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1.  An 8-Year Longitudinal Study of Overreaching in 114 Elite Female Chinese Wrestlers 
Journal of Athletic Training  2015;50(2):217-223.
Context:
Successful training involves structured overload but must avoid the combination of excessive overload and inadequate recovery.
Objective:
The aim of this study was to determine the incidence of functional overreaching (FOR), nonfunctional overreaching (NFOR), and overtraining syndrome in elite female wrestlers during their normal training and competition schedules and to explore the utility of blood markers for the early detection of overreaching. Classification of FOR, NFOR, and overtraining syndrome was based on the European Congress of Sports Medicine position statement.
Design:
Case series.
Setting:
China Institute of Sport Science.
Patients or Other Participants:
Over an 8-year period, 114 wrestlers from the women's Asian wrestling team were monitored to help identify if and when they experienced FOR, NFOR, or overtraining syndrome.
Main Outcome Measure(s):
Creatine kinase, hemoglobin, testosterone, and cortisol were measured throughout the period to identify whether wrestlers were outside the reference intervals (constructed from normal recovery data) during periods of overreaching and not overreaching.
Results:
Among the 114 athletes, there were 13 (3.6%) instances of FOR, 23 (6.4%) instances of NFOR, and 2 (0.6%) instances of overtraining syndrome. The diagnostic sensitivity for FOR was 38%, 15%, 45%, and 18% for creatine kinase, hemoglobin, testosterone, and cortisol, respectively. The diagnostic sensitivity for NFOR was 29%, 33%, 26%, and 35% for creatine kinase, hemoglobin, testosterone, and cortisol, respectively. Specificity was 79%, 88%, 90%, and 82% for creatine kinase, hemoglobin, testosterone, and cortisol, respectively. Post hoc analysis showed no mean differences in creatine kinase (F = 0.5, P = .47), hemoglobin (F = 3.8, P = .052), testosterone (F = 0.2, P = .62), or cortisol (F = 0.04, P = .85) between monitoring periods when wrestlers were and were not diagnosed with FOR and NFOR.
Conclusions:
Coaches and sports scientists should not use single blood variables as markers of overreaching in elite female wrestlers.
doi:10.4085/1062-6050-49.3.57
PMCID: PMC4495439  PMID: 25329348
blood markers; fatigue; overtraining; underperformance
2.  Serratus Anterior and Lower Trapezius Muscle Activities During Multi-Joint Isotonic Scapular Exercises and Isometric Contractions 
Journal of Athletic Training  2015;50(2):199-210.
Context:
Proper scapular function during humeral elevation, such as upward rotation, external rotation, and posterior tilting of the scapula, is necessary to prevent shoulder injury. However, the appropriate intensity of rehabilitation exercise for the periscapular muscles has yet to be clarified.
Objective:
To identify the serratus anterior, lower trapezius, infraspinatus, and posterior deltoid muscle activities during 2 free-motion exercises using 3 intensities and to compare these muscle activities with isometric contractions during quadruped shoulder flexion and external rotation and abduction of the glenohumeral joint.
Design:
Cross-sectional study.
Setting:
Health Science Laboratory.
Patients or Other Participants:
A total of 16 uninjured, healthy, active, male college students (age = 19.5 ± 1.2 years, height = 173.1 ± 6.5 cm, weight = 68.8 ± 6.6 kg).
Main Outcome Measure(s):
Mean electromyographic activity normalized by the maximal voluntary isometric contraction was analyzed across 3 intensities and 5 exercises. Intraclass correlation coefficients were calculated for electromyographic activity of the 4 muscles in each free-motion exercise.
Results:
Significant interactions in electromyographic activity were observed between intensities and exercises (P < .05). The quadruped shoulder-flexion exercise activated all 4 muscles compared with other exercises. Also, the modified robbery free-motion exercise activated the serratus anterior, lower trapezius, and infraspinatus compared with the lawn-mower free-motion exercise. However, neither exercise showed a difference in posterior deltoid electromyographic activity.
Conclusions:
Three intensities exposed the nature of the periscapular muscle activities across the different exercises. The free-motion exercise in periscapular muscle rehabilitation may not modify serratus anterior, lower trapezius, and infraspinatus muscle activities unless knee-joint extension is limited.
doi:10.4085/1062-6050-49.3.80
PMCID: PMC4495440  PMID: 25689561
upper extremity; shoulder joint; overhead performance
3.  Plasma and Electrolyte Changes in Exercising Humans After Ingestion of Multiple Boluses of Pickle Juice 
Journal of Athletic Training  2015;50(2):141-146.
Context:
Twenty-five percent of athletic trainers administer pickle juice (PJ) to treat cramping. Anecdotally, some clinicians provide multiple boluses of PJ during exercise but warn that repeated ingestion of PJ may cause hyperkalemia. To our knowledge, no researchers have examined the effect of ingesting multiple boluses of PJ on the same day or the effect of ingestion during exercise.
Objective:
To determine the short-term effects of ingesting a single bolus or multiple boluses of PJ on plasma variables and to characterize changes in plasma variables when individuals ingest PJ and resume exercise.
Design:
Crossover study.
