Miracle-dz/UniFAR-FTUs huggingface dataset:
The elusive Effect of Routing Dynamics on Traffic Anomalies

Network operators need to know the root cause of traffic anomalies to determine the appropriate action to mitigate their effect. This paper studies the one type of anomaly for which we can know the root cause: routing-induced anomalies. A major challenge in quantifying the effect of routing events on traffic is that the flows affected by routing are not easily distinguishable from the rest of the traffic. We study this problem using both logs of routing messages and traffic flow records of two research backbones. We define the notion of routing impact in order to quantify how much of the observed volume variation in the traffic matrix is caused by routing changes. Our solution involves a method to compute the traffic matrix that achieves up-to-second accuracy. Results indicate that routing-induced traffic anomalies correspond to a very small faction (< 5%) of the total volume anomalies detected by a Kalman detector. We show that most of the significant routing shifts (> 80%) remain undetected because other volume changes hide their effect, or because they have a limited impact on traffic volume. However, the routing events detected by Kalman correspond to those events that have the biggest impact on the traffic. Running Kalman on destination address or prefixes instead of packets count can improve the detection of routing anomalies. These results represent the promise of a model of routing-induced anomalies, which could be used to accurately identify routinginduced traffic shifts even when no routing messages are available.
Structured Pathway across the Transition State for Peptide Folding Revealed by Molecular Dynamics Simulations

Small globular proteins and peptides commonly exhibit two-state folding kinetics in which the rate limiting step of folding is the surmounting of a single free energy barrier at the transition state (TS) separating the folded and the unfolded states. An intriguing question is whether the polypeptide chain reaches, and leaves, the TS by completely random fluctuations, or whether there is a directed, stepwise process. Here, the folding TS of a 15-residue β-hairpin peptide, Peptide 1, is characterized using independent 2.5 μs-long unbiased atomistic molecular dynamics (MD) simulations (a total of 15 μs). The trajectories were started from fully unfolded structures. Multiple (spontaneous) folding events to the NMR-derived conformation are observed, allowing both structural and dynamical characterization of the folding TS. A common loop-like topology is observed in all the TS structures with native end-to-end and turn contacts, while the central segments of the strands are not in contact. Non-native sidechain contacts are present in the TS between the only tryptophan (W11) and the turn region (P7-G9). Prior to the TS the turn is found to be already locked by the W11 sidechain, while the ends are apart. Once the ends have also come into contact, the TS is reached. Finally, along the reactive folding paths the cooperative loss of the W11 non-native contacts and the formation of the central inter-strand native contacts lead to the peptide rapidly proceeding from the TS to the native state. The present results indicate a directed stepwise process to folding the peptide.
Phosphatidylserine (PS) induces PS receptor–mediated macropinocytosis and promotes clearance of apoptotic cells

Efficient phagocytosis of apoptotic cells is important for normal tissue development, homeostasis, and the resolution of inflammation. Although many receptors have been implicated in the clearance of apoptotic cells, the roles of these receptors in the engulfment process have not been well defined. We developed a novel system to distinguish between receptors involved in tethering of apoptotic cells versus those inducing their uptake. Our results suggest that regardless of the receptors engaged on the phagocyte, ingestion does not occur in the absence of phosphatidylserine (PS). Further, recognition of PS was found to be dependent on the presence of the PS receptor (PSR). Both PS and anti-PSR antibodies stimulated membrane ruffling, vesicle formation, and “bystander” uptake of cells bound to the surface of the phagocyte. We propose that the phagocytosis of apoptotic cells requires two events: tethering followed by PS-stimulated, PSR-mediated macropinocytosis.
The Crystal Structure of Thermotoga maritima Class III Ribonucleotide Reductase Lacks a Radical Cysteine Pre-Positioned in the Active Site

