Miracle-dz/UniFAR-FTUs huggingface dataset:
Methionine deficiency does not increase polyamine turnover through depletion of hepatic S-adenosylmethionine in juvenile Atlantic salmon

During the last few decades, plant protein ingredients such as soya proteins have replaced fishmeal in the diets of aquacultured species. This may affect the requirement and metabolism of methionine as soya contains less methionine compared with fishmeal. To assess whether methionine limitation affects decarboxylated S-adenosylmethionine availability and polyamine status, in the present study, juvenile Atlantic salmon were fed a methionine-deficient plant protein-based diet or the same diet supplemented with dl-methionine for 8 weeks. The test diets were compared with a fishmeal-based control diet to assess their effects on the growth performance of fish. Methionine limitation reduced growth and protein accretion, but when fish were fed the dl-methionine-supplemented diet their growth and protein accretion equalled those of fish fed the fishmeal-based control diet. Methionine limitation reduced free methionine concentrations in the plasma and muscle, while those in the liver were not affected. S-adenosylmethionine (SAM) concentrations were higher in the liver of fish fed the methionine-deficient diet, while S-adenosylhomocysteine concentrations were not affected. Putrescine concentrations were higher and spermine concentrations were lower in the liver of fish fed the methionine-deficient diet, while the gene expression of SAM decarboxylase (SAMdc) and the rate-limiting enzyme of polyamine synthesis ornithine decarboxylase (ODC) was not affected. Polyamine turnover, as assessed by spermine/spermidine acetyltransferase (SSAT) abundance, activity and gene expression, was not affected by treatment. However, the gene expression of the cytokine TNF-α increased in fish fed the methionine-deficient diet, indicative of stressful conditions in the liver. Even though taurine concentrations in the liver were not affected by treatment, methionine and taurine concentrations in muscle decreased due to methionine deficiency. Concomitantly, liver phospholipid and cholesterol concentrations were reduced, while NEFA concentrations were elevated. In conclusion, methionine deficiency did not increase polyamine turnover through depletion of hepatic SAM, as assessed by SSAT activity and abundance.
The K-Nearest Neighbour UCB Algorithm for Multi-Armed Bandits with Covariates

In this paper we propose and explore the k-Nearest Neighbour UCB algorithm for multi-armed bandits with covariates. We focus on a setting where the covariates are supported on a metric space of low intrinsic dimension, such as a manifold embedded within a high dimensional ambient feature space. The algorithm is conceptually simple and straightforward to implement. The k-Nearest Neighbour UCB algorithm does not require prior knowledge of the either the intrinsic dimension of the marginal distribution or the time horizon. We prove a regret bound for the k-Nearest Neighbour UCB algorithm which is minimax optimal up to logarithmic factors. In particular, the algorithm automatically takes advantage of both low intrinsic dimensionality of the marginal distribution over the covariates and low noise in the data, expressed as a margin condition. In addition, focusing on the case of bounded rewards, we give corresponding regret bounds for the k-Nearest Neighbour KL-UCB algorithm, which is an analogue of the KL-UCB algorithm adapted to the setting of multi-armed bandits with covariates. Finally, we present empirical results which demonstrate the ability of both the k-Nearest Neighbour UCB and k-Nearest Neighbour KL-UCB to take advantage of situations where the data is supported on an unknown sub-manifold of a high-dimensional feature space.
Executive control in schizophrenia: a preliminary study on the moderating role of COMT Val158Met for comorbid alcohol and substance use disorders

Abstract Background: A functional polymorphism in the catechol-O-methyltransferase (COMT) gene (Val158Met) appears to influence cognition in people with alcohol/substance use disorders (AUD/SUD) and in those with psychosis. Methods: To explore the potential moderating effect of these factors, a cross-sectional study was conducted, randomly recruiting subjects with DSM-IV diagnosis of schizophrenia. AUD/SUD was rigorously assessed, as well as COMT Val158Met polymorphism. Executive control functioning was measured using the Intra-Extra Dimensional Set Shift (IED). The effect of a possible interaction between comorbid AUD/SUD and COMT Val158Met polymorphism on IED scores was explored. Results: Subjects with schizophrenia, comorbid AUD/SUD, and MetMet carriers for SNP rs4680 of the COMT gene showed worse performance on IED completed stages scores, as compared with individuals with ValVal genotype. However, among subjects without AUD/SUD, those with the MetMet variant performed better than people carrying ValVal genotype. Conclusions: This study is the first to date examining the impact of COMT on cognition in a highly representative sample of people with schizophrenia and comorbid AUD/SUD. Differential moderating effects of COMT Val/Met genotype variations may similarly influence executive functions in people with schizophrenia and comorbid AUD/SUD.
Just add water: cannabinoid discrimination in a water T-maze with FAAH(−/−) and FAAH(+/+) mice

