DNA damage signals from somatic uterine tissue arrest oogenesis through activated DAF-16.

Germ line integrity is crucial for progeny fitness. Organisms deploy the DNA damage response (DDR) signaling to protect the germ line from genotoxic stress, facilitating the cell-cycle arrest of germ cells and DNA repair or their apoptosis. Cell-autonomous regulation of germ line quality in response to DNA damage is well studied; however, how quality is enforced cell non-autonomously on sensing somatic DNA damage is less known. Using Caenorhabditis elegans, we show that DDR disruption, only in the uterus, when insulin/IGF-1 signaling (IIS) is low, arrests oogenesis in the pachytene stage of meiosis I, in a FOXO/DAF-16 transcription factor-dependent manner. Without FOXO/DAF-16, germ cells of the IIS mutant escape the arrest to produce poor-quality oocytes, showing that the transcription factor imposes strict quality control during low IIS. Activated FOXO/DAF-16 senses DDR perturbations during low IIS to lower ERK/MPK-1 signaling below a threshold to promote germ line arrest. Altogether, we elucidate a new surveillance role for activated FOXO/DAF-16 that ensures optimal germ cell quality and progeny fitness in response to somatic DNA damage.

Prevalence and predictors of female sexual dysfunction among sexually active women in the diabetes prevention program outcomes study.

OBJECTIVE: To determine the burden and identify correlates of female sexual dysfunction (FSD) among women with prediabetes (PreD) and type 2 diabetes (T2D) enrolled in the Diabetes Prevention Program (DPP) Outcomes Study (DPPOS). METHODS: The DPPOS visit included the Female Sexual Function Index (FSFI) to determine sexual function. Of 1464 participants, 1320 (90%) completed the (FSFI) and 426 were sexually active. A backward selection multivariable logistic regression model estimated the odds of FSD for sociodemographic, clinical, and diabetes-related covariates. RESULTS: One hundred and eighty-five (43%) had a score of ≤26.55 and met the criteria for FSD. After adjustment for DPP treatment and age, urinary incontinence (UI) (odds ratio [OR] = 1.91, 95% confidence interval [CI] = 1.15-3.17) and hysterectomy (OR = 1.89, 95% CI = 1.01-3.53) were associated with increased odds of FSD. Increased body mass index was protective for FSD (OR = 0.93 per kg/m2, 95% CI = 0.89-0.96). Michigan Neuropathy Screening Instrument-based peripheral neuropathy (mean±SD scores 1.1±1.3 vs. 0.9±1.1, p < 0.0001) and Electrocardiogram (ECG)-based autonomic dysfunction measures (mean ± SD heart rate levels 64.3 ± 6.8 vs. 65.6 ± 10.2, p = 0.008) were associated with FSD. There were no differences in diabetes rates between women who did (66.5%) and did not (66%) have (p = 0.7). CONCLUSIONS: FSD is prevalent in women with PreD and T2D. Our findings suggest that FSD is associated with neuropathic complications commonly observed in PreD and T2D.

Lessons learned from COVID-19 vaccine acceptance among pregnant and lactating women from two districts in Kenya to inform demand generation efforts for future maternal RSV vaccines.

BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory infections globally, with most RSV-related deaths occurring in infants < 6 months of age. The highest burden of RSV is in low-and-middle income countries, and in sub-Saharan Africa, RSV may be responsible for almost half of all hospital admissions with severe or very severe pneumonia among infants under 1 year. There is a maternal RSV vaccine on the horizon. Our study objective was to better understand how lessons learned from the COVID-19 vaccine experience rollout among pregnant and lactating people in Kenya could inform future maternal RSV vaccine rollout. METHODS: This qualitative study interviewed 16 healthcare providers including doctors, nurses, midwives, community health workers, and vaccinators. Participants were recruited from two counties in Kenya and included healthcare providers that served diverse communities. A grounded theory approach was used to analyze the data. RESULTS: As healthcare providers interviewed were instrumental in COVID-19 vaccine rollout among pregnant women in Kenya, they provided lessons learned from the COVID-19 vaccine experience to inform future maternal RSV vaccine rollout. Community sensitization emerged as the most critical lesson learned, including communication, mobilization, and education. Using communication to ensure community awareness of RSV, community awareness of RSV harms and benefits of RSV maternal vaccines, and providing up-to-date, clear information about maternal RSV vaccines emerged as lessons. Related to mobilization, participants identified the need for healthcare providers and community leaders to gain the trust of communities, and the importance of routinizing the vaccine. Finally, for education, participants outlined critical questions patients would have about a maternal RSV vaccine, including those related to vaccine safety concerns, duration of protection, and vaccine dosing. CONCLUSIONS: This is one of the first studies that has examined how lessons learned from the COVID-19 vaccine rollout for pregnant and lactating women can inform the rollout of future maternal vaccines, including an RSV maternal vaccine. As healthcare providers are directly involved in vaccine rollout, their perspectives are crucial for successful vaccine acceptance.

Innovations in craniovertebral junction training: harnessing the power of mixed reality and head-mounted displays.

OBJECTIVE: The objective of this study was to analyze the potential and convenience of using mixed reality as a teaching tool for craniovertebral junction (CVJ) anomaly pathoanatomy. METHODS: CT and CT angiography images of 2 patients with CVJ anomalies were used to construct mixed reality models in the HoloMedicine application on the HoloLens 2 headset, resulting in four viewing stations. Twenty-two participants were randomly allocated into two groups, with each participant rotating through all stations for 90 seconds, each in a different order based on their group. At every station, objective questions evaluating the understanding of CVJ pathoanatomy were answered. At the end, subjective opinion on the user experience of mixed reality was provided using a 5-point Likert scale. The objective performance of the two viewing modes was compared, and a correlation between performance and participant experience was sought. Subjective feedback was compiled and correlated with experience. RESULTS: In both groups, there was a significant improvement in median (interquartile range [IQR]) objective performance with mixed reality compared with DICOM: 1) group A: case 1, median 6 (IQR 6-7) versus 5 (IQR 3-6), p = 0.009; case 2, median 6 (IQR 6-7) versus 5 (IQR 3-6), p = 0.02; 2) group B: case 1, median 6 (IQR 5-7) versus 4 (IQR 2-5), p = 0.04; case 2, median 6 (IQR 6-7) versus 5 (IQR 3-7), p = 0.03. There was significantly higher improvement in less experienced participants in both groups for both cases: 1) group A: case 1, r = -0.8665, p = 0.0005; case 2, r = -0.8002, p = 0.03; 2) group B: case 1, r = -0.6977, p = 0.01; case 2, r = -0.7417, p = 0.009. Subjectively, mixed reality was easy to use, with less disorientation due to the visible background, and it was believed to be a useful teaching tool. CONCLUSIONS: Mixed reality is an effective teaching tool for CVJ pathoanatomy, particularly for young neurosurgeons and trainees. The versatility of mixed reality and the intuitiveness of the user experience offer many potential applications, including training, intraoperative guidance, patient counseling, and individualized medicine; consequently, mixed reality has the potential to transform neurosurgery.

Crop type discrimination using Geo-Stat Endmember Extraction and machine learning algorithms.

