bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacological activation of myosin II paralogs to correct cell mechanics defects
Authors: Surcel Alexandra , Ng Win Pin , West-Foyle Hoku , Zhu Qingfeng , Ren Yixin , Avery Lindsay B. , Krenc Agata K. , Meyers David J. , Rock Ronald S. , Anders Robert A. , Freel Meyers Caren L. , Robinson Douglas N. 
Published: January 2015

Significance
Despite the integral role of cell mechanics, efforts to target mechanics for drug development have lagged. Here, we present an approach to identifying small molecules capable of modulating mechanics. We characterize 4-hydroxyacetophenone (4-HAP), isolated as a breakdown product of a hit from our pilot screen of over 22,000 compounds. We show that 4-HAP specifically alters the localization of the mechanoenzyme myosin II, increasing the stiffness of cells. The effect of 4-HAP on myosin II, whose specificity we have defined, occurs across phylogeny. In particular, we have demonstrated 4-HAP’s ability to convert the mechanical profile of metastasis-derived pancreatic cancer cells toward a normal WT-like state. Invasion and migration of these cells, which are hallmarks of the invasive capacity of malignant lesions, are decreased by 4-HAP.
Selective inactivation of USP18 isopeptidase activity in vivo enhances ISG15 conjugation and viral resistance
Authors: Ketscher Lars , Hannß Ronny , Morales David J. , Basters Anja , Guerra Susana , Goldmann Tobias , Hausmann Annika , Prinz Marco , Naumann Ronald , Pekosz Andrew , Utermöhlen Olaf , Lenschow Deborah J. , Knobeloch Klaus-Peter 
Published: January 2015

Significance
Viral infections still constitute a major health issue. Upon viral infection, interferon (IFN) elicits an antiviral response by activating multiple effector systems. The ubiquitin-like protein ISG15 is strongly induced by IFN and mediates its antiviral effect by being covalently conjugated to cellular and viral proteins. The protease USP18, which is also an important negative regulator of the IFN response, counteracts ISG15 conjugation. Within this study, we have generated knock-in mice expressing USP18, which selectively lacks protease activity. ISG15 modification was enhanced in these animals, but the IFN response was unaltered. This clearly shows that USP18 has enzymatic and nonenzymatic properties in vivo. Elevated ISGylation increased resistance to influenza B infections, qualifying USP18 protease inhibition as a potential antiviral strategy.
Identification of hydroxyapatite spherules provides new insight into subretinal pigment epithelial deposit formation in the aging eye
Authors: Thompson Richard B. , Reffatto Valentina , Bundy Jacob G. , Kortvely Elod , Flinn Jane M. , Lanzirotti Antonio , Jones Emrys A. , McPhail David S. , Fearn Sarah , Boldt Karsten , Ueffing Marius , Ratu Savanjeet Guy Singh , Pauleikhoff Laurenz , Bird Alan C. , Lengyel Imre 
Published: January 2015

Significance
Proteins and lipids accumulating in deposits external to the retinal pigment epithelium (RPE) represent a barrier to metabolic exchange between the retina and the choroidal capillaries. With time, these deposits can lead to age-related macular degeneration (AMD), the most common cause of blindness in the elderly in the developed world. It remains unclear how sub-RPE deposits are initiated and grow to clinically relevant features. Using a combination of high-resolution analytical techniques, we found that tiny hydroxyapatite (bone mineral) spherules with cholesterol-containing cores are present in all examined sub-RPE deposits, providing a scaffold to which proteins adhere. If the spherules are important in initiating sub-RPE deposit formation, this finding may provide attractive new approaches for early identification and treatment of AMD.
Ghrelin receptor conformational dynamics regulate the transition from a preassembled to an active receptor:Gq complex
Authors: Damian Marjorie , Mary Sophie , Maingot Mathieu , M'Kadmi Céline , Gagne Didier , Leyris Jean-Philippe , Denoyelle Séverine , Gaibelet Gérald , Gavara Laurent , Garcia de Souza Costa Mauricio , Perahia David , Trinquet Eric , Mouillac Bernard , Galandrin Ségolène , Galès Céline , Fehrentz Jean-Alain , Floquet Nicolas , Martinez Jean , Marie Jacky , Banères Jean-Louis 
Published: January 2015

