bluuebunny/crossref_metadata_2025_split huggingface dataset:
The MNS glycophorin variant GP.Mur affects differential erythroid expression of Rh/RhAG transcripts
Authors: Hsu K. , Kuo M.‐S. , Yao C.‐C. , Cheng H.‐C. , Lin H.‐J. , Chan Y.‐S. , Lin M. 
Published: August 2017

BackgroundThe band 3 macrocomplex (also known as the ankyrin‐associated complex) on the red cell membrane comprises two interacting subcomplexes: a band 3/glycophorin A subcomplex, and a Rh/RhAG subcomplex. Glycophorin B (GPB) is a component of the Rh/RhAG subcomplex that is also structurally associated with glycophorin A (GPA). Expression of glycophorin B‐A‐B hybrid GP.Mur enhances band 3 expression and is associated with lower levels of Rh‐associated glycoprotein (RhAG) and Rh polypeptides. The goal of this study was to determine whether GP.Mur influenced erythroid Rh/RhAG expression at the transcript level.Materials and MethodsGP.Mur was serologically determined in healthy participants from Taitung County, Taiwan. RNA was extracted from the reticulocyte‐enriched fraction of peripheral blood, followed by reverse transcription and quantitative PCR for RhAG, RhD and RhCcEe.ResultsQuantification by real‐time PCR revealed significantly fewer RhAG and RhCcEe transcripts in the reticulocytes from subjects with homozygous GYP*Mur. Independent from GYP.Mur, both RhAG and RhD transcript levels were threefold or higher than that of RhCcEe. Also, in GYP.Mur and the control samples alike, direct quantitative associations were observed between the transcript levels of RhAG and RhD, but not between that of RhAG and RhCcEe.ConclusionErythroid RhD and RhCcEe were differentially expressed at the transcript levels, which could be related to their different degrees of interaction or sensitivity to RhAG. Further, the reduction or absence of glycophorin B in GYP.Mur erythroid cells affected transcript expressions of RhAG and RhCcEe. Thus, GPB and GP.Mur differentially influenced Rh/RhAG expressions prior to protein translation.
Prevalence of antibiotic and heavy metal resistance in Gram negative bacteria isolated from rivers in northern Pakistan
Authors: Sair Ali Tahir , Khan Zeeshan Ali 
Published: August 2017

AbstractAntibiotic and metal resistance is a global occurring phenomenon and a universal threat. The release of antibiotics and metals into the environment like natural water bodies stimulates resistant microbes that could become a reservoir for a resistant gene pool for other pathogenic bacteria. The aim of the study was to determine microbial diversity, distribution of antibiotic and metal resistance bacteria from five rivers. The resistance of 168 Gram negative isolates was tested against 10 antibiotics and five metals. The study revealed a high incidence of bacterial isolates resistant to ampicillin (44.7%), streptomycin (37.3%) and chloramphenicol (33.9%). The highest level of antibiotic resistance was detected in the River Ravi. The multiple antibiotic resistance (MAR) index of the five rivers ranged from <0.2 to 0.6. Isolates displayed tolerance to different concentrations of heavy metals. High antibiotic and metal‐resistances in samples from the Rivers Ravi and Soan suggest co‐resistance amongst the bacterial populations.
Combined Action of Human Commensal Bacteria and Amorphous Silica Nanoparticles on the Viability and Immune Responses of Dendritic Cells
Authors: Malachin Giulia , Lubian Elisa , Mancin Fabrizio , Papini Emanuele , Tavano Regina 
Published: August 2017

