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Treprostinil is a prostacyclin analogue approved for the treatment of pulmonary arterial hypertension (PAH). It is commonly administered through a central venous catheter (CVC). Treprostinil is associated with the incidence of Gram-negative bacterial bloodstream infections (BSI), a susceptibility that has been associated with a diluent used for treprostinil. We report the case of a 14-year-old boy with idiopathic PAH on continuous intravenous treprostinil therapy who presented with fever and fatigue. A blood culture drawn from his CVC was positive for the rare Gram-negative organism Chryseomonas luteola. The patient made a complete recovery with antibacterial treatment. This is the only documented case of a C. luteola BSI in a PAH patient receiving continuous intravenous treprostinil. We recommend maintaining a high index of suspicion for both common and rare Gram-negative pathogens and the early administration of appropriate antibiotic therapy in this population. The use of an alternate diluent solution, such as Sterile Diluent for Flolan, further decreases the infection risk.

This Letter presents the result of a 3+1 sterile neutrino search using 10.7 yr of IceCube data. We analyze atmospheric muon neutrinos that traverse the Earth with energies ranging from 0.5 to 100 TeV, incorporating significant improvements in modeling neutrino flux and detector response compared to earlier studies. Notably, for the first time, we categorize data into starting and throughgoing events, distinguishing neutrino interactions with vertices inside or outside the instrumented volume, to improve energy resolution. The best-fit point for a 3+1 model is found to be at sin^{2}(2θ_{24})=0.16 and Δm_{41}^{2}=3.5  eV^{2}, which agrees with previous iterations of this Letter. The result is consistent with the null hypothesis of no sterile neutrinos with a p value of 3.1%.

We report on a measurement of astrophysical tau neutrinos with 9.7 yr of IceCube data. Using convolutional neural networks trained on images derived from simulated events, seven candidate ν_{τ} events were found with visible energies ranging from roughly 20 TeV to 1 PeV and a median expected parent ν_{τ} energy of about 200 TeV. Considering backgrounds from astrophysical and atmospheric neutrinos, and muons from π^{±}/K^{±} decays in atmospheric air showers, we obtain a total estimated background of about 0.5 events, dominated by non-ν_{τ} astrophysical neutrinos. Thus, we rule out the absence of astrophysical ν_{τ} at the 5σ level. The measured astrophysical ν_{τ} flux is consistent with expectations based on previously published IceCube astrophysical neutrino flux measurements and neutrino oscillations.

We show that ATLAS, a collider detector, can measure the flux of high-energy supernova neutrinos, which can be produced from days to months after the explosion. Using Monte Carlo simulations for predicted fluxes, we find at most O(0.1-1) starting events and O(10-100) throughgoing events from a supernova 10 kpc away. Possible Galactic supernovae from Betelgeuse and Eta Carinae are further analyzed as demonstrative examples. We argue that, even with limited statistics, ATLAS has the ability to discriminate among flavors and between neutrinos and antineutrinos, making it a unique neutrino observatory so far unmatched in this capability.

