bluuebunny/crossref_metadata_2025 huggingface dataset:
Force sensing by the vascular protein von Willebrand factor is tuned by a strong intermonomer interaction
Authors: Müller Jochen P. , Mielke Salomé , Löf Achim , Obser Tobias , Beer Christof , Bruetzel Linda K. , Pippig Diana A. , Vanderlinden Willem , Lipfert Jan , Schneppenheim Reinhard , Benoit Martin
Published: February 2016

Significance

Excessive blood loss at a site of vascular injury is prevented by recruitment of platelets to the injured vessel wall and the formation of a platelet plug. Under elevated shear flow conditions, these processes are critically mediated by the large plasma glycoprotein von Willebrand factor (VWF). Remarkably, VWF’s activation for hemostasis correlates with its abrupt elongation at sufficiently high shear rates. In this study, we have discovered a strong intermonomer interaction in VWF that is expected to tune VWF’s ability to sense hydrodynamic forces in the bloodstream. Our data will help to comprehend the force-induced activation of VWF and provide clues for understanding clotting disorders, such as von Willebrand disease and thrombosis, at the single-molecule level.
Diminished viral replication and compartmentalization of hepatitis C virus in hepatocellular carcinoma tissue
Authors: Harouaka Djamila , Engle Ronald E. , Wollenberg Kurt , Diaz Giacomo , Tice Ashley B. , Zamboni Fausto , Govindarajan Sugantha , Alter Harvey , Kleiner David E. , Farci Patrizia
Published: February 2016

Significance

Hepatocellular carcinoma (HCC) associated with hepatitis C virus (HCV) infection is the fastest-rising cause of cancer-related death in the United States. The level of intratumor HCV replication and the molecular interactions between virus and tumor remain elusive, however. Here we demonstrate that the ability of HCV to replicate in HCC is severely hampered despite unchanged miR122 expression. Surprisingly, we found that livers containing HCC harbor a more diverse viral population than that seen in cirrhotic livers without HCC. Tracking of individual variants demonstrated changes in quasispecies distribution between tumor and nontumorous areas, suggesting viral compartmentalization within the tumor. These insights into the interplay between HCV and HCC call for further investigation of whether malignant hepatocytes express or lack factors that restrict HCV entry or negatively affect viral replication.
Oyster reproduction is affected by exposure to polystyrene microplastics
Authors: Sussarellu Rossana , Suquet Marc , Thomas Yoann , Lambert Christophe , Fabioux Caroline , Pernet Marie Eve Julie , Le Goïc Nelly , Quillien Virgile , Mingant Christian , Epelboin Yanouk , Corporeau Charlotte , Guyomarch Julien , Robbens Johan , Paul-Pont Ika , Soudant Philippe , Huvet Arnaud
Published: February 2016

Significance

Plastics are a contaminant of emerging concern accumulating in marine ecosystems. Plastics tend to break down into small particles, called microplastics, which also enter the marine environment directly as fragments from a variety of sources, including cosmetics, clothing, and industrial processes. Given their ubiquitous nature and small dimensions, the ingestion and impact of microplastics on marine life are a cause for concern, notably for filter feeders. Oysters were exposed to polystyrene microparticles, which were shown to interfere with energy uptake and allocation, reproduction, and offspring performance. A drop in energy allocation played a major role in this reproductive impairment. This study provides ground-breaking data on microplastic impacts in an invertebrate model, helping to predict ecological impact in marine ecosystems.
Programmable polyproteams built using twin peptide superglues
Authors: Veggiani Gianluca , Nakamura Tomohiko , Brenner Michael D. , Gayet Raphaël V. , Yan Jun , Robinson Carol V. , Howarth Mark
Published: February 2016

Significance

Many biological events depend on proteins working together as a team. Here we establish how to program team formation, covalently linking protein modules step by step. We split a domain fromStreptococcus pneumoniaeto form a peptide and protein pair, SnoopTag and SnoopCatcher, which form an isopeptide bond when mixed together. SnoopTag/SnoopCatcher reacted with each other but not with an alternative peptide/protein pair, SpyTag/SpyCatcher. We formed polyprotein chains by alternating SpyTag reaction with SnoopTag reaction. Cellular signaling often relies on integrated activation of different receptors, so we built polyprotein teams to stimulate Death Receptor and Growth Factor receptors, finding an optimal combination for cell-death induction in cancer cells. Programmable “polyproteams” provide a simple route to investigate or harness biological teamwork.
Enhanced stability of tristetraprolin mRNA protects mice against immune-mediated inflammatory pathologies
Authors: Patial Sonika , Curtis Alan D. , Lai Wi S. , Stumpo Deborah J. , Hill Georgette D. , Flake Gordon P. , Mannie Mark D. , Blackshear Perry J.
Published: February 2016

Significance

Inflammation is involved in the pathogenesis of many chronic diseases. Many deleterious effects of inflammation are mediated through increased production of proinflammatory mediators, known as cytokines and chemokines. Many current therapies for these diseases involve blocking single proinflammatory mediators, such as TNF, using parenteral administration of recombinant binding proteins. We demonstrate here that a genetic modification in the mouse that increases the expression of an endogenous antiinflammatory protein, tristetraprolin (TTP), results in protection against mouse models for several human inflammatory diseases, including rheumatoid arthritis, psoriasis, and multiple sclerosis, presumably by decreasing the production of proinflammatory cytokines. Our results suggest that increasing TTP expression may be an effective therapeutic strategy in the treatment of certain inflammatory diseases.
Structure-based analysis of the molecular interactions between acyltransferase and acyl carrier protein in vicenistatin biosynthesis
Authors: Miyanaga Akimasa , Iwasawa Shohei , Shinohara Yuji , Kudo Fumitaka , Eguchi Tadashi
Published: February 2016

