bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neutralization of Diverse Human Cytomegalovirus Strains Conferred by Antibodies Targeting Viral gH/gL/pUL128-131 Pentameric Complex
Authors: Ha Sha , Li Fengsheng , Troutman Matthew C. , Freed Daniel C. , Tang Aimin , Loughney John W. , Wang Dai , Wang I-Ming , Vlasak Josef , Nickle David C. , Rustandi Richard R. , Hamm Melissa , DePhillips Pete A. , Zhang Ningyan , McLellan Jason S. , Zhu Hua , Adler Stuart P. , McVoy Michael A. , An Zhiqiang , Fu Tong-Ming 
Published: January 2017

ABSTRACT
Human cytomegalovirus (HCMV) is the leading cause of congenital viral infection, and developing a prophylactic vaccine is of high priority to public health. We recently reported a replication-defective human cytomegalovirus with restored pentameric complex glycoprotein H (gH)/gL/pUL128-131 for prevention of congenital HCMV infection. While the quantity of vaccine-induced antibody responses can be measured in a viral neutralization assay, assessing the quality of such responses, including the ability of vaccine-induced antibodies to cross-neutralize the field strains of HCMV, remains a challenge. In this study, with a panel of neutralizing antibodies from three healthy human donors with natural HCMV infection or a vaccinated animal, we mapped eight sites on the dominant virus-neutralizing antigen—the pentameric complex of glycoprotein H (gH), gL, and pUL128, pUL130, and pUL131. By evaluating the site-specific antibodies in vaccine immune sera, we demonstrated that vaccination elicited functional antiviral antibodies to multiple neutralizing sites in rhesus macaques, with quality attributes comparable to those of CMV hyperimmune globulin. Furthermore, these immune sera showed antiviral activities against a panel of genetically distinct HCMV clinical isolates. These results highlighted the importance of understanding the quality of vaccine-induced antibody responses, which includes not only the neutralizing potency in key cell types but also the ability to protect against the genetically diverse field strains.

IMPORTANCE
HCMV is the leading cause of congenital viral infection, and development of a preventive vaccine is a high public health priority. To understand the strain coverage of vaccine-induced immune responses in comparison with natural immunity, we used a panel of broadly neutralizing antibodies to identify the immunogenic sites of a dominant viral antigen—the pentameric complex. We further demonstrated that following vaccination of a replication-defective virus with the restored pentameric complex, rhesus macaques can develop broadly neutralizing antibodies targeting multiple immunogenic sites of the pentameric complex. Such analyses of site-specific antibody responses are imperative to our assessment of the quality of vaccine-induced immunity in clinical studies.
Klebsiella Phage ΦK64-1 Encodes Multiple Depolymerases for Multiple Host Capsular Types
Authors: Pan Yi-Jiun , Lin Tzu-Lung , Chen Ching-Ching , Tsai Yun-Ting , Cheng Yi-Hsiang , Chen Yi-Yin , Hsieh Pei-Fang , Lin Yi-Tsung , Wang Jin-Town 
Published: January 2017

ABSTRACT

The genome of the multihost bacteriophage ΦK64-1, capable of infecting
Klebsiella
capsular types K1, K11, K21, K25, K30, K35, K64, and K69, as well as new capsular types KN4 and KN5, was analyzed and revealed that 11 genes (
S1-1
,
S1-2
,
S1-3
,
S2-1
,
S2-2
,
S2-3
,
S2-4
,
S2-5
,
S2-6
,
S2-7
, and
S2-8
) encode proteins with amino acid sequence similarity to tail fibers/spikes or lyases.
S2-5
previously was shown to encode a K64 capsule depolymerase (K64dep). Specific capsule-degrading activities of an additional eight putative capsule depolymerases (S2-4 against K1, S1-1 against K11, S1-3 against K21, S2-2 against K25, S2-6 against K30/K69, S2-3 against K35, S1-2 against KN4, and S2-1 against KN5) was demonstrated by expression and purification of the recombinant proteins. Consistent with the capsular type-specific depolymerization activity of these gene products, phage mutants of
S1-2
,
S2-2
,
S2-3
, or
S2-6
lost infectivity for KN4, K25, K35, or K30/K69, respectively, indicating that capsule depolymerase is crucial for infecting specific hosts. In conclusion, we identified nine functional capsule depolymerase-encoding genes in a bacteriophage and correlated activities of the gene products to all ten hosts of this phage, providing an example of type-specific host infection mechanisms in a multihost bacteriophage.

