There is great interest in developing a sensitive method being able to quantitatively measure and compare antioxidant potencies of samples of interest against multiple reactive oxygen species (ROS) ...whose imbalance could cause oxidative stress. Here, a sensitive nanoprobe, double-stranded DNA encased single-walled carbon nanotubes (SWNTs) has been developed to determine antioxidant potencies of selected samples (caffeine, regular coffee, and decaffeinated coffee) against ROS, hydrogen peroxide, and hydroxyl radicals. Antioxidant vitamin C and uric acid are used as standards. The method focuses on unique dual optical sensing capability of SWNTs, the rate of spectral suppression when exposed to ROS, and the magnitude of spectral recovery of the ROS-suppressed SWNTs when an antioxidant is added. It is found that the dual sensing capability of SWNTs is still sustained when reacting with the reactive hydroxyl radicals. The results show that caffeine’s antioxidant potency is weak, about one millionth of those of vitamin C and uric acid. It is a better scavenger of hydrogen peroxide and a little less effective for hydroxyl radicals. In comparison, coffee, regardless of regular or decaffeinated, is a more efficient antioxidant than caffeine, having an antioxidant potency about ten thousand times stronger. This work provides a versatile detection method for evaluating the antioxidant potencies of samples of interest against various ROS for chemical, biological, and medical applications.
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IJS, KILJ, NUK, PNG, UL, UM
Concerns regarding the trajectory and long-term sustainability of the surgeon-scientist career path have been widely recognized.1–3 Today there is a lack of support for successful integration of ...basic science and surgical practice with surgical departments receiving a decreasing proportion of the total extramural funding granted by the National Institutes of Health (NIH).2 Here, we examine funding trends within academic surgical and medical departments from 2009 to 2018 in order to assess how surgeon principal investigators rank compared to both their surgical and non-surgical peers. Additionally, medical departments tended to be granted larger awards than surgical departments (Fig. 3d). ...the trend towards more funding being granted to non-clinicians is observed only in surgical departments. The National Institute of Neurological Disorders and Stroke and the American Association of Neurological Surgeons Neurosurgery Research and Education Foundation have implemented targeted research education and career development programs that have led to an increase in NIH-funded neurosurgeon scientists.5,6 In our analysis Neurosurgery had the most significant increase in number of surgeons in the top 10 departmental awardees over time, exemplifying the impact of these programs on future funding.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Glioblastoma (GBM) is highly resistant to treatment and invasion into the surrounding brain is a cancer hallmark that leads to recurrence despite surgical resection. With the emergence of precision ...medicine, patient-derived 3D systems are considered potentially robust GBM preclinical models. In this study, we screened a library of 22 anti-invasive compounds (i.e., NF-kB, GSK-3-B, COX-2, and tubulin inhibitors) using glioblastoma U-251 MG cell spheroids. We evaluated toxicity and invasion inhibition using a 3D Matrigel invasion assay. We next selected three compounds that inhibited invasion and screened them in patient-derived glioblastoma organoids (GBOs). We developed a platform using available macros for FIJI/ImageJ to quantify invasion from the outer margin of organoids. Our data demonstrated that a high-throughput invasion screening can be done using both an established cell line and patient-derived 3D model systems. Tubulin inhibitor compounds had the best efficacy with U-251 MG cells, however, in ex vivo patient organoids the results were highly variable. Our results indicate that the efficacy of compounds is highly related to patient intra and inter-tumor heterogeneity. These results indicate that such models can be used to evaluate personal oncology therapeutic strategies.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Recent studies have determined that inflammasome signaling plays an important role in driving intestinal epithelial cell (IEC) responses to bacterial infections, such as
serovar Typhimurium. There ...are two primary inflammasome pathways, canonical (involving caspase-1) and noncanonical (involving caspase-4 and -5 in humans and caspase-11 in mice). Prior studies identified the canonical inflammasome as the major pathway leading to interleukin-18 (IL-18) release and restriction of
Typhimurium replication in the mouse cecum. In contrast, the human C2Bbe1 colorectal carcinoma cell line expresses little caspase-1 but instead utilizes caspase-4 to respond to
Typhimurium infection. Intestinal enteroid culture has enabled long-term propagation of untransformed IECs from multiple species, including mouse and human. Capitalizing on this technology, we used a genetic approach to directly compare the relative importance of different inflammatory caspases in untransformed mouse and human IECs and transformed human IECs upon
Typhimurium infection
We show that caspase-1 is important for restricting intracellular
Typhimurium replication and initiating IL-18 secretion in mouse IECs but is dispensable in human IECs. In contrast, restriction of intracellular
Typhimurium and production of IL-18 are dependent on caspase-4 in both transformed and untransformed human IECs. Notably, cytosolic replication in untransformed cells from both species was less pronounced than in transformed human cells, suggesting that transformation may impact additional pathways that restrict
Typhimurium replication. Taken together, these data highlight the differences between mouse and human IECs and the utility of studying transformed and untransformed cells in parallel.