Significance

Acyltransferases (ATs) are responsible for the selection and incorporation of acyl building blocks in the biosynthesis of various polyketide natural products. Proper protein–protein interactions between AT and cognate acyl carrier protein (ACP) are critical for the functional transfer of acyl groups. However, the ACP recognition mechanism has remained elusive because the structural determination of an AT–ACP complex is hampered by the weak and transient interactions between them. Herein, we describe the first crystal structure of the AT–ACP complex. To stabilize the weak protein–protein interaction sufficiently for analysis, we prepared a covalent AT–ACP complex using a cross-linking reagent for crystallization. The determined AT–ACP complex structure provides detailed mechanistic insights into ACP recognition by AT.
SIRT6 deacetylates PKM2 to suppress its nuclear localization and oncogenic functions
Authors: Bhardwaj Abhishek , Das Sanjeev
Published: February 2016

Significance

SIRT6 (sirtuin 6) is a member of the highly conserved sirtuin family of NAD
+
-dependent deacetylases. SIRT6 regulates diverse cellular processes including tumorigenesis. However, the role of SIRT6 deacetylase activity in its tumor-suppressor functions is not well understood. Here we report that SIRT6 deacetylates nuclear PKM2 (pyruvate kinase M2). PKM2 is a glycolytic enzyme with nonmetabolic nuclear oncogenic functions. SIRT6-mediated deacetylation results in PKM2 nuclear export in an exportin 4-dependent manner. As a result of SIRT6-mediated deacetylation, PKM2 nuclear protein kinase and transcriptional coactivator functions are abolished. Thus SIRT6 suppresses PKM2-dependent cell proliferation and tumorigenesis. Taken together, our findings demonstrate the pivotal role of deacetylase activity in SIRT6 tumor-suppressor functions and delineate a mechanism of PKM2 nuclear export.
Sensor histidine kinase is a β-lactam receptor and induces resistance to β-lactam antibiotics
Authors: Li Lu , Wang Qiyao , Zhang Hui , Yang Minjun , Khan Mazhar I. , Zhou Xiaohui
Published: February 2016

Significance

Bacteria can produce β-lactamases, enzymes that destroy β-lactam antibiotics and thereby resist these potent antibiotics that target cell wall synthesis. Production of β-lactamases is often controlled by β-lactam-induced perturbations in the cell wall. Here, we have identified a new mechanism controlling β-lactamase production. We found a signaling system in which a membrane-associated histidine kinase directly binds β-lactams, triggering the expression of a β-lactamase and resistance to β-lactam antibiotics. Direct sensing of β-lactam antibiotics may enable sufficiently rapid induction of β-lactamase to degrade β-lactam antibiotics before the integrity of the cell wall is disturbed.
In vivo imaging identifies temporal signature of D1 and D2 medium spiny neurons in cocaine reward
Authors: Calipari Erin S. , Bagot Rosemary C. , Purushothaman Immanuel , Davidson Thomas J. , Yorgason Jordan T. , Peña Catherine J. , Walker Deena M. , Pirpinias Stephen T. , Guise Kevin G. , Ramakrishnan Charu , Deisseroth Karl , Nestler Eric J.
Published: February 2016

Significance

Strong associations between cocaine and the environmental contexts where cocaine is administered are thought to drive relapse. The nucleus accumbens (NAc) encodes these cue–reward associations, and here we determined how cocaine alters the ability of cells in NAc to respond to drug-associated environmental stimuli to drive drug seeking. Using fiber photometry calcium imaging we define the specific population of cells, dopamine D1 receptor-expressing neurons, that encodes information about drug associations and show that these cells can be manipulated to attenuate the strength of drug associations and prevent relapse. Together, these data define a basic circuit mechanism underlying drug–context associations and suggest that pharmacotherapeutic agents aimed at D1-type neurons may help to promote sustained abstinence in cocaine abusers.
Ligase I and ligase III mediate the DNA double-strand break ligation in alternative end-joining
Authors: Lu Guangqing , Duan Jinzhi , Shu Sheng , Wang Xuxiang , Gao Linlin , Guo Jing , Zhang Yu
Published: February 2016

Significance

DNA repair is not only extremely important for the genome stability in normal cells but also extensively involved in carcinogenesis and evolution. DNA double-strand breaks (DSBs), one of the most harmful types of DNA damage, are repaired mainly by homologous repair (HR) and nonhomologous end-joining (NHEJ). Although the components of NHEJ have been studied extensively in last two decades, in cells deficient for core classic NHEJ factors, significant DSB end-joining activities have been observed in various situations, suggesting the existence of the alternative end-joining (A-EJ) activities. Here, we dissected the roles of DNA ligases in mediating the last step of A-EJ. The results suggested the existence of multiple DNA ligase-containing complexes in A-EJ.
Streamlined discovery of cross-linked chromatin complexes and associated histone modifications by mass spectrometry
Authors: Zee Barry M. , Alekseyenko Artyom A. , McElroy Kyle A. , Kuroda Mitzi I.
Published: February 2016

