Miracle-dz/UniFAR-FTUs huggingface dataset:
IRAK4 mediates colitis-induced tumorigenesis and chemoresistance in colon cancer.

Aberrant activation of the NF-κB transcription factors underlies chemoresistance in various cancer types including colorectal cancer (CRC). Targeting the activating mechanisms, particularly with inhibitors to the upstream IκB kinase (IKK) complex, is a promising strategy to augment the effect of chemotherapy. However, clinical success has been limited largely due to low specificity and toxicities of tested compounds. In solid cancers, the IKK kinases is driven predominantly by the Toll-like/Interlekin-1 receptor family members, which signal through the Interleukin-1 Receptor-Associated Kinases (IRAKs), with isoform 4 (or IRAK4) being the most critical. The pathogenic role and therapeutic value of IRAK4 in CRC has not been investigated. We found that IRAK4 inhibition significantly abrogates colitis-induced neoplasm in APCMin/+ mice, and bone marrow transplant experiments showed an essential role of IRAK4 in immune cells during neoplastic progression. Chemotherapy significantly enhances IRAK4 and NF-κB activity in CRC cells through upregulating TLR9 expression, which can in turn be suppressed by IRAK4 and IKK inhibitors, suggesting a feedforward pathway that protects CRC cells from chemotherapy. Lastly, increased tumor phospho-IRAK4 staining or IRAK4 mRNA expression are associated with significantly worse survival in CRC patients. Our results support targeting IRAK4 to improve the effects of chemotherapy and outcomes in CRC.
Blocking Notch signal pathway suppresses the activation of neurotoxic A1 astrocytes after spinal cord injury

ABSTRACT Spinal cord injury (SCI) is a catastrophic disease which has complicated pathogenesis including inflammation, oxidative stress and glial scar formation. Astrocytes are the most abundant cells in central nervous system and fulfill homeostatic functions. Recent studies have described a new reactive phenotype of astrocytes, A1, induced by inflammation, which may have negative effects in SCI. As the Notch signaling pathway has been linked to cell differentiation and inflammation, we aimed to investigate its potential role in the differentiation of astrocytes in SCI. Contusive SCI rat model showed elevated A1 astrocyte numbers at the damage site 28 days after SCI and the expression levels of Notch signaling and its downstream genes were upregulated parallelly. Western blotting, RT-qPCR and immunofluorescence revealed that blocking of Notch pathway using γ-secretase blocker (DAPT) suppressed the differentiation of A1 astrocytes. Flow cytometry, and TUNEL staining indicated that DAPT alleviated neuronal apoptosis and axonal damage caused by A1 astrocytes likely through the Notch-dependent release of pro-inflammatory factors. CO-IP and western blotting revealed an interaction between Notch pathway and signal transducer and activator of transcription 3 (Stat3), which played a vital role in differentiation of A1 astrocytes. We conclude that phenotypic transition of A1 astrocytes and their neurotoxity were controlled by the Notch-Stat3 axis and that Notch pathway in astrocytes may serve as a promising therapeutic target for SCI.
Using State Transition Models To Explore How the Prevalence of Subtherapeutic Posaconazole Exposures Impacts the Clinical Utility of Therapeutic Drug Monitoring for Posaconazole Tablets and Oral Suspension

Therapeutic drug monitoring (TDM) has been recommended in guidelines for patients receiving posaconazole oral suspension, but its utility in patients receiving posaconazole tablet, which has an improved bioavailability, remains unclear. ABSTRACT Therapeutic drug monitoring (TDM) has been recommended in guidelines for patients receiving posaconazole oral suspension, but its utility in patients receiving posaconazole tablet, which has an improved bioavailability, remains unclear. We used state transition models with first-order Monte Carlo microsimulation to re-examine the posaconazole exposure-response relationships reported in two phase III clinical trials (prophylaxis with posaconazole oral suspension, models 1 and 2) and a third multicenter observational TDM study (model 3). We simulated the impact of TDM-guided interventions to improve initial average posaconazole concentrations (Cavg) to reduce clinical failure (in models 1 and 2) and breakthrough invasive fungal disease (bIFD) in model 3. Simulations were then repeated using posaconazole tablet Cavg distributions in place of the oral suspension formulation. In all three models with posaconazole oral suspension, TDM interventions associated with maximal improvement in posaconazole Cavg reduced absolute rates of subtherapeutic exposures (Cavg < 700 ng/ml) by 25% to 49%. Predicted reductions in absolute clinical failure rates were 11% in model 1 and 6.5% in model 2 and a 12.6% reduction in bIFD in model 3. With the tablet formulation, maximally effective TDM interventions reduced subtherapeutic exposures by approximately 5% in all three models and absolute clinical failure rates by 3.9% in model 1 and 1.6% in model 2; there was a 1.6% reduction in bIFD in model 3. Our modeling suggests that routine TDM during prophylaxis with posaconazole tablets may have limited clinical utility unless populations with higher prevalence (>10%) of subtherapeutic exposures can be identified based on clinical risk factors.
Differences in Trabecular Bone, Cortical Shell, and Endplate Microstructure Across the Lumbar Spine

