bluuebunny/crossref_metadata_2025_split huggingface dataset:
The immunological significance of tumor necrosis factor receptor-associated factors (TRAFs)
Authors: So Takanori 
Published: August 2021

Abstract
The tumor necrosis factor receptor (TNFR)-associated factor (TRAF) family of molecules are intracellular signaling adaptors and control diverse signaling pathways mediated not only by the TNFR superfamily and the Toll-like receptor/IL-1 receptor superfamily but also by unconventional cytokine receptors such as IL-6 and IL-17 receptors. There are seven family members, TRAF1 to TRAF7, in mammals. Exaggerated immune responses induced through TRAF signaling downstream of these receptors often lead to inflammatory and autoimmune diseases including rheumatoid arthritis, inflammatory bowel disease, psoriasis and autoinflammatory syndromes, and thus those signals are major targets for therapeutic intervention. For this reason, it has been very important to understand signaling mechanisms regulated by TRAFs that greatly impact on life/death decisions and the activation, differentiation and survival of cells of the innate and adaptive immune systems. Accumulating evidence suggests that dysregulated cellular expression and/or signaling of TRAFs causes overproduction of pro-inflammatory cytokines, which facilitates aberrant activation of immune cells. In this review, I will explain the structural and functional aspects that are responsible for the cellular activity and disease outcomes of TRAFs, and summarize the findings of recent studies on TRAFs in terms of how individual TRAF family molecules regulate biological and disease processes in the body in both positive and negative ways. This review also discusses how TRAF mutations contribute to human disease.
STAT5 interferes with PD-1 transcriptional activation and affects CD8+ T-cell sensitivity to PD-1-dependent immunoregulation
Authors: Wang Guanning , Tajima Masaki , Honjo Tasuku , Ohta Akio 
Published: August 2021

Abstract
Programmed cell death-1 (PD-1) is a co-inhibitory receptor that dampens immune responses upon interaction with PD-L1 and PD-L2. Although PD-1 expression on T cells is known to be activation-dependent, how cytokines modify its regulation is not fully resolved. Using polyclonal T-cell activation to study cytokine-dependent PD-1 regulation, we found that IL-2 inhibited transcriptional up-regulation of PD-1 despite the promotion of T-cell activation. The IL-2-mediated reduction in PD-1 expression augmented CD8+ T-cell activities against PD-L1-expressing target cells. To study the mechanism of PD-1 reduction, we focused on STAT5 activation in the IL-2 signaling pathway. Bioinformatic analysis suggested a novel conserved PD-1 promoter domain where NFAT and STAT5 can potentially compete with each other for binding. NFAT1 interaction with this domain revealed substantial potency in PD-1 transcription compared to STAT5A, and STAT5A overexpression could quench NFAT1-dependent PD-1 up-regulation in a sequence-specific manner. Chromatin immunoprecipitation analysis of activated T cells showed that IL-2 treatment significantly diminished the binding of NFAT1 and NFAT2 in the hypothesized competition site, while STAT5 binding to the same region was increased. These results raise the possibility that the competition of transcriptional factors might be involved in the fine-tuning of PD-1 expression by cytokines such as IL-2.
Using a new three-dimensional CUBIC tissue-clearing method to examine the brain during experimental cerebral malaria
Authors: Matsuo-Dapaah Julia , Lee Michelle Sue Jann , Ishii Ken J , Tainaka Kazuki , Coban Cevayir 
Published: August 2021

Abstract
Cerebral malaria (CM) is a life-threatening complication of the malaria disease caused by Plasmodium falciparum infection and is responsible for the death of half a million people annually. The molecular pathogenesis underlying CM in humans is not completely understood, although sequestration of infected erythrocytes in cerebral microvessels is thought to play a major role. In contrast, experimental cerebral malaria (ECM) models in mice have been thought to be distinct from human CM, and are mainly caused by inflammatory mediators. Here, to understand the spatial distribution and the potential sequestration of parasites in the whole-brain microvessels during a mouse model of ECM, we utilized the new tissue-clearing method CUBIC (Clear, Unobstructed, Brain/Body Imaging Cocktails and Computational analysis) with light-sheet fluorescent microscopy (LSFM), and reconstructed images in three dimensions (3D). We demonstrated significantly greater accumulation of Plasmodium berghei ANKA (PbANKA) parasites in the olfactory bulb (OB) of mice, compared with the other parts of the brain, including the cerebral cortex, cerebellum and brainstem. Furthermore, we show that PbANKA parasites preferentially accumulate in the brainstem when the OB is surgically removed. This study therefore not only highlights a successful application of CUBIC tissue-clearing technology to visualize the whole brain and its microvessels during ECM, but it also shows CUBIC’s future potential for visualizing pathological events in the whole ECM brain at the cellular level, an achievement that would greatly advance our understanding of human cerebral malaria.
Rapid evaluation of the substrate specificity of 3-nitrobenzoic acid dioxygenase MnbAB via colorimetric detection using Saltzman reagent
Authors: Tomita Hiroya , Katsuyama Yohei , Ohnishi Yasuo 
Published: August 2021

