Miracle-dz/UniFAR-FTUs huggingface dataset:
The Role of Markers of Inflammation in Traumatic Brain Injury

Within minutes of a traumatic impact, a robust inflammatory response is elicited in the injured brain. The complexity of this post-traumatic squeal involves a cellular component, comprising the activation of resident glial cells, microglia, and astrocytes, and the infiltration of blood leukocytes. The second component regards the secretion immune mediators, which can be divided into the following sub-groups: the archetypal pro-inflammatory cytokines (Interleukin-1, Tumor Necrosis Factor, Interleukin-6), the anti-inflammatory cytokines (IL-4, Interleukin-10, and TGF-beta), and the chemotactic cytokines or chemokines, which specifically drive the accumulation of parenchymal and peripheral immune cells in the injured brain region. Such mechanisms have been demonstrated in animal models, mostly in rodents, as well as in human brain. Whilst the humoral immune response is particularly pronounced in the acute phase following Traumatic brain injury (TBI), the activation of glial cells seems to be a rather prolonged effect lasting for several months. The complex interaction of cytokines and cell types installs a network of events, which subsequently intersect with adjacent pathological cascades including oxidative stress, excitotoxicity, or reparative events including angiogenesis, scarring, and neurogenesis. It is well accepted that neuroinflammation is responsible of beneficial and detrimental effects, contributing to secondary brain damage but also facilitating neurorepair. Although such mediators are clear markers of immune activation, to what extent cytokines can be defined as diagnostic factors reflecting brain injury or as predictors of long term outcome needs to be further substantiated. In clinical studies some groups reported a proportional cytokine production in either the cerebrospinal fluid or intraparenchymal tissue with initial brain damage, mortality, or poor outcome scores. However, the validity of cytokines as biomarkers is not broadly accepted. This review article will discuss the evidence from both clinical and laboratory studies exploring the validity of immune markers as a correlate to classification and outcome following TBI.
Spatial Simulations in Systems Biology: From Molecules to Cells

Cells are highly organized objects containing millions of molecules. Each biomolecule has a specific shape in order to interact with others in the complex machinery. Spatial dynamics emerge in this system on length and time scales which can not yet be modeled with full atomic detail. This review gives an overview of methods which can be used to simulate the complete cell at least with molecular detail, especially Brownian dynamics simulations. Such simulations require correct implementation of the diffusion-controlled reaction scheme occurring on this level. Implementations and applications of spatial simulations are presented, and finally it is discussed how the atomic level can be included for instance in multi-scale simulation methods.
Evidence for the Involvement of Type I Interferon in Pulmonary Arterial Hypertension

Rationale: Evidence is increasing of a link between interferon (IFN) and pulmonary arterial hypertension (PAH). Conditions with chronically elevated endogenous IFNs such as systemic sclerosis are strongly associated with PAH. Furthermore, therapeutic use of type I IFN is associated with PAH. This was recognized at the 2013 World Symposium on Pulmonary Hypertension where the urgent need for research into this was highlighted. Objective: To explore the role of type I IFN in PAH. Methods and Results: Cells were cultured using standard approaches. Cytokines were measured by ELISA. Gene and protein expression were measured using reverse transcriptase polymerase chain reaction, Western blotting, and immunohistochemistry. The role of type I IFN in PAH in vivo was determined using type I IFN receptor knockout (IFNAR1−/−) mice. Human lung cells responded to types I and II but not III IFN correlating with relevant receptor expression. Type I, II, and III IFN levels were elevated in serum of patients with systemic sclerosis associated PAH. Serum interferon &ggr; inducible protein 10 (IP10; CXCL10) and endothelin 1 were raised and strongly correlated together. IP10 correlated positively with pulmonary hemodynamics and serum brain natriuretic peptide and negatively with 6-minute walk test and cardiac index. Endothelial cells grown out of the blood of PAH patients were more sensitive to the effects of type I IFN than cells from healthy donors. PAH lung demonstrated increased IFNAR1 protein levels. IFNAR1−/− mice were protected from the effects of hypoxia on the right heart, vascular remodeling, and raised serum endothelin 1 levels. Conclusions: These data indicate that type I IFN, via an action of IFNAR1, mediates PAH.
Search-based fault localization