Ribonucleotide reductases (RNRs) catalyze the reduction of ribonucleotides to deoxyribonucleotides, the building blocks for DNA synthesis, and are found in all but a few organisms. RNRs use radical chemistry to catalyze the reduction reaction. Despite RNR having evolved several mechanisms for generation of different kinds of essential radicals across a large evolutionary time frame, this initial radical is normally always channelled to a strictly conserved cysteine residue directly adjacent to the substrate for initiation of substrate reduction, and this cysteine has been found in the structures of all RNRs solved to date. We present the crystal structure of an anaerobic RNR from the extreme thermophile Thermotoga maritima (tmNrdD), alone and in several complexes, including with the allosteric effector dATP and its cognate substrate CTP. In the crystal structure of the enzyme as purified, tmNrdD lacks a cysteine for radical transfer to the substrate pre-positioned in the active site. Nevertheless activity assays using anaerobic cell extracts from T. maritima demonstrate that the class III RNR is enzymatically active. Other genetic and microbiological evidence is summarized indicating that the enzyme is important for T. maritima. Mutation of either of two cysteine residues in a disordered loop far from the active site results in inactive enzyme. We discuss the possible mechanisms for radical initiation of substrate reduction given the collected evidence from the crystal structure, our activity assays and other published work. Taken together, the results suggest either that initiation of substrate reduction may involve unprecedented conformational changes in the enzyme to bring one of these cysteine residues to the expected position, or that alternative routes for initiation of the RNR reduction reaction may exist. Finally, we present a phylogenetic analysis showing that the structure of tmNrdD is representative of a new RNR subclass IIIh, present in all Thermotoga species plus a wider group of bacteria from the distantly related phyla Firmicutes, Bacteroidetes and Proteobacteria.
Adrenal functions in patients with sepsis.

The basal cortisol level and cortisol response to ACTH stimulation test were assessed in patients with sepsis, the results being compared to a control group of 30 healthy persons. The study group included 49 patients with sepsis and 30 healthy subjects as a control group. The mean age in the study group was 42.6 +/- 18.7 years and 41.4 +/- 12.1 years in the control group. Fifteen of the 49 (30.6%) patients had hospital-acquired and 34 (69.4%) patients community-acquired sepsis. Etiological agent was isolated in 35 (71.4%) patients (57.1% gram negative bacteria and 34.3% gram positive bacteria, plus 8.6% polymicrobial). Fourteen of 49 (28.6%) patients died. Mean basal cortisol level was 597.1 +/- 304.6 nmol/l (range 217.8-1667.9) in the study group and 460.2 +/- 180.8 nmol/l (range 253.6-988.9) in the control group. Mean basal cortisol level in the study group was significantly higher than that of the control group (p < 0.05). Mean basal cortisol level was found to be 725.5 +/- 448.9 nmol/l in the patients who died and 545.8 +/- 210.9 nmol/l in the patients who recovered. The difference between the two groups was found to be significant (p < 0.05). ACTH stimulation test was performed in 43 of the patients and 30 healthy subjects. Cortisol response was significantly lower (mean 277.7 +/- 216.9 nmol/l) in the patients than that detected in the control group (mean 519.6 +/- 279.2) (p < 0.001). Mean cortisol response in the patients who died was 227.2 +/- 224.5 nmol/l and 302.1 +/- 212.7 nmol/l in the patients who recovered (p > 0.05). Adrenocortical insufficiency was detected in 16.3% of the patients and 42.9% of these patients died. In conclusion, sepsis is characterized by high basal cortisol level which may show a poor prognosis and a blunted cortisol response to ACTH stimulation. A small percentage of patients with sepsis may develop adrenocortical insufficiency.
Dengue Dynamics in Binh Thuan Province, Southern Vietnam: Periodicity, Synchronicity and Climate Variability