Background: Prader-Willi syndrome (PWS) is an imprinting disorder caused by the absence of paternal expressed genes in the Prader-Willi critical region (PWCR) on chromosome 15q11.2-q13. Three molecular mechanisms have been known to cause PWS, including a deletion in the PWCR, uniparental disomy 15 and imprinting defects., Results: We report the first case of PWS associated with a single-nucleotide SNRPN variant in a 10-year-old girl presenting with clinical features consistent with PWS, including infantile hypotonia and feeding difficulty, developmental delay with cognitive impairment, excessive eating with central obesity, sleep disturbances, skin picking and related behaviour issues. Whole-exome sequencing revealed a de novo mosaic nonsense variant of the SNRPN gene (c.73C>T, p.R25X) in 10% of DNA isolated from buccal cells and 19% of DNA from patient-derived lymphoblast cells. DNA methylation study did not detect an abnormal methylation pattern in the SNRPN locus. Parental origin studies showed a paternal source of an intronic single-nucleotide polymorphism within the locus in proximity to the SNRPN variant., Conclusions: This is the first report that provides evidence of a de novo point mutation of paternal origin in SNRPN as a new disease-causing mechanism for PWS. This finding suggests that gene sequencing should be considered as part of the diagnostic workup in patients with clinical suspicion of PWS., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Powered, two-wheeled transportation devices like electric bicycles (E-bikes) and scooters are increasingly popular, but little is known about their relative injury risk compared to pedal operated bicycles., Methods: Descriptive and comparative analysis of injury patterns and trends associated with E-bikes, powered scooters and pedal bicycles from 2000 to 2017 using the US National Electronic Injury Surveillance System., Results: While persons injured using E-bikes were more likely to suffer internal injuries (17.1%; 95% CI 5.6 to 28.6) and require hospital admission (OR=2.8, 95% CI 1.3 to 6.1), powered scooter injuries were nearly three times more likely to result in a diagnosis of concussion (3% of scooter injuries vs 0.5% of E-bike injuries). E-bike-related injuries were also more than three times more likely to involve a collision with a pedestrian than either pedal bicycles (OR=3.3, 95% CI 0.5 to 23.6) or powered scooters (OR=3.3, 95% CI 0.3 to 32.9), but there was no evidence that powered scooters were more likely than bicycles to be involved in a collision with a pedestrian (OR=1.0, 95% CI 0.3 to 3.1). While population-based rates of pedal bicycle-related injuries have been decreasing, particularly among children, reported E-bike injuries have been increasing dramatically particularly among older persons., Conclusions: E-bike and powered scooter use and injury patterns differ from more traditional pedal operated bicycles. Efforts to address injury prevention and control are warranted, and further studies examining demographics and hospital resource utilisation are necessary., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The objective of the present study was to investigate the clinical efficacy of early application and ideal dosage of urokinase after minimally invasive surgery for hypertensive intracerebral hemorrhage (HICH)., Patients and Methods: We consecutively enrolled 132 patients with HICH who underwent CT-guided stereotactic intubation of the hematoma combined with dissolution using urokinase, where the urokinase was injected at 24 h after intubation. The 40 patients in the low-dosage group received 10-30 thousand units of urokinase; the 46 patients in the moderate-dosage group received 40-60 thousand units of urokinase; and the 46 patients in the high-dosage group received 70-100 thousand units of urokinase. After the drainage tubes were clamped for 4-6 h, clamps were removed for drainage for 24 h, and the intubated tubes were maintained for 3-5 d. Patients in all groups were followed up for 6 months, and the clinical outcomes were compared., Results: The clearance of hematomas in the high-dosage group was significantly improved compared with the other two groups (p<0.05), and the occurrence rates of complications in the moderate- and high-dosage groups were significantly higher than in the low-dosage group (p<0.05). During follow-up, the Chinese stroke scale and Barthel index scores in the high-dosage group were higher than those in the other two groups (p<0.05). The serum levels of matrix metalloproteinase-9 (MMP-9) and neuron-specific enolase (NSE) in the high-dosage group were lower than those in the other two groups (p<0.05)., Conclusions: CT-guided stereotactic intubation of the hematoma combined with dissolution using urokinase is effective for eliminating the hematoma for treatment of HICH with few complications. For recovery of neurological functions and improvement of regular life skills, it is considered to be associated with decreases in the serum levels of MMP-9 and NSE.

Background: The objective of the present study was to evaluate the effects of four chemicals on the fermentation quality and aerobic stability of alfalfa (Medicago sativa L.) silage. Wilted alfalfa was ensiled without additive (control), or with formic acid (FA), potassium diformate (KDF), sodium diacetate (SDA) or calcium propionate (CAP)., Results: After 60 days of ensiling, the pH values in FA, KDF and SDA silages were lower (P < 0.05) compared to that of control and CAP silages, and chemicals (P < 0.05) decreased butyric acid and ammonia N concentrations and populations of aerobic bacteria and yeasts compared to the control. The SDA and CAP silages had a higher (P < 0.05) lactic acid bacteria content compared to the FA and KDF silages. The SDA and CAP silages had higher (P < 0.05) acetic and propionic acid contents compared to the other silages, respectively. The ammonia N concentrations in the FA and KDF silages were lower compared to the other silages during the first 5 days of aerobic exposure, and then increased sharply to 105 and 100 g kg -1 total N, respectively, which was higher (P < 0.05) than that of the SDA and CAP silages on day 9 of aerobic exposure. Yeasts and aerobic bacteria counts in SDA silage slowly increased and remained at lower levels compared to the other silages after 7 days of aerobic exposure., Conclusion: Additives prolonged the aerobic stability duration compared to the control, and the SDA and CAP silages remained stable for more than 216 h, followed by the KDF and FA silages (202 and 196 h, respectively). © 2017 Society of Chemical Industry., (© 2017 Society of Chemical Industry.)