IMPORTANCE
We currently identified eight novel capsule depolymerases in a multihost
Klebsiella
bacteriophage and correlated the activities of the gene products to all hosts of this phage, providing an example of carriage of multiple depolymerases in a phage with a wide capsular type host spectrum. Moreover, we also established a recombineering system for modification of
Klebsiella
bacteriophage genomes and demonstrated the importance of capsule depolymerase for infecting specific hosts. Based on the powerful tool for modification of phage genome, further studies can be conducted to improve the understanding of mechanistic details of
Klebsiella
phage infection. Furthermore, the newly identified capsule depolymerases will be of great value for applications in capsular typing.
HIV Controllers Exhibit Enhanced Frequencies of Major Histocompatibility Complex Class II Tetramer+Gag-Specific CD4+T Cells in Chronic Clade C HIV-1 Infection
Authors: Laher Faatima , Ranasinghe Srinika , Porichis Filippos , Mewalal Nikoshia , Pretorius Karyn , Ismail Nasreen , Buus Søren , Stryhn Anette , Carrington Mary , Walker Bruce D. , Ndung'u Thumbi , Ndhlovu Zaza M. 
Published: January 2017

ABSTRACTImmune control of viral infections is heavily dependent on helper CD4+T cell function. However, the understanding of the contribution of HIV-specific CD4+T cell responses to immune protection against HIV-1, particularly in clade C infection, remains incomplete. Recently, major histocompatibility complex (MHC) class II tetramers have emerged as a powerful tool for interrogating antigen-specific CD4+T cells without relying on effector functions. Here, we defined the MHC class II alleles for immunodominant Gag CD4+T cell epitopes in clade C virus infection, constructed MHC class II tetramers, and then used these to define the magnitude, function, and relation to the viral load of HIV-specific CD4+T cell responses in a cohort of untreated HIV clade C-infected persons. We observed significantly higher frequencies of MHC class II tetramer-positive CD4+T cells in HIV controllers than progressors (P= 0.0001), and these expanded Gag-specific CD4+T cells in HIV controllers showed higher levels of expression of the cytolytic proteins granzymes A and B. Importantly, targeting of the immunodominant Gag41 peptide in the context of HLA class II DRB1*1101 was associated with HIV control (r= −0.5,P= 0.02). These data identify an association between HIV-specific CD4+T cell targeting of immunodominant Gag epitopes and immune control, particularly the contribution of a single class II MHC-peptide complex to the immune response against HIV-1 infection. Furthermore, these results highlight the advantage of the use of class II tetramers in evaluating HIV-specific CD4+T cell responses in natural infections.IMPORTANCEIncreasing evidence suggests that virus-specific CD4+T cells contribute to the immune-mediated control of clade B HIV-1 infection, yet there remains a relative paucity of data regarding the role of HIV-specific CD4+T cells in shaping adaptive immune responses in individuals infected with clade C, which is responsible for the majority of HIV infections worldwide. Understanding the contribution of HIV-specific CD4+T cell responses in clade C infection is particularly important for developing vaccines that would be efficacious in sub-Saharan Africa, where clade C infection is dominant. Here, we employed MHC class II tetramers designed to immunodominant Gag epitopes and used them to characterize CD4+T cell responses in HIV-1 clade C infection. Our results demonstrate an association between the frequency of HIV-specific CD4+T cell responses targeting an immunodominant DRB1*11-Gag41 complex and HIV control, highlighting the important contribution of a single class II MHC-peptide complex to the immune response against HIV-1 infections.
Characterizing HIV-1 Splicing by Using Next-Generation Sequencing
Authors: Emery Ann , Zhou Shuntai , Pollom Elizabeth , Swanstrom Ronald 
Published: January 2017

