Miracle-dz/UniFAR-FTUs huggingface dataset:
A Targeted Glycan-Related Gene Screen Reveals Heparan Sulfate Proteoglycan Sulfation Regulates WNT and BMP Trans-Synaptic Signaling

A Drosophila transgenic RNAi screen targeting the glycan genome, including all N/O/GAG-glycan biosynthesis/modification enzymes and glycan-binding lectins, was conducted to discover novel glycan functions in synaptogenesis. As proof-of-product, we characterized functionally paired heparan sulfate (HS) 6-O-sulfotransferase (hs6st) and sulfatase (sulf1), which bidirectionally control HS proteoglycan (HSPG) sulfation. RNAi knockdown of hs6st and sulf1 causes opposite effects on functional synapse development, with decreased (hs6st) and increased (sulf1) neurotransmission strength confirmed in null mutants. HSPG co-receptors for WNT and BMP intercellular signaling, Dally-like Protein and Syndecan, are differentially misregulated in the synaptomatrix of these mutants. Consistently, hs6st and sulf1 nulls differentially elevate both WNT (Wingless; Wg) and BMP (Glass Bottom Boat; Gbb) ligand abundance in the synaptomatrix. Anterograde Wg signaling via Wg receptor dFrizzled2 C-terminus nuclear import and retrograde Gbb signaling via synaptic MAD phosphorylation and nuclear import are differentially activated in hs6st and sulf1 mutants. Consequently, transcriptional control of presynaptic glutamate release machinery and postsynaptic glutamate receptors is bidirectionally altered in hs6st and sulf1 mutants, explaining the bidirectional change in synaptic functional strength. Genetic correction of the altered WNT/BMP signaling restores normal synaptic development in both mutant conditions, proving that altered trans-synaptic signaling causes functional differentiation defects.
Sensitivity Alkaloid Vinca-Tubulin in β Class II and Class IVb Tubulin-Targeted Drug Action : Functional Significance of Updated

Aberrant expression of B-tubulin isotypes is frequently described in tumor tissues and tubulin-binding agent (TBA)–resistant cell lines. There is limited understanding of the role of specific B-tubulin isotypes in cellular sensitivity to TBAs, and to gain insights into the functional role of BIIand BIVb-tubulin, we examined these isotypes in lung cancer cell lines NCI-H460 (H460) and Calu-6. Drug-treated clonogenic assays revealed that small interfering RNA–mediated knockdown of either BIIor BIVb-tubulin hypersensitized the lung cancer cell lines to Vinca alkaloids, with the effects more pronounced following BIVb-tubulin knockdown. In contrast, there was no change in paclitaxel sensitivity following knockdown of either isotype. Cell cycle analysis revealed a greater propensity for the BIIand BIVb-tubulin knockdown cells to undergo G2-M cell cycle block following 5 nmol/L vincristine treatment, with the BIVb knockdown cells being more sensitive than the BII-tubulin knockdown cells compared with control. In contrast to BII-tubulin knockdown, BIVb-tubulin knockdown cells showed a significant increase in the sub-G1 population (cell death) following treatment with both 5 and 40 nmol/L of vincristine compared with controls. Importantly, BIVb-tubulin knockdown in H460 cells caused a significant dose-dependent increase in Annexin V staining in response to vincristine but not paclitaxel. Therefore, increased sensitivity to induction of apoptosis is one mechanism underlying the Vinca alkaloid hypersensitivity. This study provides direct evidence that BIIor BIVb-tubulins have functionally distinct roles and expression of these isotypes may serve as strong predictors of Vinca alkaloid response and resistance. [Cancer Res 2008;68(23):9817–24]
GPR39 (Zinc Receptor) Knockout Mice Exhibit Depression-Like Behavior and CREB/BDNF Down-Regulation in the Hippocampus