Incomplete overlap in the discriminative stimulus effects of &Dgr;9-tetrahydrocannabinol (THC) and the endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol has been reported in food-reinforced tasks. The aim of this study was to examine cannabinoid discriminative stimulus effects in a nonappetitive procedure. Adult male mice lacking the gene for AEA’s major metabolic enzyme, fatty acid amide hydrolase (FAAH), and FAAH(+/+) mice were trained to discriminate THC or AEA in a water T-maze, in which the response was swimming to an escape platform on the injection-appropriate side. JZL184, a monoacylglycerol lipase inhibitor, was also tested. FAAH(−/−) mice showed faster acquisition than FAAH(+/+) mice. THC and AEA fully substituted, with only minor cross-procedure potency variations. Incomplete substitution of JZL184 was observed in THC-trained FAAH(−/−) mice in the water-maze task, as contrasted with full substitution in a food-reinforced nose-poke procedure. Stress-induced changes in AEA and/or 2-arachidonoylglycerol concentrations in the brain may have mediated this attenuation. JZL184 also partially substituted in AEA-trained FAAH(−/−) mice in the water maze, suggesting incomplete overlap in the stimulus effects of AEA and JZL184. Through the use of a novel water-maze procedure, the present study supports the work of previous behavioral pharmacologists in showing the robustness of the discrimination paradigm.
First Brazilian Real Time Network DGPS through the Internet: Development, Application and Availability Analyses

First Brazilian Real Time Network DGPS through the Internet: Development, Application and Availability Analyses The Global Positioning System (GPS) is widely used by the civil community. Differential GPS (DGPS) was developed to provide better accuracy than autonomous GPS. The DGPS concept is based on the high correlation of errors due to atmospheric effects, satellite clocks and orbits. However, as the baseline grows, its efficiency decreases because the error correlation is reduced. This limitation can be handled by using a reference station network and applying the network DGPS concept (called NDGPS). In this paper, the goal is to present aspects related to the development and application of NDGPS in real time at the São Paulo state network in Brazil. The NDGPS corrections were computed from data received via the Internet using NTRIP (Networked Transport of RTCM via Internet Protocol). Our implementation was based on BNC (BKG Ntrip Client) software. NDGPS provided RMS improvements of up to 59% in horizontal components and 31% in vertical components when compared to DGPS. The availability of the system, the first of this nature in Brazil, was also analyzed within the context of the SP State GNSS Network, located in the southeastern region of Brazil. The results also serve as an indication of the quality of local internet infrastructure for using in geodetic positioning.
The candidate tuberculosis vaccine Mtb72F/AS02A: Tolerability and immunogenicity in humans

