Miracle-dz/UniFAR-FTUs huggingface dataset:
Structural characterization of the PCV2d genotype at 3.3 Å resolution reveals differences to PCV2a and PCV2b genotypes, a tetranucleotide, and an N-terminus near the icosahedral 3-fold axes

Porcine circovirus 2 (PCV2) is a T=1 non-enveloped icosahedral virus that has a major impact on the swine industry as an agent of porcine circovirus associate disease. PCV2 capsid protein sequences have been employed by others to provide a temporal description of the emerging genotypes. PCV2a is believed to be the earliest genotype and responsible for giving rise to PCV2b, which gives rise to PCV2d. The underlying mechanism responsible for the emerging genotypes is not understood. To determine if a change in the PCV2d capsid accompanies the emergence of this genotype, we determined the cryo-electron microscopy image reconstruction of PCV2d VLP at 3.3 Å resolution and compared it to the previously reported PCV2a and PCV2b structures. Differences between the CD and GH loops identify structural changes that accompany the emergence of PCV2b from PCV2a, and PCV2d from PCV2b. We also model additional amino acids for the N-terminus near the icosahedral 3-fold axes of symmetry and a tetranucleotide between the 5- and 2-fold axes of symmetry. To interpret the sequence diversity that defines the PCV2 genotypes on a structural platform we have performed structure-based sequence comparison. Our analysis demonstrates that each genotype possesses a unique set of amino acids located on the surface of the capsid that experience a high degree of substitution. These substitutions may be a response to the PCV2 vaccination program. The structural difference between PCV2a, b and d genotypes indicate that it is important to determine the PCV2 capsid structure as the virus evolves into different genotypes. Importance PCV2 is a significant epidemic agricultural pathogen that is the causative agent of a variety of swine illnesses. PCV2 infections have significant economic impact in the swine industry and must be controlled by vaccination. Outbreaks in farms vaccinated for PCV2 suggest that improvements to the current vaccination programs are needed. Better understanding of the assembly, structure, replication and evolution of these viruses is necessary for production of improved vaccines. The ability of PCV2 to rapidly shift genotypes suggests that expression systems capable of rapidly producing large quantities of virus-like particles should be pursued. To these ends we have established a mammalian cell-based virus-like particle expression system and performed high resolution structural studies of a new PCV2 genotype. Differences between the structure of this genotype and earlier genotypes demonstrate that it is important to study the PCV2 structure as it shifts genotypes.
Neuroprotective effects of bone marrow-derived mesenchymal stem cellsand conditioned medium in mechanically injured neuroblastoma cells.

BACKGROUND/AIM Bone marrow-derived mesenchymal stem cells (BMSCs) possess self-renewal characteristics that distinguish them from other cell types. Recent studies have focused on the effects of conditioned medium (CM) that includes the extracellular matrix. Here we examined the neuroprotective effects of BMSCs and CM on damaged neuroblastoma cells. MATERIALS AND METHODS The cells were divided into five groups: 1) healthy controls, 2) damaged cells alone, 3) damaged cells treated with BMSCs, 4) damaged cells treated with CM, and 5) damaged cells treated with both BMSCs and CM. Neuroprotective effects were then evaluated based upon the levels of oxidative stress, antitransforming growth factor β1 (anti-TGFβ1) production, and apoptosis. RESULTS Significant differences were observed between healthy controls and damaged cells (P < 0.001), as well as between damaged cells and those treated with BMSCs alone (P < 0.05), CM alone (P < 0.05), and both BMSCs and CM in combination (P < 0.01). Among the treated groups, the strongest neuroprotective effects were seen in cells treated with both BMSCs and CM. CONCLUSION These results show that both BMSCs and CM exhibit neuroprotective effects in damaged neuroblastoma cells. The strongest benefits were seen following treatment with both BMSCs and CM.
Evidence That Both Exosites on Thrombin Participate in Its High Affinity Interaction with Fibrin*