Background: Zinc may act as a neurotransmitter in the central nervous system by activation of the GPR39 metabotropic receptors. Methods: In the present study, we investigated whether GPR39 knockout would cause depressive-like and/or anxiety-like behavior, as measured by the forced swim test, tail suspension test, and light/dark test. We also investigated whether lack of GPR39 would change levels of cAMP response element-binding protein (CREB),brain-derived neurotrophic factor (BDNF) and tropomyosin related kinase B (TrkB) protein in the hippocampus and frontal cortex of GPR39 knockout mice subjected to the forced swim test, as measured by Western-blot analysis. Results: In this study, GPR39 knockout mice showed an increased immobility time in both the forced swim test and tail suspension test, indicating depressive-like behavior and displayed anxiety-like phenotype. GPR39 knockout mice had lower CREB and BDNF levels in the hippocampus, but not in the frontal cortex, which indicates region specificity for the impaired CREB/BDNF pathway (which is important in antidepressant response) in the absence of GPR39. There were no changes in TrkB protein in either structure. In the present study, we also investigated activity in the hypothalamus-pituitary-adrenal axis under both zinc- and GPR39-deficient conditions. Zinc-deficient mice had higher serum corticosterone levels and lower glucocorticoid receptor levels in the hippocampus and frontal cortex. Conclusions: There were no changes in the GPR39 knockout mice in comparison with the wild-type control mice, which does not support a role of GPR39 in hypothalamus-pituitary-adrenal axis regulation. The results of this study indicate the involvement of the GPR39 Zn2+-sensing receptor in the pathophysiology of depression with component of anxiety.
Searching for a Modernized Voice: Economics, Institutions and Predictability in European Competition Law

Uncertainty has been an increasingly central theme in discussions of competition law in Europe since the beginning of “modernization” efforts in the 1990s. This may seem paradoxical, because the modernization programs – both institutional and substantive – were intended to reduce the range of variation in competition law rules and thereby increase uniformity and predictability of results throughout the expanding EU, and they were justified by claims that they would achieve these benefits. Does the chorus of concerns about the lack of predictability in European competition law mean that the modernization processes were misguided or that they have failed? In my view, the answer is “no”. They have, however, transformed and relocated uncertainty in ways that are seldom adequately recognized and rarely addressed. Insufficient recognition of these transformations and their implications has wide-ranging and potentially serious implications for competition law in Europe and even for global competition law development. How then are we to reconcile the aims of modernization with its consequences? A basic theme of this Article is that although the two forms of modernization have in some ways reduced uncertainty in EU competition law, they have also generated new forms of uncertainty that have sometimes concealed and at other times transformed it. The Article analyzes the impacts of “modernization” on competition law decision-making in the EU and thus on the substance of the law itself. It identifies the areas and forms of uncertainty that have resulted from these modernizations. While some commentators have noted elements of the relationship between modernization and uncertainty, that relationship may be more fundamental to understanding European competition law than is generally recognized.The Article also examines the conceptual tools typically used in thinking about European competition law and demonstrates how these can be inadequate for the legal situation in the wake of modernization. Often they no longer provide adequate analysis of the complex processes of decision-making in Europe today. I then go on to suggest ways in which these tools can themselves be “modernized” to account for these changing complexities. In order to deal effectively with European competition law, it is necessary to use a perspective that is specifically designed to identify the factors that shape competition law decisions.
Acyl Chain Length of Phosphatidylserine Is Correlated with Plant Lifespan

Plant lifespan is affected by factors with genetic and environmental bases. The laws governing these two factors and how they affect plant lifespan are unclear. Here we show that the acyl chain length (ACL) of phosphatidylserine (PS) is correlated with plant lifespan. Among the detected eight head-group classes of membrane lipids with lipidomics based on triple quadrupole tandem mass spectrometry, the ACL of PS showed high diversity, in contrast to the ACLs of the other seven classes, which were highly conserved over all stages of development in all plant species and organs and under all conditions that we studied. Further investigation found that acyl chains of PS lengthened during development, senescence, and under environmental stresses and that increasing length was accelerated by promoted- senescence. The acyl chains of PS were limited to a certain carbon number and ceased to increase in length when plants were close to death. These findings suggest that the ACL of PS can count plant lifespan and could be a molecular scale ruler for measuring plant development and senescence.
High Prevalence of Faecal Carriage of ESBL-Producing Enterobacteriaceae among Children in Dar es Salaam, Tanzania