The identification of crop diversity in today's world is very crucial to ensure adaptation of the crop with changing climate for better productivity as well as food security. Towards this, Hyperspectral Remote Sensing (HRS) is an efficient technique based on imaging spectroscopy that offers the opportunity to discriminate crop types based on morphological as well as physiological features due to availability of contiguous spectral bands. The current work utilized the benefits of Airborne Visible Infrared Imaging spectrometer- New Generation (AVIRIS-NG) data and explored the techniques for classification and identification of crop types. The endmembers were identified using the Geo-Stat Endmember Extraction (GSEE) algorithm for pure pixels identification and to generate the spectral library of the different crop types. Spectral feature comparison was done among AVIRIS-NG, Analytical Spectral Device (ASD)-Spectroradiometer and Continuum Removed (CR) spectra. The best-fit spectra obtained with the Reference ASD-Spectroradiometer and Pure Pixel spectral library were then used for crop discrimination using the ten supervised classifiers namely Spectral Angle Mapper (SAM), Spectral Information Divergence (SID), Support Vector Machine (SVM), Minimum Distance Classifier (MDC), Binary Encoding, deep learning-based Convolution Neural Network (CNN) and different algorithms of Ensemble learning such as Tree Bag, AdaBoost (Adaptive Boosting), Discriminant and RUSBoost (Random Under Sampling). In total, nine crop types were identified, namely, wheat, maize, tobacco, sorghum, linseed, castor, pigeon pea, fennel and chickpea. The performance evaluation of the classifiers was made using various metrics like Overall Accuracy, Kappa Coefficient, Precision, Recall and F1 score. The classifier 2D-CNN was found to be the best with Overall Accuracy, Kappa Coefficient, Precision, Recall and F1 score values of 89.065 %, 0.871,87.565%, 89.541% and 88.678% respectively. The output of this work can be utilized for large scale mapping of crop types at the species level in a short interval of time of a large area with high accuracy.

The Emerging Landscape of Social Media Influencers in Public Health Collaborations: A Scoping Review.

Social media content creators or "influencers" are an increasingly influential voice in the public discourse generally, including global perceptions and practices related to health. In response, public health entities are increasingly embracing social media influencers (SMIs) as potential health promotion collaborators. Despite burgeoning interest in the potential of these partnerships, research evaluating this strategy remains limited. To address this gap, we conducted a scoping review to characterize and describe the current landscape of health promotion collaborations with SMIs with a focus on current practices. A search of six electronic databases (PubMed, SCOPUS, Communication & Mass Media Complete, CINAHL Plus, Web of Science, and APA PsycINFO) revealed wide-ranging and inconsistent approaches to these partnerships, including their optimal practices, data reported, and their evaluation criteria. Among the 658 articles initially identified, 15 publications met our inclusion criteria, spanning 7 countries, 8 social media platforms, 11 distinct health topics, and 21 different outcome measures. Basic information necessary for comparing across interventions was often lacking. We noted a lack of consensus on what constitutes an SMI with 53% of included studies lacking any definition or criteria. Although SMIs offer substantial promise as an emerging opportunity for health promotion, particularly for populations that may be otherwise difficult to identify or reach, this review highlights how the current lack of standardized methodologies and metrics prevents meaningful comparisons between collaborations and evaluations of their effectiveness. Based on these findings, we propose four key criteria to aid practitioners in the implementation and evaluation of SMI collaborations.

Endothelin-1 as a novel target for the prevention of metabolic dysfunction with intermittent hypoxia in male participants.

We examined the effect of intermittent hypoxia (IH, a hallmark feature of sleep apnea) on adipose tissue lipolysis and the role of endothelin-1 (ET-1) in this response. We hypothesized that IH can increase ET-1 secretion and plasma free fatty acid (FFA) concentrations. We further hypothesized that inhibition of ET-1 receptor activation with bosentan could prevent any IH-mediated increase in FFA. To test this hypothesis, 16 healthy male participants (32 ± 5 yr, 26 ± 2 kg/m2) were exposed to 30 min of IH in the absence (control) and presence of bosentan (62.5 mg oral twice daily for 3 days prior). Arterial blood samples for ET-1, epinephrine, and FFA concentrations, as well as abdominal subcutaneous adipose tissue biopsies (to assess transcription of cellular receptors/proteins involved in lipolysis), were collected. Additional proof-of-concept studies were conducted in vitro using primary differentiated human white preadipocytes (HWPs). We show that IH increased circulating ET-1, epinephrine, and FFA (P < 0.05). Bosentan treatment reduced plasma epinephrine concentrations and blunted IH-mediated increases in FFA (P < 0.01). In adipose tissue, bosentan had no effect on cellular receptors and proteins involved in lipolysis (P > 0.05). ET-1 treatment did not directly induce lipolysis in differentiated HWP. In conclusion, IH increases plasma ET-1 and FFA concentrations. Inhibition of ET-1 receptors with bosentan attenuates the FFA increase in response to IH. Based on a lack of a direct effect of ET-1 in HWP, we speculate the effect of bosentan on circulating FFA in vivo may be secondary to its ability to reduce sympathoadrenal tone.

