Blockade of the interleukin-1 (IL-1) pathway has been used therapeutically in several inflammatory diseases including arthritis and cryopyrin-associated periodic syndrome (CAPS). These conditions ...frequently affect women of childbearing age and continued usage of IL-1 specific treatments throughout pregnancy has been reported. IL-1 is involved in pregnancy complications and its blockade could have therapeutic potential. We systematically reviewed all reported cases of IL-1 blockade in human pregnancy to assess safety and perinatal outcomes. We searched several databases to find reports of specific blockade of the IL-1 pathway at any stage of pregnancy, excluding broad spectrum or non-specific anti-inflammatory intervention. Our literature search generated 2439 references of which 22 studies included, following extensive review. From these, 88 different pregnancies were assessed. Most (64.8%) resulted in healthy term deliveries without any obstetrical/neonatal complications. Including pregnancy exposed to Anakinra or Canakinumab, 12 (15.0%) resulted in preterm birth and one stillbirth occurred. Regarding neonatal complications, 2 cases of renal agenesis (2.5%) were observed, and 6 infants were diagnosed with CAPS (7.5%). In conclusion, this systematic review describes that IL-1 blockade during pregnancy is not associated with increased adverse perinatal outcomes, considering that treated women all presented an inflammatory disease associated with elevated risk of pregnancy complications.
Ribosomal RNAs (rRNAs) are the most abundant cellular RNAs, and their synthesis from rDNA repeats by RNA polymerase I accounts for the bulk of all transcription. Despite substantial variation in rRNA ...transcription rates across cell types, little is known about cell-type-specific factors that bind rDNA and regulate rRNA transcription to meet tissue-specific needs. Using hematopoiesis as a model system, we mapped about 2,200 ChIP-seq datasets for 250 transcription factors (TFs) and chromatin proteins to human and mouse rDNA and identified robust binding of multiple TF families to canonical TF motifs on rDNA. Using a 47S-FISH-Flow assay developed for nascent rRNA quantification, we demonstrated that targeted degradation of C/EBP alpha (CEBPA), a critical hematopoietic TF with conserved rDNA binding, caused rapid reduction in rRNA transcription due to reduced RNA Pol I occupancy. Our work identifies numerous potential rRNA regulators and provides a template for dissection of TF roles in rRNA transcription.
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•Multiple cell-type-specific TFs bind canonical motifs on rDNA•The hematopoietic TF CEBPA binds to active rDNA alleles at a conserved site•CEBPA promotes RNA Pol I occupancy and rRNA transcription in myeloid progenitors•We present “47S-FISH-Flow,” a sensitive assay to quantify nascent rRNA
Antony et al. mapped existing ChIP-seq datasets to human and mouse rDNA and identified binding profiles of cell-type-specific transcription factors (TFs). The myeloid TF CEBPA bound rDNA at a conserved motif, and its degradation reduced rDNA occupancy of the RNA Pol I-RRN3 complex and nascent 47S rRNA transcription.
Introduction
The EXTRACT‐PE trial evaluated the safety and performance of the Indigo Aspiration System (Penumbra Inc.) with an 8F continuous mechanical aspiration thrombectomy system for the ...treatment of pulmonary embolism (PE). This subgroup analysis evaluates performance outcomes of patients with main pulmonary artery (PA) emboli versus discrete unilateral or bilateral PA emboli without main PA involvement.
Methods
The EXTRACT‐PE trial was a prospective, single‐arm, multicenter trial that enrolled 119 patients with acute submassive PE. Emboli location was collected at the time of enrollment, CT obstruction was measured and assessed by a Core Lab, and patients were grouped on whether emboli involved the main PA (with or without branch vessels) or not (branch vessels alone). Procedural device time, changes in the right ventricle to left ventricle (RV/LV) ratio, and systolic PA pressure from pre‐and posttreatment were compared between the two groups.