Exosite 1 on thrombin mediates low affinity binding to sites on the NH2 termini of the α- and β-chains of fibrin. A subpopulation of fibrin molecules (γA/γ′-fibrin) has an alternate COOH terminus of the normal γ-chain (γA/γA-fibrin) that binds thrombin with high affinity. To determine the roles of exosites 1 and 2 in the high affinity interaction of thrombin with γA/γ′-fibrin, binding studies were done with thrombin variants and exosite 1- or 2-directed ligands. α-Thrombin bound γA/γ′-fibrin via high and low affinity binding sites. A peptide analog of the COOH terminus of the γ′-chain that binds α-thrombin via exosite 2 blocked the high affinity binding of α-thrombin to γA/γ′-fibrin, suggesting that the interaction of α-thrombin with the γ′-chain is exosite 2-mediated. In support of this concept, (a) γ-thrombin, which lacks a functional exosite 1, bound to γA/γ′-fibrin, but not to γA/γA-fibrin; (b) thrombin R93A/R97A/R101A, an exosite 2-defective variant, bound only to γA/γ′-fibrin via low affinity sites; and (c) exosite 2-directed ligands reduced α-thrombin binding to γA/γ′-fibrin. However, several lines of evidence indicate that exosite 1 contributes to the high affinity interaction of thrombin with γA/γ′-fibrin. First, the affinity of γ-thrombin for γA/γ′-fibrin was lower than that of α-thrombin. Second, removal of a low affinity binding site on the β-chain of γA/γ′-fibrin reduced its affinity for α-thrombin. Third, exosite 1-directed ligands reduced α-thrombin binding to γA/γ′-fibrin. Taken together, these data suggest that, although exosite 2 mediates the interaction of thrombin with the γ′-chain of γA/γ′-fibrin, simultaneous ligation of exosite 1 by low affinity binding sites is essential for the high affinity interaction of thrombin with γA/γ′-fibrin.
Coupled neural systems underlie the production and comprehension of naturalistic narrative speech

Significance Successful verbal communication requires the finely orchestrated interaction between production-based processes in the speaker’s brain and comprehension-based processes in the listener’s brain. Here we first develop a time-warping tool that enables us to map all brain areas reliably activated during the production of real-world speech. The results indicate that speech production is not localized to the left hemisphere but recruits an extensive bilateral network of linguistic and extralinguistic brain areas. We then directly compare the neural responses during speech production and comprehension and find that the two systems respond in similar ways. Our results argue that a shared neural mechanism supporting both production and comprehension facilitates communication and underline the importance of studying comprehension and production within unified frameworks. Neuroimaging studies of language have typically focused on either production or comprehension of single speech utterances such as syllables, words, or sentences. In this study we used a new approach to functional MRI acquisition and analysis to characterize the neural responses during production and comprehension of complex real-life speech. First, using a time-warp based intrasubject correlation method, we identified all areas that are reliably activated in the brains of speakers telling a 15-min-long narrative. Next, we identified areas that are reliably activated in the brains of listeners as they comprehended that same narrative. This allowed us to identify networks of brain regions specific to production and comprehension, as well as those that are shared between the two processes. The results indicate that production of a real-life narrative is not localized to the left hemisphere but recruits an extensive bilateral network, which overlaps extensively with the comprehension system. Moreover, by directly comparing the neural activity time courses during production and comprehension of the same narrative we were able to identify not only the spatial overlap of activity but also areas in which the neural activity is coupled across the speaker’s and listener’s brains during production and comprehension of the same narrative. We demonstrate widespread bilateral coupling between production- and comprehension-related processing within both linguistic and nonlinguistic areas, exposing the surprising extent of shared processes across the two systems.
Age, serum 25-hydroxyvitamin D and vitamin D receptor (VDR) expression and function in peripheral blood mononuclear cells

