A customizable secure DIY web application for accessing, sharing, and browsing aggregate experimental results and metadata.

Summary: A problem spanning across many research fields is that processed data and research results are often scattered, which makes data access, analysis, extraction, and team sharing more challenging. We have developed a platform for researchers to easily manage tabular data with features like browsing, bookmarking, and linking to external open knowledge bases. The source code, originally designed for genomics research, is customizable for use by other fields or data, providing a no- to low-cost DIY system for research teams. Availability and implementation: The source code of our DIY app is available on https://github.com/Carmona-MoraUCD/Human-Genomics-Browser. It can be downloaded and run by anyone with a web browser, Python3, and Node.js on their machine. The web application is licensed under the MIT license.

A Comparative Study of Histotripsy Parameters for the Treatment of Fibrotic ex-vivo Human Benign Prostatic Hyperplasia Tissue.

Histotripsy is a noninvasive focused ultrasound therapy that mechanically fractionates tissue to create well-defined lesions. In a previous clinical pilot trial to treat benign prostatic hyperplasia (BPH), histotripsy did not result in consistent objective improvements in symptoms, potentially because of the fibrotic and mechanically tough nature of this tissue. In this study, we aimed to identify the dosage required to homogenize BPH tissue by different histotripsy modalities, including boiling histotripsy (BH) and cavitation histotripsy (CH). A method for histotripsy lesion quantification via entropy (HLQE) analysis was developed and utilized to quantify lesion area of the respective treatments. These data were correlated to changes in mechanical stiffness measured by ultrasound shear-wave elastography before and after treatment with each parameter set and dose. Time points corresponding to histologically observed complete lesions were qualitatively evaluated and quantitatively measured. For the BH treatment, complete lesions occurred with >=30s treatment time, with a corresponding maximum reduction in stiffness of -90.9±7.2(s.d.)%. High pulse repetition frequency (PRF) CH achieved a similar reduction to that of BH at 288s (-91.6±6.0(s.d.)%), and low-PRF CH achieved a (-82.1±5.1(s.d.)%) reduction in stiffness at dose >=144s. Receiver operating characteristic curve analysis showed that a >~75% reduction in stiffness positively correlated with complete lesions observed histologically, and can provide an alternative metric to track treatment progression.

Mycobacterium tuberculosis resides in lysosome-poor monocyte-derived lung cells during chronic infection.

Mycobacterium tuberculosis (Mtb) infects lung myeloid cells, but the specific Mtb-permissive cells and host mechanisms supporting Mtb persistence during chronic infection are incompletely characterized. We report that after the development of T cell responses, CD11clo monocyte-derived cells harbor more live Mtb than alveolar macrophages (AM), neutrophils, and CD11chi monocyte-derived cells. Transcriptomic and functional studies revealed that the lysosome pathway is underexpressed in this highly permissive subset, characterized by less lysosome content, acidification, and proteolytic activity than AM, along with less nuclear TFEB, a regulator of lysosome biogenesis. Mtb infection does not drive lysosome deficiency in CD11clo monocyte-derived cells but promotes recruitment of monocytes that develop into permissive lung cells, mediated by the Mtb ESX-1 secretion system. The c-Abl tyrosine kinase inhibitor nilotinib activates TFEB and enhances lysosome functions of macrophages in vitro and in vivo, improving control of Mtb infection. Our results suggest that Mtb exploits lysosome-poor lung cells for persistence and targeting lysosome biogenesis is a potential host-directed therapy for tuberculosis.

Mycobacterium tuberculosis resides in lysosome-poor monocyte-derived lung cells during chronic infection.

Mycobacterium tuberculosis (Mtb) persists in lung myeloid cells during chronic infection. However, the mechanisms allowing Mtb to evade elimination are not fully understood. Here, we determined that in chronic phase, CD11clo monocyte-derived lung cells termed MNC1 (mononuclear cell subset 1), harbor more live Mtb than alveolar macrophages (AM), neutrophils, and less permissive CD11chi MNC2. Transcriptomic and functional studies of sorted cells revealed that the lysosome biogenesis pathway is underexpressed in MNC1, which have less lysosome content, acidification, and proteolytic activity than AM, and less nuclear TFEB, a master regulator of lysosome biogenesis. Mtb infection does not drive lysosome deficiency in MNC1. Instead, Mtb recruits MNC1 and MNC2 to the lungs for its spread from AM to these cells via its ESX-1 secretion system. The c-Abl tyrosine kinase inhibitor nilotinib activates TFEB and enhances lysosome function of primary macrophages and MNC1 and MNC2 in vivo, improving control of Mtb infection. Our results indicate that Mtb exploits lysosome-poor monocyte-derived cells for in vivo persistence, suggesting a potential target for host-directed tuberculosis therapy.