Setting:
Laboratory.
Patients or Other Participants:
Nine euhydrated men (age = 23 ± 4 years, height = 180.9 ± 5.8 cm, mass = 80.7 ± 13.8 kg, urine specific gravity = 1.009 ± 0.005).
Intervention(s):
On 3 days, participants rested for 30 minutes, and then a blood sample was collected. Participants ingested 0 or 1 bolus (1 mL·kg−1 body weight) of PJ, donned sweat suits, biked vigorously for 30 minutes (approximate temperature = 37°C, relative humidity = 18%), and had a blood sample collected. They either rested for 60 seconds (0- and 1-bolus conditions) or ingested a second 1 mL·kg−1 body weight bolus of PJ (2-bolus condition). They resumed exercise for another 35 minutes. A third blood sample was collected, and they exited the environmental chamber and rested for 60 minutes (approximate temperature = 21°C, relative humidity = 18%). Blood samples were collected at 30 and 60 minutes postexercise.
Main Outcome Measure(s):
Plasma sodium concentration, plasma potassium concentration, plasma osmolality, and changes in plasma volume.
Results:
The number of PJ boluses ingested did not affect plasma sodium concentration, plasma potassium concentration, plasma osmolality, or changes in plasma volume over time. The plasma sodium concentration, plasma potassium concentration, and plasma osmolality did not exceed 144.6 mEq·L−1 (144.6 mmol·L−1), 4.98 mEq·L−1 (4.98 mmol·L−1), and 289.5 mOsm·kg−1H2O, respectively, in any condition at any time.
Conclusions:
Ingesting up to 2 boluses of PJ and resuming exercise caused negligible changes in blood variables. Ingesting up to 2 boluses of PJ did not increase plasma sodium concentration or cause hyperkalemia.
doi:10.4085/1062-6050-50.2.07
PMCID: PMC4495441  PMID: 25562454
hyperkalemia; hypernatremia; osmolality; potassium; sodium
4.  Table of Contents 
Journal of Athletic Training  2015;50(2):115-116.
doi:10.4085/1062-6050-50.2.115
PMCID: PMC4495442
5.  Physical Activity Participation and Constraints Among Athletic Training Students 
Journal of Athletic Training  2015;50(2):163-169.
Context:
Researchers have examined the physical activity (PA) habits of certified athletic trainers; however, none have looked specifically at athletic training students.
Objective:
To assess PA participation and constraints to participation among athletic training students.
Design:
Cross-sectional study.
Setting:
Entry-level athletic training education programs (undergraduate and graduate) across the United States.
Patients or Other Participants:
Participants were 1125 entry-level athletic training students.
Main Outcome Measure(s):
Self-reported PA participation, including a calculated PA index based on a typical week. Leisure constraints and demographic data were also collected.
Results:
Only 22.8% (252/1105) of athletic training students were meeting the American College of Sports Medicine recommendations for PA through moderate-intensity cardiorespiratory exercise. Although 52.3% (580/1105) were meeting the recommendations through vigorous-intensity cardiorespiratory exercise, 60.5% (681/1125) were meeting the recommendations based on the combined total of moderate or vigorous cardiorespiratory exercise. In addition, 57.2% (643/1125) of respondents met the recommendations for resistance exercise. Exercise habits of athletic training students appear to be better than the national average and similar to those of practicing athletic trainers. Students reported structural constraints such as lack of time due to work or studies as the most significant barrier to exercise participation.
Conclusions:
Athletic training students experienced similar constraints to PA participation as practicing athletic trainers, and these constraints appeared to influence their exercise participation during their entry-level education. Athletic training students may benefit from a greater emphasis on work-life balance during their entry-level education to promote better health and fitness habits.
doi:10.4085/1062-6050-49.3.56
PMCID: PMC4495443  PMID: 25689560
exercise; leisure constraints; leisure-time exercise questionnaire; work-life balance
6.  Career and Family Aspirations of Female Athletic Trainers Employed in the National Collegiate Athletic Association Division I Setting 
Journal of Athletic Training  2015;50(2):170-177.
Context:
Female athletic trainers (ATs) tend to depart the profession of athletic training after the age of 30. Factors influencing departure are theoretical. Professional demands, particularly at the collegiate level, have also been at the forefront of anecdotal discussion on departure factors.
Objective:
To understand the career and family intentions of female ATs employed in the collegiate setting.
Design:
Qualitative study.
Setting:
National Collegiate Athletic Association Division I.
Patients or Other Participants:
Twenty-seven female ATs (single = 14, married with no children = 6, married with children = 7) employed in the National Collegiate Athletic Association Division I setting.
Data Collection and Analysis:
All female ATs responded to a series of open-ended questions via reflective journaling. Data were analyzed via a general inductive approach. Trustworthiness was established by peer review, member interpretive review, and multiple-analyst triangulation.