The relationship between age, vitamin D status, expression and functionality of the vitamin D receptor (VDR), and key genes in the vitamin D pathway in immune cells is unclear. We enrolled adults 50 to 69 years old (20 subjects) and 70+ (20 subjects) and measured: 1) 25(OH)D levels by liquid chromatography/mass spectrometry; and 2) mRNA expression of VDR, 1α-OHase, 1,25D3-MARRS, TREM-1, cathelicidin, RIG-I, and interferon-β by qRT-PCR. Mean serum 25(OH)D was 30 ± 4 ng/mL and was not associated with age. Baseline expression of VDR, 1α-OHase, 1,25D3-MARRS, TREM-1, and RIG-I also did not differ by age; IFN-β expression, however, was higher in the 70+ year old group. 25(OH)D3- and 1,25(OH)2D3-induced VDR, TREM-1 and cathelicidin expression were similar between age groups, as was LPS-induced expression of VDR and of 1α-OHase. Ligand-induced 1,25D3-MARRS expression was higher in subjects ≥ 70 years. Serum 25(OH)D was inversely associated with LPS-stimulated VDR expression and with baseline or vitamin D-induced TREM-1 expression, adjusting for age, self-rated health, and functional status. In healthy adults ≥ 50 years, the expression and functionality of the VDR, 1α-OHase and key vitamin D pathway genes were not consistently associated with age.
Cell biology of Smad2/3 linker region phosphorylation in vascular smooth muscle

1. The transforming growth factor (TGF)‐β superfamily of ligands regulates a diverse set of cellular functions. Transforming growth factor‐β induces its biological effects through Type I and Type II transmembrane receptors that have serine/threonine kinase activities and weak tyrosine kinase activity. In vascular smooth muscle, TGF‐β binds to the TGF‐β Type II receptor (TβRII) at the cell surface, recruiting the Type I receptor (TβRI) to form a heterocomplex. Consequently, after phosphorylation and activation of TβRI, the transcription factors receptor activated (R‐) Smad2 and Smad3 are recruited and activated through phosphorylation of C terminal residues. Overall, Smad2/3 and co‐Smad4 have similar structures consisting of three regions an N‐terminal MH1 domain, a C‐terminal MH2 domain and a central linker region.
Network Interconnectivity and Entry into Platform Markets

Digital technologies have led to the emergence of many platforms in our economy today. In certain platform networks, buyers in one market purchase services from providers in many other markets, whereas in others, buyers primarily purchase services from providers within the same market. Accordingly, network interconnectivity—which measures the degree to which consumers in one market purchase services from service providers in a different market—varies across different industries. We examine how network interconnectivity affects interactions between an incumbent platform serving multiple markets and an entrant platform seeking to enter one of these markets. Our model yields several interesting results. First, even if the entrant can advertise at no cost, it still may not want to make every user in a local market aware of its service, as doing so may trigger a competitive response from the incumbent. Second, having more mobile buyers, which increases interconnectivity between markets, can reduce the incumbent’s incentive to fight and, thus, increase the entrant’s incentive to expand. Third, stronger interconnectivity between markets may or may not make the incumbent more defensible: when advertising is not costly and mobile buyers consume in both their local markets and the markets they visit, a large number of mobile buyers will increase the entrant’s profitability, thereby making it difficult for the incumbent to deter entry. However, when advertising is costly or mobile buyers only consume in the markets they travel to, a large number of mobile buyers will help the incumbent deter entry. When advertising cost is at an intermediate level, the entrant prefers a market with moderate interconnectivity between markets. Fourth, we find that even if advanced targeting technologies can enable the entrant to also advertise to mobile buyers, the entrant may choose not to do so in order to avoid triggering the incumbent’s competitive response. Finally, we find that the presence of network effects is likely to decrease the entrant’s profit. Our results offer managerial implications for platform firms and help understand their performance heterogeneity.
Critical assessment of pendimethalin in terms of persistence, bioaccumulation, toxicity, and potential for long-range transport

ABSTRACT Pendimethalin (PND, CAS registry number 40487-42-1) is a dinitroaniline herbicide that selectively controls broad-leaf and grassy weeds in a variety of crops and in noncrop areas. It has been on the market for about 30 yr and is currently under review for properties related to persistence (P), bioaccumulation (B), and toxicity (T) in the European Union (EU). A critical review of these properties as well as potential for long-range transport (LRT) was conducted. Pendimethalin has a geometric mean (GM) half-life of 76–98 d in agriculturally relevant soils under aerobic conditions in the lab. The anaerobic half-life was 12 d. The GM for field half-lives was 72 d. The GM half-life for sediment-water tests in the lab was 20 d and that in field aquatic cosms ranged from 45 to 90 d. From these data PND is not persistent as defined in the Annex II of EC regulation 1107/2009. The GM bioconcentration factor for PND was 1878, less than the criterion value. This was consistent with lack of biomagnification or accumulation in aquatic and terrestrial food chains. The GM no-observed-effect concentration (NOEC) value for fish was 43 µg/L, and 11 µg/L for algae. These do not trigger the criterion value for toxicity. In air, the DT50 of PND was estimated to be 0.35 d, which is well below the criterion of 2 d for LRT under the United Nations Economic Commission for Europe (UNECE) Aarhus protocol. Modeling confirmed lack of LRT. Because of its volatility, PND may be transported over short distances in air and was found in samples in local and semiremote regions; however, these concentrations are not of toxicological concern. Unlike other current-use pesticides, PND has not been found in samples from remote regions since 2000 and there is no apparent evidence that this herbicide accumulates in food chains in the Arctic.
AKT2 Confers Protection Against Aortic Aneurysms and Dissections

