bluuebunny/crossref_metadata_2025 huggingface dataset:
Structure of CARDS toxin, a unique ADP-ribosylating and vacuolating cytotoxin from
Mycoplasma pneumoniae
Authors: Becker Argentina , Kannan T. R. , Taylor Alexander B. , Pakhomova Olga N. , Zhang Yanfeng , Somarajan Sudha R. , Galaleldeen Ahmad , Holloway Stephen P. , Baseman Joel B. , Hart P. John
Published: April 2015

Significance

The airway pathogen
Mycoplasma pneumoniae
(
Mp
) produces a virulence factor with ADP-ribosyltransferase and vacuolating activities known as Community-Acquired Respiratory Distress Syndrome Toxin (CARDS TX). Mammalian cells exposed to recombinant CARDS TX exhibit distinct patterns of ADP-ribosylated proteins and unusual vacuolation phenotypes with disruption of monolayer integrity, leading to cell death. Recombinant CARDS TX administered to naive mice induces an allergic-type inflammatory response and airway hyperreactivity, suggesting that an analogous response in humans may play a causal role in
Mp
-associated asthma. Here we present the structure of CARDS TX, the newest member of the well-recognized group of ADP-ribosylating toxins. The structure enhances understanding of
Mp
pathogenicity and provides a platform for the development of therapies to treat
Mp
-associated acute and chronic airway diseases.
NADPH oxidase DUOX1 promotes long-term persistence of oxidative stress after an exposure to irradiation
Authors: Ameziane-El-Hassani Rabii , Talbot Monique , de Souza Dos Santos Maria Carolina , Al Ghuzlan Abir , Hartl Dana , Bidart Jean-Michel , De Deken Xavier , Miot Françoise , Diallo Ibrahima , de Vathaire Florent , Schlumberger Martin , Dupuy Corinne
Published: April 2015

Significance

Increasing evidence supports the role of chronic oxidative stress in late radiation-induced effects, including malignancy and genetic instability. To date, elevated levels of reactive oxygen species (ROS) have been considered a cause of persistent instability, but until now the mechanism(s) underlying the perpetuation of ROS generation in irradiated cells and their progeny was undetermined. Cells can produce ROS through activation and/or induction of NADPH oxidases. The present investigation identifies the DUOX1-based NADPH oxidase as a ROS-generating system induced after irradiation, causing delayed DNA breakage. Overexpression of DUOX1 in radio-induced thyroid tumors suggests that DUOX1 may contribute to a chronic oxidative stress promoting genomic instability and tumorigenesis.
Stoichiometric control of DNA-grafted colloid self-assembly
Authors: Vo Thi , Venkatasubramanian Venkat , Kumar Sanat , Srinivasan Babji , Pal Suchetan , Zhang Yugang , Gang Oleg
Published: April 2015

Significance

Recently, there has been an increased interest in understanding the self-assembly of DNA-grafted colloids into different morphologies. Conventional approaches assume that the critical design parameters are the size and number of DNA grafts on each particle. Stoichiometry is viewed as a secondary variable and its exact role in this context is unresolved. In contrast with these expectations, our experiments show that the equilibrium lattice structure can be tuned through variations in the imposed stoichiometry. These findings are captured through simple extensions of the complementary contact model. Stoichiometry is thus shown to be a powerful handle to control these self-assembled structures.
Cell-autonomous activation of Hedgehog signaling inhibits brown adipose tissue development
Authors: Nosavanh LaGina , Yu Da-Hai , Jaehnig Eric J. , Tong Qiang , Shen Lanlan , Chen Miao-Hsueh
Published: April 2015

Significance

The function of brown adipose tissue (BAT), which converts chemical energy into heat, has been widely characterized, but how BAT forms and what signaling molecules regulate its formation are largely unknown. In this paper, we report that Hedgehog (Hh) signaling inhibits the formation of BAT during development. Activation of Hh signaling, specifically in the BAT of mice during development, resulted in the loss of interscapular BAT due to the impairment of brown-preadipocyte differentiation. Remarkably, the majority of the BAT cells in the neck were replaced by skeletal muscle-like cells in embryos with elevated Hh activity. These findings indicate that Hh is an essential regulator of BAT development and that developing BAT depots respond differentially to Hh signaling.
Edaravone alleviates Alzheimer’s disease-type pathologies and cognitive deficits
Authors: Jiao Shu-Sheng , Yao Xiu-Qing , Liu Yu-Hui , Wang Qing-Hua , Zeng Fan , Lu Jian-Jun , Liu Jia , Zhu Chi , Shen Lin-Lin , Liu Cheng-Hui , Wang Ye-Ran , Zeng Gui-Hua , Parikh Ankit , Chen Jia , Liang Chun-Rong , Xiang Yang , Bu Xian-Le , Deng Juan , Li Jing , Xu Juan , Zeng Yue-Qin , Xu Xiang , Xu Hai-Wei , Zhong Jin-Hua , Zhou Hua-Dong , Zhou Xin-Fu , Wang Yan-Jiang
Published: April 2015