ABSTRACT Background The quality of the vertebral body structures such as endplate, cortex, and trabecular bone is important for understanding the performance of implants, particularly at the bone-implant interface. Although vertebral body structures have been analyzed separately in the literature, there is no comprehensive study to assess these anatomical measurements along with their interrelationships in the lumbar spine. Therefore, the purpose of this study was to assess variations in trabecular microstructure, vertebral endplate thickness and concavity, and vertebral body cortex thickness within the lumbar spine. Methods A total of 80 lumbar vertebrae (L1-L5) were dissected from 16 human cadaver specimens and imaged with microcomputed tomography to determine trabecular microstructure, vertebral cortex thickness, endplate thickness, and maximum endplate concavity depth. A paired t test and regression analysis were used to determine significant differences (P < .05) between different vertebral levels and correlations between the analyzed anatomical parameters. Results L1 vertebra had significantly better (P < .02) trabecular bone microstructure (eg, trabecular bone volume fraction) than all other lumbar vertebrae. However, L1 vertebra also had significantly thinner (P ≤ .02) anterior, left, and right cortices compared to all other vertebral levels. Within L3-L5 intervertebral disc spaces, cranial endplates had significantly greater (P ≤ .03) thickness and maximum concavity depth compared to their respective caudal endplates. No strong correlations were observed between trabecular bone microstructure, maximum endplate concavity depth, vertebral cortex, and endplate thickness parameters. Conclusions Detailed reference data of these anatomical parameters for each lumbar vertebral body can aid in improved understanding of bone quality, particularly when assessing different implant designs and fixation approaches. Moreover, such anatomical knowledge may help clinicians with optimal implant design selection and surgical placement of these devices into their respective locations.
Effect of intravenous alteplase on ischaemic lesion water homeostasis

Intravenous (IV) lysis with alteplase is known to increase biomarkers of blood–brain barrier breakdown and has therefore been associated with secondary injuries such as hemorrhagic transformation. The impact of alteplase on brain edema formation, however, has not been investigated yet. The purpose was to examine the effects of IV alteplase on ischaemic lesion water homeostasis differentiated from final tissue infarct in patients with and without successful endovascular therapy (sET).
A Multidisciplinary Evaluation of a Virtually Supervised Home-Based High-Intensity Interval Training Intervention in People With Type 1 Diabetes

OBJECTIVE Adopt a multidisciplinary approach to evaluate a virtually supervised home-based high-intensity interval training (Home-HIT) intervention in people with type 1 diabetes. RESEARCH DESIGN AND METHODS Eleven individuals with type 1 diabetes (seven women; age 30 ± 3 years; 2.5 ± 0.2 L/min; duration of diabetes 10 ± 2 years) completed 6 weeks of Home-HIT. A heart rate monitor and mobile phone application were used to provide feedback to the participants and research team on exercise intensity (compliance) and adherence. RESULTS Training adherence was 95 ± 2%, and compliance was 99 ± 1%. Home-HIT increased by 7% (P = 0.017) and decreased insulin dose by 13% (P = 0.012). Blood glucose concentration did not change from baseline to immediately or 1 h post Home-HIT. Qualitative perceptions of Home-HIT and the virtual-monitoring system were positive, supporting that the intervention successfully removed exercise barriers in people with type 1 diabetes. CONCLUSIONS Virtually monitored Home-HIT resulted in high adherence alongside increased and decreased insulin dose.
Effect of Behavioral and Pelvic Floor Muscle Therapy Combined With Surgery vs Surgery Alone on Incontinence Symptoms Among Women With Mixed Urinary Incontinence: The ESTEEM Randomized Clinical Trial.