Results
Out of the 119 patients enrolled, 118 had core lab‐assessed clot locations. Forty‐five (38.1%) had emboli that involved the main PA and 73 (61.9%) had only branch emboli. No significant difference was observed between these groups for 30‐day mortality, procedural device time, changes in RV/LV ratio, reduction in CT Obstruction Index, or for systolic PA pressure from pre‐and posttreatment. The mean absolute reduction in clot burden was significant in both groups.
Conclusion
Continuous mechanical aspiration thrombectomy with the 8F Indigo Aspiration System was effective at improving clinical outcomes for submassive PE patients regardless of emboli location, and clot burden was significantly reduced in both groups.
The broad-line region (BLR) of active galactic nuclei (AGNs) traces gas close to the central supermassive black hole (BH). Recent reverberation mapping (RM) and interferometric spectro-astrometry ...data have enabled detailed investigations of the BLR structure and dynamics as well as estimates of the BH mass. These exciting developments have motivated comparative investigations of BLR structures using different broad emission lines. In this work, we have developed a method to simultaneously model multiple broad lines of the BLR from a single-epoch spectrum. We applied this method to the five strongest broad emission lines (H α , H β , H γ , Pa β , and He I λ 5876) in the UV-to-near-IR spectrum of NGC 3783, a nearby Type I AGN that has been well studied by RM and interferometric observations. Fixing the BH mass to the published value, we fit these line profiles simultaneously to constrain the BLR structure. We find that the differences between line profiles can be explained almost entirely as being due to different radial distributions of the line emission. We find that using multiple lines in this way also enables one to measure some important physical parameters, such as the inclination angle and virial factor of the BLR. The ratios of the derived BLR time lags are consistent with the expectation of theoretical model calculations and RM measurements.
Abstract
Auction-derived steers (n = 36; initial BW = 284 ± 11 kg) were received to compare performance, rumination characteristics, and rumen pH differences due to alternative ration energy ...densities and feed management strategies during a 56 d receiving study. Cattle were weighed on day -1 and randomized to 1 of 3 treatments. Time spent ruminating was quantified with a three-axis accelerometer ear-tag. Rumen pH and temperature were logged in a random subset (n = 6 per treatment) by a ruminal bolus. Cattle were processed identically and housed in individual pens. The modified-live virus respiratory vaccination was delayed until day 28. The finisher (FIN) cattle were provided their daily feed as a high energy density (1.39 Mcal NEg/kg) diet. The finisher + hay (FIN+H) cattle were provided the same diet but were also offered 0.5% BW DM as coastal Bermudagrass hay on days 1, 4, 7, 10, 13, 16, 19, 22, 25, and 28. The control (CON) cattle were fed a low energy density (0.93 Mcal NEg/kg) diet from day 0 to 7, then transitioned to the FIN diet by replacing an additional 25% of the daily feed call with FIN every 7 d until 100% of the diet was FIN on day 29. Feed offering for CON was increased more aggressively (0.45 kg DM daily for days 1 to 7, every other day for day 8 to 14) than FIN and FIN+H (0.45 kg DM every other day for days 1 to 7, daily for days 8 to 14). Performance and DMI were analyzed using PROC MIXED in SAS with treatment as a fixed effect. Rumination, pH, and temperature models included repeated measures. There was no treatment difference observed for BW, average daily gain (ADG), or G:F (P ≥ 0.12). There was a treatment × day interaction (P = 0.06) for rumen temperature, where FIN increased more rapidly following vaccination on day 28 compared to CON (P ≤ 0.04). Daily rumination minutes were greater (P < 0.01) for CON than FIN from days 7 to 22. Additionally, CON had the greatest (P < 0.01) hourly rumination from 2000 to 0800 hours. Lower minimum daily rumen pH occurred in FIN+H (P ≤ 0.06) on weeks 1, 2 and 6 to 8 compared to CON. There were minimal statistical differences in area under the curve or time below pH thresholds, probably due to large animal-to-animal variation. Hourly rumen pH was reduced (P ≤ 0.05) for FIN vs. FIN+H and CON during the initial 28 d, but greater (P = 0.05) for FIN and FIN+H during the final 28 d. When cattle are individually fed, greater energy density rations can be fed initially without compromising performance, but this needs to be evaluated in group pens where greater DMI variation is probable.