Significance

Alzheimer’s disease (AD) is a devastating disease that results in the progressive cognitive deficits of elderly and has become one of major social and economic burdens worldwide. There is no effective drug or therapy to prevent or halt the progressive cognitive dysfunctions due to the complex mechanisms such as accumulation of amyloid-β (Aβ), increase in oxidative stress, and formation of neurofibrillary tangle that drive the development of the disease. We found here that Edaravone, a drug that has been used for ischemic stroke, is able to prevent and treat AD by targeting multiple pathways of AD pathogenesis and rescuing the cognitive deficits of a mouse model of AD. Our study suggests Edaravone is a promising drug candidate for AD.
Panoramic view of a superfamily of phosphatases through substrate profiling
Authors: Huang Hua , Pandya Chetanya , Liu Chunliang , Al-Obaidi Nawar F. , Wang Min , Zheng Li , Toews Keating Sarah , Aono Miyuki , Love James D. , Evans Brandon , Seidel Ronald D. , Hillerich Brandan S. , Garforth Scott J. , Almo Steven C. , Mariano Patrick S. , Dunaway-Mariano Debra , Allen Karen N. , Farelli Jeremiah D.
Published: April 2015

Significance

Here, we examine the activity profile of the haloalkanoic acid dehalogenase (HAD) superfamily by screening a customized library against >200 enzymes from a broad sampling of the superfamily. From this dataset, we can infer the function of nearly 35% of the superfamily. Overall, the superfamily was found to show high substrate ambiguity, with 75% of the superfamily utilizing greater than five substrates. In addition, the HAD members with the least amount of structural accessorization of the Rossmann fold were found to be the most specific, suggesting that elaboration of the core domain may have led to increased substrate range of the superfamily.
Mitigation of acute kidney injury by cell-cycle inhibitors that suppress both CDK4/6 and OCT2 functions
Authors: Pabla Navjotsingh , Gibson Alice A. , Buege Mike , Ong Su Sien , Li Lie , Hu Shuiying , Du Guoqing , Sprowl Jason A. , Vasilyeva Aksana , Janke Laura J. , Schlatter Eberhard , Chen Taosheng , Ciarimboli Giuliano , Sparreboom Alex
Published: April 2015

Significance

Acute kidney injury (AKI) is a common clinical condition caused by loss of kidney function. Lack of therapeutic options has contributed to high mortality rates in AKI patients. Drug-induced AKI, as observed during cisplatin-based anticancer therapy, is responsible for about 20% of renal failure cases. The initial injury triggers a proliferative response in renal tubular cells, which in the presence of cellular damage can further accelerate renal injury. Our study provides evidence that the small-molecule cell-cycle inhibitors palbociclib and LEE011 can prevent cisplatin-induced AKI by inhibiting two relevant targets: renal cell-cycle progression and organic cation transporter 2, a renal uptake transporter of cisplatin. The future development of cyclin-dependent kinase 4/6 inhibitors as renal protective agents could have significant clinical benefits.
Environmental constraints drive the partitioning of the soundscape in fishes
Authors: Ruppé Laëtitia , Clément Gaël , Herrel Anthony , Ballesta Laurent , Décamps Thierry , Kéver Loïc , Parmentier Eric
Published: April 2015

Significance

More and more studies stress the potential deleterious effect of anthropogenic sounds on fish acoustic communication. Paradoxically, how the communication between fishes in a community is organized remains extremely poorly known, as studies using passive acoustic recordings are typically restricted to one or two species. At a single site, we were able to follow 16 different vertebrate sounds for 15 days. We demonstrate that the fish population can be distributed into two groups: one diurnal and one nocturnal. Most interestingly, fish calling at night do not show overlap at the level of the main calling frequency, in contrast to fish calling during the day. This shows that at night, in the absence of visual cues, sound communication is more important.
Base-enhanced catalytic water oxidation by a carboxylate–bipyridine Ru(II) complex
Authors: Song Na , Concepcion Javier J. , Binstead Robert A. , Rudd Jennifer A. , Vannucci Aaron K. , Dares Christopher J. , Coggins Michael K. , Meyer Thomas J.
Published: April 2015

Significance

Development of rapid, robust water oxidation catalysts remains an essential element in solar water splitting by artificial photosynthesis. We report here dramatic rate enhancements with added buffer bases for a robust Ru(II) polypyridyl catalyst with a calculated half-time for water oxidation of ∼7 μs in 1.0 M phosphate. The results of detailed kinetic studies provide insight into the water oxidation mechanism and an important role for added buffer bases in accelerating water oxidation by concerted atom–proton transfer.
Small molecule-induced oxidation of protein disulfide isomerase is neuroprotective
Authors: Kaplan Anna , Gaschler Michael M. , Dunn Denise E. , Colligan Ryan , Brown Lewis M. , Palmer Arthur G. , Lo Donald C. , Stockwell Brent R.
Published: April 2015

Significance

Protein disulfide isomerase (PDI) is a chaperone protein in the endoplasmic reticulum. It is up-regulated in mouse models of, and brains of patients with, neurological protein folding diseases. Irreversible inhibition of PDI activity by the small molecule 16F16 results in protection in cell and organotypic brain slice culture models of Huntington disease. Here, we identified lead optimized compound (LOC)14 as a nanomolar, reversible inhibitor of PDI that protects PC12 cells and medium spiny neurons from the toxic mutant huntingtin protein. LOC14 has improved potency compared with 16F16 and displays favorable pharmaceutical properties, making it a suitable compound to evaluate the therapeutic potential of inhibiting PDI in multiple disease models.
Cadmium–cysteine coordination in the BK inner pore region and its structural and functional implications
Authors: Zhou Yu , Xia Xiao-Ming , Lingle Christopher J.
Published: April 2015