ABSTRACT

Dendritic cells (DCs) regulate the host-microbe balance in the gut and skin, tissues likely exposed to nanoparticles (NPs) present in drugs, food, and cosmetics. We analyzed the viability and the activation of DCs incubated with extracellular media (EMs) obtained from cultures of commensal bacteria (
Escherichia coli
,
Staphylococcus epidermidis
) or pathogenic bacteria (
Pseudomonas aeruginosa
,
Staphylococcus aureus
) in the presence of amorphous silica nanoparticles (SiO
2
NPs). EMs and NPs synergistically increased the levels of cytotoxicity and cytokine production, with different nanoparticle dose-response characteristics being found, depending on the bacterial species.
E. coli
and
S. epidermidis
EMs plus NPs at nontoxic doses stimulated the secretion of interleukin-1β (IL-1β), IL-12, IL-10, and IL-6, while
E. coli
and
S. epidermidis
EMs plus NPs at toxic doses stimulated the secretion of gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), IL-4, and IL-5. On the contrary,
S. aureus
and
P. aeruginosa
EMs induced cytokines only when they were combined with NPs at toxic concentrations. The induction of maturation markers (CD86, CD80, CD83, intercellular adhesion molecule 1, and major histocompatibility complex class II) by commensal bacteria but not by pathogenic ones was improved in the presence of noncytotoxic SiO
2
NP doses. DCs consistently supported the proliferation and differentiation of CD4
+
and CD8
+
T cells secreting IFN-γ and IL-17A. The synergistic induction of CD86 was due to nonprotein molecules present in the EMs from all bacteria tested. At variance with this finding, the synergistic induction of IL-1β was prevalently mediated by proteins in the case of
E. coli
EMs and by nonproteins in the case of
S. epidermidis
EMs. A bacterial costimulus did not act on DCs after adsorption on SiO
2
NPs but rather acted as an independent agonist. The inflammatory and immune actions of DCs stimulated by commensal bacterial agonists might be altered by the simultaneous exposure to engineered or environmental NPs.
Towards a Universal Molecular Microbiological Test
Authors: Allcock Richard J. N. , Jennison Amy V. , Warrilow David 
Published: August 2017

ABSTRACT
The standard paradigm for microbiological testing is dependent on the presentation of a patient to a clinician. Tests are then requested based on differential diagnoses using the patient's symptoms as a guide. The era of high-throughput genomic methods has the potential to replace this model for the first time with what could be referred to as “hypothesis-free testing.” This approach utilizes one of a variety of methodologies to obtain a sequence from potentially any nucleic acid in a clinical sample, without prior knowledge of its content. We discuss the advantages of such an approach and the challenges in making this a reality.
ZIC2 Is Essential for Maintenance of Latency and Is a Target of an Immediate Early Protein during Kaposi's Sarcoma-Associated Herpesvirus Lytic Reactivation
Authors: Lyu Yuanzhi , Nakano Kazushi , Davis Ryan R. , Tepper Clifford G. , Campbell Mel , Izumiya Yoshihiro 
Published: August 2017

ABSTRACT
Bivalent histone modifications are defined as repressive and activating epigenetic marks that simultaneously decorate the same genomic region. The H3K27me3 mark silences gene expression, while the H3K4me3 mark prevents the region from becoming permanently silenced and prepares the domain for activation when needed. Specific regions of Kaposi's sarcoma-associated herpesvirus (KSHV) latent episomes are poised to be activated by the KSHV replication and transcription activator (K-Rta). How KSHV episomes are prepared such that they maintain latent infection and switch to lytic replication by K-Rta remains unclear. K-Rta transactivation activity requires a protein degradation function; thus, we hypothesized that identification of cellular substrates of K-Rta may provide insight into the maintenance of KSHV latent infection and the switch to lytic replication. Here we show that a zinc finger protein, ZIC2, a key regulator for central nervous system development, is a substrate of K-Rta and is responsible for maintaining latency. K-Rta directly interacted with ZIC2 and functioned as an E3 ligase to ubiquitinate ZIC2. ZIC2 localized at immediate early and early gene cluster regions of the KSHV genome and contributed to tethering of polycomb repressive complex 2 through physical interaction, thus maintaining H3K27me3 marks at the K-Rta promoter. Accordingly, depletion of ZIC2 shifted the balance of bivalent histone modifications toward more active forms and induced KSHV reactivation in naturally infected cells. We suggest that ZIC2 turnover by K-Rta is a strategy employed by KSHV to favor the transition from latency to lytic replication.

