Non-coding nucleotides and amino acids near the active site regulate peptide deformylase expression and inhibitor susceptibility in Chlamydia trachomatis

Chlamydia trachomatis, an obligate intracellular bacterium, is a highly prevalent human pathogen. Hydroxamic-acid-based matrix metalloprotease inhibitors can effectively inhibit the pathogen both in vitro and in vivo, and have exhibited therapeutic potential. Here, we provide genome sequencing data indicating that peptide deformylase (PDF) is the sole target of the inhibitors in this organism. We further report molecular mechanisms that control chlamydial PDF (cPDF) expression and inhibition efficiency. In particular, we identify the σ66-dependent promoter that controls cPDF gene expression and demonstrate that point mutations in this promoter lead to resistance by increasing cPDF transcription. Furthermore, we show that substitution of two amino acids near the active site of the enzyme alters enzyme kinetics and protein stability

Sleep quality in individuals diagnosed with colorectal cancer: Factors associated with sleep disturbance as patients transition off treatment

To identify patient characteristics associated with sleep disturbance and worsening of sleep in individuals diagnosed with localized colorectal cancer and assess heterogeneity in these relationships. Methods: Data were from the MY-Health study, a community-based observational study of adults diagnosed with cancer. Patient-Reported Outcomes Measurement Information System® Sleep Disturbance, Anxiety, Depression, Fatigue, and Pain Interference measures were administered. Participants self-reported demographics, comorbidities, and treatment information. Regression mixture and multiple regression models were used to evaluate the relationship between sleep disturbance and patient characteristics cross-sectionally at an average of 10 months after diagnosis (n = 613) as well as change in sleep disturbance over a 6-month period (n = 361). Results: Pain, anxiety, fatigue, and the existence of multiple comorbid conditions had statistically significant relationships with sleep disturbance (B = 0.09, 0.22, 0.29, and 1.53, respectively; P < 0.05). Retirement (B = -2.49) was associated with sleep quality in the cross-sectional model. Worsening anxiety (B = 0.14) and fatigue (B = 0.20) were associated with worsening sleep disturbance, and more severe sleep disturbance 10 months after diagnosis (B = -0.21) was associated with improvement in sleep quality after diagnosis (P < 0.05). No evidence of latent subgroups of patients (heterogeneity) was present. Conclusions: Pain, anxiety, fatigue, employment, and comorbid conditions were associated with sleep disturbance, but regression coefficients were small (< |2.5|). Results suggest that screening for anxiety, depression, fatigue, or pain is not sufficient for identifying sleep disturbance. Given the negative consequences of sleep disturbance, sleep disturbance screening may be warranted

Relationship between sleep and exercise as colorectal cancer survivors transition off treatment

Purpose The primary objective of this study was to evaluate the relationship between exercise and sleep disturbance in a sample of individuals diagnosed with stage I, II, and III colorectal cancer (CRC) as patients transitioned off first-line treatment. We also sought to identify heterogeneity in the relationship between sleep disturbance and exercise. Methods Data were obtained from the MY-Health study, a community-based observational study of adults diagnosed with cancer. Patient-Reported Outcomes Measurement Information System® (PROMIS) measures (e.g., PROMIS Sleep) were administered, and participants self-reported demographics, comorbidities, cancer treatment, and exercise. Regression mixture and multiple regression models were used to evaluate the relationship between sleep disturbance and exercise cross-sectionally at an average of 10 months after diagnosis, and the change in sleep disturbance over a 7-month period, from approximately 10 to 17 months post-diagnosis. Results Patients whose exercise was categorized as likely at or above American College of Sports Medicine’s guidelines did not report statistically better sleep quality compared to patients who were classified as not active. However, retirement (B = − 2.4), anxiety (B = 0.21), and fatigue (B = 0.24) had statistically significant relationships with sleep disturbance (p < 0.05). Increase in exercise was not significantly associated with a decrease in sleep disturbance. No statistical heterogeneity was revealed in the relationship between sleep and exercise. Conclusions Further prospective research using an objective measure of exercise is warranted to confirm or refute the nature of the relationship between exercise and sleep disturbance in individuals diagnosed with CRC transitioning off first-line treatment

Neuroinflammation and Neuronal Loss Precede Aβ Plaque Deposition in the hAPP-J20 Mouse Model of Alzheimer’s Disease

Recent human trials of treatments for Alzheimer's disease (AD) have been largely unsuccessful, raising the idea that treatment may need to be started earlier in the disease, well before cognitive symptoms appear. An early marker of AD pathology is therefore needed and it is debated as to whether amyloid-βAβ? plaque load may serve this purpose. We investigated this in the hAPP-J20 AD mouse model by studying disease pathology at 6, 12, 24 and 36 weeks. Using robust stereological methods, we found there is no neuron loss in the hippocampal CA3 region at any age. However loss of neurons from the hippocampal CA1 region begins as early as 12 weeks of age. The extent of neuron loss increases with age, correlating with the number of activated microglia. Gliosis was also present, but plateaued during aging. Increased hyperactivity and spatial memory deficits occurred at 16 and 24 weeks. Meanwhile, the appearance of plaques and oligomeric Aβ were essentially the last pathological changes, with significant changes only observed at 36 weeks of age. This is surprising given that the hAPP-J20 AD mouse model is engineered to over-expresses Aβ. Our data raises the possibility that plaque load may not be the best marker for early AD and suggests that activated microglia could be a valuable marker to track disease progression.Funding provided by Iain S. Gray Foundation, Stanley and John Roth, Patricia A. Quick foundation, David King, Doug Battersby, Tony and Vivian Howland-Rose, Walter and Edith Sheldon, Gleneagle Securities, Bill Gruy, Geoffrey Towner, Amadeus Energy Ltd., Nick and Melanie Kell, J. O. and J. R. Wicking Trust and the Mason Foundation, the New South Wales Government, through their office for Science and Medical Research, and SpinalCure Australia. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Towards Efficient Detection of Small Near-Earth Asteroids Using the Zwicky Transient Facility (ZTF)