Importance Mixed urinary incontinence, including both stress and urgency incontinence, has adverse effects on a woman's quality of life. Studies evaluating treatments to simultaneously improve both components are lacking. Objective To determine whether combining behavioral and pelvic floor muscle therapy with midurethral sling is more effective than sling alone for improving mixed urinary incontinence symptoms. Design, Setting, and Participants Randomized clinical trial involving women 21 years or older with moderate or severe stress and urgency urinary incontinence symptoms for at least 3 months, and at least 1 stress and 1 urgency incontinence episode on a 3-day bladder diary. The trial was conducted across 9 sites in the United States, enrollment between October 2013 and April 2016; final follow-up October 2017. Interventions Behavioral and pelvic floor muscle therapy (included 1 preoperative and 5 postoperative sessions through 6 months) combined with midurethral sling (n = 209) vs sling alone (n = 207). Main Outcomes and Measures The primary outcome was change between baseline and 12 months in mixed incontinence symptoms measured by the Urogenital Distress Inventory (UDI) long form; range, 0 to 300 points; minimal clinically important difference, 35 points, with higher scores indicating worse symptoms. Results Among 480 women randomized (mean [SD] age, 54.0 years [10.7]), 464 were eligible and 416 (86.7%) had postbaseline outcome data and were included in primary analyses. The UDI score in the combined group significantly decreased from 178.0 points at baseline to 30.7 points at 12 months, adjusted mean change -128.1 points (95% CI, -146.5 to -109.8). The UDI score in the sling-only group significantly decreased from 176.8 to 34.5 points, adjusted mean change -114.7 points (95% CI, -133.3 to -96.2). The model-estimated between-group difference (-13.4 points; 95% CI, -25.9 to -1.0; P = .04) did not meet the minimal clinically important difference threshold. Related and unrelated serious adverse events occurred in 10.2% of the participants (8.7% combined and 11.8% sling only). Conclusions and Relevance Among women with mixed urinary incontinence, behavioral and pelvic floor muscle therapy combined with midurethral sling surgery compared with surgery alone resulted in a small statistically significant difference in urinary incontinence symptoms at 12 months that did not meet the prespecified threshold for clinical importance. Trial Registration ClinicalTrials.gov Identifier: NCT01959347.
Identification and characterization of major constituents in different-colored rapeseed petals by UPLC-HESI-MS/MS.

Oilseed rape (Brassica napus L.) is the second highest yielding oil crop worldwide. In addition to being used as an edible oil and a feed for livestock, rapeseed has high ornamental value. In this study, we identified and characterized the main floral major constituents, including phenolic acids and flavonoids components, in rapeseed accessions with different-colored petals. A total of 144 constituents were identified using ultrahigh-performance liquid chromatography-HESI-mass spectrometry (UPLC-HESI-MS/MS), 57 of which were confirmed and quantified using known standards, mainly contained phenolic acids, flavonoids and glucosinolates compounds. Most of epicatechin, quercetin and isorhamnetin derivates were found in red and pink petals of B. napus, while kaempferol derivates were in yellow and pale white petals. Moreover, petal-specific compounds, including putative hydroxycinnamic acid derivative, sinapoyl malate 1-O-sinapoyl-beta-D-glucose, feruloyl glucose, naringenin-7-O-glucoside, cyanidin 3-glucoside, cyanidin 3,5-di-O-glucoside, petunidin-3-O-beta-glucopyranoside, is-3-O-glucoside, km-3-O-glucoside-7-O-glucoside, qn-3,4'-O-di-beta-glucopyranoside, qn-3-O-glucoside, and delphinidin-3-O-glucoside, which might contribute to a variety of petal colors in B. napus. In addition, bound phenolics were tentatively identified and contained three abundant compounds (p-coumaric acid, ferulic acid and 8-O-4'diferulic acid). These results provide insight into the molecular mechanisms underlying petal color and suggest strategies for breeding rapeseed with a specific petal color in the future.
The sociodemographic context of observed solitary and social smoking behaviours using a behavioural ecological approach