Tuberculosis (TB) remains uncontrolled in many parts of the world and the development of an effective vaccine against TB represents a high priority unmet medical need. Healthy PPD (tuberculin purified protein derivative)-negative adult volunteers, aged 18-40 years received three doses of the candidate Mtb72F/AS02A vaccine according to a 0-1-2 months schedule in an open-label Phase I study (NCT00730795). Solicited, unsolicited and serious adverse events (AEs), hematological and biochemical laboratory parameters were assessed. Mtb72F-specific humoral responses were assessed by ELISA and cell-mediated immune (CMI) responses by intracellular cytokine staining (ICS) and short-term ELISPOT assays. CMI responses to the component peptides (Mtb39a and the Mtb32a C- and N-terminal antigen domains, Mtb32C and Mtb32N) were also assessed by ICS. The Mtb72F/AS02A vaccine appeared to be mainly locally reactogenic but this was considered acceptable, since these AEs were usually transient and resolved within 1-2 days. Most AEs reported were mild in intensity, no serious AEs occurred, no medically significant biochemical or hematological abnormalities related to vaccination were measured and all AEs resolved without sequelae. The vaccine induced statistically significant changes in humoral and CMI response measures. The Mtb72F antigen induced good production of IL-2 and IFN γ in the ELISPOT assay and CD4+T cells expressing at least 2 activation markers (mainly CD40-L and IL-2) were observed with ICS. A similar CMI profile was observed with Mtb39a and Mtb32N. The induced CMI responses persisted for at least 6 months post-vaccination. All subjects were seropositive for anti-Mtb72F antibodies one month post-dose 2 and 6 months post-dose 3. This first trial in humans found Mtb72F/AS02A to have an, acceptable tolerability, to be immunogenic in healthy adults and warrants further development of the vaccine.
Disorders of the Nervous System Dopamine Development in the Mouse Orbital Prefrontal Cortex Is Protracted and Sensitive to Amphetamine in Adolescence

The prefrontal cortex (PFC) is divided into subregions, including the medial and orbital prefrontal cortices. Dopamine connectivity in the medial PFC (mPFC) continues to be established throughout adolescence as the result of the continuous growth of axons that innervated the nucleus accumbens (NAcc) prior to adolescence. During this period, dopamine axons remain vulnerable to environmental influences, such as drugs used recreationally by humans. The developmental trajectory of the orbital prefrontal dopamine innervation remains almost completely unstudied. Nonetheless, the orbital PFC (oPFC) is critical for some of the most complex functions of the PFC and is disrupted by drugs of abuse, both in adolescent humans and rodents. Here, we use quantitative neuroanatomy, axon-initiated viral-vector recombination, and pharmacology in mice to determine the spatiotemporal development of the dopamine innervation to the oPFC and its vulnerability to amphetamine in adolescence. We find that dopamine innervation to the oPFC also continues to increase during adolescence and that this increase is due to the growth of new dopamine axons to this region. Furthermore, amphetamine in adolescence dramatically reduces the number of presynaptic sites on oPFC dopamine axons. In contrast, dopamine innervation to the piriform cortex is not protracted across adolescence and is not impacted by amphetamine exposure during adolescence, indicating that dopamine development during adolescence is a uniquely prefrontal phenomenon. This renders these fibers, and the PFC in general, particularly vulnerable to environmental risk factors during adolescence, such as recreational drug use.
PDB-NMA of a protein homodimer reproduces distinct experimental motility asymmetry

We have extended our analytically derived PDB-NMA formulation, Atomic Torsional Modal Analysis or ATMAN (Tirion and ben-Avraham 2015 Phys. Rev. E 91 032712), to include protein dimers using mixed internal and Cartesian coordinates. A test case on a 1.3 A˚ resolution model of a small homodimer, ActVA-ORF6, consisting of two 112-residue subunits identically folded in a compact 50 A˚ sphere, reproduces the distinct experimental Debye–Waller motility asymmetry for the two chains, demonstrating that structure sensitively selects vibrational signatures. The vibrational analysis of this PDB entry, together with biochemical and crystallographic data, demonstrates the cooperative nature of the dimeric interaction of the two subunits and suggests a mechanical model for subunit interconversion during the catalytic cycle.
Design of Testable Multipliers for Fixed-Width Data Paths

The usage of multipliers in fixed-width data-dominated architectures (also termed data paths) poses serious testability problems. Due to truncation of their outputs, the fault observability of the multipliers degrades, and the resulting output patterns are inadequate to completely test functional blocks that are driven by them. Consequently, the overall random pattern testability of data paths deteriorates substantially. In this paper, we propose new generic design schemes, based on residue number system arithmetic, to improve the overall testability of data paths. The approach uses, in the test mode, the truncated least significant bits of the product to increase the variety of patterns at the output of a multiplier. This, in turn, improves the fault detectability of multipliers, and consequently, have a remarkable impact on the overall testability of data paths. The proposed techniques can be incorporated with a minimal performance degradation and area overhead, and are independent of the multiplier architecture. Experimental analysis performed on four high-level synthesis benchmarks exhibits a significant improvement in the overall testability of the corresponding data-path implementations.
Instability of ZPI Complexes with Factors Xa and

