Miracle-dz/UniFAR-FTUs huggingface dataset:
HCN3 ion channels: roles in sensory neuronal excitability and pain

HCN ion channels conducting the Ih current control the frequency of firing in peripheral sensory neurons signalling pain. Previous studies have demonstrated a major role for the HCN2 subunit in chronic pain but the potential involvement of HCN3 in pain has not been investigated. HCN3 was found to be widely expressed in all classes of sensory neurons (small, medium, large) where it contributes to Ih. HCN3 deletion increased the firing rate of medium but not small, sensory neurons. Pain sensitivity both acutely and following neuropathic injury was largely unaffected by HCN3 deletion, with the exception of a small decrease of mechanical hyperalgesia in response to a pinprick. We conclude that HCN3 plays little role in either acute or chronic pain sensation.
Toxins from scratch? Diverse, multimodal gene origins in the predatory robber fly Dasypogon diadema indicate a dynamic venom evolution in dipteran insects

Abstract Background Venoms and the toxins they contain represent molecular adaptations that have evolved on numerous occasions throughout the animal kingdom. However, the processes that shape venom protein evolution are poorly understood because of the scarcity of whole-genome data available for comparative analyses of venomous species. Results We performed a broad comparative toxicogenomic analysis to gain insight into the genomic mechanisms of venom evolution in robber flies (Asilidae). We first sequenced a high-quality draft genome of the hymenopteran hunting robber fly Dasypogon diadema, analysed its venom by a combined proteotranscriptomic approach, and compared our results with recently described robber fly venoms to assess the general composition and major components of asilid venom. We then applied a comparative genomics approach, based on 1 additional asilid genome, 10 high-quality dipteran genomes, and 2 lepidopteran outgroup genomes, to reveal the evolutionary mechanisms and origins of identified venom proteins in robber flies. Conclusions While homologues were identified for 15 of 30 predominant venom protein in the non-asilid genomes, the remaining 15 highly expressed venom proteins appear to be unique to robber flies. Our results reveal that the venom of D. diadema likely evolves in a multimodal fashion comprising (i) neofunctionalization after gene duplication, (ii) expression-dependent co-option of proteins, and (iii) asilid lineage-specific orphan genes with enigmatic origin. The role of such orphan genes is currently being disputed in evolutionary genomics but has not been discussed in the context of toxin evolution. Our results display an unexpected dynamic venom evolution in asilid insects, which contrasts the findings of the only other insect toxicogenomic evolutionary analysis, in parasitoid wasps (Hymenoptera), where toxin evolution is dominated by single gene co-option. These findings underpin the significance of further genomic studies to cover more neglected lineages of venomous taxa and to understand the importance of orphan genes as possible drivers for venom evolution.
Assessing the Impact of Improvements in PASI and Itch Scores on Patients' Quality of Life in the Treatment of Psoriasis.

1https://www.medicaljournals. se/acta/content/abstract/10.2340/00015555-3254 Psoriasis is a chronic disease that is associated with significant disease burden and negative impact on the quality of life of patients. The efficacy and safety of ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin 17A (1), are well established (2, 3) and patients treated with ixekizumab achieve more rapid improvements, both in health-related quality of life (HRQoL) and itch, compared with patients treated with etanercept (ETN) and placebo (PBO) (4). During the initial 16 weeks of multiple biologic treatment, a strong correlation was reported between reduction in Psoriasis Area and Severity Index (PASI) score and Dermatology Life Quality Index (DLQI) score (5). However, HRQoL may not always correspond to severity of skin disease. Pruritus, an invisible, but tangible, symptom of psoriasis, was identified as an important mediator of the association between improvements in disease severity and HRQoL in ixekizumab-treated patients (6). The present post hoc analysis was therefore conducted to assess the independent, relative effects of early improvements in pruritus (itch) and PASI score on changes in DLQI score using multi-mediator analysis.
The Nutritional Environment Influences the Impact of Microbes on Drosophila melanogaster Life Span