Rationale: Aortic aneurysm and dissection (AAD) are major diseases of the adult aorta caused by progressive medial degeneration of the aortic wall. Although the overproduction of destructive factors promotes tissue damage and disease progression, the role of protective pathways is unknown. Objective: In this study, we examined the role of AKT2 in protecting the aorta from developing AAD. Methods and Results: AKT2 and phospho-AKT levels were significantly downregulated in human thoracic AAD tissues, especially within the degenerative medial layer. Akt2-deficient mice showed abnormal elastic fibers and reduced medial thickness in the aortic wall. When challenged with angiotensin II, these mice developed aortic aneurysm, dissection, and rupture with features similar to those in humans, in both thoracic and abdominal segments. Aortas from Akt2-deficient mice displayed profound tissue destruction, apoptotic cell death, and inflammatory cell infiltration that were not observed in aortas from wild-type mice. In addition, angiotensin II–infused Akt2-deficient mice showed significantly elevated expression of matrix metalloproteinase-9 (MMP-9) and reduced expression of tissue inhibitor of metalloproteinase-1 (TIMP-1). In cultured human aortic vascular smooth muscle cells, AKT2 inhibited the expression of MMP-9 and stimulated the expression of TIMP-1 by preventing the binding of transcription factor forkhead box protein O1 to the MMP-9 and TIMP-1 promoters. Conclusions: Impaired AKT2 signaling may contribute to increased susceptibility to the development of AAD. Our findings provide evidence of a mechanism that underlies the protective effects of AKT2 on the aortic wall and that may serve as a therapeutic target in the prevention of AAD.
Forest Garrote

Variable selection for high-dimensional linear models has received a lot of attention lately, mostly in the context of l1-regularization. Part of the attraction is the variable selection effect: parsimonious models are obtained, which are very suitable for interpretation. In terms of predictive power, however, these regularized linear models are often slightly inferior to machine learning procedures like tree ensembles. Tree ensembles, on the other hand, lack usually a formal way of variable selection and are difficult to visualize. A Garrote-style convex penalty for trees ensembles, in particular Random Forests, is proposed. The penalty selects functional groups of nodes in the trees. These could be as simple as monotone functions of individual predictor variables. This yields a parsimonious function fit, which lends itself easily to visualization and interpretation. The predictive power is maintained at least at the same level as the original tree ensemble. A key feature of the method is that, once a tree ensemble is fitted, no further tuning parameter needs to be selected. The empirical performance is demonstrated on a wide array of datasets.
An additional coordination group leads to extremely efficient chiral iridium catalysts for asymmetric hydrogenation of ketones.

The production of enantiopure chiral compounds is important for pharmaceutical and agrochemical industries because enantiomers can exhibit distinct biological activities. Therefore, processes that directly produce the desired enantiomer are desirable. First reported by Knowles, Horner et al. in 1968, catalytic asymmetric hydrogenation of unsaturated compounds such as olefins, ketones, and imines is one of the most commonly used methods for producing enantiopure chiral compounds. Great progress has been made in this field, and many chiral catalysts are developed for a wide range of unsaturated substrates. It is noteworthy that some of these synthetic chiral catalysts, which are much smaller and simpler than enzymes, exhibit activities and selectivities comparable to those of enzymes: in some cases, one molecule of catalyst can produce millions of new molecules enantioselectively. For example, the diphosphine/diamine ruthenium catalyst reported by Noyori et al. and the iridium ferrocenyl catalyst Ir-(R,S)Xyliphos developed by a team from Novartis (Scheme 1)
m-TSNE: A Framework for Visualizing High-Dimensional Multivariate Time Series

