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SAR on NRF2 inhibitor MSU38225 has led to a compound that inhibits expression of NRF2 target genes, reduces proliferation of lung cancer cells through G2/M arrest, and lowers cell migration.

Liquid crystalline elastomers (LCEs) are crosslinked polymer networks that combine the elastic properties of rubber with the anisotropic properties of liquid crystals. Multifunctionality and responsivity can be programmed into LCEs by patterning their local orientation, which is difficult to achieve in other monolithic material systems. Advances in the synthesis and alignment of LCEs have paved the way for their functional integration in robotics, optics, consumer products, energy and healthcare devices. In this Review, we discuss recent advances in materials chemistry and processing that have contributed to the resurgence in LCE research. We examine the mechanical response of LCEs to stimuli and survey approaches for mechanical alignment, surface-enforced alignment, field-induced alignment and rheological alignment. The Review concludes with an over-the-horizon outlook discussing current challenges and emerging research opportunities. Liquid crystalline elastomers are stimuli-responsive polymeric materials whose mechanical properties can be programmed by patterning their local orientation, making them promising candidates to serve as low-density actuators and functional elements in various applications. This Review discusses the synthesis and processing of liquid crystalline elastomers, with a focus on alignment methods and potential applications.

Activation of myosin light-chain kinase (MLCK) by calcium ions (Ca2+) and calmodulin (CaM) plays an important role in numerous cellular functions including vascular smooth muscle contraction and cellular motility. Despite extensive biochemical analysis of this system, aspects of the mechanism of activation remain controversial, and competing theoretical models have been proposed for the binding of Ca2+and CaM to MLCK. The models are analytically solvable for an equilibrium steady state and give rise to distinct predictions that hold regardless of the numerical values assigned to parameters. These predictions form the basis of a recently proposed, multi-part experimental strategy for model discrimination. Here we implement this strategy by measuring CaM-MLCK binding using anin vitroFRET system. This system uses the CaM-binding region of smooth muscle MLCK protein to link two fluorophores to form an MLCK FRET Reporter (FR). Biochemical and biophysical experiments have established that FR can be reliably used to analyze MLCK-CaM binding. We assessed the binding of either wild-type CaM, or mutant CaM with one or more defective EF-hand domains, to FR. Interpretation of binding data in light of the mathematical models suggests a partially ordered mechanism for binding of CaM to MLCK. Complementary data collected using orthogonal approaches that directly quantify CaM-MLCK binding further supports our conclusions.

Disruptions to the maternally inherited allele UBE3A, encoding for an E3 ubiquitin ligase, leads to the manifestation of Angelman Syndrome (AS). While this disorder is rare, the symptoms are severe and lifelong including but not limited to: intractable seizures, abnormal EEG's, ataxic gait, lack of speech, and most notably an abnormally happy demeanor with easily provoked laughter. Currently, little is known about the neurophysiological underpinnings of UBE3A leading to such globally severe phenotypes. Utilizing the newest AS rat model, comprised of a full UBE3A deletion, we aimed to elucidate novel mechanistic actions and potential therapeutic targets. This report demonstrates for the first time that catalytically active UBE3A protein is detectable within cerebrospinal fluid (CSF) of wild type rats but distinctly absent in AS rat CSF. Microdialysis within the rat hippocampus also showed that UBE3A protein is located in the interstitial fluid of wild type rat brains but absent in AS animals. This protein maintains catalytic activity and appears to be regulated in a dynamic activity-dependent manner. LAY SUMMARY: Angelman syndrome (AS) is a rare genetic disorder caused by the loss of the UBE3A gene within the central nervous system. Although we have identified the gene responsible for AS, we still have a long way to go to fully understand its function in vivo. Here we report that UBE3A is present within normal cerebrospinal fluid (CSF) but distinctly absent in AS CSF. Furthermore, we demonstrate that UBE3A is secreted and that this may occur in a dynamic activity-dependent fashion. Extracellular UBE3A maintained its ubiquitinating activity, thus suggesting that UBE3A may have a novel role outside of neurons. Autism Res 2021, 14: 645-655. © 2021 International Society for Autism Research and Wiley Periodicals LLC.