D. melanogaster ingests microorganisms growing within its rotting vegetation diet. Some of these microbes form associations with flies, while others pass through the gut with meals. Fly-microbe-diet interactions are dynamic, and changes to the fly culture medium can influence microbial growth in the overall environment. In turn, these alterations in microbial growth may not only impact the nutritional value of fly meals but also modulate behavior and health, at least in part due to direct contributions to fly nutrition. The interactive ecology between flies, microbes, and their environment can cause a specific microbe to be either beneficial or detrimental to fly life span, indicating that the environment should be considered a key influential factor in host-microbe interactions. ABSTRACT Microbes can extend Drosophila melanogaster life span by contributing to the nutritional value of malnourishing fly culture medium. The beneficial effect of microbes during malnutrition is dependent on their individual ability to proliferate in the fly environment and is mimicked by lifelong supplementation of equivalent levels of heat-killed microbes or dietary protein, suggesting that microbes can serve directly as a protein-rich food source. Here, we use nutritionally rich fly culture medium to demonstrate how changes in dietary composition influence monocolonized fly life span; microbes that extend fly life span on malnourishing diets can shorten life on rich diets. The mechanisms employed by microbes to affect host health likely differ on low- or high-nutrient diets. Our results demonstrate how Drosophila-associated microbes can positively or negatively influence fly life span depending on the nutritional environment. Although controlled laboratory environments allow focused investigations on the interaction between fly microbiota and nutrition, the relevance of these studies is not straightforward, because it is difficult to mimic the nutritional ecology of natural Drosophila-microbe interactions. As such, caution is needed in designing and interpreting fly-microbe experiments and before categorizing microbes into specific symbiotic roles based on results obtained from experiments testing limited conditions. IMPORTANCE D. melanogaster ingests microorganisms growing within its rotting vegetation diet. Some of these microbes form associations with flies, while others pass through the gut with meals. Fly-microbe-diet interactions are dynamic, and changes to the fly culture medium can influence microbial growth in the overall environment. In turn, these alterations in microbial growth may not only impact the nutritional value of fly meals but also modulate behavior and health, at least in part due to direct contributions to fly nutrition. The interactive ecology between flies, microbes, and their environment can cause a specific microbe to be either beneficial or detrimental to fly life span, indicating that the environment should be considered a key influential factor in host-microbe interactions.
Factors Associated With Antibiotic Prescribing and Outcomes for Pediatric Pneumonia in the Emergency Department

Supplemental digital content is available in the text. Objectives Chest radiographs (CXRs) are often performed in children with respiratory illness to inform the decision to prescribe antibiotics. Our objective was to determine the factors associated with clinicians' plans to treat with antibiotics prior to knowledge of CXR results and the associations between preradiograph plans with antibiotic prescription and return to medical care. Methods Previously healthy children aged 3 months to 18 years with a CXR for suspected pneumonia were enrolled in a prospective cohort study in the emergency department. Our primary outcomes were antibiotic prescription or administration in the emergency department and medical care sought within 7 to 15 days after discharge. Inverse probability treatment weighting was used to limit bias due to treatment selection. Inverse probability treatment weighting was included in a logistic regression model estimating the association between the intention to give antibiotics and outcomes. Results Providers planned to prescribe antibiotics prior to CXR in 68 children (34.9%). There was no difference in the presence of radiographic pneumonia between those with and without a plan for antibiotics. Children who had a plan for antibiotics were more likely to receive antibiotics than those without (odds ratio [OR], 6.39; 95% confidence interval [CI], 3.7–11.0). This association was stronger than the association between radiographic pneumonia and antibiotic receipt (OR, 3.49; 95% CI, 1.98–6.14). Children prescribed antibiotics were more likely to seek care after discharge than children who were not (OR, 1.85; 95% CI, 1.13–3.05). Conclusions Intention to prescribe antibiotics based on clinical impression was the strongest predictor of antibiotic prescription in our study. Prescribing antibiotics may lead to subsequent medical care after controlling for radiographic pneumonia.
Boron Isotopes in the Puga Geothermal System, India, and Their Implications for the Habitat of Early Life.