Significance

Scientists have developed many affinity pulldown methods to characterize protein networks. Three persistent challenges with current approaches are capturing labile interactions, isolating insoluble DNA-bound complexes, and preserving modifications potentially important for binding specificity. This report presents a cross-linked affinity approach to meet these challenges and effectively capture interactions that otherwise may be intractable with native affinity techniques. We isolate several
Drosophila
and human protein complexes to demonstrate the technique’s scalability across a range of initial cell amounts and sources, and we develop the ability to identify the breadth of associated histone and nonhistone modifications in parallel. Our results indicate that cross-linked affinity pulldowns should be broadly useful for comprehensive analyses of chromatin networks.
Breakdown of interdependent directed networks
Authors: Liu Xueming , Stanley H. Eugene , Gao Jianxi
Published: February 2016

Significance

Real-world complex systems interact with one another, and these interactions increase the probability of catastrophic failure. Using interdependent networks to model these phenomena helps understand a system’s robustness and enables design of more robust infrastructures. Previous research has been limited to an idealized case where each layer is undirected, but almost all real-world networks are directed and exhibit in-degree and out-degree correlations. Therefore, we develop a general theoretical framework for analyzing the breakdown of interdependent directed networks with, or without, in-degree and out-degree correlations, and apply it to real-world international trade networks. Surprisingly, we find that the robustness of interdependent heterogeneous networks increases, whereas that of interdependent homogeneous networks with strong coupling strengths decreases with in-degree and out-degree correlations.
MHC class II super-enhancer increases surface expression of HLA-DR and HLA-DQ and affects cytokine production in autoimmune vitiligo
Authors: Cavalli Giulio , Hayashi Masahiro , Jin Ying , Yorgov Daniel , Santorico Stephanie A. , Holcomb Cherie , Rastrou Melinda , Erlich Henry , Tengesdal Isak W. , Dagna Lorenzo , Neff C. Preston , Palmer Brent E. , Spritz Richard A. , Dinarello Charles A.
Published: February 2016

Significance

Vitiligo is a classic autoimmune disease genetically associated with SNPs in the MHC class II region. To date, the impact of HLA molecules on autoimmunity has focused on structural diversity of antigen presentation. Here, we describe the properties of a 47-nucleotide high-risk haplotype of three SNPs within an intergenic “super-enhancer” located between theHLA-DRB1andHLA-DQA1genes, localized by a genome-wide association study of 2,853 subjects with vitiligo. Monocytes from healthy subjects homozygous for the high-risk haplotype have increased surface expression of HLA-DR and -DQ, and peripheral blood mononuclear cells from high-risk subjects produce more IL-1β and IFN-γ upon engagement of dectin-1, mannose, and Toll-like receptors. This study underscores the importance of transcriptional regulation ofHLAgenes to the risk of developing an autoimmune disease.
Tissue nonautonomous effects of fat body methionine metabolism on imaginal disc repair in
Drosophila
Authors: Kashio Soshiro , Obata Fumiaki , Zhang Liu , Katsuyama Tomonori , Chihara Takahiro , Miura Masayuki
Published: February 2016

Significance

Interactions between damaged and surrounding tissues are suggested to be critical for maintaining tissue homeostasis in multicellular organisms. In this study, we reveal the tissue nonautonomous contribution of the methionine metabolism in the fat body to the repair and regeneration processes of disc epithelia in fruit flies,
Drosophila melanogaster
. Fat body corresponds to the mammalian liver and adipose tissue, and methionine metabolism is a broadly conserved metabolic pathway from bacteria to human, which plays important roles through transmethylation, transsulfuration, and polyamine biosynthesis. We propose the regulatory roles of the methionine metabolism in the fat body for systemic regulation of tissue repair.
Enterovirus D68 receptor requirements unveiled by haploid genetics
Authors: Baggen Jim , Thibaut Hendrik Jan , Staring Jacqueline , Jae Lucas T. , Liu Yue , Guo Hongbo , Slager Jasper J. , de Bruin Jost W. , van Vliet Arno L. W. , Blomen Vincent A. , Overduin Pieter , Sheng Ju , de Haan Cornelis A. M. , de Vries Erik , Meijer Adam , Rossmann Michael G. , Brummelkamp Thijn R. , van Kuppeveld Frank J. M.
Published: February 2016

Significance

Enterovirus D68 (EV-D68) is an emerging pathogen that recently caused a large outbreak of severe respiratory disease in the United States and is associated with cases of paralysis. Little is known about EV-D68 host factor requirements. Here, using a genome-wide knockout approach, we identified several genes in sialic acid (Sia) biology as being essential for infection. We also showed that not only α2,6-linked Sia, which mainly occurs in the upper respiratory tract, but also α2,3-linked Sia, which mainly occurs in the lower respiratory tract, can serve as the receptor. Moreover, we identified recent EV-D68 isolates that can use an alternative, nonsialylated receptor. Our findings are essential to understand tropism and pathogenesis of EV-D68 as well as the potential of using Sia-targeting inhibitors to treat EV-D68 infections.
Hyaluronan synthesis is necessary for autoreactive T-cell trafficking, activation, and Th1 polarization
Authors: Kuipers Hedwich F. , Rieck Mary , Gurevich Irina , Nagy Nadine , Butte Manish J. , Negrin Robert S. , Wight Thomas N. , Steinman Lawrence , Bollyky Paul L.
Published: February 2016

Significance

4-methylumbelliferone (4-MU) is an oral drug that inhibits synthesis of hyaluronan, an extracellular matrix polymer implicated in autoimmunity. In the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS), 4-MU drives the polarization of T cells away from a Th1 phenotype, associated with disease progression, and toward a FoxP3
+
regulatory T-cell phenotype, associated with disease prevention. Moreover, 4-MU inhibits the reactive response of astrocytes, immunocompetent resident cells of the CNS, and prevents trafficking of activated T cells to the CNS. These data suggest that the extracellular matrix, and hyaluronan in particular, may be an active contributor to autoimmune pathogenesis in EAE and, furthermore, that 4-MU is a promising strategy for treatment of CNS autoimmunity.
Aminoacyl β-naphthylamides as substrates and modulators of AcrB multidrug efflux pump
Authors: Kinana Alfred D. , Vargiu Attilio V. , May Thithiwat , Nikaido Hiroshi
Published: February 2016