Lupus Cardiomyopathy and Nephritis Associated With Adalimumab and Cytomegalovirus Infection in a Patient With Seronegative Rheumatoid Arthritis: A Case of Rhupus Syndrome.

Tumor necrosis factor-alpha (TNF-α) inhibitors are associated with lupus-like disease, known as anti-TNF-α-induced lupus (ATIL). Cytomegalovirus (CMV) was reported to exacerbate lupus in the literature. To date, systemic lupus erythematosus (SLE) triggered by adalimumab in the setting of CMV infection has never been described. We present an unusual case of a 38-year-old female with a past medical history of seronegative rheumatoid arthritis (SnRA) who developed SLE associated with the use of adalimumab and CMV infection. She had severe SLE features including lupus nephritis and cardiomyopathy. The medication was discontinued. She was initiated on pulse steroid therapy and discharged with an aggressive regimen for SLE, including prednisone, mycophenolate mofetil, and hydroxychloroquine. She remained on the medications until a year later upon follow-up. ATIL from adalimumab usually manifests only mild symptoms of SLE such as arthralgia, myalgia, and pleurisy. Nephritis is very rare, and cardiomyopathy is unprecedented. Concomitant CMV infection might contribute to disease severity. Patients with SnRA may have an increased risk of developing SLE later when exposed to such medications and infection.

Mycobacterium tuberculosis resides in lysosome-poor monocyte-derived lung cells during chronic infection.

Mycobacterium tuberculosis (Mtb) infects cells in multiple lung myeloid cell subsets and causes chronic infection despite innate and adaptive immune responses. However, the mechanisms allowing Mtb to evade elimination are not fully understood. Here, using new methods, we determined that after T cell responses have developed, CD11clo monocyte-derived lung cells termed MNC1 (mononuclear cell subset 1), harbor more live Mtb compared to alveolar macrophages (AM), neutrophils, and less permissive CD11chi MNC2. Bulk RNA sequencing of sorted cells revealed that the lysosome biogenesis pathway is underexpressed in MNC1. Functional assays confirmed that Mtb-permissive MNC1 have less lysosome content, acidification, and proteolytic activity than AM, and less nuclear TFEB, a master regulator of lysosome biogenesis. Mtb infection does not drive lysosome deficiency in MNC1 in vivo. Instead, Mtb recruits MNC1 and MNC2 to the lungs for its spread from AM to these cell subsets as a virulence mechanism that requires the Mtb ESX-1 secretion system. The c-Abl tyrosine kinase inhibitor nilotinib activates TFEB and enhances lysosome function of primary macrophages in vitro and MNC1 and MNC2 in vivo, improving control of Mtb infection. Our results indicate that Mtb exploits lysosome-poor monocyte-derived cells for in vivo persistence, suggesting a potential target for host-directed tuberculosis therapy.

Physical Activity as a Predictor of Chronic Pain Following Pediatric Spinal Surgery.

OBJECTIVES: (1) Characterize objective physical activity patterns via actigraphy over 4 months postspinal fusion surgery, and (2) examine associations between activity patterns at 2-week and chronic postsurgical pain (CPSP) status at 4 months. MATERIALS AND METHODS: Data from 109 youth (10 to 18 y) who underwent spinal fusion surgery at a children's hospital in the Northwestern United States were analyzed. Youth completed questionnaires and actigraphic assessment of physical activity presurgery, and 2 weeks and 4 months postsurgery. RESULTS: Eighteen percent of youth developed CPSP at 4 months. Presurgery physical activity was similar for youth with and without CPSP. At 2 weeks postsurgery, daily activity levels were lower for youth who developed CPSP as compared with those who did not, including lower mean activity (168 vs. 212 counts/min, P=0.01), fewer activity bouts (n=1.7 vs. 2.6, P=0.02), and shorter bout duration (27 vs. 40 min, P=0.02). Differences in activity were maintained at 4 months such that youth with CPSP had lower mean activity (284 vs. 334 counts/min, P=0.03), as well as greater proportion time spent sedentary and lower proportion time in light activity than youth without CPSP. In adjusted models examining 2-week actigraphy as a predictor of 4-month pain status, mean activity (odds ratio=0.99, P=0.04) and number of activity bouts (odds ratio=0.79, P=0.02) were associated with subsequent CPSP status over and above 2-week pain intensity. DISCUSSION: Lower activity engagement during the initial weeks following spinal fusion surgery was associated with development of CPSP, suggesting early physical activity limitations as a risk factor for CPSP in youth. Understanding recovery patterns is critical for identifying those at risk for chronic pain and implementing early interventions.