Background Faecal carriage of ESBL-producing bacteria is a potential risk for transmission and infection. Little is known about faecal carriage of antibiotic resistance in Tanzania. This study aimed to investigate the prevalence of faecal carriage of ESBL-producing Enterobacteriaceae and to identify risk factors for carriage among young children in Tanzania. Methodology/Principal Findings From August 2010 to July 2011, children below 2 years of age were recruited in Dar es Salaam, including healthy community children (n = 250) and children hospitalized due to diarrhoea (n = 250) or other diseases (n = 103). ChromID ESBL agar and ChromID CARBA SMART agar were used for screening. Antimicrobial susceptibility testing was performed by the disk diffusion method. ESBL genotypes were identified by Real-Time PCR and sequencing. The overall prevalence of ESBL carriage was 34.3% (207/ 603). The prevalence of ESBL carriage was significantly higher among hospitalized children (50.4%), compared to community children (11.6%; P < 0.001; OR = 7.75; 95% CI: 4.99–12.03). We found high prevalence of Multidrug-resistance (94%) among Escherichia coli and Klebsiella pneumoniae isolates. No resistance to carbapenems was detected. For the majority of isolates (94.7%) we detected a blaCTX-M-15-like gene. In addition, the plasmid mediated AmpC beta-lactamase CMY-2 was detected for the first time in Tanzania. ESBL prevalence was significantly higher among HIV positive (89.7%) than HIV negative (16.9%) children (P = 0.001; OR = 9.99; 95% CI: 2.52–39.57). Use of antibiotics during the past 14 days and age below 1 year was also associated with ESBL carriage. Conclusions/Significance We report a high rate of faecal carriage of ESBL-producing Enterobacteriaceae among children below 2 years of age in Tanzania, particularly those with HIV-infection. Resistance to a majority of the available antimicrobials commonly used for children in Tanzania leaves few treatment options for infections when caused by these bacteria.
K-variates++: More Pluses in the K-means++

k-means++ seeding has become a de facto standard for hard clustering algorithms. In this paper, our first contribution is a two-way generalisation of this seeding, k-variates++, that includes the sampling of general densities rather than just a discrete set of Dirac densities anchored at the point locations, and a generalisation of the well known Arthur-Vassilvitskii (AV) approximation guarantee, in the form of a bias+variance approximation bound of the global optimum. This approximation exhibits a reduced dependency on the "noise" component with respect to the optimal potential -- actually approaching the statistical lower bound. We show that k- variates++ reduces to efficient (biased seeding) clustering algorithms tailored to specific frameworks; these include distributed, streaming and on-line clustering, with direct approximation results for these algorithms. Finally, we present a novel application of k-variates++ to differential privacy. For either the specific frameworks considered here, or for the differential privacy setting, there is little to no prior results on the direct application of k-means++ and its approximation bounds--state of the art contenders appear to be significantly more complex and / or display less favorable (approximation) properties. We stress that our algorithms can still be run in cases where there is no closed form solution for the population minimizer. We demonstrate the applicability of our analysis via experimental evaluation on several domains and settings, displaying competitive performances vs state of the art.
Evaluation of Physical and Mechanical Properties of Porous Poly (Ethylene Glycol)-co-(L-Lactic Acid) Hydrogels during Degradation