Background: Bone–patellar tendon–bone (BTB) and hamstring autografts are the most common grafts used for anterior cruciate ligament (ACL) reconstruction. Patient preferences should be accounted for as a part of shared decision making. Purpose/Hypothesis: The purpose of this study was to perform a discrete choice experiment that evaluated patient preferences toward ACL autografts. We hypothesized that there would be no difference in patient preferences between groups. Study Design: Cross-sectional study. Methods: Patients aged 18 to 25 years who underwent shoulder arthroscopy at a single institution between 2013 and 2019 were included in the study as a proxy for healthy controls. Patients with a history of ACL tear were excluded. A discrete choice experiment was developed from a literature search and used the following data points as they pertain to BTB or hamstring autograft: risk of developing a significant complication, return-to-play rate, risk of anterior knee pain with kneeling, and risk of additional surgery due to graft failure. Included patients completed a custom survey in which they were asked to choose between “surgery A” (hamstring) and “surgery B” (BTB). Results: A total of 107 participants were included in the analysis. Of these participants, 39 (36.5%) chose surgery A (hamstring) and 68 (63.6%) chose surgery B (BTB). When comparing the hamstring group with the BTB group, there was no significant difference in age, sex, body mass index, race, level of education, or employment status. However, 80.5% of self-reported athletes preferred BTB ( P = .008). When controlling for age, sex, and body mass index, patients in the BTB group were more likely to rate return to sport (risk ratio [RR] = 1.49 [95% CI, 1.18-1.98]; P = .001) and the risk of requiring additional surgery due to graft failure (RR = 1.26 [95% CI, 1.02-1.58]; P = .037) as highly important. Conversely, they were less likely than patients in the hamstring group to rate pain while kneeling (RR = 0.65 [95% CI, 0.98-1.05]; P < .001) and complication risk (RR = 0.75 [95% CI, 0.59-0.94]; P = .013) as important. Conclusion: The study hypothesis was rejected, as patient values did affect ACL graft choice preference. Utilizing patient-selected values in a quantifiable way can benefit the shared decision-making process before ACL reconstruction.

A total of 710 pigs (Line 400 × 200, DNA, Columbus, net energy (NE)) were used in two experiments (Exp. 1: initially, 6.3 ± 0.05 kg; Exp. 2: initially, 6.8 ± 0.05 kg) to evaluate the effects of two medium-chain fatty acid (MCFA) based products on nursery pig growth performance. Following their arrival at the nursery facility, pigs were randomized to pens (five pigs per pen) and allowed a 4-d acclimation period. Thereafter, pens of pigs were blocked by initial weight and randomized to dietary treatment. In Exp. 1, the dietary treatments were a dose titration of: 0%, 0.5%, 1.0%, or 2.0% MCFA-based additive, as well as a diet including 1.0% MCFA from a 1:1:1 blend of C6:0, C8:0, and C10:0. In Exp.2, dietary treatments consisted of a basal diet containing no MCFA (control), the control diet with a 1.0% inclusion of four different blends of MCFA, lactic acid, and monolaurin or a diet with 1.0% added MCFA (a 1:1:1 blend of C6:0, C8:0, and C10:0). The four blends consisted of 50% C6:0, 20% lactic acid, and increasing levels of monolaurin (0%, 10%, 20%, and 30%) at the expense of C12:0 (30%, 20%, 10%, and 0%). Treatment diets were formulated and manufactured in two dietary phases. Data were analyzed as a randomized complete block design with pen as the experimental unit. In Exp. 1, overall (days 0–34), increasing CaptiSURE increased (linear, P ≤ 0.014) average daily gain (ADG) and average daily feed intake (ADFI). Feed efficiency improved (quadratic, P = 0.002) with increasing CaptiSURE up to 1.0% of the diet with no benefit thereafter. There was no evidence for differences between pigs fed 1.0% CaptiSURE and pigs fed the 1.0% MCFA blend of C6:0, C8:0, and C10:0. In Exp. 2, overall (days 0–35), pigs fed the 1.0% 1:1:1 MCFA blend had increased (P < 0.034) ADFI and ADG resulting in 0.9 kg greater final weight (P = 0.014) compared with the control group. There was no evidence that the mean performance of pigs fed the four blends of MCFA, lactic acid, and monolaurin were different from the pigs fed the control diet. In summary, the addition of a 1.0% 1:1:1 blend of C6:0, C8:0, and C10:0 in nursery pig diets improved ADG, ADFI, and gain to feed ratio (G:F) compared with pigs fed the control diet. In addition, providing nursery pigs with the MCFA product CaptiSURE, up to 2% of the diet, resulted in linear improvements in ADG and ADFI. Altering the C12:0 to monolaurin ratio and adding lactic acid did not improve growth performance compared with pigs fed the control diet.

