bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Capacity of
Mycobacterium tuberculosis
To Survive Iron Starvation Might Enable It To Persist in Iron-Deprived Microenvironments of Human Granulomas
Authors: Kurthkoti Krishna , Amin Hamel , Marakalala Mohlopheni J. , Ghanny Saleena , Subbian Selvakumar , Sakatos Alexandra , Livny Jonathan , Fortune Sarah M. , Berney Michael , Rodriguez G. Marcela 
Published: August 2017

ABSTRACT

This study was conducted to investigate the role of iron deprivation in the persistence of
Mycobacterium tuberculosis
. We present evidence of iron restriction in human necrotic granulomas and demonstrate that under iron starvation
M. tuberculosis
persists, refractive to antibiotics and capable of restarting replication when iron is made available. Transcriptomics and metabolomic analyses indicated that the persistence of
M. tuberculosis
under iron starvation is dependent on strict control of endogenous Fe utilization and is associated with upregulation of pathogenicity and intrinsic antibiotic resistance determinants.
M. tuberculosis
mutants compromised in their ability to survive Fe starvation were identified. The findings of this study advance the understanding of the physiological settings that may underpin the chronicity of human tuberculosis (TB) and are relevant to the design of effective antitubercular therapies.

IMPORTANCE
One-third of the world population may harbor persistent
M. tuberculosis
, causing an asymptomatic infection that is refractory to treatment and can reactivate to become potentially lethal tuberculosis disease. However, little is known about the factors that trigger and maintain
M. tuberculosis
persistence in infected individuals. Iron is an essential nutrient for
M. tuberculosis
growth. In this study, we show, first, that in human granulomas the immune defense creates microenvironments in which
M. tuberculosis
likely experiences drastic Fe deprivation and, second, that Fe-starved
M. tuberculosis
is capable of long-term persistence without growth. Together, these observations suggest that Fe deprivation in the lung might trigger a state of persistence in
M. tuberculosis
and promote chronic TB. We also identified vulnerabilities of iron-restricted persistent
M. tuberculosis
, which can be exploited for the design of new antitubercular therapies.
Inhibitors of the Histone Methyltransferases EZH2/1 Induce a Potent Antiviral State and Suppress Infection by Diverse Viral Pathogens
Authors: Arbuckle Jesse H. , Gardina Paul J. , Gordon David N. , Hickman Heather D. , Yewdell Jonathan W. , Pierson Theodore C. , Myers Timothy G. , Kristie Thomas M. 
Published: August 2017

ABSTRACT

Epigenetic regulation is based on a network of complexes that modulate the chromatin character and structure of the genome to impact gene expression, cell fate, and development. Thus, epigenetic modulators represent novel therapeutic targets used to treat a range of diseases, including malignancies. Infectious pathogens such as herpesviruses are also regulated by cellular epigenetic machinery, and epigenetic therapeutics represent a novel approach used to control infection, persistence, and the resulting recurrent disease. The histone H3K27 methyltransferases EZH2 and EZH1 (EZH2/1) are epigenetic repressors that suppress gene transcription via propagation of repressive H3K27me3-enriched chromatin domains. However, while EZH2/1 are implicated in the repression of herpesviral gene expression, inhibitors of these enzymes suppressed primary herpes simplex virus (HSV) infection
in vitro
and
in vivo
. Furthermore, these compounds blocked lytic viral replication following induction of HSV reactivation in latently infected sensory ganglia. Suppression correlated with the induction of multiple inflammatory, stress, and antipathogen pathways, as well as enhanced recruitment of immune cells to
in vivo
infection sites. Importantly, EZH2/1 inhibitors induced a cellular antiviral state that also suppressed infection with DNA (human cytomegalovirus, adenovirus) and RNA (Zika virus) viruses. Thus, EZH2/1 inhibitors have considerable potential as general antivirals through the activation of cellular antiviral and immune responses.