Abstract
The study objectives were to determine the effect of oral hydration therapy and bovine respiratory disease (BRD) on rumination behavior, rumen pH, and rumen temperature. A random subset of ...high-risk, auction-sourced bulls from 3 truckload blocks (initial BW = 188.9 ± 19.1 kg) were fitted with a collar containing a 3-axis accelerometer to quantify rumination time and activity (n = 58) and administered a rumen pH and temperature data logging bolus (n = 33). At arrival, subset calves (n = 2 per pen) were balanced across treatment pens (n = 15 per treatment; n = 10 animals per pen) and randomized to receive 0.57 L water/45.4 kg BW from a modified oral drenching apparatus (H2O) or no water administration (CON). Standard arrival processing procedures were implemented including surgical castration. Modified-live virus respiratory vaccination was delayed until day 28. Technicians assigned a clinical illness score (CIS) daily; calves with CIS ≥ 2 and rectal temperature ≥ 40 °C were considered a BRD case (RCASE) and treated with an antimicrobial. The fixed effect of BRD cases vs. nontreated cohorts (RCON) was determined retrospectively using data from the accelerometer collar (n = 19 and 29) and rumen bolus (n = 12 and 21, for RCASE and RCON, respectively). Daily means and hourly means across days throughout the 56-d observation period were generated. Fixed effects were analyzed using the mixed model procedure with repeated measures. Daily rumen temperature was altered (P = 0.04) such that peak rumen temperature occurred earlier for H2O, whereas CON had increased (P ≤ 0.01) rumen temperature following delayed vaccination on day 28. Calves diagnosed with BRD had a transiently decreased (P = 0.04) active minutes between days 9 and 32, decreased (P < 0.01) active minutes between 0800 and 2000 h, decreased (P < 0.01) rumination time between 2000 and 0400 h, greater (P < 0.01) rumen temperature until delayed vaccination on day 28, and greater (P < 0.01) hourly rumen temperature between 0900 and 0300, and altered (P < 0.01) rumen pH. Earlier peak rumen temperature observed in H2O may indicate physiological modification enabling a more pronounced inflammatory response. Differences in rumination behavior and activity may be useful for early BRD detection.
Micronutrient deficiencies are common in pregnant women due to low dietary intake and increased requirements for fetal development. Low maternal micronutrient status is associated with a range of ...pregnancy pathologies involving placental dysfunction, including fetal growth restriction (FGR), small-for-gestational age (SGA), pre-eclampsia and preterm birth. However, clinical trials commonly fail to convincingly demonstrate beneficial effects of supplementation of individual micronutrients, attributed to heterogeneity and insufficient power, potential interactions and lack of mechanistic knowledge of effects on the placenta. We aimed to provide current evidence of relationships between selected micronutrients (vitamin D, vitamin A, iron, folate, vitamin B12) and adverse pregnancy outcomes, combined with understanding of actions on the placenta. Following a systematic literature search, we reviewed data from clinical,
and
studies of micronutrient deficiency and supplementation. Key findings are potential effects of micronutrient deficiencies on placental development and function, leading to impaired fetal growth. Studies in human trophoblast cells and rodent models provide insights into underpinning mechanisms. Interestingly, there is emerging evidence that deficiencies in all micronutrients examined induce a pro-inflammatory state in the placenta, drawing parallels with the inflammation detected in FGR, pre-eclampsia, stillbirth and preterm birth. Beneficial effects of supplementation are apparent
and in animal models and for combined micronutrients in clinical studies. However, greater understanding of the roles of these micronutrients, and insight into their involvement in placental dysfunction, combined with more robust clinical studies, is needed to fully ascertain the potential benefits of supplementation in pregnancy.