Background Dengue is a major global public health problem with increasing incidence and geographic spread. The epidemiology is complex with long inter-epidemic intervals and endemic with seasonal fluctuations. This study was initiated to investigate dengue transmission dynamics in Binh Thuan province, southern Vietnam. Methodology Wavelet analyses were performed on time series of monthly notified dengue cases from January 1994 to June 2009 (i) to detect and quantify dengue periodicity, (ii) to describe synchrony patterns in both time and space, (iii) to investigate the spatio-temporal waves and (iv) to associate the relationship between dengue incidence and El Niño-Southern Oscillation (ENSO) indices in Binh Thuan province, southern Vietnam. Principal Findings We demonstrate a continuous annual mode of oscillation and a multi-annual cycle of around 2–3-years was solely observed from 1996–2001. Synchrony in time and between districts was detected for both the annual and 2–3-year cycle. Phase differences used to describe the spatio-temporal patterns suggested that the seasonal wave of infection was either synchronous among all districts or moving away from Phan Thiet district. The 2–3-year periodic wave was moving towards, rather than away from Phan Thiet district. A strong non-stationary association between ENSO indices and climate variables with dengue incidence in the 2–3-year periodic band was found. Conclusions A multi-annual mode of oscillation was observed and these 2–3-year waves of infection probably started outside Binh Thuan province. Associations with climatic variables were observed with dengue incidence. Here, we have provided insight in dengue population transmission dynamics over the past 14.5 years. Further studies on an extensive time series dataset are needed to test the hypothesis that epidemics emanate from larger cities in southern Vietnam.
Effect of Gender on NADPH-Oxidase Activity, Expression, and Function in the Cerebral Circulation: Role of Estrogen

Background and Purpose— This study tested whether NADPH-oxidase activity, expression, and functional effects on vascular tone are influenced by gender in the rat cerebral circulation and whether such differences are estrogen-dependent. Methods— NADPH-stimulated superoxide production by cerebral (basilar [BA]; middle cerebral) arteries from male and female Sprague-Dawley rats was measured using lucigenin-enhanced chemiluminescence and dihydroethidium. Protein expression of Nox1, Nox2, Nox4, superoxide dismutase 1 (SOD1), SOD2, and SOD3 was measured using Western blotting. Vascular responses of BA to NADPH were assessed in a myograph. Some female rats were ovariectomized and treated with either vehicle (dimethyl sulfoxide) or 17&bgr;-estradiol. Results— NADPH-stimulated superoxide production by BA and middle cerebral arteries from males was approximately 2-fold greater than vessels from females. Superoxide production was virtually abolished by the NADPH-oxidase inhibitor, diphenyleneiodonium. Protein expression of Nox1 and Nox4 in BA was also higher in males than in females (2.4- and 2.8-fold, respectively), whereas Nox2, SOD1, SOD2, and SOD3 expression did not differ between genders. NADPH induced greater vasorelaxant effects in BA from males versus females (P<0.05). The hydrogen peroxide scavenger, catalase, abolished these NADPH-induced relaxations. NADPH-stimulated superoxide production by BA from ovariectomized rats treated with vehicle was 3-fold greater than levels in intact females. Treatment of ovariectomized rats with 17&bgr;-estradiol decreased superoxide production (P<0.05). NADPH-induced relaxations of BA were smaller in 17&bgr;-estradiol-treated than in vehicle-treated ovariectomized rats (P<0.05). Conclusions— NADPH-oxidase activity and function are lower in cerebral arteries of female rats. These gender differences are estrogen-dependent and are associated with lower Nox1 and Nox4 expression.
Reinforcement and Imitation Learning via Interactive No-Regret Learning

Recent work has demonstrated that problems-- particularly imitation learning and structured prediction-- where a learner's predictions influence the input-distribution it is tested on can be naturally addressed by an interactive approach and analyzed using no-regret online learning. These approaches to imitation learning, however, neither require nor benefit from information about the cost of actions. We extend existing results in two directions: first, we develop an interactive imitation learning approach that leverages cost information; second, we extend the technique to address reinforcement learning. The results provide theoretical support to the commonly observed successes of online approximate policy iteration. Our approach suggests a broad new family of algorithms and provides a unifying view of existing techniques for imitation and reinforcement learning.
Analysis of Data Reduction: Transformations give evidence for non-existence of polynomial kernels

In this paper, we introduce a new technique to give evidence for combinatorial problems that they cannot be preprocessed in polynomial time such that resulting instances always have a size bounded by a polynomial in a specified parameter (or, in short: do not have a polynomial kernel); these results are assuming the validity of certain complexity theoretic assumptions. We build upon a framework by Bodlaender et al. [6], and add a notion of transformation to this framework. Using these transformations, we show that Disjoint Cycles, and Disjoint Paths do not have polynomial kernels, unless the or-distillation conjecture does not hold, which would imply by a result of Fortnow and Santhanam [12] that NP ⊆ coNP/poly, and we show that Hamiltonian Circuit parameterized by treewidth does not have a polynomial kernel, unless the and-distillation conjecture does not hold. We also show that the problem to determine if there are k edge disjoint cycles has a polynomial kernel.
Understanding How Attitudes Affect Physician Compliance with Legal Behavioral Constraints