IMPORTANCE
Posttranslational histone modifications regulate the accessibility of transcriptional factors to DNA; thus, they have profound effects on gene expression (e.g., viral reactivation). KSHV episomes are known to possess bivalent chromatin domains. How such KSHV chromatin domains are maintained to be reactivatable by K-Rta remains unclear. We found that ZIC2, a transcriptional factor essential for stem cell pluripotency, plays a role in maintaining KSHV latent infection in naturally infected cells. We found that ZIC2 degradation by K-Rta shifts bivalent histone marks to a more active configuration, leading to KSHV reactivation. ZIC2 interacts with and maintains polycomb repressor complex 2 at the K-Rta promoter. Our findings uncover (i) a mechanism utilized by KSHV to maintain latent infection, (ii) a latency-lytic cycle switch operated by K-Rta, and (iii) a molecular mechanism of ZIC2-mediated local histone modification.
Expression and Subcellular Localization of the Kaposi's Sarcoma-Associated Herpesvirus K15P Protein during Latency and Lytic Reactivation in Primary Effusion Lymphoma Cells
Authors: Smith Caitlin G. , Kharkwal Himanshu , Wilson Duncan W. 
Published: August 2017

ABSTRACT

The K15P membrane protein of Kaposi's sarcoma-associated herpesvirus (KSHV) interacts with multiple cellular signaling pathways and is thought to play key roles in KSHV-associated endothelial cell angiogenesis, regulation of B-cell receptor (BCR) signaling, and the survival, activation, and proliferation of BCR-negative primary effusion lymphoma (PEL) cells. Although full-length K15P is ∼45 kDa, numerous lower-molecular-weight forms of the protein exist as a result of differential splicing and poorly characterized posttranslational processing. K15P has been reported to localize to numerous subcellular organelles in heterologous expression studies, but there are limited data concerning the sorting of K15P in KSHV-infected cells. The relationships between the various molecular weight forms of K15P, their subcellular distribution, and how these may differ in latent and lytic KSHV infections are poorly understood. Here we report that a cDNA encoding a full-length, ∼45-kDa K15P reporter protein is expressed as an ∼23- to 24-kDa species that colocalizes with the
trans
-Golgi network (TGN) marker TGN46 in KSHV-infected PEL cells. Following lytic reactivation by sodium butyrate, the levels of the ∼23- to 24-kDa protein diminish, and the full-length, ∼45-kDa K15P protein accumulates. This is accompanied by apparent fragmentation of the TGN and redistribution of K15P to a dispersed peripheral location. Similar results were seen when lytic reactivation was stimulated by the KSHV protein replication and transcription activator (RTA) and during spontaneous reactivation. We speculate that expression of different molecular weight forms of K15P in distinct cellular locations reflects the alternative demands placed upon the protein in the latent and lytic phases.

IMPORTANCE
The K15P protein of Kaposi's sarcoma-associated herpesvirus (KSHV) is thought to play key roles in disease, including KSHV-associated angiogenesis and the survival and growth of primary effusion lymphoma (PEL) cells. The protein exists in multiple molecular weight forms, and its intracellular trafficking is poorly understood. Here we demonstrate that the molecular weight form of a reporter K15P molecule and its intracellular distribution change when KSHV switches from its latent (quiescent) phase to the lytic, infectious state. We speculate that expression of different molecular weight forms of K15P in distinct cellular locations reflects the alternative demands placed upon the protein in the viral latent and lytic stages.
Human Papillomavirus 16 (HPV-16), HPV-18, and HPV-31 E6 Override the Normal Phosphoregulation of E6AP Enzymatic Activity
Authors: Thatte Jayashree , Banks Lawrence 
Published: August 2017