The objective of this study was to determine the effect of ensiling different ratios of whole crop oat to lucerne on fermentation quality, aerobic stability and in vitro digestibility of silage on the Tibetan plateau. Four experimental treatments were produced varying in the ratio of forages on a fresh matter (FM) basis: 1) 100% oat (control, dry matter (DM) content: 317 g/kg), 2) 90% oat + 10% lucerne (OL10, DM content: 316 g/kg), 3) 80% oat+ 20% lucerne (OL20, DM content: 317 g/kg) and 4) 70% oat+ 30% lucerne (OL30, DM content: 318 g/kg). All treatments were packed into laboratory-scale silos and ensiled for 60 days and then subjected to an aerobic stability test for 15 days. Further, the four experimental treatments were incubated in vitro with buffered rumen fluid to study the nutrient digestibility. All silages were well preserved with low pH and NH 3 -N contents, and high lactic acid contents and V-scores (evaluation of silage quality). Increasing the lucerne proportion increased (p < 0.05) crude protein (CP) content of silage, whereas neutral (NDF) and acid (ADF) detergent fibre contents were not affected. Under aerobic conditions, the control silage showed higher (p < 0.05) yeast counts (>10 5  cfu/g FM) followed by OL10 silage, and OL10 silage improved aerobic stability for 74 h. OL20 and OL30 silages showed fewer (p < 0.05) yeasts (<10 5  cfu/g FM) and markedly (p < 0.05) improved the aerobic stability (>360 h). After 48-h incubation, OL30 silage increased (p < 0.05) in vitro dry matter digestibility (IVDMD) and neutral detergent fibre digestibility (IVNDFD) compared with the control silage. These results suggest that replacing oat with lucerne had no unfavourable effects on fermentation quality of silage, but improved CP content, aerobic stability IVDMD and IVNDFD. OL30 silage was the best among the three mixed silages., (Journal of Animal Physiology and Animal Nutrition © 2016 Blackwell Verlag GmbH.)

This study was designed using 360 21-day-old chicks to determine the influences of diet supplementation with glutamine (5 g/kg), γ-aminobutyric acid (GABA, 100 mg/kg) or their combinations on performance and serum parameters exposed to cycling high temperatures. From 22 to 35 days, the experimental groups (2 × 2) were subjected to circular heat stress by exposing them to 30-34 °C cycling, while the positive control group was exposed to 23 °C constant. The blood of broilers was collected to detect serum parameters on days 28 and 35. Compared with the positive control group, the cycling high temperature decreased (p < 0.05) the feed consumption, weight gain and serum total protein (TP), glucose, thyroxine (T4), insulin, alkaline phosphatase (ALP), glutamine, GABA and glutamate levels, while increased (p < 0.05) the serum triglyceride (TG), corticosterone (CS), glucagon (GN), creatine kinase (CK), glutamic oxaloacetic transaminase (GOT), nitric oxide synthase (NOS), glutamate pyruvate transaminase (GPT) and lactate dehydrogenase (LDH) levels during 22-35 days. However, dietary glutamine (5 g/kg) increased (p < 0.05) the feed consumption, weight gain and serum levels of glutamine, TP, insulin and ALP, but decreased (p < 0.05) the serum TG, CK, GOT, NOS and GPT levels. Diet supplemented with GABA also increased (p < 0.05) weight gain and the serum levels of TP, T4, ALP, GABA and glutamine. In addition, the significant interactions (p < 0.05) between glutamine and GABA were found in the feed consumption, weight gain and the serum ALP, CK, LDH, GABA, T3 and T4 levels of heat-stressed chickens. This research indicated that dietary glutamine and GABA improved the antistress ability in performance and serum parameters of broilers under hot environment., (Journal of Animal Physiology and Animal Nutrition © 2015 Blackwell Verlag GmbH.)