IMPORTANCE
A significant proportion of the world’s population is infected with herpes simplex virus. Primary infection and subsequent recurrent reactivation can result in diseases ranging from mild lesions to severe ocular or neurological damage. Herpesviruses are subject to epigenetic regulation that modulates viral gene expression, lytic replication, and latency-reactivation cycles. Thus, epigenetic pharmaceuticals have the potential to alter the course of infection and disease. Here, while the histone methyltransferases EZH2/1 are implicated in the suppression of herpesviruses, inhibitors of these repressors unexpectedly suppress viral infection
in vitro
and
in vivo
by induction of key components of cellular innate defense pathways. These inhibitors suppress infection by multiple viral pathogens, indicating their potential as broad-spectrum antivirals.
TIFA Signaling in Gastric Epithelial Cells Initiates thecagType 4 Secretion System-Dependent Innate Immune Response toHelicobacter pyloriInfection
Authors: Gall Alevtina , Gaudet Ryan G. , Gray-Owen Scott D. , Salama Nina R. 
Published: August 2017

ABSTRACTHelicobacter pyloriis a bacterial pathogen that colonizes the human stomach, causing inflammation which, in some cases, leads to gastric ulcers and cancer. The clinical outcome of infection depends on a complex interplay of bacterial, host genetic, and environmental factors. AlthoughH. pyloriis recognized by both the innate and adaptive immune systems, this rarely results in bacterial clearance. Gastric epithelial cells are the first line of defense againstH. pyloriand alert the immune system to bacterial presence. Cytosolic delivery of proinflammatory bacterial factors through thecagtype 4 secretion system (cag-T4SS) has long been appreciated as the major mechanism by which gastric epithelial cells detectH. pylori. Classically attributed to the peptidoglycan sensor NOD1, recent work has highlighted the role of NOD1-independent pathways in detectingH. pylori; however, the bacterial and host factors involved have remained unknown. Here, we show that bacterially derived heptose-1,7-bisphosphate (HBP), a metabolic precursor in lipopolysaccharide (LPS) biosynthesis, is delivered to the host cytosol through thecag-T4SS, where it activates the host tumor necrosis factor receptor-associated factor (TRAF)-interacting protein with forkhead-associated domain (TIFA)-dependent cytosolic surveillance pathway. This response, which is independent of NOD1, drives robust NF-κB-dependent inflammation within hours of infection and precedes NOD1 activation. We also found that the CagA toxin contributes to the NF-κB-driven response subsequent to TIFA and NOD1 activation. Taken together, our results indicate that the sequential activation of TIFA, NOD1, and CagA delivery drives the initial inflammatory response in gastric epithelial cells, orchestrating the subsequent recruitment of immune cells and leading to chronic gastritis.IMPORTANCEH. pyloriis a globally prevalent cause of gastric and duodenal ulcers and cancer.H. pyloriantibiotic resistance is rapidly increasing, and a vaccine remains elusive. The earliest immune response toH. pyloriis initiated by gastric epithelial cells and sets the stage for the subsequent immunopathogenesis. This study revealed that host TIFA andH. pylori-derived HBP are critical effectors of innate immune signaling that account for much of the inflammatory response toH. pyloriin gastric epithelial cells. HBP is delivered to the host cell via thecag-T4SS at a time point that precedes activation of the previously described NOD1 and CagA inflammatory pathways. Manipulation of the TIFA-driven immune response in the host and/or targeting of ADP-heptose biosynthesis enzymes inH. pylorimay therefore provide novel strategies that may be therapeutically harnessed to achieve bacterial clearance.
Ureaplasma parvumcausing life-threatening disease in a susceptible patient
Authors: Korytny Alexander , Nasser Roni , Geffen Yuval , Friedman Tom , Paul Mical , Ghanem-Zoubi Nesrin 
Published: August 2017