Significance

Resistance-nodulation division family efflux pumps, exemplified by AcrB ofEscherichia coli, play an important role in multidrug resistance of Gram-negative bacteria by actively pumping out a very wide range of antimicrobial agents. Yet it is unclear with how much affinity and with how much rate this pumping process works, except for our earlier studies on cephalosporins and penicillins. Here we succeeded in determining these parameters for the earliest-discovered inhibitor Phenylalanyl-argenine β-naphthylamide and its relatives, and examined the binding of these compounds to AcrB binding sites by docking and molecular dynamics simulations. The results suggest how an inhibitor, even when it is itself pumped out, can reduce the pumping of other substrates.
Asymmetric ecological conditions favor Red-Queen type of continued evolution over stasis
Authors: Nordbotten Jan Martin , Stenseth Nils C.
Published: February 2016

Significance

The work presented here demonstrates analytically for the very first time (to our knowledge) that, within a very general theoretical framework, both Red-Queen type of continuous evolution and evolutionary stasis may be the outcomes of ecological interactions within a multispecies ecological community. Whether or not evolution will cease or continue in an abiotically stable environment (i.e., where there are only biotic forces) has been an unsettled problem within evolutionary biology. Our contribution specifies the ecological conditions for which Red-Queen type of continuous evolution and stasis will result. The new and general eco-evolutionary model provides a profoundly new basis for further theoretical and empirical work within the field of coevolution within multispecies ecological systems.
Multiplexed autoantigen microarrays identify HLA as a key driver of anti-desmoglein and -non-desmoglein reactivities in pemphigus
Authors: Sajda Thomas , Hazelton Julian , Patel Milan , Seiffert-Sinha Kristina , Steinman Lawrence , Robinson William , Haab Brian B. , Sinha Animesh A.
Published: February 2016

Significance

Although the pathogenicity of autoantibodies (autoAbs) targeting the desmosomal cadherins desmoglein (Dsg) 3 and 1 is well established in pemphigus vulgaris (PV), the disease relevance of other autoAbs remains an area of intense research. By using disease-specific protein microarrays to characterize the autoAb response in PV, we identified Dsg and non-Dsg antigens as primary targets of patient autoAbs. Additionally, we found that healthy first- or second-degree relatives of patients with PV, specifically those expressing HLA DRB1*0402 or DQB1*0503 (PV susceptibility alleles) exhibit patterns of autoreactivity similar to that of patients with PV. These findings suggest a potential role for non-Dsg autoAbs in disease pathogenesis and implicate HLA as a primary driver of autoAb specificity in PV.
Common BRAF(V600E)-directed pathway mediates widespread epigenetic silencing in colorectal cancer and melanoma
Authors: Fang Minggang , Hutchinson Lloyd , Deng April , Green Michael R.
Published: February 2016

Significance

In many cancers, specific genes affecting cellular growth control are hypermethylated and transcriptionally repressed, a phenomenon known as epigenetic silencing. However, the mechanistic basis of epigenetic silencing is not well understood. One model, called the “instructive model,” posits that epigenetic silencing occurs through a specific pathway, comprising a defined set of components, initiated by an oncoprotein. We have previously shown that in colorectal cancer, B-Raf proto-oncogene (BRAF) directs widespread promoter methylation and epigenetic silencing by up-regulating the transcriptional repressor v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog G (MAFG), which, in turn, recruits a set of corepressors, resulting in transcriptional repression. Here, we show that this same BRAF-directed pathway also mediates widespread epigenetic silencing in melanoma. Our results provide strong support for the instructive model of oncoprotein-directed epigenetic silencing.
TLR4/MD-2 activation by a synthetic agonist with no similarity to LPS
Authors: Wang Ying , Su Lijing , Morin Matthew D. , Jones Brian T. , Whitby Landon R. , Surakattula Murali M. R. P. , Huang Hua , Shi Hexin , Choi Jin Huk , Wang Kuan-wen , Moresco Eva Marie Y. , Berger Michael , Zhan Xiaoming , Zhang Hong , Boger Dale L. , Beutler Bruce
Published: February 2016

Significance

The Toll-like receptor 4 (TLR4)/myeloid differentiation factor 2 (MD-2) complex recognizes lipopolysaccharide (LPS) on Gram-negative bacteria to induce an innate immune response. Neoseptins, chemically synthesized peptidomimetics that bind and activate the mouse TLR4 (mTLR4)/MD-2 complex independent of LPS, were discovered through unbiased screening and reverse genetic studies, and improved by chemical modification. NMR and X-ray crystallography of the TLR4/MD-2/Neoseptin-3 complex determined the mechanism by which Neoseptin-3 activates mTLR4/MD-2 and triggers myeloid differentiation primary response gene 88- and Toll-interleukin 1 receptor domain-containing adaptor inducing IFN-beta-dependent signaling. Neoseptin-3 binds as a dimer within the hydrophobic pocket of MD-2, contacting residues distinct from those contacted by LPS or lipid A, yet triggering a conformational change very similar to that elicited by LPS or lipid A. Natural peptides might conceivably produce similar effects.
Ptch2 loss drives myeloproliferation and myeloproliferative neoplasm progression
Authors: Klein Claudius , Zwick Anabel , Kissel Sandra , Forster Christine Ulrike , Pfeifer Dietmar , Follo Marie , Illert Anna Lena , Decker Sarah , Benkler Thomas , Pahl Heike , Oostendorp Robert A.J. , Aumann Konrad , Duyster Justus , Dierks Christine
Published: February 2016