Convalescent plasma - An insight into a novel treatment of covid-19 ICU patients.

INTRODUCTION: Various therapies have been tried for Covid disease including the use of antivirals, steroids, monoclonal antibodies and convalescent plasma. METHOD: The study was conducted on convalescent plasma transfused ICU patients. Part A of the study involves clinical outcomes based on gender, age, comorbidities, blood group,and the average length of stay. Part B investigates clinical outcomes in patients transfused with convalescent plasma before and after the November 2021 guidelines. Part C of the study includes patients in cytokine storm and the efficacy of tocilizumab in these patients. RESULT: Out of the 326 ICU patients transfused with convalescent plasma the overall mortality was 152 (53.3 %). On comparing blood groups and clinical outcomes, a clinically significant result was found. A clinically significant association was also seen on comparing the clinical outcome of 18-50 years and 61-70 years age group and in female gender patients. The average number of ICU days had a positive impact on the overall patient survival. Out of the patients in 'cytokine storm' (n = 109), on day 20, the survival percentage in the non-Tocilizumab group showed a downward trend throughout. However, in the Tocilizumab group, the survival percentage remained stable throughout till around day 50. CONCLUSION: Amongst the convalescent plasma transfused ICU patients, females, having blood group B, and an average length of stay of fewer than 20 days had a better chance of survival. The patients given tocilizumab and convalescent plasma had a better chance of survival compared to tocilizumab alone.

Utility of illness symptoms for predicting COVID-19 infections in children.

BACKGROUND: The Centers for Disease Control and Prevention and the American Academy of Pediatrics recommend that symptomatic children remain home and get tested to identify potential coronavirus disease 2019 (COVID-19) cases. As the pandemic moves into a new phase, approaches to differentiate symptoms of COVID-19 versus other childhood infections can inform exclusion policies and potentially prevent future unnecessary missed school days. METHODS: Retrospective analysis of standardized symptom and exposure screens in symptomatic children 0-18 years tested for SARS-CoV-2 at three outpatient sites April to November 2020. Likelihood ratios (LR), number needed to screen to identify one COVID-19 case, and estimated missed school days were calculated. RESULTS: Of children studied (N = 2,167), 88.9% tested negative. Self-reported exposure to COVID-19 was the only factor that statistically significantly increased the likelihood of a positive test for all ages (Positive LR, 5-18 year olds: 5.26, 95% confidence interval (CI): 4.37-6.33; 0-4 year olds: 5.87, 95% CI: 4.67-7.38). Across ages 0-18, nasal congestion/rhinorrhea, sore throat, abdominal pain, and nausea/vomiting/diarrhea were commonly reported, and were either not associated or had decreased association with testing positive for COVID-19. The number of school days missed to identify one case of COVID-19 ranged from 19 to 48 across those common symptoms. CONCLUSIONS: We present an approach for identifying symptoms that are non-specific to COVID-19, for which exclusion would likely lead to limited impact on school safety but contribute to school-days missed. As variants and symptoms evolve, students and schools could benefit from reconsideration of exclusion and testing policies for non-specific symptoms, while maintaining testing for those who were exposed.

Consumer behavior towards cultured meat: A review since 2014.