A 56-year-old man with lymphoma developed orchitis followed by septic arthritis of his right glenohumeral joint. Synovial fluid cultures were negative but PCR amplification test was positive forUreaplasmaparvum.The patient was treated with doxycycline. Two and a half years later, the patient presented with shortness of breath and grade III/IV diastolic murmur on auscultation. Echocardiography revealed severely dilated left heart chambers, severe aortic regurgitation and several mobile masses on the aortic valve cusps suspected to be vegetations. He underwent valve replacement; valve tissue culture was negative but the 16S rRNA gene amplification test was positive forU. parvum.He was treated again with doxycycline. In an outpatient follow-up 1 year and 3 months later, the patient was doing well. Repeated echocardiography showed normal aortic prosthesis function.
Fever and generalised lymphadenopathy in an HIV-positive patient: a diagnostic challenge
Authors: Neves Bernardo , Raimundo Pedro , Farinha Pedro 
Published: August 2017

Fever and generalised lymphadenopathy is a common presentation of a variety of diseases and a thorough investigation is often necessary for appropriate diagnosis.We present a 53-year-old male patient admitted with fever, weight loss of 15 kg in 3 months and abdominal discomfort. Examination was only remarkable for axillary and inguinal lymphadenopathy. Blood tests showed normocytic normochromic anaemia, cholestasis and a previously unknown HIV-1 infection with lymphocyte CD4 +count of 239 cells/mm3and viral load 3.172.370 copies/mL. A body CT scan showed multiple axillary, mediastinal, lumbar, aortic, iliac and pelvic lymphadenopathy as well as hepatosplenomegaly. An excisional biopsy of the left axillary lymphadenopathy was performed and histology ultimately revealed multicentric Castleman’s disease associated with Human Herpes Virus-8. After initiation of antiretroviral therapy, rituximab was given and progressive clinical improvement occurred.
Characteristics of primary extranodal marginal zone B-cell lymphoma in Korea: conjunctiva versus other ocular adnexa
Authors: Nam Seung Wan , Woo Kyung In , Kim Yoon-Duck 
Published: August 2017

AimsTo compare the clinical characteristics and prognosis of primary conjunctival versus other ocular adnexal extranodal marginal zone B-cell lymphoma (EMZL).MethodsRetrospective review of clinical records for all consecutive patients with primary ocular adnexal EMZL treated from March 1995 to December 2015.Results198 patients were evaluated including 81 with primary conjunctival and 117 with other ocular adnexal EMZL. Conjunctival EMZL was found at a younger age (40.3±10.3vs 54.3±13.4 years, p<0.0001) with a female predilection (75.3%vs35.9%, p<0.0001) and had a higher rate of bilaterality (40.7%vs11.1%, p<0.0001) and a lower rate of systemic involvement (1.2%vs9.4%, p=0.030) compared with other ocular adnexal EMZLs. Conjunctival EMZL also showed a higher rate of complete response to primary treatment (98.8%vs89.5%, p=0.016) than other ocular adnexal EMZLs; however, recurrence and lymphoma-related death rates were not different between the two groups (p>0.05). Kaplan-Meier estimates for disease-specific survival at 5 and 10 years were 98.2% and 98.2% in conjunctival and 98.6%, respectively, and 95.2% in other ocular adnexal EMZLs. Univariate analysis showed that systemic involvement was negatively associated with conjunctival tumour location and positively associated with age (OR=0.35 and OR=1.05, p=0.045 and p=0.012, respectively), and treatment response was positively associated with conjunctival tumour location and negatively associated with age (OR=3.02 and OR=0.95, p=0.035 and p=0.009, respectively).ConclusionsConjunctival EMZL shows unique demographic characteristic compared with other ocular adnexal EMZLs. Long-term follow-up is required due to late recurrence in ocular adnexal EMZL.
Targeting a Single Alternative Polyadenylation Site Coordinately Blocks Expression of Androgen Receptor mRNA Splice Variants in Prostate Cancer
Authors: Van Etten Jamie L. , Nyquist Michael , Li Yingming , Yang Rendong , Ho Yeung , Johnson Rachel , Ondigi Olivia , Voytas Daniel F. , Henzler Christine , Dehm Scott M. 
Published: August 2017