Isolation of Shigella in the bloodstream is a rare sequela of Shigella infections. Shigellemia typically occurs in patients with immature immune responses or in immunocompromised adults. Herein, we present a case of shigellemia in a 40-year-old male who presented with diabetic ketoacidosis (DKA), severe diarrhea, hypovolemic hyponatremia, and altered mental status. Stool cultures were found to be positive for Shigella, and broad-spectrum antibiotic therapy was initiated. Because of the patient’s reported sexual exposures, a rapid HIV point of care test was done and returned negative. In spite of intervention, the patient’s vitals, labs, and symptoms failed to improve, and he developed septic shock requiring pressor support in the intensive care unit. Further workup for the etiology of the patient’s sepsis included a CT abdomen and pelvis which showed findings concerning infectious colitis. Blood cultures later returned positive for Shigella, which was found to be resistant to multiple antibiotics. The patient was started on IV ceftriaxone with an improvement of and eventual resolution of symptoms. Shigellemia is a rare complication of infection with Shigella and necessitates further workup to avoid overlooking potential predisposing factors such as HIV or other immunocompromising conditions. Its susceptibilities should also be evaluated, as Shigella strains are more frequently becoming resistant to antibiotics that had previously been the therapies of choice.

Broadcast-spawning scleractinian corals undergo mass spawning annually, the timing of which is determined by a series of environmental and chemical cues. Flower Garden Banks reefs (FGB, NW Gulf of Mexico) have high coral cover compared to the rest of the Tropical Western Atlantic and exhibit highly synchronous coral spawning, although spawning observations have been largely limited to shallower depths (17–24 m). Using a remotely operated vehicle (ROV), we report observations of mesophotic (39–42 m) broadcast spawning of three major reef-building coral species at East FGB. We observed spawning of 20 Montastraea cavernosa colonies, an order of magnitude more than has been previously reported for this population at mesophotic depths. Spawning times of the three target species (M. cavernosa, Orbicella franksi, and Pseudodiploria strigosa) ranged from 45 min prior to sunset up to 1 h, 33 min after sunset, consistent with shallow conspecifics. We place these observations in the context of other spawning reports of the same species at the FGB and throughout the Tropical Western Atlantic. In addition, the ROV was directed to collect eight genetically unique fragments of gravid Orbicella faveolata and employed a novel gamete collection device designed to capture gametes from actively spawning colonies in situ. These data and collection techniques highlight the benefits of using ROV technology for coral-spawning research, particularly for mesophotic coral reef ecosystems, where gamete release occurs across time ranges exceeding limits imposed by recreational diving. Finally, our observations of overlap in the timing of spawning along the shallow to mesophotic continuum at the FGB suggest—at least for the corals monitored here—that the potential for cross fertilization across depths exists.