Protein Z (PZ) is a 62 kDa vitamin K-dependent plasma protein that serves as a cofactor for the inhibition of factor Xa by protein Z-dependent protease inhibitor (ZPI). ZPI is a recently identified 72 kDa member of the serpin superfamily of proteinase inhibitors that contains a tyrosine at its reactive center. PZ circulates in plasma in a complex with ZPI. Inhibition of factor Xa by ZPI in the presence of phospholipids and Ca++ is enhanced 1000-fold by PZ, but ZPI also inhibits factor XIa in a process that does not require PZ, phospholipids or Ca++. ZPI activity is consumed during coagulation through proteolysis mediated by factor Xa with PZ and factor XIa. Concomitant PZ deficiency dramatically increases the severity of the prothrombotic phenotype of factor VLeiden mice. Studies to determine the potential roles of PZ and ZPI deficiency in human thrombosis are in progress.
Hyperthyroidism in an infant of a mother with autoimmune hypothyroidism with positive TSH receptor antibodies

Abstract Background: Neonatal hyperthyroidism is rare, seen in infants of mothers with Graves’ disease (GD), with transplacental transfer of thyroid-stimulating hormone receptor (TSHR) antibodies (TRAbs). We describe a neonate with severe hyperthyroidism due to TRAbs, born to a mother with autoimmune hypothyroidism. Case presentation: A baby boy born preterm at 35 weeks had irritability, tachycardia and proptosis after birth. The mother had autoimmune hypothyroidism, from age 10, with thyroxine replacement and normal thyroid function throughout her pregnancy. She had never been thyrotoxic. There was a family history of Hashimoto’s thyroiditis (HT) and GD. The baby’s thyroid function on day 3 demonstrated gross thyrotoxicosis, TSH<0.01 mIU/L (normal range [NR]<10 mIU/L), free thyroxine (FT4)>77 pmol/L (20–35), free triiodothyronine (FT3) 15.4 pmol/L (4.2–8.3) and TRAb 18.4 IU/L (<1.8). The mother’s TRAb was 24.7 IU/L. Thyrotoxicosis required propranolol and carbimazole (CBZ). Thyroid function normalized within 10 days. The baby was weaned off medication by 7 weeks. He remains euthyroid. Conclusions: We postulate that this mother had co-existing destructive thyroiditis and thyroid-stimulating antibodies (TSAbs) and TSHR blocking antibodies (TBAb), rendering her unable to raise a thyrotoxic response to the TSAbs but with predominant TSAb transmission to her infant. Maternal history of any thyroid disorder may increase the risk of transmission to an infant, requiring a careful clinical assessment of the neonate, with important implications for future pregnancies.
A Novel Class of Schistosoma mansoni Histone Deacetylase 8 (HDAC8) Inhibitors Identified by Structure-Based Virtual Screening and In Vitro Testing

A promising means in the search of new small molecules for the treatment of schistosomiasis (amongst other parasitic ailments) is by targeting the parasitic epigenome. In the present study, a docking based virtual screening procedure using the crystal structure of histone deacetylase 8 from Schistosoma mansoni (smHDAC8) was designed. From the developed screening protocol, we were able to identify eight novel N-(2,5-dioxopyrrolidin-3-yl)-n-alkylhydroxamate derivatives as smHDAC8 inhibitors with IC50 values ranging from 4.4–20.3 µM against smHDAC8. These newly identified inhibitors were further tested against human histone deacetylases (hsHDAC1, 6 and 8), and were found also to be exerting interesting activity against them. In silico prediction of the docking pose of the compounds was confirmed by the resolved crystal structure of one of the identified hits. This confirmed these compounds were able to chelate the catalytic zinc ion in a bidentate fashion, whilst showing an inverted binding mode of the hydroxamate group when compared to the reported smHDAC8/hydroxamates crystal structures. Therefore, they can be considered as new potential scaffold for the development of new smHDAC8 inhibitors by further investigation of their structure–activity relationship.
Placental growth factor, vascular endothelial growth factor, and hypoxia-inducible factor-1α in the placentas of women with pre-eclampsia

