Miracle-dz/UniFAR-FTUs huggingface dataset:
Structural insights into the unique inhibitory mechanism of Kunitz type trypsin inhibitor from Cicer arietinum L.

Abstract Kunitz-type trypsin inhibitors bind to the active pocket of trypsin causing its inhibition. Plant Kunitz-type inhibitors are thought to be important in defense, especially against insect pests. From sequence analysis of various Kunitz-type inhibitors from plants, we identified CaTI2 from chickpea as a unique variant lacking the functionally important arginine residue corresponding to the soybean trypsin inhibitor (STI) and having a distinct and unique inhibitory loop organization. To further explore the implications of these sequence variations, we obtained the crystal structure of recombinant CaTI2 at 2. 8Å resolution. It is evident from the structure that the variations in the inhibitory loop facilitates non-substrate like binding of CaTI2 to trypsin, while the canonical inhibitor STI binds to trypsin in substrate like manner. Our results establish the unique mechanism of trypsin inhibition by CaTI2, which warrant further research into its substrate spectrum. AbbreviationsBApNA Nα-Benzoyl-L-arginine 4-nitroanilideBPT bovine pancreatic trypsinCaTI2 Cicer arietinum L trypsin inhibitor 2DrTI Delonix regia Trypsin inhibitorEcTI Enterolobium contortisiliquum trypsin inhibitorETI Erythrina caffra trypsin inhibitorKTI Kunitz type inhibitorSTI soybean trypsin inhibitorTKI Tamarindus indica Kunitz inhibitor Communicated By Ramaswamy H. Sarma
Smart Portable Devices Suitable for Cultural Heritage: A Review

This article reviews recent portable sensor technologies to apply in the Cultural Heritage (CH) fields. The review has been prepared in the form of a retrospective description of the sensor’s history and technological evolution, having: new nanomaterials for transducers, miniaturized, portable and integrated sensors, the wireless transmission of the analytical signals, ICT_Information Communication Technology and IoT_Internet of Things to apply to the cultural heritage field. In addition, a new trend of movable tattoo sensors devices is discussed, referred to in situ analysis, which is especially important when scientists are in the presence of un-movable and un-tangible Cultural Heritage and Art Work objects. The new proposed portable contact sensors (directly applied to art work objects and surfaces) are non-invasive and non-destructive to the different materials and surfaces of which cultural heritage is composed.
A Qualitative Study on Factors Modulating Tinnitus Experience

Objectives: It is well recognized that tinnitus can severely interfere with important aspects of life such as sleep, concentration abilities, social activities, and mood. However, the impact of tinnitus may vary greatly from one individual to another, with some being severely affected and others only experiencing a slight handicap. Information from participants’ experiences with tinnitus could help explain such variability. The full experience of living with tinnitus from a patient’s perspective has been under-investigated, especially in comparison with the large and extensive body of qualitative research on hearing loss. This study aims to contribute to fill this gap and assess participants’ experience of living with tinnitus. Design: As part of a larger mixed design study, this inquiry used qualitative analyses to investigate participant’s experiences with tinnitus. Twenty-seven tinnitus participants of different ages, sexes, audiometric profiles, and tinnitus severities were invited to discuss their tinnitus through semistructured interviews and journal entries. The interviews took place 1 month after participants completed a 3-week trial period with tinnitus maskers. Results: The findings were grouped into three main themes: participants’ appraisal of their tinnitus, factors modulating tinnitus experience, and consequences of tinnitus. Regarding participants’ appraisal of their tinnitus, a dissociation between the tinnitus sensation (pitch, loudness) and tinnitus experience (annoyance/distress) was reported. Factors modulating tinnitus experience were classified as environmental factors and individual-specific factors, which were further divided into soundscape and other environmental factors for the former and attentional focus, stress level, physical state, fatigue, and auditory effort for the latter. Consequences of tinnitus included distraction, disrupted mental health and mood, headaches, fatigue, sleep disturbances, hearing difficulties, disrupted social life, and frustration. Conclusions: Two of the main themes (participants’ appraisal of their tinnitus and consequences of tinnitus) were consistent with findings from a few previous qualitative studies. Factors modulating tinnitus experience also emerged as a prominent theme. Indeed, participants described a plethora of factors that affected their experiences of tinnitus. On the basis of these findings, an attentional model is proposed to account for how these factors might modulate the effects of tinnitus.
Site-specific oxidation of flavanone and flavone by cytochrome P450 2A6 in human liver microsomes