Psychosocial Predictors of Acute and Chronic Pain in Adolescents Undergoing Major Musculoskeletal Surgery.

Acute and chronic pain delay recovery and impair outcomes after major pediatric surgery. Understanding unique risk factors for acute and chronic pain is critical to developing effective treatments for youth at risk. We aimed to identify adolescent and family psychosocial predictors of acute and chronic postsurgical pain after major surgery in adolescents. Participants included 119 youth age 10 to 18 years (Mage = 14.9; 78.2% white) undergoing major musculoskeletal surgery and their parents. Participants completed presurgery baseline questionnaires, with youth reporting on baseline pain, anxiety, depression, insomnia and sleep quality, and parents reporting on parental catastrophizing and family functioning. At baseline, 2-week, and 4-month postsurgery, youth completed 7 days of daily pain diaries and reported on health-related quality of life. Sequential logistic regression models examined presurgery predictors of acute and chronic postsurgical pain, defined as significant pain with impairment in health-related quality of life. Acute pain was experienced by 27.2% of youth at 2 weeks, while 19.8% of youth met criteria for chronic pain at 4 months. Baseline pain predicted acute pain (odds ratio [OR] = 1.96; 95% confidence interval [CI] = 1.32-2.90), while depressive symptoms (OR = 1.22; 95%CI = 1.01-1.47), and sleep quality (OR = 0.26; 95%CI = 0.08-0.83) predicted chronic pain. Tailored interventions need to be developed and incorporated into perioperative care to address risk factors for acute and chronic pain. PERSPECTIVE: Longitudinal results demonstrate adolescents' presurgery pain severity predicts acute postsurgical pain, while depressive symptoms and poor sleep quality predict chronic postsurgical pain. Tailored interventions should address separate risk factors for acute and chronic pain after adolescent surgery.

A Review of Recent Advances in Ultrasound, Placed in the Context of Pain Diagnosis and Treatment.

Ultrasound plays a significant role in the diagnosis and treatment of pain, with significant literature reaching back many years, especially with regard to diagnostic ultrasound and its use for guiding needle-based delivery of drugs. Advances in ultrasound over at least the last decade have opened up new areas of inquiry and potential clinical efficacy in the context of pain diagnosis and treatment. Here we offer an overview of the recent literature associated with ultrasound and pain in order to highlight some promising frontiers at the intersection of these two subjects. We focus first on peripheral application of ultrasound, for which there is a relatively rich, though still young, literature. We then move to central application of ultrasound, for which there is little literature but much promise.

Innate and ozone-induced airway hyperresponsiveness in obese mice: role of TNF-α.

Innate airway hyperresponsiveness (AHR) and augmented responses to ozone, an asthma trigger, are characteristics of obese mice. Systemic inflammation, a condition of increased circulating concentrations of inflammatory moieties, occurs in obesity. We hypothesized that TNF-α, via its effects as a master effector of this systemic inflammation, regulates innate AHR and augmented responses to ozone in obese mice. Therefore, we examined pulmonary inflammation and airway responsiveness in unexposed or ozone-exposed (2 ppm for 3 h) lean wild-type and obese Cpe(fat) mice that were TNF-α sufficient or deficient. Cpe(fat) mice lack carboxypeptidase E, which regulates satiety. Compared with wild type, Cpe(fat) mice had elevated serum IL-17A, G-CSF, KC, MCP-1, IL-9, MIG, and leptin, indicating systemic inflammation. Despite reductions in most of these moieties in TNF-α-deficient vs. -sufficient Cpe(fat) mice, we observed no substantial difference in airway responsiveness in these two groups of mice. Ozone-induced increases in bronchoalveolar lavage (BAL) neutrophils and macrophages were lower, but ozone-induced AHR and increases in BAL hyaluronan, osteopontin, IL-13, and protein carbonyls, a marker of oxidative stress, were augmented in TNF-α-deficient vs. -sufficient Cpe(fat) mice. Our data indicate that TNF-α has an important role in promoting the systemic inflammation but not the innate AHR of obesity, suggesting that the systemic inflammation of obesity is not the major driver of this AHR. TNF-α is required for the augmented effects of acute ozone exposure on pulmonary inflammatory cell recruitment in obese mice, whereas TNF-α protects against ozone-induced AHR in obese mice, possibly by suppressing ozone-induced oxidative stress.