Porous hydrogels of poly(ethylene glycol) (PEG) have been shown to facilitate vascularized tissue formation. However, PEG hydrogels exhibit limited degradation under physiological conditions which hinders their ultimate applicability for tissue engineering therapies. Introduction of poly(L-lactic acid) (PLLA) chains into the PEG backbone results in copolymers that exhibit degradation via hydrolysis that can be controlled, in part, by the copolymer conditions. In this study, porous, PEG-PLLA hydrogels were generated by solvent casting/particulate leaching and photopolymerization. The influence of polymer conditions on hydrogel architecture, degradation and mechanical properties was investigated. Autofluorescence exhibited by the hydrogels allowed for three-dimensional, non-destructive monitoring of hydrogel structure under fully swelled conditions. The initial pore size depended on particulate size but not polymer concentration, while degradation time was dependent on polymer concentration. Compressive modulus was a function of polymer concentration and decreased as the hydrogels degraded. Interestingly, pore size did not vary during degradation contrary to what has been observed in other polymer systems. These results provide a technique for generating porous, degradable PEG-PLLA hydrogels and insight into how the degradation, structure, and mechanical properties depend on synthesis conditions.
Partial recording protocols performance on the assessment of periodontitis severity and extent: bias magnitudes, sensibility, and specificity

* Corresponding author. Correio eletrónico: vmachado@egasmoniz.edu. pt (Vanessa Machado). http://doi.org/10.24873/j.rpemd. 2018.11. 239 1646-2890/© 2017 Sociedade Portuguesa de Estomatologia e Medicina Dentária. Published by SPEMD. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). rev port estomatol med dent cir maxilofac. 2018;59(3) :145-153
Correlation between Liver Metastases and the Level of PRL-3 mRNA Expression in Patients with Primary Colorectal Cancer

Purpose Phosphatase of regenerating liver-3 (PRL-3) has been associated with metastasis promotion. However, clinical applications of this association have not yet been clearly demonstrated. In this study, we evaluated the relation of PRL-3 mRNA level in primary colorectal cancer to the corresponding stage and to other clinicopathologic factors. Methods Two hundred forty-five patients with histologically-proven colorectal cancer underwent surgery between January 2004 and December 2006. RNA was extracted and cDNA was prepared by using reverse transcription. Quantification of PRL-3 was done using a real-time polymerase chain reaction. Results Eighty-six cases with well-preserved specimens were enrolled: 53 males and 33 females. The mean age was 63.4 years. According to tumour node metastasis (TNM) stage of the American Joint Committee on Cancer (AJCC), stage I was 11 cases, stage II was 38 cases, stage III was 23 cases, and stage IV was 14 cases. Among stage IV cases, one case was combined with liver and lung metastases, and one case was combined with liver metastases and peritoneal dissemination. The remaining stage IV patients were combined with only liver metastases. There was a significant correlation in PRL-3 mRNA expression between primary colorectal cancer and corresponding tumor stage. PRL-3 mRNA expression was increased in the liver metastases cases. Lymphatic and vascular invasion were significantly related with PRL-3 mRNA levels. Conclusion Advanced stage prediction may be obtained by measuring the level of PRL-3 mRNA expression in primary colorectal cancer. Especially, the risk of liver metastases may be predicted by measuring the level of PRL-3 mRNA expression in primary colorectal cancer. Further study is required to confirm these preliminary results.
Robust correlation of encrypted attack traffic through stepping stones by manipulation of interpacket delays

Network based intruders seldom attack directly from their own hosts, but rather stage their attacks through intermediate "stepping stones" to conceal their identity and origin. To identify attackers behind stepping stones, it is necessary to be able to correlate connections through stepping stones, even if those connections are encrypted or perturbed by the intruder to prevent traceability.The timing-based approach is the most capable and promising current method for correlating encrypted connections. However, previous timing-based approaches are vulnerable to packet timing perturbations introduced by the attacker at stepping stones. In this paper, we propose a novel watermark-based correlation scheme that is designed specifically to be robust against timing perturbations. The watermark is introduced by slightly adjusting the timing of selected packets of the flow. By utilizing redundancy techniques, we have developed a robust watermark correlation framework that reveals a rather surprising result on the inherent limits of independent and identically distributed (iid) random timing perturbations over sufficiently long flows. We also identify the tradeoffs between timing perturbation characteristics and achievable correlation effectiveness. Experiments show that the new method performs significantly better than existing, passive, timing-based correlation in the presence of random packet timing perturbations.
Continuous and discrete state reconstruction for nonlinear switched systems via high-order sliding-mode observers