Abstract The following study investigates how physicians in one state (Illinois) attitudinally cope with a recent law mandating physician behaviors. Specifically, this study focuses on OB/GYN physician compliance with The Sexual Assault Survivors Emergency Treatment Act (Public Law 92–156, 2002), which requires hospitals in the state of Illinois to have an approved plan for treating sexual assault survivors. What makes this research setting interesting are the potential linkages between the legal mandate, physician attitudes, and the ongoing controversy concerning abortion. The results of a census of OB/GYN physicians within the state suggest (1) this physician group is largely supportive of the letter and spirit of this law, (2) the emerging attitude models such as Perugini and Bagozzi's (2001) MGB model explaining the formation of behavioral intentions must be treated with caution when generalizing to situations mandating legal behaviors, and (3) moderating influences such as attitude strength and religiosity have no apparent effect in how attitudes relate to physician motivation to comply with such laws. The managerial and research implicationsofthe reported study arepresented and discussed.
Factor analysis of metabolic syndrome among the middle‐aged Bengalee Hindu men of Calcutta, India

The prevalence of coronary heart disease (CHD) is known to be very high in the people of Indian origin. In India, rates are rising and CHD has been predicted to rank first among the causes of death in the Indian population by 2015. The reasons for the increased susceptibility of Indians to CHD are yet to be understood completely. However, studies hinted that clustering of risk variables of the metabolic syndrome (MS) could be responsible for the increasing incidence of CHD in the Indians. Therefore, identification of the components of the MS could be one aspect in the way to curb the increasing incidence of CHD among the Asian Indians.
Structural insight into DNA binding and oligomerization of the multifunctional Cox protein of bacteriophage P2

The Cox protein from bacteriophage P2 is a small multifunctional DNA-binding protein. It is involved in site-specific recombination leading to P2 prophage excision and functions as a transcriptional repressor of the P2 Pc promoter. Furthermore, it transcriptionally activates the unrelated, defective prophage P4 that depends on phage P2 late gene products for lytic growth. In this article, we have investigated the structural determinants to understand how P2 Cox performs these different functions. We have solved the structure of P2 Cox to 2.4 Å resolution. Interestingly, P2 Cox crystallized in a continuous oligomeric spiral with its DNA-binding helix and wing positioned outwards. The extended C-terminal part of P2 Cox is largely responsible for the oligomerization in the structure. The spacing between the repeating DNA-binding elements along the helical P2 Cox filament is consistent with DNA binding along the filament. Functional analyses of alanine mutants in P2 Cox argue for the importance of key residues for protein function. We here present the first structure from the Cox protein family and, together with previous biochemical observations, propose that P2 Cox achieves its various functions by specific binding of DNA while wrapping the DNA around its helical oligomer.
This Work Is Licensed under a Creative Commons Attribution 4.0 International License Date Deposited: Developmental Telomere Attrition Predicts Impulsive Decision-making in Adult Starlings

Developmental telomere attrition predicts impulsive decision-making in adult starlings. Animals in a poor biological state face reduced life expectancy, and as a consequence should make decisions that prioritize immediate survival and reproduction over long-term benefits. We tested the prediction that if, as has been suggested, developmental telomere attrition is a biomarker of state and future life expectancy, then individuals who have undergone greater developmental telomere attrition should display greater choice impulsivity as adults. We measured impulsive decision-making in a cohort of European starlings (Sturnus vulgaris) in which we had previously manipulated developmental tel-omere attrition by cross-fostering sibling chicks into broods of different sizes. We show that as predicted by state-dependent optimality models, individuals who had sustained greater developmental telomere attrition and who had shorter current telomeres made more impulsive foraging decisions as adults, valuing smaller, sooner food rewards more highly than birds with less attrition and longer telomeres. Our findings shed light on the biological embedding of early adversity and support a functional explanation for its consequences that could be applicable to other species, including humans.
Activation of TRKA receptor elicits mastocytosis in mice and is involved in the development of resistance to KIT-targeted therapy