We describe ZStreak, a semi-real-time pipeline specialized in detecting small, fast-moving near-Earth asteroids (NEAs) that is currently operating on the data from the newly-commissioned Zwicky Transient Facility (ZTF) survey. Based on a prototype originally developed by Waszczak et al. (2017) for the Palomar Transient Factory (PTF), the predecessor of ZTF, ZStreak features an improved machine-learning model that can cope with the $10\times$ data rate increment between PTF and ZTF. Since its first discovery on 2018 February 5 (2018 CL), ZTF/ZStreak has discovered $45$ confirmed new NEAs over a total of 232 observable nights until 2018 December 31. Most of the discoveries are small NEAs, with diameters less than $\sim100$ m. By analyzing the discovery circumstances, we find that objects having the first to last detection time interval under 2 hr are at risk of being lost. We will further improve real-time follow-up capabilities, and work on suppressing false positives using deep learning.Comment: PASP in pres

Measuring Coverage in MNCH:A Validation Study Linking Population Survey Derived Coverage to Maternal, Newborn, and Child Health Care Records in Rural China

Accurate data on coverage of key maternal, newborn, and child health (MNCH) interventions are crucial for monitoring progress toward the Millennium Development Goals 4 and 5. Coverage estimates are primarily obtained from routine population surveys through self-reporting, the validity of which is not well understood. We aimed to examine the validity of the coverage of selected MNCH interventions in Gongcheng County, China.We conducted a validation study by comparing women's self-reported coverage of MNCH interventions relating to antenatal and postnatal care, mode of delivery, and child vaccinations in a community survey with their paper- and electronic-based health care records, treating the health care records as the reference standard. Of 936 women recruited, 914 (97.6%) completed the survey. Results show that self-reported coverage of these interventions had moderate to high sensitivity (0.57 [95% confidence interval (CI): 0.50-0.63] to 0.99 [95% CI: 0.98-1.00]) and low to high specificity (0 to 0.83 [95% CI: 0.80-0.86]). Despite varying overall validity, with the area under the receiver operating characteristic curve (AUC) ranging between 0.49 [95% CI: 0.39-0.57] and 0.90 [95% CI: 0.88-0.92], bias in the coverage estimates at the population level was small to moderate, with the test to actual positive (TAP) ratio ranging between 0.8 and 1.5 for 24 of the 28 indicators examined. Our ability to accurately estimate validity was affected by several caveats associated with the reference standard. Caution should be exercised when generalizing the results to other settings.The overall validity of self-reported coverage was moderate across selected MNCH indicators. However, at the population level, self-reported coverage appears to have small to moderate degree of bias. Accuracy of the coverage was particularly high for indicators with high recorded coverage or low recorded coverage but high specificity. The study provides insights into the accuracy of self-reports based on a population survey in low- and middle-income countries. Similar studies applying an improved reference standard are warranted in the future

Implications of MMP9 for Blood Brain Barrier Disruption and Hemorrhagic Transformation Following Ischemic Stroke.

Numerous studies have documented increases in matrix metalloproteinases (MMPs), specifically MMP-9 levels following stroke, with such perturbations associated with disruption of the blood brain barrier (BBB), increased risk of hemorrhagic complications, and worsened outcome. Despite this, controversy remains as to which cells release MMP-9 at the normal and pathological BBB, with even less clarity in the context of stroke. This may be further complicated by the influence of tissue plasminogen activator (tPA) treatment. The aim of the present review is to examine the relationship between neutrophils, MMP-9 and tPA following ischemic stroke to elucidate which cells are responsible for the increases in MMP-9 and resultant barrier changes and hemorrhage observed following stroke

Association of triglyceride-glucose index with clinical outcomes in patients with acute ischemic stroke receiving intravenous thrombolysis.

Intravenous tissue plasminogen activator (tPA) remains the cornerstone of recanalization therapy for acute ischemic stroke (AIS), albeit with varying degrees of response. The triglyceride-glucose (TyG) index is a novel marker of insulin resistance, but association with outcomes among AIS patients who have received tPA has not been well elucidated. We studied 698 patients with AIS who received tPA from 2006 to 2018 in a comprehensive stroke centre. TyG index was calculated using the formula: ln[fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]. TyG index was significantly lower in patients that survived at 90-days than those who died (8.61 [Interquartile Range: 8.27-8.99] vs 8.76 [interquartile range: 8.39-9.40], p = 0.007). In multivariate analysis, TyG index was significantly associated with 90-day mortality (OR: 2.12, 95% CI: 1.39-3.23, p = 0.001), poor functional outcome (OR: 1.41 95% CI: 1.05-1.90, p = 0.022), and negatively associated with early neurological improvement (ENI) (OR: 0.68, 95% CI: 0.52-0.89, p = 0.004). There was no association between TyG index and symptomatic intracranial hemorrhage. 'High TyG' (defined by TyG index ≥ 9.15) was associated with mortality, poor functional outcomes and no ENI. In conclusion, the TyG index, a measure of insulin resistance, was significantly associated with poorer clinical outcomes in AIS patients who received tPA