To better understand the effects of DNA methylation on the expression patterns of dmrt1 (Doublesex and Mab-3-related transcription factor 1) and cyp19a (Cytochrome P450 19a) in the Japanese flounder Paralichthys olivaceus, quantitative expressions, cellular distributions and cytosine-p-guanine (CpG) methylation patterns of these two genes in the gonads were analysed. The results showed that P. olivaceus dmrt1 expression was 70 times higher in the testis than in the ovary (P < 0·05). Its mRNA was detected clearly in spermatocytes and Sertoli cells of the testis, but weakly in the ovary. Paralichthys olivaceus cyp19a expression was 40 times higher in the ovary than in the testis (P < 0·01). Its mRNA was detected clearly in follicular cells of the ovary, but weakly in spermatocytes of the testis. The dmrt1 promoter CpGs were not methylated in the testis, whereas 57·69% were methylated in the ovary. For the cyp19a promoter CpGs, 97·5% were methylated in the testis and 73·33% were methylated in the ovary. These findings demonstrate that P. olivaceus dmrt1 and cyp19a are sex-related genes with sexual dimorphic expression, CpG methylation levels of the two genes are consistent with their expression quantities, and this epigenetic modification can influence the differential expression of genes in the gonads of P. olivaceus., (© 2013 The Fisheries Society of the British Isles.)

Cyclic AMP-response element-binding protein (CREB) is a transcription factor implicated in growth factor-dependent cell proliferation and survival, glucose homeostasis, spermatogenesis, circadian rhythms, and synaptic plasticity associated with memory. To study the phenotype of CREB overexpression in vivo, we generated CREB transgenic (TG) mice in which a myeloid specific hMRP8 promoter drives CREB expression. CREB TG mice developed spontaneous skin abscesses more frequently than wild type (WT) mice. To understand the role of CREB in myeloid function and innate immunity, chemokine expression in bone marrow derived macrophages (BMDMs) from CREB TG mice were compared with BMDMs from WT mice. Our results demonstrated decreased Keratinocyte-derived cytokine (KC) in CREB TG BMDMs but not TNFα protein production in response to lipid A (LPA). In addition, mRNA expression of KC and IL-1β (Interleukin)-1β was decreased in CREB TG BMDMs; however, there was no difference in the mRNA expression of TNFα, MCP-1, IL-6 and IL-12p40. The mRNA expression of IL-1RA and IL-10 was decreased in response to LPA. Nuclear factor kappa B (NFκB) expression and a subset of its target genes were upregulated in CREB TG mouse BMDMs. Although neutrophil migration was the same in both CREB TG and WT mice, Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity was significantly increased in neutrophils from CREB TG mice. Taken together, CREB overexpression in myeloid cells results in increased abscess formation in vivo and aberrant cytokine and chemokine response, and neutrophil function in vitro.

CREB is a transcription factor that regulates diverse cellular responses, including proliferation, survival, and differentiation. CREB is induced by a variety of growth factors and inflammatory signals and subsequently mediates the transcription of genes containing a cAMP-responsive element. Several immune-related genes possess this cAMP-responsive element, including IL-2, IL-6, IL-10, and TNF-α. In addition, phosphorylated CREB has been proposed to directly inhibit NF-κB activation by blocking the binding of CREB binding protein to the NF-κB complex, thereby limiting proinflammatory responses. CREB also induces an antiapoptotic survival signal in monocytes and macrophages. In T and B cells, CREB activation promotes proliferation and survival and differentially regulates Th1, Th2, and Th17 responses. Finally, CREB activation is required for the generation and maintenance of regulatory T cells. This review summarizes current advances involving CREB in immune function--a role that is continually being defined.