Cultured meat, also known as 'in-vitro meat' or 'clean meat', holds the potential solution to environmental sustainability along with conventional meat alternatives, including plant-based meat, insects, algae, and pulses. A critical step to its widescale acceptance is consumer perception. Both qualitative research and quantitative analysis are being carried out to enhance the acceptability of cultured meat. In this review, consumer behavior towards cultured meat is accessed to understand the current market scenario. Psychological factors that can hinder or improve cultured meat acceptance are discussed. Consumer social factors geared towards consumer behavior on cultured meat are also summarized. As per the research findings, meat lovers are more likely to try cultured meat owing to the attached sustainability claims. The consumers' concerns about the unnaturalness of cultured meat should be addressed in order to encourage them to get more acquainted with the product and modify their attitudes about it. Marketing tactics of labeling it as 'clean meat' rendered better purchasing as compared to other terms. Furthermore, educating the masses likely reduced the unfamiliarity with newly marketed products resulting in improved consumer perception of cultured meat.

Denoising AVIRIS-NG Data for Generation of New Chlorophyll Indices.

The availability of Airborne Visible and Infrared Imaging Spectrometer-Next Generation (AVIRIS-NG) data has enormous possibilities for quantification of Leaf Chlorophyll Content (LCC). The present study used the AVIRIS-NG campaign site of Western India for generation and validation of new chlorophyll indices by denoising the AVIRIS-NG data. For validation, concurrent to AVIRIS-NG flight overpass, field samplings were performed. The acquired AVIRIS-NG was subjected to Spectral Angle Mapper (SAM) classifier for discriminating the crop types. Three smoothing techniques i.e., Fast-Fourier Transform (FFT), Mean and Savitzky-Golay filters were evaluated for their denoising capability. Raw and filtered data was used for developing new chlorophyll indices by optimizing AVIRIS-NG bands using VIs based on parametric regression algorithms. In total, 20 chlorophyll indices and corresponding 20 models were developed for mapping LCC in the area. SAM identified 17 crop types in the area, while FFT found to be the best for filtering. Performance of these models when checked based on Pearson correlation coefficient (r) and Centered Root Mean Square Difference (CRMSD), indicated that LCC-CCI10 based on normalized difference type index formed through Near Infrared band and blue band is the best estimator of LCC (rcal = 0.73, rval = 0.66, CRMSD = 4.97). The approach was also tested using AVIRIS-NG image of the year 2018, which also showed a promising correlation (r = 0.704, CRSMD = 8.98, Bias = -0.5) between modeled and field LCC.

First-in-human evaluation of [11C]PS13, a novel PET radioligand, to quantify cyclooxygenase-1 in the brain.

PURPOSE: This study assessed whether the newly developed PET radioligand [11C]PS13, which has shown excellent in vivo selectivity in previous animal studies, could be used to quantify constitutive levels of cyclooxygenase-1 (COX-1) in healthy human brain. METHODS: Brain test-retest scans with concurrent arterial blood samples were obtained in 10 healthy individuals. The one- and unconstrained two-tissue compartment models, as well as the Logan graphical analysis were compared, and test-retest reliability and time-stability of total distribution volume (VT) were assessed. Correlation analyses were conducted between brain regional VT and COX-1 transcript levels provided in the Allen Human Brain Atlas. RESULTS: In the brain, [11C]PS13 showed highest uptake in the hippocampus and occipital cortex. The pericentral cortex also showed relatively higher uptake compared with adjacent neocortices. The two-tissue compartment model showed the best fit in all the brain regions, and the results from the Logan graphical analysis were consistent with those from the two-tissue compartment model. VT values showed excellent test-retest variability (range 6.0-8.5%) and good reliability (intraclass correlation coefficient range 0.74-0.87). VT values also showed excellent time-stability in all brain regions, confirming that there was no radiometabolite accumulation and that shorter scans were still able to reliably measure VT. Significant correlation was observed between VT and COX-1 transcript levels (r = 0.82, P = 0.007), indicating that [11C]PS13 binding reflects actual COX-1 density in the human brain. CONCLUSIONS: These results from the first-in-human evaluation of the ability of [11C]PS13 to image COX-1 in the brain justifies extending the study to disease populations with neuroinflammation. CLINICAL TRIAL REGISTRATION: NCT03324646 at https://clinicaltrials.gov/ . Registered October 30, 2017. Retrospectively registered.