γδ T cells are required for pulmonary IL-17A expression after ozone exposure in mice: role of TNFα.

Ozone is an air pollutant that causes pulmonary symptoms. In mice, ozone exposure causes pulmonary injury and increases bronchoalveolar lavage macrophages and neutrophils. We have shown that IL-17A is important in the recruitment of neutrophils after subacute ozone exposure (0.3 ppm for 24-72 h). We hypothesized that γδ T cells are the main producers of IL-17A after subacute ozone. To explore this hypothesis we exposed wildtype mice and mice deficient in γδ T cells (TCRδ-/-) to ozone or room air. Ozone-induced increases in BAL macrophages and neutrophils were attenuated in TCRδ-/- mice. Ozone increased the number of γδ T cells in the lungs and increased pulmonary Il17a mRNA expression and the number of IL-17A+ CD45+ cells in the lungs and these effects were abolished in TCRδ-/- mice. Ozone-induced increases in factors downstream of IL-17A signaling, including G-CSF, IL-6, IP-10 and KC were also decreased in TCRδ-/- versus wildtype mice. Neutralization of IL-17A during ozone exposure in wildtype mice mimicked the effects of γδ T cell deficiency. TNFR2 deficiency and etanercept, a TNFα antagonist, also reduced ozone-induced increases in Il17a mRNA, IL-17A+ CD45+ cells and BAL G-CSF as well as BAL neutrophils. TNFR2 deficient mice also had decreased ozone-induced increases in Ccl20, a chemoattractant for IL-17A+ γδ T cells. Il17a mRNA and IL-17A+ γδ T cells were also lower in obese Cpefat versus lean WT mice exposed to subacute ozone, consistent with the reduced neutrophil recruitment observed in the obese mice. Taken together, our data indicate that pulmonary inflammation induced by subacute ozone requires γδ T cells and TNFα-dependent recruitment of IL-17A+ γδ T cells to the lung.

Augmented pulmonary responses to acute ozone exposure in obese mice: roles of TNFR2 and IL-13.

BACKGROUND: Acute ozone (O(3)) exposure results in greater inflammation and airway hyperresponsiveness (AHR) in obese versus lean mice. OBJECTIVES: We examined the hypothesis that these augmented responses to O(3) are the result of greater signaling through tumor necrosis factor receptor 2 (TNFR2) and/or interleukin (IL)-13. METHODS: We exposed lean wild-type (WT) and TNFR2-deficient (TNFR2(-/-)) mice, and obese Cpe(fat) and TNFR2-deficient Cpe(fat) mice (Cpe(fat)/TNFR2(-/-)), to O(3) (2 ppm for 3 hr) either with or without treatment with anti-IL-13 or left them unexposed. RESULTS: O(3)-induced increases in baseline pulmonary mechanics, airway responsiveness, and cellular inflammation were greater in Cpe(fat) than in WT mice. In lean mice, TNFR2 deficiency ablated O(3)-induced AHR without affecting pulmonary inflammation; whereas in obese mice, TNFR2 deficiency augmented O(3)-induced AHR but reduced inflammatory cell recruitment. O(3) increased pulmonary expression of IL-13 in Cpe(fat) but not WT mice. Flow cytometry analysis of lung cells indicated greater IL-13-expressing CD(4+) cells in Cpe(fat) versus WT mice after O(3) exposure. In Cpe(fat) mice, anti-IL-13 treatment attenuated O(3)-induced increases in pulmonary mechanics and inflammatory cell recruitment, but did not affect AHR. These effects of anti-IL-13 treatment were not observed in Cpe(fat)/TNFR2(-/-) mice. There was no effect of anti-IL-13 treatment in WT mice. CONCLUSIONS: Pulmonary responses to O(3) are not just greater, but qualitatively different, in obese versus lean mice. In particular, in obese mice, O(3) induces IL-13 and IL-13 synergizes with TNF via TNFR2 to exacerbate O(3)-induced changes in pulmonary mechanics and inflammatory cell recruitment but not AHR.

Obesity and airway responsiveness: role of TNFR2.