JAK2V617F+ myeloproliferative neoplasms (MPNs) frequently progress into leukemias, but the factors driving this process are not understood. Here, we find excess Hedgehog (HH) ligand secretion and loss of PTCH2 in myeloproliferative disease, which drives canonical and noncanonical HH-signaling. Interestingly, Ptch2−/− mice mimic dual pathway activation and develop a MPN-phenotype with leukocytosis (neutrophils and monocytes), strong progenitor and LKS mobilization, splenomegaly, anemia, and loss of lymphoid lineages. HSCs exhibit increased cell cycling with improved stress hematopoiesis after 5-FU treatment, and this results in HSC exhaustion over time. Cytopenias, LKS loss, and mobilization are all caused by loss of Ptch2 in the niche, whereas hematopoietic loss of Ptch2 drives leukocytosis and promotes LKS maintenance and replating capacity in vitro. Ptch2−/− niche cells show hyperactive noncanonical HH signaling, resulting in reduced production of essential HSC regulators (Scf, Cxcl12, and Jag1) and depletion of osteoblasts. Interestingly, Ptch2 loss in either the niche or in hematopoietic cells dramatically accelerated human JAK2V617F-driven pathogenesis, causing transformation of nonlethal chronic MPNs into aggressive lethal leukemias with >30% blasts in the peripheral blood. Our findings suggest HH ligand inhibitors as possible drug candidates that act on hematopoiesis and the niche to prevent transformation of MPNs into leukemias.
miR-23∼27∼24 clusters control effector T cell differentiation and function
Authors: Cho Sunglim , Wu Cheng-Jang , Yasuda Tomoharu , Cruz Leilani O. , Khan Aly Azeem , Lin Ling-Li , Nguyen Duc T. , Miller Marina , Lee Hyang-Mi , Kuo Ming-Ling , Broide David H. , Rajewsky Klaus , Rudensky Alexander Y. , Lu Li-Fan
Published: February 2016

Coordinated repression of gene expression by evolutionarily conserved microRNA (miRNA) clusters and paralogs ensures that miRNAs efficiently exert their biological impact. Combining both loss- and gain-of-function genetic approaches, we show that the miR-23∼27∼24 clusters regulate multiple aspects of T cell biology, particularly helper T (Th) 2 immunity. Low expression of this miRNA family confers proper effector T cell function at both physiological and pathological settings. Further studies in T cells with exaggerated regulation by individual members of the miR-23∼27∼24 clusters revealed that miR-24 and miR-27 collaboratively limit Th2 responses through targeting IL-4 and GATA3 in both direct and indirect manners. Intriguingly, although overexpression of the entire miR-23 cluster also negatively impacts other Th lineages, enforced expression of miR-24, in contrast to miR-23 and miR-27, actually promotes the differentiation of Th1, Th17, and induced regulatory T cells, implying that under certain conditions, miRNA families can fine tune the biological effects of their regulation by having individual members antagonize rather than cooperate with each other. Together, our results identify a miRNA family with important immunological roles and suggest that tight regulation of miR-23∼27∼24 clusters in T cells is required to maintain optimal effector function and to prevent aberrant immune responses.
Dimensions of some locally analytic representations
Authors: Schmidt Tobias , Strauch Matthias
Published: February 2016

LetGGbe the group of points of a split reductive group over a finite extension ofQp\mathbb {Q}_p. In this paper, we compute the dimensions of certain classes of locally analyticGG-representations. This includes principal series representations and certain representations coming from homogeneous line bundles onpp-adic symmetric spaces. As an application, we compute the dimensions of the unitaryGL2(Qp)\textrm {GL}_2(\mathbb {Q}_p)-representations appearing in Colmez’pp-adic local Langlands correspondence.
Ability to Work and Employment Rates in Human Immunodeficiency Virus (HIV)-1-Infected Individuals Receiving Combination Antiretroviral Therapy: The Swiss HIV Cohort Study
Authors: Elzi Luigia , Conen Anna , Patzen Annalea , Fehr Jan , Cavassini Matthias , Calmy Alexandra , Schmid Patrick , Bernasconi Enos , Furrer Hansjakob , Battegay Manuel ,   the Swiss HIV Cohort Study Group, Barth J. , Battegay M. , Bernasconi E. , Böni J. , Bucher H.C. , Bürgisser P. , Burton-Jeangros C. , Calmy A. , Cavassini M. , Dubs R. , Egger M. , Elzi L. , Fehr J. , Fischer M. , Flepp M. , Furrer H. , Fux C.A. , Gorgievski M. , Günthard H. , Hasse B. , Hirsch H.H. , Hirschel B. , Hösli I. , Kahlert C. , Kaiser L. , Keiser O. , Kind C. , Klimkait T. , Kovari H. , Ledergerber B. , Martinetti G. , Martinez de Tejada B. , Müller N. , Nadal D. , Pantaleo G. , Rauch A. , Regenass S. , Rickenbach M. , Rudin C. , Schmid P. , Schultze D. , Schöni-Affolter F. , Schüpbach J. , Speck R. , Taffé P. , Tarr P. , Telenti A. , Trkola A. , Vernazza P. , von Wyl V. , Weber R. , Yerly S.
Published: February 2016

Background.  Limited data exist on human immunodeficiency virus (HIV)-infected individuals' ability to work after receiving combination antiretroviral therapy (cART). We aimed to investigate predictors of regaining full ability to work at 1 year after starting cART.