Many spectrum-based fault localization measures have been proposed in the literature. However, no single fault localization measure completely outperforms others: a measure which is more accurate in localizing some bugs in some programs is less accurate in localizing other bugs in other programs. This paper proposes to compose existing spectrum-based fault localization measures into an improved measure. We model the composition of various measures as an optimization problem and present a search-based approach to explore the space of many possible compositions and output a heuristically near optimal composite measure. We employ two search-based strategies including genetic algorithm and simulated annealing to look for optimal solutions and compare the effectiveness of the resulting composite measures on benchmark software systems. Compared to individual spectrum-based fault localization techniques, our composite measures perform statistically significantly better.
Central giant cell granuloma of the jaws and giant cell tumor of long bones: an immunohistochemical comparative study.

OBJECTIVE This study investigated whether some components of the extracellular matrix and CD68 expression may drive the differences between the central giant cell granuloma (CGCG) of the jaws and giant cell tumor (GCT) of long bones, which present distinct evolution and clinical behavior. MATERIAL AND METHODS Eight cases of CGCG and 7 cases of GCT were selected and immunohistochemically analyzed to verify the pattern of expression of CD68, tenascin (Tn) and fibronectin (Fn). RESULTS A large number of the mononuclear cells and multinucleated giant cells CD68+ was observed in both of the studied lesions, indicating histiocyte/ macrophage origin. Seven cases of CGCG of the jaws showed intense staining of Fn, with uniform distribution predominantly. In all 7 cases of GCT of long bones the Fn displayed intense expression, with distribution pattern varying from uniform to reticulate/fibrillar. Six cases of CGCG were intensively stained by Tn, presenting focal expression in half of specimens, and reticulate/ fibrillar pattern of expression in 4 cases. All cases of GCT of the long bones presented intense expression of Tn, uniform distribution, and reticulate/fibrillar pattern of expression in four cases. CONCLUSIONS The immunoexpression of CD68 in mononuclear cells and multinucleated giant cells and staining patterns of Fn and Tn were similar in both entities. These findings indicate that these proteins could not be used to explain the differences between the CGCG of the jaws and GCT of the long bones.
Cross-resistance and possible mechanisms of chlorpyrifos resistance in Laodelphax striatellus (Fallén).

BACKGROUND Laodelphax striatellus (Fallén) is a major pest of cultivated rice and is commonly controlled in China with the organophosphate insecticides. To develop a better resistance management strategy, a chlorpyrifos-resistant strain of L. striatellus was selected in the laboratory, and its cross-resistance to other insecticides and possible mechanisms of the chlorpyrifos resistance were investigated. RESULTS After 25 generations of selection with chlorpyrifos, the selected strain of L. striatellus developed 188-fold resistance to chlorpyrifos in comparison with the susceptible strain, and showed 14- and 1.6-fold cross-resistance to dichlorvos and thiamethoxam respectively. There was no apparent cross-resistance to abamectin. Chlorpyrifos was synergised by the inhibitor triphenyl phosphate; the carboxylesterase synergistic ratio was 3.8 for the selected strain, but only 0.92 for the susceptible strain. The carboxylesterase activity of the selected strain was approximately 4 times that of the susceptible strain, whereas there was no significant change in the activities of alkaline phosphatase, acid phosphatase, glutathione S-transferase and cytochrome P450 monooxygenase between the strains. The Michaelis constant of acetylcholinesterase, maximum velocity of acetylcholinesterase and median inhibitory concentration of chlorpyrifos-oxon on acetylcholinesterase were 1.7, 2.5 and 5 times higher respectively in the selected strain. CONCLUSION The high cross-resistance to the organophosphate dichlorvos in the chlorpyrifos-resistant strain suggests that other non-organophosphate insecticides would be necessary to counter resistance, should it arise in the field. Enhanced activities of carboxylesterase and the acetylcholinesterase insensitivity appear to be important mechanisms for chlorpyrifos resistance in L. striatellus.
Systematic analysis of BRAFV600E melanomas reveals a role for JNK/c-Jun pathway in adaptive resistance to drug-induced apoptosis