Boron is associated with several Archean stromatolite deposits, including the tourmaline-rich Barberton stromatolites in South Africa and tourmaline-bearing pyritic laminae associated with stromatolites of the 3.48 Ga Dresser Formation in the Pilbara Craton, Australia. Boron is also a critical element in prebiotic organic chemistry, including in the formation of ribose, a crucial component in RNA. As geological evidence and advances in prebiotic chemistry are now suggesting that hot spring activity may be associated with the origins of life, an understanding of boron and its mobility and isotopic fractionation in geothermal settings may provide important insights into the setting for the origin of life. Here, we report on the boron isotopic compositions and elemental concentrations in a range of fluid, sediment, and mineral samples from the active, boron-rich Puga geothermal system in the Himalayas, India. This includes one of the lowest boron isotope values ever recorded in modern settings: diatom-rich sediments (δ11B = -41.0‰) in a multiphase fractionation system where evaporation is not the dominant form of isotope fractionation. Instead, the extreme boron isotopic fractionation is ascribed to the incorporation of tetrahedral 10B borate anions in precipitating amorphous silica. These findings expand the known limits and drivers of boron isotope fractionation, as well as provide insight into the concentration and fractionation of boron in Archean hot spring environments.
Isoflurane Increases Tolerance to Renal Ischemia Reperfusion Injury Compared to Propofol: An Experimental Study in Pigs

Abstract Purpose: To compare two clinically relevant anesthetic agents, i.e., isoflurane versus propofol with respect to protection of the kidney in a porcine renal ischemia reperfusion model. Materials and Methods: 14 hybrid pigs were randomized to anesthesia with either isoflurane or propofol prior to laparoscopic surgery. Following anesthesia, the left kidney hilum was clamped for 60 min and the right kidney removed. After 48 h of reperfusion, urine was sampled for analysis of neutrophil gelatinase-associated lipocalin (NGAL), albumin, and creatinine. The left kidney was harvested for histologic scoring of injury. Results: Histologic examination of renal injury revealed a statistically significant difference in favor of isoflurane on denuded basement membrane score (isoflurane group 1.58 ± 0.38 vs. propofol 2.42 ± 0.80, p = .026). Median (25–75 percentile) urinary albumin 3.4 g/L (2.25–7.48) vs. 8.9 g/L (3.73–13.8), (p = .041) and urinary albumin/creatinine ratio 1.17 (0.76–1.82) vs. 1.76 (1.63–5.99), (p = .026) were both significantly lower in the isoflurane group. Median (25–75 percentile) urinary NGAL was 167 (51–215) pg/ml in the isoflurane group compared with 362 (149–508) pg/ml in the propofol group (p = .093). Conclusion: Isoflurane increases tolerance to renal ischemia reperfusion injury compared to propofol in this model.
A positive feedback loop of SIRT1 and miR17HG promotes the repair of DNA double-stranded breaks

ABSTRACT Long noncoding RNAs (lncRNAs) have emerged as critical regulators for gene expression in multiple levels and thus are involved in various physiological and pathological processes. Sirtuin 1 (SIRT1) has been established to exert key roles in the diverse biological process through deacetylation of substrates, including DNA damage repair. Nevertheless, the regulatory relationship between SIRT1 and lncRNAs, and the effect of lncRNA on SIRT1-mediated functions were still far to be elucidated. We herein uncovered that lncRNA miR17HG was notably down-regulated in SIRT1-deficient cells, and significantly up-regulated after ectopic expression of SIRT1. Subsequently, the results of dual luciferase reporter (DLR) showed that SIRT1 dramatically enhanced the promoter activity of the miR-17-92 cluster. Furthermore, we specifically knocked down the previous demonstrated transcription factor for the miR-17-92 cluster, C-Myc, which was the validated substrate of SIRT1. As expected, miR17HG and miR-17-92 miRNAs were evidently down-regulated after silencing of C-Myc; and silencing of C-Myc significantly reversed the effect of SIRT1 on miR17HG expression, suggesting that SIRT1 endowed cells with elevated miR17HG expression through stabilization of C-Myc. What is more, silencing of miR17HG significantly inhibited the repair of DNA DSBs, while enforced expression of miR17HG promoted DSBs repair. Fascinatingly, overexpression of miR17HG evidently enhanced the deacetylation activity of SIRT1, while silencing of miR17HG conferred diminished deacetylation activity. In addition, the results of RIP unraveled the physical interaction between miR17HG and SIRT1. Taken together, we presented evidences that miR17HG and SIRT1 probably formed a positive feedback loop, which exerted a crucial effect on DSBs repair.
Current treatment strategies for measurable residual disease in patients with acute myeloid leukemia