Abstract The roles of human cytochrome P450 (P450 or CYP) 2A6 in the oxidation of flavanone [(2R)- and (2S)-enantiomers] and flavone were studied in human liver microsomes and recombinant human P450 enzymes. CYP2A6 was highly active in oxidizing flavanone to form flavone, 2′-hydroxy-, 4′-, and 6-hydroxyflavanones and in oxidizing flavone to form mono- and di-hydroxylated products, such as mono-hydroxy flavones M6, M7, and M11 and di-hydroxy flavones M3, M4, and M5. Liver microsomes prepared from human sample HH2, defective in coumarin 7-hydroxylation activity, were very inefficient in forming 2′-hydroxyflavanone from flavanone and a mono-hydroxylated product, M6, from flavone. Coumarin and anti-CYP2A6 antibodies strongly inhibited the formation of these metabolites in microsomes prepared from liver samples HH47 and 54, which were active in coumarin oxidation activities. Molecular docking analysis showed that the C2′-position of (2R)-flavanone (3.8 Å) was closer to the iron center of CYP2A6 than the C6-position (10 Å), while distances from C2′ and C6 of (2S)-flavanone to the CYP2A6 were 6.91 Å and 5.42 Å, respectively. These results suggest that CYP2A6 catalyzes site-specific oxidation of (racemic) flavanone and also flavone in human liver microsomes. CYP1A2 and CYP2B6 were also found to play significant roles in some of the oxidations of these flavonoids by human liver microsomes.
Foam-driven fracture

Significance Hydraulic fracturing plays an important role in meeting today’s energy demands. However, the substantial use of fresh water in fracturing and wastewater returning to the surface pose risks to the environment. Alternative technology has been developed that reduces the water-related risks by injecting aqueous foam instead of water to fracture shale formations, but the mechanism is poorly understood. Here, we show, using laboratory experiments, that the injection of foam instead of water dramatically changes the fracture dynamics when the foam compressibility is important. We develop a scaling argument for the fracture dynamics that exhibits excellent agreement with the experimental results. Our findings extend to other systems involving compressible foams, including fire-fighting, energy storage using compressed foams, and enhanced oil recovery. In hydraulic fracturing, water is injected at high pressure to crack shale formations. More sustainable techniques use aqueous foams as injection fluids to reduce the water use and wastewater treatment of conventional hydrofractures. However, the physical mechanism of foam fracturing remains poorly understood, and this lack of understanding extends to other applications of compressible foams such as fire-fighting, energy storage, and enhanced oil recovery. Here we show that the injection of foam is much different from the injection of incompressible fluids and results in striking dynamics of fracture propagation that are tied to the compressibility of the foam. An understanding of bubble-scale dynamics is used to develop a model for macroscopic, compressible flow of the foam, from which a scaling law for the fracture length as a function of time is identified and exhibits excellent agreement with our experimental results.
Lysosomal cathepsin D is upregulated in Alzheimer's disease neocortex and may be a marker for neurofibrillary degeneration