Significance

The voltage- and Ca
2+
-activated BK-type (BK) K
+
channels serve as a key regulator of electrical and Ca
2+
signaling as well as a model system for studying allosteric regulation of protein. By examining Cd
2+
coordination with cysteines placed in BK S6 inner helix, our work reveals a previously undefined structural feature in the BK S6 at a position critical for the coupling between voltage sensor activation and channel opening. In addition, we show that BK S6 does not form an ion permeation gate in its cytosolic end. These results define specific structural constraints in the BK inner pore region that differ from voltage-dependent K
+
(Kv) channels.
Salmonella
promotes virulence by repressing cellulose production
Authors: Pontes Mauricio H. , Lee Eun-Jin , Choi Jeongjoon , Groisman Eduardo A.
Published: April 2015

Significance

Salmonella enterica
and a number of phylogenetically distant intracellular bacterial pathogens require the MgtC virulence protein for both intraphagosomal replication and normal growth in magnesium-limited conditions. MgtC operates by interacting with and inhibiting the F
1
F
O
ATP synthase, reducing ATP levels within the bacterium. We show that by lowering ATP levels, MgtC prevents a rise in cyclic diguanylate, a second messenger that promotes biofilm formation in bacteria. We demonstrate that MgtC represses the biosynthesis of cellulose, a major structural component of
Salmonella
biofilms, and that cellulose interferes with replication inside macrophages and virulence in mice. Our results indicate that virulence genes can function to repress the expression of traits that interfere with virulence.
Mechanical cloak design by direct lattice transformation
Authors: Bückmann Tiemo , Kadic Muamer , Schittny Robert , Wegener Martin
Published: April 2015

Significance

Calculating the behavior or function of a given material microstructure in detail can be difficult, but it is conceptually straightforward. The inverse problem is much harder. Herein, one searches for a microstructure that performs a specific targeted function. For example, one may want to guide a wave or a force field around some obstacle as though no obstacle were there. Such function can be represented by a coordinate transformation. Transformation optics maps arbitrary coordinate transformations onto concrete material-parameter distributions. Unfortunately, mapping this distribution onto a microstructure poses another inverse problem. Here, we suggest an alternative approach that directly maps a coordinate transformation onto a concrete one-component microstructure, and we apply the approach to the case of static elastic–solid mechanics.
Architecture of the cerebral cortical association connectome underlying cognition
Authors: Bota Mihail , Sporns Olaf , Swanson Larry W.
Published: April 2015

Significance

Connections between cerebral cortex regions are known as association connections, and neural activity in the network formed by these connections is thought to generate cognition. Network analysis of microscopic association connection data produced over the last 40 years in a small, easily studied mammal suggests a new way to describe the organization of the cortical association network. Basically, it consists of four modules with an anatomical shell–core arrangement and asymmetric connections within and between modules, implying at least partly “hardwired,” genetically determined biases of information flow through the cortical association network. The results advance the goal of achieving a global nervous system wiring diagram of connections and provide another step toward understanding the cellular architecture and mechanisms underpinning cognition.
Acoustic separation of circulating tumor cells
Authors: Li Peng , Mao Zhangming , Peng Zhangli , Zhou Lanlan , Chen Yuchao , Huang Po-Hsun , Truica Cristina I. , Drabick Joseph J. , El-Deiry Wafik S. , Dao Ming , Suresh Subra , Huang Tony Jun
Published: April 2015

Significance

The separation and analysis of circulating tumor cells (CTCs) provides physicians a minimally invasive way to monitor the response of cancer patients to various treatments. Among the existing cell-separation methods, acoustic-based approaches provide significant potential to preserve the phenotypic and genotypic characteristics of sorted cells, owing to their safe, label-free, and contactless nature. In this work, we report the development of an acoustic-based device that successfully demonstrates the isolation of rare CTCs from the clinical blood samples of cancer patients. Our work thus provides a unique means to obtain viable and undamaged CTCs, which can subsequently be cultured. The results presented here offer unique pathways for better cancer diagnosis, prognosis, therapy monitoring, and metastasis research.
Endothelin-1 critically influences cardiac function via superoxide-MMP9 cascade
Authors: Hathaway Catherine K. , Grant Ruriko , Hagaman John R. , Hiller Sylvia , Li Feng , Xu Longquan , Chang Albert S. , Madden Victoria J. , Bagnell C. Robert , Rojas Mauricio , Kim Hyung-Suk , Wu Bingruo , Zhou Bin , Smithies Oliver , Kakoki Masao
Published: April 2015