Obese mice exhibit innate airway hyperresponsiveness (AHR), a feature of asthma. Tumor necrosis factor alpha (TNFα) is implicated in the disease progression and chronic inflammatory status of both obesity and asthma. TNF acts via two TNF receptors, TNFR1 and TNFR2. To examine the role of TNFR2 in the AHR observed in obese mice, we generated obese Cpe(fat) mice that were either sufficient or deficient in TNFR2 (Cpe(fat) and Cpe(fat)/TNFR2(-/-) mice, respectively) and compared them with their lean controls (WT and TNFR2(-/-) mice). Compared to WT mice, Cpe(fat) mice exhibited AHR to aerosolized methacholine (measured using the forced oscillation technique) which was ablated in Cpe(fat)/TNFR2(-/-) mice. Bioplex or ELISA assay indicated significant increases in serum leptin, G-CSF, IL-7, IL-17A, TNFα, and KC in obese versus lean mice, as well as significant obesity-related increases in bronchoalveolar lavage fluid (BALF) G-CSF and IP-10, regardless of TNFR2 status. Importantly, BALF IL-17A was significantly increased over lean controls in Cpe(fat) but not Cpe(fat)/TNFR2(-/-) mice. Functional annotation clustering of significantly affected genes identified from microarray analysis comparing gene expression in lungs of Cpe(fat) and WT mice, identified blood vessel morphogenesis as the gene ontology category most affected by obesity. This category included several genes associated with AHR, including endothelin and trkB. Obesity increased pulmonary mRNA expression of endothelin and trkB in TNFR2 sufficient but not deficient mice. Our results indicate that TNFR2 signaling is required for the innate AHR that develops in obese mice, and suggest that TNFR2 may act by promoting IL-17A, endothelin, and/or trkB expression.

Role of TNFR1 in the innate airway hyperresponsiveness of obese mice.

The purpose of this study was to examine the role of tumor necrosis factor receptor 1 (TNFR1) in the airway hyperresponsiveness characteristic of obese mice. Airway responsiveness to intravenous methacholine was measured using the forced oscillation technique in obese Cpe(fat) mice that were either sufficient or genetically deficient in TNFR1 (Cpe(fat) and Cpe(fat)/TNFR1(-/-) mice) and in lean mice that were either sufficient or genetically deficient in TNFR1 [wild-type (WT) and TNFR1(-/-) mice]. Compared with lean WT mice, Cpe(fat) mice exhibited airway hyperresponsiveness. Airway hyperresponsives was also greater in Cpe(fat)/TNFR1(-/-) than in Cpe(fat) mice. Compared with WT mice, Cpe(fat) mice had increases in bronchoalveolar lavage fluid concentrations of several inflammatory moieties including eotaxin, IL-9, IP-10, KC, MIG, and VEGF. These factors were also significantly elevated in Cpe(fat)/TNFR1(-/-) vs. TNFR1(-/-) mice. Additional moieties including IL-13 were also elevated in Cpe(fat)/TNFR1(-/-) vs. TNFR1(-/-) mice but not in Cpe(fat) vs. WT mice. IL-17A mRNA expression was greater in Cpe(fat)/TNFR1(-/-) vs. Cpe(fat) mice and in TNFR1(-/-) vs. WT mice. Analysis of serum indicated that obesity resulted in systemic as well as pulmonary inflammation, but TNFR1 deficiency had little effect on this systemic inflammation. Our results indicate that TNFR1 is protective against the airway hyperresponsiveness associated with obesity and suggest that effects on pulmonary inflammation may be contributing to this protection.

Impact of aging on pulmonary responses to acute ozone exposure in mice: role of TNFR1.

CONTEXT: Chamber studies in adult humans indicate reduced responses to acute ozone with increasing age. Age-related changes in TNFα have been observed. TNFα induced inflammation is predominantly mediated through TNFR1. OBJECTIVE: To examine the impact of aging on inflammatory responses to acute ozone exposure in mice and determine the role of TNFR1 in age-related differences. MATERIALS AND METHODS: Wildtype and TNFR1 deficient (TNFR1(-/-)) mice aged 7 or 39 weeks were exposed to ozone (2 ppm for 3 h). Four hours after exposure, bronchoalveolar lavage (BAL) was performed and BAL cells, cytokines, chemokines, and protein were examined. RESULTS: Ozone-induced increases in BAL neutrophils and in neutrophil chemotactic factors were lower in 39- versus 7-week-old wildtype, but not (TNFR1(-/-)) mice. There was no effect of TNFR1 genotype in 7-week-old mice, but in 39-week-old mice, BAL neutrophils and BAL concentrations of MCP-1, KC, MIP-2, IL-6 and IP-10 were significantly greater following ozone exposure in TNFR1(-/-) versus wildtype mice. BAL concentrations of the soluble form of the TNFR1 receptor (sTNFR1) were substantially increased in 39-week-old versus 7-week-old mice, regardless of exposure. DISCUSSION AND CONCLUSION: The data suggest that increased levels of sTNFR1 in the lungs of the 39-week-old mice may neutralize TNFα and protect these older mice against ozone-induced inflammation.