Identifying Hypoperfusion in Moyamoya Disease With Arterial Spin Labeling and an [15O]-Water Positron Emission Tomography/Magnetic Resonance Imaging Normative Database.

Background and Purpose- Noninvasive imaging of brain perfusion has the potential to elucidate pathophysiological mechanisms underlying Moyamoya disease and enable clinical imaging of cerebral blood flow (CBF) to select revascularization therapies for patients. We used hybrid positron emission tomography (PET)/magnetic resonance imaging (MRI) technology to characterize the distribution of hypoperfusion in Moyamoya disease and its relationship to vessel stenosis severity, through comparisons with a normative perfusion database of healthy controls. Methods- To image CBF, we acquired [15O]-water PET as a reference and simultaneously acquired arterial spin labeling (ASL) MRI scans in 20 Moyamoya patients and 15 age-matched, healthy controls on a PET/MRI scanner. The ASL MRI scans included a standard single-delay ASL scan with postlabel delay of 2.0 s and a multidelay scan with 5 postlabel delays (0.7-3.0s) to estimate and account for arterial transit time in CBF quantification. The percent volume of hypoperfusion in patients (determined as the fifth percentile of CBF values in the healthy control database) was the outcome measure in a logistic regression model that included stenosis grade and location. Results- Logistic regression showed that anterior ( P<0.0001) and middle cerebral artery territory regions ( P=0.003) in Moyamoya patients were susceptible to hypoperfusion, whereas posterior regions were not. Cortical regions supplied by arteries with stenosis on MR angiography showed more hypoperfusion than normal arteries ( P=0.001), but the extent of hypoperfusion was not different between mild-moderate versus severe stenosis. Multidelay ASL did not perform differently from [15O]-water PET in detecting perfusion abnormalities, but standard ASL overestimated the extent of hypoperfusion in patients ( P=0.003). Conclusions- This simultaneous PET/MRI study supports the use of multidelay ASL MRI in clinical evaluation of Moyamoya disease in settings where nuclear medicine imaging is not available and application of a normative perfusion database to automatically identify abnormal CBF in patients.

Low leptin concentration may identify heart failure patients with central sleep apnea.

Low leptin concentration has been shown to be associated with central sleep apnea in heart failure patients. We hypothesized that low leptin concentration predicts central sleep apnea. Consecutive ambulatory New York Heart Association (NYHA) classes I-IV heart failure patients were studied prospectively, including measurement of serum leptin, echocardiography and polysomnography. Sleep apnea was defined by type (central/mixed/obstructive) and by apnea-hypopnea index ≥5 by polysomnography. Subjects were divided into four groups by polysomnography: (1) central sleep apnea, (2) mixed apnea, (3) no apnea and (4) obstructive sleep apnea. Fifty-six subjects were included. Eighteen subjects were diagnosed with central sleep apnea, 15 with mixed apnea, 12 with obstructive apnea and 11 with no sleep apnea. Leptin concentration was significantly lower in central sleep apnea compared to obstructive apnea (8 ± 10.7 ng mL-1 versus 19.7 ± 14.7 ng mL-1 , P Ë‚ 0.01) or no sleep apnea (8 ± 10.7 ng mL-1 versus 17.1 ± 8.4 ng mL-1 , P Ë‚ 0.01). Logistic regression showed leptin to be associated independently with central sleep apnea [odds ratio (OR): 0.19; 95% confidence interval (CI): 0.06-0.62; area under the curve (AUC): 0.80, P < 0.01]. For the detection of central sleep apnea, a cut-off value for leptin concentration 5 ng mL-1 yielded a sensitivity of 50% and specificity of 89%. In conclusion, a low leptin concentration may have utility for the screening of heart failure patients for central sleep apnea.

Disparities in Hypertension Among African-Americans: Implications of Insufficient Sleep.