Nonmotor symptoms are common among patients with Parkinson's disease (PD) and some may precede disease diagnosis.
We conducted a meta-analysis on the prevalence of selected nonmotor symptoms before ...and after PD diagnosis, using random-effect models. We searched PubMed (1965 through October/November 2012) for the following symptoms: hyposmia, constipation, rapid eye movement sleep behavior disorder, excessive daytime sleepiness, depression, and anxiety. Eligible studies were publications in English with original data on one or more of these symptoms.
The search generated 2,373 non-duplicated publications and 332 met the inclusion criteria, mostly (n = 320) on symptoms after PD diagnosis. For all symptoms, the prevalence was substantially higher in PD cases than in controls, each affecting over a third of the patients. Hyposmia was the most prevalent (75.5% in cases vs. 19.1% in controls), followed by constipation (50% vs. 17.7%), anxiety (39.9% vs. 19.1%), rapid eye movement sleep behavior disorder (37.0% vs. 7.0%), depression (36.6% vs. 14.9%), and excessive daytime sleepiness (33.9% vs. 10.5%). We observed substantial heterogeneities across studies and meta-regression analyses suggested that several factors might have contributed to this. However, the prevalence estimates were fairly robust in several sensitivity analyses. Only 20 studies had data on any symptoms prior to PD diagnosis, but still the analyses revealed higher prevalence in future PD cases than in controls.
These symptoms are common among PD patients both before and after diagnosis. Further studies are needed to understand the natural history of nonmotor symptoms in PD and their etiological and clinical implications.
Inherited peripheral neuropathies (IPNs) represent a broad group of genetically and clinically heterogeneous disorders, including axonal Charcot-Marie-Tooth type 2 (CMT2) and hereditary motor ...neuropathy (HMN). Approximately 60%-70% of cases with HMN/CMT2 still remain without a genetic diagnosis. Interestingly, mutations in HMN/CMT2 genes may also be responsible for motor neuron disorders or other neuromuscular diseases, suggesting a broad phenotypic spectrum of clinically and genetically related conditions. Thus, it is of paramount importance to identify novel causative variants in HMN/CMT2 patients to better predict clinical outcome and progression.
We designed a collaborative study for the identification of variants responsible for HMN/CMT2. We collected 15 HMN/CMT2 families with evidence for autosomal recessive inheritance, who had tested negative for mutations in 94 known IPN genes, who underwent whole-exome sequencing (WES) analyses. Candidate genes identified by WES were sequenced in an additional cohort of 167 familial or sporadic HMN/CMT2 patients using next-generation sequencing (NGS) panel analysis.
Bioinformatic analyses led to the identification of novel or very rare variants in genes, which have not been previously associated with HMN/CMT2 (
,
,
and
); in genes previously associated with HMN/CMT2 but in combination with different clinical phenotypes (
and
), and in the
gene, which has been linked to HMN/CMT2 in only a few cases. These findings were further validated by Sanger sequencing, segregation analyses and functional studies.
These results demonstrate the broad spectrum of clinical phenotypes that can be associated with a specific disease gene, as well as the complexity of the pathogenesis of neuromuscular disorders.
