate recognition by this family of proteins important for bacterial virulence.
Strawberry and Achenes Hydroalcoholic Extracts and Their Digested Fractions Efficiently Counteract the AAPH-Induced Oxidative Damage in HepG2 Cells

Strawberry fruits are highly appreciated by consumers worldwide due to their bright red color, typical aroma, and juicy texture. While the biological activity of the complete fruit has been widely studied, the potential beneficial effects of the achenes (commonly named seeds) remain unknown. In addition, when raw fruit and achenes are consumed, the digestion process could alter the release and absorption of their phytochemical compounds, compromising their bioactivity. In the present work, we evaluated the protective effects against oxidative damage of nondigested and digested extracts from strawberry fruit and achenes in human hepatocellular carcinoma (HepG2) cells. For that purpose, cells were treated with different concentration of the extracts prior to incubation with the stressor agent, AAPH (2,2′-azobis(2-amidinopropane) dihydrochloride). Subsequently, intracellular accumulation of reactive oxygen species (ROS) and the percentage of live, dead, and apoptotic cells were determined. Our results demonstrated that all the evaluated fractions were able to counteract the AAPH-induced damage, suggesting that the achenes also present biological activity. The positive effects of both the raw fruit and achenes were maintained after the in vitro digestion process.
Leisure athletes at risk of medical complications: outcomes of pre-participation screening among 15,778 endurance runners - SAFER VII

ABSTRACT Objective: International guidelines for pre-participation screening of masters/leisure athletes to identify those that require medical assessment exist, but have not been implemented in mass-community based sports events. We determined the prevalence of runners who, according to these guidelines, would require a medical assessment before participating in a distance running event. Methods: Participants of the 2012 Two Oceans races (21.1 and 56 km) in South Africa (n = 15,778) completed an online pre-race medical screening questionnaire using European pre-participation screening guidelines. We determined the prevalence of runners that would require a pre-race medical assessment, based on risk factors, symptoms, and disease. Results: The pre-participation “self assessment of risk” screening identified 4,941 runners (31.3%; 95% CI 30.6–32.0) that would need to undergo a full pre-participation medical assessment prior to running, if the current pre-participation screening guidelines are applied. Although musculoskeletal complaints and prescription medication use were the main triggers for a medical assessment, 16.8% (n = 2657) runners should undergo medical evaluation for suspected cardiac disease based on the questionnaire results: 3.4% (n = 538) reporting existing CVD (very high risk) and 13.4% (n = 2119) reporting multiple CVD risk factors (high risk). Other possible risk factors were reported as follows: history of chronic diseases (respiratory = 13.1%, gastro-intestinal = 4.3%, nervous system = 3.8%, metabolic/endocrine = 3.5%, allergies = 13.9%); chronic prescription medication = 14.8%, used medication before or during races = 15.6%; past history of collapse during a race = 1.4%. Conclusions: Current guidelines identified that > 30% runners would require a full medical assessment before race participation – mainly linked to runners reporting musculoskeletal conditions. We suggest a revision of guidelines and propose that pre-race screening should be considered to identify runners with a “very high,” “high,” and “intermediate risk” for medical complications during exercise. Pre-race screening and educational intervention could be implemented to reduce medical complications during exercise.
In silico site-directed mutagenesis of neutralizing mAb 4C4 and analysis of its interaction with G-H loop of VP1 to explore its therapeutic applications against FMD

Abstract Investigating the behaviour of bio-molecules through computational mutagenesis is gaining interest to facilitate the development of new therapeutic solutions for infectious diseases. The antigenetically variant genotypes of foot and mouth disease virus (FMDV) and their subsequent infections are challenging to tackle with traditional vaccination. In such scenario, neutralizing antibodies might provide an alternate solution to manage the FMDV infection. Thus, we have analysed the interaction of the mAb 4C4 with a synthetic G-H loop of FMDV-VP1 through in silico mutagenesis and molecular modelling. Initially, a set of 25,434 mutants were designed and the mutants having better energetic stability than 4C4 were clustered based on sequence identity. The best mutant representing each cluster was selected and evaluated for its binding affinity with the antigen in terms of docking scores, interaction energy and binding energy. Six mutants have confirmed better binding affinities towards the antigen than 4C4. Further, interaction of these mutants with the natural G-H loop that is bound to mAb SD6 was also evaluated. One 4C4 variant having mutations at the positions 2034(N→L), 2096(N→C), 2098(D→Y), 2532(T→K) and 2599(A→G) has revealed better binding affinities towards both the synthetic and natural G-H loops than 4C4 and SD6, respectively. A molecular dynamic simulation for 50 ns was conducted for mutant and wild-type antibody structures which supported the pre-simulation results. Therefore, these mutations on mAb 4C4 are believed to provide a better antibody-based therapeutic option for FMD. Communicated by Ramaswamy H. Sarma
Proteomic evidence of dietary sources in ancient dental calculus

Archaeological dental calculus has emerged as a rich source of ancient biomolecules, including proteins. Previous analyses of proteins extracted from ancient dental calculus revealed the presence of the dietary milk protein β-lactoglobulin, providing direct evidence of dairy consumption in the archaeological record. However, the potential for calculus to preserve other food-related proteins has not yet been systematically explored. Here we analyse shotgun metaproteomic data from 100 archaeological dental calculus samples ranging from the Iron Age to the post-medieval period (eighth century BC to nineteenth century AD) in England, as well as 14 dental calculus samples from contemporary dental patients and recently deceased individuals, to characterize the range and extent of dietary proteins preserved in dental calculus. In addition to milk proteins, we detect proteomic evidence of foodstuffs such as cereals and plant products, as well as the digestive enzyme salivary amylase. We discuss the importance of optimized protein extraction methods, data analysis approaches and authentication strategies in the identification of dietary proteins from archaeological dental calculus. This study demonstrates that proteomic approaches can robustly identify foodstuffs in the archaeological record that are typically under-represented due to their poor macroscopic preservation.
Exploring the way sexually explicit material informs sexual beliefs, understanding and practices of young men: A qualitative survey

Little research has examined how exposure to sexually explicit material may affect beliefs, attitudes and actions of young men. This study explored self-reported effects on young males. A ‘snowballed’ sample of males aged 18–25 years was recruited within one workplace (11/40 response rate). The qualitative survey data were analysed using thematic analysis. Key themes included increased levels of availability/extreme content of sexually explicit material, seen by young men having negative effects on sexual attitudes/behaviours. Participants reported confusion between real and sexually explicit material which informed expectations of a healthy sex life but may be mediated by potential ‘buffers’ of family openness or sex education.