Significance

Congestive heart failure develops in human patients and experimental animals when the left ventricle becomes dilated. In the present study, mice were generated having graded genetic levels of endothelin-1 from 20% normal to 350% normal by modifying the 3′ untranslated region of the endothelin-1 gene. The 20% and 65% hypomorphs develop dilated cardiomyopathy, whereas the 350% hypermorph has a hypertrophic heart. Increases in superoxide levels and overexpression of matrix metalloproteinase 9 (MMP9) are involved in the development of the dilated cardiomyopathy in the 20% hypomorph. Our results show that endothelin-1 is critical for maintaining normal cardiac contractile function, for controlling superoxide and Mmp9 levels, and for ensuring that the myocardium has sufficient collagen to prevent overstretching.
Mimicking the magnetic properties of rare earth elements using superatoms
Authors: Cheng Shi-Bo , Berkdemir Cuneyt , Castleman A. W.
Published: April 2015

Significance

Superatom concept has been found to be promising in designing atomic clusters to mimic the chemistry of scarce or expensive elements. Also, longstanding interest and challenge exist in searching for suitable candidates to mimic the valuable properties of rare earth elements owing to their highly important application in modern technologies and extremely low yield. Herein, by using photoelectron imaging spectroscopy, we provide direct experimental evidence that well-designed boron-doped clusters, namely LaB and NdB, could be promising candidates to mimic the magnetic properties of corresponding rare earth atoms Nd and Eu, respectively, because the same numbers of valence electrons, unpaired electrons, and magnetic moments are found in both of the counterparts. This finding opens up an exciting possibility for rare earth mimicry using the superatom concept.
Alternative approach to protein structure prediction based on sequential similarity of physical properties
Authors: He Yi , Rackovsky S. , Yin Yanping , Scheraga Harold A.
Published: April 2015

Significance

The traditional approaches to alignment, in general, are based on evolutionary preconceptions. As a result, prebiasing encoded in these methodologies produces results that tend to be in accordance with initial expectation. A method of sequence alignment in which residue equivalence is based entirely on the physical properties of amino acids is introduced here. This approach has no bias in favor of any sequence dataset, eliminates much of the computational complexity inherent in traditional approaches, and gives good results for structures that were poorly predicted in the two most recent CASP exercises.
Estrogen receptor β exon 3-deleted mouse: The importance of non-ERE pathways in ERβ signaling
Authors: Maneix Laure , Antonson Per , Humire Patricia , Rochel-Maia Sabrina , Castañeda Jessica , Omoto Yoko , Kim Hyun-Jin , Warner Margaret , Gustafsson Jan-Åke
Published: April 2015

Significance

Estrogen receptor β (ERβ) is thought to be the predominant nuclear receptor that regulates estrogen signaling in a wide variety of tissues. In several circumstances, it can oppose the effects of ERα. Here, we generated a novel ERβ exon 3-deleted mouse model (ERβ-Δex3) in which the first zinc finger of the DNA binding domain is missing but the remaining C-terminus part of the receptor is present. We observed that mutant male mice were normal but females were anovulatory. Thus, this work demonstrates that most of the physiological functions of ERβ do not involve estrogen response element binding.
Extraction of crude polysaccharides from Duchesnea indica (Andrews) Focke: optimization by response surface methodology
Authors: Chen Jing , Sun Chao , Han Liang , Lin Xi , Wang Li , Shen Minna , Yu Fei , Chen Jianhua
Published: April 2015

A full set of optimization procedure was applied to the extraction of anti-viral polysaccharides from Duchesnea indica (Andrews) Focke. By Plackett–Burman factorial design, three parameters (extraction time, extraction temperature, and ratio of water to raw material) were identified as significant to the extraction yield. However, no significant parameters had been identified for antiviral activity. A three-level-three-factor Box–Behnken factorial design was then employed to further optimize the extraction condition. The experimental data were fitted to a second-order polynomial equation using multiple regression analysis and also examined using appropriate statistical methods. This led to the construction of a response surface indicating the optimal values for each parameter and response studied. Concerning the extraction yield, an extraction at 98.51 ºC for 6.16 h with a ratio of water to raw material of 30.94 mL/g was found to be optimal. Under the optimized conditions, the experimental yield was 6.430 ± 0.078%, which was well matched with the predicted yield of 6.509%.
SMY2 and SYH1 suppress defects in ribosome biogenesis caused by ebp2 mutations
Authors: Okano Akira , Wan Kun , Kanda Kazuhiro , Yabuki Yukari , Funato Kouichi , Mizuta Keiko
Published: April 2015

Ebp2 is an assembly factor of the 60S ribosomal subunit in yeast. We demonstrate that overexpression of SMY2 or SYH1 partially suppresses defects in growth and ribosome biogenesis of ebp2 mutants, and that smy2Δ and syh1Δ exhibit synthetic growth defects with the ebp2 allele. These results suggest that Smy2 and Syh1 may be involved in ribosome biogenesis in relation to Ebp2.
Localization and functional characterization of the extrinsic subunits of photosystem II: an update
Authors: Ifuku Kentaro
Published: April 2015