ABSTRACT
The human papillomavirus (HPV) E6 oncoproteins recruit the cellular ubiquitin ligase E6AP/UBE3A to target cellular substrates for proteasome-mediated degradation, and one consequence of this activity is the E6 stimulation of E6AP autoubiquitination and degradation. Recent studies identified an autism-linked mutation within E6AP at T485, which was identified as a protein kinase A phosphoacceptor site and which could directly regulate E6AP ubiquitin ligase activity. In this study, we have analyzed how T485-mediated regulation of E6AP might affect E6 targeting of some of its known substrates. We show that modulation of T485 has no effect on the ability of E6 to direct either p53 or Dlg for degradation. Furthermore, T485 regulation has no effect on HPV-16 or HPV-31 E6-induced autodegradation of E6AP but does affect HPV-18 E6-induced autodegradation of E6AP. In cells derived from cervical cancers, we find low levels of both phosphorylated and nonphosphorylated E6AP in the nucleus. However, ablation of E6 results in a dramatic accumulation of phospho-E6AP in the cytoplasm, whereas nonphosphorylated E6AP accumulates primarily in the nucleus. Interestingly, E6AP phosphorylation at T485 confers association with 14-3-3 proteins, and this interaction seems to be important, in part, for the ability of E6 to recruit phospho-E6AP into the nucleus. These results demonstrate that HPV E6 overrides the normal phosphoregulation of E6AP, both in terms of its enzymatic activity and its subcellular distribution.

IMPORTANCE
Recent reports demonstrate the importance of phosphoregulation of E6AP for its normal enzymatic activity. Here, we show that HPV E6 is capable of overriding this regulation and can promote degradation of p53 and Dlg regardless of the phosphorylation status of E6AP. Furthermore, E6 interaction with E6AP also significantly alters how E6AP is subject to autodegradation and suggests that this is not a simple stimulation of an already-existing activity but rather a redirection of E6AP activity toward itself. Furthermore, E6-mediated regulation of the subcellular distribution of phospho-E6AP appears to be dependent, in part, upon the 14-3-3 family of proteins.
Acute hypoxia in a simulated high-altitude airdrop scenario due to oxygen system failure
Authors: Ottestad William , Hansen Tor Are , Pradhan Gaurav , Stepanek Jan , Høiseth Lars Øivind , Kåsin Jan Ivar 
Published: August 2017

High-Altitude High Opening (HAHO) is a military operational procedure in which parachute jumps are performed at high altitude requiring supplemental oxygen, putting personnel at risk of acute hypoxia in the event of oxygen equipment failure. This study was initiated by the Norwegian Army to evaluate potential outcomes during failure of oxygen supply, and to explore physiology during acute severe hypobaric hypoxia. A simulated HAHO without supplemental oxygen was carried out in a hypobaric chamber with decompression to 30,000 ft (9,144 m) and then recompression to ground level with a descent rate of 1,000 ft/min (305 m/min). Nine subjects were studied. Repeated arterial blood gas samples were drawn throughout the entire hypoxic exposure. Additionally, pulse oximetry, cerebral oximetry, and hemodynamic variables were monitored. Desaturation evolved rapidly and the arterial oxygen tensions are among the lowest ever reported in volunteers during acute hypoxia. PaO2 decreased from baseline 18.4 (17.3–19.1) kPa, 138.0 (133.5–143.3) mmHg, to a minimum value of 3.3 (2.9–3.7) kPa, 24.8 (21.6–27.8) mmHg, after 180 (60–210) s, [median (range)], N = 9. Hyperventilation with ensuing hypocapnia was associated with both increased arterial oxygen saturation and cerebral oximetry values, and potentially improved tolerance to severe hypoxia. One subject had a sharp drop in heart rate and cardiac index and lost consciousness 4 min into the hypoxic exposure. A simulated high-altitude airdrop scenario without supplemental oxygen results in extreme hypoxemia and may result in loss of consciousness in some individuals. NEW & NOTEWORTHY This is the first study to investigate physiology and clinical outcome of oxygen system failure in a simulated HAHO scenario. The acquired knowledge is of great value to make valid risk-benefit analyses during HAHO training or operations. The arterial oxygen tensions reported in this hypobaric chamber study are among the lowest ever reported during acute hypoxia.
Targeting Phosphatidylinositol 3-Kinase Signaling Pathway for Therapeutic Enhancement of Vascular-Targeted Photodynamic Therapy
Authors: Kraus Daniel , Palasuberniam Pratheeba , Chen Bin 
Published: August 2017

