bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD8
+
T Cell Breadth and
Ex Vivo
Virus Inhibition Capacity Distinguish between Viremic Controllers with and without Protective HLA Class I Alleles
Authors: Koofhethile Catherine K. , Ndhlovu Zaza M. , Thobakgale-Tshabalala Christina , Prado Julia G. , Ismail Nasreen , Mncube Zenele , Mkhize Lungile , van der Stok Mary , Yende Nonhlanhla , Walker Bruce D. , Goulder Philip J. R. , Ndung'u Thumbi 
Published: May 2016

ABSTRACT

The mechanisms of viral control and loss of viral control in chronically infected individuals with or without protective HLA class I alleles are not fully understood. We therefore characterized longitudinally the immunological and virological features that may explain divergence in disease outcome in 70 HIV-1 C-clade-infected antiretroviral therapy (ART)-naive South African adults, 35 of whom possessed protective HLA class I alleles. We demonstrate that, over 5 years of longitudinal study, 35% of individuals with protective HLA class I alleles lost viral control compared to none of the individuals without protective HLA class I alleles (
P
= 0.06). Sustained HIV-1 control in patients with protective HLA class I alleles was characteristically related to the breadth of HIV-1 CD8
+
T cell responses against Gag and enhanced ability of CD8
+
T cells to suppress viral replication
ex vivo
. In some cases, loss of virological control was associated with reduction in the total breadth of CD8
+
T cell responses in the absence of differences in HIV-1-specific CD8
+
T cell polyfunctionality or proliferation. In contrast, viremic controllers without protective HLA class I alleles possessed reduced breadth of HIV-1-specific CD8
+
T cell responses characterized by reduced ability to suppress viral replication
ex vivo
. These data suggest that the control of HIV-1 in individuals with protective HLA class I alleles may be driven by broad CD8
+
T cell responses with potent viral inhibitory capacity while control among individuals without protective HLA class I alleles may be more durable and mediated by CD8
+
T cell-independent mechanisms.

IMPORTANCE
Host mechanisms of natural HIV-1 control are not fully understood. In a longitudinal study of antiretroviral therapy (ART)-naive individuals, we show that those with protective HLA class I alleles subsequently experienced virologic failure compared to those without protective alleles. Among individuals with protective HLA class I alleles, viremic control was associated with broad CD8
+
T cells that targeted the Gag protein, and CD8
+
T cells from these individuals exhibited superior virus inhibition capacity. In individuals without protective HLA class I alleles, HIV-1-specific CD8
+
T cell responses were narrow and poorly inhibited virus replication. These results suggest that broad, highly functional cytotoxic T cells (cytotoxic T lymphocytes [CTLs]) against the HIV-1 Gag protein are associated with control among those with protective HLA class I alleles and that loss of these responses eventually leads to viremia. A subset of individuals appears to have alternative, non-CTL mechanisms of viral control. These controllers may hold the key to an effective HIV vaccine.
A Novel Open and Infectious Form of Echovirus 1
Authors: Myllynen Mira , Kazmertsuk Artur , Marjomäki Varpu 
Published: May 2016

ABSTRACT

One of the hallmarks of enterovirus genome delivery is the formation of an uncoating intermediate particle. Based on previous studies of mostly heated picornavirus particles, intermediate particles were shown to have externalized the innermost capsid protein (VP4) and exposed the N terminus of VP1 and to have reduced infectivity. Here, in addition to the native and intact particle type, we have identified another type of infectious echovirus 1 (E1) particle population during infection. Our results show that E1 is slightly altered during entry, which leads to the broadening of the major virion peak in the sucrose gradient. In contrast, CsCl gradient separation revealed that in addition to the light intact and empty particles, a dense particle peak appeared during infection in cells. When the broad peak from the sucrose gradient was subjected to a CsCl gradient, it revealed light and dense particles, further suggesting that the shoulder represents the dense particle. The dense particle was permeable to SYBR green II, it still contained most of its VP4, and it was able to bind to its receptor α
2
β
1
integrin and showed high infectivity. A thermal assay further showed that the α
2
β
1
integrin binding domain (I-domain) stabilized the virus particle. Finally, heating E1 particles to superphysiological temperatures produced more fragile particles with aberrant ultrastructural appearances, suggesting that they are distinct from the dense E1 particles. These results describe a more open and highly infectious E1 particle that is naturally produced during infection and may represent a novel form of an uncoating intermediate.