Photosystem II (PSII), which catalyzes photosynthetic water oxidation, is composed of more than 20 subunits, including membrane-intrinsic and -extrinsic proteins. The extrinsic proteins of PSII shield the catalytic Mn4CaO5 cluster from exogenous reductants and serve to optimize oxygen evolution at physiological ionic conditions. These proteins include PsbO, found in all oxygenic organisms, PsbP and PsbQ, specific to higher plants and green algae, and PsbU, PsbV, CyanoQ, and CyanoP in cyanobacteria. Furthermore, red algal PSII has PsbQ′ in addition to PsbO, PsbV, and PsbU, and diatoms have Psb31 in supplement to red algal-type extrinsic proteins, exemplifying the functional divergence of these proteins during evolution. This review provides an updated summary of recent findings on PSII extrinsic proteins and discusses their binding, function, and evolution within various photosynthetic organisms.
Lady Liberty and Godfather Death as candidates for linguistic relativity? Scrutinizing the gender congruency effect on personified allegories with explicit and implicit measures
Authors: Bender Andrea , Beller Sieghard , Klauer Karl Christoph
Published: April 2015

Linguistic relativity—the idea that language affects thought by way of its grammatical categorizations—has been controversially debated for decades. One of the contested cases is the grammatical gender of nouns, which is claimed to affect how their referents are conceptualized (i.e., as rather female or male in congruence with the grammatical gender of the noun), especially when used allegorically. But is this association strong enough to be detected in implicit measures, and, if so, can we disentangle effects of grammatical gender and allegorical association? Three experiments with native speakers of German tackled these questions. They revealed a gender congruency effect on allegorically used nouns, but this effect was stronger with an explicit measure (assignment of biological sex) than with an implicit measure (Extrinsic Affective Simon Task) and disappeared in the implicit measure when grammatical gender and allegorical associations were set into contrast. Taken together, these findings indicate that the observed congruency effect was driven by the association of nouns with personifications rather than by their grammatical gender. In conclusion, we also discuss implications of these findings for linguistic relativity.
Phosphorylated ubiquitin chain is the genuine Parkin receptor
Authors: Okatsu Kei , Koyano Fumika , Kimura Mayumi , Kosako Hidetaka , Saeki Yasushi , Tanaka Keiji , Matsuda Noriyuki
Published: April 2015

PINK1 selectively recruits Parkin to depolarized mitochondria for quarantine and removal of damaged mitochondria via ubiquitylation. Dysfunction of this process predisposes development of familial recessive Parkinson’s disease. Although various models for the recruitment process have been proposed, none of them adequately explain the accumulated data, and thus the molecular basis for PINK1 recruitment of Parkin remains to be fully elucidated. In this study, we show that a linear ubiquitin chain of phosphomimetic tetra-ubiquitin(S65D) recruits Parkin to energized mitochondria in the absence of PINK1, whereas a wild-type tetra-ubiquitin chain does not. Under more physiologically relevant conditions, a lysosomal phosphorylated polyubiquitin chain recruited phosphomimetic Parkin to the lysosome. A cellular ubiquitin replacement system confirmed that ubiquitin phosphorylation is indeed essential for Parkin translocation. Furthermore, physical interactions between phosphomimetic Parkin and phosphorylated polyubiquitin chain were detected by immunoprecipitation from cells and in vitro reconstitution using recombinant proteins. We thus propose that the phosphorylated ubiquitin chain functions as the genuine Parkin receptor for recruitment to depolarized mitochondria.
DUSP4 deficiency caused by promoter hypermethylation drives JNK signaling and tumor cell survival in diffuse large B cell lymphoma
Authors: Schmid Corina A. , Robinson Mark D. , Scheifinger Nicole A. , Müller Sebastian , Cogliatti Sergio , Tzankov Alexandar , Müller Anne
Published: April 2015

The epigenetic dysregulation of tumor suppressor genes is an important driver of human carcinogenesis. We have combined genome-wide DNA methylation analyses and gene expression profiling after pharmacological DNA demethylation with functional screening to identify novel tumor suppressors in diffuse large B cell lymphoma (DLBCL). We find that a CpG island in the promoter of the dual-specificity phosphatase DUSP4 is aberrantly methylated in nodal and extranodal DLBCL, irrespective of ABC or GCB subtype, resulting in loss of DUSP4 expression in 75% of >200 examined cases. The DUSP4 genomic locus is further deleted in up to 13% of aggressive B cell lymphomas, and the lack of DUSP4 is a negative prognostic factor in three independent cohorts of DLBCL patients. Ectopic expression of wild-type DUSP4, but not of a phosphatase-deficient mutant, dephosphorylates c-JUN N-terminal kinase (JNK) and induces apoptosis in DLBCL cells. Pharmacological or dominant-negative JNK inhibition restricts DLBCL survival in vitro and in vivo and synergizes strongly with the Bruton’s tyrosine kinase inhibitor ibrutinib. Our results indicate that DLBCL cells depend on JNK signaling for survival. This finding provides a mechanistic basis for the clinical development of JNK inhibitors in DLBCL, ideally in synthetic lethal combinations with inhibitors of chronic active B cell receptor signaling.
American Women's History: A Very Short Introduction
Authors: Ware Susan
Published: April 2015

What does U.S. history look like with women at the center of the story? From Pocahantas to military women serving in the Iraq war, American Women's History: A Very Short Introduction chronicles the contributions, recognized and unrecognized, that women have made to the American experience. It recognizes the diversity of American women's experiences defined by race, ethnicity, and class, but also geography, sexual orientation, age, and religion. At the core of the narrative is the recognition that gender—the changing historical and cultural constructions of roles assigned to the biological differences of the sexes—is central to understanding the history of American women's lives, and the history of the United States.
MetaMapR: pathway independent metabolomic network analysis incorporating unknowns
Authors: Grapov Dmitry , Wanichthanarak Kwanjeera , Fiehn Oliver
Published: April 2015