Patients with acute myeloid leukemia (AML) who achieve a morphologic complete remission still can have measurable residual disease (MRD) detected by multiparametric flow cytometry, molecular methods, or cytogenetics. Such patients with MRD have a high risk of disease recurrence over a short timeframe, but optimal treatment strategies are unknown. Outcomes with conventional treatment, including allogeneic hematopoietic cell transplantation, are worse than those for patients without MRD. Herein, the authors review current strategies, including novel clinical trials, targeted toward patients with MRD.
Soy isoflavones prevent bone resorption and loss, a systematic review and meta-analysis of randomized controlled trials

Abstract Background Osteoporosis is a common bone disease characterized by reduced bone mass resulting from continuous bone resorption. Methods PubMed, Scopus, and Embase were searched to find published trials on the effect of soy isoflavones on bone mineral density (BMD) and bone turnover markers (bone-specific alkaline phosphatase, osteocalcin, osteoprotegerin, pyridinoline, deoxypyridinoline, C-telopeptide, and N-telopeptide). Random-effects inverse-variance model was used to calculate the pooled effects. Results A total of 5313 articles were found, screened, and assessed for eligibility, and finally 52 trials were included in the meta-analysis. Consumption of soy isoflavones caused significant improvement in BMD of lumbar spine (mean difference (MD) = 0.76%; 95% CI: 0.09, 1.42%; p = 0.03), hip (MD = 0.22%; 95% CI: 0.02, 0.42%; p = 0.04), and femoral neck (MD = 2.27%; 95% CI: 1.22, 3.31%; p < 0.001). Subgroup analysis showed that in all 3 sites, the improvement was significant in normal weight subjects and interventions longer than a year, although trial location and dosage were also factors influencing isoflavones’ impact on BMD. Among markers of bone turnover, osteoprotegerin (MD = 5.79; 95% CI: 3.08, 8.51 pg/ml; p < 0.001), pyridinoline (MD = −5.13; 95% CI: −7.76, −2.50 nmol/mmol; p < 0.001), and C-telopeptides (MD = −0.08; 95% CI: −0.16, −0.00 ng/ml; p = 0.04) were favorably affected by isoflavones while osteocalcin and bone alkaline phosphatase did not change. Subgroup analysis of bone markers showed that in overweight/obese individuals and dosages <90 mg/day, isoflavones are more effective. Conclusions Soy isoflavones prevent osteoporosis-related bone loss in any weight status or treatment duration. They increase BMD in normal weight subjects and diminish bone resorption in overweight/obese individuals. Although bone resorption may be decelerated over short-term isoflavone consumption, periods longer than a year are probably needed to affect BMD. Isoflavones also appear benefits on bone in any dose or subjects’ ethnicity.
PIP degron-stabilized Dacapo/p21Cip1 and mutations in ago act in an anti- versus pro-proliferative manner, yet both trigger an increase in Cyclin E levels

ABSTRACT During cell cycle progression, the activity of the CycE-Cdk2 complex gates S-phase entry. CycE-Cdk2 is inhibited by CDK inhibitors (CKIs) of the Cip/Kip family, which include the human p21Cip1 and Drosophila Dacapo (Dap) proteins. Both the CycE and Cip/Kip family proteins are under elaborate control via protein degradation, mediated by the Cullin-RING ligase (CRL) family of ubiquitin ligase complexes. The CRL complex SCFFbxw7/Ago targets phosphorylated CycE, whereas p21Cip1 and Dap are targeted by the CRL4Cdt2 complex, binding to the PIP degron. The role of CRL-mediated degradation of CycE and Cip/Kip proteins during CNS development is not well understood. Here, we analyse the role of ago (Fbxw7)-mediated CycE degradation, and of Dap and p21Cip1 degradation during Drosophila CNS development. We find that ago mutants display over-proliferation, accompanied by elevated CycE expression levels. By contrast, expression of PIP degron mutant Dap and p21Cip1 transgenes inhibit proliferation. However, surprisingly, this is also accompanied by elevated CycE levels. Hence, ago mutation and PIP degron Cip/Kip transgenic expression trigger opposite effects on proliferation, but similar effects on CycE levels. Summary: Mutating the PIP degron stabilizes Dacapo/p21Cip1, making them strongly anti-proliferative. Yet stabilized Dacapo/p21Cip1 trigger a major increase in Cyclin E levels.
Extraction and Characterization of Alginate from an Edible Brown Seaweed (Cystoseira barbata) Harvested in the Romanian Black Sea