Abstract
Nitroaromatic compounds are essential materials for chemical industry, but they are also potentially toxic environmental pollutants. Therefore, their sensitive detection and degradation are important concerns. The microbial degradation pathways of nitroaromatic compounds have been studied in detail, but their usefulness needs to be evaluated to understand their potential applications in bioremediation. Here, we developed a rapid and relatively sensitive assay system to evaluate the activities and substrate specificities of nitroaromatic dioxygenases involved in the oxidative biodegradation of nitroaromatic compounds. In this system, nitrous acid, which was released from the nitroaromatic compounds by the dioxygenases, was detected and quantified using the Saltzman reagent. Escherichia coli producing the 3-nitrobenzoic acid dioxygenase complex MnbAB from Comamonas sp. JS46 clearly showed the apparent substrate specificity of MnbAB as follows. MnbAB accepted not only 3-nitrobenzoic acid but also several other p- and m-nitrobenzoic acid derivatives as substrates, although it much preferred 3-nitrobenzoic acid to others. Furthermore, the presence of a hydroxy or an amino group at the ortho position of the nitro group decreased the activity of MnbAB. In addition, MnbAB accepted 2-(4-nitrophenyl)acetic acid as a substrate, which has one additional methylene group between the aromatic ring and the carboxy group of 3-nitrobenzoic acid. This is the first report about the detailed substrate specificity of MnbAB. Our system can be used for other nitroaromatic dioxygenases and contribute to their characterization.
Underserved Pacific Islanders With Locally Advanced Cervical Cancer Receive Higher Rates of Standard-of-Care Radiation Treatment Through the Pacific Island Health Care Project and Military Health System Compared to the Average U.S. Population
Authors: Sitler Collin , Bunch Kristen P , Padro David , Miller Caela R 
Published: August 2021

ABSTRACTIntroductionBrachytherapy, with external beam radiation, increases survival in the treatment of locally advanced cervical cancer (LACC). In 2016, Robin et al. reported only 44% of patients received standard-of-care (SOC) brachytherapy in the USA. The Pacific Island Health Care Project has provided humanitarian medical care to women from the U.S. Associated Pacific Islands (USAPI) for three decades at Tripler Army Medical Center (TAMC), a military health care system (MHS) facility. We evaluated whether this underserved and understudied patient population received SOC treatment for LACC at TAMC.Materials and MethodsThe TAMC tumor registry was searched for all cervical cancer cases from 1997 to 2019. Subjects were excluded if they did not have stage IB2-IVA disease and were not from USAPI. The primary outcome was the overall utilization of brachytherapy, and statistical analysis was performed using the chi-square test.ResultsWe identified 214 women with cervical cancer treated at TAMC, of which 67 met the study criteria. Ninety-two percent had squamous cell carcinoma on histology. Of the patients identified, 48 (71.6%, P &lt; .001) were treated with brachytherapy. Fifteen (22.4%) patients received external radiation alone, and four (6.0%) received chemoradiation without brachytherapy. A post-hoc power analysis was conducted with a power of 91.3%.ConclusionsWomen with cervical cancer from USAPI in the PIHCP program treated at TAMC received significantly higher rates of SOC radiation treatment than the U.S. population on average. This highlights the ability of PIHCP, through the MHS, to deliver SOC treatment for cervical cancer to an otherwise underserved patient population.
The Relation of Surgical Volume to Competence: When Is Enough, Enough?
Authors: Carnduff Mary , Place Ronald 
Published: August 2021

ABSTRACT
Given the inherent risk in surgical intervention and the need for the optimal utilization of health care resources, achieving high-quality surgical care is a priority for the American health care system, and competent surgeons are critical to reaching this goal. Despite the multifactorial nature of patient safety and satisfaction, surgeon competence is often oversimplified to an assessment of volume because of the ease of collection and comparison. In any practice model, the analysis of competence is complex, but the components of clinical skill for military surgeons further include multiple areas of expertise, which, although superficially unrelated to surgical currency, augment the overall care delivered by these clinicians. Thus, volume as a solitary indicator of skill excludes the unique circumstances encompassed in military service. In this paper, the factors comprising volume and competence are explained, as well as the additional factors unique to military medicine. Furthermore, process improvements are proposed for assessing and optimizing surgical competence in the Military Health System.
NuSTAR and Swift observations of the extragalactic black hole X-ray binaries
Authors: Jana Arghajit , Naik Sachindra , Chatterjee Debjit , Jaisawal Gaurava K 
Published: August 2021