Drugs that inhibit RAF/MEK signaling, such as vemurafenib, elicit profound but often temporary anti‐tumor responses in patients with BRAFV600E melanoma. Adaptive responses to RAF/MEK inhibition occur on a timescale of hours to days, involve homeostatic responses that reactivate MAP kinase signaling and compensatory mitogenic pathways, and attenuate the anti‐tumor effects of RAF/MEK inhibitors. We profile adaptive responses across a panel of melanoma cell lines using multiplex biochemical measurement, single‐cell assays, and statistical modeling and show that adaptation involves at least six signaling cascades that act to reduce drug potency (IC50) and maximal effect (i.e., Emax ≪ 1). Among these cascades, we identify a role for JNK/c‐Jun signaling in vemurafenib adaptation and show that RAF and JNK inhibitors synergize in cell killing. This arises because JNK inhibition prevents a subset of cells in a cycling population from becoming quiescent upon vemurafenib treatment, thereby reducing drug Emax. Our findings demonstrate the breadth and diversity of adaptive responses to RAF/MEK inhibition and a means to identify which steps in a signaling cascade are most predictive of phenotypic response.
NONCODE v3.0: integrative annotation of long noncoding RNAs

Facilitated by the rapid progress of high-throughput sequencing technology, a large number of long noncoding RNAs (lncRNAs) have been identified in mammalian transcriptomes over the past few years. LncRNAs have been shown to play key roles in various biological processes such as imprinting control, circuitry controlling pluripotency and differentiation, immune responses and chromosome dynamics. Notably, a growing number of lncRNAs have been implicated in disease etiology. With the increasing number of published lncRNA studies, the experimental data on lncRNAs (e.g. expression profiles, molecular features and biological functions) have accumulated rapidly. In order to enable a systematic compilation and integration of this information, we have updated the NONCODE database (http://www.noncode.org) to version 3.0 to include the first integrated collection of expression and functional lncRNA data obtained from re-annotated microarray studies in a single database. NONCODE has a user-friendly interface with a variety of search or browse options, a local Genome Browser for visualization and a BLAST server for sequence-alignment search. In addition, NONCODE provides a platform for the ongoing collation of ncRNAs reported in the literature. All data in NONCODE are open to users, and can be downloaded through the website or obtained through the SOAP API and DAS services.
The Drosophila LIN54 homolog Mip120 controls two aspects of oogenesis

ABSTRACT The conserved multi-protein MuvB core associates with the Myb oncoproteins and with the RB-E2F-DP tumor suppressor proteins in complexes that regulate cell proliferation, differentiation, and apoptosis. Drosophila Mip120, a homolog of LIN54, is a sequence-specific DNA-binding protein within the MuvB core. A mutant of Drosophila mip120 was previously shown to cause female and male sterility. We now show that Mip120 regulates two different aspects of oogenesis. First, in the absence of the Mip120 protein, egg chambers arrest during the transition from stage 7 to 8 with a failure of the normal program of chromosomal dynamics in the ovarian nurse cells. Specifically, the decondensation, disassembly and dispersion of the endoreplicated polytene chromosomes fail to occur without Mip120. The conserved carboxy-terminal DNA-binding and protein-protein interaction domains of Mip120 are necessary but not sufficient for this process. Second, we show that a lack of Mip120 causes a dramatic increase in the expression of benign gonial cell neoplasm (bgcn), a gene that is normally expressed in only a small number of cells within the ovary including the germline stem cells. Summary: Drosophila Mip120/LIN54, regulates ovarian nurse cell chromosome disassembly and germline-specific gene expression. These functions of Mip120 require its less conserved N-terminus in addition to its CXC DNA-binding and HCH protein-interaction domains.
Biphasic Extracellular Proteolytic Enzyme Activity in Benthic Water and Sediment in the Northwestern Mediterranean Sea

ABSTRACT In this study, we used the fact that bacteria are able to cleave a fluorogenic substrate analog (l-leucine-7-amido-4-methylcoumarin) to determine the maximal ectoproteolytic activities (Vm) and affinities (Km) of natural benthic microbial communities by the multiconcentration kinetic method. This investigation was performed during the winter and summer of 1997 with a set of 36 samples of near-bottom water and sediment collected from a coastal area and an offshore area in the western part of the Gulf of Lions. The existence of biphasic microbial ectoproteolysis was statistically confirmed for both the near-bottom water and the sediment, regardless of the spatial and seasonal conditions. Globally, 72.2% of the entire set of bacterial consortia collected at the water-sediment boundary layer showed biphasic microbial kinetics. A specific estimator of the biphasicity indicated that deep benthic bacterial consortia responded better with episodic nutrient supplies than shallower benthic bacterial consortia responded.
Common mechanisms for calorie restriction and adenylyl cyclase type 5 knockout models of longevity