Abstract
Vascular-targeted photodynamic therapy (PDT) selectively disrupts vascular function by inducing oxidative damages to the vasculature, particularly endothelial cells. Although effective tumor eradication and excellent safety profile are well demonstrated in both preclinical and clinical studies, incomplete vascular shutdown and angiogenesis are known to cause tumor recurrence after vascular-targeted PDT. We have explored therapeutic enhancement of vascular-targeted PDT with PI3K signaling pathway inhibitors because the activation of PI3K pathway was involved in promoting endothelial cell survival and proliferation after PDT. Here, three clinically relevant small-molecule inhibitors (BYL719, BKM120, and BEZ235) of the PI3K pathway were evaluated in combination with verteporfin-PDT. Although all three inhibitors were able to synergistically enhance PDT response in endothelial cells, PDT combined with dual PI3K/mTOR inhibitor BEZ235 exhibited the strongest synergism, followed in order by combinations with pan-PI3K inhibitor BKM120 and p110α isoform-selective inhibitor BYL719. Combination treatments of PDT and BEZ235 exhibited a cooperative inhibition of antiapoptotic Bcl-2 family protein Mcl-1 and induced more cell apoptosis than each treatment alone. In addition to increasing treatment lethality, BEZ235 combined with PDT effectively inhibited PI3K pathway activation and consequent endothelial cell proliferation after PDT alone, leading to a sustained growth inhibition. In the PC-3 prostate tumor model, combination treatments improved treatment outcomes by turning a temporary tumor regrowth delay induced by PDT alone to a more long-lasting treatment response. Our study strongly supports the combination of vascular-targeted PDT and PI3K pathway inhibitors, particularly mTOR inhibitors, for therapeutic enhancement. Mol Cancer Ther; 16(11); 2422–31. ©2017 AACR.
Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers
Authors: Goodman Aaron M. , Kato Shumei , Bazhenova Lyudmila , Patel Sandip P. , Frampton Garrett M. , Miller Vincent , Stephens Philip J. , Daniels Gregory A. , Kurzrock Razelle 
Published: August 2017

Abstract
Immunotherapy induces durable responses in a subset of patients with cancer. High tumor mutational burden (TMB) may be a response biomarker for PD-1/PD-L1 blockade in tumors such as melanoma and non–small cell lung cancer (NSCLC). Our aim was to examine the relationship between TMB and outcome in diverse cancers treated with various immunotherapies. We reviewed data on 1,638 patients who had undergone comprehensive genomic profiling and had TMB assessment. Immunotherapy-treated patients (N = 151) were analyzed for response rate (RR), progression-free survival (PFS), and overall survival (OS). Higher TMB was independently associated with better outcome parameters (multivariable analysis). The RR for patients with high (≥20 mutations/mb) versus low to intermediate TMB was 22/38 (58%) versus 23/113 (20%; P = 0.0001); median PFS, 12.8 months vs. 3.3 months (P ≤ 0.0001); median OS, not reached versus 16.3 months (P = 0.0036). Results were similar when anti-PD-1/PD-L1 monotherapy was analyzed (N = 102 patients), with a linear correlation between higher TMB and favorable outcome parameters; the median TMB for responders versus nonresponders treated with anti-PD-1/PD-L1 monotherapy was 18.0 versus 5.0 mutations/mb (P &lt; 0.0001). Interestingly, anti-CTLA4/anti-PD-1/PD-L1 combinations versus anti-PD-1/PD-L1 monotherapy was selected as a factor independent of TMB for predicting better RR (77% vs. 21%; P = 0.004) and PFS (P = 0.024). Higher TMB predicts favorable outcome to PD-1/PD-L1 blockade across diverse tumors. Benefit from dual checkpoint blockade did not show a similarly strong dependence on TMB. Mol Cancer Ther; 16(11); 2598–608. ©2017 AACR.
A Brain Phenotype for Stressor‐Evoked Blood Pressure Reactivity
Authors: Gianaros Peter J. , Sheu Lei K. , Uyar Fatma , Koushik Jayanth , Jennings J. Richard , Wager Tor D. , Singh Aarti , Verstynen Timothy D. 
Published: August 2017