ABSTRACT

Full-length human immunodeficiency virus type 1 (HIV-1) RNA serves as the genome or as an mRNA, or this RNA undergoes splicing using four donors and 10 acceptors to create over 50 physiologically relevant transcripts in two size classes (1.8 kb and 4 kb). We developed an assay using Primer ID-tagged deep sequencing to quantify HIV-1 splicing. Using the lab strain NL4-3, we found that A5 (
env
/
nef
) is the most commonly used acceptor (about 50%) and A3 (
tat
) the least used (about 3%). Two small exons are made when a splice to acceptor A1 or A2 is followed by activation of donor D2 or D3, and the high-level use of D2 and D3 dramatically reduces the amount of
vif
and
vpr
transcripts. We observed distinct patterns of temperature sensitivity of splicing to acceptors A1 and A2. In addition, disruption of a conserved structure proximal to A1 caused a 10-fold reduction in all transcripts that utilized A1. Analysis of a panel of subtype B transmitted/founder viruses showed that splicing patterns are conserved, but with surprising variability of usage. A subtype C isolate was similar, while a simian immunodeficiency virus (SIV) isolate showed significant differences. We also observed transsplicing from a downstream donor on one transcript to an upstream acceptor on a different transcript, which we detected in 0.3% of 1.8-kb RNA reads. There were several examples of splicing suppression when the
env
intron was retained in the 4-kb size class. These results demonstrate the utility of this assay and identify new examples of HIV-1 splicing regulation.

IMPORTANCE
During HIV-1 replication, over 50 conserved spliced RNA variants are generated. The splicing assay described here uses new developments in deep-sequencing technology combined with Primer ID-tagged cDNA primers to efficiently quantify HIV-1 splicing at a depth that allows even low-frequency splice variants to be monitored. We have used this assay to examine several features of HIV-1 splicing and to identify new examples of different mechanisms of regulation of these splicing patterns. This splicing assay can be used to explore in detail how HIV-1 splicing is regulated and, with moderate throughput, could be used to screen for structural elements, small molecules, and host factors that alter these relatively conserved splicing patterns.
The Role and Function of Fcγ Receptors on Myeloid Cells
Authors: Bournazos Stylianos , Wang Taia T. , Ravetch Jeffrey V. 
Published: January 2017

ABSTRACTA key determinant for the survival of organisms is their capacity to recognize and respond efficiently to foreign antigens. This is largely accomplished by the orchestrated activity of the innate and adaptive branches of the immune system. Antibodies are specifically generated in response to foreign antigens, facilitating thereby the specific recognition of antigens of almost infinite diversity. Receptors specific for the Fc domain of antibodies, Fc receptors, are expressed on the surface of the various myeloid leukocyte populations and mediate the binding and recognition of antibodies by innate leukocytes. By directly linking the innate and the adaptive components of immunity, Fc receptors play a central role in host defense and the maintenance of tissue homeostasis through the induction of diverse proinflammatory, anti-inflammatory, and immunomodulatory processes that are initiated upon engagement by the Fc domain. In this chapter, we discuss the mechanisms that regulate Fc domain binding to the various types of Fc receptors and provide an overview of the astonishing diversity of effector functions that are mediated through Fc-FcR interactions on myeloid cells. Lastly, we discuss the impact of FcR-mediated interactions in the context of IgG-mediated inflammation, autoimmunity, susceptibility to infection, and responsiveness to antibody-based therapeutics.
Regulation of Immunity to Tuberculosis
Authors: Brighenti Susanna , Ordway Diane J. 
Published: January 2017

ABSTRACTImmunity againstMycobacterium tuberculosisrequires a balance between adaptive immune responses to constrain bacterial replication and the prevention of potentially damaging immune activation. Regulatory T (Treg) cells express the transcription factor Foxp3+ and constitute an essential counterbalance of inflammatory Th1 responses and are required to maintain immune homeostasis. The first reports describing the presence of Foxp3-expressing CD4+ Treg cells in tuberculosis (TB) emerged in 2006. Different Treg cell subsets, most likely specialized for different tissues and microenvironments, have been shown to expand in both human TB and animal models of TB. Recently, additional functional roles for Treg cells have been demonstrated during different stages and spectrums of TB disease. Foxp3+ regulatory cells can quickly expand during early infection and impede the onset of cellular immunity and persist during chronic TB infection. Increased frequencies of Treg cells have been associated with a detrimental outcome of active TB, and may be dependent on theM. tuberculosisstrain, animal model, local environment, and the stage of infection. Some investigations also suggest that Treg cells are required together with effector T cell responses to obtain reduced pathology and sterilizing immunity. In this review, we will first provide an overview of the regulatory cells and mechanisms that control immune homeostasis. Then, we will review what is known about the phenotype and function of Treg cells from studies in human TB and experimental animal models of TB. We will discuss the potential role of Treg cells in the progression of TB disease and the relevance of this knowledge for future efforts to prevent, modulate, and treat TB.
The Minimal Unit of Infection:Mycobacterium tuberculosisin the Macrophage
Authors: VanderVen Brian C. , Huang Lu , Rohde Kyle H. , Russell David G. 
Published: January 2017