The angular size of the broad line region (BLR) of the nearby active galactic nucleus NGC 3783 has been spatially resolved by recent observations with VLTI/GRAVITY. A reverberation mapping (RM) ...campaign has also recently obtained high quality light curves and measured the linear size of the BLR in a way that is complementary to the GRAVITY measurement. The size and kinematics of the BLR can be better constrained by a joint analysis that combines both GRAVITY and RM data. This, in turn, allows us to obtain the mass of the supermassive black hole in NGC 3783 with an accuracy that is about a factor of two better than that inferred from GRAVITY data alone. We derive
M
BH
= 2.54
−0.72
+0.90
× 10
7
M
⊙
. Finally, and perhaps most notably, we are able to measure a geometric distance to NGC 3783 of 39.9
−11.9
+14.5
Mpc. We are able to test the robustness of the BLR-based geometric distance with measurements based on the Tully–Fisher relation and other indirect methods. We find the geometric distance is consistent with other methods within their scatter. We explore the potential of BLR-based geometric distances to directly constrain the Hubble constant,
H
0
, and identify differential phase uncertainties as the current dominant limitation to the
H
0
measurement precision for individual sources.
Chronic obstructive pulmonary disease (COPD) is a condition punctuated by acute exacerbations commonly triggered by viral and/or bacterial infection. Early identification of exacerbation triggers is ...important to guide appropriate therapy, but currently available tests are slow and imprecise. Volatile organic compounds (VOCs) can be detected in exhaled breath and have the potential to be rapid tissue-specific biomarkers of infection etiology.
To determine whether volatile organic compound measurement could distinguish viral from bacterial infection in COPD.
We used serial sampling within
and
studies to elucidate the dynamic changes that occur in VOC production during acute respiratory viral infection. Highly sensitive gas chromatography-mass spectrometry techniques were used to measure VOC production from infected airway epithelial-cell cultures and in exhaled breath samples from healthy subjects experimentally challenged with rhinovirus (RV)-A16 and from subjects with COPD with naturally occurring exacerbations.
We identified a novel VOC signature comprising decane and other long-chain alkane compounds that is induced during RV infection of cultured airway epithelial cells and is also increased in the exhaled breath from healthy subjects experimentally challenged with RV and from patients with COPD during naturally occurring viral exacerbations. These compounds correlated with the magnitude of antiviral immune responses, viral burden, and exacerbation severity but were not induced by bacterial infection, suggesting that they represent a specific virus-inducible signature.
Our study highlights the potential for measurement of exhaled breath VOCs as rapid, noninvasive biomarkers of viral infection. Further studies are needed to determine whether measurement of these signatures could be used to guide more targeted therapy with antibiotic/antiviral agents for COPD exacerbations.
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•Key material and technique developments to prepare nano-colloidal particle probes.•Particles attached were minimally affected by glue and localized on the cantilever apex.•The probes ...were also functional in a model Metered Dose Inhaler liquid medium.•Nano-probes allow the study of fundamental forces in nano-colloidal systems.
Current colloidal probe preparation techniques face several challenges in the production of functional probes using particles ⩽5μm. Challenges include: glue encapsulated particles, glue altered particle properties, improper particle or agglomerate attachment, and lengthy procedures. We present a method to rapidly and reproducibly produce functional micro and nano-colloidal probes.
Using a six-step procedure, cantilevers mounted on a custom designed 45° holder were used to approach and obtain a minimal amount of epoxy resin (viscosity of ∼14,000cP) followed by a single micron/nano particle on the apex of a tipless cantilever. The epoxy and particles were prepared on individual glass slides and subsequently affixed to a 10× or 40× optical microscope lens using another custom designed holder. Scanning electron microscopy and comparative glue–colloidal probe measurements were used to confirm colloidal probe functionality.
The method presented allowed rapid and reproducible production of functional colloidal probes (80% success). Single nano-particles were prominently affixed to the apex of the cantilever, unaffected by the epoxy. Nano-colloidal probes were used to conduct topographical, instantaneous force, and adhesive force mapping measurements in dry and liquid media conveying their versatility and functionality in studying nano-colloidal systems.
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