1. The present study was conducted to investigate the effects of dietary glutamine (Gln) supplementation on growth performance, carcase characteristics and meat quality in broilers exposed to high ambient temperature. 2. A total of 240 35-d-old male Arbor Acres broilers were randomly assigned to 4 treatment groups (three replicates of 20 birds per cage). The broilers were kept in a temperature-controlled room at either 23 degrees C (no-stress groups, NS) or 28 degrees C (heat stress groups, HS). The broilers were fed either on a basal diet (control, NS) or on the basal diet supplemented with 0, 0.5 or 1.0% Gln (HS). 3. Compared with the NS, the HS (0% Gln) group gained less weight and consumed less feed, had lower final body weight, gain-to-feed ratio, and abdominal fat yield. Breast meat in HS (0% Gln) had lower pH, water-holding capacity (WHC), a* value, ether extract (EE) content and crude protein (CP) content, and had higher shear force (SF) and L* value. 4. Linear increase were found in groups supplemented with Gln (0, 0.5% and 1.0%) for final body weight, weight gain, feed consumption, gain-to-feed ratio and abdominal fat yield. Supplementation with Gln improved breast meat pH, WHC, SF, L* value, a* value, EE content and CP content in broilers exposed to heat stress. No significant difference was observed in all the indices determined between the HS (1% Gln) and the NS. 5. Heat stress caused obvious breast meat discoloration in L*, a* and b* values. However, dietary supplementation with Gln gave a better colour stability. 6. The results indicated that dietary supplementation with Gln may alleviate heat stress-caused deterioration in growth performance, carcase characteristics, meat quality and meat colour stability of broilers.

Molecular chaperones assist the folding of newly translated and stress-denatured proteins. In prokaryotes, overlapping sets of chaperones mediate both processes. In contrast, we find that eukaryotes evolved distinct chaperone networks to carry out these functions. Genomic and functional analyses indicate that in addition to stress-inducible chaperones that protect the cellular proteome from stress, eukaryotes contain a stress-repressed chaperone network that is dedicated to protein biogenesis. These stress-repressed chaperones are transcriptionally, functionally, and physically linked to the translational apparatus and associate with nascent polypeptides emerging from the ribosome. Consistent with a function in de novo protein folding, impairment of the translation-linked chaperone network renders cells sensitive to misfolding in the context of protein synthesis but not in the context of environmental stress. The emergence of a translation-linked chaperone network likely underlies the elaborate cotranslational folding process necessary for the evolution of larger multidomain proteins characteristic of eukaryotic cells.

Molecular chaperones such as Hsp70 use ATP binding and hydrolysis to prevent aggregation and ensure the efficient folding of newly translated and stress-denatured polypeptides. Eukaryotic cells contain several cytosolic Hsp70 subfamilies. In yeast, these include the Hsp70s SSB and SSA as well as the Hsp110-like Sse1/2p. The cellular functions and interplay between these different Hsp70 systems remain ill-defined. Here we show that the different cytosolic Hsp70 systems functionally interact with Hsp110 to form a chaperone network that interacts with newly translated polypeptides during their biogenesis. Both SSB and SSA Hsp70s form stable complexes with the Hsp110 Sse1p. Pulse-chase analysis indicates that these Hsp70/Hsp110 teams, SSB/SSE and SSA/SSE, transiently associate with newly synthesized polypeptides with different kinetics. SSB Hsp70s bind cotranslationally to a large fraction of nascent chains, suggesting an early role in the stabilization of nascent chains. SSA Hsp70s bind mostly post-translationally to a more restricted subset of newly translated polypeptides, suggesting a downstream function in the folding pathway. Notably, loss of SSB dramatically enhances the cotranslational association of SSA with nascent chains, suggesting SSA can partially fulfill an SSB-like function. On the other hand, the absence of SSE1 enhances polypeptide binding to both SSB and SSA and impairs cell growth. It, thus, appears that Hsp110 is an important regulator of Hsp70-substrate interactions. Based on our data, we propose that Hsp110 cooperates with the SSB and SSA Hsp70 subfamilies, which act sequentially during de novo folding.