IMPORTANCE
In this paper, we have characterized a possible uncoating intermediate particle of E1 that is produced in cells during infection. Before releasing their genome into the host cytosol, enteroviruses go through structural changes in their capsid, forming an uncoating intermediate particle. It was shown previously that structural changes can be induced by receptor interactions and, in addition, by heating the native virion to superphysiological temperatures. Here, we demonstrate that an altered, still infectious E1 particle is found during infection. This particle has a more open structure, and it cannot be formed by heating. It still contains the VP4 protein and is able to bind to its receptor and cause infection. Moreover, we show that in contrast to some other enteroviruses, the receptor-virion interaction has a stabilizing effect on E1. This paper highlights the differences between enterovirus species and further increases our understanding of various uncoating forms of enteroviruses.
Transformation by Polyomavirus Middle T Antigen Involves a Unique Bimodal Interaction with the Hippo Effector YAP
Authors: Rouleau Cecile , Pores Fernando Arun T. , Hwang Justin H. , Faure Nathalie , Jiang Tao , White Elizabeth A. , Roberts Thomas M. , Schaffhausen Brian S. 
Published: May 2016

ABSTRACT
Murine polyomavirus has repeatedly provided insights into tumorigenesis, revealing key control mechanisms such as tyrosine phosphorylation and phosphoinositide 3-kinase (PI3K) signaling. We recently demonstrated that polyomavirus small T antigen (ST) binds YAP, a major effector of Hippo signaling, to regulate differentiation. Here we characterize YAP as a target of middle T antigen (MT) important for transformation. Through a surface including residues R103 and D182, wild-type MT binds to the YAP WW domains. Mutation of either R103 or D182 of MT abrogates YAP binding without affecting binding to other signaling molecules or the strength of PI3K or Ras signaling. Either genetic abrogation of YAP binding to MT or silencing of YAP via short hairpin RNA (shRNA) reduced MT transformation, suggesting that YAP makes a positive contribution to the transformed phenotype. MT targets YAP both by activating signaling pathways that affect it and by binding to it. MT signaling, whether from wild-type MT or the YAP-binding MT mutant, promoted YAP phosphorylation at S127 and S381/397 (YAP2/YAP1). Consistent with the known functions of these phosphorylated serines, MT signaling leads to the loss of YAP from the nucleus and degradation. Binding of YAP to MT brings it together with protein phosphatase 2A (PP2A), leading to the dephosphorylation of YAP in the MT complex. It also leads to the enrichment of YAP in membranes. Taken together, these results indicate that YAP promotes MT transformation via mechanisms that may depart from YAP's canonical oncogenic transcriptional activation functions.

IMPORTANCE
The highly conserved Hippo/YAP pathway is important for tissue development and homeostasis. Increasingly, changes in this pathway are being associated with cancer. Middle T antigen (MT) is the primary polyomavirus oncogene responsible for tumor formation. In this study, we show that MT signaling promotes YAP phosphorylation, loss from the nucleus, and increased turnover. Notably, MT genetics demonstrate that YAP binding to MT is important for transformation. Because MT also binds PP2A, YAP bound to MT is dephosphorylated, stabilized, and localized to membranes. Taken together, these results indicate that YAP promotes MT transformation via mechanisms that depart from YAP's canonical oncogenic transcriptional activation functions.
Dynein Regulators Are Important for Ecotropic Murine Leukemia Virus Infection
Authors: Valle-Tenney Roger , Opazo Tatiana , Cancino Jorge , Goff Stephen P. , Arriagada Gloria 
Published: May 2016

ABSTRACT
During the early steps of infection, retroviruses must direct the movement of the viral genome into the nucleus to complete their replication cycle. This process is mediated by cellular proteins that interact first with the reverse transcription complex and later with the preintegration complex (PIC), allowing it to reach and enter the nucleus. For simple retroviruses, such as murine leukemia virus (MLV), the identities of the cellular proteins involved in trafficking of the PIC in infection are unknown. To identify cellular proteins that interact with the MLV PIC, we developed a replication-competent MLV in which the integrase protein was tagged with a FLAG epitope. Using a combination of immunoprecipitation and mass spectrometry, we established that the microtubule motor dynein regulator DCTN2/p50/dynamitin interacts with the MLV preintegration complex early in infection, suggesting a direct interaction between the incoming viral particles and the dynein complex regulators. Further experiments showed that RNA interference (RNAi)-mediated silencing of either DCTN2/p50/dynamitin or another dynein regulator, NudEL, profoundly reduced the efficiency of infection by ecotropic, but not amphotropic, MLV reporters. We propose that the cytoplasmic dynein regulators are a critical component of the host machinery needed for infection by the retroviruses entering the cell via the ecotropic envelope pathway.