Methods.  Antiretroviral-naive HIV-infected individuals <60 years who started cART from January 1998 through December 2012 within the framework of the Swiss HIV Cohort Study were analyzed. Inability to work was defined as a medical judgment of the patient's ability to work as 0%.

Results.  Of 5800 subjects, 4382 (75.6%) were fully able to work, 471 (8.1%) able to work part time, and 947 (16.3%) were unable to work at baseline. Of the 947 patients unable to work, 439 (46.3%) were able to work either full time or part time at 1 year of treatment. Predictors of recovering full ability to work were non-white ethnicity (odds ratio [OR], 2.06; 95% confidence interval [CI], 1.20–3.54), higher education (OR, 4.03; 95% CI, 2.47–7.48), and achieving HIV-ribonucleic acid <50 copies/mL (OR, 1.83; 95% CI, 1.20–2.80). Older age (OR, 0.55; 95% CI, .42–.72, per 10 years older) and psychiatric disorders (OR, 0.24; 95% CI, .13–.47) were associated with lower odds of ability to work. Recovering full ability to work at 1 year increased from 24.0% in 1998–2001 to 41.2% in 2009–2012, but the employment rates did not increase.

Conclusions.  Regaining full ability to work depends primarily on achieving viral suppression, absence of psychiatric comorbidity, and favorable psychosocial factors. The discrepancy between patients' ability to work and employment rates indicates barriers to reintegration of persons infected with HIV.
Alterations of amygdala-prefrontal connectivity with real-time fMRI neurofeedback in BPD patients
Authors: Paret Christian , Kluetsch Rosemarie , Zaehringer Jenny , Ruf Matthias , Demirakca Traute , Bohus Martin , Ende Gabriele , Schmahl Christian
Published: February 2016

With the use of real-time functional magnetic resonance imaging neurofeedback (NF), amygdala activitiy can be visualized in real time. In this study, continuous amygdala NF was provided to patients with borderline personality disorder (BPD) with the instruction to down-regulate. During four sessions of NF training, patients viewed aversive pictures and received feedback from a thermometer display, which showed the amygdala blood oxygenation level-dependent signal. Conditions of regulation and viewing without regulation were presented. Each session started with a resting-state scan and was followed by a transfer run without NF. Amygdala regulation, task-related and resting-state functional brain connectivity were analyzed. Self-ratings of dissociation and difficulty in emotion regulation were collected. BPD patients down-regulated right amygdala activation but there were no improvements over time. Task-related amygdala-ventromedial prefrontal cortex connectivity was altered across the four sessions, with an increased connectivity when regulating vs viewing pictures. Resting-state amygdala-lateral prefrontal cortex connectivity was altered and dissociation, as well as scores for ‘lack of emotional awareness’, decreased with training. Results demonstrated that amygdala NF may improve healthy brain connectivity, as well as emotion regulation. A randomized-controlled trial is needed to investigate whether amygdala NF is instrumental for improving neural regulation and emotion regulation in BPD patients.
OCULAR MANIFESTATIONS OF PRIMARY MYELOFIBROSIS
Authors: Lin Albert L. , Burnham Jordan M. , Pang Victor , Idowu Omolola , Iyer Siva
Published: February 2016

Purpose:

To report ocular manifestations of idiopathic primary myelofibrosis in a patient with relapsed primary myelofibrosis.

Methods:

Observational case report.

Results:

A 57-year-old African American male with history of primary myelofibrosis, diagnosed by bone marrow aspirate and biopsy, believed to be in remission was referred to us for bilateral angle-closure glaucoma refractory to medical treatment and laser peripheral iridotomy. His fundus examination revealed serous retinal detachments, choroidal effusions, and Roth spots, and B-scan revealed his angle closure was due to annular anterior ciliochoroidal effusions. The patient was taken to surgery for a pars plana vitrectomy with radial sclerotomies performed to relieve the patient's eye pressure in the left eye. Cytologic analysis of the choroidal effusions revealed neutrophilic infiltrates with immature forms and erythroid precursors, suggesting a neoplastic infiltration from the patient's primary myelofibrosis. The patient's vision and ocular symptoms significantly improved after chemotherapy. Repeat bone marrow aspiration and biopsy confirmed the patient's primary myelofibrosis with no progression to acute leukemia despite his high leukocyte count.

Conclusion:

Neoplastic infiltration of primary idiopathic myelofibrosis into the eye and surrounding structures, which is scantly described in the current literature, may be an early sign of new onset or relapsing primary myelofibrosis. Chemotherapy can be very effective in the ultimate treatment and remission of these ocular symptoms.
An Analysis of Conjunctival Map Biopsies in Sebaceous Carcinoma
Authors: McConnell Lindsay K. , Syed Nasreen A. , Zimmerman Miriam B. , Carter Keith D. , Nerad Jeffery A. , Allen Richard C. , Shriver Erin M.
Published: February 2016

Purpose:

To evaluate the need for standardized conjunctival map biopsies in periocular sebaceous carcinoma and to formulate recommendations regarding map biopsy number, location, size, and utility based on analysis of biopsy locations, results, and outcomes.

Methods:

Retrospective consecutive series of patients with sebaceous carcinoma treated at a tertiary care hospital from 1988 to 2013. Main outcome measures included conjunctival biopsy locations, number, size, and pathology.