Alzheimer's disease (AD) is characterized by accumulation of β‐amyloid plaques (AP) and neurofibrillary tangles (NFT) in the cortex, together with synaptic loss and amyloid angiopathy. Perturbations in the brain lysosomal system, including the cathepsin family of proteases, have been implicated in AD where they may be involved in proteolytic clearance of misfolded and abnormally aggregated peptides. However, the status of cathepsin D (catD) is unclear in Lewy body dementia, the second most common form of neurodegenerative dementia after AD, and characterized by Lewy bodies (LB) containing aggregated α‐synuclein. Furthermore, earlier reports of catD changes in AD have not been entirely consistent. We measured CatD immunoreactivities in the temporal (Brodmann area BA21) and parietal (BA40) cortices of well characterized AD brains as well as two clinical subtypes of Lewy body dementia, namely Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLB), known to show varying degrees of concomitant AD pathology. Increased catD immunoreactivities in AD were found for both neocortical regions measured, where they also correlated with neuropathological NFT scores and phosphorylated pSer396 tau burden, and appeared to co‐localize at least partly to NFT‐containing neurons. In contrast, catD was increased only in BA40 in DLB and not at all in PDD, did not correlate with LB scores, and did not appreciably co‐localize with α‐synuclein inclusions. Our study suggests that catD upregulation may be an adaptive response to AD‐related processes leading to neurofibrillary degeneration, but may not be directly associated with formation of α‐synuclein inclusions in Lewy body dementia.
Higher vegetable protein consumption, assessed by an isoenergetic macronutrient exchange model, is associated with a lower presence of overweight and obesity in the web-based Food4me European study

Abstract The objective was to evaluate differences in macronutrient intake and to investigate the possible association between consumption of vegetable protein and the risk of overweight/obesity, within the Food4Me randomised, online intervention. Differences in macronutrient consumption among the participating countries grouped by EU Regions (Western Europe, British Isles, Eastern Europe and Southern Europe) were assessed. Relation of protein intake, within isoenergetic exchange patterns, from vegetable or animal sources with risk of overweight/obesity was assessed through the multivariate nutrient density model and a multivariate-adjusted logistic regression. A total of 2413 subjects who completed the Food4Me screening were included, with self-reported data on age, weight, height, physical activity and dietary intake. As success rates on reducing overweight/obesity are very low, form a public health perspective, the elaboration of policies for increasing intakes of vegetable protein and reducing animal protein and sugars, may be a method of combating overweight/obesity at a population level.
Seasonal Variability of the Biochemical Composition and Antioxidant Properties of Fucus spiralis at Two Azorean Islands

This study evaluates, for the first time, the seasonal (winter and summer) and geographical (São Miguel–SMG and Santa Maria–SMA Islands) variability of Fucus spiralis (Fs) biochemical composition (dry weight basis) and antioxidant properties. Protein and carbohydrates presented higher values in Fs-SMGwinter, lipids, total dietary fiber, and energy value in Fs-SMAsummer, and ash and soluble dietary fiber/insoluble dietary fiber ratio in Fs-SMAwinter. The fatty acid (FA) profiles showed a lower SFA in Fs-SMGsummer, whereas MUFA and PUFA presented higher values in Fs-SMGsummer and Fs-SMGwinter, respectively. Excellent dietary ratios of n6/n3 PUFA and hypocholesterolemic/hypercholesterolemic FA were found, with lower values in Fs-SMAwinter and higher in Fs-SMGsummer, respectively. The highest total phenolics was found in Fs-SMAsummer acetone:water extract and total flavonoids showed the higher value in Fs-SMGwinter methanol extract. The best free radical-scavenging activity was observed in the Fs-SMAwinter methanol (EC50 = 0.045 mg/mL) and acetone:water (EC50 = 0.059 mg/mL) extracts. The ferric-reducing antioxidant power showed the best results in Fs-SMAwinter methanol extract (EC50 = 0.016 mg/mL) and Fs-SMAsummer acetone:water extract (EC50 = 0.017 mg/mL). The best ferrous ion-chelating activity was found in Fs-SMGwinter acetone:water extract. Overall, results revealed that F. spiralis nutritional and functional bioactivity values have geographical and seasonal variations and that its regular consumption may add benefits to human health.
Brain investigations of rodent disease models by chemical exchange saturation transfer at 21.1 T