PURPOSE OF REVIEW: Sleep deficiency has been proposed as a potential contributor to racial disparities in cardiovascular health. We present contemporary evidence on the unequal burden of insufficient sleep in Blacks/African-Americans and the repercussions for disparate risk of hypertension. RECENT FINDINGS: The prevalence of insufficient sleep is high and rising and has been recognized as an important cardiovascular risk factor. Presumably due to a constellation of environmental, psychosocial, and individual determinants, these risks appear exacerbated in Blacks/African-Americans, who are more likely to experience short sleep than other ethnic/racial groups. Population-based data suggest that the risk of hypertension associated with sleep deficiency is greater in those of African ancestry. However, there is a paucity of experimental evidence linking short sleep duration to blood pressure levels in African-Americans. Blacks/African-Americans may be more vulnerable to sleep deficiency and to its hypertensive effects. Future research is needed to unequivocally establish causality and determine the mechanism underlying the postulated racial inequalities in sleep adequacy and consequent cardiovascular risk.

2-(4-Methylsulfonylphenyl)pyrimidines as Prospective Radioligands for Imaging Cyclooxygenase-2 with PET-Synthesis, Triage, and Radiolabeling.

Cyclooxygenase 2 (COX-2) is an inducible enzyme responsible for the conversion of arachidonic acid into the prostaglandins, PGG2 and PGH2. Expression of this enzyme increases in inflammation. Therefore, the development of probes for imaging COX-2 with positron emission tomography (PET) has gained interest because they could be useful for the study of inflammation in vivo, and for aiding anti-inflammatory drug development targeting COX-2. Nonetheless, effective PET radioligands are still lacking. We synthesized eleven COX-2 inhibitors based on a 2(4-methylsulfonylphenyl)pyrimidine core from which we selected three as prospective PET radioligands based on desirable factors, such as high inhibitory potency for COX-2, very low inhibitory potency for COX-1, moderate lipophilicity, and amenability to labeling with a positronemitter. These inhibitors, namely 6-methoxy-2-(4-(methylsulfonyl)phenyl-N-(thiophen-2ylmethyl)pyrimidin-4-amine (17), the 6-fluoromethyl analogue (20), and the 6-(2-fluoroethoxy) analogue (27), were labeled in useful yields and with high molar activities by treating the 6-hydroxy analogue (26) with [11C]iodomethane, [18F]2-fluorobromoethane, and [d2-18F]fluorobromomethane, respectively. [11C]17, [18F]20, and [d2-18F]27 were readily purified with HPLC and formulated for intravenous injection. These methods allow these radioligands to be produced for comparative evaluation as PET radioligands for measuring COX-2 in healthy rhesus monkey and for assessing their abilities to detect inflammation.

Exosomal RNA from Mycobacterium tuberculosis-Infected Cells Is Functional in Recipient Macrophages.

Exosomes are extracellular vesicles released by cells that carry proteins, lipids and nucleic acids and function in intercellular communication. Previously, we determined that exosomes released from Mycobacterium tuberculosis (M.tb)-infected macrophages carry mycobacterial proteins and lipids. However, the RNA composition within these exosomes has not been defined. In this study, we characterized the exosomes released from M.tb-infected macrophages and identified a cohort of mouse messenger RNA (mRNA) and microRNA (miRNA). Quantitative reverse-transcriptase polymerase chain reaction analysis showed less abundance of miRNAs in exosomes released from infected compared with uninfected macrophages. Moreover, more than 100 transcripts were found to be enriched or unique to exosomes from infected cells including transcripts involved in regulating an immune response. The exosomal RNA could be transferred and expressed in naïve macrophages and was biologically active, stimulating production of inflammatory mediators and inducing apoptosis in recipient cells. Interestingly, we also identified mycobacterial transcripts in exosomes released from infected macrophages. To our knowledge, this is the first study to identify bacterial-derived RNA in exosomes. Our results suggest that exosomal RNA released from M.tb-infected macrophages may have functional and diagnostic potential in the context of a mycobacterial infection.

Long-Delay Arterial Spin Labeling Provides More Accurate Cerebral Blood Flow Measurements in Moyamoya Patients: A Simultaneous Positron Emission Tomography/MRI Study.