IMPORTANCE
Retroviruses must access the chromatin of host cells to integrate the viral DNA, but before this crucial event, they must reach the nucleus. The movement through the cytoplasm—a crowded environment where diffusion is slow—is thought to utilize retrograde transport along the microtubule network by the dynein complex. Different viruses use different components of this multisubunit complex. We found that the preintegration complex of murine leukemia virus (MLV) interacts with the dynein complex and that regulators of this complex are essential for infection. Our study provides the first insight into the requirements for retrograde transport of the MLV preintegration complex.
Resistance training reduces systolic blood pressure in metabolic syndrome: a systematic review and meta-analysis of randomised controlled trials
Authors: Lemes Ítalo Ribeiro , Ferreira Paulo Henrique , Linares Stephanie Nogueira , Machado Aryane Flauzino , Pastre Carlos Marcelo , Netto Jayme 
Published: May 2016

AimTo evaluate the effects of resistance training on metabolic syndrome risk factors through comparison with a control group.DesignMeta-analysis comparing resistance training interventions with control groups. Two independent reviewers selected the studies and assessed their quality and data. The pooled mean differences between resistance training and the control group were calculated using a fixed-effects model.Data sourcesThe MEDLINE, PEDro, EMBASE, SPORTDiscus and The Cochrane Library databases were searched from their earliest records to 10 January 2015.Eligibility criteria for selecting studiesRandomised controlled trials that compared the effect of resistance training on metabolic syndrome risk factors with a control group were included. All types of resistance training, irrespective of intensity, frequency or duration, were eligible.ResultsOnly systolic blood pressure was significantly reduced, by 4.08 mm Hg (95% CI 1.33 to 6.82; p<0.01), following resistance training. The pooled effect showed a reduction of 0.04 mmol/L (95% CI −0.12, 0.21; p>0.05) for fasting plasma glucose, 0.00 (95% CI −0.05, 0.04; p>0.05) for high-density lipoprotein (HDL) cholesterol, 0.03 (95% CI −0.14, 0.20; p>0.05) for triglycerides, 1.39 mm Hg (95% CI −0.19, 2.98; p=0.08) for diastolic blood pressure and 1.09 cm (95% CI −0.12, 2.30; p=0.08) for waist circumference. Inconsistency (I2) for all meta-analysis was 0%.ConclusionsResistance training may help reduce systolic blood pressure levels, stroke mortality and mortality from heart disease in people with metabolic syndrome.Trial registration numberCRD42015016538.
Towards real-time earthquake impact alerting in Indonesia
Authors: Pramono Sigit , Allen Trevor I. , Bugden Craig , Pandhu Rakhindro , Nindya Isabella , Ghasemi Hadi , Masturyono  
Published: May 2016

Abstract
The Government of Indonesia has committed to deploying a network of 500 strong-motion sensors throughout the nation. The data from these sensors have the potential to provide critical near-real-time information on the level of ground shaking and potential impact from Indonesian earthquakes near communities. We describe the implementation of real-time ‘ShakeMaps’ within Indonesia's Agency of Meteorology, Climatology and Geophysics (BMKG). These ShakeMaps are intended to underpin real-time earthquake situational awareness tools.