Results:

A diffuse eyelid pattern was evident on presentation in 28/51 patients (54.9%) versus a solitary eyelid nodule in 23/51 (45.1%). Forty-five patients underwent a total of 429 conjunctival biopsies. The conjunctiva was negative in 277 specimens (64.6%), positive in 121 (28.2%), suspicious in 26 (6.1%), and nondiagnostic in 5 (1.2%). Intraepithelial conjunctival involvement was present in 36 patients (70.6%) of whom 23 (63.9%) presented with a diffuse eyelid appearance. There was no statistically significant correlation between primary tumor location and sites of positive biopsies or biopsy size. The pattern at presentation and location of primary tumor did not correlate with biopsy results. Clinical assessment regarding conjunctival involvement was incorrect in 10 of 23 patients (43.5%) with a solitary nodule. Despite primary tumor resection with clear margins confirmed on pathology, 5 of 45 (11%) patients had locally recurrent sebaceous carcinoma.

Conclusions:

Conjunctival biopsy size does not correlate with the presence of tumor in the biopsy. Primary tumor location and pattern of tumor at presentation do not correlate with conjunctival biopsy results. Irrespective of the clinical tumor features, standardized conjunctival map biopsies are essential in staging periocular sebaceous carcinoma.
Comparison of Recommendations in Clinical Practice Guidelines for Acute Gastroenteritis in Children
Authors: Lo Vecchio Andrea , Dias Jorge Amil , Berkley James A. , Boey Chris , Cohen Mitchell B. , Cruchet Sylvia , Liguoro Ilaria , Salazar Lindo Eduardo , Sandhu Bhupinder , Sherman Philip , Shimizu Toshiaki , Guarino Alfredo
Published: February 2016

Objective:

Acute gastroenteritis (AGE) is a major cause of child mortality and morbidity. This study aimed at systematically reviewing clinical practice guidelines (CPGs) on AGE to compare recommendations and provide the basis for developing single universal guidelines.

Methods:

CPGs were identified by searching MEDLINE, Cochrane‐Library, National Guideline Clearinghouse and Web sites of relevant societies/organizations producing and/or endorsing CPGs.

Results:

The definition of AGE varies among the 15 CPGs identified. The parameters most frequently recommended to assess dehydration are skin turgor and sunken eyes (11/15, 73.3%), general appearance (11/15, 66.6%), capillary refill time, and mucous membranes appearance (9/15, 60%). Oral rehydration solution is universally recognized as first‐line treatment. The majority of CPGs recommend hypo‐osmolar (Na+ 45–60 mmol/L, 11/15, 66.6 %) or low‐osmolality (Na+ 75 mmol/L, 9/15, 60%) solutions. In children who fail oral rehydration, most CPGs suggest intravenous rehydration (66.6%). However, nasogastric tube insertion for fluid administration is preferred according by 5/15 CPGs (33.3%). Changes in diet and withdrawal of food are discouraged by all CPGs, and early refeeding is strongly recommended in 13 of 15 (86.7%). Zinc is recommended as an adjunct to ORS by 10 of 15 (66.6%) CPGs, most of them from low‐income countries. Probiotics are considered by 9 of 15 (60%) CPGs, 5 from high‐income countries. Antiemetics are not recommended in 9 of 15 (60%) CPGs. Routine use of antibiotics is discouraged.

Conclusions:

Key recommendations for the management of AGE in children are similar in CPGs. Together with accurate review of evidence‐base this may represent a starting point for developing universal recommendations for the management of children with AGE worldwide.
Fatty Acid Composition in Feeds and Plasma of Canadian Premature Infants
Authors: Hossain Zakir , MacKay Dylan , Friel James K.
Published: February 2016

Objectives:

The objective of the present exploratory study was to investigate how the fatty acid (FA) composition of different food sources for preterm infants including breast milk (BM), formula (F), human milk fortifiers (HMFs), and total parenteral nutrition (TPN) impacted preterm infant's plasma FA. The associations between FA content of plasma with antioxidant enzyme activity and cognition were also evaluated.

Methods:

Thirty‐two premature infants were included in the present study. Five different feeds (BM, F, BM + F, BM + HMF, and TPN) were provided. Foods and preterm infant plasma samples were collected at the same time on the same day biweekly where possible. Separation and identification of the plasma and food FA methyl esters were performed by gas‐liquid chromatography. Antioxidant enzymes were measured. The Bayley Scale of Infant Development version III was used to evaluate cognition.

Results:

In food sources, BM contained significantly lower stearic acid (C18:0) (P < 0.05), oleic acid (C18:1n9) (P < 0.01), linoleic acid (C18:2n6) (P < 0.01), α‐linoleic acid (C18:3n3) (P < 0.01), and arachidonic acid (C20:4n6) (P < 0.05) compared with the F. Palmitic acid (C16:0) was significantly higher (P < 0.05) in the BM + HMF compared with the BM. Stearic acid (C18:0) was significantly higher (P < 0.05) in the BM + F and BM + HMF compared with the BM. In the plasma lauric acid (C12:0) (P < 0.05) and myristic acid (C14:0) (P < 0.001) were higher in the BM‐fed babies compared with the F‐fed or TPN‐recipient groups. Antioxidant enzymes, activities and cognition scores did not differ by feeding groups, however the study may not have been powered to detect these differences.