Multivariate time series (MTS) have become increasingly common in healthcare domains where human vital signs and laboratory results are collected for predictive diagnosis. Recently, there have been increasing efforts to visualize healthcare MTS data based on star charts or parallel coordinates. However, such techniques might not be ideal for visualizing a large MTS dataset, since it is difficult to obtain insights or interpretations due to the inherent high dimensionality of MTS. In this paper, we propose 'm-TSNE': a simple and novel framework to visualize high-dimensional MTS data by projecting them into a low-dimensional (2-D or 3-D) space while capturing the underlying data properties. Our framework is easy to use and provides interpretable insights for healthcare professionals to understand MTS data. We evaluate our visualization framework on two real-world datasets and demonstrate that the results of our m-TSNE show patterns that are easy to understand while the other methods' visualization may have limitations in interpretability.
Characterization of soft contact lens edge fitting using ultra-high resolution and ultra-long scan depth optical coherence tomography.

PURPOSE To characterize the edge fitting of soft contact lenses using ultra-high resolution optical coherence tomography (UHR-OCT) and ultra-long scan depth optical coherence tomography (UL-OCT). METHODS A total of 20 participants (11 men, 9 women; mean age, 32.3 years) were recruited. Four different types of soft contact lenses were randomly fitted to both eyes of each subject on two separate visits. After 30 minutes, the horizontal meridians of the corneal center, midperiphery, and limbus were imaged by UHR-OCT. UL-OCT imaged each lens in vitro and the ocular surface of a physical model eye. RESULTS Angle-edged lenses had significantly less conjunctival buildup than did round-edged lenses (P = 0.008). Limbal post-lens tear film gaps were present in 42% of the eyes, with the round-edged lenses having the most at 68%. Similarly, post-lens tear film gaps at the corneal mid-periphery were present in 47% of all eyes, with the round-edged lens having the most at 75%. Mismatches between the lens and the ocular surface were simulated based on UL-OCT images of the in vitro lenses and the model eye. The existence of tear film gaps and touching points were predicted in the simulation. CONCLUSIONS The soft contact lens edge fitting was characterized by the conjunctival buildup and tear film gaps. Different types of contact lenses presented different levels of conjunctival buildup as well as different frequencies of tear film gaps. The findings by UHR-OCT were predicted in the simulation by UL-OCT. The application of these new technologies may open new ways of designing lenses and evaluating their fit.
Effects of mastitis on ovarian function and fertility in dairy cows

Mastitis has a deleterious effect on reproductive responses and fertility of dairy cows, which depends on whether it occurs before or after artificial insemination (AI). Subclinical intramammary infection (IMI) before AI reduced steroid concentrations in the preovulatory follicle of approximately one third of lactating cows, and was associated with low expression of major steroidogenic genes. Consequently, IMI induced an attenuated LH surge and delayed ovulation in 30% of cows with subclinical IMI; the remaining 70% exhibited normal responses. The reason for the diversity in reproductive responses of individual cows to subclinical IMI is unclear. Mastitis induced by Gram-negative or Gram-positive bacteria disrupted the developmental competence of the pool of oocytes at the germinal vesicle stage, resulting in low blastocyst rates. The specific immune/inflammatory molecules involved in impairment of reproductive responses in subclinical mastitic cows are poorly documented. Exposure of small antral follicles to subclinical mastitis induced by Gram-positive bacterial toxins had a long-term effect by reducing estradiol concentrations of preovulatory follicles. Unlike chronic subclinical mastitis, the disruptive effect of short-term clinical IMI before AI is time-dependent and involves lowered conception when IMI occurs close to the time of insemination. The effect of clinical intramammary infection on corpus luteum function is equivocal. In a recent study, inter-estrus interval and progesterone concentration were unaltered in most (95%) E. coli-mastitic cows treated with anti-inflammatory drugs. Fertility studies showed that fertility of subclinical mastitic cows is improved by the Ovsynch program, probably because of synchronized timing of ovulation relative to AI in cows that could otherwise exhibit delayed ovulation.