The use of the new strong-motion network is demonstrated for two recent earthquakes in northern Sumatra: the 2 July 2013 M
w
6.1 Bener Meriah, Sumatra and the 10 October 2013 M
w
5.4 Aceh Besar earthquakes. The former earthquake resulted in 35 fatalities, with a further 2400 reported injuries. The recently integrated ShakeMap system automatically generated shaking estimates calibrated by BMKG's strong-motion network within 7 min of the Bener Meriah earthquake's origin, which assisted the emergency response efforts. Recorded ground motions are generally consistent with theoretical models. However, more analysis is required to fully characterize the attenuation of strong ground motion in Indonesia.
Cancer Therapy Directed by Comprehensive Genomic Profiling: A Single Center Study
Authors: Wheler Jennifer J. , Janku Filip , Naing Aung , Li Yali , Stephen Bettzy , Zinner Ralph , Subbiah Vivek , Fu Siqing , Karp Daniel , Falchook Gerald S. , Tsimberidou Apostolia M. , Piha-Paul Sarina , Anderson Roosevelt , Ke Danxia , Miller Vincent , Yelensky Roman , Lee J. Jack , Hong David S. , Kurzrock Razelle 
Published: May 2016

AbstractInnovative molecular diagnostics deployed in the clinic enable new ways to stratify patients into appropriate treatment regimens. These approaches may resolve a major challenge for early-phase clinical trials, which is to recruit patients who, while having failed previous treatments, may nevertheless respond to molecularly targeted drugs. We report the findings of a prospective, single-center study conducted in patients with diverse refractory cancers who underwent comprehensive genomic profiling (CGP; next-generation sequencing, 236 genes). Of the 500 patients enrolled, 188 (37.6%) received either matched (N = 122/188, 65%) or unmatched therapy (N = 66/188, 35%). The most common reasons that patients were not evaluable for treatment included insufficient tissue, death, or hospice transfer. The median number of molecular alterations per patient was five (range, 1–14); median number of prior therapies, four. The most common diagnoses were ovarian cancer (18%), breast cancer (16%), sarcoma (13%), and renal cancer (7%). Of the 339 successfully profiled patients, 317 (93.5%) had at least one potentially actionable alteration. By calculating matching scores, based on the number of drug matches and genomic aberrations per patient, we found that high scores were independently associated with a greater frequency of stable disease ≥6 months/partial/complete remission [22% (high scores) vs. 9% (low scores), P = 0.024], longer time-to-treatment failure [hazard ratio (HR) = 0.52; 95% confidence interval (CI) = 0.36–0.74; P = 0.0003], and survival (HR = 0.65; 95% CI = 0.43–1.0; P = 0.05). Collectively, this study offers a clinical proof of concept for the utility of CGP in assigning therapy to patients with refractory malignancies, especially in those patients with multiple genomic aberrations for whom combination therapies could be implemented. Cancer Res; 76(13); 3690–701. ©2016 AACR.
Burden of Nonsynonymous Mutations among TCGA Cancers and Candidate Immune Checkpoint Inhibitor Responses
Authors: Colli Leandro M. , Machiela Mitchell J. , Myers Timothy A. , Jessop Lea , Yu Kai , Chanock Stephen J. 
Published: May 2016

Abstract
Immune checkpoint inhibitor treatment represents a promising approach toward treating cancer and has been shown to be effective in a subset of melanoma, non–small cell lung cancer (NSCLC), and kidney cancers. Recent studies have suggested that the number of nonsynonymous mutations (NsM) can be used to select melanoma and NSCLC patients most likely to benefit from checkpoint inhibitor treatment. It is hypothesized that a higher burden of NsM generates novel epitopes and gene products, detected by the immune system as foreign. We conducted an assessment of NsM across 7,757 tumor samples drawn from 26 cancers sequenced in the Cancer Genome Atlas (TCGA) Project to estimate the subset of cancers (both types and fractions thereof) that fit the profile suggested for melanoma and NSCLC. An additional independent set of 613 tumors drawn from 5 cancers were analyzed for replication. An analysis of the receiver operating characteristic curves of published data on checkpoint inhibitor response in melanoma and NSCLC data estimates a cutoff of 192 NsM with 74% sensitivity and 59.3% specificity to discriminate potential clinical benefit. Across the 7,757 samples of TCGA, 16.2% displayed an NsM count that exceeded the threshold of 192. It is notable that more than 30% of bladder, colon, gastric, and endometrial cancers have NsM counts above 192, which was also confirmed in melanoma and NSCLC. Our data could inform the prioritization of tumor types (and subtypes) for possible clinical trials to investigate further indications for effective use of immune checkpoint inhibitors, particularly in adult cancers. Cancer Res; 76(13); 3767–72. ©2016 AACR.
Emodin Inhibits Breast Cancer Growth by Blocking the Tumor-Promoting Feedforward Loop between Cancer Cells and Macrophages
Authors: Iwanowycz Stephen , Wang Junfeng , Hodge Johnie , Wang Yuzhen , Yu Fang , Fan Daping 
Published: May 2016