Conclusions:

The type, and therefore quality, of fatty acids is an important consideration when selecting what is fed to premature infants because differences in feed fatty acids were seen in some plasma fatty acids in the study.
A trip down memory lane about sex differences in the brain
Authors: Shors Tracey J.
Published: February 2016

Scientific studies funded by the United States government must now include both males and females as experimental subjects. This is a welcomed change for those of us who have been reporting on sex differences for decades. That said, there are some issues to consider; I focus on one in this review:
females used in animal models of mental illness and health are almost always virgins and yet most adult females around the world, irrespective of species, are not virgins.
I am not advocating that all scientists include non-virgin females in laboratory studies, but rather to consider the dynamic nature of the female brain when drawing conclusions through discovery. Stressful life experiences, including those related to sexual aggression and trauma, can have a lasting impact on processes of learning related to mental health and plasticity in the female brain. Her response to stress can change rather dramatically as she emerges from puberty to become pregnant and produce offspring, as she must learn to care for those offspring. The inclusion of females in scientific research has been a long time coming but it comes with a history. Going forward, we should take advantage of that history to generate hypotheses that are both reasonable and meaningful.
Decoupling global biases and local interactions between cell biological variables
Authors: Zaritsky Assaf , Obolski Uri , Gan Zhuo , Reis Carlos R. , Kadlecova Zuzana , Du Yi , Schmid Sandra L. , Danuser Gaudenz
Published: February 2016

Analysis of coupled variables is a core concept of cell biological inference, with co-localization of two molecules as a proxy for protein interaction being a ubiquitous example. However, external effectors may influence the observed co-localization independently from the local interaction of two proteins. Such global bias, although biologically meaningful, is often neglected when interpreting co-localization. Here, we describe DeBias, a computational method to quantify and decouple global bias from local interactions between variables by modeling the observed co-localization as the cumulative contribution of a global and a local component. We showcase four applications of DeBias in different areas of cell biology, and demonstrate that the global bias encapsulates fundamental mechanistic insight into cellular behavior. The DeBias software package is freely accessible online via a web-server athttps://debias.biohpc.swmed.edu.

Impact statement: DeBias, a generic method to decompose and quantify the confounding, global factors and direct interactions of pairwise interacting variables.
Sequence amplification via cell passaging creates spurious signals of positive adaptation in influenza H3N2 hemagglutinin
Authors: McWhite Claire D. , Meyer Austin G. , Wilke Claus O.
Published: February 2016

Clinical influenza A isolates are frequently not sequenced directly. Instead, a majority of these isolates (~70% in 2015) are first subjected to passaging for amplification, most commonly in non-human cell culture. Here, we find that this passaging leaves distinct signals of adaptation in the viral sequences, which can confound evolutionary analyses of the viral sequences. We find distinct patterns of adaptation to Madin-Darby (MDCK) and monkey cell culture absent from unpassaged hemagglutinin sequences. These patterns also dominate pooled datasets not separated by passaging type, and they increase in proportion to the number of passages performed. By contrast, MDCK-SIAT1 passaged sequences seem mostly (but not entirely) free of passaging adaptations. Contrary to previous studies, we find that using only internal branches of the influenza phylogenetic trees is insufficient to correct for passaging artifacts. These artifacts can only be safely avoided by excluding passaged sequences entirely from subsequent analysis. We conclude that future influenza evolutionary analyses should appropriately control for potentially confounding effects of passaging adaptations.
Skew in ovarian activation depends on domicile size in a facultatively social thrips
Authors: Gilbert J. D. J. , Wells A. , Simpson S. J.
Published: February 2016

Costs and benefits of group living are a fundamental topic in behavioural ecology. Resource availability affects individuals breeding prospects alone and in groups, as well as how reproduction is distributed within groups (“reproductive skew”). Here, we provide correlational evidence in facultatively social thrips that breeding resources are associated with (1) whether solitary or social living is favoured, and (2) the degree of ovarian skew.

Dunatothrips aneurae(Thysanoptera, Phlaeothripidae) cooperatively build silk “domiciles” on Australian Acacias, feeding exclusively from internal phyllode surfaces.Per capitaproductivity scaled differently with group size depending on domicile volume – females in small domiciles did better alone than in groups, whereas in large domiciles single and group-nesting females did equally well. Ovarian dissections revealed that in small domiciles some females were nonreproductive, indicating ovarian (i.e. reproductive) skew. Skew increased as domicile size decreased and group size increased. Breeders had smaller oocyte volume in smaller domiciles, especially those containing nonreproductives.

These findings suggest group formation and reproductive skew inD. aneuraemay be influenced by reproductive competition for breeding resources. Nonreproductive females in small domiciles may be reproductively suppressed, subfertile, or waiting to reproduce. We speculate they may avoid eviction by contributing as “helpers” to domicile maintenance.
Crystal structure of 3-{5-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-1H-pyrazol-1-yl}indolin-2-one ethanol monosolvate
Authors: Rahman Md. Lutfor , Kulkarni Ajaykumar D. , Mohd. Yusoff Mashitah , Kwong Huey Chong , Quah Ching Kheng
Published: February 2016

The title indolin-2-one compound, C28H23FN4O·C2H6O, crystallizes as a 1:1 ethanol solvate. The ethanol molecule is disordered over two positions with refined site occupancies of 0.560 (14) and 0.440 (14). The pyrazole ring makes dihedral angles of 84.16 (10) and 85.33 (9)° with the indolin-2-one and indole rings, respectively, whereas the dihedral angle between indolin-2-one and indole rings is 57.30 (7)°. In the crystal, the components are linked by N—H...O and O—H...O hydrogen bonds, forming an inversion molecule–solvate 2:2 dimer withR44(12) ring motifs. The crystal structure is consolidated by π–π interaction between pairs of inversion-related indolin-2-one rings [interplanar spacing = 3.599 (2) Å].