ABSTRACTThe interaction betweenMycobacterium tuberculosisand its host cell is highly complex and extremely intimate. Were it not for the disease, one might regard this interaction at the cellular level as an almost symbiotic one. The metabolic activity and physiology of both cells are shaped by this coexistence. We believe that where this appreciation has greatest significance is in the field of drug discovery. Evolution rewards efficiency, and recent data from many groups discussed in this review indicate thatM. tuberculosishas evolved to utilize the environmental cues within its host to control large genetic programs or regulons. But these regulons may represent chinks in the bacterium’s armor because they include off-target effects, such as the constraint of the metabolic plasticity ofM. tuberculosis. A prime example is how the presence of cholesterol within the host cell appears to limit the ability ofM. tuberculosisto fully utilize or assimilate other carbon sources. And that is the reason for the title of this review. We believe firmly that, to understand the physiology ofM. tuberculosisand to identify new drug targets, it is imperative that the bacterium be interrogated within the context of its host cell. The constraints induced by the environmental cues present within the host cell need to be preserved and exploited. TheM. tuberculosis-infected macrophage truly is the “minimal unit of infection.”
Tuberculosis and Pregnancy—Maternal, Fetal, and Neonatal Considerations
Authors: Gould Jane M. , Aronoff Stephen C. 
Published: January 2017

ABSTRACT
The issue of tuberculosis during pregnancy is not simply a historical inquiry but rather an increasingly familiar clinical problem facing industrial nations as well as the developing countries of the world. This review focuses on the maternal aspects of tuberculous infection, as well as transmission to the fetus and newborn.
Bromodomains in Protozoan Parasites: Evolution, Function, and Opportunities for Drug Development
Authors: Jeffers Victoria , Yang Chunlin , Huang Sherri , Sullivan William J. 
Published: January 2017

SUMMARY

Parasitic infections remain one of the most pressing global health concerns of our day, affecting billions of people and producing unsustainable economic burdens. The rise of drug-resistant parasites has created an urgent need to study their biology in hopes of uncovering new potential drug targets. It has been established that disrupting gene expression by interfering with lysine acetylation is detrimental to survival of apicomplexan (
Toxoplasma gondii
and
Plasmodium
spp.) and kinetoplastid (
Leishmania
spp. and
Trypanosoma
spp.) parasites. As “readers” of lysine acetylation, bromodomain proteins have emerged as key gene expression regulators and a promising new class of drug target. Here we review recent studies that demonstrate the essential roles played by bromodomain-containing proteins in parasite viability, invasion, and stage switching and present work showing the efficacy of bromodomain inhibitors as novel antiparasitic agents. In addition, we performed a phylogenetic analysis of bromodomain proteins in representative pathogens, some of which possess unique features that may be specific to parasite processes and useful in future drug development.
Appropriateness of the metabolic equivalent (MET) as an estimate of exercise intensity for post-myocardial infarction patients
Authors: Woolf-May Kate , Meadows Steve 
Published: January 2017