Abstract Background: Although the exact mechanism of pre-eclampsia – high blood pressure and proteinuria after 20 gestational weeks – is not yet fully understood, placental growth factor (PLGF), vascular endothelial growth factor (VEGF), and hypoxia-inducible factor (HIF) are known to play important roles in vascularization and in the pathology of pre-eclampsia. Methods: PLGF, VEGF, and HIF-1α were evaluated by immunohistochemistry in the placentas of Sudanese women with mild or severe pre-eclampsia, and in normal controls. Results: Sixty-two women had severe pre-eclampsia, 102 had mild pre-eclampsia and 101 women served as healthy controls. Immunohistochemical staining of PLGF was significantly lower in placentas of women with severe pre-eclampsia (16%) compared with those with mild pre-eclampsia (8.8%) and placentas of normotensive women (40.6%; p < .001). Significantly more of the pre-eclamptic placentas expressed VEGF: in 32%, 17.6%, and 14.9% (p = .020) of the placentas of women with severe or mild pre-eclampsia and in controls, respectively. Significantly more of the pre-eclamptic placentas expressed HIF-1α: in 15%, 10.8%, and 5.0% of the placentas of women with severe or mild pre-eclampsia, and in controls, respectively (p = .044). Conclusion: The current study showed that PLGF, VEGF, and HIF-1α are involved in the pathophysiology of pre-eclampsia.
Listeria monocytogenes: The Impact of Cell Death on Infection and Immunity

Listeria monocytogenes has evolved exquisite mechanisms for invading host cells and spreading from cell-to-cell to ensure maintenance of its intracellular lifecycle. As such, it is not surprising that loss of the intracellular replication niche through induction of host cell death has significant implications on the development of disease and the subsequent immune response. Although L. monocytogenes can activate multiple pathways of host cell death, including necrosis, apoptosis, and pyroptosis, like most intracellular pathogens L. monocytogenes has evolved a series of adaptations that minimize host cell death to promote its virulence. Understanding how L. monocytogenes modulates cell death during infection could lead to novel therapeutic approaches. In addition, as L. monocytogenes is currently being developed as a tumor immunotherapy platform, understanding how cell death pathways influence the priming and quality of cell-mediated immunity is critical. This review will focus on the mechanisms by which L. monocytogenes modulates cell death, as well as the implications of cell death on acute infection and the generation of adaptive immunity.
Hyperhomocysteinemia Is a Risk Factor of Recurrent Venous Thromboembolism

Summary Hyperhomocysteinemia is a risk factor of venous thromboembolism. The risk of recurrence in patients with hyperhomocysteinemia is unknown, and the optimal therapy for these patients after acute venous thromboembolism is uncertain. In a multicenter study, 264 patients with an objectively documented single episode of idiopathic venous thromboembolism were prospectively followed after discontinuation of oral anticoagulants. Patients were classified as hyperhomocysteinemic if their homocysteine levels exceeded the 95th percentile of the controls. The outcome events studied were objectively confirmed deep-vein thrombosis and/or pulmonary embolism. Homocysteine levels were elevated in 66 patients (25%) and normal in 198 patients (75%). Recurrent venous thromboembolism occurred in 12 of 66 patients with hyperhomocysteinemia (18.2%) and in 16 of 198 patients without hyperhomocysteinemia (8.1%). The cumulative probability of recurrence 24 months after discontinuation of oral anticoagulants was 19.2 percent (95 percent confidence interval 8.7-27) in patients with hyperhomocysteinemia and was 6.3 percent (95 percent confidence interval 2.4-10.1; p = 0.001) in those without hyperhomocysteinemia. The relative risk of recurrent thrombosis was higher in patients with hyperhomocysteinemia [RR 2.7 (1.3-5.8), p = 0.009]. Patients with hyperhomocysteinemia are at high risk of recurrent venous thromboembolism. The high prevalence of hyperhomocysteinemia in thrombosis patients together with the increased risk of recurrence warrants extended patient screening. The impact on the risk of recurrence of prolonged anticoagulation, supplementation of folate and vitamin B12, or both have to be investigated.