A new calculation module within the PopStats module of the CODIS software package, based on the underlying mathematics presented in the MixKin software package, has been developed for assigning the ...Likelihood Ratio (LR) of DNA mixture profiles. This module uses a semi-continuous model that allows for population structure and allelic drop-out and drop-in but does not require allelic peak heights or other laboratory-specific parameters. This new implementation (named SC Mixture), like MixKin, does not specify or estimate a probability of drop-out. Instead, each contributor to a mixture has an independent drop-out rate, and the probability of the mixture profile for a specified proposition concerning the contributors is integrated over the range of possible drop-out rates. The allelic drop-in rate and the population structure parameter, theta, used by the software are specified by the user. The user can examine up to five contributors to a mixture, however, conditioning on assumed contributors and limiting the number of unknowns in both numerator and denominator hypotheses greatly improves performance. We report results from an extensive validation study performed for ten mixtures with each of one (single source), two, three, four, or five contributors, with four combinations of drop-in rate and a population structure parameter. Each mixture was run as a complete profile or with the random removal of alleles to simulate drop-out. All 1620 combinations were evaluated with PopStats, MixKin, and LRmix and considerable consistency was found among the results with all three packages.
•Semi-continuous model for interpretation of mixtures has been implemented in the PopStats software package of CODIS.•Allows interpretation of cold cases where peak height information is not available.•Allows for population structure, allelic drop-out and drop-in.•Drop-out rates do not need to be specified or estimated.•Extensive validation against existing software.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Asthma is a chronic inflammatory lung disease that affects 18.7 million U.S. adults. Electronic health records (EHRs) are a unique source of information that can be leveraged to understand factors ...associated with asthma in real-life populations. In this study, we identify demographic factors and comorbidities associated with asthma exacerbations among adults according to EHR-derived data and compare these findings to those of epidemiological studies.
We obtained University of Pennsylvania Hospital System EHR-derived data for asthma encounters occurring between 2011 and 2014. Regression analyses were performed to model asthma exacerbation frequency as explained by age, sex, race/ethnicity, health insurance type, smoking status, body mass index (BMI) and various comorbidities. We analyzed data from the National Health and Nutrition Examination Survey (NHANES) from 2001 to 2012 to compare findings with those from the EHR-derived data.
Based on data from 9068 adult patients with asthma, 33.37% had at least one exacerbation over the four-year study period. In a proportional odds logistic regression predicting number of exacerbations during the study period (levels: 0, 1-2, 3-4, 5+ exacerbations), after controlling for age, race/ethnicity, sex, health insurance type, and smoking status, the highest odds ratios (ORs) of significantly associated factors were:
(2.70),
(1.50),
(1.39),
(1.35),
(1.32), and
(1.28). An analysis of NHANES data showed associations for
,
and
with exacerbation frequency in an adjusted model controlling for age, race/ethnicity, sex, financial class and smoking status.
EHR-derived data is helpful to understand exacerbations in real-life asthma patients, facilitating design of detailed studies and interventions tailored for specific populations.
Recent spatial gene expression technologies enable comprehensive measurement of transcriptomic profiles while retaining spatial context. However, existing analysis methods do not address the limited ...resolution of the technology or use the spatial information efficiently. Here, we introduce BayesSpace, a fully Bayesian statistical method that uses the information from spatial neighborhoods for resolution enhancement of spatial transcriptomic data and for clustering analysis. We benchmark BayesSpace against current methods for spatial and non-spatial clustering and show that it improves identification of distinct intra-tissue transcriptional profiles from samples of the brain, melanoma, invasive ductal carcinoma and ovarian adenocarcinoma. Using immunohistochemistry and an in silico dataset constructed from scRNA-seq data, we show that BayesSpace resolves tissue structure that is not detectable at the original resolution and identifies transcriptional heterogeneity inaccessible to histological analysis. Our results illustrate BayesSpace's utility in facilitating the discovery of biological insights from spatial transcriptomic datasets.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
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