Results:
Our participants indicated a strong desire to focus on family or to start a family as part of their personal aspirations. Professionally, many female ATs were unsure of their longevity within the Division I collegiate setting or even the profession itself, with 2 main themes emerging as factors influencing decisions to depart: family planning persistence and family planning departure. Six female ATs planned to depart the profession entirely because of conflicts with motherhood and the role of the AT. Only 3 female ATs indicated a professional goal of persisting at the Division I setting regardless of their family or marital status, citing their ability to maintain work-life balance because of support networks. The remaining 17 female ATs planned to make a setting change to balance the roles of motherhood and AT because the Division I setting was not conducive to parenting.
Conclusions:
Our results substantiate those of previous researchers, which indicate the Division I setting can be problematic for female ATs and stimulate departure from the setting and even the profession.
doi:10.4085/1062-6050-49.3.59
PMCID: PMC4495444  PMID: 25329349
retention; attrition; work-life balance
7.  Physical Activity And Risk Of End Stage Kidney Disease In The Singapore Chinese Health Study 
Nephrology (Carlton, Vic.)  2015;20(2):61-67.
Background
Physical inactivity is a modifiable risk factor for cardiovascular disease. However, the relationship between physical activity and risk of end-stage kidney disease (ESKD) is not clear.
Methods
We analyzed data on a prospective cohort of 59,552 Chinese adults aged 45-74 years enrolled in the Singapore Chinese Health Study. Information on physical activity was collected with a structured questionnaire. Physically active individuals were defined as those who engaged in any moderate activities for 2 hours or more per week, and any strenuous activities 30 minutes or more per week. Incident ESKD was identified via record linkage with the Singapore Registry of Birth and Death and Singapore Renal Registry. Cox proportional hazards regression method was used for analysis for risk of incident ESKD alone or ESKD plus death associated with physical activity. Multivariable models were used to account for the potential confounding effect of sociodemographic, life style factors, and known co-morbidites on the physical activity-ESKD risk association.
Results
During a median follow-up of 15.3 years, a total of 642 incident ESKD occurred, and 9808 study participants died. A 24% lower adjusted risk of ESKD [hazard ratio (HR): 0.76; 95% confidence interval (CI): 0.62-0.93] was associated with moderate or strenuous physical activities compared to no regular physical activity. This association appeared to be dose dependent with the lowest risk for subjects at highest intensity of physical activity (p trend <0.003). Similar results were observed for risk of ESKD plus death.
Conclusions
Higher levels of physical activity are associated with lower risk of ESKD. Our findings highlight the role of physical activity for prevention of ESKD, which deserves further evaluation in intervention trials.
doi:10.1111/nep.12355
PMCID: PMC4495910  PMID: 25346108
end stage kidney disease; exercise; physical activity
8.  Neutrophils Play an Important Role in Protective Immunity against Coxiella burnetii Infection 
Infection and Immunity  2015;83(8):3104-3113.
Coxiella burnetii is an obligate intracellular Gram-negative bacterium that causes the zoonotic disease Q fever. Although Q fever is mainly transmitted by aerosol infection, study of the immune responses in the lung following pulmonary C. burnetii infection is lacking. Neutrophils are considered the first immune cell to migrate into the lung and play an important role in host defense against aerosol infection with microbial pathogens. However, the role of neutrophils in the host defense against C. burnetii infection remains unclear. To determine the role of neutrophils in protective immunity against C. burnetii infection, the RB6-8C5 antibody was used to deplete neutrophils in mice before intranasal infection with C. burnetii. The results indicated that neutrophil-depleted mice developed more severe disease than their wild-type counterparts, suggesting that neutrophils play an important role in host defense against C. burnetii pulmonary infection. We also found that neither CXC chemokine receptor 2 (CXCR2) nor interleukin-17 (IL-17) receptor (IL-17R) deficiency changed the severity of disease following intranasal C. burnetii challenge, suggesting that keratinocyte-derived chemokine and IL-17 may not play essential roles in the response to C. burnetii infection. However, significantly higher C. burnetii genome copy numbers were detected in the lungs of IL-1R−/− mice at 14 days postinfection. This indicates that IL-1 may be important for the clearance of C. burnetii from the lungs following intranasal infection. Our results also suggest that neutrophils are involved in protecting vaccinated mice from C. burnetii challenge-induced disease. This is the first study to demonstrate an important role for neutrophils in protective immunity against C. burnetii infection.
doi:10.1128/IAI.00042-15
PMCID: PMC4496591  PMID: 26015476
9.  Aerobactin, but Not Yersiniabactin, Salmochelin, or Enterobactin, Enables the Growth/Survival of Hypervirulent (Hypermucoviscous) Klebsiella pneumoniae Ex Vivo and In Vivo 
Infection and Immunity  2015;83(8):3325-3333.