Abstract
Prostate cancer is the second leading cause of male cancer deaths due to disease progression to castration-resistant prostate cancer (CRPC). Androgen receptor (AR) splice variants including AR-V7 function as constitutively active transcription factors in CRPC cells, thereby promoting resistance to AR-targeted therapies. To date, there are no AR variant–specific treatments for CRPC. Here we report that the splicing of AR variants AR-V7 as well as AR-V1 and AR-V9 is regulated coordinately by a single polyadenylation signal in AR intron 3. Blocking this signal with morpholino technology or silencing of the polyadenylation factor CPSF1 caused a splice switch that inhibited expression of AR variants and blocked androgen-independent growth of CRPC cells. Our findings support the development of new therapies targeting the polyadenylation signal in AR intron 3 as a strategy to prevent expression of a broad array of AR variants in CRPC. Cancer Res; 77(19); 5228–35. ©2017 AACR.
ВПЛИВ ПРЕПАРАТУ “ТІОТРИАЗОЛІН” НА СТАН ЕНДОГЕННОЇ ІНТОКСИКАЦІЇ У ПІЗНІЙ ПЕРІОД РОЗВИТКУ ВИРАЗКОВОЇ ХВОРОБИ ШЛУНКА В УМОВАХ ЕКСПЕРИМЕНТАЛЬНОЇ ПНЕВМОНІЇ
Authors: Furdychko L. О. 
Published: August 2017

Пневмонія і виразкова хвороба шлунка – одні з найбільш поширених захворювань людини, які в ХХІ ст. залишаються важливими медико-соціальними проблемами.Мета дослідження – встановити ступінь ендогенної інтоксикації у пізній період розвитку виразкової хвороби шлунка (ВХШ) і експериментальної пневмонії (ЕП), а також вплив препарату “Tіотриазолін” на порушені показники.Матеріали і методи дослідження. Дослідження проводили на 49 морських свинках-самцях масою 180–210 г. Експериментальну пневмонію викликали за методом В. Н. Шляпникова, Т. Л. Солодова, виразкову хворобу шлунка моделювали за методом В. И. Комарова. Визначали вміст МСМ при довжині хвилі 254 нм за методом І. А. Волчегорского, Д. А. Дятлова, Е. І. Львовскої та ін., еритроцитарний індекс інтоксикації (ЕІІ) за методом А. А. Тогобаєва, А. В. Кургузкіна, І. В. Рікуна та ін. Тіотриазолін вводили внутрішньом’язово у дозі 100 мг на 1 кг маси щоденно з 10 до 18 доби експерименту і декапітували тварин під ефірним наркозом на 10 та 18 доби формування запального процесу в легенях і виразкової хвороби шлунка.Результати досліджень та їх обговорення. Еритроцитарний індекс інтоксикації в крові у тварин із ВХШ і ЕП на 10 добу значно підвищився – 85,2 % (p<0,05) відносно контрольних тварин. Результати подальших досліджень ЕІІ на 18 добу цих моделей хвороб виявили його зростання, порівняно з інтактними тваринами, – підвищився на 96,3 % (p<0,05). Рівень МСМ на 10 добу зріс відносно тварин першої групи на 98,5 % (p<0,05), а надалі цей показник зазнав свого апогею – 107,2 % (p<0,05).Висновки. Виявлено наростання ендогенної інтоксикації у пізній період розвитку ЕП і ВХШ. Використання препарату “Тіотриазолін” зумовлює позитивний його вплив на концентрацію ЕІІ і МСМ за умов розвитку ЕП і ВХШ.
ПЕРВИННИЙ ГІПЕРАЛЬДОСТЕРОНІЗМ – ЯК ЙОГО ДІАГНОСТУВАТИ
Authors: Rybakov S. Y. , Shidlovskyi V. O. , Shidlovskyi O. V. 
Published: August 2017