Significance
G protein-coupled receptors (GPCRs), one of the largest cell surface receptor families, transmit their signals through the coupling of intracellular partners, such as the G proteins. Knowing how this coupling occurs is essential, because it governs the entire signaling process. To address this open question, we used a purified GPCR as a model to which we applied various state-of-the-art biochemical and biophysical approaches. By doing so, we provide direct experimental evidence of a signaling mechanism in which receptor conformational changes are directly linked to a rearrangement of a preassembled complex between the receptor and its cognate Gq protein. This sheds light on the way in which a GPCR interacts with G proteins to trigger signaling.
Microtubule-targeting agents augment the toxicity of DNA-damaging agents by disrupting intracellular trafficking of DNA repair proteins
Authors: Poruchynsky Marianne S. , Komlodi-Pasztor Edina , Trostel Shana , Wilkerson Julia , Regairaz Marie , Pommier Yves , Zhang Xu , Kumar Maity Tapan , Robey Robert , Burotto Mauricio , Sackett Dan , Guha Udayan , Fojo Antonio Tito 
Published: January 2015

Significance
Drugs targeting microtubules are among the most active anticancer agents. In vitro and in preclinical models, these agents are said to interfere with mitosis. However human tumors divide too slowly for this paradigm to apply, evidenced by the failure of over a dozen well-designed antimitotic agents targeting the aurora kinases and kinesin spindle protein that had minimal antitumor activity but caused severe bone marrow suppression. We have proposed that microtubule-targeting agents interfere with the trafficking of critical proteins in interphase microtubules. If true, then one must identify critical proteins whose traffic on microtubules is impacted. We identify nine DNA repair proteins that traffic on microtubules, explaining why combinations of a microtubule-targeting agent and a DNA-damaging agent are frequently used in cancer therapy.
NAD kinase controls animal NADP biosynthesis and is modulated via evolutionarily divergent calmodulin-dependent mechanisms
Authors: Love Nick R. , Pollak Nadine , Dölle Christian , Niere Marc , Chen Yaoyao , Oliveri Paola , Amaya Enrique , Patel Sandip , Ziegler Mathias 
Published: January 2015

Significance
Metabolism relies on a set of molecules that provide the chemical framework for all cellular activities. Among these molecules is NADP, a metabolite synthesized from vitamin B3 that is critical for basic metabolism, calcium signaling, and antiinflammatory processes. Despite NADP’s fundamental importance, very little is known about how animal cells regulate their NADP pool. This study shows that the enzyme NAD kinase is required for maintaining NADP levels in animals, is essential for embryonic development, and exhibits conserved regulatory mechanisms among evolutionarily diverse animals such as humans and sea urchins. Together, these results reveal new insights into why vitamin B3 is essential and how it is converted to NADP, and suggests new therapeutic avenues to improve human and animal metabolism.
Climate, vocal folds, and tonal languages: Connecting the physiological and geographic dots
Authors: Everett Caleb , Blasi Damián E. , Roberts Seán G. 
Published: January 2015

Significance
The sound systems of human languages are not generally thought to be ecologically adaptive. We offer the most extensive evidence to date that such systems are in fact adaptive and can be influenced, at least in some respects, by climatic factors. Based on a survey of laryngology data demonstrating the deleterious effects of aridity on vocal cord movement, we predict that complex tone patterns should be relatively unlikely to evolve in arid climates. This prediction is supported by careful statistical sampling of climatic and phonological data pertaining to over half of the world’s languages. We conclude that human sound systems, like those of some other species, are influenced by environmental variables.
A methyltransferase required for proper timing of the vernalization response in
Arabidopsis
Authors: Lee Joohyun , Yun Jae-Young , Zhao Wei , Shen Wen-Hui , Amasino Richard M. 
Published: January 2015

Significance
Proper timing of flowering is a key factor in reproductive success. Certain plant species require prolonged cold exposure during winter to flower in the spring; however, how plants measure the duration of cold exposure is not well understood. In this study, we describe the identification of a methyltransferase that is required for proper measurement of the duration of cold exposure.
Functional human antibody CDR fusions as long-acting therapeutic endocrine agonists
Authors: Liu Tao , Zhang Yong , Liu Yan , Wang Ying , Jia Haiqun , Kang Mingchao , Luo Xiaozhou , Caballero Dawna , Gonzalez Jose , Sherwood Lance , Nunez Vanessa , Wang Danling , Woods Ashley , Schultz Peter G. , Wang Feng 
Published: January 2015

Significance
Many therapeutic proteins suffer from short plasma half-lives and, as a consequence, require frequent injections to be therapeutically effective; this in turn can adversely affect patient compliance and quality of life. In contrast, therapeutic antibodies typically have half-lives of weeks in humans. Consequently, there is considerable interest in generating functional antibodies with agonist or antagonist activities. Based on the structure of a natural bovine antibody with an ultralong, well-folded heavy-chain complementarity-determining region, we have developed a strategy for the generation of functional human antibody–hormone chimeras with biological activities comparable to native hormones and significantly enhanced pharmacological properties. This approach likely provides a general, relatively straightforward platform for generating antibody agonists and antagonists for a range of therapeutic applications.
Population dynamics of islet-infiltrating cells in autoimmune diabetes
Authors: Magnuson Angela M. , Thurber Greg M. , Kohler Rainer H. , Weissleder Ralph , Mathis Diane , Benoist Christophe 
Published: January 2015