The siderophore aerobactin is the dominant siderophore produced by hypervirulent Klebsiella pneumoniae (hvKP) and was previously shown to be a major virulence factor in systemic infection. However, strains of hvKP commonly produce the additional siderophores yersiniabactin, salmochelin, and enterobactin. The roles of these siderophores in hvKP infection have not been optimally defined. To that end, site-specific gene disruptions were created in hvKP1 (wild type), resulting in the generation of hvKP1ΔiucA (aerobactin deficient), hvKP1ΔiroB (salmochelin deficient), hvKP1ΔentB (enterobactin and salmochelin deficient), hvKP1Δirp2 (yersiniabactin deficient), and hvKP1ΔentBΔirp2 (enterobactin, salmochelin, and yersiniabactin deficient). The growth/survival of these constructs was compared to that of their wild-type parent hvKP1 ex vivo in human ascites fluid, human serum, and human urine and in vivo in mouse systemic infection and pulmonary challenge models. Interestingly, in contrast to aerobactin, the inability to produce enterobactin, salmochelin, or yersiniabactin individually or in combination did not decrease the ex vivo growth/survival in human ascites or serum or decrease virulence in the in vivo infection models. Surprisingly, none of the siderophores increased growth in human urine. In human ascites fluid supplemented with exogenous siderophores, siderophores increased the growth of hvKP1ΔiucA, with the relative activity being enterobactin > aerobactin > yersiniabactin > salmochelin, suggesting that the contribution of aerobactin to virulence is dependent on both innate biologic activity and quantity produced. Taken together, these data confirm and extend a role for aerobactin as a critical virulence factor for hvKP. Since it appears that aerobactin production is a defining trait of hvKP strains, this factor is a potential antivirulence target.
doi:10.1128/IAI.00430-15
PMCID: PMC4496593  PMID: 26056379
10.  In Contrast to Chlamydia trachomatis, Waddlia chondrophila Grows in Human Cells without Inhibiting Apoptosis, Fragmenting the Golgi Apparatus, or Diverting Post-Golgi Sphingomyelin Transport 
Infection and Immunity  2015;83(8):3268-3280.
The Chlamydiales are an order of obligate intracellular bacteria sharing a developmental cycle inside a cytosolic vacuole, with very diverse natural hosts, from amoebae to mammals. The clinically most important species is Chlamydia trachomatis. Many uncertainties remain as to how Chlamydia organizes its intracellular development and replication. The discovery of new Chlamydiales species from other families permits the comparative analysis of cell-biological events and may indicate events that are common to all or peculiar to some species and more or less tightly linked to “chlamydial” development. We used this approach in the infection of human cells with Waddlia chondrophila, a species from the family Waddliaceae whose natural host is uncertain. Compared to C. trachomatis, W. chondrophila had slightly different growth characteristics, including faster cytotoxicity. The embedding in cytoskeletal structures was not as pronounced as for the C. trachomatis inclusion. C. trachomatis infection generates proteolytic activity by the protease Chlamydia protease-like activity factor (CPAF), which degrades host substrates upon extraction; these substrates were not cleaved in the case of W. chondrophila. Unlike Chlamydia, W. chondrophila did not protect against staurosporine-induced apoptosis. C. trachomatis infection causes Golgi apparatus fragmentation and redirects post-Golgi sphingomyelin transport to the inclusion; both were absent from W. chondrophila-infected cells. When host cells were infected with both species, growth of both species was reduced. This study highlights differences between bacterial species that both depend on obligate intracellular replication inside an inclusion. Some features seem principally dispensable for intracellular development of Chlamydiales in vitro but may be linked to host adaptation of Chlamydia and the higher virulence of C. trachomatis.
doi:10.1128/IAI.00322-15
PMCID: PMC4496594  PMID: 26056386
11.  The Staphylococcus aureus Protein-Coding Gene gdpS Modulates sarS Expression via mRNA-mRNA Interaction 
Infection and Immunity  2015;83(8):3302-3310.
Staphylococcus aureus is an important Gram-positive pathogen responsible for numerous diseases ranging from localized skin infections to life-threatening systemic infections. The virulence of S. aureus is essentially determined by a wide spectrum of factors, including cell wall-associated proteins and secreted toxins that are precisely controlled in response to environmental changes. GGDEF domain protein from Staphylococcus (GdpS) is the only conserved staphylococcal GGDEF domain protein that is involved not in c-di-GMP synthesis but in the virulence regulation of S. aureus NCTC8325. Our previous study showed that the inactivation of gdpS generates an extensive change of virulence factors together with, in particular, a major Spa (protein A) surface protein. As reported, sarS is a direct positive regulator of spa. The decreased transcript levels of sarS in the gdpS mutant compared with the parental NCTC8325 strain suggest that gdpS affects spa through interaction with sarS. In this study, site mutation and complementary experiments showed that the translation product of gdpS was not involved in the regulation of transcript levels of sarS. We found that gdpS functioned through direct RNA-RNA base pairing with the 5′ untranslated region (5′UTR) of sarS mRNA and that a putative 18-nucleotide region played a significant role in the regulatory process. Furthermore, the mRNA half-life analysis of sarS in the gdpS mutant showed that gdpS positively regulates the mRNA levels of sarS by contributing to the stabilization of sarS mRNA, suggesting that gdpS mRNA may regulate spa expression in an RNA-dependent pathway.
doi:10.1128/IAI.00159-15
PMCID: PMC4496595  PMID: 26056387
12.  Noncanonical Activation of β-Catenin by Porphyromonas gingivalis 
Infection and Immunity  2015;83(8):3195-3203.