ABSTRACT
We present the results obtained from detailed spectral and timing studies of extragalactic black hole X-ray binaries LMC X–1 and LMC X–3, using simultaneous observations with Nuclear Spectroscopic Telescope Array (NuSTAR) and Neil Gehrels Swift observatories. The combined spectra in the 0.5–30 keV energy range, obtained between 2014 and 2019, are investigated for both sources. We do not find any noticeable variability in 0.5–30 keV light curves, with 0.1–10 Hz fractional rms estimated to be &lt;2 per cent. No evidence of quasi-periodic oscillations is found in the power density spectra. The sources are found to be in the high soft state during the observations with disc temperature Tin ∼ 1 keV, photon index, Γ &gt; 2.5 and thermal emission fraction, fdisc &gt; 80 per cent. An Fe Kα emission line is detected in the spectra of LMC X–1, though no such feature is observed in the spectra of LMC X–3. From the spectral modelling, the spins of the black holes in LMC X–1 and LMC X–3 are estimated to be in the range of 0.92–0.95 and 0.19−0.29, respectively. The accretion efficiency is found to be, η ∼ 0.13 and η ∼ 0.04 for LMC X–1 and LMC X–3, respectively.
Efficacy of romosozumab for osteoporosis in a patient with osteogenesis imperfecta: A case report
Authors: Uehara Masashi , Nakamura Yukio , Nakano Masaki , Miyazaki Akiko , Suzuki Takako , Takahashi Jun 
Published: August 2021

ABSTRACT
The efficacy of romosozumab for severe osteoporosis is uncertain in patients with osteogenesis imperfecta (OI). This report introduced a severe osteoporotic case of OI to examine the effect of romosozumab on bone fragility. A 64-year-old man with OI was referred to our department for finding out the cause of his repeated fractures. He was medicated with alendronate for only 1 year, 8 years ago, but it did not prevent repeated fractures, and thus, he had not received any treatments for osteoporosis since then. However, recently, the frequency of fractures had increased. At presentation, his lumbar and bilateral total hip bone mineral density (BMD) values were severely decreased to 0.546 and 0.209 g/cm2, respectively. Because of his severe osteoporosis, we started romosozumab treatment with eldecalcitol. Romosozumab (210 mg) was injected subcutaneously every month. At 12 months after drug initiation, his lumbar and total hip BMD increased by 22.0% and 136.4% versus pre-treatment levels, respectively. Bone formation markers increased, and bone resorption markers decreased at 12 months of the therapy. Neither hypocalcaemia nor any other severe adverse effects were observed in this severe osteoporotic case. This study revealed good responses of BMD and bone turnover markers to romosozumab treatment, which can be considered as an effective treatment option for osteoporotic OI patients.
Neurosarcoidosis pathologically diagnosed via biopsy of a normal-sized inguinal lymph node with fluorodeoxyglucose accumulation on positron emission tomography/computed tomography in a patient with a history of brain Ewing’s sarcoma
Authors: Fuwa Masayuki , Tateyama Shodai , Kato Ayaka , Asano Motochika , Taguchi Koichiro , Mori Ichiro , Ikeda Takahide , Kanayama Tomohiro , Shizui Natsuko , Morita Hiroyuki 
Published: August 2021

ABSTRACT
Neurosarcoidosis is a rare disease and is often difficult to diagnose. Herein, we report a case of neurosarcoidosis in a patient with a history of Ewing’s sarcoma of the brain. He presented with fever of unknown origin, and a pathological diagnosis was obtained via biopsy of a normal-sized inguinal lymph node with fluorodeoxyglucose (FDG) accumulation on positron emission tomography/computed tomography (PET/CT). The condition could not have been diagnosed without FDG-PET/CT.
Aspergillus lentulus: An Under-recognized Cause of Antifungal Drug-Resistant Aspergillosis
Authors: Nematollahi Saman , Permpalung Nitipong , Zhang Sean X , Morales Megan , Marr Kieren A 
Published: August 2021