Background

Individuals who exhibit large‐magnitude blood pressure (
BP
) reactions to acute psychological stressors are at risk for hypertension and premature death by cardiovascular disease. This study tested whether a multivariate pattern of stressor‐evoked brain activity could reliably predict individual differences in
BP
reactivity, providing novel evidence for a candidate neurophysiological source of stress‐related cardiovascular risk.

Methods and Results

Community‐dwelling adults (N=310; 30–51 years; 153 women) underwent functional magnetic resonance imaging with concurrent
BP
monitoring while completing a standardized battery of stressor tasks. Across individuals, the battery evoked an increase systolic and diastolic
BP
relative to a nonstressor baseline period (M ∆systolic BP/∆diastolic BP=4.3/1.9 mm Hg [95% confidence interval=3.7–5.0/1.4–2.3 mm Hg]). Using cross‐validation and machine learning approaches, including dimensionality reduction and linear shrinkage models, a multivariate pattern of stressor‐evoked functional magnetic resonance imaging activity was identified in a training subsample (N=206). This multivariate pattern reliably predicted both systolic BP (
r
=0.32;
P
<0.005) and diastolic BP (
r
=0.25;
P
<0.01) reactivity in an independent subsample used for testing and replication (N=104). Brain areas encompassed by the pattern that were strongly predictive included those implicated in psychological stressor processing and cardiovascular responding through autonomic pathways, including the medial prefrontal cortex, anterior cingulate cortex, and insula.

Conclusions

A novel multivariate pattern of stressor‐evoked brain activity may comprise a phenotype that partly accounts for individual differences in
BP
reactivity, a stress‐related cardiovascular risk factor.
Local Characteristics of the Nocturnal Boundary Layer in Response to External Pressure Forcing
Authors: van der Linden Steven J. A. , Baas Peter , Antoon van Hooft J. , van Hooijdonk Ivo G. S. , Bosveld Fred C. , van de Wiel Bas J. H. 
Published: August 2017

AbstractGeostrophic wind speed data, derived from pressure observations, are used in combination with tower measurements to investigate the nocturnal stable boundary layer at Cabauw, the Netherlands. Since the geostrophic wind speed is not directly influenced by local nocturnal stability, it may be regarded as an external forcing parameter of the nocturnal stable boundary layer. This is in contrast to local parameters such as in situ wind speed, the Monin–Obukhov stability parameter (z/L), or the local Richardson number. To characterize the stable boundary layer, ensemble averages of clear-sky nights with similar geostrophic wind speeds are formed. In this manner, the mean dynamical behavior of near-surface turbulent characteristics and composite profiles of wind and temperature are systematically investigated. The classification is found to result in a gradual ordering of the diagnosed variables in terms of the geostrophic wind speed. In an ensemble sense the transition from the weakly stable to very stable boundary layer is more gradual than expected. Interestingly, for very weak geostrophic winds, turbulent activity is found to be negligibly small while the resulting boundary cooling stays finite. Realistic numerical simulations for those cases should therefore have a comprehensive description of other thermodynamic processes such as soil heat conduction and radiative transfer.