Porphyromonas gingivalis is an established pathogen in periodontal disease and an emerging pathogen in serious systemic conditions, including some forms of cancer. We investigated the effect of P. gingivalis on β-catenin signaling, a major pathway in the control of cell proliferation and tumorigenesis. Infection of gingival epithelial cells with P. gingivalis did not influence the phosphorylation status of β-catenin but resulted in proteolytic processing. The use of mutants deficient in gingipain production, along with gingipain-specific inhibitors, revealed that gingipain proteolytic activity was required for β-catenin processing. The β-catenin destruction complex components Axin1, adenomatous polyposis coli (APC), and GSK3β were also proteolytically processed by P. gingivalis gingipains. Cell fractionation and Western blotting demonstrated that β-catenin fragments were translocated to the nucleus. The accumulation of β-catenin in the nucleus following P. gingivalis infection was confirmed by immunofluorescence microscopy. A luciferase reporter assay showed that P. gingivalis increased the activity of the β-catenin-dependent TCF/LEF promoter. P. gingivalis did not increase Wnt3a mRNA levels, a finding consistent with P. gingivalis-induced proteolytic processing causing the increase in TCF/LEF promoter activity. Thus, our data indicate that P. gingivalis can induce the noncanonical activation of β-catenin and disassociation of the β-catenin destruction complex by gingipain-dependent proteolytic processing. β-Catenin activation in epithelial cells by P. gingivalis may contribute to a proliferative phenotype.
doi:10.1128/IAI.00302-15
PMCID: PMC4496596  PMID: 26034209
13.  Streptococcus pyogenes Triggers Activation of the Human Contact System by Streptokinase 
Infection and Immunity  2015;83(8):3035-3042.
Severe invasive infectious diseases remain a major and life-threatening health problem. In serious cases, a systemic activation of the coagulation cascade is a critical complication that is associated with high mortality rates. We report here that streptokinase, a group A streptococcal plasminogen activator, triggers the activation of the human contact system. Activation of contact system factors at the surface of the Streptococcus pyogenes serotype M49 is dependent on streptokinase and plasminogen. Our results also show that secreted streptokinase is an efficient contact system activator, independent from a contact surface. This results in the processing of high-molecular-weight kininogen and the release of bradykinin, a potent vascular mediator. We further investigated whether the ability of 50 different clinical S. pyogenes isolates to activate the contact system is associated with an invasive phenotype. The data reveal that isolates from invasive infections trigger an activation of the contact system more potently than strains isolated from noninvasive infections. The present study gives new insights into the mechanisms by which S. pyogenes triggers the human contact system and stresses the function of soluble and surface located plasmin exploited as a group A streptococcal virulence factor through the action of streptokinase.
doi:10.1128/IAI.00180-15
PMCID: PMC4496597  PMID: 25987706
14.  Tim-3 Induces Th2-Biased Immunity and Alternative Macrophage Activation during Schistosoma japonicum Infection 
Infection and Immunity  2015;83(8):3074-3082.
T cell immunoglobulin- and mucin-domain-containing molecule 3 (Tim-3) has been regarded as an important regulatory factor in both adaptive and innate immunity. Recently, Tim-3 was reported to be involved in Th2-biased immune responses in mice infected with Schistosoma japonicum, but the exact mechanism behind the involvement of Tim-3 remains unknown. The present study aims to understand the role of Tim-3 in the immune response against S. japonicum infection. Tim-3 expression was determined by flow cytometry, and increased Tim-3 expression was observed on CD4+ and CD8+ T cells, NK1.1+ cells, and CD11b+ cells from the livers of S. japonicum-infected mice. However, the increased level of Tim-3 was lower in the spleen than in the liver, and no increase in Tim-3 expression was observed on splenic CD8+ T cells or CD11b+ cells. The schistosome-induced upregulation of Tim-3 on natural killer (NK) cells was accompanied by reduced NK cell numbers in vitro and in vivo. Tim-3 antibody blockade led to upregulation of inducible nitric oxide synthase and interleukin-12 (IL-12) mRNA in CD11b+ cells cocultured with soluble egg antigen and downregulation of Arg1 and IL-10, which are markers of M2 macrophages. In summary, we observed schistosome-induced expression of Tim-3 on critical immune cell populations, which may be involved in the Th2-biased immune response and alternative activation of macrophages during infection.
doi:10.1128/IAI.00517-15
PMCID: PMC4496598  PMID: 25987707
16.  Identifying Francisella tularensis Genes Required for Growth in Host Cells 
Infection and Immunity  2015;83(8):3015-3025.