Summary: Metabolic network mapping is a widely used approach for integration of metabolomic experimental results with biological domain knowledge. However, current approaches can be limited by biochemical domain or pathway knowledge which results in sparse disconnected graphs for real world metabolomic experiments. MetaMapR integrates enzymatic transformations with metabolite structural similarity, mass spectral similarity and empirical associations to generate richly connected metabolic networks. This open source, web-based or desktop software, written in the R programming language, leverages KEGG and PubChem databases to derive associations between metabolites even in cases where biochemical domain or molecular annotations are unknown. Network calculation is enhanced through an interface to the Chemical Translation System, which allows metabolite identifier translation between >200 common biochemical databases. Analysis results are presented as interactive visualizations or can be exported as high-quality graphics and numerical tables which can be imported into common network analysis and visualization tools.

Availability and Implementation: Freely available at http://dgrapov.github.io/MetaMapR/. Requires R and a modern web browser. Installation instructions, tutorials and application examples are available at http://dgrapov.github.io/MetaMapR/.

Contact:  ofiehn@ucdavis.edu
How Do You Make the Diagnosis?
Authors: Brody David L
Published: April 2015

To make a diagnosis of concussion, you need a reliable history of two things: (1) an acute external physical force applied to the brain and (2) an impairment in the function of the brain directly caused by the external physical force. One or the other is not enough. You need both. You do not need a scan to make the diagnosis. No scan can “rule in” or “rule out” concussion. You do not need to perform a detailed neurological exam to make the diagnosis. The neurological exam is usually unremarkable except for immediately after the concussion. no exam findings “rule in” or “rule out” concussion. A collateral source is key to obtaining a reliable history. The impairment in brain function occurs immediately after the event. The impairment is worst immediately after the event, then gradually improves. There is no other obvious explanation for the impairment.
Which Problems Do You Address First?
Authors: Brody David L
Published: April 2015

Concussion patients often have a lot of things going on at the same time. Consider these three principles: (1) Ask the patient what’s bothering him the most. Often it is pain. Migraine headaches, for example, can be terrible. Try to deeply understand the patient’s life to figure out what matters most. (2) Ask the collateral source what is causing the most problems in the patient’s life. Often it is mood instability. “He’s not the same person” is a common complaint. Sometimes, the most important problems following concussion are not immediately apparent to the patient. (3) Look for the “top of the cascade”—one single problem that is the root cause of one or more additional problems. For example, sleep disruption can in turn worsen memory, attention, pain, mood disorders and many other symptoms. Major depression can impair virtually every aspect of life including energy, sleep, pain, attention, and memory.
General Treatment Strategies
Authors: Brody David L
Published: April 2015

This chapter discusses the top 10 general priorities in treating concussion: (1) Do one thing at a time. (2) Stop or taper impairing medications before adding new ones. (3) Minimize side effects of medications. (4) Offer rehabilitative therapy and lifestyle modification interventions as well as medications. (5) Educate and comfort. (6) Give an honest prognosis with a positive spin. (7) Use a healthy dose of “Vitamin P” (“placebo”) in an appropriate way. (8) Under the right circumstances, it’s ok to use a big dose of “Vitamin S” (the “therapeutic scare”) also. (9) Offer follow-up and appropriate referrals. (10) Support the family.
Headaches
Authors: Brody David L
Published: April 2015

This chapter presents four rules for treating concussion headache: (1) Triage is more important than diagnosis. Take a careful history by asking specific hypothesis testing questions. Examine the patient. This is important. You can’t do it over the phone. (2) Migraines are really common after concussion; an atypical presentation of migraine is still more likely than most other types of headaches. Consider nonpharmacological measures, triptans, over the counter analgesics, and good prophylaxis as for regular migraine. (3) Patients can have more than one type of headache at the same time. (4) Patients with medication overuse headache aren’t going to get better from anything you do until the medication overuse is addressed. Consider admitting patients with medication overuse headaches to the hospital.
Attention Deficit
Authors: Brody David L
Published: April 2015

Many concussion patients who complain about problems with memory actually have an attention deficit. General measures: treat insomnia, stop alcohol, prescribe moderate cardiovascular exercise, and refer for cognitive rehabilitation (occupational and speech therapy). Consider treatment with a stimulant such as methylphenidate (Ritalin), amphetamine mixed salts (Adderall), and atomoxetine (Strattera), if appropriate, with careful monitoring for side effects. Contraindications include uncontrolled seizures, dangerous anxiety, active cardiovascular or cerebrovascular disease, active psychosis, drug abuse, irresponsible criminal behavior, dangerously underweight, and uncontrolled headaches. Recommend use is 6 days per week 51 weeks per year to reduce tolerance. Some patients find additional benefit from donepezil, rivastigmine, and regulated caffeine use. Approach options: “aggressive,” involving treatment with stimulants primarily based on history; “moderate,” involving treatment with stimulants only in patients with attention performance impairments documented with neuropsychological evaluation; and “conservative,” not including stimulants unless there is a well-documented history of preinjury attention deficit disorder.
Mood Instability
Authors: Brody David L
Published: April 2015