Abstract
Aspergillus lentulus is a drug-resistant species that is phenotypically similar to A. fumigatus. It was discovered as a cause of azole-breakthrough disease, consistent with in vitro resistance. Clinical labs can misidentify the species as fumigatus based on phenotypic typing. We describe 4 recent cases and provide a brief review.
Development of a digital pill and respondent behavioral intervention (PrEPSteps) for HIV pre-exposure prophylaxis adherence among stimulant using men who have sex with men
Authors: Chai Peter R , Mohamed Yassir , Goodman Georgia , Bustamante Maria J , Sullivan Matthew C , Najarro Jesse , Mendez Lizette , Mayer Kenneth H , Boyer Edward W , O’Cleirigh Conall , Rosen Rochelle K 
Published: August 2021

Abstract
The efficacy of pre-exposure prophylaxis (PrEP) for HIV prevention in men who have sex with men (MSM) is contingent upon consistent adherence. Digital pill systems (DPS) provide real-time, objective measurement of ingestions and can inform behavioral adherence interventions. Qualitative feedback was solicited from MSM who use stimulants to optimize a cognitive behavioral therapy (CBT)-based intervention (LifeSteps), used in conjunction with a DPS, to promote PrEP adherence (PrEPSteps). Seven focus groups and one individual qualitative interview were conducted in Boston, MA with cisgender, HIV-negative MSM who reported stimulant use and current PrEP use or interest. Focus groups and interviews explored reactions to the DPS and PrEPSteps messaging components: contingent reinforcement (CR), corrective feedback (CF), LifeSteps, and substance use Screening, Brief Intervention, and Referral to Treatment (SBIRT). Quantitative assessments were administered. Qualitative data were analyzed using applied thematic analysis. Twenty MSM participated. Most were White (N = 12), identified as homosexual or gay (N = 15), and college-educated (N = 15). Ages ranged from 24 to 68 years (median 35.5). Participants were willing to engage with the DPS and viewed it as beneficial for promoting adherence. Confirmatory CR messages were deemed acceptable, and a neutral tone was preferred. CF messages were viewed as most helpful and as promoting individual responsibility. LifeSteps was perceived as useful for contextualizing nonadherence. However, SBIRT was a barrier to DPS use; concerns around potential substance use stigma were reported. MSM who use stimulants were accepting of the DPS and PrEPSteps intervention. CR, CF, and LifeSteps messages were viewed as helpful, with modifications pertaining to tone and content; SBIRT messages were not preferred.
Iodoacetic Acid, a Water Disinfection Byproduct, Disrupts Hypothalamic, and Pituitary Reproductive Regulatory Factors and Induces Toxicity in the Female Pituitary
Authors: Gonzalez Rachel V L , Weis Karen E , Gonsioroski Andressa V , Flaws Jodi A , Raetzman Lori T 
Published: August 2021

Abstract
Iodoacetic acid (IAA) is a water disinfection byproduct (DBP) formed by reactions between oxidizing disinfectants and iodide. In vitro studies have indicated that IAA is one of the most cyto- and genotoxic DBPs. In humans, DBPs have been epidemiologically associated with reproductive dysfunction. In mouse ovarian culture, IAA exposure significantly inhibits antral follicle growth and reduces estradiol production. Despite this evidence, little is known about the effects of IAA on the other components of the reproductive axis: the hypothalamus and pituitary. We tested the hypothesis that IAA disrupts expression of key neuroendocrine factors and directly induces cell damage in the mouse pituitary. We exposed adult female mice to IAA in drinking water in vivo and found 0.5 and 10 mg/l IAA concentrations lead to significantly increased mRNA levels of kisspeptin (Kiss1) in the arcuate nucleus although not affecting Kiss1 in the anteroventral periventricular nucleus. Both 10 mg/l IAA exposure in vivo and 20 μM IAA in vitro reduced follicle stimulating hormone (FSHβ)-positive cell number and Fshb mRNA expression. IAA did not alter luteinizing hormone (LHβ) expression in vivo although exposure to 20 μM IAA decreased expression of Lhb and glycoprotein hormones, alpha subunit (Cga) mRNA in vitro. IAA also had toxic effects in the pituitary, inducing DNA damage and P21/Cdkn1a expression in vitro (20 μM IAA) and DNA damage and Cdkn1a expression in vivo (500 mg/l). These data implicate IAA as a hypothalamic-pituitary-gonadal axis toxicant and suggest the pituitary is directly affected by IAA exposure.
Mast Cells Promote Nitrogen Mustard-Mediated Toxicity in the Lung Associated With Proinflammatory Cytokine and Bioactive Lipid Mediator Production
Authors: Cruz-Hernandez Angela , Mendoza Ryan P , Nguyen Kathleen , Harder Anna , Evans Christopher M , Bauer Alison K , Tewari-Singh Neera , Brown Jared M 
Published: August 2021