Francisella tularensis is a highly virulent Gram-negative intracellular pathogen capable of infecting a vast diversity of hosts, ranging from amoebae to humans. A hallmark of F. tularensis virulence is its ability to quickly grow to high densities within a diverse set of host cells, including, but not limited to, macrophages and epithelial cells. We developed a luminescence reporter system to facilitate a large-scale transposon mutagenesis screen to identify genes required for growth in macrophage and epithelial cell lines. We screened 7,454 individual mutants, 269 of which exhibited reduced intracellular growth. Transposon insertions in the 269 growth-defective strains mapped to 68 different genes. FTT_0924, a gene of unknown function but highly conserved among Francisella species, was identified in this screen to be defective for intracellular growth within both macrophage and epithelial cell lines. FTT_0924 was required for full Schu S4 virulence in a murine pulmonary infection model. The ΔFTT_0924 mutant bacterial membrane is permeable when replicating in hypotonic solution and within macrophages, resulting in strongly reduced viability. The permeability and reduced viability were rescued when the mutant was grown in a hypertonic solution, indicating that FTT_0924 is required for resisting osmotic stress. The ΔFTT_0924 mutant was also significantly more sensitive to β-lactam antibiotics than Schu S4. Taken together, the data strongly suggest that FTT_0924 is required for maintaining peptidoglycan integrity and virulence.
doi:10.1128/IAI.00004-15
PMCID: PMC4496600  PMID: 25987704
17.  Transcriptome Reprogramming by Plasmid-Encoded Transcriptional Regulators Is Required for Host Niche Adaption of a Macrophage Pathogen 
Infection and Immunity  2015;83(8):3137-3145.
Rhodococcus equi is a facultative intracellular pathogen of macrophages, relying on the presence of a conjugative virulence plasmid harboring a 21-kb pathogenicity island (PAI) for growth in host macrophages. The PAI encodes a family of 6 virulence-associated proteins (Vaps) in addition to 20 other proteins. The contribution of these to virulence has remained unclear. We show that the presence of only 3 virulence plasmid genes (of 73 in total) is required and sufficient for intracellular growth. These include a single vap family member, vapA, and two PAI-located transcriptional regulators, virR and virS. Both transcriptional regulators are essential for wild-type-level expression of vapA, yet vapA expression alone is not sufficient to allow intracellular growth. A whole-genome microarray analysis revealed that VirR and VirS substantially integrate themselves into the chromosomal regulatory network, significantly altering the transcription of 18% of all chromosomal genes. This pathoadaptation involved significant enrichment of select gene ontologies, in particular, enrichment of genes involved in transport processes, energy production, and cellular metabolism, suggesting a major change in cell physiology allowing the bacterium to grow in the hostile environment of the host cell. The results suggest that following the acquisition of the virulence plasmid by an avirulent ancestor of R. equi, coevolution between the plasmid and the chromosome took place, allowing VirR and VirS to regulate the transcription of chromosomal genes in a process that ultimately promoted intracellular growth. Our findings suggest a mechanism for cooption of existing chromosomal traits during the evolution of a pathogenic bacterium from an avirulent saprophyte.
doi:10.1128/IAI.00230-15
PMCID: PMC4496601  PMID: 26015480
18.  A Short-Term Borrelia burgdorferi Infection Model Identifies Tissue Tropisms and Bloodstream Survival Conferred by Adhesion Proteins 
Infection and Immunity  2015;83(8):3184-3194.
Borrelia burgdorferi, the causative agent of Lyme disease in the United States, is able to persist in the joint, heart, skin, and central nervous system for the lifetime of its mammalian host. Borrelia species achieve dissemination to distal sites in part by entry into and travel within the bloodstream. Much work has been performed in vitro describing the roles of many B. burgdorferi outer surface proteins in adhesion to host cell surface proteins and extracellular matrix components, although the biological relevance of these interactions is only beginning to be explored in vivo. A need exists in the field for an in vivo model to define the biological roles of B. burgdorferi adhesins in tissue-specific vascular interactions. We have developed an in vivo model of vascular interaction of B. burgdorferi in which the bacteria are injected intravenously and allowed to circulate for 1 h. This model has shown that the fibronectin binding protein BB0347 has a tropism for joint tissue. We also have shown an importance of the integrin binding protein, P66, in binding to vasculature of the ear and heart. This model also revealed unexpected roles for Borrelia adhesins BBK32 and OspC in bacterial burdens in the bloodstream. The intravenous inoculation model of short-term infection provides new insights into critical B. burgdorferi interactions with the host required for initial survival and tissue colonization.
doi:10.1128/IAI.00349-15
PMCID: PMC4496602  PMID: 26015482
19.  Sources of Health Information among Select Asian American Immigrant Groups in New York City 
Health communication  2015;31(2):207-216.
Health information can potentially mitigate adverse health outcomes among ethnic minority populations, but little research has examined how minorities access health information. The aim of this study was to examine variations in the use of health information sources among Asian American (AA) subgroups and to identify differences in characteristics associated with the use of these sources. We analyzed data from a foreign-born community sample of 219 Asian Indians, 216 Bangladeshis, 484 Chinese, and 464 Koreans living in New York City. Results found that use of health information sources varied by AA subgroup. Print media source use, which included newspapers, magazines and/or journals, was highest among Chinese (84%), Koreans (75%), and Bangladeshis (80%), while radio was most utilized by Chinese (48%) and Koreans (38%). Television utilization was highest among Bangladeshis (74%) and Koreans (64%). Koreans (52%) and Chinese (40%) were most likely to use the Internet to access health information. Radio use was best explained by older age and longer time lived in the US, while print media was more utilized by older individuals. Results also highlighted differences in native language versus non-native language media sources for health information by subgroup. Media sources can be used as a vehicle to disseminate health information among AAs.
doi:10.1080/10410236.2014.944332
PMCID: PMC4628554  PMID: 26266574
Asian American; Disparities; Health Sources; Health Information
20.  Therapeutics for postexposure treatment of Ebola virus infection 
Future virology  2015;10(3):221-232.