Діагностика первинного гіперальдостеронізму базується на аналізі декількох блоків даних: клінічної картини (анамнез, фізикальний огляд); результатів лабораторного (в основному гормони, функціональні проби) й інструментального обстежень (топічна діагностика). Клінічна картина захворювання, на жаль, надає мало опорних даних для діагностики цієї патології. Процедура діагностики первинного гіперальдостеронізму при підозрі на наявність цієї патології складається з трьох основних етапів: I – встановлення наявності гіперальдостеронізму шляхом визначення концентрації альдостерону, активності реніну в плазмі крові; II – виконання одного або декількох тестів, що підтверджують діагноз; III – визначення форми (варіанта) гіперальдостеронізму за допомогою деяких гормональних проб, функціональних тестів, методів топічної діагностики. Мета дослідження – ознайомити лікарів-кардіологів, ендокринологів, лаборантів, променевих діагностів з методами і принципами діагностики гіперальдостеронізму.Матеріали і методи. Проаналізовано опубліковані результати досліджень багатьох авторів, які присвячені діагностиці гіперальдостеронізму.Результати досліджень та їх обговорення. В огляді проведено аналіз діагностики гіперальдостеронізму за трьома напрямками – клінічним, лабораторним та інструментальним. Кожний із цих напрямків розглянуто з метою встановлення наявності гіперальдостеронізму, виконання підтверджувальних тестів і проб, виявлення його варіанта або форми і топічної діагностики. Крім того, розглянуто різні варіанти співвідношення результатів пропонованих тестів і їх використання для встановлення ді агнозу.Висновки. Діагностика гіперальдостеронізму базується на клінічних тестах. Перевагу у встановленні діагнозу віддають функціональним пробам, лабораторно-інструментальному обстеженню, а в топічній діагностиці – результатам МРТ, КТ, сцинтиграфії.
Plato, Hyperides, and Hellenistic Cult Practice
Authors: Heßler Jan Erik 
Published: August 2017

AbstractThis paper investigates the commemoration of the dead as practised in the Epicurean school: for this purpose, it first discusses the remembrance of the past and of the deceased as constitutive elements of the cult community of the Kepos. The community of the Epicureans is studied in the context of other contemporary associations and Hellenistic ruler cults, and with a view to (possible) connections with the cult of the god Dionysus. In a next step, the paper examines Epicurean testimonies on the subject of commemorating the dead in comparison with passages in Plato and theepitaphioi logoi, especially theepitaphioswritten by Hyperides. This way, some striking parallels emerge, and it becomes evident how deeply Epicurean doctrine and practice were embedded in the context of the late Classical and Hellenistic polis.
Comparing activity engagement of people aged 18 to 64 years with and without Parkinson’s disease
Authors: Bryant Chloe , Gustafsson Louise , Liddle Jacki , Stillerova Tereza 
Published: August 2017

Introduction Measuring activity engagement using the Activity Card Sort Australia (18–64) supports occupational therapists and clients to identify goals for therapeutic interventions. The aim of this study was to investigate activity engagement for people aged 18 to 64 years with and without Parkinson’s disease. Method Thirty-two participants, 16 people with Parkinson’s disease (mean age 57.8) and 16 healthy adults (mean age 53.1), were required to sort 85 visual activity cards into one of five categories: ‘never done’, ‘do not do now’, ‘do now’, ‘do less now’ and ‘given up’. The retained activity values were calculated and compared using the Mann–Whitney U Test. Results The overall retained activity scores were not significantly different ( p = .81); however, the group with Parkinson’s disease had higher retained scores in the physical activities domain ( p = .04) Conclusion The preventative exercise regimes of people with Parkinson’s disease seems to influence activity engagement patterns. A more detailed understanding of activity engagement may further help form the basis of meaningful interventions.
Two Physical Activity Measures: Paffenbarger Physical Activity Questionnaire Versus Aerobics Center Longitudinal Study as Predictors of Adult-Onset Type 2 Diabetes in a Follow-Up Study
Authors: Tonstad Serena , Herring Patti , Lee Jerry , Johnson Jennifer Duxbury 
Published: August 2017