BACKGROUND AND PURPOSE: Arterial spin labeling (ASL) MRI is a promising, noninvasive technique to image cerebral blood flow (CBF) but is difficult to use in cerebrovascular patients with abnormal, long arterial transit times through collateral pathways. To be clinically adopted, ASL must first be optimized and validated against a reference standard in these challenging patient cases. METHODS: We compared standard-delay ASL (post-label delay=2.025 seconds), multidelay ASL (post-label delay=0.7-3.0 seconds), and long-label long-delay ASL acquisitions (post-label delay=4.0 seconds) against simultaneous [15O]-positron emission tomography (PET) CBF maps in 15 Moyamoya patients on a hybrid PET/MRI scanner. Dynamic susceptibility contrast was performed in each patient to identify areas of mild, moderate, and severe time-to-maximum (Tmax) delays. Relative CBF measurements by each ASL scan in 20 cortical regions were compared with the PET reference standard, and correlations were calculated for areas with moderate and severe Tmax delays. RESULTS: Standard-delay ASL underestimated relative CBF by 20% in areas of severe Tmax delays, particularly in anterior and middle territories commonly affected by Moyamoya disease (P<0.001). Arterial transit times correction by multidelay acquisitions led to improved consistency with PET, but still underestimated CBF in the presence of long transit delays (P=0.02). Long-label long-delay ASL scans showed the strongest correlation relative to PET, and there was no difference in mean relative CBF between the modalities, even in areas of severe delays. CONCLUSIONS: Post-label delay times of ≥4 seconds are needed and may be combined with multidelay strategies for robust ASL assessment of CBF in Moyamoya disease.

Moderate-to-severe obstructive sleep apnea is associated with telomere lengthening.

Obstructive sleep apnea (OSA) is associated with cardiometabolic diseases. Telomere shortening is linked to hypertension, diabetes mellitus, and cardiovascular diseases. Because these conditions are highly prevalent in OSA, we hypothesized that telomere length (TL) would be reduced in OSA patients. We identified 106 OSA and 104 non-OSA subjects who underwent polysomnography evaluation. Quantitative PCR was used to measure telomere length in genomic DNA isolated from peripheral blood samples. The association between OSA and TL was determined using unadjusted and adjusted linear models. There was no difference in TL between the OSA and non-OSA (control) group. However, we observed a J-shaped relationship between TL and OSA severity: the longest TL in moderate-to-severe OSA [4,918 ± 230 (SD) bp] and the shortest TL in mild OSA (4,735 ± 145 bp). Mean TL in moderate-to-severe OSA was significantly longer than in the control group after adjustment for age, sex, body mass index, hypertension, dyslipidemia, and depression (ß = 96.0, 95% confidence interval: 15.4-176.6, P = 0.020). In conclusion, moderate-to-severe OSA is associated with telomere lengthening. Our findings support the idea that changes in TL are not unidirectional processes, such that telomere shortening occurs with age and disease but may be prolonged in moderate-to-severe OSA.NEW & NOTEWORTHY Here, we show that moderate-to-severe obstructive sleep apnea is associated with longer telomeres, independent of age and cardiovascular risk factors, challenging the hypothesis that telomere shortening is a unidirectional process related to age/disease. A better understanding of the mechanisms underlying telomere dynamics may identify targets for therapeutic intervention in cardiovascular aging/other chronic diseases.

Exosomes and other extracellular vesicles in host-pathogen interactions.

An effective immune response requires the engagement of host receptors by pathogen-derived molecules and the stimulation of an appropriate cellular response. Therefore, a crucial factor in our ability to control an infection is the accessibility of our immune cells to the foreign material. Exosomes-which are extracellular vesicles that function in intercellular communication-may play a key role in the dissemination of pathogen- as well as host-derived molecules during infection. In this review, we highlight the composition and function of exosomes and other extracellular vesicles produced during viral, parasitic, fungal and bacterial infections and describe how these vesicles could function to either promote or inhibit host immunity.