The neurotrophins (NTs) play a key role in neuronal survival and maintenance. The TRK (tropomyosin-related kinase) tyrosine kinase receptors (TRKA, TRKB, TRKC) are high affinity receptors for NTs. There is increasing data demonstrating an important role of the TRK family in cancer initiation and progression. NTs have been known for many years to promote chemotaxis, maturation, and survival of mast cells. However, the role of NT signaling in the pathogenesis of mastocytosis is not well understood. In this study, we demonstrate that activation of TRKA by its ligand nerve growth factor (NGF) is potent to trigger a disease in mice with striking similarities to human systemic mastocytosis (SM). Moreover, activation of TRKA by NGF strongly rescues KIT inhibition-induced cell death of mast cell lines and primary mast cells from patients with SM, and this rescue effect can be efficiently blocked by entrectinib (a new pan TRK specific inhibitor). HMC-1 mast cell leukemia cells that are resistant to KIT inhibition induced by TRKA activation show reactivation of MAPK/ERK (extracellular signal-regulated kinase) and strong upregulation of early growth response 3 (EGR3), suggesting an important role of MAPK-EGR3 axis in the development of resistance to KIT inhibition. Targeting both TRK and KIT significantly prolongs survival of mice xenotransplanted with HMC-1 cells compared with targeting KIT alone. Thus, these data strongly suggest that TRKA signaling can improve neoplastic mast cell fitness. This might explain at least in part why treatment with KIT inhibitors alone so far has been disappointing in most published clinical trials for mastocytosis. Our data suggest that targeting both KIT and TRKs might improve efficacy of molecular therapy in SM with KIT mutations.
Flowering retardation by high temperature in chrysanthemums: involvement of FLOWERING LOCUS T-like 3 gene repression

Flowering time of the short-day plant Chrysanthemum morifolium is largely dependent upon daylength, but it is also distinctly influenced by other environmental factors. Flowering is delayed by summer heat. Here, the underlying basis for this phenomenon was investigated. Heat-induced flowering retardation occurred similarly in C. morifolium and C. seticuspe, a wild-type diploid chrysanthemum. In both plants, this flowering retardation occurred mainly because of inhibition of capitulum development. Concurrently, expression of flowering-related genes in the shoot tip was delayed under high temperature conditions. In chrysanthemums, FLOWERING LOCUS T-like 3 (FTL3) has been identified as a floral inducer produced in the leaves after short-day stimuli and transported to the shoot tip. In C. seticuspe, heat-induced flowering retardation was accompanied by a reduction in FTL3 expression in the leaves. Two C. morifolium cultivars with flowering times that are differently affected by growth temperature were also examined. High temperature-induced FTL3 repression was observed in the leaves of both cultivars, although the degree of repression was greater in the heat-sensitive cultivar than in the heat-tolerant cultivar. When a scion of the heat-sensitive cultivar was grafted onto the stock of the heat-tolerant cultivar, flowering in the shoot tip was less sensitive to heat. Conversely, a scion of the heat-tolerant cultivar grafted onto the heat-sensitive cultivar showed increased heat sensitivity. Thus, several lines of evidence suggest that the reduction of FTL3 signalling from the leaves to the shoot tip at high temperatures is involved in flowering retardation in chrysanthemums.
Performance-driven simultaneous placement and routing for FPGA's

Sequential place and route tools for field programmable gate arrays (FPGA's) are inherently weak at addressing both wirability and timing optimizations. This is primarily due to the difficulty of accurately predicting wirability and delay during placement. A set of new performance-driven simultaneous placement/routing techniques has been developed for both row-based and island-style FPGA designs. These techniques rely on an iterative improvement placement algorithm augmented with fast, complete routing heuristics in the placement loop. For row-based designs, this new layout strategy yielded up to 28% improvements in timing and 33% in wirability for several MCNC benchmarks when compared to a traditional sequential place and route system in use at Texas Instruments. On a set of industrial designs for Xilinx 4000-series island-style FPGA's, our scheme produced 100% routed designs with 8-15% improvement in delay when compared to the Xilinx XACT5.0 place and route system.