Significance
In many autoimmune diseases, self-reactive lymphocytes lead to immunocyte infiltration in the target tissue, whose evolution over time is regulated. Such lesions can be well-tolerated and lead to minimal damage, or have more drastic consequences. We show here, for the insulitis of the nonobese diabetic (NOD) mouse model of autoimmune diabetes, that the autoimmune infiltrate is an open and dynamic cell population, with a high turnover and constant reseeding with fresh cells coming from the general lymphoid circulation; this implies that such a lesion is susceptible to extraneous events and influences, which could either provoke overt disease or instill stronger immunosuppression.
Structural insights into mis-regulation of protein kinase A in human tumors
Authors: Cheung Jonah , Ginter Christopher , Cassidy Michael , Franklin Matthew C. , Rudolph Michael J. , Robine Nicolas , Darnell Robert B. , Hendrickson Wayne A. 
Published: January 2015

Significance
Mutations in the catalytic subunit of protein kinase A (PKA) have been found in tumors associated with the kidney disorder Cushing’s syndrome and with the rare liver cancer fibrolamellar hepatocellular carcinoma (FL-HCC). Crystal structures and biochemical characterizations of the relevant PKA mutants clarify the molecular basis for disease caused by these mutations. We find contrasting underlying mechanisms for increased PKA signaling in these cancers. In Cushing’s syndrome, the L205R PKA mutation abolishes regulatory-subunit binding, whereas in FL-HCC, the recurring DnaJ–PKA fusion that results from a chromosomal deletion exhibits wild-type characteristics, but is overproduced by a more active promoter. Our findings provide a structural basis for designing selective drugs that may lead to effective treatments for these diseases.
Force-dependent transition in the T-cell receptor β-subunit allosterically regulates peptide discrimination and pMHC bond lifetime
Authors: Das Dibyendu Kumar , Feng Yinnian , Mallis Robert J. , Li Xiaolong , Keskin Derin B. , Hussey Rebecca E. , Brady Sonia K. , Wang Jia-Huai , Wagner Gerhard , Reinherz Ellis L. , Lang Matthew J. 
Published: January 2015

Significance
The αβ T-cell receptor (TCR) on mammalian T lymphocytes recognizes intracellular pathogens to afford protective immunity. Detection of various foreign peptides bound to MHC molecules as TCR ligands occurs during immune surveillance where mechanical forces are generated through cell movement. Using single-molecule optical tweezer assays, we show with isolated and complete receptors on single T cells that both sensitivity and specificity of the biological T-lymphocyte response is dependent upon force-based interactions. Our work demonstrates a catch-and-release αβTCR structural conversion correlating with ligand potency wherein a strongly binding/compact state transitions to a weakly binding/extended state. An allosteric mechanism controls bond strength and lifetime, supporting a model in which quaternary αβTCR subunit associations regulate TCR recognition under load.
Tomato extract suppresses the production of proinflammatory mediators induced by interaction between adipocytes and macrophages
Authors: Kim Young-il , Mohri Shinsuke , Hirai Shizuka , Lin Shan , Goto Tsuyoshi , Ohyane Chie , Sakamoto Tomoya , Takahashi Haruya , Shibata Daisuke , Takahashi Nobuyuki , Kawada Teruo 
Published: January 2015

Abstract
Obese adipose tissue is characterized by enhanced macrophage infiltration. A loop involving monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNFα) between adipocytes and macrophages establishes a vicious cycle that augments inflammatory changes and insulin resistance in obese adipose tissue. Tomatoes, one of the most popular crops worldwide, contain many beneficial phytochemicals that improve obesity-related diseases such as diabetes. Some of them have also been reported to have anti-inflammatory properties. In this study, we focused on the potential protective effects of phytochemicals in tomatoes on inflammation. We screened fractions of tomato extract using nitric oxide (NO) assay in lipopolysaccharide (LPS)-stimulated RAW264 macrophages. One fraction, RF52, significantly inhibited NO production in LPS-stimulated RAW264 macrophages. Furthermore, RF52 significantly decreased MCP-1 and TNFα productions. The coculture of 3T3-L1 adipocytes and RAW264 macrophages markedly enhanced MCP-1, TNFα, and NO productions compared with the control cultures; however, the treatment with RF52 inhibited the production of these proinflammatory mediators. These results suggest that RF52 from tomatoes may have the potential to suppress inflammation by inhibiting the production of NO or proinflammatory cytokines during the interaction between adipocytes and macrophages.
Haagerup approximation property for quantum reflection groups
Authors: Lemeux François 
Published: January 2015