Purpose: To compare 2 self-report methods of measuring weekly minutes of physical activity based on the Aerobics Center Longitudinal Study (ACLS) questionnaire and question 6 of the Paffenbarger Physical Activity Questionnaire (PPAQ) to determine the better predictor of adult-onset type 2 diabetes mellitus (T2DM). Design: An observational, prospective study. Setting: Survey data from the Adventist Health Study-2 (AHS-2) collected between 2002 and 2006 (baseline) and the Psychosocial Manifestations of Religion Sub-Study (PsyMRS), an AHS-2 subset collected 1 to 4 years later. Patients: Nine thousand eight hundred seventy-three male and female participants aged 23 to 106 years (mean, 63 years). Three hundred eighty participants reported adult-onset T2DM at follow-up. Measures: Question 6 from the PPAQ and a question adopted from the ACLS were assessed at baseline. Incident diabetes was defined as participants who reported receiving treatment for adult-onset T2DM in the last 12 months in the PsyMRS and not at baseline. Analysis: Multivariate logistic regression analyses controlled for age, gender, ethnicity, education, body mass index (BMI), diet, and sedentary activity. Each exposure variable was compared to nonexercisers. Results: The PPAQ (odds ratio [OR]: 0.998; 95% confidence interval [CI]: 0.997-1.000) and the ACLS (OR: 0.999; 95% CI: 0.998-1.001) exhibited similar likelihood of predicting incident adult-onset T2DM in a healthy, mixed-gender population when controlling for several confounders. Conclusions: The demonstrative nomenclature of the PPAQ may be more effectual in capturing physically active individuals than the ACLS notwithstanding generalizability and response bias limitations.
Real-world utilization of darbepoetin alfa in cancer chemotherapy patients
Authors: Pan Xiaoyun (Lucy) , Nordstrom Beth L , MacLachlan Sharon , Lin Junji , Xu Hairong , Sharma Anjali , Chandler David , Li Xiaoyan (Shawn) 
Published: August 2017

Objectives To provide an understanding of darbepoetin alfa dose patterns in cancer patients undergoing myelosuppressive chemotherapy starting from 2011. Study design This is a retrospective cohort study using a proprietary outpatient oncology database. Methods Metastatic, solid tumor cancer patients receiving concomitant myelosuppressive chemotherapy and darbepoetin alfa with an associated hemoglobin <10 g/dL during 2011–2015 were identified. The analysis was restricted to the first continuous exposure to chemotherapy agents (maximum allowable gap of 90 days between consecutive exposures) with darbepoetin alfa for each eligible patient. Initial, maintenance, weekly, and cumulative doses of darbepoetin alfa were examined across all darbepoetin alfa users. Subgroup analyses were conducted by chemotherapy type, baseline hemoglobin level, year of chemotherapy, solid tumor type, and initial dosing schedule. Differences in weekly doses across subgroups were evaluated using Wilcoxon rank-sum tests. Results Among 835 eligible patients, over 90% were 50 years or older. Mean chemotherapy course duration was 248 days, and mean duration of darbepoetin alfa treatment was 106 days. The mean weekly darbepoetin alfa dose was 110 µg. Patients received a mean of 4.3 darbepoetin alfa injections in the first chemotherapy course. There were no statistically significant differences (all P values > .05) in weekly dose by chemotherapy type, baseline hemoglobin level, year of chemotherapy, or solid tumor type. Conclusion The average weekly darbepoetin alfa dose among metastatic cancer patients with chemotherapy-induced anemia from this study was 110 µg, which was lower than the labeled dosage for most adults. This estimate did not differ over time, across chemotherapy regimens, baseline hemoglobin levels, or solid tumor types.