This study explores opportunities opened up by ultrahigh fields for in vivo saturation transfer brain magnetic resonance imaging experiments. Fast spin‐echo images weighted by chemical exchange saturation transfer (CEST) effects were collected on Sprague–Dawley rats at 21.1 T, focusing on two neurological models. One involved a middle cerebral artery occlusion emulating ischemic stroke; the other involved xenografted glioma cells that were followed over the course of several days as they developed into brain tumors. A remarkably strong saturation‐derived contrast was observed for the growing tumors when calculating magnetization transfer ratios at c. 3.8 ppm. This large contrast originated partially from an increase in the contribution of the amide CEST effect, but mostly from strong decreases in the Overhauser and magnetization transfer contributions to the upfield region, whose differential attenuations could be clearly discerned thanks to the ultrahigh field. The high spectral separation arising at 21.1 T also revealed numerous CEST signals usually overlapping at lower fields. Ischemic lesions were also investigated but, remarkably, magnetization and saturation transfer contrasts were nearly absent when computing transfer asymmetries using either high or low saturation power schemes. These behaviors were consistently observed at 24 hours post‐occlusion, regardless of the data processing approach assayed. Considerations related to how various parameters defining these experiments depend on the magnetic field, primarily chemical shifts and T1 values, are discussed.
Microglia have a more extensive and divergent response to interferon‐α compared with astrocytes

Type I interferons (IFN‐I) are crucial for effective antimicrobial defense in the central nervous system (CNS) but also can cause severe neurological disease (termed cerebral interferonopathy) as exemplified by Aicardi‐Goutières Syndrome. In the CNS, microglia and astrocytes have essential roles in host responses to infection and injury, with both cell types responding to IFN‐I. While the IFN‐I signaling pathways are the same in astrocytes and microglia, the extent to which the IFN‐I responses of these cells differ, if at all, is unknown. Here we determined the global transcriptional responses of astrocytes and microglia to the IFN‐I, IFN‐α. We found that under basal conditions, each cell type has a unique gene expression pattern reflective of its developmental origin and biological function. Following stimulation with IFN‐α, astrocytes and microglia also displayed a common core response that was characterized by the increased expression of genes required for pathogen detection and elimination. Compared with astrocytes, microglia had a more extensive and diverse response to IFN‐α with significantly more genes with expression upregulated (282 vs. 141) and downregulated (81 vs. 3). Further validation was documented for selected IFN‐I‐regulated genes in a murine model of cerebral interferonopathy. In all, the findings highlight not only overlapping but importantly divergent responses to IFN‐I by astrocytes versus microglia. This suggests specialized roles for these cells in host defense and in the development of cerebral interferonopathy.
Robustness to fundamental uncertainty in AGI alignment

The AGI alignment problem has a bimodal distribution of outcomes with most outcomes clustering around the poles of total success and existential, catastrophic failure. Consequently, attempts to solve AGI alignment should, all else equal, prefer false negatives (ignoring research programs that would have been successful) to false positives (pursuing research programs that will unexpectedly fail). Thus, we propose adopting a policy of responding to points of philosophical and practical uncertainty associated with the alignment problem by limiting and choosing necessary assumptions to reduce the risk of false positives. Herein we explore in detail two relevant points of uncertainty that AGI alignment research hinges on---meta-ethical uncertainty and uncertainty about mental phenomena---and show how to reduce false positives in response to them.
The Clinical Significance of Relative Bradycardia.

INTRODUCTION Relative bradycardia is a poorly understood paradoxical phenomenon that refers to a clinical sign whereby the pulse rate is lower than expected for a given body temperature. OBJECTIVE To provide an overview and describe infectious and noninfectious causes of relative bradycardia. METHODS PubMed and Medline databases were searched using individual and Medical Subject Headings terms including relative bradycardia, fever, pulse-temperature dissociation and pulsetemperature deficit in human studies published from inception to October 2, 2016. The causes and incidence of relative bradycardia were reviewed. RESULTS Relative bradycardia is found in a wide variety of infectious and noninfectious diseases. The pathogenesis remains poorly understood with proposed mechanisms including release of inflammatory cytokines, increased vagal tone, direct pathogenic effect on the myocardium, and electrolyte abnormalities. The incidence of this sign varies widely, which may be attributable to multiple factors, including population size, time course for measuring pulse and temperature, and lack of a consistent definition used. The fact that this sign is not consistently identified in case series suggests that relative bradycardia is caused by mechanisms presumably involving or influenced by pathogen and host factors. CONCLUSIONS Relative bradycardia is a sensitive but nonspecific clinical sign that may be an important bedside tool for narrowing the differential diagnosis of potential infectious and noninfectious etiologies. Recognizing this relationship may assist the clinician by providing bedside clinical clues into potential etiologies of disease, particularly in the setting of infectious diseases and in circumstances when other stigma of disease is absent.
A new structural class of bacterial thioester domains reveals a slipknot topology