Adenylyl cyclase type 5 knockout mice (AC5 KO) live longer and are stress resistant, similar to calorie restriction (CR). AC5 KO mice eat more, but actually weigh less and accumulate less fat compared with WT mice. CR applied to AC5 KO results in rapid decrease in body weight, metabolic deterioration, and death. These data suggest that despite restricted food intake in CR, but augmented food intake in AC5 KO, the two models affect longevity and metabolism similarly. To determine shared molecular mechanisms, mRNA expression was examined genome‐wide for brain, heart, skeletal muscle, and liver. Significantly more genes were regulated commonly rather than oppositely in all the tissues in both models, indicating commonality between AC5 KO and CR. Gene ontology analysis identified many significantly regulated, tissue‐specific pathways shared by the two models, including sensory perception in heart and brain, muscle function in skeletal muscle, and lipid metabolism in liver. Moreover, when comparing gene expression changes in the heart under stress, the glutathione regulatory pathway was consistently upregulated in the longevity models but downregulated with stress. In addition, AC5 and CR shared changes in genes and proteins involved in the regulation of longevity and stress resistance, including Sirt1, ApoD, and olfactory receptors in both young‐ and intermediate‐age mice. Thus, the similarly regulated genes and pathways in AC5 KO and CR mice, particularly related to the metabolic phenotype, suggest a unified theory for longevity and stress resistance.
The Changing Character of the California Sierra Nevada as a Natural Reservoir

The mountains of the Western United States provide a vital natural service through the storage and release of mountain snowpack, lessening impacts of seasonal aridity and satiating summer water demand. However, climate change continues to undermine these important processes. To understand how snowpack may change in the headwaters of California's major reservoirs, the North American Coordinated Regional Climate Downscaling Experiment is analyzed to assess peak water volume, peak timing, accumulation rate, melt rate, and snow season length across both latitudinal and elevational gradients. Under a high‐emissions scenario, end‐of‐century peak snowpack timing occurs 4 weeks earlier and peak water volume is 79.3% lower. The largest reductions are above Shasta, Oroville, and Folsom and between 0‐ and 2,000‐m elevations. Regional climate model and global forcing data set choice is important in determining historical snowpack character, yet by end century all models show a significant and similar decline in mountain snowpack.
Multiferroic Hysteresis Loop

Multiferroics, showing both ferroelectric and magnetic order, are promising candidates for future electronic devices. Especially, the fundamental understanding of ferroelectric switching is of key relevance for further improvements, which however is rarely reported in literature. On a prime example for a spin-driven multiferroic, LiCuVO4, we present an extensive study of the ferroelectric order and the switching behavior as functions of external electric and magnetic fields. From frequency-dependent polarization switching and using the Ishibashi-Orihara theory, we deduce the existence of ferroelectric domains and domain-walls. These have to be related to counterclockwise and clockwise spin-spirals leading to the formation of multiferroic domains. A novel measurement—multiferroic hysteresis loop—is established to analyze the electrical polarization simultaneously as a function of electrical and magnetic fields. This technique allows characterizing the complex coupling between ferroelectric and magnetic order in multiferroic LiCuVO4.
Kill thy neighbour: an individulalistic argument for the evolution of flammability

The idea that flammability has evolved in many fire-prone communities has been criticised for being group-selectionist. However flammability may enhance inclusive fitness if the resulting fires kill neighbouring less flammable individuals and also open recruitment possibilities. We modelled the evolution of flammability using cellular automata to simulate neighbourhood effects of burning. For plants that survive fire only from unbumt canopies (non-sprouters), increased flammability would cause them to burn to death. Flammability traits can evolve in such species only if they result in fire preading to kill less flammable neighbours and only if they carry additional fitness benefits. In species that resprout from roots or stem bases after fire, flammability can evolve merely by increasing neighbour mortality but is more likely to do so if the associated traits had other benefits. Most flammability-enhancing traits, both structural and biochemical, are likely to have such additional benefits. We predict that flammability traits will be associated with dense populations where the effect on neighbours is most marked and suggest several tests. Fire has been a key, but neglected, evolutionary force. Alteration of the fire regime through the evolution of flammability, even in a single species contribution heavily to fuel loads, would result in the selective exclusion or admission of other species to an ecosystem depending on the compatibility of their pre-existing traits with fire
Trimethoprim-sulfamethoxazole compared with pentamidine for treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. A prospective, noncrossover study.