Objective: To assess the acceptability, safety and efficacy of the PPH Butterfly, a new uterine compression device, in women with postpartum haemorrhage (PPH). Design: A phase two clinical device trial using matched historical controls, with accompanying grounded theory study. Setting: UK university consultant obstetric unit. Population: women with PPH after vaginal birth unresponsive to initial oxytocin therapy. Outcomes were compared to historical controls matched on blood loss, parity and type of birth. Methods: after oral consent, trained staff used the device in additional to normal care. Main Outcome Measures: The primary outcome was additional blood loss >1000mls. Qualitative interviews assessed device feasibility and acceptability. Results: Of the 57 recruits, two-thirds were primiparous and almost half had undergone operative birth. Two percent of recruited women had additional blood loss of over 1000mls compared to 8% of 113 controls (adjusted odds ratio 0.13, 95% CI (0.02 to 1.09)). Women treated with the device received significantly more additional treatments and had higher rates of exclusive breast-feeding at discharge. There were no serious adverse events related to the device. In 47 interviews, participants, birth partners, clinicians and attending midwives viewed the device positively. Clinicians found it useful to stop blood loss and diagnose the source of bleeding. Conclusions: the PPH Butterfly is acceptable and may have clinical benefits: it is a promising device for PPH management. Funding: National Institute for Health Research invention for innovation (i4i) program (II-LA-0715-200008) Keywords: postpartum haemorrhage, childbirth, oxytocin, third stage of labour, uterine compression. Registration: prospective ISRCTN (15452399); www.isrctn.com/ISRCTN15452399

Modern feed quality sorghum grain has been bred to reduce anti-nutrients, most conspicuously condensed tannins, but its inclusion in the diets of monogastric animals can still result in variable performance that is only partially understood. Sorghum grain contains several negative intrinsic factors, including non-tannin phenolics and polyphenols, phytate, and kafirin protein, which may be responsible for these muted feed performances. To better understand the non-tannin phenolic and polyphenolic metabolites that may have negative effects on nutritional parameters, the chemical composition of sorghum grain polyphenol extracts from three commercial varieties (MR-Buster, Cracka, and Liberty) was determined through the use of an under-studied, alternative analytical approach involving Fourier-transform infrared (FT-IR) spectroscopy and direct ionization mass spectrometry. Supervised analyses and interrogation of the data contributing to variation resulted in the identification of a variety of metabolites, including established polyphenols, lignin-like anti-nutrients, and complex sugars, as well as high levels of fatty acids which could contribute to nutritional variation and underperformance in monogastrics. FT-IR and mass spectrometry could both discriminate among the different sorghum varieties indicating that FT-IR, rather than more sophisticated chromatographic and mass spectrometric methods, could be incorporated into quality control applications.

Introduction. The clinical course of Coronavirus Disease 2019 (COVID-19) is highly heterogenous, ranging from asymptomatic to fatal forms. The identification of clinical and laboratory predictors of poor prognosis may assist clinicians in monitoring strategies and therapeutic decisions. Materials and Methods. In this study, we retrospectively assessed the prognostic value of a simple tool, the complete blood count, on a cohort of 664 patients ( F 260; 39%, median age 70 (56-81) years) hospitalized for COVID-19 in Northern Italy. We collected demographic data along with complete blood cell count; moreover, the outcome of the hospital in-stay was recorded. Results. At data cut-off, 221/664 patients (33.3%) had died and 453/664 (66.7%) had been discharged. Red cell distribution width (RDW) ( χ 2 10.4; p < 0.001 ), neutrophil-to-lymphocyte (NL) ratio ( χ 2 7.6; p = 0.006 ), and platelet count ( χ 2 5.39; p = 0.02 ), along with age ( χ 2 87.6; p < 0.001 ) and gender ( χ 2 17.3; p < 0.001 ), accurately predicted in-hospital mortality. Hemoglobin levels were not associated with mortality. We also identified the best cut-off for mortality prediction: a NL ratio > 4.68 was characterized by an odds ratio for in-hospital mortality OR = 3.40 (2.40-4.82), while the OR for a RDW > 13.7 % was 4.09 (2.87-5.83); a platelet count > 166,000 /μL was, conversely, protective (OR: 0.45 (0.32-0.63)). Conclusion. Our findings arise the opportunity of stratifying COVID-19 severity according to simple lab parameters, which may drive clinical decisions about monitoring and treatment.