In this paper we prove that the duals of the quantum reflection groups

H
N

s
+

H_N^{s+}

have the Haagerup property for all

N
≥
4

N\ge 4

and

s
∈
[
1
,
∞
)

s\in [1,\infty )

. We use the canonical arrow

π
:
C
(

H
N

s
+

)
→
C
(

S
N
+

)

\pi : C(H_N^{s+})\to C(S_N^+)

onto the quantum permutation groups, and we describe how the characters of

C
(

H

N

s
+

)

C(H_{N}^{s+})

behave with respect to this morphism

π
\pi

thanks to the description of the fusion rules binding irreducible corepresentations of

C
(

H
N

s
+

)

C(H_N^{s+})

as in Banica and Vergnioux, 2009. This allows us to construct states on the central

C
∗

C^*

-algebra

C
(

H
N

s
+

)
0

C(H_N^{s+})_0

generated by the characters of

C
(

H

N

s
+

)

C(H_{N}^{s+})

and to use a fundamental theorem proved by M. Brannan giving a method to construct nets of trace-preserving, normal, unital and completely positive maps on the von Neumann algebra of a compact quantum group

G

\mathbb {G}

of Kac type.
Clofazimine for the Treatment of Multidrug-Resistant Tuberculosis: Prospective, Multicenter, Randomized Controlled Study in China
Authors: Tang Shenjie , Yao Lan , Hao Xiaohui , Liu Yidian , Zeng Linhai , Liu Gang , Li Mingwu , Li Fujian , Wu Meiying , Zhu Yousheng , Sun Hua , Gu Jin , Wang Xiafang , Zhang Zhanjun 
Published: January 2015

Abstract
Background.  Clofazimine (Cfz) has shown activity against Mycobacterium tuberculosis, including multidrug-resistant (MDR) strains in vitro and in animal studies. Here we evaluate the clinical efficacy and tolerability of using Cfz to treat MDR tuberculosis in China.
Methods.  We enrolled 105 patients who had sputum culture–positive MDR tuberculosis in 6 major tuberculosis specialty hospitals in China. Patients were randomly assigned to either the Cfz therapy group (n = 53) or control group (n = 52). Patients in the 2 groups were given 21 months of individual-based chemotherapy regimens based on medication history and drug susceptibility test results. The Cfz therapy group regimens incorporated 100 mg of Cfz once daily for 21 months.
Results.  Three patients in each group discontinued therapy because of side effects or other reasons. Sputum culture conversion to negative was earlier in patients who received Cfz compared with controls (P = .042 by log-rank test). Chest computed tomography showed cavitary changes in 46 patients in the Cfz therapy group and 45 in the control group. Cavity closure was earlier in patient who received Cfz compared with controls (P = .047 by log-rank test). The treatment success rate in the Cfz group was 73.6%, higher than that in control group (53.8%; P = .035). Side effects in skin only occurred in the Cfz group. The rates of skin discoloration and ichthyosis were 94.3% and 47.2%, respectively.
Conclusions.  Using Cfz to treat MDR tuberculosis promotes cavity closure, accelerates sputum culture conversion, and improves treatment success rates.
Aminoglycoside-modifying enzymes determine the innate susceptibility to aminoglycoside antibiotics in rapidly growing mycobacteria
Authors: Maurer Florian P. , Bruderer Vera L. , Castelberg Claudio , Ritter Claudia , Scherbakov Dimitri , Bloemberg Guido V. , Böttger Erik C. 
Published: January 2015

Abstract

Objectives
Infections caused by the rapidly growing mycobacterium (RGM) Mycobacterium abscessus are notoriously difficult to treat due to the innate resistance of M. abscessus to most clinically available antimicrobials. Aminoglycoside antibiotics (AGA) are a cornerstone of antimicrobial chemotherapy against M. abscessus infections, although little is known about intrinsic drug resistance mechanisms. We investigated the role of chromosomally encoded putative aminoglycoside-modifying enzymes (AME) in AGA susceptibility in M. abscessus.