This study used a behavioural ecological approach by observing whether solitary and social smoking varied as a function of gender and stress. In sample 1 (N = 414), the result was consistent with the tend-and-befriend hypothesis, in that more female smokers were observed to engage in social smoking during high stress. When the number of smokers observed by stress condition was controlled for in sample 2 (N = 587), this effect was non-significant. Effect sizes were small for both samples. Discrepancies with previous research suggest that self-reported data might overestimate the interaction of various psychosocial factors on smoking behaviours.
An Ultra High-Density Arabidopsis thaliana Crossover Map That Refines the Influences of Structural Variation and Epigenetic Features

Rowan et al. generated a dataset of over 17,000 meiotic crossovers (COs) from over 2000 F2 individuals from a single Arabidopsis thaliana cross. The unprecedented density of COs and the high-quality reference genomes of the two. Many environmental, genetic, and epigenetic factors are known to affect the frequency and positioning of meiotic crossovers (COs). Suppression of COs by large, cytologically visible inversions and translocations has long been recognized, but relatively little is known about how smaller structural variants (SVs) affect COs. To examine fine-scale determinants of the CO landscape, including SVs, we used a rapid, cost-effective method for high-throughput sequencing to generate a precise map of >17,000 COs between the Col-0 and Ler-0 accessions of Arabidopsis thaliana. COs were generally suppressed in regions with SVs, but this effect did not depend on the size of the variant region, and was only marginally affected by the variant type. CO suppression did not extend far beyond the SV borders and CO rates were slightly elevated in the flanking regions. Disease resistance gene clusters, which often exist as SVs, exhibited high CO rates at some loci, but there was a tendency toward depressed CO rates at loci where large structural differences exist between the two parents. Our high-density map also revealed in fine detail how CO positioning relates to genetic (DNA motifs) and epigenetic (chromatin structure) features of the genome. We conclude that suppression of COs occurs over a narrow region spanning large- and small-scale SVs, representing an influence on the CO landscape in addition to sequence and epigenetic variation along chromosomes.
Rotavirus Epidemiology and Vaccine Effectiveness: Continuing Successes and Ongoing Challenges

* Abbreviations: AGE — : acute gastroenteritis ORV — : oral rotavirus vaccine RVGE — : rotavirus-associated gastroenteritis VE — : vaccine effectiveness The success of live-attenuated oral rotavirus vaccines (ORVs) in high-income countries has been extraordinary. In this issue of Pediatrics , Maguire et al1 provide an important addition to this literature with an analysis of Rotarix (GlaxoSmithKline, Brentford, United Kingdom) vaccine effectiveness (VE) and rotavirus epidemiology among children in New South Wales, Australia, from 2010 to 2017 (including during a 2017 outbreak). They found high 1-year VE of 89.5%, which decreased to 77.0% among those vaccinated 5 to 10 years previously. The median age of infection increased from 3.9 to 7.1 years over the study period. Interestingly, during the 2017 outbreak, the emerging equine-like G3P[8] and novel G8P[8] strains predominated in most age groups. Rotaviruses are the leading global cause of dehydrating acute gastroenteritis (AGE) in young children.2 Rotaviruses are segmented, double-stranded RNA viruses categorized according to the structural proteins VP7 and VP4, which define G and P genotypes, respectively. The introduction of Rotarix and RotaTeq (Merck & Co, Inc, Kenilworth, NJ) into national immunization programs in the mid-2000s led to dramatic, sustained reductions in rotavirus incidence, hospitalizations for all-cause AGE and rotavirus-associated gastroenteritis (RVGE), and diarrheal mortality.3 High VE (≥80%) in preventing RVGE hospitalizations among children younger than 5 years and evidence of herd immunity are consistently demonstrated in high-income countries,4,5 where today’s pediatric trainees may complete residency without having diagnosed a single case … Address correspondence to Benjamin Lee, MD, Department of Pediatrics, Larner College of Medicine, University of Vermont, 95 Carrigan Dr, Stafford Hall 308, Burlington, VT 05405. E-mail: benjamin.lee. 1{at}med.uvm. edu
Circadian Function in Multiple Cell Types Is Necessary for Proper Timing of the Preovulatory LH Surge