AimsTo explore: (1) whether during exercise metabolic equivalents (METs) appropriately indicate the intensity and/or metabolic cost for post-myocardial infarction (MI) males and (2) whether post-exercise VO2parameters provide insight into the intensity and/or metabolic cost of the prior exercise.Methods15 male phase-IV post-MIs (64.4±6.5 years) and 16 apparently healthy males (63.0±6.4 years) participated. Participants performed a graded cycle ergometer test (CET) of 50, 75 and 100 W, followed by 10 min active recovery (at 50 W) and 22 min seated recovery. Participants’ heart rate (HR, bpm), expired air parameters and ratings of perceived exertion (exercise only) were measured.ResultsGeneral linear model analysis showed throughout significantly lower HR values in post-MI participants that were related to β-blocker medication (F(2,5)=18.47, p<0.01), with significantly higher VCO2/VO2(F(2,5)=11.25, p<0.001) and gross kcals/LO2/min (F(2,5)=11.25, p<0.001). Analysis comparing lines of regression showed, during the CET: post-MI participants worked at higher percentage of their anaerobic threshold (%AT)/MET than controls (F(2,90)=18.98, p<0.001), as well as during active recovery (100–50 W) (F(2,56)=20.81, p<0.001); during seated recovery: GLM analysis showed significantly higher values of VCO2/VO2for post-MI participants compared with controls (F(2,3)=21.48, p=0.001) as well as gross kcals/LO2/min (F(2,3)=21.48, p=0.001).ConclusionSince METs take no consideration of any anaerobic component, they failed to reflect the significantly greater anaerobic contribution during exercise per MET for phase-IV post-MI patients. Given the anaerobic component will be greater for those with more severe forms of cardiac disease, current METs should be used with caution when determining exercise intensity in any patient with cardiac disease.
Diagnoses of sexual abuse and their common registered comorbidities in the total population of Stockholm
Authors: Rajan Gita , Ljunggren Gunnar , Wändell Per , Wahlström Lars , Svedin Carl-Göran , Carlsson Axel C 
Published: January 2017

BackgroundPrior research based on self-reports has proven sexual abuse to be a risk factor for pain and psychiatric disorders. However, less is known about how this is reflected within the healthcare system. The aim of this study was to study the 2-year prevalence of diagnosis of sexual abuse and concomitant conditions.MethodsUsing data from VAL, the study population included all living persons in Stockholm County, Sweden, between 1 January 2008 and 31 December 2014 (N=2 549 496). Diagnoses of sexual abuse were identified during 2013–2014, with information on the concomitant conditions somatic pain, depression, anxiety, psychotic disorders and bipolar disorders, stress disorders and alcohol and substance abuse. All diagnoses were prospectively registered. Age and neighbourhood socioeconomic status-adjusted ORs with 95% CIs for individuals with a diagnosis of sexual abuse, using individuals without sexual abuse as referents, were calculated.ResultsGirls at the ages 13–17 years had the highest 2-year prevalence (0.69%) of sexual abuse followed by girls 5–12 years (0.11%), and girls 0–4 years (0.04%). For women 45 years and older the 2-year prevalence rates were substantially lower (0.008–0.004%). The highest 2-year prevalence of sexual abuse in men was seen in boys 5–12 (0.03%) years. The total 2-year prevalence of diagnoses of sexual abuse among the population in the material was 0.04%. The highest ORs of comorbidities for girls (ages 0–17 years) with sexual abuse versus those without sexual abuse were: Stress disorder; 15.7 (13.1 to 18.9), drug abuse; 10.0 (7.7 to 13.0), and alcohol abuse; 9.7(7.8 to 12.0). For boys (ages 0–17 years), the highest ORs of comorbidities were: Stress disorder 12.4 (6.0 to 25.7), anxiety disorders; 5.5 (2.6 to 11.5), and alcohol abuse; 3.9 (1.4 to 11.3). The highest ORs of comorbidities for women (18–) with sexual abuse versus those without sexual abuse were: alcohol abuse; 19.3 (12.6 to 29.6), drug abuse; 16.7 (10.7 to 26.1) and psychotic disorders; 15.3 (8.0 to 29.4). For men (18–) the highest ORs of comorbidities were: alcohol abuse; 25.8 (15.2 to 43.9), anxiety disorders; 14.3 (8.5 to 24.2) stress disorder; 12.9 (7.5 to 22.1) and drug abuse; 12.9 (6.9 to 24.1).ConclusionsDiagnoses of drug and alcohol abuse, psychotic, bipolar, stress anxiety disorders, depression and somatic pain are more common among individuals with a diagnosis of sexual abuse than among individuals without a diagnosis of sexual abuse.