AbstractSulfur mustard (SM) has been widely used as a chemical warfare agent including most recently in Syria. Mice exposed to SM exhibit an increase in pro-inflammatory cytokines followed by immune cell infiltration in the lung, however, the mechanisms leading to these inflammatory responses has not been completely elucidated. Mast cells are one of the first responding innate immune cells found at the mucosal surfaces of the lung and have been reported to be activated by SM in the skin. Therefore, we hypothesized that nitrogen mustard (NM: a surrogate for SM) exposure promotes activation of mast cells causing chronic respiratory inflammation. To assess the role of mast cells in NM-mediated pulmonary toxicity, we compared the effects of NM exposure between C57BL/6 and B6.Cg-KitW-sh/HNihrJaeBsmJ (KitW-sh; mast cell deficient) mice. Lung injury was observed in C57BL/6J mice following NM exposure (0.125 mg/kg) at 72 h, which was significantly abrogated in KitW-sh mice. Although both strains exhibited damage from NM, C57BL/6J mice had higher inflammatory cell infiltration and more elevated prostaglandin D2 (PGD2) present in bronchoalveolar lavage fluid compared with KitW-sh mice. Additionally, we utilized murine bone marrow-derived mast cells to assess NM-induced early and late activation. Although NM exposure did not result in mast cell degranulation, we observed an upregulation in PGD2 and IL-6 levels following exposure to NM. Results suggest that mast cells play a prominent role in lung injury induced by NM and may contribute to the acute and potentially long-term lung injury observed caused by SM.
Exploring traffic safety climate with driving condition and driving behaviour: a random parameter structural equation model approach
Authors: Xiao Daiquan , Jin Xiaofei , Xu Xuecai , Ma Changxi , Yuan Quan 
Published: August 2021

Abstract
This study aimed to explore traffic safety climate by quantifying driving conditions and driving behaviour. To achieve the objective, the random parameter structural equation model was proposed so that driver action and driving condition can address the safety climate by integrating crash features, vehicle profiles, roadway conditions and environment conditions. The geo-localized crash open data of Las Vegas metropolitan area were collected from 2014 to 2016, including 27 arterials with 16 827 injury samples. By quantifying the driving conditions and driving actions, the random parameter structural equation model was built up with measurement variables and latent variables. Results revealed that the random parameter structural equation model can address traffic safety climate quantitatively, while driving conditions and driving actions were quantified and reflected by vehicles, road environment and crash features correspondingly. The findings provide potential insights for practitioners and policy makers to improve the driving environment and traffic safety culture.
Direct Comparison of Antibody Responses to Four SARS-CoV-2 Vaccines in Mongolia
Authors: Dashdorj Naranjargal J. , Wirz Oliver F. , Röltgen Katharina , Haraguchi Emily , Buzzanco Anthony S. , Sibai Mamdouh , Wang Hannah , Miller Jacob A. , Solis Daniel , Sahoo Malaya K. , Byambabaatar Sumiya , Bat-Ulzii Purevjargal , Enkhbat Anir , Batbold Enkhtuul , Zulkhuu Delgersaikhan , Ochirsum Byambasuren , Khurelsukh Tungalag , Dalantai Ganbold , Burged Natsagdorj , Baatarsuren Uurtsaikh , Ariungerel Nomin , Oidovsambuu Odgerel , Bungert Andreas S. , Genden Zulkhuu , Yagaanbuyant Dahgwahdorj , Mordorj Altankhuu , Jardetzky Theodore , Wilbur James L. , Wohlstadter Jacob N. , Sigal George B. , Pinsky Benjamin A. , Boyd Scott D. , Dashdorj Naranbaatar D. 
Published: August 2021

AbstractDifferent vaccines for SARS-CoV-2 are approved in various countries, but few direct comparisons of the antibody responses they stimulate have been reported. We collected plasma specimens in July 2021 from 196 Mongolian participants fully vaccinated with one of four Covid vaccines: Pfizer/BioNTech, AstraZeneca, Sputnik V and Sinopharm. Functional antibody testing with a panel of nine SARS-CoV-2 viral variant RBD proteins reveal marked differences in the vaccine responses, with low antibody levels and RBD-ACE2 blocking activity stimulated by the Sinopharm and Sputnik V vaccines in comparison to the AstraZeneca or Pfizer/BioNTech vaccines. The Alpha variant caused 97% of infections in Mongolia in June and early July 2021. Individuals who recover from SARS-CoV-2 infection after vaccination achieve high antibody titers in most cases. These data suggest that public health interventions such as vaccine boosting, potentially with more potent vaccine types, may be needed to control the COVID-19 pandemic in Mongolia and worldwide.