The timing of the preovulatory surge of luteinizing hormone (LH), which occurs on the evening of proestrus in female mice, is determined by the circadian system. The identity of cells that control the phase of the LH surge is unclear: evidence supports a role of arginine vasopressin (AVP) cells of the suprachiasmatic nucleus (SCN), but it is not known whether vasopressinergic neurons are necessary or sufficient to account for circadian control of ovulation. Among other cell types, evidence also suggests important roles of circadian function of kisspeptin cells of the anteroventral periventricular nucleus (AvPV) and gonadotropin-releasing hormone (GnRH) neurons of the preoptic area (POA), whose discharge is immediately responsible for the discharge of LH from the anterior pituitary. The present studies used an ovariectomized, estradiol-treated preparation to determine critical cell types whose clock function is critical to the timing of LH secretion. As expected, the LH surge occurred at or shortly after ZT12 in control mice. In further confirmation of circadian control, the surge was advanced by 2 h in tau mutant animals. The timing of the surge was altered to varying degrees by conditional deletion of Bmal1 in AVPCre, KissCreBAC, and GnRHCreBAC mice. Excision of the mutant Cnsk1e (tau) allele in AVP neurons resulted in a reversion of the surge to the ZT12. Conditional deletion of Bmal1 in Kiss1 or GnRH neurons had no noticeable effect on locomotor rhythms, but targeting of AVP neurons produced variable effects on circadian period that did not always correspond to changes in the phase of LH secretion. The results indicate that circadian function in multiple cell types is necessary for proper timing of the LH surge.
Enhancement of Opioid Antinociception by Nicotine

Nicotine can produce antinociception in preclinical pain models; however, the ability of nicotine to augment the antinociceptive effects of opioid agonists has not been investigated. The present experiments were conducted to determine how nicotine modifies the effects of opioid agonists differing in efficacy. Male squirrel monkeys responded for the delivery of milk under a fixed ratio 10 schedule of reinforcement. During the 30-second timeout period following each milk delivery, the subject’s tail was immersed in 35, 50, 52, or 55°C water, and the latency to remove the tail was recorded. Dose-response functions for tail-withdrawal latency and operant performance were determined for fentanyl, oxycodone, buprenorphine, and nalbuphine alone and after treatment with nicotine. Excepting nalbuphine, all opioids produced dose-related disruptions in food-maintained responding and increases in tail-withdrawal latency at each water temperature. Nicotine did not exacerbate the behaviorally disruptive effects of the μ-opioids on operant performance but produced a significant mecamylamine-sensitive enhancement of the antinociceptive potency of each opioid. Failure of arecoline to augment the antinociceptive effects of oxycodone and antagonism by mecamylamine suggests this nicotine-induced augmentation of prescription opioid antinociception was nicotinic acetylcholine receptor (nAChR) mediated. This was reflected in leftward shifts in the antinociceptive dose–response curve of each opioid, ranging from 2- to 7-fold increases in the potency of oxycodone across all water temperatures to an approximately 70-fold leftward shift in the antinociceptive dose-response curve of nalbuphine at the lower and intermediate water temperatures. These results suggest that nicotine may enhance μ-opioid antinociceptive effects without concomitantly exacerbating their behaviorally disruptive effects. SIGNIFICANCE STATEMENT Prescription opioids remain the most effective pain-management pharmacotherapeutics but are limited by their adverse effects. The present results indicate that nicotine enhances antinociceptive effects of various opioid agonists in nonhuman primates without increasing their disruptive effects on operant performance. These results suggest that nicotine might function as an opioid adjuvant for pain management by enabling decreased clinically effective analgesic doses of prescription opioids without exacerbating their adverse behavioral effects.
Polyhydroxybutyrate Production from Natural Gas in A Bubble Column Bioreactor: Simulation Using COMSOL

In this study, the simulation of microorganism ability for the production of poly-β-hydroxybutyrate (PHB) from natural gas (as a carbon source) was carried out. Based on the Taguchi algorithm, the optimum situations for PHB production from natural gas in the columnar bubble reactor with 30 cm length and 1.5 cm diameter at a temperature of 32 °C was evaluated. So, the volume ratio of air to methane of 50:50 was calculated. The simulation was carried out by COMSOL software with two-dimensional symmetric mode. Mass transfer, momentum, density-time, and density-place were investigated. The maximum production of biomass concentration reached was 1.63 g/L, which shows a 10% difference in contrast to the number of experimental results. Furthermore, the consequence of inlet gas rate on concentration and gas hold up was investigated Andres the simulation results were confirmed to experimental results with less than 20% error.