The current Ebola virus disease (EVD) outbreak in West Africa is the largest with over 5100 deaths in four West African countries as of 14 November 2014. EVD has high case-fatality rates but no licensed treatment or vaccine is yet available. Several vaccine candidates that protected nonhuman primates are not yet available for clinical use. Slow development of vaccine-stimulated immunity, sporadic nature and fast progression of EVD underlines the need for the development of effective postexposure therapeutic drugs. WHO encouraged the use of untested drugs for EVD to curb the fast-spreading outbreak. Here, we summarize therapeutics for EVD including monoclonal antibody-based therapy and inhibitors of viral replication including our recently developed small-molecule inhibitors of VP30 dephosphorylation.
doi:10.2217/fvl.14.109
PMCID: PMC4508675  PMID: 26213559
1E7-03; antibody therapy; Ebola virus; postexposure drugs
21.  A mechanistic overview of dendritic cell-mediated HIV-1 trans infection: the story so far 
Future virology  2015;10(3):257-269.
Despite progress in antiretroviral therapy, HIV-1 rebound after cessation of antiretroviral therapy suggests that establishment of long-term cellular reservoirs of virus is a significant barrier to functional cure. There is considerable evidence that dendritic cells (DCs) play an important role in systemic virus dissemination. Although productive infection of DCs is inefficient, DCs capture HIV-1 and transfer-captured particles to CD4+ T cells, a mechanism of DC-mediated HIV-1 trans infection. Recent findings suggest that DC-mediated trans infection of HIV-1 is dependent on recognition of GM3, a virus-particle-associated host-derived ligand, by CD169 expressed on DCs. In this review, we describe mechanisms of DC-mediated HIV-1 trans infection and discuss specifically the role of CD169 in establishing infection in CD4+ T cells.
doi:10.2217/fvl.15.2
PMCID: PMC4508676  PMID: 26213560
CD169; cell-associated virus transfer; dendritic cells; GM3; HIV; trans infection
22.  Normal Perceptual Sensitivity Arising From Weakly Reflective Cone Photoreceptors 
Purpose
To determine the light sensitivity of poorly reflective cones observed in retinas of normal subjects, and to establish a relationship between cone reflectivity and perceptual threshold.
Methods
Five subjects (four male, one female) with normal vision were imaged longitudinally (7–26 imaging sessions, representing 82–896 days) using adaptive optics scanning laser ophthalmoscopy (AOSLO) to monitor cone reflectance. Ten cones with unusually low reflectivity, as well as 10 normally reflective cones serving as controls, were targeted for perceptual testing. Cone-sized stimuli were delivered to the targeted cones and luminance increment thresholds were quantified. Thresholds were measured three to five times per session for each cone in the 10 pairs, all located 2.2 to 3.3° from the center of gaze.
Results
Compared with other cones in the same retinal area, three of 10 monitored dark cones were persistently poorly reflective, while seven occasionally manifested normal reflectance. Tested psychophysically, all 10 dark cones had thresholds comparable with those from normally reflecting cones measured concurrently (P = 0.49). The variation observed in dark cone thresholds also matched the wide variation seen in a large population (n = 56 cone pairs, six subjects) of normal cones; in the latter, no correlation was found between cone reflectivity and threshold (P = 0.0502).
Conclusions
Low cone reflectance cannot be used as a reliable indicator of cone sensitivity to light in normal retinas. To improve assessment of early retinal pathology, other diagnostic criteria should be employed along with imaging and cone-based microperimetry.
Using photoreceptor-specific microstimulation, we found there was no significant difference in psychophysical threshold between normally and poorly reflective cones. These findings provide good evidence that cone reflectivity is not firmly tied to cone function.
doi:10.1167/iovs.15-16547
PMCID: PMC4509056  PMID: 26193919
adaptive optics; cone sensitivity; retinal imaging
23.  Differences in the Genetic Susceptibility to Age-Related Macular Degeneration Clinical Subtypes 
Purpose
We compared across age-related macular degeneration (AMD) subtypes the effect of AMD risk variants, their predictive power, and heritability.
Methods
The prevalence of AMD was estimated among active non-Hispanic white Kaiser Permanente Northern California members who were at least 65 years of age as of June 2013. The genetic analysis included 5,170 overall AMD cases ascertained from electronic health records (EHR), including 1,239 choroidal neovascularization (CNV) cases and 1,060 nonexudative AMD cases without CNV, and 23,130 controls of non-Hispanic white ancestry from the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. Imputation was based on the 1000 Genomes Project reference panel.