Cystoseira barbata is an edible brown seaweed, traditionally used in the Black Sea area as functional food. Both alginate and brown seaweed biomass are well known for their potential use as adsorbents for heavy metals. Alginate was extracted from C. barbata recovered from the Romanian coast on the Black Sea with a yield of 19 ± 1.5% (w/w). The structural data for the polysaccharide was obtained by HPSEC-MALS, 1H-NMR. The M/G ratio was determined to be 0.64 with a molecular weight of 126.6 kDa with an intrinsic viscosity of 406.2 mL/g. Alginate beads were used and their adsorption capacity with respect to Pb2+ and Cu2+ ions was determined. The adsorption kinetics of C. barbata dry biomass was evaluated and it was shown to have an adsorption capacity of 279.2 ± 7.5 mg/g with respect to Pb2+, and 69.3 ± 2 with respect to Cu2+. Alginate in the form of beads adsorbs a maximum of 454 ± 4.7 mg/g of Pb2+ ions and 107.3 ± 1.7 mg/g of Cu2+ ions.
Understanding variation in unplanned admissions of people aged 85 and over: a systems-based approach

Aim To examine system characteristics associated with variations in unplanned admission rates in those aged 85+. Design Mixed methods. Setting Primary care trusts in England were ranked according to changes in admission rates for people aged 85+ between 2007 and 2009, and study sites selected from each end of the distribution: three ‘improving’ sites where rates had declined by more than 4% and three ‘deteriorating’ sites where rates had increased by more than 20%. Each site comprised an acute hospital trust, its linked primary care trust/clinical commissioning group, the provider of community health services and adult social care. Participants A total of 142 representatives from these organisations were interviewed to understand how policies had been developed and implemented. McKinsey’s 7S framework was used as a structure for investigation and analysis. Results In general, improving sites provided more evidence of comprehensive system focused strategies backed by strong leadership, enabling the development and implementation of policies and procedures to avoid unnecessary admissions of older people. In these sites, primary and intermediate care services appeared more comprehensive and better integrated with other parts of the system, and policies in emergency departments were more focused on providing alternatives to admission. Conclusions Health and social care communities which have attenuated admissions of people aged 85+ prioritised developing a shared vision and strategy, with sustained implementation of a suite of interventions.
Genome-wide association study revealed novel loci which aggravate asymptomatic hyperuricaemia into gout

Objective The first ever genome-wide association study (GWAS) of clinically defined gout cases and asymptomatic hyperuricaemia (AHUA) controls was performed to identify novel gout loci that aggravate AHUA into gout. Methods We carried out a GWAS of 945 clinically defined gout cases and 1003 AHUA controls followed by 2 replication studies. In total, 2860 gout cases and 3149 AHUA controls (all Japanese men) were analysed. We also compared the ORs for each locus in the present GWAS (gout vs AHUA) with those in the previous GWAS (gout vs normouricaemia). Results This new approach enabled us to identify two novel gout loci (rs7927466 of CNTN5 and rs9952962 of MIR302F) and one suggestive locus (rs12980365 of ZNF724) at the genome-wide significance level (p<5.0×10– 8). The present study also identified the loci of ABCG2, ALDH2 and SLC2A9. One of them, rs671 of ALDH2, was identified as a gout locus by GWAS for the first time. Comparing ORs for each locus in the present versus the previous GWAS revealed three ‘gout vs AHUA GWAS’-specific loci (CNTN5, MIR302F and ZNF724) to be clearly associated with mechanisms of gout development which distinctly differ from the known gout risk loci that basically elevate serum uric acid level. Conclusions This meta-analysis is the first to reveal the loci associated with crystal-induced inflammation, the last step in gout development that aggravates AHUA into gout. Our findings should help to elucidate the molecular mechanisms of gout development and assist the prevention of gout attacks in high-risk AHUA individuals.