Often the complaint of mood instability comes from the collateral source. The first priority is to assess safety. Severe mood instability can lead to suicide. Next, determine whether the problem is actually mood instability, as opposed to sustained major anxiety, depression, or post-traumatic stress disorder. Nonpharmacological interventions are the most important, and include education, sleep management, prescription for cardiovascular exercise, pain control, cessation of alcohol and other disinhibiting substances such as levetiracetam (Keppra), and cognitive behavioral therapy. Preferred pharmacological options that do not substantially impair cognitive recovery include lamotrigine (Lamictal) and oxcarbazepine (Trileptal). Other options include carbamazepine (Tegretol) when cost is an issue, propranolol (Inderal) when violence is a concern, and low dose atypical antipsychotics.
Balance Problems
Authors: Brody David L
Published: April 2015

Balance problems after concussion can be episodic or persistent. Episodic balance impairment due to intoxication by medications/alcohol/or other drugs can be treated by stopping the offending substance. Episodic balance impairment due to concussion-related benign paroxysmal positional vertigo can be treated with repositioning maneuvers. Assess for this using the Dix-Hallpike maneuver. Episodic balance impairment due to migraine aura (even without actual headache) can be treated with migraine abortive medications and/or prophylactics. For persistent balance impairments, assess balance using the balance error scoring system (BESS) or Berg balance test. Advise the patients to stop drinking alcohol, or cut down to a max of one alcoholic drink in any 24-hour period, and if possible stop medications that impair balance. Consider referral to physical therapy for balance training. Consider prescribing additional self-directed balance exercises such as tai chi, yoga, and dance. Emphasize that balance training is also part of prevention of future concussions.
Excessive Sleepiness
Authors: Brody David L
Published: April 2015

The definition of clinically important hypersomnia is excessive sleep that interferes with other aspects of life. Take a careful history including from the collateral source. Administer the Epworth sleepiness scale to assess severity. Restrict driving if necessary: A severely hypersomnolent patient can be just as dangerous as an epileptic patient. Refer for an overnight polysomnogram (“sleep study”) at a licensed sleep lab, then treat any underlying disorders causing poor quality sleep. Assess for depression and, if appropriate, treat with an activating antidepressant. Take a careful medication history for substances that can cause hypersomnia and stop them if possible. Rule out a systemic cause. If these are not present or hypersomnia is still impairing after treatment, consider prescribing a very gradually progressive exercise program, a trial of caffeine, modafinil, or a direct stimulant in the most refractory cases.
Psychosis
Authors: Brody David L
Published: April 2015

New onset hallucinations and delusions are rare after isolated concussion and should trigger a search for other causes: Schizophrenia (relatively common in young adults), drug abuse, alcohol or drug withdrawal, and delirium due to infection or sleep deprivation should be considered. Importantly, if the psychosis is dangerous or potentially dangerous, think about safety first. This may require inpatient admission to a psychiatric service. If outpatient treatment is required, atypical antipsychotics should be used in as low a dose as possible to minimize cognitive side effects. Aripiprazole (Abilify) is associated with less weight gain than others. Risperidone (Risperdal) is the least expensive. Quetiapine (Seroquel) or, rarely, clozaril are the best choices when parkinsonism is a comorbidity.
Return to School
Authors: Brody David L
Published: April 2015

Consider a graded, stepwise approach to return to school, analogous to the strategy for return to play. This requires coordination with teachers, administrators, school nursing/medical providers, parents, and often classmates. The steps include mental rest, light cognitive activity (e.g., reading familiar material), moderate cognitive activity (e.g., new material in the student’s strongest subject), back to school with accommodations and extra rest, back to school without accommodations, catch up on missed work, then resume extracurricular activities. For complex concussions, reduce barriers to optimal cognitive performance such as sleep disorders, headache, depression, and anxiety. There is no point in trying to return to school when any of these are substantially impairing.
Staffing
Authors: Brody David L
Published: April 2015

Pick the right people: a concussion clinic requires greater than average interpersonal skills to handle patients with mood instability and cognitive impairment. The clinic administrator needs to have good judgment. The administrator needs to be able to determine whether to contact the provider right away for an urgent issue, whether to recommend that the patient go straight to an emergency department, or whether a patient would be more appropriate for another clinic. Options: Physical therapist in clinic to perform balance testing and exertional testing and psychometrician in clinic to perform brief cognitive testing,
Typical Flow for a Concussion Clinic
Authors: Brody David L
Published: April 2015

Many variations are possible. Our clinic runs as follows:Patient is referred to the clinic. Clinic administrator requests medical records. Provider reviews the records and approves initial office visit. Clinic administrator schedules the initial office visit as routine or semi-urgent. Clinic administrator makes sure that the patient brings a reliable collateral source. Patient completes Rivermead Post-Concussive Symptoms Questionnaire. Provider obtains history and exam with documentation performed on a preprinted sheet outlining the most important issues following concussion. Physical therapist and psychometrician see the patient. Provider reviews the data from the physical therapist and psychometrician, performs additional testing, obtains additional history, formulates assessment and discusses plans with patient and collateral source. Provider gives the patient and collateral source a brief hand-written or printed summary of the assessment and plan, then sends medical records to other medical providers.
Preventing Hospital Infections
Authors: Saint Sanjay , Krein Sarah , Stock Robert
Published: April 2015