Methods
Clinical isolates of M. abscessus were tested for susceptibility to a series of AGA with different substituents at positions 2′, 3′ and 4′ of ring 1 in MIC assays. Cell-free extracts of M. abscessus type strain ATCC 19977 and Mycobacterium smegmatis strains SZ380 [aac(2′)-Id+], EP10 [aac(2′)-Id−] and SZ461 [aac(2′)-Id+, rrs A1408G] were investigated for AGA acetylation activity using thin-layer chromatography (TLC). Cell-free ribosome translation assays were performed to directly study drug–target interaction.

Results
Cell-free translation assays demonstrated that ribosomes of M. abscessus and M. smegmatis show comparable susceptibility to all tested AGA. MIC assays for M. abscessus and M. smegmatis, however, consistently showed the lowest MIC values for 2′-hydroxy-AGA as compared with 2′-amino-AGA, indicating that an aminoglycoside-2′-acetyltransferase, Aac(2′), contributes to innate AGA susceptibility. TLC experiments confirmed enzymatic activity consistent with Aac(2′). Using M. smegmatis as a model for RGM, acetyltransferase activity was shown to be up-regulated in response to AGA-induced inhibition of protein synthesis.

Conclusions
Our findings point to AME as important determinants of AGA susceptibility in M. abscessus.
Risk factors for acute kidney injury (AKI) in patients treated with polymyxin B and influence of AKI on mortality: a multicentre prospective cohort study
Authors: Rigatto Maria Helena , Behle Tainá F. , Falci Diego R. , Freitas Thiela , Lopes Natane T. , Nunes Mariá , Costa Leonardo W. , Zavascki Alexandre P. 
Published: January 2015

Abstract

Objectives
The objectives of this study were to assess risk factors for acute kidney injury (AKI) in patients treated with polymyxin B, a last resort antibiotic against Gram-negative bacteria, with a focus on dose, and to determine the impact of AKI on mortality of these patients.

Methods
A multicentre prospective cohort study was performed including patients ≥18 years treated with intravenous polymyxin B for ≥48 h. The primary outcome was AKI defined by RIFLE criteria. Secondary outcomes were 30 day mortality and failure stage of AKI. Multivariate analysis with a Cox regression model was performed. The probability of developing AKI was determined in a logistic regression model.

Results
Four-hundred-and-ten patients were included. AKI occurred in 189 (46.1%) patients. Polymyxin B dose ≥150 mg/day was a risk factor for AKI: adjusted HR = 1.95, 95% CI = 1.31–2.89, P = 0.01. Higher weight and age were also independently associated with AKI. The probability of developing AKI significantly increased with doses between 150 and 199 mg/day, regardless of patient weight, with no significant increase with higher doses. Higher weight also increased the risk in patients receiving the same daily doses. AKI was barely associated with increased risk for 30 day mortality (adjusted HR = 1.35, 95% CI = 0.99–1.85, P = 0.06), while ≥150 mg/day did not increase this risk despite its association with AKI.

Conclusions
Polymyxin B total dose is highly related to the risk of AKI, regardless of patient weight. Thirty-day mortality tended to be higher in patients who developed AKI. The relationship between dose, AKI and mortality must be further investigated in studies specifically designed to evaluate this latter outcome.
A KALA-modified lipid nanoparticle containing CpG-free plasmid DNA as a potential DNA vaccine carrier for antigen presentation and as an immune-stimulative adjuvant
Authors: Miura Naoya , Shaheen Sharif M. , Akita Hidetaka , Nakamura Takashi , Harashima Hideyoshi 
Published: January 2015

Abstract
Technologies that delivery antigen-encoded plasmid DNA (pDNA) to antigen presenting cell and their immune-activation are required for the success of DNA vaccines. Here we report on an artificial nanoparticle that can achieve these; a multifunctional envelope-type nanodevice modified with KALA, a peptide that forms α-helical structure at physiological pH (KALA-MEND). KALA modification and the removal of the CpG-motifs from the pDNA synergistically boosted transfection efficacy. In parallel, transfection with the KALA-MEND enhances the production of multiple cytokines and chemokines and co-stimulatory molecules via the Toll-like receptor 9-independent manner. Endosome-fusogenic lipid envelops and a long length of pDNA are essential for this immune stimulation. Furthermore, cytoplasmic dsDNA sensors that are related to the STING/TBK1 pathway and inflammasome are involved in IFN-β and IL-1β production, respectively. Consequently, the robust induction of antigen-specific cytotoxic T-lymphoma activity and the resulting prophylactic and therapeutic anti-tumor effect was observed in mice that had been immunized with bone marrow-derived dendritic cells ex vivo transfected with antigen-encoding pDNA. Collectively, the KALA-MEND possesses dual functions; gene transfection system and immune-stimulative adjuvant, those are both necessary for the successful DNA vaccine.