STUDY OBJECTIVE To ascertain the efficacy and toxicity of trimethoprim-sulfamethoxazole or pentamidine when either is given alone during the entire treatment period for Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome (AIDS). DESIGN Prospective, randomized, noncrossover comparison of trimethoprim-sulfamethoxazole with pentamidine. Trimethoprim-sulfamethoxazole dosage was adjusted to maintain serum trimethoprim at 5 to 8 micrograms/mL. Pentamidine dosage was reduced by 30% to 50% for an absolute rise in serum creatinine of more than 88 mumol/L (1 mg/dL). SETTING Tertiary care hospital and AIDS clinic. PATIENTS Thirty-six patients were treated with trimethoprim-sulfamethoxazole and 34 with pentamidine. Pretreatment clinical features and laboratory test results were similar in the two groups. MEASUREMENTS AND MAIN RESULTS Thirty-six recipients of trimethoprim-sulfamethoxazole and 33 recipients of pentamidine completed therapy without crossover. Trimethoprim-sulfamethoxazole caused a rash (44%) and anemia (39%) more frequently (P less than or equal to 0.03, whereas pentamidine caused nephrotoxicity (64%), hypotension (27%), or hypoglycemia (21%) more frequently (P less than or equal to 0.01). The (A - a)DO2 improved by greater than 1.3 kPa (10 mmHg) 8 days earlier for trimethoprim-sulfamethoxazole recipients (95% CI for the difference in response, -1 to 17; P = 0.04). Thirty-one (86%) patients treated with trimethoprim-sulfamethoxazole and 20 (61%) with pentamidine survived and were without respiratory support at completion of treatment (95% CI for the difference in response, 5% to 45%; P = 0.03). CONCLUSIONS For most patients with AIDS and P. carinii pneumonia, successful treatment with a single agent is possible. Toxicity associated with the two standard treatments is rarely life-threatening and may be diminished if the trimethoprim-sulfamethoxazole dosage is modified by pharmacokinetic monitoring and the pentamidine dosage is reduced for nephrotoxicity. Oxygenation improved more quickly and survival was better with trimethoprim-sulfamethoxazole.
Application of low-pressure gas adsorption to nanopore structure characterisation of organic-rich lower Cambrian shale in the Upper Yangtze Platform, South China

ABSTRACT The pores in shales are mainly on a nanometer scale, and the pore-size distribution is vital with regard to the preservation and exploitation of shale gas. This study focuses on the organic-rich lower Cambrian black shale in the Upper Yangtze Platform, South China and investigates their TOC, mineralogical composition and nanopore structure. Low-pressure N2 and CO2 adsorption experiments were conducted at 77.35 K and 273.15 K, respectively, and the nanopore structures were characterised by the modified Brunauer–Emmett–Teller, Dubinin–Radushkevich, t-plot, Barrett–Joyner–Halenda and density functional theory (DFT) methods. The results indicate the following. (1) The lower Cambrian shale has a high TOC content (1.77–7.23 wt%) and a high quartz content (27.7–51.6 vol%). The total specific surface area varies from 12.02 to 28.87 m2/g. Both the total specific surface area and quartz content are positively associated with the TOC content. (2) Shale samples with a higher TOC content have a greater number of micropores, resulting in more complicated nanopore structures. Micropore volumes/surface areas and non-micropore surface areas all increase with increasing TOC content, indicating that TOC is the key factor determining the nanopore structure of the lower Cambrian shale. (3) A combination of N2 and CO2 adsorption provides the most suitable detection range (∼0.3–60 nm) and is both highly reliable and accurate with regard to nanopore structure characterisation.