An increasing number of surface‐associated proteins identified in Gram‐positive bacteria are characterized by intramolecular cross‐links in structurally conserved thioester, isopeptide, and ester domains (TIE proteins). Two classes of thioester domains (TEDs) have been predicted based on sequence with, to date, only representatives of Class I structurally characterized. Here, we present crystal structures of three Class II TEDs from Bacillus anthracis, vancomycin‐resistant Staphylococcus aureus, and vancomycin‐resistant Enterococcus faecium. These proteins are structurally distinct from Class I TEDs due to a β‐sandwich domain that is inserted into the conserved TED fold to form a slipknot structure. Further, the B. anthracis TED domain is presented in the context of a full‐length sortase‐anchored protein structure (BaTIE). This provides insight into the three‐dimensional arrangement of TIE proteins, which emerge as very abundant putative adhesins of Gram‐positive bacteria.
Concurrent Learning of Semantic Relations

Discovering whether words are semantically related and identifying the specific semantic relation that holds between them is of crucial importance for NLP as it is essential for tasks like query expansion in IR. Within this context, different methodologies have been proposed that either exclusively focus on a single lexical relation (e.g. hypernymy vs. random) or learn specific classifiers capable of identifying multiple semantic relations (e.g. hypernymy vs. synonymy vs. random). In this paper, we propose another way to look at the problem that relies on the multi-task learning paradigm. In particular, we want to study whether the learning process of a given semantic relation (e.g. hypernymy) can be improved by the concurrent learning of another semantic relation (e.g. co-hyponymy). Within this context, we particularly examine the benefits of semi-supervised learning where the training of a prediction function is performed over few labeled data jointly with many unlabeled ones. Preliminary results based on simple learning strategies and state-of-the-art distributional feature representations show that concurrent learning can lead to improvements in a vast majority of tested situations.
Argatroban plus aspirin versus aspirin in acute ischemic stroke

ABSTRACT Objectives: Anticoagulant therapy in the acute phase of AIS remains controversial. The aim of this study was to investigate whether argatroban benefited early stroke outcomes compared with antiplatelet treatment. Methods: We reviewed data from 1,485 patients with AIS hospitalized at Tianjin Union Medical Center (TUMC) between 1 January 2013 and 31 December 2015 from the TUMC registry database. Patients were divided into two groups: an antiplatelet group (aspirin 300 mg daily) and an argatroban group (argatroban 60 mg for 2 days followed by 20 mg daily; or 20 mg daily – both regimens combination with aspirin 100 mg daily). Two primary outcomes, change in NIHSS score (baseline–discharge) and intracerebral hemorrhage, were investigated. Results: No major symptomatic intracerebral hemorrhages were observed in either group. Both groups had significantly decreased NIHSS scores at discharge (Z = −14.617, P < 0.001 and Z = −6.385, P < 0.001, respectively), and there were no significant group differences in NIHSS score change (Z = −1.888, P = 0.059). In the mild stroke subgroup, the argatroban group had a worse NIHSS score at discharge (Z = −6.148, P = 0.002), while the aspirin group had an improved NIHSS score (Z = −4,423, P < 0.001). In the moderate stroke subgroup, both groups had significantly decreased NIHSS scores at discharge (Z = −13.260, P < 0.001 and Z = −7.108, P < 0.001, respectively) and there were no significant group differences in NIHSS score changes (Z = −1.888, P = 0.059). Conclusion: Argatroban is effective and safe for the treatment of moderate AIS with similar efficacy to high-dose aspirin in the acute phase of AIS, although no additional benefit on short-term outcome was observed. For patients with mild AIS, argatroban may be inferior to high-dose aspirin.