Nearly 2 million Americans develop a healthcare-associated infection each year, and some 100,000 of them die as a result. Such infections are highly preventable, particularly through the adoption and implementation of evidence-based methods for reducing patient infection at the point of care. Preventing Hospital Infections leads readers through a step-by-step description of a quality improvement intervention as it might unfold in a model hospital, pinpointing the likely obstacles and offering practical strategies for how to overcome them. It draws on the extensive personal clinical experience of the authors, including examples, anecdotes, and down-to-earth, practical guidance. Whereas most resources focus on the technical aspects of healthcare-associated infections, this title offers the first manual for effecting real, practical change.
Types of Interventions
Authors: Saint Sanjay
Published: April 2015

Infection prevention programs were slow to develop—they were a rarity as recently as the 1950s—but they have become a staple of modern-day hospitals. Great strides have been made to identify clinician activities that can control or prevent various healthcare-associated infections (HAIs). This chapter describes the contents of infection prevention bundles for CAUTI, CLABSI, and VAP. In the case of CAUTI, the so-called bladder bundle sets forth appropriate and inappropriate use of indwelling catheters. A nursing checklist, on paper or as a template in the electronic medical record, is used to track patients’ daily urinary catheter status. Doctors and nurses are asked to rethink when a Foley is called for, what alternatives should be considered, what catheter equipment should be used, and how long the Foley should remain in place.
Building the Team
Authors: Saint Sanjay
Published: April 2015

The recruitment of a nurse champion and a physician champion is described in detail. At in-person meetings and via online presentations, team members familiarize themselves with current catheter practices and absorb the new protocols. They decide which medical floor unit will be the first target and pilot site for the initiative. Their criteria: a unit with a track record for cooperating with interventions that also has a sizable number of Foleys and CAUTI cases. The project manager, champions, and other team members work out implementation details—promoting the project’s goals throughout the hospital, coordinating with other ongoing quality improvement initiatives in the hospital, identifying those people who will need special convincing. The changes will drive staff from their comfort zones, add to their workload, and challenge traditional relationships between nurses and doctors.
The Importance of Leadership and Followership
Authors: Saint Sanjay
Published: April 2015

Leadership in a hospital setting differs substantially from that in a for-profit corporation, both in terms of mission and practice, and that is evident during a quality improvement initiative. Top administrative and clinical leaders need to continually communicate the value and scientific validity of the project to staff members by all available means—including personal cheerleading. Project managers and team champions have to energize the staff with their own enthusiasm for the initiative, capitalizing on the trust and respect they have earned. What’s called for is transformational leadership and substantial emotional intelligence. Leaders on all levels need to devote themselves to helping colleagues to become exemplary followers. The major characteristics of the leaders of successful infection prevention projects are described.
Toward Sustainability
Authors: Saint Sanjay
Published: April 2015

After the formal initiative is finished, the project team continues working to secure and perpetuate the progress made in reducing Foley usage and institutionalizing the bladder bundle checklist. Members put into effect plans formulated during the initiative’s early days. The evaluation of catheter use and of infection rates goes on, though the data collection intervals are farther apart. Successes are promoted throughout the hospital, a reminder that the initiative continues. A major mission: To identify backsliders and realign them. Because of the possibility that champions will leave the hospital or be reassigned, current champions are urged to develop their replacements. And the team makes sure that the orientation process for new arrivals to the hospital includes CAUTI prevention information and the hospital’s protocols concerning Foley insertion and removal.
Intensive and acute cardiac care: an introduction
Authors: Price Susanna , Tubaro Marco , Vranckx Pascal , Vrints Christiaan
Published: April 2015

Cardiovascular diseases (CVDs) are a major cause of premature death worldwide and an important cause of loss of disability-adjusted life years. For most types of CVD, early diagnosis and intervention are independent drivers of patient outcome. Clinicians must be properly trained and centers appropriately equipped in order to deal with these critically ill cardiac patients. The textbook explores the intricate nature of Intensive and Acute Cardiovascular Care and provides assistance for diagnosis and preventive care across the multitude of cardiovascular diseases.
Patient safety and clinical governance
Authors: Haxby Elizabeth , Walker Susanna
Published: April 2015

Clinical governance appeared as a concept in the UK in the late 1990s following scandals in which patients were harmed as a consequence of health care failures. Further international research estimates that one in ten inpatients suffer harm as a result of their health care, leading to death in some cases. Clinical governance is a framework centred around domains of patient safety, clinical effectiveness, and patient experience, underpinned by effective teamwork, leadership, and communication. Its aim is to ensure consistent, reliable, high-quality care delivered by competent individuals in a safe environment. Understanding why things go wrong in health care is key to finding solutions to ensure patient safety. Health care is an increasingly high-risk activity at organizational, departmental, and individual levels, and hazard identification and management are important. Recent recognition of human factors as contributing to many adverse events has facilitated the exploration of how health care professionals function within the context of a high-pressure, unpredictable environment. Lessons from non-health care industries have changed focus from blaming individuals for errors to understanding systems and how they can promote or mitigate failure. The development of non-technical skills, such as teamwork, is vital, and a number of approaches to improving this element of human behaviour are described.