Abstract
Macrophage infiltration correlates with severity in many types of cancer. Tumor cells recruit macrophages and educate them to adopt an M2-like phenotype through the secretion of chemokines and growth factors, such as MCP1 and CSF1. Macrophages in turn promote tumor growth through supporting angiogenesis, suppressing antitumor immunity, modulating extracellular matrix remodeling, and promoting tumor cell migration. Thus, tumor cells and macrophages interact to create a feedforward loop supporting tumor growth and metastasis. In this study, we tested the ability of emodin, a Chinese herb–derived compound, to inhibit breast cancer growth in mice and examined the underlying mechanisms. Emodin was used to treat mice bearing EO771 or 4T1 breast tumors. It was shown that emodin attenuated tumor growth by inhibiting macrophage infiltration and M2-like polarization, accompanied by increased T-cell activation and reduced angiogenesis in tumors. The tumor inhibitory effects of emodin were lost in tumor-bearing mice with macrophage depletion. Emodin inhibited IRF4, STAT6, and C/EBPβ signaling and increased inhibitory histone H3 lysine 27 tri-methylation (H3K27m3) on the promoters of M2-related genes in tumor-associated macrophages. In addition, emodin inhibited tumor cell secretion of MCP1 and CSF1, as well as expression of surface anchoring molecule Thy-1, thus suppressing macrophage migration toward and adhesion to tumor cells. These results suggest that emodin acts on both breast cancer cells and macrophages and effectively blocks the tumor-promoting feedforward loop between the two cell types, thereby inhibiting breast cancer growth and metastasis. Mol Cancer Ther; 15(8); 1931–42. ©2016 AACR.
Plumbing, philosophy and psychiatry
Authors: Rosenman Stephen 
Published: May 2016

Objectives: To briefly examine shortcomings in the foundation concepts that underlie theory and thought in contemporary psychiatry and to argue that these shortcomings mislead research and practice. Conclusions: Psychiatry stands on a complex of ideas and concepts that cannot be reduced to a satisfying or unifying underlying conceptual system or idea. The ideas and concepts have been patched together ad hoc and function until things go wrong. Growing professional dispute and public disquiet indicates that things are going wrong. I suggest that professional philosophers need to be engaged in the necessary infrastructure repairs.
Big insights from small volumes: deciphering complex leukocyte behaviors using microfluidics
Authors: Irimia Daniel , Ellett Felix 
Published: May 2016

Abstract
Inflammation is an indispensable component of the immune response, and leukocytes provide the first line of defense against infection. Although the major stereotypic leukocyte behaviors in response to infection are well known, the complexities and idiosyncrasies of these phenotypes in conditions of disease are still emerging. Novel tools are indispensable for gaining insights into leukocyte behavior, and in the past decade, microfluidic technologies have emerged as an exciting development in the field. Microfluidic devices are readily customizable, provide tight control of experimental conditions, enable high precision of ex vivo measurements of individual as well as integrated leukocyte functions, and have facilitated the discovery of novel leukocyte phenotypes. Here, we review some of the most interesting insights resulting from the application of microfluidic approaches to the study of the inflammatory response. The aim is to encourage leukocyte biologists to integrate these new tools into increasingly more sophisticated experimental designs for probing complex leukocyte functions.
Pollen morphology of rare species of Linum L. (Linaceae) from Poland
Authors: Kluza-Wieloch Magdalena , Maciejewska-Rutkowska Irmina , Wójtowicz Wanda , Wiland-Szymańska Justyna 
Published: May 2016

Abstract
The aim of the study was to describe pollen morphology and its variability of four Linum species: L. perenne subsp. extraaxillare, L. hirsutum, L. flavum and L. austriacum, all derived from Poland, but occurring in few natural sites within the country. Light and scanning electron microscopy was used and statistical analyses of quantitative pollen traits were performed. All taxa shared pollen grains which were 3-zonocolpate, isopolar, radiosymmetric, spheroidal and medium to large in size. Grains were semitectate, with the sculptural elements of the exine as gemmae or clavae. Additionally, upper parts of gemmae and clavae had a microstriate pattern. Despite great similarity among the investigated Linum species in pollen morphology, distinguishing features were determined.