A class of nonlinear switched systems is studied, and a finite-time converging state observer is proposed. The observer strategy, based on the high-order sliding-mode approach, is able to reconstruct both the continuous and discrete states of the switched system based on output measurements and on the knowledge of the set of possible system's dynamics. All the ‘operating modes’ of the switched system are required to satisfy certain observability-like and boundedness restrictions. The observer provides a finite-time converging estimate and, after a switching of the active mode, it features an arbitrarily fast transient to recover the correct (continuous and discrete) state estimate. A numerical example illustrates the performance of the proposed observer.
Reliability of triggering postinhibitory rebound bursts in deep cerebellar neurons

Deep cerebellar nuclear (DCN) neurons exhibit distinct phenotypes of rebound discharge following current-evoked membrane hyperpolarizations that arise from specific CaV3 T-type Ca2+ channel isoforms and Ca2+-activated K+ channels. The probability of evoking rebound bursts following a brief train of GABAergic inhibitory synaptic input from cerebellar Purkinje cells was recently questioned for stimulus intensities adjusted to evoke a long post-stimulus pause in spike firing. We revisited this issue to examine the potential for generating rebound bursts in DCN cells in response to synaptic inputs in vitro. Both a Transient and Weak Burst phenotype could be distinguished in on-cell extracellular recordings or whole-cell recordings in response to inhibitory synaptic input. We found that the rebound burst response was a sensitive function of stimulus intensity, such that increasing stimulus intensity significantly raised the probability for evoking bursts while decreasing pause duration. The threshold for reliably generating rebound bursts was ~40 percent of maximum intensity, a level that evokes an IPSC corresponding to only a small number of the inhibitory terminals known to impinge on DCN cells. The probability for evoking rebound bursts is thus very high for moderate levels of stimulation in vitro, leaving the potential role for rebound discharge to contribute to signal processing in vivo an open question.
Uneven distribution of enamel in the tooth crown of a Plains Zebra (Equus quagga)

Unworn teeth of herbivorous mammals are not immediately functional. They have to be partially worn to expose enamel ridges which can then act as shear-cutting blades to break the food down. We use the Plains Zebra (Equus quagga) as a hypsodont, herbivorous model organism to investigate how initial wear of the tooth crown is controlled by underlying structures. We find that the enamel proportion is smaller at the apical half of the tooth crown in all upper tooth positions and suggest that lower enamel content here could promote early wear. Besides this uneven enamel distribution, we note that the third molar has a higher overall enamel content than any other tooth position. The M3 is thus likely to have a slightly different functional trait in mastication, resisting highest bite forces along the tooth row and maintaining functionality when anterior teeth are already worn down.
A general lower bound for mixing of single-site dynamics on graphs

We prove that any Markov chain that performs local, reversible updates on randomly chosen vertices of a bounded-degree graph necessarily has mixing time at least /spl Omega/(n log n), where it is the number of vertices. Our bound applies to the so-called "Glauber dynamics" that has been used extensively in algorithms for the Ising model, independent sets, graph colorings and other structures in computer science and statistical physics, and demonstrates that many of these algorithms are optimal up to constant factors within their class. Previously no super-linear lower bound for this class of algorithms was known. Though widely conjectured, such a bound had been proved previously only in very restricted circumstances, such as for the empty graph and the path. We also show that the assumption of bounded degree is necessary by giving a family of dynamics on graphs of unbounded degree with mixing time O(n).