Results
The narrow-sense heritability due to common autosomal single nucleotide polymorphisms (SNPs) was 0.37 for overall AMD, 0.19 for AMD unspecified, 0.20 for nonexudative AMD, and 0.60 for CNV. For the 19 previously reported AMD risk loci, the area under the receiver operating characteristic (ROC) curve was 0.675 for overall AMD, 0.640 for AMD unspecified, 0.678 for nonexudative AMD, and 0.766 for CNV. The individual effects on the risk of AMD for 18 of the 19 SNPs were in a consistent direction with those previously reported, including a protective effect of the APOE ε4 allele. Conversely, the risk of AMD was significantly increased in carriers of the ε2 allele.
Conclusions
These findings provide an independent confirmation of many of the previously identified AMD risk loci, and support a potentially greater role of genetic factors in the development of CNV. The replication of established associations validates the use of EHR in genetic studies of ophthalmologic traits.
A number of genetic loci have been identified that influence the risk of age-related macular degeneration (AMD). In this study, we examine how these loci influence the risk of AMD clinical subtypes.
doi:10.1167/iovs.15-16533
PMCID: PMC4509058  PMID: 26176866
age-related macular degeneration; prevalence; heritability; ApoE
24.  Stereo Photo Measured ONH Shape Predicts Development of POAG in Subjects With Ocular Hypertension 
Purpose
To identify objective, quantitative optic nerve head (ONH) structural features and model the contributions of glaucoma.
Methods
Baseline stereoscopic optic disc images of 1635 glaucoma-free participants at risk for developing primary open-angle glaucoma (POAG) were collected as part of the Ocular Hypertension Treatment Study. A stereo correspondence algorithm designed for fundus images was applied to extract the three-dimensional (3D) information about the ONH. Principal component analysis was used to identify ONH 3D structural features and the contributions of demographic features, clinical variables, and disease were modeled using linear regression and linear component analysis. The computationally identified features were evaluated based on associations with glaucoma and ability to predict which participants would develop POAG.
Results
The computationally identified features were significantly associated with future POAG, POAG-related demographics (age, ethnicity), and clinical measurements (horizontal and vertical cup-to-disc ratio, central corneal thickness, and refraction). Models predicting future POAG development using the OHTS baseline data and STEP features achieved an AUC of 0.722 in cross-validation testing. This was a significant improvement over using only demographics (age, sex, and ethnicity), which had an AUC of 0.599.
Conclusions
Methods for identifying objective, quantitative measurements of 3D ONH structure were developed using a large dataset. The identified features were significantly associated with POAG and POAG-related variables. Further, these features increased predictive model accuracy in predicting future POAG. The results indicate that the computationally identified features might be useful in POAG early screening programs or as endophenotypes to investigate POAG genetics.
In this study, quantitative features of optic nerve head structure were identified from stereo color photos in a large cohort. We show that these features are as powerful as cup-to-disc ratio and pattern standard deviation for predicting future conversion to glaucoma.
doi:10.1167/iovs.14-16142
PMCID: PMC4509059  PMID: 26193923
primary open-angle glaucoma; optic nerve head; stereo fundus; image analysis; structural modeling
25.  Dexamethasone Stiffens Trabecular Meshwork, Trabecular Meshwork Cells, and Matrix 
Purpose
Treatment with corticosteroids can result in ocular hypertension and may lead to the development of steroid-induced glaucoma. The extent to which biomechanical changes in trabecular meshwork (TM) cells and extracellular matrix (ECM) contribute toward this dysfunction is poorly understood.
Methods
Primary human TM (HTM) cells were cultured for either 3 days or 4 weeks in the presence or absence of dexamethasone (DEX), and cell mechanics, matrix mechanics and proteomics were determined, respectively. Adult rabbits were treated topically with either 0.1% DEX or vehicle over 3 weeks, and mechanics of the TM were determined.
Results
Treatment with DEX for 3 days resulted in a 2-fold increase in HTM cell stiffness, and this correlated with activation of extracellular signal-related kinase 1/2 (ERK1/2) and overexpression of α-smooth muscle actin (αSMA). Further, the matrix deposited by HTM cells chronically treated with DEX is approximately 4-fold stiffer, more organized, and has elevated expression of matrix proteins commonly implicated in glaucoma (decorin, myocilin, fibrillin, secreted frizzle-related protein [SFRP1], matrix-gla). Also, DEX treatment resulted in a 3.5-fold increase in stiffness of the rabbit TM.
Discussion
This integrated approach clearly demonstrates that DEX treatment increases TM cell stiffness concurrent with elevated αSMA expression and activation of the mitogen-activated protein kinase (MAPK) pathway, stiffens the ECM in vitro along with upregulation of Wnt antagonists and fibrotic markers embedded in a more organized matrix, and increases the stiffness of TM tissues in vivo. These results demonstrate glucocorticoid treatment can initiate the biophysical alteration associated with increased resistance to aqueous humor outflow and the resultant increase in IOP.
We demonstrate, that cells from the TM, when treated with steroids, change cytoskeletal dynamics and rigidity, and deposit a stiffer and altered matrix. Using an adult rabbit model, we also demonstrated that the biomechanical properties of the in vivo TM were altered.
doi:10.1167/iovs.15-16739
PMCID: PMC4509060  PMID: 26193921
cell and matrix mechanics; steroid-induced glaucoma; extracellular matrix; elastic modulus; proteomics

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